key: cord-356223-8qn164k5 authors: yu, hannah j.; kiernan, daniel f.; eichenbaum, david; sheth, veeral s.; wykoff, charles c. title: home monitoring of age-related macular degeneration: real-world utility of the foreseehome device for detection of neovascularization date: 2020-08-15 journal: ophthalmol retina doi: 10.1016/j.oret.2020.08.003 sha: doc_id: 356223 cord_uid: 8qn164k5 purpose: to evaluate real-world utility of the foreseehome monitoring device for the detection of conversion from intermediate age-related macular degeneration (iamd) to neovascular amd (namd) and compare with results published by the home study. design: retrospective analysis of electronic health records. subjects: eyes prescribed use of the foreseehome device across 4 retinal practices in the usa. methods: usage information was collected from the online foreseehome portal for all eyes prescribed. for a pre-determined subset of eyes, additional clinical information was collected through chart review and analyzed for clinical utility. main outcome measures: outcome measures include frequency and length of use, number of eyes that used the device, established baseline and converted to namd, and number of alerts. results: 775 eyes of 448 patients were prescribed use of the foreseehome device. 649 eyes (83.7%) used the device at least once; among this population, 478 (73.7%) established baseline. patients who established baseline were significantly younger than those who did not establish baseline (p<0.001). among eyes that established baseline, 126 (26.4%) had an overall inadequate frequency of use (≥2 tests per week), and 250 (52.3%) did not use the device as frequently as instructed by the manufacturer (≥3 tests per week); 112 (24.7%) discontinued use within one year. over a mean of 20.35 months, 106 patients had 152 alerts, indicating possible conversions to namd. out of the 136 eyes that established baseline among 211 eyes prescribed the device at one clinical site, 52 alerts were recorded, 3 (6.8%) correctly identified conversion to namd and 47 (93.2%) represented false-positive alerts. conclusions: compared to the prospective home study, utility of the foreseehome device in the current analysis of real-world clinical-practice application was limited. a meaningful proportion of eyes never used the device or could not establish baseline. overall frequency of use was low and continuous usage of the device decreased over time. there is a need for improvement in home monitoring technology for eyes with iamd at risk of conversion to namd. although this is still a widely used method of self-monitoring, it has shown low levels of 118 sensitivity and poor patient compliance. 32,33 more recent technology, however, has 119 shown promise in the use of daily home telemonitoring of iamd. in 2014, the home study reported beneficial results from a randomized trial using the 122 foreseehome device (notal vision ltd, tel aviv, israel) for early detection of 123 conversion to namd. 34 the purpose of the current analysis was to determine the compliance of patients for each patient, the eye prescribed, age at first use, length of use, days since last 159 exam, total number of tests, ability to establish baseline, alert number and alert types 160 were collected from the foreseehome portal (www.foreseehomeonline.com). eyes 161 were considered "active" if they had a test within 30 days of january 3, 2020. eyes 162 classified as "never used" included eyes that never filled their prescription and eyes that 163 filled their prescription but never used the device. overall frequency of use over total 164 length of use was calculated from the total number of tests and the length of use. in the month before the alert was also captured. two frequencies of use were calculated 174 to investigate compliance: "adequate" frequency was defined by the home study at ≥2 175 tests per week; "instructed" frequency was defined at ≥3 tests per week as specified by proportion of eyes that could not establish initial baseline, mean frequency of use, mean 202 age, proportion of subjects within the home study age range, proportion of subjects 203 within the home study va range, and proportion of od study eyes. chi square tests 204 were performed to test for significant differences among proportions and 1-way analysis 205 of variance (anova) was used to test for significant differences among mean values. a 206 p-value less than 0.05 was considered statistically significant and a t-test distribution 207 was used to calculate 95% confidence intervals (ci). for ≥1 year, 24.7% stopped before 1 year; among eyes with the potential to have been 235 tested for ≥2 years, 13.8% stopped between 1 and 2 years; among eyes with the 236 potential to have been tested for ≥3 years, 13.8% stopped between years 2 and 3. the current study demonstrated a higher rate of false-positive alerts per patient per year 355 than did the home study. the home study reported 0.24 false alerts per person per oct technology is that the assessment of meaningful change will be passive following 407 patient initiation of the at-home test. this would eliminate the limitation of patient data 408 entry from which foreseehome and many other home monitoring devices suffer. 409 finally, increased understanding of the reasoning behind patient noncompliance may 410 help aid in the creation of optimal telemonitoring devices. difficult to evaluate how compliance with device usage was encouraged by physicians 420 and staff longitudinally. it is also unknown how thoroughly patients were pre-screened 421 before prescription of the device for their ability to use a computer mouse. the cost of 422 the device for each patient was also not assessed and the influence of cost could not be 423 evaluated. additionally, eyes that were classified as "never used" did not distinguish 424 whether patients had never filled their prescription or filled their prescription and never 425 used the device. the current study was also limited in its follow-up of test score change 426 alerts and its confirmation of dry amd or namd diagnosis; in the home study, every in summary, the current study investigated the utility of the foreseehome device in 434 routine clinical practice. compared to results from the home trial, patient compliance 435 and ability to use the device were more limited, as clinically meaningful proportions of 436 patients never used the device or were unable to establish a baseline. continuous 437 usage of the device was low and decreased over time, and the overall false-positive 438 rate was 93.2%, a higher rate than reported in the home trial. these results prevalence of age-related maculopathy the framingham eye study. i. outline and 446 major prevalence findings cataracts and macular degeneration in older americans causes and prevalence of visual impairment 452 among adults in the united states global update of available data on visual 455 impairment: a compilation of population-based prevalence studies prevalence of age-related macular 458 degeneration in the united states age-related macular degeneration (amd) tables. national eye institute, national institute 461 of health age-related eye disease study research group. a randomized, placebo-controlled, 466 clinical trial of high-dose supplementation with vitamins c and e, beta carotene, and zinc 467 for age-related macular degeneration and vision loss: areds report no ophthalmol chic ill age-related macular degeneration preferred 470 age-related macular 472 degeneration: etiology, pathogenesis, and therapeutic strategies consensus nomenclature for reporting neovascular 475 age-related macular degeneration data age-related macular degeneration and blindness due to 478 neovascular maculopathy smoking and age related macular degeneration: the 481 number of pack years of cigarette smoking is a major determinant of risk for both 482 geographic atrophy and choroidal neovascularisation risk factors associated with age-related 485 macular degeneration. a case-control study in the age-related eye disease study associations of cardiovascular disease and its risk 489 factors with age-related macular degeneration: the pola study age-related macular degeneration and incident 492 cardiovascular disease: the multi-ethnic study of atherosclerosis hypertension, cardiovascular disease, and age-495 related macular degeneration. age-related macular degeneration risk factors study 496 arch ophthalmol chic ill lutein and zeaxanthin in the diet and serum 499 and their relation to age-related maculopathy in the third national health and nutrition 500 examination survey age-related macular 502 degeneration and antioxidant status in the pola study oculaires liées à l'age. arch ophthalmol chic ill dietary intake of antioxidants and risk 506 of age-related macular degeneration the 509 relationship of dietary carotenoid and vitamin a, e, and c intake with age-related macular 510 degeneration in a case-control study age-related eye disease study 2 research group. lutein + zeaxanthin and omega-3 513 fatty acids for age-related macular degeneration: the age-related eye disease study 2 514 (areds2) randomized clinical trial ω-3 long-chain 517 polyunsaturated fatty acid intake and 12-y incidence of neovascular age-related macular 518 degeneration and central geographic atrophy: areds report 30, a prospective cohort 519 study from the age-related eye disease study ranibizumab versus verteporfin for neovascular 522 age-related macular degeneration intravitreal aflibercept (vegf trap-eye) in wet age-525 related macular degeneration comparison of age-related macular degeneration treatments trials (catt) ranibizumab and bevacizumab for treatment of 529 neovascular age-related macular degeneration: two-year results ranibizumab for predominantly classic neovascular 532 age-related macular degeneration: subgroup analysis of first-year anchor results baseline predictors for one-year visual outcomes with 535 ranibizumab or bevacizumab for neovascular age-related macular degeneration earliest symptoms of diseases of the macula a brief history of macular grids: from thomas reid to edvard munch and 540 fine sl. early detection of extrafoveal neovascular membranes by daily central field 542 evaluation macular function surveillance revisited earliest symptoms caused 546 by neovascular membranes in the macula randomized trial of 549 a home monitoring system for early detection of choroidal neovascularization home 550 monitoring of the eye (home) study randomized trial of the foreseehome 553 monitoring device for early detection of neovascular age-related macular degeneration the home monitoring of the eye (home) study design -home study foreseehome amd monitoring program comparison of 24-hour holter monitoring with 559 14-day novel adhesive patch electrocardiographic monitoring effectiveness of 562 telemonitoring in obstetrics: scoping review cardiac monitoring in patients with syncope: making 565 that elusive diagnosis home telemonitoring in copd: a systematic review of 568 methodologies and patients' adherence patient adherence to a mobile phone-based heart 571 failure telemonitoring program: a longitudinal mixed-methods study optimal duration and 574 predictors of diagnostic utility of patient-activated ambulatory ecg monitoring measurements during home telemonitoring: analysis of the intervention arm in a before 578 and after trial choroidal neovascularization in age-related macular degeneration using ophthalmology practices hit hard by covid-19 closures current concepts and modalities for 586 monitoring the fellow eye in neovascular age-related macular 587 degeneration: an expert panel consensus. retina phila pa graphical methods for the detection and progress assessment of visual distortion 591 caused by macular disorders. vis basel switz age, mean (sd) key: cord-323227-ctsamv69 authors: bonner, c.; cornell, s.; batcup, c.; fajardo, m.; doust, j.; mcgeechan, k.; trevena, l. title: protocol for a systematic review of qualitative and quantitative effects of cardiovascular disease risk communication using heart age concepts date: 2020-05-08 journal: nan doi: 10.1101/2020.05.03.20089938 sha: doc_id: 323227 cord_uid: ctsamv69 introduction: the concept of heart age is increasingly used for health promotion and alongside clinical guidelines for cardiovascular disease (cvd) prevention. these tools have been used by millions of consumers around the world, and many health organisations promote them as a way of encouraging lifestyle change. however, heart age tools vary widely in terms of their underlying risk models and display formats, the effectiveness of these tools compared to other cvd risk communication formats remains unclear, and doctors have raised concerns over their use to expand testing of healthy low risk adults. methods and analysis: we aim to systematically review both qualitative and quantitative evidence of the effects of heart age when presented to patients or consumers for the purpose of cvd risk communication. four electronic databases will be search until april 2020 and reference lists from similar review articles will be searched. studies will be considered eligible if they meet the following criteria: (1) published from the inception of the database to april 2020, in peer-reviewed journals, (2) used an adult population (over 18 years of age) or, if not explicit regarding age, are clear that participants were not children, (3) present the concept of heart age to patients or consumers for the purpose of cvd risk communication, (4) report qualitative themes or quantitative outcomes relating to psychological and/or behavioural responses to heart age. two reviewers will perform study selection, data extraction and quality assessment. reporting of the review will be informed by preferred reporting items for systematic review and meta-analysis guidance. ethics and dissemination: ethical approval is not required as it is a protocol for a systematic review. findings will be disseminated through peer-reviewed publications and conference presentations. similar review articles will be searched. studies will be considered eligible if they meet the following criteria: (1) published from the inception of the database to april 2020, in peer-reviewed journals, (2) used an adult population (over 18 years of age) or, if not explicit regarding age, are clear that participants were not children, (3) present the concept of 'heart age' to patients or consumers for the . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint herat age review protocol, version 1, 4 th may 2020 purpose of cvd risk communication, (4) report qualitative themes or quantitative outcomes relating to psychological and/or behavioural responses to heart age. two reviewers will perform study selection, data extraction and quality assessment. reporting of the review will be informed by preferred reporting items for systematic review and meta-analysis guidance. ethical approval is not required as it is a protocol for a systematic review. findings will be disseminated through peer-reviewed publications and conference presentations. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint the concept of 'heart age' is increasingly used for health promotion and alongside clinical guidelines for cardiovascular disease (cvd) prevention. 1 these tools have been used by millions of consumers around the world, and many health organisations promote them as a way of encouraging lifestyle change. 2-3 however, heart age tools vary widely in terms of their underlying risk models and display formats, the effectiveness of these tools compared to other cvd risk communication formats remains unclear, and doctors have raised concerns over their use to expand testing of healthy low risk adults. 1, 4 a review of cvd risk communication in 2011 identified heart age as a potentially useful concept that needed more research. 5 a 2016 review of vascular age concepts in clinical applications found limited trials testing the effects of communicating this concept, 6 but a recent rapid review in 2020 highlighted the increasing number of studies on age-based risk formats, suggesting there may now be more evidence available. 7 earlier reviews relating to the heart age concept have not made a distinction between the comparison groups involved in trials (standard care or absolute risk), have not clearly identified the behaviour change techniques included within the heart age intervention, and/or have not included qualitative studies that can provide additional insights into why these tools are so widely used in spite of limited evidence for their effectiveness. we will systematically review both qualitative and quantitative evidence of the effects of heart age when presented to patients or consumers for the purpose of cvd risk communication. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint herat age review protocol, version 1, 4 th may 2020 the aim of the systematic review is to identify and review investigations which sought to determine the effectiveness of communicating 'heart age' to patients to change their lifestyle behaviours or which identified the feasibility of using 'heart age' to communicate risk of a cardiac event. the primary objectives of the systematic review will be to review the qualitative and quantitative literature on the effects of communicating the 'heart age' concept to patients and consumers. this will be achieved by: describing the positive and negative effects of communicating heart age: using qualitative and quantitative research. exploring the reasons why heart age is psychologically impactful: using qualitative research. comparing the effect of heart age to other risk communication strategies: using quantitative rcts. investigating what behaviour change techniques are included in the heart age interventions: using qualitative and quantitative research where full intervention content is accessible. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint herat age review protocol, version 1, 4 th may 2020 this protocol has been developed following the preferred reporting items for systematic review and meta-analysis protocols (prisma-p) guidelines. reporting of the systematic review will be informed by preferred reporting items for systematic review and meta-analysis guidance. any relevant amendments made to the protocol will be documented and published alongside the results of the systematic review. studies will be considered eligible if they meet the following criteria: (1) published from the inception of the database to april 2020, in peer-reviewed journals, (2) used an adult population (over 18 years of age) or, if not explicit regarding age, are clear that participants were not children, (3) present the concept of 'heart age' to patients or consumers for the purpose of cvd risk communication, (4) report qualitative themes or quantitative outcomes relating to psychological and/or behavioural responses to heart age. studies that are not peer reviewed journal articles such as; conference proceedings, dissertations or government reports will be excluded. the study must include the heart age concept being communicated to patients or consumers. therefore, protocol papers, opinion papers, reviews, online user descriptions and heart age algorithm development or validation will be excluded, and where the algorithm has been applied to population data but not presented to that population. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. herat age review protocol, version 1, 4 th may 2020 all studies will involve an adult population. studies using participants <18 years of age will be excluded, as will animal studies. any study that presents the concept of heart age to patients or consumers for the purpose of cvd communication, either alone or alongside other risk information. interventions may be delivered in settings such as general practices, hospitals, health clinics or community centres, or online. studies that do not report on heart age as a communication intervention will be excluded. investigations may include an intervention group with or without a control or comparator group, such as usual care in clinical practice or absolute cvd risk assessment alone. we will search the following databases: the cochrane central register of controlled trials (via ovidsp), medline (via ovidsp), embase (via ovidsp) and psychinfo (via ovidsp) up to april 2020. the search terms are based on the earlier vascular age review in 2016 with additional free text terms based on known relevant papers. the full list of terms is based on a previous review and includes: vascular/vessel/arterial/heart/cardiovascular/coronary/risk + age/ages/ageing/aging; or heart forecast; and limited to human studies. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint herat age review protocol, version 1, 4 th may 2020 we will search the citations and references of final included studies and two previous reviews of vascular age models and more general age-related risk concepts. we will also include any papers mentioned on publicly accessible heart age websites. we will download references identified in searches (electronic databases and additional searches) into excel. duplicates will then be removed, and a copy of this spreadsheet will be made to enable two reviewers to screen the titles and abstracts of each study included. the screening process will be undertaken by two review authors individually. each reviewer will independently assess a study's suitability to be included in the review by way of marking as such against each study on an excel spreadsheet, which will contain the title and abstract. studies that do not meet the inclusion criteria will be excluded at this stage. we will obtain the full text of the remaining papers and will then assess these remaining papers against the full inclusion terms for the review to determine their eligibility for inclusion. non-english language papers will be translated into english using google translate and verified for inclusion/exclusion by speakers of the relevant language. the review authors will resolve disagreements through a consensus-based decision-making process, or when necessary, discussion with a third review author. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint two review authors will use a pre-defined data extraction form to collect data from the included studies. reviewers will pilot the data extraction form with a sample of included papers and amendments will be made if necessary. reviewers will contact study authors if additional information is required. an excel database will be used to extract quantitative and qualitative data from the included studies as follows: quantitative data to be extracted will include: year, country, study design, study population (age, education, socio-economic status, health literacy, race/culture/ethnicity), number of participants, intervention format (online, paper), comparison groups (standard care, absolute risk alone), clinical measures (blood pressure, cholesterol, weight, body mass index, waist circumference, prescribed medications) behavioural measures (medication adherence, lifestyle intentions or self-report), psychological measures (risk perceptions, emotional responses, credibility, recall), summary of significant effects of heart age communication. qualitative data to be extracted will include: behavioural themes (e.g. lifestyle change), psychological themes (e.g. emotional reaction), stated benefits of heart age (e.g. motivates people to take action), stated problems with heart age (e.g. reduces credibility). intervention content data will include: additional risk communication formats (e.g. absolute risk, risk level, graphs), underlying model (e.g. 5 year or 10 year risk cvd risk model), behaviour change techniques (e.g. email prompts, action plans) based on michie et al.'s taxonomy. 8 this will be done for interventions where the full content is accessible, either within the publication, online or through contacting the authors. studies will be critically appraised independently by two review authors using the relevant johanna briggs institute tools for the study design (https://joannabriggs.org/ebp/critical_appraisal_tools). disagreement will be resolved by discussion and the involvement of a third reviewer if necessary. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 8, 2020. herat age review protocol, version 1, 4 th may 2020 authors will be contacted if further information is required to make an assessment. sensitivity analyses will be performed on included studies with a high risk of bias. funnel plots will be generated to assess publication bias only if at least ten studies with comparable quantitative outcomes can be included in a meta-analysis. to meet our research aims and objectives, the outcomes of interest for this study include the following: 1. lifestyle risk factors for cvd (diet, exercise, smoking) 2. clinical risk factors for cvd (blood pressure, cholesterol, weight-related measures) 3. risk perceptions (perceived risk accuracy, severity, susceptibility, perceived control) 4. emotional response (positive e.g. happy/motivated, negative e.g. sad/anxious) 5. recall (exact heart age result, general result being older/younger than current age) 6 . perceived credibility (how believable the heart age result is) 7. information seeking behaviour (accessing further information, seeing a doctor) this review will update previous related reviews with a more comprehensive list of search terms, the inclusion of both qualitative and quantitative studies, and more detailed analyses of the nature of heart age interventions in terms of the behaviour change techniques included alongside the heart age risk result itself. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint should heart age calculators be used alongside absolute cardiovascular disease risk assessment? web-based self-assessment health tools: who are the users and what is the impact of missing input information? neufingerl n online self-assessment of cardiovascular risk using the joint british societies (jbs3)-derived heart age tool: a descriptive study what are effective strategies to communicate cardiovascular risk information to patients? a systematic review vascular age to determine cardiovascular disease risk: a systematic review of its concepts, definitions, and clinical applications how effective are 'age' tools at changing patient behaviour? a rapid review the behavior change technique taxonomy (v1 hierarchically-clustered techniques: building an international consensus for the reporting of behavior change interventions international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity the copyright holder for this preprint this version posted may 8, 2020. . https://doi.org/10.1101/2020.05.03.20089938 doi: medrxiv preprint key: cord-317519-yhzv2yjs authors: barzilai, nir; appleby, james c; austad, steven n; cuervo, ana maria; kaeberlein, matt; gonzalez-billault, christian; lederman, stephanie; stambler, ilia; sierra, felipe title: geroscience in the age of covid-19 date: 2020-07-23 journal: aging dis doi: 10.14336/ad.2020.0629 sha: doc_id: 317519 cord_uid: yhzv2yjs the data on covid-19 is clear on at least one point: older adults are most vulnerable to hospitalization, disability and death following infection with the novel coronavirus. therefore, therapeutically addressing degenerative aging processes as the main risk factors appears promising for tackling the present crisis and is expected to be relevant when tackling future infections, epidemics and pandemics. therefore, utilizing a geroscience approach, targeting aging processes to prevent multimorbidity, via initiating broad clinical trials of potential geroprotective therapies, is recommended. multiple age-related chronic diseases at the same time. geroscientists have long hypothesized that by targeting the biology of aging, all diseases of aging can be delayed [3] . hallmarks of aging have been established and shown that they are all interconnected, thus targeting any single hallmark results in improvements in others [4, 5] . in animal preclinical studies, health span and life span have been dramatically increased by targeting those hallmarks, using genetic tools and drugs, demonstrating that aging is a modifiable condition [6, 7] . of particular importance are the hallmarks of immune dysfunction underlying the vulnerability of older adults to infections and the inflammation which accounts for the response to those infections [8] . but beyond improving immunity and inflammation to younger levels, such approaches also increase individuals' resiliency to withstand the sickness itself, as the whole body needs to respond to this major stressor. older people are at such risk in part because the vigor of our immune response flags as we age. in addition to age, many of us are also weakened by coexisting age-related conditions that diminish our resilience further. so, until a vaccine or treatment becomes available, how do we defend ourselves from infection beyond physical distancing and careful hand washing? we can focus on eating well, exercising as regularly as possible (at home and even in increasingly confined long-term care facilities), managing our stress, and getting enough sleep behaviors we know help improve our immune responses at any age. public health interventions that ensure access to healthy foods and safe environments are also critical. in addition to this healthy lifestyle, interventions with existing drugs with established safety profiles that target the biology of aging, immune mechanisms and resiliency (i.e. "geroprotectors" or "gerotherapeutics"), should be explored. while many geroprotectors have been successfully tested in pre-clinical settings, to date none of them has been approved as geroprotectors for use in humans. consequently, self-medication with any of these compounds is highly discouraged. one such drug is metformin which has been shown to target multiple hallmarks of aging [9] and increase health span and life span in animals. in addition, both clinical and observational trials in humans show that the use of this drug is associated with less type 2 diabetes mellitus (t2dm), cardiovascular diseases, cancer, cognitive decline and overall mortality [10] . previous research from as far back as the 1940s, however, has pointed to metformin and metformin-like biguanide drugs as preventing influenza [11] and increasing in vivo and in vitro immune response in humans [12] . it is the first line of treatment for t2dm with 60 years of experience, exceptional safety record and is both generic and cheap. metformin has already indicated protective capacity against covid-19. thus, in a retrospective analysis of 283 t2dm patients from wuhan, china, with confirmed covid-19, investigators found no difference in the length of stay in hospital, but persons taking metformin had significantly lower in-hospital mortality (3 of 104, 2.9%) than those not taking metformin (22 of 179, 12.3%) [13] . moreover, it was reported that diabetic women on metformin had ~20% decrease in mortality and ~80% decrease in the inflammatory marker tnfα [14] . a second line of drugs are mtor inhibitors, which have been shown to increase healthspan and lifespan in almost all animals tested, from yeast to rodents. the mtor inhibitor rapamycin reverses age-related declines in influenza vaccine response in mice [15] and two phase 2 clinical trials completed by restorbio inc. showed that the rapamycin derivative everolimus could enhance influenza vaccine response in healthy elderly people [16, 17] . the second phase 2 trial also reported that those treated with mtor inhibitors for 6 weeks had significantly fewer respiratory tract infections over the next year compared to those that received the placebo [17] . thus, it appears that short-term inhibition of mtor may confer protection not only against the flu, but also other common viruses including other coronaviruses. given the current public health crisis that is disproportionately affecting our aging population, it is imperative that we start discussing pragmatic approaches to rapidly implement the testing of such drugs in the face of the covid-19 pandemic and an aging global population. at this stage, broad clinical trials of potential geroprotective therapies are needed, to enable extensive data collection and analysis of their potential benefits and indications. development and use of drugs like rapamycin and metformin by the at-risk population, notably older adults, may confer broad health benefits by targeting multiple aspects of biological aging and in this way raise the chances that these people can ward off the worst effects of covid-19. metformin for example is already used chronically by more than 100 million people around the world today. metformin is broadly available and low-cost (just a little more than $.10/day). it should be tested rapidly to allow even a small percentage of older people to avoid hospitalization and death from covid-19. the absolute benefits will be substantial. rapamycin has also been used clinically for many years with a wellestablished dosing and safety profile. while significant side effects are associated with high-doses in patients undergoing daily rapamycin treatment, there is accumulating evidence that lower-dose treatment with rapamycin or its derivatives has minimal side-effects in healthy individuals [18, 19] and may confer substantial improvements in immune function [16, 17] . randomized, controlled clinical trials to assess the ability of rapamycin, metformin and other potential geroprotective drugs [20] , to boost response to an eventual covid-19 vaccine in the elderly, as well as protect against covid-19 infection altogether, could have a substantial impact on survival in vulnerable populations and should be pursued. ongoing basic research on geroscience will produce a 'pipeline' into a whole raft of novel compounds that are being developed by biotech around the world. this may provide new insights into how we can modify the aging process and boost our immune response, perhaps even improving the performance of a vaccine for covid-19 whenever it becomes available. epidemiological data indicates that covid-19 is particularly aggressive among older adults. however, even within that group there is a large heterogeneity of response, with some individuals suffering severe effects and/or death, while others recover with little more side effects than those observed in younger cohorts. in fact, heterogeneity of response is a major characteristic of older populations [21] , which is why there is a need to identify those individuals, within an age cohort, that are physiologically younger or older than their chronological age. so, while a percentage of older adults are more robust than expected, so a fraction is more fragile. while no clear data exists yet in humans, those more fragile (i.e., physiologically older) are likely to be the ones who would most benefit from geroscience-based approaches to improve their health. just like there is heterogeneity among older adults, significant heterogeneity has been identified even among younger individuals [21] . it is likely that individuals who are chronologically young, but who display an advanced physiological age will also benefit from a geroscience approach. those include, among others, high-risk individuals such as those with additional multimorbidity in addition to sars-cov-2 infection, as well as those with previous events that leave sequalae, such as controlled-hiv infection, previous chemotherapy or radiation, the disabled, obese and even poor people who cannot modify their interactions with the environment. multimorbidities in general and old-age multimorbidities in particular have proven to be the main risk factors for bad outcomes in covd-19 patients [22, 23] . often, in older patients, multiple aging-related diseases are affected by multiple risk factors, further increasing the disability and mortality. therefore, there is an urgent need to develop and implement analytical methodologies that would allow a diagnostic evaluation of the contribution of several co-existing diseases to covid-19 outcomes. there is a need to identify either unique or combinatorial parameters to identify appropriate biomarkers, or risk factors for severity of disease in covid-19 patients. the ability to weigh risks from multiple diseases and their combinations may also have critical implications for healthcare and social policy, both during the current crisis and in planning for future emergencies. particular contributing factors that may be crucial for outcomes in elderly subjects, for better or worse, may include their drug medications, e.g. ace inhibitors [24] , vaccinations, vitamins and other supplements, and other interventions more prevalent in and differentially affecting the older persons. the effectiveness of specific therapeutic regimens and protocols (such as different modes of oxygen delivery and resuscitation, drugs, vaccines and adjuvants) need to be evaluated and adjusted specifically for older patients whose management may dramatically differ from younger subjects with critical implications for outcomes. the role of multimorbidities and interactions across diseases as synergistically affecting the outcomes should be addressed not only in retrospective analysis, but also when designing new experimental studies. this multimorbidity evaluation should be combined with a systematic assessment of the aging and frailty status, using standardized methods and measures. such standard methods and measures are needed to start creating prospective information on the differential vulnerability of older persons. strategies must be developed for periodic frailty assessment with continuous longitudinal follow-up of older persons which may reveal not only global determinants that are conserved, but also local singularities involved in differential aging health around the world. standard evaluation of biological and physiological age, with appropriate biomarkers, should be developed, both to assess and predict risks of agingrelated ill health and to evaluate the effectiveness of potential geroscience therapies [25] [26] [27] . wide public should be actively involved in such evaluation studies, not just as test subjects, but as active and empowered "citizen-scientists". there is a need to increase public science education in the field of geroscience to inform the public and enhance their ability to evaluate evidence. for the development and advantageous utilization of such evaluation methodologies, it is essential to improve access, openness, sharing and interoperability of clinical data on large cohorts of subjects, preferentially longitudinal data, including their clinical conditions and diseases (with or without covid-19), demographic characteristics, and a wide set of evaluation parameters, including biochemical, metabolic, immunological, physiological, functional and other parameters, most of which are routinely available both in clinical practice and experimental settings. the development and utilization of such methods, on large clinical datasets, will help establish the most significant risk factors and their combinations, for multiple age-related diseases, and their joint contribution to covid-19 outcomes, and facilitate recommendations for the effective combined therapy to mitigate covid-19 and its risk factors. the covid-19 global emergency has emphasized to vast masses of people the vital need to prevent old-age multimorbidity, protect the elderly and improve their health span. proponents of geroscience have argued for the importance of such preventive measures for many years. now we see in front of our own eyes the disastrous consequences of the deficit in such preventive measures, and the portent this gap in our approach represents for the future. we are witnessing how this new infectious disease is wreaking havoc among individuals, the healthcare system and the entire social fabric around the world, while the rapid aging of the population represents the main risk factor and aggravating condition. therefore, arguably, one of the most important lessons to be learned from this pandemic, is the need to therapeutically address degenerative aging processes to prevent aging-related ill health as a whole. this understanding should translate to public health and research policies supportive of geroscience research, development and clinical application [5, 28, 29] , improving the funding, incentives, education and institutional support for the field. with sufficient support and deployment, the preventive geroscience approach may help avoid or mitigate the effects of this and current devastating pandemics of aging-related ill health, presently and for the future. conquering the current pandemic will require a multipronged approach, including primarily an 'offensive' approach represented by the development of vaccines and treatments, as well as a 'defensive' approach focused on strengthening the resilience of affected individuals. importantly, the offensive part of our arsenal requires the urgent development of a new vaccine, curative and palliative treatments for each successive pandemic and epidemic confronting the world. this aspect of our approach is unfortunately both slow and specific to the currently relevant virus or pathogen. in contrast, the defensive arm proposed here is pathogenblind insofar as the interventions are pathogen independent. therefore, a geroscience-focused response to the covid-19 pandemic can be deployed not only against the current emergency, but the same approach will certainly be relevant to future infections, be them pandemic, epidemic, endemic, or even those affecting any one individual. characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention extending life: scientific prospects and political obstacles geroscience and the trans-nih geroscience interest group the hallmarks of aging geroscience: linking aging to chronic disease interventions to slow aging in humans: are we ready? healthy aging: the ultimate preventative medicine immunosenescence: emerging challenges for an ageing population benefits of metformin in attenuating the hallmarks of aging metformin as a tool to target aging metformin: historical overview metformin improves in vivo and in vitro b cell function in individuals with obesity and type-2 diabetes metformin treatment was associated with decreased mortality in covid-19 patients with diabetes in a retrospective analysis observational study of metformin and risk of mortality in patients hospitalized with covid-19 mtor regulation and therapeutic rejuvenation of aging hematopoietic stem cells mtor inhibition improves immune function in the elderly torc1 inhibition enhances immune function and reduces infections in the elderly a randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: immunological, physical performance, and cognitive effects rapamycin for longevity: opinion article innate and adaptive immunity in aging and longevity: the foundation of resilience quantification of biological aging in young adults prevalence of comorbidities and its effects in patients infected with sars-cov-2: a systematic review and meta-analysis presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area renin-angiotensin-aldosterone system inhibitors in patients with covid-19 strategies and challenges in clinical trials targeting human aging recognizing degenerative aging as a treatable medical condition: methodology and policy measuring biological aging in humans: a quest the critical need to promote research of aging and aging-related diseases to improve health and longevity of the elderly population aging health and r&d for healthy longevity must be included into the who work program the scientific director of the american federation for aging research (nb), the nathan shock center of excellence for the biology of aging p30ag038072 (nb), american federation for aging research (sm), and glenn center for the biology of human aging paul glenn foundation grant (nb). key: cord-322024-yrqpq9cf authors: jevšnik, monika; steyer, andrej; zrim, tamara; pokorn, marko; mrvič, tatjana; grosek, štefan; strle, franc; lusa, lara; petrovec, miroslav title: detection of human coronaviruses in simultaneously collected stool samples and nasopharyngeal swabs from hospitalized children with acute gastroenteritis date: 2013-02-05 journal: virol j doi: 10.1186/1743-422x-10-46 sha: doc_id: 322024 cord_uid: yrqpq9cf background: human coronaviruses (hcovs) are a well-known cause of respiratory infections but their role in gastrointestinal infections is unclear. the objective of our study was to assess the significance of hcovs in the etiology of acute gastroenteritis (age) in children <6 years of age. methods: stool samples and nasopharyngeal (np) swabs collected from 260 children hospitalized for age (160 also had respiratory symptoms) and 157 otherwise healthy control children admitted for elective surgery were tested for the presence of four hcovs using real time rt-pcr. registered at clinicaltrials.gov (reg. nct00987519). results: hcovs were more frequent in patients with age than in controls (23/260, 8.8% versus 4/151, 2.6%; odds ratio, or 3.3; 95% confidence interval, ci 1.3–10.0; p = 0.01). three of four hcov-positive members in the control group, asymptomatic when sampled, recalled gastrointestinal or respiratory symptoms within the previous 14 days. in patients with age, hcovs were present in np samples more often than in stools (22/256, 8.6%, versus 6/260, 2.3%; p = 0.0004). in 5/6 children with hcovs detected in stools, the viruses were also detected in np swabs. patients had a significantly higher probability of hcov detection in stool (or 4; 95% ci 1.4–15.3; p = 0.006) and also in stool and/or np (or 3.3, 95% ci 1.3–10.0; p = 0.01) than healthy controls. all four hcovs species were detected in stool and np samples. conclusions: although hcovs were more frequently detected in patients with age than in the control group, high prevalence of hcovs in np swabs compounded by their low occurrence in stool samples and detection of other viruses in stool samples, indicate that hcovs probably play only a minor role in causing gastrointestinal illness in children <6 years old. human coronaviruses (hcovs), known since the late 1960s, have been recognized as a frequent cause of mild respiratory tract infections (rtis) and occasionally as a potential cause of severe lower rti in premature infants and children with underlying diseases [1] . their role in enteric infections is less clear. even though coronavirus-like particles have been seen by electron microscopy in stool samples from patients with diarrhea, they have been also found in healthy individuals [2] . however, coronaviruses are associated with diarrheal disease in several animal species. thus, a dual enteric and respiratory tropism has been reported for the bovine coronavirus causing winter dysentery in calves [3] . interest in coronaviruses in relation to enteric diseases in humans increased with the emergence of severe acute respiratory syndrome (sars) and identification of sars-cov in 2003 [4, 5] . sars was characterized clinically by signs/ symptoms of severe lower rti but several patients also had gastrointestinal complaints [6, 7] . diarrhea has also been a prominent clinical feature in several patients with respiratory infection caused by other hcovs [8] [9] [10] . furthermore, all hcov species were recently detected in stool samples of patients with acute gastroenteritis (age) by modern molecular methods, but their role in human gastrointestinal infections remains uncertain [11] [12] [13] . in previous studies, hcovs were demonstrated in patients with gastrointestinal and/or respiratory involvement, but in none of these studies was concurrent collection of stool and respiratory samples performed. the main objective of the present study was to evaluate the presence of hcovs in simultaneously collected stool samples and nasopharyngeal (np) swabs in children with age (with or without associated respiratory symptoms) and in control subjects, with the aim of appraising their role in the etiology of age. from october 2009 to september 2011, 765 children <6 years of age were referred to the department of infectious disease with the diagnosis of age. of them 260 were enrolled in the study. the others did not meet inclusion criteria for age (250 children), were not enrolled because their parents did not consent with the inclusion in the study (182 children) or because they did not pass stool during hospital stay (73 children). the median age of included children was 18.9 months. the female: male subject ratio was 1: 1.13 (122/260; 46.9% girls). in 100 of the subjects (39.5%), signs and symptoms were limited to the gastrointestinal tract, while 160 (61.5%) also had signs and symptoms compatible with acute rti such as rhinitis, pharyngitis, conjunctivitis, otitis or bronchiolitis. in the group of children with age, both samples (stool sample and np swab) were obtained from 256/260 patients (only stool sample was acquired from four of them). from 157 children comprising the healthy control group, both samples were available from 150 patients, only a stool sample from one child and only a np swab from six. samples obtained at follow-up examination 14 days after initial testing were available for 192/260 (73.8%) children with age. unfortunately, 68 remaining children did not respond and did not come to follow up visit 14 days after acute illness. children who did not come to the follow up visit had similar clinical characteristics as those who attended the follow up visit. therefore, authors assumed that they were representative of the entire study population. in 174 of the patients, both stool and np swab samples were obtained, while only stool sample was obtained from nine children and solely np swab was available from nine others. hcovs were detected in 6/260 stool samples from children with age (2.3%; 95% ci 0.9-5.0%)-among which 5/6 were detected also in np samples-and in 22/256 np swabs (8.6%, 95% ci 5.5-12.7%). hcovs were more often detected in np swabs than in stool samples (p = 0.0004 by mcnemar's test). four of six (67%, 95% ci 22-96%) children with hcov-positive stool samples had symptoms of respiratory and gastrointestinal infection ( table 1) . of the six hcov-positive stool samples, three were characterized as oc43, one as nl63, one as hku1 and one as 229e. in two (33.3%) stool samples hcov (one 229e and one oc43) was detected as a single pathogen, while in four samples the presence of other viruses was also established (table 2) . of 22 positive np samples, 13 (59%, 95% ci 36-79%) originated from children with age associated with rti. the species distribution was as follows: nine oc43 (41%), seven hku1 (32%), three 229e (14%) and three nl63 (14%; table 2 ). fifteen (68.2%) of 22 hcovs positive np swabs were detected as a single viral pathogen; also in this subgroup the most common was oc43 (7/15, 46.7%). hcovs was detected as a single viral pathogen in np swab in 8/9 (88.9%) children with age as the only clinical sign and in 7/13 (53.8%) np swabs of children who had age associated with signs/symptoms of rti (or = 6.3; 95% ci 0.5-353; p = 0.16). hcovs were not detected in any of 183 follow-up stool samples. of 183 follow-up np swabs, 15 (8.2%, 95% ci 4.7-13.1%) were positive for hcovs: eight were typed as hku1, four as nl63 and two as oc43; one positive sample remained untyped because of the low viral load. in 10 of 15 positive children, hcovs were demonstrated only in the follow-up sample, while in five children the presence of hcovs was established in the first and follow-up np swab; four of these also had hcovs in stools at the first sampling (table 2 ). at the time of follow-up testing, 1/15 children (7%, 95% ci 0.2-31.9%) with hcov-positive np swab had gastrointestinal signs/symptoms; 10/15 (67%, 95% ci 38-88%) had rti and four (26.7%, 95% ci 8-55%) were asymptomatic. none of the 38 samples from 33 children positive for hcovs in np swabs and/or stool sample had viruses detected in blood sample taken simultaneously. hcovs were detected in 1/151 stool samples (0.7%, 95% ci 0-3.6%) and in 3/150 np swabs (1.9%, 95% ci 0.4-5.7%) from the control group. the hcov from the stool sample remained untyped whereas respiratory samples revealed one nl63, one 229e and one hcov that was untyped. hcovs remained untyped because of the low viral load. all 151 children included in the control group were asymptomatic on the day of sampling; however a detailed history showed that three out of four children who were found to be hcov positive reported symptoms indicating respiratory or gastrointestinal infections within 14 days before sampling. patients with age had a significantly higher probability of hcov detection in stool samples than controls (or 4; 95% ci 1.4-15.3; p = 0.006), while a weaker association was observed using np samples (or 2.6; 95% ci 0.5-24.7; p = 0.26). if positive stool samples and/ or np swabs were considered together, the association remained statistically significant (or 3.3; 95% ci 1.3-10.0; p = 0.01). hcovs are recognized as causes of respiratory infections but their role in gastrointestinal infections has not been clarified. in the present study we assessed the significance of hcovs in the etiology of age in children <6 years old by testing samples from stools and np swabs for the presence of four hcovs by rt-pcr. in the patients with age, follow-up sampling was performed 14 days after the initial testing and we acquired detailed clinical information for each participant. our study revealed that hcovs were present in patients with age and that viruses were more prevalent in the patients than in the control group (23/260, 8.8% versus 4/151, 2.6%, or 3.3, 95% ci 1.3-10.0%, p = 0.01). moreover, the higher probability of hcov detection in the stool samples of patients with age than among controls (or 4; 95% ci 1.4-15.3; p = 0.006) indicated a causal association of hcovs with age. this was supported by the observation that three of four hcov-positive members of the control group, who were asymptomatic at the time of sampling, reported symptoms within a 14day period before sampling. however, in patients with age one would think that the etiologic agent is more likely to be demonstrated predominantly in stool samples, whereas in our study hcovs were detected more often in np swabs than in stools (22/256, 8 .6% versus 6/ 260, 2.3%; p = 0.0004). in addition, in five of six children with hcovs detected in the stool samples, the viruses were also demonstrated in np swabs. there are several partial explanations for this. the course of the events in hcovs infection might have been similar to those known to be operative in animals and as suggested for sars-cov [6, 14] . thus, fecal-oral transmission is followed by intestinal damage, leading to viremia and respiratory infection. however, we tested all patients with hcovs found in stool samples or np swabs for the presence of the viruses in blood but did not get any positive result. in addition, viremia usually results in the involvement of the lower rti whereas upper rti is usually the result of direct spread of infection through neighboring tissues. although we cannot exclude viremia that was missed in our patients, it seems more likely that hcovs did not cause viremia. the other possibility is that oral transmission of hcovs is followed by gastrointestinal infection in patients with age and in the majority of children by symptomatic or asymptomatic np infections because of the direct spread of viruses from the oral cavity to the nasopharynx, or secondarily from the gastrointestinal region from vomiting (69.6% of our children experienced vomiting in addition to diarrhea). because enveloped hcovs viruses are not stable in stools, their persistence is much more limited and transient than in the upper respiratory tract. this could explain the lower detection rate of hcovs in stools than in np swabs. the third possibility is that the primary location of hcovs replication is in the nasopharynx, resulting in asymptomatic or symptomatic respiratory infections, and that the hcovs occasionally found in stool samples had their origin in the respiratory system but were passed down the alimentary tract. this theory would enable an elegant explanation for the higher proportion of np swabs positive for hcovs than in stools and for the finding that all but one patient with hcovs in the stool samples also had them present in np swabs, but does not explain age, which should have been caused by other agent. the theory is further supported by the finding that only in two children hcovs were found as a sole viral agent in stool while in four cases the presence of other viruses known to cause age was also established. surprisingly, hcovs were detected as a single viral pathogen in 8/9 (88.9%) np swabs from children with age without concomitant respiratory symptoms. more than half (160/260, 61.5%) of children with age also had respiratory symptoms at the time of sampling. this proportion was similar for patients with hcovpositive np swabs (59.1%) and for those with hcovpositive stool samples (66.7%), whereas it was higher (80%) for children with hcovs detected in both samples. however, there were very few patients with hcovs in stool samples and with viruses found in both sources (six and five, respectively) and the difference was not statistically significant. in a report from finland, 50% of children with age and hcov-positive stool samples had respiratory symptoms at the time of sampling, while in a study from the usa both symptoms appeared in 75% of children [11, 13] . the median duration of illness and of hospitalizations were similar for hcovs positive and negative children (table 1) , and the differences were not statistically significant (duration of illness: p = 0.91 for stool samples, p = 0.63 for np swabs, duration of hospitalization: p = 0.11 for stool samples and p = 0.13 for np swabs). no significant difference was found between the proportion of hcovs present at the time of acute illness information on the occurrence of hcovs in healthy persons is limited. our finding that hcovs were rare in stool samples from healthy children (0.7%, 95% ci 0-3.6%) and in np swabs (1.9%, 95% ci 0.4-5.7%) is consistent with a report finding hcovs in only 1.8% of stools from healthy children [11] . all four hcovs species were detected in stool and np samples; the most common was oc43 (50% in stool samples, 41% in np samples). 229e occurred only in children with age without respiratory symptoms, whereas nl63 was found only in children with rti as an additional sign. in conclusion, the presence of hcovs in patients with age, the more frequent demonstration of these viruses in patients than in the control group and the higher probability of hcovs detection in the stools of patients with age than in controls indicates some causal association of hcovs with age. however, interpretation of the role of hcovs in age is complex because the viruses were more often demonstrated in np swabs than in stool samples, because of detection of other viruses known to cause age in stool samples and because more than half of the children with age had also signs and symptoms of rti. the findings of the present study suggest that hcovs probably played only a minor role in gastrointestinal illness in these children. this was a part of a prospective study on viral respiratory and gastrointestinal infections in children <6 years. children in this age group who had been admitted to the department of infectious diseases of the university medical centre ljubljana, from october 2009 to september 2011, with the diagnosis of age (defined as the passage of three or more loose or liquid stools in 24 h) were eligible for the study. stool specimens, np swabs and blood samples were obtained at admission and at a followup visit 14 days after the initial sampling. children in the same age group admitted to the department of pediatric surgery and intensive care for planned elective surgical procedures (i.e. inguinal hernia repair, testicular retention or hydrocele) were selected as a healthy control group. only children without infections in last four weeks preceding the surgery were eligible for surgery admission. all children were clinically examined and only those without any symptoms of infection were admitted. approximately one third of the admitted children have not been included due to parents' refusal of entering the study or due to logistical problems with sample collection. in this group, stool samples and np swabs were collected at admission. at this time, information was obtained on the presence of signs and symptoms compatible with gastrointestinal and/ or respiratory infection within the last 14 days. to minimize children's discomfort nasopharyngeal sampling was performed after patients underwent anesthesia. the study protocol was approved by the national medical ethics committee of the republic of slovenia (no. 87/08/09). written informed consent was obtained from all parents of participating patients and control subjects. the principles of the helsinki declaration, the oviedo convention on human rights and biomedicine and the slovene code of medicine deontology were strictly followed in the conduct of this research. the study protocol was also submitted to clinicaltrials.gov registry with the title viral respiratory and gastrointestinal infections in children under 6 years of age (reg. nct00987519). stool samples were diluted in sterile phosphate-buffered saline (pbs) to a 10% suspension. aliquots of 180 μl of magna pure bacteria lysis buffer (roche applied science, mannheim, germany) and 20 μl of proteinase k (qiagen, hilden, germany) were added to 190 μl of stool suspension. np swabs were collected using flocked-tip swabs and transported to the laboratory in the copan universal transport medium (utm-rt) system (copan italia, brescia, italy). before the extraction procedure, 5 μl of equine herpesvirus 1 and 5 μl of equine arthritis virus isolates were added to all samples. specific target sequences of these viruses were subsequently amplified in separate real time reverse transcription polymerase chain reactions (rt-pcrs) as an internal control to ensure that negative results were not caused by poor nucleic acid extraction or inhibition of the rt-pcr assay [15, 16] . the initial volume used for extracting total nucleic acids was 400 μl of stool suspension, 190 μl of vigorously vortexed np swab medium and 190 μl of whole blood samples. nucleic acids were extracted using total nucleic acid isolation kits on a magna pure compact instrument (roche applied science), according to the manufacturer's instructions. coronaviruses including hku1, nl63, 229e and oc43 were detected in stool samples, np swabs and whole blood samples by molecular methods using primers and probes as described by kuypers et al. [17] . for amplification of 85-100 bp fragments of the polymerase 1b gene of coronaviruses, a one-step real-time rt-pcr assay was used in a stepone real-time pcr system (applied biosystems, carlsbad, ca). briefly, 5 μl of total nucleic acid was added to 15 μl of reaction mixture including 2 × reaction mix, superscript w iii rt/platinum w taq mix (invitrogen, carlsbad, ca) with an additional 6 mm mgso 4 . the cycling conditions were as follows: 20 min at 50°c, 2 min at 95°c and 45 cycles of 15 s at 95°c and 45 s at 60°c. all np swabs and stool samples in which hcovs were established were also tested for the presence of other viruses. in np swabs respiratory syncytial virus (rsv), influenza viruses a and b (flu a-b), parainfluenza viruses 1-3 (piv 1-3), metapneumovirus (hmpv), human bocavirus (hbovs), adenovirus (adv) and rhinovirus (hrv) [18] [19] [20] [21] [22] [23] [24] were searched for by real-time rt-pcr. stool samples were tested for the presence of hbovs and adv using molecular methods as described previously [22, 23] , and for other gastroenteric viruses by electron microscopy (em). the presence of norovirus genogroups i and ii and astrovirus was ascertained by real-time rt-pcr [25, 26] , while group a rotavirus and adenovirus type 40/41 were detected by antigen-elisa premier rotaclone and premier adenoclone (meridian bioscience, cincinnati, oh). data are reported as the frequency (percentage) and 95% confidence intervals (cis) for proportions obtained using exact binomial tail areas. mcnemar's test was used to compare the frequency of hcov positivity of patients at baseline and after 14 days of follow-up. univariate logistic regression models with firth's correction were used to assess the association between hcov positivity and study group (patient or control) and the results are reported as the odds ratio (or) with 95% ci and two-sided p values. mann-whitney test was used to compare the median duration of illness and of hospitalization of hcovs positive and hcovs negative children. the tecumseh study of respiratory illness vi. frequency of and relationship between outbreaks of coronavirus infection the human enteric coronaviruses dual enteric and respiratory tropisms of winter dysentery bovine coronavirus in calves identification of a novel coronavirus in patients with severe acute respiratory syndrome coronavirus as a possible cause of severe acute respiratory syndrome enteric involvement of severe acute respiratory syndrome-associated coronavirus infection clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study impact of human coronavirus infections in otherwise healthy children who attended an emergency department epidemiology and clinical presentations of human coronavirus nl63 infections in hong kong children clinical and molecular epidemiological features of coronavirus hku1-associated community-acquired pneumonia detection of human coronaviruses in children with acute gastroenteritis detection of the new human coronavirus hku1: a report of 6 cases human coronaviruses are uncommon in patients with gastrointestinal illness viremia and nasal and rectal shedding of rotavirus in gnotobiotic pigs inoculated with wa human rotavirus detection of equine herpesvirus type 1 using a real-time polymerase chain reaction comparison of different molecular methods for assessment of equine arteritis virus (eav) infection: a novel one-step mgb real-time rt-pcr assay, pcr-elisa and classical rt-pcr for detection of highly diverse sequences of slovenian eav variants clinical disease in children associated with newly described coronavirus subtypes evaluation of quantitative and typespecific real-time rt-pcr assays for detection of respiratory syncytial virus in respiratory specimens from children comparison of real-time pcr assays with fluorescent-antibody assays for diagnosis of respiratory virus infections in children real-time rt-pcr assays for type and subtype detection of influenza a and b viruses real-time reverse transcriptase pcr assay for detection of human metapneumoviruses from all known genetic lineages real-time pcr assays for detection of bocavirus in human specimens simultaneous detection of human bocavirus and adenovirus by multiplex real-time pcr in a belgian paediatric population diagnosis of human metapneumovirus and rhinovirus in patients with respiratory tract infections by an internally controlled multiplex real-time rna pcr broadly reactive and highly sensitive assay for norwalk-like viruses based on real-time quantitative reverse transcription-pcr novel approach for detection of enteric viruses to enable syndrome surveillance of acute viral gastroenteritis submit your next manuscript to biomed central and take full advantage of: • convenient online submission • thorough peer review • no space constraints or color figure charges • immediate publication on acceptance • inclusion in pubmed, cas, scopus and google scholar • research which is freely available for redistribution hcovs: human coronaviruses; np swab: nasopharyngeal swab; rti: respiratory tract infections; age: acute gastroenteritis. the authors declare that they have no competing interests. this study was supported by the slovenian research agency (research program p3-0083) and institutional department funds. key: cord-294501-1nf98mpb authors: bonafè, massimiliano; prattichizzo, francesco; giuliani, angelica; storci, gianluca; sabbatinelli, jacopo; olivieri, fabiola title: inflamm-aging: why older men are the most susceptible to sars-cov-2 complicated outcomes date: 2020-05-03 journal: cytokine growth factor rev doi: 10.1016/j.cytogfr.2020.04.005 sha: doc_id: 294501 cord_uid: 1nf98mpb severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection is characterized by a high mortality of elderly men with age-related comorbidities. in most of these patients, uncontrolled local and systemic hyperinflammation induces severe and often lethal outcomes. the aging process is characterized by the gradual development of a chronic subclinical systemic inflammation (inflamm-aging) and by acquired immune system impairment (immune senescence). here, we advance the hypothesis that four well-recognized features of aging contribute to the disproportionate sars-cov-2 mortality suffered by elderly men: i. the presence of subclinical systemic inflammation without overt disease, ii. a blunted acquired immune system and type i interferon response due to the chronic inflammation; iii. the downregulation of ace2 (i.e. the sars-cov-2 receptor); and iv. accelerated biological aging. the high mortality rate of sars-cov-2 infection suggests that clarification of the mechanisms of inflamm-aging and immune senescence can help combat not only age-related disorders but also sars-cov-2 infection. a novel coronavirus, severe acute respiratory syndrome corona virus 2 (sars-cov-2), has been spreading across the world since december 2019. sars-cov-2 causes an atypical pneumonia associated with acute respiratory distress syndrome, acute respiratory failure, and other potentially lethal complications [1] including a deadly "cytokine storm", i.e. a strong increase in the plasma concentration of multiple cytokines [2] . in march 2020 corona virus disease 2019 (covid19) , the disorder caused by sars-cov-2, was declared a pandemic by the world health organization [3] . its high infectivity seems to be mostly due to intrinsic characteristics of the virus [4] and to the lack of previous exposure of the population to the strain. the elderly and patients with pre-existing comorbidities are bearing the brunt of the high casefatality rate (cfr) of the disease, which is affecting the frailest groups of the population [5] . data released by the chinese center for disease control and prevention [6] suggest that the overall cfr of covid-19 in china was 2.3%. in particular, whereas there were no fatalities among patients aged up to 9 years, the cfr of those aged 70-79 years and of those aged ≥ 80 years was 8.0% and 14.8%, respectively. critically, pre-existing comorbidities were associated with a cfr of 10.5% (cardiovascular disease), 7.3% (diabetes), 6.3% (chronic respiratory disease), 6.0% (hypertension), and 5.6% (cancer) [7] . moreover, men were more likely to die (2.8%) than women (1.7%) [6] . thus, old age and male gender were among the main risk factors for an adverse outcome [8] . these data are similar to those of italy, where on march 30th infections were 97,780 [9] . the median age of the deceased was 80 years (interquartile range, 30-103); only 1.1% of those who died were aged less than 50 years. notably, 70.9% of fatalities were men, whose mean age was 78 years compared to the 82 years of women; men were also 78.5% of deceased patients aged less than 50 years. about 1.4% of the patients who died in italy suffered from no pre-existing condition, whereas 51.2% had three or more age-related diseases (ards), such as cardiac ischemia, hypertension, type ii diabetes mellitus, and chronic obstructive pulmonary disease. similar mortality patterns have been https://doi.org/10.1016/j.cytogfr.2020.04.005 described for severe acute respiratory syndrome (sars) and middle east respiratory syndrome outbreaks, both of which are due to viral strains of the same family [10] . these data indicate that advanced age and male gender are risk factors for an adverse outcome. two chinese studies comparing the extreme patient phenotypes, i.e. discharged and deceased individuals, found that the most powerful clinical predictors of mortality covid-19 were the levels of two markers of heart damage, myoglobin and cardiac troponin, and of three major proinflammatory mediators, high-sensitivity c-reactive protein (crp), interleukin (il)-6 [11] , and d-dimer [8] . in most patients with severe disease the infection was associated with a cytokine storm [12] [13] [14] . in particular, higher levels of circulating il-6 have been reported in patients with more severe disease [8, 15] . aging is characterized by the gradual development of a chronic subclinical systemic inflammation, which has been designated inflammaging [16] , and by acquired immune system impairment, i.e. immune senescence [17] . the rate of inflamm-aging is higher in men [18] . il-6 elevation is typical of aging [19] . persistent il-6 elevation can promote lung tissue inflammation and injury [20] and foster viral replication [21] . targeting il-6, the "cytokine for gerontologists" [22] , helps attenuate the cytokine storm [23] . tocilizumab, a biological drug approved for rheumatoid arthritis, is currently being evaluated for its efficacy against the effects of systemic il-6 elevation (clinicaltrial.gov, nct04317092, nct04320615, nct04306705). the evidence reviewed above suggested to us that the two key features of the aging processinflamm-aging and immune senescenceand their implications can explain why older men with ards are the most prone to the adverse outcomes of sars−cov2 infection. inflamm-aging affects all individuals irrespective of their health status [16] ; inflammation is also a key pathogenic mechanism of covid-19 disease (fig. 1) . in the elderly, especially men, il-6 is chronically upregulated [16, 18] ; its elevation also predicts mortality due to sars-cov-2 [8, 11] . the gender bias has also been characterized at the molecular level. the stronger age-dependent activation of the innate proinflammatory pathways demonstrated in men compared to women [24] is consistent with men's higher rate of inflamm-aging [18] . inflamm-aging is regarded as a major risk factor for the common ards, in line with the mounting evidence that an inflammatory pathogenesis is shared by most common ards [16] . the situation is different in centenarians, who are characterized by specific prolongevity traits and anti-inflammatory markers that delay ard onset, which seem to protected them against the adverse outcomes of sustained inflammation [25, 26] . in older men with ards, who have the highest rate of inflammaging, the inflammatory response induced by sars-cov2 infection seems to favor a poorer outcome. the elderly population is the most vulnerable to infection with influenza virus (ifv) and varicella-zoster virus (vzv), two major pathogens that are responsible for the most common infectious diseases worldwide [27] . the high mortality from seasonal flu affecting the elderly, which most countries address with extensive vaccine campaigns [28] , is a consequence of immune senescence, which seems to be the result of lifelong immunogenic stimulation of the immune system by exogenous subclinical infections and endogenous agents [29] . endogenous factors such as misplaced nucleic acids [30, 31] induce a shift of t and b lymphocytes from naïve to memory effector cells and impair the ability of the adaptive immune system to fight pathogens [17] ; since the impairment includes the proliferative exhaustion of memory cells, it involves both unencountered and previously encountered antigens [32] . a recent study has found that the depletion of b lymphocytedriven acquired immunity affects predominantly men [24] . thus, in older men the chronic inflammatory status is coupled with a dramatic depletion of b lymphocyte-driven acquired immunity. notably, aging also attenuates the upregulation of co-stimulatory molecules critical for t cell priming and reduces antiviral interferon (ifn) production by alveolar macrophages and dendritic cells (dcs) in response to ifv [33] . consistent with this finding, the ability of dcs and macrophages to elicit cd8 + t cell response and proliferation and to release antiviral cytokines is impaired in elderly individuals [34] ; in parallel, these subjects are characterized by a reduced activity of plasmacytoid dcs, the main sources of type i ifns, which underpin the antiviral response and provide the first-line sentinels in immune surveillance, also in the lung [35] . an important animal study has found that aged cynomolgus macaques infected with sars-cov1 (which was responsible for the sars-cov1 epidemic in 2003-2004) developed more severe disease than their young adult counterparts and showed a blunted type i ifn response coupled with an elevated production of proinflammatory factors including il-6 [36] . notably, as in other acquired immune system compartments, the impairment of the plasmacytoid dc type i ifn pathway is more pronounced in men compared to women [37] . both responses help clear the virus: the former is aimed at providing a local/contained response, whereas the latter enhances the local and systemic response also through the recruitment of large numbers of leukocytes. the elevated production of proinflammatory factors may ultimately induce local and systemic damage by unleashing a cytokine storm [38] . in sars-cov-1-infected pneumocytes, the antiviral response triggered by plasmacytoid dcs is blunted by proinflammatory cytokines released from pneumocytes [36] . notably, the gender-biased association of inflamm-aging and immune-senescence is not simply correlative. indeed, the two phenomena are recognized as being closely coupled in patients suffering from acute critical conditions such as sepsis and cytokine release syndrome (crs), which is characterized by simultaneous systemic inflammation and immune paralysis [39] . a reciprocal inhibition between antiviral type-i ifn response and inflammation has been demonstrated in viral infections [40] . therefore, in older men the fine balance between the antiviral response supported by t lymphocytes, b lymphocytes, and plasmacytoid dcs and inflammation is tilted in favor of inflammation. 4. in older men with age-related diseases, the aging-dependent reduction in ace2 activity worsens sars-cov-2 infection outcomes angiotensin-converting enzyme (ace)2, the main sars-cov2 host cell receptor, plays a crucial role in virus entry into the cell, as previously demonstrated in sars and nl63 human coronaviruses [41] . ace cleaves angiotensin i to generate angiotensin ii, whereas ace2 is a terminal carboxypeptidase that reduces angiotensin ii levels, thus playing important functions in the negative regulation of the reninangiotensin system [42] . ace2 is expressed in the lung, oral mucosa (epithelial cells of the tongue), intestine (enterocytes), and endothelial cells [43, 44] . mounting evidence indicates that it plays a protective anti-inflammatory role on endothelial and lung function. notably, ace2 underexpression in the lung is implicated in respiratory diseases associated to severe infection [45] . in the mouse lung, attenuation of ace2 activity in the setting of endotoxin inhalation enhanced neutrophil infiltration, exaggerated lung inflammation-induced injury by activating the des-arg9 bradykinin (dabk)/bradykinin receptor b1 (bkb1r) axis [46] , and elicited the release of proinflammatory chemokines (cxcl5, c-x-c motif chemokine 5), macrophage inflammatory protein-2 (mip2), and tnf-α from airway epithelia [46] . intriguingly, the spike protein of sars-cov induces downregulation of ace2 expression through an increased release of proinflammatory chemokines and cytokines, thus enhancing inflammation and vascular permeability and promoting neutrophil recruitment to the lung [27] . accordingly, lung ace2 underexpression and the consequent impaired inhibition of dabk/bkb1r signaling result in abundant neutrophil infiltration and severe lung inflammation. in mice, in vivo injection of sars-cov spike protein worsens acute lung failure, which can be attenuated by blocking the renin-angiotensin pathway [47] . as regards ace2 expression in endothelial cells, vasculitis has been described during viral infection [48] . several studies suggest that ace2 is downregulated in aging [49] , explaining, at least in part, the increased susceptibility to vascular injury and cardiovascular disease affecting the elderly [49] . interestingly, ace2 overexpression has been reported in asian females compared to males as well as in other ethnic groups [50] . in contrast, ace2 is significantly downregulated in patients with type ii diabetes as well as in most aged diabetic men with severe covid-19 outcomes [51] . several aspects of inflamm-aging are still being investigated [30, 52] . the accumulation of senescent cells during aging is one of the most likely contributors to inflamm-aging, due to their acquisition of the senescence-associated secretory phenotype (sasp) [53] . senescence affects most cell types including macrophages, which serve as sentinels against infection [16] . inflamm-aging has also been designated as macroph-aging, due to the important role played by this cell type in secreting proinflammatory mediators at the local and systemic level [54] . notably, studies of the modulation of circulating monocyte/ macrophage polarization during aging suggest different age-related trends for the m2 subset [55] . macrophages are recruited to the lung by sars-cov-2-infected cells expressing ace2 [56] . the stronger inflammatory state described in circulating monocytes from men compared to women [24] suggests that senescent-like macrophages compound the inflammation induced by covid-19 through the production of proinflammatory cytokines like il-6 [57, 58] , in a combination that in older men is especially lethal. telomere shortening, i.e. the loss of chromosome ends [59, 60] , is a hallmark of aging. older men, particularly those suffering from ards, show reduced telomere length (tl) compared to age-matched women [61] . interestingly, telomeres released outside cells may exert an antiinflammatory action, while shortened telomeres may favor the production of proinflammatory molecular species [62, 63] . telomere shortening is seen in ards and is associated to an impaired response to infective agents, suggesting that leukocyte tl may be a marker of general immune competence [64] . telomere research supports the notion that tl may play a role in inflamm-aging, which in older men is commonly accelerated. other measures of biological aging, such as changes in epigenetic patterns, also exhibit a different expression in older men compared to age-matched women [61, 65] . the data reviewed above support the notion that the aging process is associated to inflamm-aging and immune senescence and that biological aging is accelerated in men compared to women. the mechanisms underpinning the chronic inflammatory state characterizing older men are the subject of intense research. we speculate that these mechanisms provide crucial insights into covid-19 pathobiology and natural history and that their further investigation can lead to novel therapeutic interventions. a variety of repurposed antiviral drugs (e.g. remdesivir, lopinavir/ ritonavir) and anti-inflammatory agents, including chloroquine (clinicaltrial.gov, nct04323527, nct04324463, nct04303507) and 1 . overview of the framework where inflamm-aging is the main phenomenon contributing to the high covid-19 mortality rate seen in male, elderly, and frail patients. in these individuals, acute sars-cov-2 infection compounds their chronic, subclinical, aging-related proinflammatory state (inflamm-aging) which, together with immune senescence and the age-and gender-specific distribution of ace2 in the airway epithelia, could blunt the antiviral response to inflammation. this model could explain the delayed viral clearance and the high rate of adverse outcomes observed in older patients in the late disease stages. the assessment of selected biological and immunological aging markers could be a valuable strategy for covid-19 patient risk stratification in the earliest disease stage irrespective of their chronological age. figure based on the classification of covid-19 disease states proposed by siddiqi and mehra and adapted from the accompanying paper [78] . ace2, angiotensin converting enzyme 2; cfdna, cell-free dna; ifn, interferon. tocilizumab (nct04317092, nct04320615, nct04306705) are being tested to treat covid-19 infection [66] . it is conceivable that drugs that modulate inflamm-aging could help treat elderly and/or frail patients with sars-cov-2 infection [67] . in particular, "senolytic" compounds, which selectively promote senescent cell clearance, might help reduce systemic as well as local inflammation in such patients. pilot trials are already in progress [67, 68] , but a substantial number of potential senolytics with a low toxicity profile have been identified and can safely be explored [69] . another approach could rely on harnessing the antiinflammatory ability of free telomeric end oligonucleotides [70, 71] , whose airway administration in aerosol form has been studied in a model of mouse lung injury [72] . this approach would not be limited to elderly covid-19 patients. the rate of biological aging (including inflamm-aging) varies among subjects as a result of interactions among genetic make-up, epigenetic modulation, environment, and random factors and can be traced and measured by biomarkers such as tl, circulating nucleic acids, epigenetic changes involving extracellular vesicles, and the expression of inflammatory cytokines such as il-6 [26, 59, [73] [74] [75] [76] . the ability to measure "real" biological age would help determine a person's aging rate. attaining this goal clearly requires more accurate and possibly more numerous biomarkers of biological aging capable of predicting functional capacity at a later age than chronological age. since the variance of aging phenotypes widens over time, owing to different individual trajectories of aging [75, 77] , immunological/biological age rather than chronological age appears to be a more sensitive approach also to assess individual susceptibility to the adverse outcomes of covid-19 infection. consequently, a panel of biomarkers of immunological/biological aging could help identify subjects at risk of adverse covid-19 outcomes also among the younger population. thus, young people whose inflamm-aging signature is not consistent with their chronological agewho may therefore be particularly prone to develop not only ards, but also a deadly communicable disease such as covid-19 infectionwould also benefit from aging research. all authors: no conflict. sars-cov-2 is an appropriate name for the new coronavirus cytokine release syndrome world health organization, who director-general's opening remarks at the media briefing on covid-19 aerosol and surface stability of sars-cov-2 as compared with sars-cov-1 novel coronavirus pneumonia emergency response epidemiology team, vital surveillances: the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19)-china singapore novel coronavirus outbreak research, epidemiologic features and clinical course of patients clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study characteristics of covid-19 patients dying in italy report based on available data on characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology clinical features of patients infected with 2019 novel coronavirus in reducing mortality from 2019-ncov: host-directed therapies should be an option inflamm-aging. an evolutionary perspective on immunosenescence the integration of inflammaging in age-related diseases a gender-dependent genetic predisposition to produce high levels of il-6 is detrimental for longevity interleukin-6 in aging and chronic disease: a magnificent pathway the role of interleukin-6 in pulmonary inflammation and injury induced by exposure to environmental air pollutants the role of interleukin 6 during viral infections interleukin-6: a cytokine for gerontologists current concepts in the diagnosis and management of cytokine release syndrome sexual-dimorphism in human immune system aging inflammaging as a major characteristic of old people: can it be prevented or cured? genomic stability, anti-inflammatory phenotype, and up-regulation of the rnaseh2 in cells from centenarians aging and the immune system: the impact of immunosenescence on viral infection, immunity and vaccine immunogenicity recommendations on influenza vaccination during the 2019-2020 winter season cytokine and growth factor reviews xxx (xxxx) xxx-xxx influenza-vaccination-during-the-20192020-winter-season immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front ribosomal dna instability: an evolutionary conserved fuel for inflammaging inflammaging and' garb-aging vaccination in the elderly: the challenge of immune changes with aging inflammaging and the lung age-related alterations in immune responses to west nile virus infection control of coronavirus infection through plasmacytoid dendritic-cellderived type i interferon exacerbated innate host response to sars-cov in aged non-human primates sex differences in plasmacytoid dendritic cell levels of irf5 drive higher ifn-alpha production in women into the eye of the cytokine storm, microbiol new frontiers in precision medicine for sepsis-induced immunoparalysis inflammation. 25-hydroxycholesterol suppresses interleukin-1-driven inflammation downstream of type i interferon interaction of severe acute respiratory syndrome-coronavirus and nl63 coronavirus spike proteins with angiotensin converting enzyme-2 a novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9 high expression of ace2 receptor of 2019-ncov on the epithelial cells of oral mucosa tissue distribution of ace2 protein, the functional receptor for sars coronavirus, a first step in understanding sars pathogenesis sars coronavirus-induced lung injury attenuation of pulmonary ace2 activity impairs inactivation of des-arg(9) bradykinin/bkb1r axis and facilitates lps-induced neutrophil infiltration the discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice the clinical pathology of severe acute respiratory syndrome (sars): a report from china endothelial cell senescence in aging-related vascular dysfunction individual variation of the sars-cov2 receptor ace2 gene expression and regulation comparative genetic analysis of the novel coronavirus (2019-ncov/ sars-cov-2) receptor ace2 in different populations inflammaging 2018: an update and a model senescence-associated secretory phenotypes reveal cellnonautonomous functions of oncogenic ras and the p53 tumor suppressor senescence associated macrophages and "macroph-aging": are they pieces of the same puzzle? age-related m1/m2 phenotype changes in circulating monocytes from healthy/unhealthy individuals single cell rna sequencing of 13 human tissues identify cell types and receptors of human coronaviruses cells exhibiting strong p16 (ink4a) promoter activation in vivo display features of senescence pai-1 regulation of tgf-beta1-induced alveolar type ii cell senescence, sasp secretion, and sasp-mediated activation of alveolar macrophages the telomere world and aging: analytical challenges and future perspectives the hallmarks of aging sex differences in telomeres and lifespan changes in the biochemical taste of cytoplasmic and cell-free dna are major fuels for inflamm-aging exploiting the telomere machinery to put the brakes on inflamm-aging shorter leukocyte telomere length is associated with higher risk of infections: a prospective study of 75,309 individuals from the general population dna methylation age of human tissues and cell types regeneron, sanofi to test arthritis drug as coronavirus treatment, wall street senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease anti-senescence compounds: a potential nutraceutical approach to healthy aging repetitive elements in mammalian telomeres suppress bacterial dna-induced immune activation a suppressive oligodeoxynucleotide expressing ttaggg motifs modulates cellular energetics through the mtor signaling pathway suppressive oligonucleotides inhibit inflammation in a murine model of mechanical ventilator induced lung injury biological age predictors where metabolism meets senescence: focus on endothelial cells measuring biological aging in humans: a quest small extracellular vesicles deliver mir-21 and mir-217 as pro-senescence effectors to endothelial cells circulating mirnas and mirna shuttles as biomarkers: perspective trajectories of healthy and unhealthy aging covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal we are grateful to word designs for text editing (www. silviamodena.com). key: cord-335635-41u0cq1h authors: huynh, hieu trung; nguyen, hoang title: joint age estimation and gender classification of asian faces using wide resnet date: 2020-08-27 journal: sn comput doi: 10.1007/s42979-020-00294-w sha: doc_id: 335635 cord_uid: 41u0cq1h two key facial features, age and gender, have been widely explored. companies and organizations have investigated in related applications in several fields including insurance, retails, marketing, etc. it would bring tremendous benefit, which allow companies to easily identify their customer demographics. several approaches have been proposed with remarkable results. however, because of the lack of open and multi-ethnic datasets, most modern age and gender estimating models were trained solely based on white people with western facial features, and thus fall short with non-caucasian people. in this paper, we developed an applicable wide resnet model to estimate the age and the gender of asian faces. the model was trained with a newly improved asian face database. the experiments have shown promising results, as it can match the performance of microsoft’s how-old api estimator in a specific dataset. the age and gender estimation problem has been investigated by several researchers due to its application ability in many fields such as insurance, retails, marketing, etc. several industrial corporations are always actively searching for ways to utilize technologies to get an insight of their customer segments. any company that comes into possession of such tools can harvest a massive amount of data, smoothly increase their revenues and benefits, surpass the competitors, and dominate the corresponding market. another application of age and gender estimation is in surveillance systems, it can help to authorize people for buying restricted goods or adult products such as alcohol or tobacco. it can integrate with other biometric information to improve the accuracy of recognition systems. in addition, a recent report [1] has shown that the covid-19 virus spread has the relevance of age, gender, and place of residence in population. hence, these factors will provide the key information to guide the preparedness and response in healthcare facilities and the definition of policy interventions. collecting personal information on a large scale is not always easy, because it is relatively sensitive and not all people have the spare time to fill out multiple surveys at once. however, the task of facial image collection probably could be done simpler. it could be performed by installing several surveillance cameras around the facilities and it should be rather easy for companies and organizations to extract facial pictures of their visitors for security and research purpose. this may result in urgent needs for companies and organizations to have trust-worthy tools that can reasonably predict their visitor identity features, using just the faces. in recent years, with the rise of deep learning and computer vision, researchers have been looking deeply into the age and gender estimation problem due to its practical influences. in this paper, we investigate in collecting and improving upon a multi-purpose asian face dataset with the intention of partially addressing the problem of age and gender estimation of asian people. ultimately, the final aim of my paper is to make the best use of the data, as well as the existing deep learning techniques to put together a wellrounded implementation of wide resnet to create a reliable program that can be able to extract the age and gender of a certain asian person with reasonable accuracy on both aspects. the rest of this paper is organized as follows. section 2 reviews related works for age and gender estimation. in sect. 3, we propose a new approach for joint age estimation and gender classification. experiments are described in sect. 4. results and discussion are presented in sect. 5. finally, we make a conclusion in sect. 6. the problem of age and gender estimation is not new. it has been investigated by several teams, from which several different architectures have been proposed, including state-ofthe-art ones. in [2] , chang-ling ku et al. proposed a method to examine many pictorial frames of a same person to make a more robust and stable prediction. whereas in [3] , hayashi suggested that instead of completely leaving the featureextraction step to the convolutional neural network (cnn) model as a black-box, it is advisable to manually extract facial identification landmarks such as wrinkles and use that to enhance the model performance, as they are indications of age. those are all plausible approaches to such problem. tian and chen [4] proposed a joint learning method for age and gender estimation based on support vector machine (svm) and ordinal regression methods. four datasets were evaluated including fg-net, morph album i, album ii, and images of groups. another approach based on support vector machine was proposed by aswathy et al. [5] . this approach estimates the facial attributes using drop-svm and knn from the images of faces acquired in the wild conditions. in [6] and [7] , rothe et al. came up with a revolutionary method called deep expectation (dex). the method is strikingly simple. in the beginning stage, the faces were cropped and aligned using available toolkits, and then, a regular vgg-16 network was used for the age detection as a classification task with 101 classes (representing the age from 0 to 100). finally, after receiving the softmax distribution for the 101-dimension vector, the output values were determined by performing a dot product operation between that vector and another vector containing discrete values from 0 to 100. it is argued that this process is more robust and stable than both the logistic regression and the linear regression approach, while yielding a better result at the same time. as presented in [7] , authors claimed that their implementation is the current state-of-the-art in predicting the subject's apparent age, as tested on the imdb-wiki dataset [6, 7] . these two papers are the main academic resources whose concept we will utilize into the model to achieve the desirable results. smith and chen [8] proposed a method using transfer learning with deep cnns. the transfer learning is based on vgg19 and vggfaces with deep cnn hierarchy. first, the subject is classified based on gender. the male and female models were used to predict the age. this approach was evaluated on morph ii dataset [9] . most modern age and gender estimating models were trained based on white people with western facial features, and the application on asian faces has limitations. our proposed scheme is depicted in fig. 1 . the training process is described in fig. 1a , which includes two stages. the first stage is the image augmentation by using random erasing and mixup processes. the wide resnet model is trained in the second stage. the trained network is then used for age estimation and gender classification, as shown in fig. 1b . to prevent the model from overfitting, conventional regularization and image augmentation should be applied, and they may consist of the l 1 , l 2 regularization, batch normalization, dropout, image shifting, rotating, and flipping. however, from experiments, it came to our attention that the model still heavily suffers from the state of overfitting. we eventually tackle the troublesome problem using random erasing and mixup. fig. 1 the proposed scheme for age and gender estimation. the left is training process and the right is testing process. a training process. b testing process random erasing: the idea behind this method is truly intuitive. it would observe that human can still perceive the information conveyed by the image even if there are slight distortions, as long as the distorted portion is not too big that it covers important structure parts. a powerful model should be able to perform at the same level, grasp the context of an image from structure of the overall object architecture, rather than each individual pixel in block. the random erasing was introduced to assist model in reaching that intelligent stage. in which, any image will either be kept unchanged or randomly have a rectangle region of an arbitrary size assigned with arbitrary pixel values. by simply introducing a reasonable noise to the training sample, this method may enhance the model to become less prone to overfitting. we enforced the algorithm with similar set of hyper-parameters as concluded in [10] . to further elaborate, the process can be described as a sequence of mathematical operations. before training process, each image i has a probability of p of activating random eraser, and inherently, a probability of 1p to remain unchanged. the original size of the image is: where w and h are the width and height of image, respectively. a randomly selected rectangle region i e with area ratio s a is chosen between s l and s h . an aspect ratio r e is also uniformly randomly initialized between r 1 and r 2 . the area of i e can be computed as: which is then used to calculate: afterwards, another point p = (x e , y e ) is arbitrarily chosen within i, and the region i e = (x e , y e , x e + w e , y e + h e ) is then set to a certain value in the range [0, 255]. if i e falls outside i, p is re-selected until the requirement is satisfied. in our implementation, we set p = 0.5, s l = 0.02, s h = 0.4, r 1 = 0.3, r 2 = 1/0.3, similar to [10] . the resulting images are forwarded to the next stage. an example of random erasing is shown in fig. 2 . in fig. 2b , a random portion is erased, but it affects very little our perception of the subject's age and gender. after pre-processing with random erasing, an extra measurement is taken to further guarantee the generalization of the same model. in essence, rather than handling each image independently, mixup [11] groups pairs of samples and their labels together before training the model on a convex combination of such pairs. a weakly trained model will design an overly complex mapping between an image and its label, and then fail to recognize very similar images with slight modification or adversarial generation. to tackle such problem, the mixup helps regularizing the neural network to favor simple linear behavior in-between training sample instead of complex correlations. the method is proven to enhance robustness, stability, and accuracy of models on popular dataset like imagenet, cifar-10, and cifaf-100 dataset, resulting in state-of-the-art architecture. despite its powerful capability, mixup can be easily implemented within a few lines of code with minimal overhead. to put it briefly, mixup creates virtual training samples through the formula: where x i and x j are raw input vectors; y i and y j are one-hot encoding labels; (x i , y i ) and (x j , y j ) are two randomly drawn examples from the mini training batch, and ∈ [0, 1] . in the proposed model, for simplicity purposes, we draw from a beta distribution with α = β = 0.2, λ ~ beta(0.2, 0.2) [11] . the output is now ready to be fed into the model for training. an example of random erasing and mixup is shown in fig. 3 . the residual networks (resnet) have achieved state-of-theart in several benchmarks, including object classification and detection [12, 13] . the order of activations in the residual networks representing identity mappings in the residual blocks may affect the training performance. the residual block with identity mapping is represented mathematically as in eq. (7) [13] : where o l and o l+1 are the input and output of the lth block in the network, and f and w l are residual function and its parameters. various residual blocks can be used including a combination of convolutional layers with batch normalization (bn) and relu preceding convolution. to increase the representational power of residual block, the popular methods could be applied including (1) add more convolutional layers per block; (2) increase the filter sizes in convolutional layers; or (3) widen the convolutional layers by extending feature channels. regarding our model architecture for age and gender estimation, we have utilized the variation of the popular ima-genet-champion residual network, called wide residual network, or wide resnet. it was introduced by zagoruyko and komodakis in [14] . the fundamental concept lies behind this network is that in addition to making the use of the skip connection like the regular resnet, the order of layers in a block is rearranged from conv-bn-relu to bn-reluconv to enhance its feature-extraction capability. it is also expanded in terms of the feature channels by a widening factor k. as for the rearrangement of the layer order, authors [14] showed through experimental results that the new order, indeed, executes faster than the original one while achieving a better accuracy level. in terms of the feature channel extension, there is an ongoing debate on whether the width or the depth of the network contributes more to the overall success of the model. conventionally, the original resnet model suggests that to achieve higher accuracy, ones could just simply increase the deepening factor n, also referred to as the number of blocks in a certain stage, or the number of stages in general without having worry about gradient vanishing/exploding like older architecture due to the powerful skip connection. in other words, keeping on stacking more layers until reaching a desirable result was the most straightforward method. however, deeper network also subsequently increases the number of parameters in linear time and may make it longer and harder to converge. furthermore, there is also the problem of diminishing feature reuse (a few residual blocks learning useful representations or many blocks sharing very little information with small contribution to the final goal) in very deep and thin residual networks. thus, instead of senselessly stacking more layers and waste computational resources, a wide resnet suggests addressing the above problems by increasing the number of channels by a factor of k. it allows each block to learn a more meaningful feature representation of the data. although this makes the total number of parameters grows in quadratic time, most modern gpus are programmed to make parallel computation on large tensors for efficiencies, hence reducing the total amount of time needed for training a model [15] . furthermore, adding a simple dropout layer between two bn-relu-conv sequences also gives more room for model generalization. the specific architecture is described in table 1 . similar to the original wide resnet, our implementation begins with a 2d convolutional layer to extract the early features, with a 3 × 3 convolution block and a 16 feature channels. the main difference with our model is that instead of taking the input shape 32 × 32 × 3, we decided to double it to 64 × 64 × 3, since the megaage_asian dataset [16] contains pictures with higher resolution, which gives clearer edge and facial feature to detect. following that, there are three main groups; each group consists of two convolutional blocks (here, n = 2) and an additional dropout layer with the dropout probability of 0.2 between those blocks to prevent overfitting. each block contains one bn layer, one relu layer, and one convolutional layer. during the transition between two groups, the size of features is halved, while the channel planes are doubled. in the case where the input and output size do not share the same dimension, a 1d convolutional layer is applied to resize them for matching dimensionality. finally, after all the convolutional groups have been performed, the data then flow through one average pooling layer (with block size of 8 × 8) and flattened out. two final fully connected layers are then applied simultaneously to the flatten feature vector to perform both the age estimation and gender classification. the gender classification layer is a 2-dimensional softmax vector, representing the distribution probability that the person is either a male or a female. similarly, the age estimation vector is 10-dimensional, relative to the possible human age between 0 and 100 (here we presumed that people only live up to 100 year for simplicity). conventionally, most research teams refer to the imdb-wiki dataset when they tackle the age and gender detection problem, since it is among the most popular public datasets, with 523,051 images of celebrities along with their age and gender. however, it only contains an extremely small portion of people with asian background. therefore, models trained on that dataset unsurprisingly underperformed when presented with asian descendants. considering that asian people makes up to ~ 60% of the world population, that is indeed a serious downfall for such models. consequently, we did a handful of research and finally came across the megaage_asian dataset collected by mmlab, the chinese university of hong kong or sensetime [16] . the dataset consists of 40,000 up-close, frontal, and non-blurry asian facial images, along with the subject's age and gender, stored in a separate.txt file. the images in the dataset mostly belong to people from different asian ethnicity such as thailand, vietnam, or japan, cropped and aligned centering around their faces, varying from different angles and light direction. the age of the subject ranges between 1 and 70 which is truly diversified. some samples from the dataset are shown in fig. 4 . in the figure, the first string shows the gender of subject that is either male or female, and the following number is the subject's age. this format follows for subsequent figures as well if not otherwise specified. for clearance, identifying subject's gender is not as challenging as figuring out subject's age, as a normal human can execute the former task almost flawlessly. although our gender labels are not professionally verified, it still holds certain merits. the dataset consists of 40 thousand images for training, and 3945 other images for testing, which is a reasonable amount for the task at hands. the female:male ratio is 20,684:23,261, or roughly 9:10. the distribution of the age range can be interpreted from fig. 5 . the entire wide resnet is implemented using python programming language along with its libraries such as opencv, numpy, and keras deep learning framework, trained on amazon web service (aws), with 8 gb of gpu and 60 gb of memory. the entire code and our implementations can be found at: https ://githu b.com/amida drago n/asian -age-gende r-estim ation -2. the complete workflow of our methods is described as following. to start, all images are rescaled to the size of 64 × 64. afterwards, the dataset is separated into training set and validation set with the ratio of 9:1, which has 36,000 and 4000 images relatively. each mini-batch of 32 training samples consecutively undergoes a pre-processing series of random erasing and mixup before feeding onto the network. regarding the wide resnet, the parameters are randomly initialized using the he random formula [17] : where w [l] is the parameters of layer l, x ~ n(0,1) and n l−1 is the number of neurons in the previous layer (layer l − 1). this initialization method allows models to converge to a global minimum faster and more efficient. the weights are optimized by the mini-batch gradient descent with the initialized learning rate α set as 0.1; it is decayed overtime through the formula: where α new is new learning rate, α prev is the previous learning rate, epoch_nums is the epoch number, and decay_rate is the decay rate and set as 1e −6 . after each epoch, the model is freshly tested on a new validation set that it has never observed before to evaluate its generalization power and make necessary adjustments. only the model which has the best scores on the validation dataset is saved and used for further inspections. the training history of the wide resnet model is depicted in fig. 6 . it can be interpreted from the figure that the gender validation accuracy peaked at 92%, which is a rather reasonable result compared to the other proposed methods. however, the fascinating discovery lies within the age classification. its accuracy peaks at 15% around epoch 80, but that is not the metrics that we intent to examine for the age estimation problem, since precisely predicting a person age is a challenging task for any person, or even professional anthropologists. hence, we utilize the dex method mentioned in [6, 7] to calculate the predicted age value. in terms of the dex method, the softmax distribution only serves as an intermediate means to determine the final age prediction, unlike the traditional estimation models. the expected value for the subject's age is calculated by the formula: where o = {o 0 , o 1 ,…,o 100 } is the softmax output probabilities and y i 's are the discrete years, ranging from 0 to 100, corresponding to each class i. e(o) is the final prediction value for a subject's age. with e(o) at our disposal, we compute the mae over the 4000 testing images by: where n is the number of images, and ŷ i and e i (o) are the actual and predicted age of person in the image i, respectively. for the validation set, mae ≈ 4.2. to avoid bias in the model selection step, we also perform the exact measurement with the 3945 testing images, which yields mae = 4.05. the result indicates that, on average, the model misses a subject's age by a margin of roughly 4 years. it may note that, excluding the young childhood phase when the face might alter dramatically, generally person face does not change too much in a 4-year period. it may state that the gender aspect is easier to predict, because there exist only two options to choose, either male or female, and it is also an effortless task for human to perform with very high accuracy. however, the age feature is definitely significantly harder to recognize, because there are more than 100 possible cases. each individual person has different facial features, depending on their living conditions and ethnicity. in addition, the light direction and facial angle could also affect how old a certain people may look. some images where our model makes the most plausible guesses are shown in fig. 7 , and the predicted and actual ages are given in the first and second number, respectively. it can be observed that they have natural filter and light, as well as neutral emotion. there are still some images which result in low accuracy by our model, as shown in fig. 8 , and the predicted and actual ages are given in left and right values, respectively. some faces emerging such images make up unnaturally or have a big smile. they result in more wrinkles and eventually give out a feeling that individuals in the image appear different from they actually are. it could also be that they just possess different facial features in general. on the other hand, there are also images with heavy photoshop, resulting in noticeably and undeniably younger. since an mae score can be difficult to fully interpret, we also trained the same model, with similar hyper-parameters on the same data with age mapped to a certain age range, based on different phases of a human life circle, as shown in table 2 . it includes toddlers, teenagers, young adults, adults, midlife, and seniors. the new model achieved an accuracy level of 67.66% and a 96.3% 1-off accuracy, and the confusion matrix is illustrated in fig. 9 . from the confusion matrix, we can infer that most of the mistakes are between group 2 (19-25) and group 3 (26-32). a reasonable explanation would be that, at these phases, they reach a certain maturity and stable facial fig. 7 some accurately predicted images. the number on the left is the subject actual age, and the right is that of our prediction model. a 1, 1. b 13, 11 . c 30, 28. d 51, 53 toddlers and teenagers, on the other hands, go through dramatic changes with their hormones level, resulting in distinct facial features. with our best knowledge, it is difficult to find the previous studies which have run on experiment with the same testing dataset. authors in [6] and [7] provide that they achieved the mae score of 5.0 on the imdb-wiki dataset, but that is not to be compared to ours, since their data are much larger, and also, the distribution is differ greatly. however, microsoft published a similar api to predict age and gender of a certain person through just one submitted image. we requested the api to check out its accuracy on the same testing dataset. the result is quite surprising as it turned out. our model got 1% better than the microsoft in terms of gender accuracy, and 0.2 less of in term of mae score. this is not in anyway a statement that our model outperforms those of microsoft. microsoft deep leaning model presumably generalizes better to non-asian individuals, while our model would not make such rivalry prediction. however, with a limited amount of only 40,000 images, and 48 h of gpu training, we were able to partially match the performance of microsoft, who has in their possession a big dataset of images and gpu computational power. this could place a foundation for future development using similar network architecture (fig. 10 ). the age and gender estimation could be applied in many real-world applications, it has been investigated by several researchers and several models have been proposed. however, they have limitations relating to population. in this study, we have introduced an approach to partially addressing that problem, by focusing only on the asian population. the proposed approach utilizes the state-of-the-art deep learning and computer vision algorithms to achieve high accuracy. the well-rounded wide resnet model and image augmentation techniques have been applied. experimental results shown that the proposed approach obtains promising outcomes with a small error rate and a reasonable accuracy level. the model could easily be applied for non-asian population. age, gender, and territory of covid-19 infections and fatalities age and gender estimation using multiple-image features age and gender estimation based on facial image analysis joint gender classification and age estimation by nearly orthogonalizing their semantic spaces texture-based estimation of age and gender from wild conditions dex: deep expectation of apparent age from a single image deep expectation of real and apparent age from a single image without facial landmarks transfer learning with deep cnns for gender recognition and age estimation morph: a longitudinal image database of normal adult age-progression random erasing data augmentation mixup: beyond empirical risk minimization. corr deep residual learning for image recognition identity mappings in deep residual networks wide residual networks my model matched that of microsoft in some instances understand deep residual networks-a simple, modular learning framework that has redefined state-of-the-art quantifying facial age by posterior of age comparisons delving deep into rectifiers: surpassing human-level performance on imagenet classification conflict of interest the authors declare that they have no conflict of interest. key: cord-323582-7y8pt72r authors: ahamad, martuza; aktar, sakifa; rashed-al-mahfuz; uddin, shahadat; lió, pietro; xu, haoming; summers, matthew a.; quinn, julian m.w.; moni, mohammad ali title: a machine learning model to identify early stage symptoms of sars-cov-2 infected patients date: 2020-06-20 journal: expert syst appl doi: 10.1016/j.eswa.2020.113661 sha: doc_id: 323582 cord_uid: 7y8pt72r the recent outbreak of the respiratory ailment covid-19 caused by novel coronavirus sars-cov2 is a severe and urgent global concern. in the absence of effective treatments, the main containment strategy is to reduce the contagion by the isolation of infected individuals; however, isolation of unaffected individuals is highly undesirable. to help make rapid decisions on treatment and isolation needs, it would be useful to determine which features presented by suspected infection cases are the best predictors of a positive diagnosis. this can be done by analyzing patient characteristics, case trajectory, comorbidities, symptoms, diagnosis, and outcomes. we developed a model that employed supervised machine learning algorithms to identify the presentation features predicting covid-19 disease diagnoses with high accuracy. features examined included details of the individuals concerned, e.g., age, gender, observation of fever, history of travel, and clinical details such as the severity of cough and incidence of lung infection. we implemented and applied several machine learning algorithms to our collected data and found that the xgboost algorithm performed with the highest accuracy (>85%) to predict and select features that correctly indicate covid-19 status for all age groups. statistical analyses revealed that the most frequent and significant predictive symptoms are fever (41.1%), cough (30.3%), lung infection (13.1%) and runny nose (8.43%). while 54.4% of people examined did not develop any symptoms that could be used for diagnosis, our work indicates that for the remainder, our predictive model could significantly improve the prediction of covid-19 status, including at early stages of infection. there has recently been a rapid spread of the novel sars-cov2 coronavirus (gorbalenya et al., 2020) (designated by the world health organization) which gives rise to a respiratory disease covid-19 (who, 2020). the first human coronaviruses, 229e and oc43, were identified during the 1960s from human nasal secretions (lippi & plebani, 2020) . other individual virus types classified in this family have been distinguished (such as hcov nl63 and hku1) and are thought to arise from zoonotic infections (huang et al., 2020) as they are endemic in various bat populations. the coronavirus infections known were originally viewed as giving rise to innocuous respiratory human conditions that were not life-threatening. the development incidence of serious and deadly respiratory disorders attributed to beta-coronavirus subfamily members occurred in the last twenty years with the severe acute respiratory syndrome (sars) and the middle east respiratory syndrome (mers). the sars-cov infections arose first in foshan, china in 2002 and mers-cov in 2012 in saudi arabia (zhavoronkov et al., 2020) , both causing international alarm and containment efforts due to their rapid spread and high mortality rates. sars and mers were associated with mortality rates of 9.6% and 36%, respectively (peeri et al., 2020) , among those diagnosed patients. these identified coronavirus infections as a significant threat to human health with the potential to cause extreme and lethal respiratory tract infections in people, particularly if person-to-person infection occurs easily (chan et al., 2020) . the development and spread of the novel coronavirus (nishiura et al., 2020) causing covid-19 has vastly outpaced the rate of vaccine and therapeutic development. nev-ertheless, within weeks of the first observations of covid-19 disease, the virus was isolated and characterised. one of the most significant sars-cov2 protein targets is a 3c-like protease for which the structure is already known. much effort has been centred around re-purposing known clinicallytested drugs and virtual screening for possible targets using protein structure data (zhavoronkov et al., 2020) . priority has been given to the identification of infected individuals in order to isolate and (if necessary) treat them. central to this is the use of clinical symptoms to optimise identification of infected individuals. one of the earliest published studies (tian et al., 2020) showed an analysis of 262 individuals confirmed as covid-19 infected to determine their clinical and epidemiological characteristics in beijing, china and found that respiratory and extra respiratory transmission routes may explain the rapid spread of disease. in february 2020, the noted case fatality rate for covid-19 in wuhan, china, was 1.4% . however, accurate global estimates are far more challenging due to the vastly different response country to country. for example, in italy during march 2020, it showed a case fatality rate of 7.2% (onder et al., 2020) . this may partly reflect the demographic differences between nations, with 23% of the italian population being over 65. however, even when stratified by age, infection rates remain higher in italians over 70 years of age compared to china (onder et al., 2020) . this highlights the critical need to have improved screening and prediction methods to stratify those at higher risk of infection in discrete populations in different track changes is on 39 nations. to this end, machine learning algorithms are ideally suited for improving patient stratification and can be widely and rapidly applied as needed during a pandemic. in this study, we developed a machine learning methodology to identify the most important and significant clinical symptoms that predict true covid-19 positive cases. we validated these predictions using covid-19 patient data from seven provinces in china. the primary features of this machine learning approach are: • extraction of features from unstructured raw data (hospitalized patient information in text format) using string matching algorithms and use of this data to construct a processed dataset. • identification of the significant symptoms of covid-19 patients by analyzing their association using five different machine learning approaches. • developing a comprehensive predictive model to predict covid-19 positive patients among suspected and confirmed individuals. • analyzing the relationship between patient age and covid-19 confirmation. • identifying patient travel history and measure how it influences disease progression. • use statistical analysis to calculate the impact and contribution of particular patient features to covid-19 diagnosis. we collected raw hospital data, obtained through github repository (covid-19-tracker, 2020) . a record of their information is made available in anonymised form when a person has presented to hospitals and clinics for diagnosis and treatment. in our datasets, there were data from 6,512 patients from seven different provinces (anhui, guangdong, henan, jiangsu, shandong, shanxi, and zhejiang) in china. the original dataset was written in mandarin chinese, which was translated by google translator, and was checked and validated by a native chinese speaker and researcher (haoming xu) to confirm its accuracy. with the spread of the novel coronavirus, the accumulation of related national epidemiology data, and its availability can be used for ml studies. however, much of this data was in the form of unstructured text information which can be difficult to process. the data used here were collected from a study by a group at beijing university's big data high-accuracy center. they collected these datasets from the official channels of the national government websites (covid-19-tracker, 2020) . the detail of the dataset is as follows -basic information regarding gender, age, habitual residence, work and wuhan/hubei contact history; trajectory information is time, place, transportation and event up to february 20, 2020. we extracted important features of basic information (age, gender), symptoms (fever, cough, muscle soreness), diagnostic results (lung infection, radiographic imaging), prior disease/symptom history (pneumonia, diarrhea, runny nose) and some trajectory information (isolation treatment status, travel history) that are directly or indirectly related to covid-19 disease. the original chinese datasets did not include information about which patients were suspected positive and which were confirmed for all patients. the definition of a suspected case is the patients who develop symptoms and have communication with confirmed covid-19 patients but didn't confirm as covid-19 after diagnosis. moreover, confirmed cases defined as, the patients who are confirmed as positive for covid-19 in the cdc approved test report or the doctors mentioned confirmed cases after diagnosis in the root dataset. the data contain patient symptoms in a text format. for this reason, we find symptoms of every individual patient and some trajectory information applying various string matching algorithms. in detail, we selected some keywords for each feature then we matched those keywords to text data and extract the features individually. lastly, we generated our final dataset which contained the following features (described in the table-1): gender, age, fever, tussis (cough), rhinorrhoea (runny nose), pneumonia, lung in1% missing values only in the gender and age fields, and the propensity for the data point to be missing gender and age fields were completely random, i.e., missing completely at random (mcar) types of missing data. there's no relationship between whether a data point is missing and any values in the dataset. thus we imputed the gender field with random values according to the male/female ratio fo the total data and impute age with random values within the interquartile range (iqr) values. in our dataset most of the values were binary, but the age field was as an integer value, so feature scaling was done on the age field by using standard scaling methods. feature scaling is a technique to standardise the re-scaling technique which uses 0 as a mean value and 1 as variance (gupta, 2019) . the new feature value for a feature is calculated by, = ( − )∕ . after those two steps, we obtained a structured, clean and preprocessed dataset. since identifying the most predictive symptoms is challenging at the early stages of disease, we used ml models to identify them. our methodology is shown in figure 1. as indicated, using the training datasets we trained five ml algorithms that are described below decision tree algorithms can be utilized to optimize both classification and data regression (karim & rahman, 2013) . it utilizes tree representation in which each leaf node corresponds to a group of attributes and a branch corresponds to a value. this algorithm is developed in a recursive man-ner.consider we have a variable whose potential values have probabilities 1 , 2 , ., . the estimations of on the observation is known as the entropy. is characterised as (li et al., 2009 ) this main idea of decision tree algorithms is to build a tree for the entire data and process a unique output at every leaf. according to the target classification, how well a given attribute separates the training set can be measured by a statistical property, known as information gain. an attribute at a node with high information gain can split the training data to achieve improve classification accuracy. we can calculate the information gain of an attribute , relative to a set of training data , where is entropy, ashere, the set of values of the attribute is defined as ( ) and is the subset of for which the attribute has value . for a particular node in the tree, information gain is calculated for all the attributes, and the attribute with the highest information gain is selected as the best attribute that splits the data properly. random forest is an ensemble of regression and classification trees, which can train a similar size of training datasets called bootstraps, and at the end combine them for a more accurate result. the bootstraps are created by random resampling from the training dataset (sarica et al., 2017) . random forests perform far better than a single tree. this approach can work with higher dimensional large datasets with comparatively greater accuracy. the model will be built with the following equations (sing, 2019) -calculate the constant value and initialise the model here, ( ) is a model, ( , ) is a training set and ( , ( )) is differentiable loss function. gradient boosting machine (gbm) is a fixed size decision tree-based learning algorithm that combines many simple predictors (biau et al., 2019) . it fabricates the model in a phase insightful manner as other boosting strategies do, and it sums them up by permitting enhancement of a selfassertive differentiable loss function. a definitive objective of the gbm is to discover a function ( ), which limits its loss function ( , ( )), through iterative back-fitting as * = e , ( , ( )) by definition, a supported predicted model is a weighted straight of the base learners where ( ; ) is a base learners parameter. extreme gradient boosting (xgboost) is another decision tree-based machine learning algorithm that uses a gradient boosting framework. it is an end to end tree boosting scalable system widely used in data science. xgboost can solve real-world scale problem utilizing comparatively fewer resources (chen et al., 2016) . suppose, a dataset consists with examples and features, = ( , ) where, | | = , ℝ , ℝ. so the decision tree model uses additive functions to forecast the output (chen et al., 2016) . where indicates to the structure of each tree that maps a guide to the relating leaves nodes and is the amount of the leafs in the tree. every relates to an autonomous tree structure and leaf loads . support vector machine (svm) is one of the most wellknown, flexible supervised machine learning algorithms. it is utilized for both regression and classifications tasks. it is typically favoured for medium and little-measured informational collection. the primary target of svm is to locate the ideal hyper-plane which directly isolates the information focuses on two-part by augmenting the edge. the svm can guarantee the advancement capacity of the machine model, so it is generally utilized in different fields. the goal of the support vector machine algorithm is to discover a hyper-plane in -dimensional space ( -the quantity of highlights) that particularly classifies the information focuses (wei & hui-mei, 2014 ). there are various assessment parameters in our approach, for example, precision, recall, f1-score, log loss, and area under the roc curve (auc). these parameters are used to estimate our prediction accuracy. • precision: precision is a legitimate finding of assessment metric when we need to be extremely positive about our prediction. it measures the proportion of anticipated positives that are true positives. so it is dependant on true positive (tp) and false positive (fp) values (agarwal, 2019) . • recall: recall is another admissible decision of assessment metric when we need to identify the number of positives as could reasonably be expected (agarwal, 2019). it indicates the ratio of actual positives correctly classified. true positive (tp) and false negative (fn) values are used to measure recall. • f1 score: f1 score keeps up a harmony between the precision and recall for your classifier. the f1 score is a number somewhere in the range of 0 and 1 and is the consonant means of precision & recall (agarwal, 2019) . • area under the curve (auc): auc is the area under the roc curve and demonstrates, how well the probabilities from the positive classes are isolated from the negative classes. where true positive rate or tpr is only the range of trues we are utilizing our calculation (agarwal, 2019) . • log loss: log loss is the most significant order metric dependent on probabilities. it's difficult to decipher raw log-loss values, yet log-loss is a decent measurement for looking at models. a lower log-loss value implies better predictions (kiapour, 2018) . the function of log-loss iswhere is the level of target variable, ( ) is the predicted probability of the point for the target value and ( ) is the calculated value of log loss. in this study, some statistical analysis was also performed using the statistical package for the social sciences (spss) software version 25.0 (ibm corp., armonk, ny). the median age of the individuals studied was 43 years (range 0 years to 96 years), the interquartile range (iqr) was 32 to 55 years for 3,367 males (51.6%). in table-2, shows the association of patient covid-19 confirmation and some selected demographic information including symptoms. we performed mann-whitney u test on age field and chi-square test on the remaining fields and found that age, travel history, isolation treatment is significant as demographic information; and most of the symptoms including fever, cough, runny nose, pneumonia, and lung infection are significant with p-value <0.001. from those studied patients, there was 2,971 (45.6%) patient who displayed some symptoms whereas, among confirmed patient's 49.3% develops symptoms. it is also seen, 2,675 patients (41.1%) have a fever, which is the most frequent symptom, and their body temperature was equal or above 38-degree centigrade. some patients had fatigue, dizziness and headache with fever. the cough was the second most common symptom, with 1,975 (30.3%) affected patients. some of these patients had a dry cough, and some had coughing with sputum. radio-graphic or pulmonary or chest imaging results showed that 855 patients (13.1%) had a lung infection. only 26 patients (0.4%), 37 patients (0.57%), had muscle soreness and diarrhea. travel history is another important issue in covid-19 infection, 4,239 patients (65.1%) had travelled recently to one or more places in china or abroad. all patients were hospitalized for treatment, but among those 1,413 patients (21.7%) were received treatment in full isolation. the comparison of suspected and confirmed patients according to developing symptoms, we found that more confirmed patient's 1,466 (93.26%) develops symptoms than 1,505 (30.47%) suspected patients. there are 1,242 (79.01%) fever, 1,188 (75.57%) cough, 502 (31.93%) runny nose, 402 (25.57%) pneumonia, and 786 (50%) lung infection in confirmed patient's; on the other hand 1,433 (29.01%) fever, 787 (15.93%) cough, 47 (0.95%) runny nose, 85 (1.72%) pneumonia, and 69 (1.4%) lung infection is suspected patients; which is much lower than confirmed. in figure-2 is illustrated the age-wise total number of patients. in the age range of 25 years to 65 years, the rate of individuals affected is high. in children and the older adults the affected rate is comparatively low. however, the death rate in older men is high. in figure-3, is indicated the frequency of each feature, with most patients displaying fever, cough, lung infection and/or pneumonia. some patients had a recent travel history; others received treatment in isolation. firstly we developed a model for our application. in figure 1 is shown the pictorial representation of our research. in our workflow, we divided our work into different sections. the first section is data collection, which was described earlier. we prepared our dataset that can be capable to work with different machine learning (ml) approaches. after preprocessing, we divided our dataset into four criteria (age 0-20, age 21-60, age 61-96 and age 0-96). we divided our dataset into two parts, one part (70%) for train-ing and another part (30%) for testing. then we applied the five machine learning algorithms to train our models. the dataset was fitted to ml approaches using the python programming language (python 3) (larose et al., 2019) . the algorithms used included decision tree, random forest, xg-boost, gradient boosting machine (gbm) and support vector machine (svm). then we analyzed the performances of the algorithms. for each algorithm, we calculated the accuracy of the test dataset. to validate the accuracy, we find confusion matrix, precision, recall, f1-score, auc and logloss values. then we find the feature importance for every algorithm. we calculated the coefficient values for each feature that are significant for covid-19 patients. finally, we identified the six most significant features (shown in table-5) that are strictly related to covid-19 positive status. in our analysis results, we found that every algorithm achieved 88% (0.88) or above accuracy score. the performances of our used algorithms for the different datasets are described below. • age (0-to 20): in the coefficient values of every feature were consistent in finding the most significant features for this age range were lung infection, cough, fever, travel history, and pneumonia. • age (0-96) : on the accuracy measurement table-3, the results for individuals in the age range 0 to 96 years is indicated. we observed that the gbm and svm algorithms achieved the highest accuracy 0.97 using precision evaluation metrics. xgboost, random forest and decision tree showed 0.93, 0.92, & 0.91 accuracy. on the other hand, xgboost gained the highest 0.91 score using recall evaluation metrics we also analyzed the same parameters using the whole dataset combined (age 0 to 96 years). we compared combined outcomes with individual outcomes, and we found that there were a few variations in the different age groups, such as lung infection and cough are most significant for all types of age groups. however, in age group 0-20, fever and isolation treatment, in the age group 21-60 and 61-96, fever and pneumonia, in the age group 0-96, age, runny nose and pneumonia were also significant with a lung infection and cough. figure-4 shows the feature ranking according to coefficient values for each applied algorithm. every algorithm found almost the same sequence of features for all the age groups. from the above analysis, we also found that among those who displayed a fever, they had body temperatures equal to or above 38-degree centigrade. a small number of individuals also presented with chest tightness. some patients had a cough with sputum or dry cough, nasal congestion, fatigue, discomfort, pharyngeal discomfort, respiratory symptoms, shortness of breath, headache, dizziness, weakness, nausea, among other symptoms. the development of the covid-19 pandemic currently represents a dangerous threat to global health. the key to stopping this spread is the development of methods to identify infected individuals as early as possible. this can be challenging given the delay in symptom presentation; however, machine learning algorithms provide a promising approach to address this problem that can be rapidly and cheaply applied in a pandemic situation. in our study, we developed and tested a range of machine learning approaches and found the most significant clinical covid-19 predictive features were (in descending order): lung infection, cough, pneumonia, runny nose, travel history, fever, isolation, age, muscle soreness, diarrhea, and gender. our models were able to predict the stage of covid-19 based on basic patient informa-tion (age and gender), travel and isolation, and clinical symptoms (including fever, cough and runny nose and pneumonia). the accuracy of our algorithms was highest for the age range 0-20 years, with the svm algorithm with 93% accuracy, but it was notable that the other algorithms performed almost as well with greater than 85% accuracy. in the age range 21 to 60 years the situation was similar, with the highest accuracy of 90% of xgboost, and others(e.g. svm, random forest and gbm and decision tree algorithms) also performed well. in the age range of 61 to 96 years, again xgboost achieved 86% accuracy but the others gave above 80% accuracy. as might be expected given similar results across different ages (indicating that the symptoms develop similarly in individuals of any age) this pattern is also seen when the whole range of 0 to 96 years was studied and also get above 85% accuracy of prediction. accordingly, we were able to rank the features that are of importance to the disease prediction. according to the statistics, the median age was 43 years with iqr 32-55, composed of approximately half males and half females. most of the patients presented with fever, cough and radio-graphic chest imaging results that indicated that around 50% of confirmed patients had one or both lungs af-fected by the infection. in suspected patients, 29.01% were affected with fever, whereas 79.01% confirmed patients have fever & 75.57% have a cough. travel history was notable for being one of the major associated features to covid-19 infection, as would be expected with 65.1% of patients having recently travelled a long distance. some other symptoms were also related to covid-19 status but were less commonly seen, including muscle soreness and diarrhea; these features, particularly diarrhea, were much more prominent in the earlier sars epidemic. however, it is striking that 6.74% of the confirmed covid-19 positive and 69.53% of the suspected patients did not develop any type of symptoms. as these patients cannot be detected or predicted by symp-toms alone, our machine learning approach is of no use for assessing these people, although it is possible that they may have other factors that may lend themselves to detection in this way. however, the importance of particular social factors are likely to vary over time; notably, foreign travel may come to be less critical as local community transmission becomes the most common form of infection. contact with infected individuals would be and remains an excellent predictor, but this relies on rigorous contact tracing and social network analysis. mann-whitney u test and chi-square tests indicated that all the features were impacted except muscle soreness and diarrhea. these significant symptoms matched with findings from our machine learning analysis. we implemented machine learning algorithms on different clinical features of patients with covid-19 infections in a new dataset from mainland china and utilized different classifiers to examine information criterion and assess performance. our ability to predict the probability and course of covid-19 infection will improve the capacity of doctors to identify infected patients at an early stage by utilizing predictor clinical features. some of the classifiers did not, however, show reliable outcomes, presumably because while they demonstrated exactitude, they created one-sided results for these datasets. however, the size of the covid-19 dataset was probably not extensive enough to give enough statistical power to resolve these issues. in future studies, using much larger datasets, we will have improved capacity to circumvent these limitations and further improve our predictive accuracy. accelerated gradient boosting a familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster xgboost: a scalable tree boosting system the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2 clinical features of patients infected with 2019 novel coronavirus in wuhan decision tree and naïve bayes algorithm for classification and generation of actionable knowledge for direct marketing bayes, e-bayes and robust bayes premium estimation and prediction under the squared log error loss function data science using python and r uncertain data decision tree classification algorithm procalcitonin in patients with severe coronavirus disease 2019 (covid-19): a meta-analysis the extent of transmission of novel coronavirus case-fatality rate and characteristics of patients dying in relation to covid-19 in italy covid-19) epidemics, the newest and biggest global health threats: what lessons have we learned? random forest algorithm for the classification of neuroimaging data in alzheimers disease: a systematic review characteristics of covid-19 infection in beijing an improved ga-svm algorithm estimating clinical severity of covid-19 from the transmission dynamics in wuhan, china potential 2019-ncov 3c-like protease inhibitors designed using generative deep learning approaches the 5 classification evaluation metrics every data scientist must know naming the coronavirus disease (covid-19) and the virus that causes it mathematics behind random forest and xgboost key: cord-312840-jvdph782 authors: white, laura f; archer, brett; pagano, marcello title: determining the dynamics of influenza transmission by age date: 2014-03-21 journal: emerg themes epidemiol doi: 10.1186/1742-7622-11-4 sha: doc_id: 312840 cord_uid: jvdph782 background: it is widely accepted that influenza transmission dynamics vary by age; however methods to quantify the reproductive number by age group are limited. we introduce a simple method to estimate the reproductive number by modifying the method originally proposed by wallinga and teunis and using existing information on contact patterns between age groups. we additionally perform a sensitivity analysis to determine the potential impact of differential healthcare seeking patterns by age. we illustrate this method using data from the 2009 h1n1 influenza pandemic in gauteng province, south africa. results: our results are consistent with others in showing decreased transmission with age. we show that results can change markedly when we make the account for differential healthcare seeking behaviors by age. conclusions: we show substantial heterogeneity in transmission by age group during the influenza a h1n1 pandemic in south africa. this information can greatly assist in targeting interventions and implementing social distancing measures. the importance of the dynamics of influenza transmission between age groups is well-appreciated [1] [2] [3] [4] [5] [6] . several studies have assessed the non-uniformity of the impact of influenza, particularly pandemic influenza, on different age groups [1] [2] [3] [4] [7] [8] [9] . the overarching interest in these studies is to gather information in order to influence policy to best determine a strategy to impact on the spread of outbreaks. which age groups carry the greatest disease burden and which groups are responsible for the greatest amount of disease transmission is an important component of this information. one key aspect of this work is to estimate the extent to which people in different age groups interact with one another and to what degree they are in contact. this information can then be used as a surrogate for transmission probabilities between age groups [10] [11] [12] . several studies have generated matrices with estimated numbers of contacts between various age groups [5, 12, 13] . additionally, social network models have been used to estimate these contact patterns [7] . a common finding amongst these studies is that children tend to mix mostly with each other, and to a lesser extent with their parents, while adults mix with individuals from a larger range of ages [5, 7] . these matrices have subsequently been used in modeling exercises to better understand the dynamics of disease spread by age. when determining which groups to target for interventions in an outbreak, one strategy is to target those who potentially carry the greatest burden of disease [14] , which has typically been found to be children [1, 5, 7, 8, 13] . for instance, bansel et al. [4] consider data from influenza pandemics over the past century and show that the burden of disease is highest amongst children during a pandemic and then shifts to adults the following season. to better understand the utility of targeting the groups with the greatest burden of disease, it is also important to determine when different age groups tend to have their peak incidence of cases. this can also be seen as a surrogate measure for the age group that is driving an outbreak [15] [16] [17] . most recently schanzer et al. [16] used 10 years of canadian surveillance data of laboratory confirmed cases of influenza and found that during seasonal influenza the 10-19 and 20-29 year-old age groups tended to peak one week earlier than other groups. during the pandemic in 2009, the peak came earliest for only the 10-19 year old age group. this is inconsistent with the findings of brownstein et al. [15] who found that children aged 3-4 were consistently the first to peak. a different tactic for determining which groups should be the target of interventions is to select those groups most responsible for transmission [18] . studies examining disease transmission by age have consistently shown that children have higher estimated values of the reproductive number than adults. recent work has focused on the dynamics during the 2009 influenza pandemic. during the initial phase of the pandemic in japan, nishiura et al. [19] report that children were transmitting illness at higher rates than adults. glass et al. [2] used japanese data and a novel method to estimate the reproductive number, r 0 , for adults and children that assume particular forms for a nextgeneration matrix and estimate the parameters of this matrix, leading to outbreak specific estimates of r 0 . they estimate r 0 to be between 2.8 and 3.6 for children and between 0.2 and 0.7 for adults, depending on the assumptions made. in a later study, glass et al. [3] used serosurvey data and estimate r 0 from the final size of the epidemic to be 1.6 for kids and less than 1 for adults. wallinga et al. [18] have similarly shown that the rate in change of the reproductive number for a particular group is related to the incidence of infection and force of infection and suggest allocating resources based on examining these two quantities. in the present study, we present a new approach to estimating the reproductive number by age group by modifying a method initially proposed by wallinga and tuenis [20] . we study age dynamics in south africa during the 2009 influenza h1n1 pandemic and illustrate the importance of an appropriately estimated measure of the transmission dynamics on final estimates. finally, we discuss our results and their implications for future studies on how to respond during an emerging outbreak. we use de-identified data previously reported in [21] that includes a line list of the 12,543 confirmed cases reported in south africa during that outbreak. included in the data are the ages of the individuals, the provinces where the specimens were collected, the sex of the individuals, the dates of onset of symptoms, and the dates of the reporting of specimens. the information on the date of symptom onset was reported for 758 cases (6%). we use multiple imputation techniques to create 500 different datasets with the missing onset times imputed, as predicted by the province and an indicator of whether the specimen was collected on a weekday or weekend, using poisson regression [22] . we report the averages and ranges over the 500 imputed datasets. contact tracing information was collected on 100 initial cases, to provide an estimate of the serial interval, as has been previously reported [21] . we only use data from gauteng province (n = 5579, 44% of cases) to avoid confounding the results with potential spatial variation in transmission. gauteng province is the most populous, yet smallest geographically, of the nine provinces in south africa, with over 10 million inhabitants, predominantly in the cities of johannesburg and pretoria. wallinga and teunis [20] (denoted wt method hereafter) proposed a method for the estimation of the effective reproductive number by making use of the epidemic curve, n = {n 1 ,…, n t }, where n t is the number of cases at time point t, and an estimate of the serial interval, p 1 ,…, p k , where p i describes the probability of a serial interval of length i and the maximum serial interval length is k. we review this method in appendix 1. the estimator they obtain for the effective reproductive number for individual j on day t' is where n s denotes the number with symptom onset on day s and q s,t denotes the relative probability that case s was infected by case t. we propose the use of additional structure in this method to describe the probability of an infection event occurring between two cases that incorporates information on their ages by modifying the probability of transmission to be: where a j is the age group of individual j and w a i 0 a j is a measure of the likelihood of transmission between individuals in age group a i and a j . the matrix w = { w a i a j } does not necessarily have to be symmetric. this method requires information on the likelihood of infectious contact between different age groups, or the w a i a j . increasingly studies are being conducted to obtain such information by assuming that transmission is directly related to contact patterns. we use the results of two such studies: the first is a study of 571 randomly selected individuals in a south africa township performed in 2010 and reported by johnstone-robertson et al. [12] . the authors report two matrices with age specific contact patterns in five year intervals up to a 45+ category. the first matrix only considers contacts that involve all close contacts while the second includes information on only those contacts that involve physical touch. the second set of matrices we use comes from the european based polymod study of mossong et al. [5] . this study includes information on 97,904 contacts amongst 7,290 participants from eight countries in europe: belgium, finland, great britain, germany, italy, luxembourg, the netherlands, and poland. contact matrices describe all close contacts, and then separately, close contacts that involve physical touch. the matrices report age-specific values for five year age groups up to 70+. we modify these matrices to match those presented by johnstone-robertson et al. [12] and to match the demographics of south africa's young population by averaging all values above 45 years of age to create a single 45+ age category. in our results we focus on those obtained using the contact matrices from south africa, as these matrices would seem more appropriate for the data at hand. we report results from the polymod matrices as a sensitivity analysis. we estimate r t and r 0 using the 18 matrices described above with the imputed epidemic data from south africa, and report age specific estimates of these quantities, as well as aggregate estimates across age groups. the reproductive numbers for each age group represent the expected number of infections generated across the population by an individual in that particular age group. in the appendices, we further report the results of two sensitivity analyses: first we test the sensitivity of the results to potential errors in the reporting dates by selecting a single imputed dataset and randomly jittering the onset dates of 10% of the individuals, within 30 days of their observed (or imputed) onset date (appendix 2). we create 50 such datasets and repeat all analyses on these datasets and compare these results to those obtained without jittering the data. the second sensitivity analysis tests the impact of differential healthcare seeking behaviors by age. we smooth the distribution of the proportion of cases that were hospitalized by age group to serve as a surrogate distribution of healthcare seeking behavior and/or reporting patterns by age. this distribution is u-shaped, indicating that the very young and very old are more likely to seek medical care, a finding that has been reported elsewhere [23] . we attach various weights to this distribution and augment 25 of our imputed datasets according to this distribution. we reanalyze this augmented data to determine the potential impact of differential case reporting by age group on the results (appendix 3). figure 1 provides the epidemic curves across all age groups. here, school age children and young adults tend to have the greatest number of cases initially in the outbreak. ther t estimates are similar regardless of the type of contact matrix assumed (close contact versus those involving physical contact). overall,r t is much higher for those in the 15-19 and 20-24 year old groups throughout much of the epidemic, with the 10-14 and 25-29 year old age groups rapidly achieving high values, as well. those over 45 initially have fairly high estimates ofr t but these taper off quickly. estimates ofr t are not obtainable for those between 5 and 9 and those less than 5 until the outbreak is well under way, due to the paucity of observed cases for those age groups early on in the epidemic. we obtain estimates of r 0 , the basic reproductive number, by averaging the estimates of r t during the epidemic period. in reality this can be viewed as a pseudo-r 0 given the prior immunity to this strain of influenza. we will refer to it as r 0 throughout the text. we assume that the epidemic period corresponds to the point at which transmission was sustained in gauteng province until the overall number of cases peaked. this corresponds to the period between 22 june 2009 and 21 august 2009. figure 3 and table 1 show the estimates of r 0 across age groups along with the number of individuals in each age group who were reported infected throughout the epidemic. regardless of the choice of matrix, supercritical values of r 0 are obtained for those between the age of 5 and 24, with the highest values being observed for those in the 10-14 age-group (r 0 = 1.53 for close contacts). we contrast these estimates with those obtained using contact matrices from europe [5] . figures 3a and 3b shows the estimates of r 0 across the 10 age groups obtained when using contact patterns from south africa and the eight european countries in the polymod study for all close contacts (figure 3a ) and all contacts involving physical touch (figure 3b ). there are few notable differences between the estimates. in figure 4 , the mean estimates of r 0 are shown for each age group. we observe a similar overall trend for the estimate of r 0 across the age groups. finally we provide the overall estimate of r 0 collapsed over all age groups ( table 2) . for comparison purposes, we first estimate r 0 by using a traditional analysis that assumes homogenous mixing among the age groups (r 0 =1.28, range: 1.26-1.31). this is similar to that obtained for all the other contact matrices considered. additionally there are virtually no differences observed between results from the two contact matrices. our first sensitivity analysis, which jitters the onset dates of a subset of the population, (additional file 1: table s1 ) provides results that are consistent with the results presented. not surprisingly, the impact of reassigning onset dates to a portion of the dataset has the impact of flattening the epidemic curve and thus lowering the estimates of r 0 . however the results remain consistent and, coupled with the imputation variability reported, provide insight on the overall variability of the estimates reported. in our second sensitivity analysis (additional file 2: table s2 and additional file 3: figure s1 ), examining the potential impact of differential reporting by age, we note a page 5 of 10 http://www.ete-online.com/content/11/1/4 dramatic impact on the results. as we assume a greater underreporting of cases among those who are middle aged, we estimate the bulk of transmission being attributable to those who are older and less transmission being attributed to the very young, a finding contrary to the original results we present. we present a novel approach to estimating the effective and basic reproductive number by age group, and have applied this method to data from the 2009 influenza h1n1pdm in gauteng province in south africa. this method requires some estimate of contact patterns between age groups. we show results for 18 different possible contact matrices and the impact that these matrices have on the estimates. additionally, as with the original method proposed by wallinga and teunis [20] , it is necessary to have an estimate of the serial interval and we use an estimate obtained from contact trace data in south africa. as has been previously noted, that the burden of disease appears to be greatest amongst the young [21] , a finding consistent with other studies [1, 4, 7] . these data argue that aiming interventions at youth would target the group that carries the largest burden and should have the best chance of success in limiting transmission. this finding is consistent with the strategy proposed by wallinga et al. [18] and provides further information in the form of actual estimates of the reproductive number. our results also illustrate the importance of accounting for the age structure when estimating reproduction numbers. though the overall estimates of r 0 are unaffected by the incorporation of this information, we obtain much richer information with the ability to obtain age-specific estimates of the reproductive number. this analysis provides greater insight into the dynamics of disease transmission and informs intervention strategies. the results obtained using information on transmission dynamics from the study based in south africa [12] as well as that of the polymod study [5] , appear to corroborate previous results for influenza pandemics [2, 3, 19] which seem to imply that school aged children are responsible for the bulk of disease transmission. specifically we estimate thatr 0 is highest for 10-14 year olds when using south african contact trace matrices (close contacts:r 0 = 1.53, range, 1.49-1.58; physical touch contacts:r 0 = 1.47, range, 1.44-1.51). these results are similar to the results from other studies [2, 19] and those obtained using the european based contact matrices. interestingly, it does not appear to make a substantial difference which contact pattern matrix we use in our analysis. one would assume that the matrices obtained in south africa would be most relevant to the outbreak data we are analyzing and indeed, we have chosen to present the majority of our results using these matrices. we note, however, that when we use contact patterns from other european countries, where the demographics, climate, healthcare system, government, overall health, etc. are different from that of south africa, there are only minor changes in the results. indeed, the contact patterns observed in the polymod study and the south african contact study are not substantially different, however they are not identical. this appears to argue that using some form of adjustment is superior to assuming homogenous mixing, but the method we propose is not overly sensitive to the form the adjustments take [24] . this result is similar to that of glass et al. [2] who experimented with four forms of next generation matrices to estimate the reproductive number for adults and children separately. they found that the estimates of the reproductive numbers were not overly sensitive to the matrix forms that they assumed. however, one should still take care in the assumptions used when implementing this method, or others like it. our study is only one instance and it is not clear that the results we obtain would replicate in other settings. for instance, if one were to always use the polymod study information for studies throughout the world, there is still the potential for errors if contact patterns do differ dramatically from those observed in europe. while it is impossible to know with certainty if this is the case without detailed contact pattern information for the area of study, one can, at the least conduct a sensitivity analysis to determine the potential impact of the contact matrix on the analysis. additionally we implicitly assume that contact patterns are directly related to transmission probabilities, an assumption that has yet to be rigorously tested. there is also work to show that contact patterns can change considerably during illness [25, 26] . our work relies on the contact patterns of healthy individuals. while we suspect, based on our sensitivity analyses, that this will not have a substantial impact on our results, this is important to note. it is important to note the caveats and limitations of this study. our results would be impacted if reporting was inconsistent throughout the outbreak among the age groups. for instance if reporting was very good among one age group initially but declined in quality as the outbreak progressed, we can expect that our results would be biased [27] . in general the default assumption is that the pyramid of disease reporting described in [28, 29] is the same for all age groups. our second sensitivity analysis (appendix 3) explores the impact of this assumption and shows that if reporting or healthcare seeking behavior is much lower among middle aged groups than the very old and very young, our results will change dramatically. in the extreme case, we see that transmission is mostly attributable to those who are at least 30 years old and that the very young are unable to sustain transmission. while this result is contrary to what has been reported in the scientific literature to date, the potential for reporting inconsistencies that we explore are not unlikely, and have not been recognized and corrected for in other analyses that we are aware of. brooks-pollock et al. [23] report results from a survey conducted during the 2009 h1n1 influenza pandemic in the uk that showed that the very young and very old were more likely to seek healthcare when ill. the impact of correcting surveillance data to accommodate this phenomenon was to shift the burden of illness from the very young to the middle-aged. further investigation into potential reporting inconsistencies is important to better understand infectious disease dynamics by age similar to what was previously done but not incorporating age [27] . another reporting issue arises from silent infections, or those who carry infection and have the potential to transmit it, but are asymptomatic. we did not investigate the impact of these individuals, though the issues are similar to those we have just described. additional reporting inconsistencies are possible spatially or across other socio-economic factors. our analysis was only performed on data from gauteng province, the most urban province in south africa. it is possible that reporting would not be as dramatically variable as it would be if we were to make use of data from the entire country. it is also important to note that we chose to limit our analysis to gauteng province so as to limit the impact of spatial effects and make the assumption of homogenous mixing more reasonable. this could limit generalizability. we have also assumed that the contact matrices we use are correct and do not allow for any uncertainty in their estimation. these results might be improved upon and made more realistic by allowing for greater stochastic effects and/or flexibility in the transmission matrix. ideally we would estimate these parameters in our study, but we do not have sufficient data to do so in the present framework. glass et al. [2] have shown how to do this for a matrix with adults and children, but are limited to two by two matrices that presume a pre-specified structure and are unable to consider a larger number of age groups, thus limiting their ability to gain a more thorough and detailed understanding of transmission. we have applied a novel method to estimate transmission patterns between individuals from different age groups during the 2009 influenza h1n1pdm in south africa. we show that assumptions regarding the assumed contact patterns between age groups do not substantially impact the conclusions one draws from the data analyses in our study. our results are consistent with other studies that show children are much more likely to become ill and transmit disease than adults during a pandemic, if the completeness of the data reported is independent of the age of the patients. these methods can be used to estimate heterogeneity in transmission parameters in real time by using the modification proposed by cauchemez et al. [30] and thus inform the use of targeted interventions by age group. wallinga and teunis (20) (denoted wt method hereafter) proposed a method for the estimation of the effective reproductive number by making use of the epidemic curve, n = {n 1 ,…, n t }, where n t is the number of cases at time point t, and an estimate of the serial interval, p 1 ,…, p k , where p i describes the probability of a serial interval of length i and the maximum serial interval length is k. for ease of presentation, we assume that the time step is a day. individuals are placed in a network temporally by symptom onset date and the probability of transmission occurring between two individuals in the network is determined by the serial interval. the calculation of r t occurs in three steps. in what follows, we let t i denote the i th individual with symptom onset on day t, where i = 1,…,n t . 1. for the i th individual with symptom onset on day t, calculate the probabilities of infection by all those with symptom onset on prior days t 2 (t2 < t.) these probabilities equal the serial interval probability for the distance in time between the potential infector, t j 2 , and infectee, t i , p (t j ' →t i ) = p t i −t 0 j . calculate the relative probability that the case t i was infected by the j th case on day p (t j ' →t i ), denoted by q t i ;t j 0 , q t i ;t j 0 ¼ where n s denotes the number with symptom onset on day s. sensitivity analysis: impact of errors in reporting dates in this analysis, we choose a single imputed dataset and randomly jitter the onset dates of 10% of the sample within 30 days of their observed (or imputed) onset date. we create 50 such datasets and repeat all analyses on these datasets and compare them to the results on the non-jittered dataset. household transmission of influenza (h1n1-2009) in japan: age-specificity and reduction of household transmission risk by zanamivir treatment estimating reproduction numbers for adults and children from case data pandemic influenza h1n1: reconciling serosurvey data with estimates of the reproduction number the shifting demographic landscape of influenza social contacts and mixing patterns relevant to the spread of infectious diseases age-specific contacts and travel patterns in the spatial spread of 2009 h1n1 influenza pandemic mixing patterns between age groups in social networks age-dependent patterns of infection and severity explaining the low impact of 2009 influenza a (h1n1): evidence from serial serologic surveys in the netherlands searching for sharp drops in the incidence of pandemic a/h1n1 influenza by single year of age close encounters of the infectious kind: methods to measure social mixing behaviour social contact patterns in vietnam and implications for the control of infectious diseases social mixing patterns within a south african township community: implications for respiratory disease transmission and control using data on social contacts to estimate age-specific transmission parameters for respiratory-spread infectious agents h1n1 surveillance group. improving the evidence base for decision making during a pandemic: the example of 2009 influenza a/h1n1 identifying pediatric age groups for influenza vaccination using a real-time regional surveillance system age-specific differences in influenza a epidemic curves: do children drive the spread of influenza epidemics? age-related trends in the timeliness and prediction of medical visits, hospitalizations and deaths due to pneumonia and influenza optimizing infectious disease interventions during an emerging epidemic transmission potential of the new influenza a(h1n1) virus and its age-specificity in japan different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures interim report on pandemic h1n1 influenza virus infections in south africa epidemiology and factors associated with fatal cases reproductive number and serial interval of the first wave of influenza a (h1n1) pdm09 virus in south africa using an online survey of healthcare-seeking behaviour to estimate the magnitude and severity of the 2009 h1n1v influenza epidemic in england estimating the reproductive number in the presence of spatial heterogeneity of transmission patterns the impact of illness and the impact of school closure on social contact patterns the impact of illness on social networks: implications for transmission and control of influenza reporting errors in infectious disease outbreaks, with an application to pandemic influenza a/h1n1 estimates of the prevalence of pandemic (h1n1) 2009, united states food-related illness and death in the united states estimating in real time the efficacy of measures to control emerging communicable diseases determining the dynamics of influenza transmission by age the project described was supported by award number u54gm088558 from the national institute of general medical sciences to l.f.w. and m.p. the content is solely the responsibility of the authors and does not necessarily represent the official views of the national institute of general medical sciences or the national institutes of health. sensitivity analysis: impact of differential reporting by agewe assume that the reporting distribution by age follows a u-shaped distribution, implying that the very young and very old are most likely to seek healthcare and have their cases reported. to obtain a distribution that follows this shape, we use the distribution of hospitalized cases by age in our data, rescale it so that the highest proportion is one, and smooth the distribution using a loess smoother (additional file 3: figure s1 ).we use 25 of our imputed datasets and augment each dataset using the distribution f (x), where f (x) is a function of the original age distribution observed in the data, g (x), and the reporting distribution shown in additional file 3: figure s1 , h (x), as follows:here λ ranges between 0 and 1. we run analyses for λ = 0.0, 0.25, 0.50, 0.75 and 1.0 (corresponding to the original analysis). results for all 25 datasets are shown in additional file 2: table s2 . additional file 1: table s1 . results for the sensitivity analysis using the south african based age contact information. result presented is the estimate obtained from the original dataset and the values in the parentheses represent the range of values obtained over the 50 datasets generated for the sensitivity analysis.additional file 2: table s2 . estimates of r 0 using 25 of the 500 imputations described in the original text. results shown are the mean and range of estimates across the 25 imputed datasets. λ=1.00 corresponds to the results from the original analysis.additional file 3: figure s1 . smoothed distribution to reflect potential rates of healthcare seeking behavior and/or case-reporting by age. the authors report no conflicts of interest. key: cord-352620-a0tt0ldm authors: lawler, dennis; becker, julia; reetz, jennifer; goodmann, pat; evans, richard; rubin, david; tangredi, basil; widga, christopher; sackman, jill; martin, terrence; kohn, luci; smith, gail title: pathology of gray wolf shoulders: lessons in species and aging date: 2016-07-30 journal: anat rec (hoboken) doi: 10.1002/ar.23380 sha: doc_id: 352620 cord_uid: a0tt0ldm we examined scapula glenoids (n = 14) and proximal articular humeri (n = 14) of seven gray wolves that were maintained in a sanctuary park setting. immediately after death, observations were made visually in situ and by radiography. further observations were made in a museum laboratory setting, prior to and following clearing of soft tissues. selected dry bone specimens were evaluated using computed tomography. significant cartilage erosion and osteoarthropathy were identified in all shoulder joints. no single evaluation method yielded maximal information. plain film radiography revealed only more severe changes. computed tomography yielded more detail and clarity than standard radiography. direct examination of articular cartilage informed about joint soft tissue, and dry bone informed about externally visible bone pathology. these data provide a basis for biological, biomedical, ecological, and archaeological scientists to improve retrospective interpretations of bone lesions. they further support developing plausible differential diagnoses for features of ancient and modern animal bones. we noted a dog‐like capacity for wolf longevity in a non‐free‐roaming environment. however, aged wolves' life spans far exceeded those of similar‐sized domestic dogs and breeds, suggesting the possibility of an important species difference that should be explored. we suggest also a hypothesis that the driving force for joint pathology in sheltered non‐domestic species may relate significantly to achieving the longevity that is possible biologically, but is uncommon in the wild because of differential stochastic influences. anat rec, 299:1338–1347, 2016. © 2016 wiley periodicals, inc. the opportunity to examine normal or diseased joints of aged wild animals occurs infrequently. existing literature supports the idea of numerous ecological impacts on joint diseases during aging (peterson et al., 2010) , including effects of the microecology of the internal environment of physical forces (thomopoulos et al., 2007) . however, there is little indication that degenerative joint disease is a direct outcome of a long-term sheltered ecology for wild animals. this should not be surprising, since degenerative joint disease is known to be nonspecific, with many possible contributing factors (pedersen et al., 2000) . we found no literature reports of shoulder disease in gray wolves. by comparison, many studies of shoulder diseases of domestic dogs have focused on imaging modalities, osteochondroses (olsson, 1982) , and a variety of congenital or acquired problems involving tendon, ligament, muscle, joint capsule, and nerve structures that surround the joint (sumner-smith, 1993) . thus, parallels between gray wolves and domestic dogs need to be examined. we describe pathological features of the scapula glenoids and proximal humeri of seven aged gray wolves (canis lupus linnaeus 1758, now c. l. lupus). our observations include: gross postmortem evaluation; radiography and selected dry bone specimens for computed tomography; articular and surrounding soft tissue prior to bone clearing; and dry bone after soft tissues were cleared. we provide data to support developing differential diagnoses of joint-related lesions in archaeological, ecological, and biosciences investigations. we suggest that the driving force for joint pathology in sheltered nondomestic species is not sheltering, but rather achieving biologically possible aging and longevity. the study population consisted of 7 adult gray wolves (3 females and 4 males). among the wolves were various causes of death, at ages ranging from 5 to 17 years. postmortem evaluation was done by the attending veterinarian following the death of each wolf ( table 1) . none of the wolves that we evaluated were born in the wild. six wolves (chetan, ruedi, miska, marion, dharma, and tristan) were life-long residents at the wolf park, battle ground in. the seventh (eclipse) spent part of her adult life at another sanctuary. we examined familial relationships among these seven wolves. depending on age, season, grouping, and activity, the shelter has housing enclosures of 17.0, 6.8, 1.5, 0.5, 0.2, and 0.06 acres. free-roaming and behavioral exercise is facilitated by opportunities for roaming the 17-acre fenced pasture with a small herd of bison. bison are formidable prey and were chosen because of their antipredation behaviors. wolves walked, trotted, loped, sprinted, raced, and dodged, when engaging with bison. beginning in late 2011, exercise in the 17.0-acre enclosure was curtailed in favor of increased use of the 6.8acre enclosure, without bison. the wolves' primary diet is raw whole animal carcass, apportioned so that all wolves have access to all carcass parts at least monthly. animal carcass feeding includes primarily white-tailed deer, domestic cattle or deceased calves, and occasionally horse, donkey, goat, or sheep. remains such as hog and fish usually are refused. the wolves self-supplement by hunting small animal prey, and may accept commercial dog foods. none of the wolves were obese during life or at the time of death. the wolves are vaccinated for rabies, distemper, leptospirosis, parvovirus, coronavirus, adenovirus, parainfluenza virus, and lyme disease. those that exhibit evidence of illness are isolated and examined, and given appropriate treatment by the attending veterinarian. extraction of bone and joint tissue was done by wolf park permit. the attending veterinarian completed the following evaluations: (a) after death, the shoulders, spine, thorax, abdomen, and other major diarthrodial joints were radiographed; (b) the shoulder joint was opened from the lateral aspect, but not disarticulated, and photographs were taken of the glenoid fossa and proximal humeral articulation; (c) after en bloc shoulder extraction, radiographs again were taken to maximize radiographic image quality; (d) the remainder of the gross post-mortem examination was completed. the specimens were transferred to the illinois state museum research and collections center, springfield il, either frozen (n 5 6 wolves) or preserved in 10% buffered neutral formalin (miska) . specimen processing at the research and collections center involved initial trimming of soft tissue, description and photography of intact cartilage and peri-articulum, and incubation in hot water (408c245 8 c) solutions to macerate remaining nonossified tissue by bacterial action. following incubation of several weeks, soaking in 15% ammonia solution promoted further removal of fat from bone. a brushing step in detergent frequently was needed to remove tightly adhered exuded fat. following clearing, bones were rinsed in water and dried. the following features were evaluated at each stage of bone processing (table 1) . radiology. articular surfaces; articular margins; peri-articular structures; sub-articular condition; humeral intertubercular groove. in situ. visible articular cartilage; visible articular margins and peri-articular soft tissue structures; visual color variation; shapes of features on articular surfaces; joint capsule. pre-clearing soft tissue. articular cartilage; articular margins and peri-articular structures; visual color variation; shapes of features on articular surfaces; humeral intertubercular groove; joint capsule. cleared dried bone. articular bone, articular margins and peri-articular structures; visual color variation; feature formation in relation to cartilage observations; humeral intertubercular groove. severity scores were assigned subjectively as normal (0), mild pathology (1), moderate pathology (2), or severe pathology (3). some observations were difficult to score, even qualitatively; these were tabulated by presence in right and left shoulder tissues. only limited statistical evaluation was considered appropriate. we compared subjective joint feature scores by summing within-wolf and comparing the 4 very elderly wolves with the 3 "younger" wolves for each evaluation method, using a chi-square test. among this group of seven wolves, one died spontaneously and six were euthanized. three advanced-life deaths occurred from malignancy (15, 16, 17 years). a fourth aged wolf (19 years) experienced a rapid terminal deterioration from unknown underlying causes. among three younger wolves, death resulted from trauma (n 5 1, 5 years), severe multiple hip and spinal disease (n 5 1, 8 years), and unknown spontaneous cause (n 5 1, 9 years) ( table 1) . diseases observed during life predominately were chronic symptomatic orthopedic disorders in six of the seven wolves (table 1) . neoplasias most probably were short-term late-life events. their collective medical histories otherwise were not remarkable. there was no suggestion of health (e.g., infection, metabolic diseases) or environmental (e.g., severe trauma, nutritional deficit or a § severity 0-normal; 1-mild pathology; 2-moderate pathology; 3-severe pathology. pathology of gray wolf shoulders excess) contributions to degenerative shoulder joint disease, with the possible exception of ruedi. as a puppy, ruedi experienced nutritional secondary hyperparathyroidism that left him with limb and spinal deformities that may have contributed to degenerative joint disease secondary to chronically altered force vectors during movement. three family groupings were identified: ruedi and tristan were son and sire, respectively, but were unrelated to the other five wolves. dharma was entirely unrelated to the other wolves. miska, chetan, eclipse, and marion formed a loose family grouping built on an "uncle" and several half-sibling relationships (table 2) . the exposures that were taken post-extraction offered the best quality images for radiographic interpretation. plain film radiography underestimated osteoarthropathy identified by other observational methods (table 3) (fig. 1) . narrowed left shoulder radiographic joint space in the most severely affected wolf (chetan) did correctly predict severe loss of articular cartilage. regional soft tissues were difficult to evaluate because of projection limitations and post-mortem artifact (table 4) . bones from chetan and miska were selected for computed tomography to evaluate subchondral bone, confirming that subchondral sclerosis was present (fig. 2) . as expected, computed tomography afforded observation in greater detail, compared with plain film radiography. in situ studies physically exposed more tissue than would be seen by arthroscopy, and enabled recognition of thickened capsules of all joints. the examinations also revealed irregular articular cartilage surfaces; periarticular osteophytes; osteophytes impinging articular surfaces; cartilage color variation; feature orientation in bands across articular surfaces; and cartilage erosion (table 3) (fig. 3) . as with radiography, whether peri-articular osteophytes were encircling the articular surface or were nonencircling was not predicted well in situ. as expected, articular bone changes remained masked by overlying (table 3) (fig. 3) . pre-clearing visual studies suggested some modification of superficial articular cartilage following in situ evaluation, even though the shoulders were either frozen or formalin-preserved. irregular and eroded articular cartilage surfaces; peri-articular and joint surface-impinging osteophytes; cartilage color variation; feature orientation in bands across articular surfaces; and osteophytes along the humeral intertubercular groove, all were recognized by visual inspection (table 3) (figs. 4a and 5a) . the minor modification of superficial articular cartilage by freezing and thawing did not affect outcomes. dry bone, evaluated post-clearing, revealed pathological changes that were obscured by previous evaluations. observations included irregular articular bone surfaces; peri-articular and joint surface-impinging osteophytes; bone color variation; feature orientation in bands across articular surfaces; and osteophytes along the humeral intertubercular groove (table 3) (figs. 4b and 5b ). additional observations revealed that pathological features observed on cleared bone related spatially to overlying cartilage pathology during life. further, the severity of pathological changes on dry bone reflected the severity of overlying cartilage pathology (figs. 4a,4b and 5a,b). limited statistical evaluation (table 3) showed that (a) imaging was less revealing than direct observation; (b) older wolves had generally higher numerical pathology scores (fig. 6) . no association was found between examination method and age group (x 2 5 0.49; df 5 3; p 5 0.92). (1949) published a treatise on shoulder morphology and function in ursidae. the work described the planar alignment of the tetrapod carnivore shoulder and forelimb, functioning: (a) in load transmission (body to limb); (b) as a strut system of lateral extrinsic (origin off the limb, insertion on limb bones) muscles opposing medial extrinsic muscles for support and movement; and (c) as an intrinsic (origin and insertion on limb bones) muscle levering system to achieve motion on anteroposterior, transverse, and rotational axes. skeletal and functional features among carnivora suggest that the range of expression of degenerative joint changes might be similar across the order, ursids being thus typical in this respect. in this context, we consider potential implications of our observations. gray wolves are immediate ancestors to domestic dogs, and the two are biologically capable of interbreeding. considering the close species relationship, we suggest several population implications of our results: 1. observing similar pathological joint changes among closely related species likely reflects phylogenetic conservation of physiological response capacity (lawler, 2011) , as well as fixed traits that define physical limits for morphological responses (ham, 1969) . a question for further study involves implications of similar degenerative joint pathology among species in circumstances of distant phylogenetic relationship, especially co-occurring with ecological dissimilarity. the latter could imply broad evolutionary conservation of response capacities, and would raise the additional question of the role(s) of conserved joint biology in the aging process (lawler, 2011 (lawler, , 2015 . 2. mech (1970) estimated that 20% of an ontario wolf population was over age 5 years, and showed (1998) that 6% of an alaska wolf population was over age 5 years. halfpenny (2003) described 20% loss of yellowstone (usa) wolves by age 2 years, with survival beyond 2 years bringing an expected 5 years' longevity; 10 years longevity was uncommon. mech (2006) described a wolf population in northeastern minnesota, indicating that just 12% of "non-pups" were over age 5 years. mech (1988) also summarized studies suggesting that sheltered wolves might live 9 2 16 years. population-based age estimates can vary for many reasons. influences that change population demographics over time can include climate impacts, population health, food availability, deliberate persecution, predation, accidents, and some level of sheltering by humans. further, methods of age assessment sometimes suffer from biological inadequacy (landon et al., 1998) and social or logistical barriers (musiani and paquet, 2004) , thus compromising interpretations. nonetheless, the survival estimates from the aforementioned studies are consistent with unlikely survival into late life for wolves in the wild. further, the documented advanced ages of the wolves we evaluated clearly demonstrate the genomic capacity for advanced age in this species. more generally, olshansky (2010) observed that agingrelated diseases are uncommon outside of domestication or a sheltered environment. frailty, malnutrition, and predation reflect the rigors of free-roaming existence, and mean life spans in populations are reduced in result (olshanksy, 2010) . on the other hand, events observed in sheltered populations reflect genomically possible population outcomes when stochastic causes of death are minimized and advanced life occurs more frequently. our data serve as another confirmation of olshansky's observations, and underscore the importance of excluding stochastic causes for mortality in studies of natural biological aging. 3. another genomic consideration concerns our demonstration that gray wolves have the same capacity for longevity as do domestic dogs. it is further noteworthy that the older wolves expressed a capacity for longevity that rarely is observed in the largest domestic dogs. the explanation for this difference presently is unclear, but we advance a hypothesis that post-victorian breeding selection practices applied to domestic dogs by humans have created a subspecies contrast in this respect. the igf-1 gene of domestic dogs was found to explain 50% of population variation in breed size (sutter et al., 2007) , which with our observations, supports considering new research in comparative quantitative trait inheritance among canids. comparing circulating igf-1 levels in young and elderly wolves to those of large and giant breed dogs of different ages especially should be enlightening. 4. none of the wolves that we evaluated were born in the wild. does sheltering lead to the pathology that we observed? the wolves in our study were not freeroaming, but were not confined in the manner of a zoological garden or domestic pets. the wolves' clinical histories document no lifetime history of obesity, ruling out a ubiquitous major causal co-morbidity for degenerative joint disease of domestic dogs . the most and least severely affected wolves were dharma and chetan, the two youngest at ages 5 and 8 years, which reflects variability expected in domestic dog populations chase et al., 2011) . by favorable comparison, a recent study of a japanese village population offers species-comparative data, revealing an age basis for shoulder joint osteoarthritis, with greater occurrence in persons over age 65 years (kobayashi et al., 2014) . it has been reported that onset of overt symptoms of degenerative joint disease in dogs frequently follows morphological onset by several years . thus, the time of morphological onset cannot be defined without having serial radiographs over the lifetime of dog or wolf. the clear implication is that extrapolative interpretation of (longevity x pathology) outcomes is tenuous without longitudinal data. 1. in a previous report of shoulder pathology of domestic dogs, a high percentage of a study population had radiographic evidence of osteoarthritis by age 8 years, with progression in the population from the 6 th year (runge et al., 2008) . by comparison, 6 of the 7 wolves in our study were age 8 years, and all 7 had radiographically visible shoulder pathology. the comparative observation raises the question of whether an "aging threshold" exists in the gray wolf, as lifetime data appear to suggest for the domestic dog . beyond such a threshold, various degenerative processes should be more readily identified, as shown by the late life occurrence of neoplasia in our study population. only a quantity of new research will clarify the threshold question. our observations also align with those reported from post-mortem examinations of 88 domestic dogs of similar chronological ages as the wolves (ljunggren and olsson, 1975) . lesions in the dogs were caudocentralized on the humeral and glenoid articular surfaces. peripheral fibrosis and osteophytosis occurred with more advanced cartilage degradation. the authors noted relatively high frequency of age-related lesions, with lesion patterns that did not respect sex or body size. also noted was lack of clear inciting causes beyond aging (ljunggren and olsson, 1975) . the bone pathologies reported by ljunggren and olsson are spatially and characteristically the same as those we recorded for the gray wolf, except that our study did not involve osteochondrosis that tends to occur in younger subjects (ljunggren and olsson, 1975) . we observed a spatial relationship between cartilage erosion and underlying bone features, consistent with chronic, deep erosive processes in cartilage that involve underlying bone secondarily. simon and colleagues (1973) demonstrated that scapular and humeral articular contact varies from 47% (flexed) to 62% (standing) in domestic dogs, the humeral articular surface being much larger. thus, in the canine shoulder, the scapular glenoid, and articular proximal humerus, are not in constant full point-to-point contact. korvick and athanasiou (1997) evaluated scapular and humeral articulations from seven normal dogs, observing that cartilage damage does not occur in adult dogs as the result of differential mechanical properties between scapular and humeral cartilage. thus, the accumulated data suggest that cartilage degradation and its associated progressive histological inflammatory process are responsible for the aligned articular bone features that we observed in the gray wolves. a thought should be added with respect to pain-related debilitation. individuals perceive pain differently, some being more sensitive than others (johnston, 2000) . maddox et al. (2013) noted that computed tomography findings in dogs were not always associated with shoulder pain, and that age was a risk factor for shoulder osteoarthritis. thus, the degree of morphological severity of degenerative joint disease is not an obligate indicator of the degree of debilitation. inferring a severity-debilitation relationship in postmortem and archaeological specimens is possible only in a general way. interpreting the relationship as the cause of death from archaeological specimens is tenuous at best. lastly, the range of fatal and non-fatal diseases that were recognized in the wolves we studied is not unlike those that can be found in domestic dog populations (ljunggren and olsson, 1975; lawler et al., 2008 , chase et al., 2011 . again, the comparative evaluation suggests a high degree of similarity or identity between wolf and dog joint aging, and raises the new question of similar parallels among other canidae. 2. data from field studies of wolf mortality are weighted heavily toward traumatic death (wobeser, 1992) , documenting early-to-midlife attrition from stochastic causes. fritts and caywood (1980) described a radiotracked canis lupus lupus with severe osteoarthrosis of shoulders and other evidence of prior trauma. cross (1940) described two adult timber wolves (canis lupus lycaon), both with osteoarthrosis of diarthrodial joints and vertebral pathology, along with other evidence of prior trauma. both authors probably misdiagnosed the wolves' ages by overestimation, given that dental condition reflects nutrition, environment, behavior, and health in various ways. it appears that one author also overlooked the role of repeated trauma in chronic bone changes. even so, the pattern of wolf osteoarthropathy resembled that seen in domestic dogs. 3. methodological comparison of shoulder osteochondrosis using magnetic resonance imaging (mri), arthrography, arthroscopy, and histology, revealed correlations among the methods (van bree et al., 1993) . in that study, mri demonstrated low-signal foci coincident with inflammation of subchondral bone, as well as mixed signaling from degenerative cartilage. in another study, ultrasonographic examination was shown to be useful as an imaging approach to canine shoulder osteochondrosis, joint mice, joint effusion, and (quoting the authors) "distinct new bone formation" (vandevelde et al., 2006) . a more recent report indicated that both methodology (including mri) and positioning for evaluation are important to diagnosis of osteochondrosis (wall et al., 2014) , and the authors recommended more frequent use of advanced imaging in suspected occurrences. our data indicate that computed tomography yielded more information than radiography, while direct examination of postmortem specimens afforded greater opportunity to interpret other observations. thus, imaging modalities that are used should reflect study circumstances as well as the information that investigators are seeking. 4. olsson (1971) reported morphology of subchondral sclerosis and joint margin osteophytes, again reflecting compatibility with our observations of gray wolves. involved subchondral bone becomes hypomineralized, microfractured, and develops microstructural alterations resembling cysts (li et al., 2013) . when interpreting archaeological canid dry bone specimens, it is useful to retain this mental view of the overall process of degenerative joint disease, as observed in the domestic dog. 5. gross morphology and histology of the glenoid labrum in dogs has defined the relationship among articular cartilage, subchondral bone, and the collection of supporting structures and their attachments (sager et al., 2013) . the close association among the tendon of origin of the biceps muscle, fibrocartilagenous labrum, medial and lateral glenohumeral ligaments, and a meniscoid fold, illustrate the complexity of the mammalian shoulder support system (sager et al., 2013) . the elucidated anatomical relationships underscore the potential for soft tissue injury immediately proximate to the articular surface, and thus expand the list of potential differential diagnoses in biomedical and archaeological investigations of degenerative joint disease. clearly, further studies of degenerative joint disease in wildlife should include investigation of the shoulder joint support system. 6. studies of induced or naturally occurring osteoarthritis have identified various cytokines, chemokines, and matrix metalloproteases that can be detected in biological fluids. further elucidating molecular events that occur during development of canid degenerative joint disease will support new understanding of response commonality across species (garner et al., 2011) and the nature of its origins in genetic conservation. the data that we present here support developing improved and more accurate interpretation of archaeological observations of articular and periarticular bone. imaging technologies can be very useful, but should be chosen carefully, based on the study circumstances and the information that is desired. the spatial alignment of cartilage degeneration and effects on subchondral bone, while not unexpected, were well-defined in the wolf shoulders, and provide reference for investigators studying features of dry articular and periarticular bone. the startling longevity noted in sanctuary wolves, compared to free-roaming wolves, strongly indicates that stochastic events shorten genomically possible life span, rather than sheltering "inducing" increased longevity. an important corollary observation is that gray wolves appear to have a subspecies-related capacity for longevity that far exceeds that of the largest domestic dogs. further research examining this observation would be instructive, and especially informing to the idea of programmed aging. thus, the question of comparative age-based relationships to the observed pathologies might be phrased: is there a biologically programmed age basis for degenerative joint pathology, and could naturally-occurring joint disease in the dog and wolf serve as a model for programmed aging (lawler 2011)? age relationships of postmortem observations in portuguese water dogs arthritis among wolves the shoulder architecture of bears and other carnivores. fieldiana -zoology osteoarthritis in a wolf (canis lupus) radio-tracked in minnesota using animal models in osteoarthritis biomarker research yellowstone wolves in the wild histology. 6th ed. philadelphia: saunders variations in the mechanical properties of cartilage from the canine scapulohumeral joint pain: identification prevalence of and risk factors for shoulder osteoarthritis in japanese middle-aged and elderly populations evaluation of age determination techniques for gray wolves diet restriction and ageing in the dog: major observations over two decades the changing understanding of ageing. part 3: diseases of ageing aging as a purposeful biological program subchondral bone in osteoarthritis: insight into risk factors and microstructural changes osteoarthrosis of the shoulder and elbow joints in dogs: a pathologic and radiographic study of a necropsy material comparison between shoulder computed tomography and clinical findings in 89 dogs presented for thoracic lameness the wolf: the ecology and behavior of an endangered species longevity in wild wolves the wolves of denali estimated age structure of wolves in northeastern minnesota the practices of wolf persecution, protection, and restoration in canada and the united states the law of mortality revisited: interspecies comparisons of mortality degenerative joint disease (osteoarthrosis): a review with special reference to the dog morphology and physiology of the growth cartilage under normal and pathologic conditions textbook of veterinary internal medicine ecology of arthritis the effects of lifetime food restriction on the development of osteoarthritis in the canine shoulder histological variations of the glenoid labrum in dogs a correlation of joint congruence and thickness of articular cartilage in dogs textbook of small animal surgery. philadelphia: saunders a single igf1 allele is a major determinant of small size in dogs decreased muscle loading delays maturation of the tendon enthesis during postnatal development pathologic correlations with magnetic resonance images of osteochondrosis lesions in canine shoulders comparison of the ultransonographic appearance of osteochondrosis lesions in the canine shoulder with radiography, arthrography, and arthroscopy diagnostic sensitivity of radiography, ultrasonography, and magnetic resonance imaging for detecting shoulder osteochondrosis/osteochondritis dissecans in dogs traumatic, degenerative, and developmental lesions in wolves and coyotes from saskatchewan the authors gratefully acknowledge wolf park, battle ground in, for providing specimens, medical and historical data, and radiology. the illinois state museum provided laboratory space and equipment. key: cord-322486-qwl7nzkr authors: omori, ryosuke; matsuyama, ryota; nakata, yukihiko title: the age distribution of mortality from novel coronavirus disease (covid-19) suggests no large difference of susceptibility by age date: 2020-10-06 journal: sci rep doi: 10.1038/s41598-020-73777-8 sha: doc_id: 322486 cord_uid: qwl7nzkr among italy, spain, and japan, the age distributions of covid-19 mortality show only small variation even though the number of deaths per country shows large variation. to understand the determinant for this situation, we constructed a mathematical model describing the transmission dynamics and natural history of covid-19 and analyzed the dataset of mortality in italy, spain, and japan. we estimated the parameter which describes the age-dependency of susceptibility by fitting the model to reported data, including the effect of change in contact patterns during the epidemics of covid-19, and the fraction of symptomatic infections. our study revealed that if the mortality rate or the fraction of symptomatic infections among all covid-19 cases does not depend on age, then unrealistically different age-dependencies of susceptibilities against covid-19 infections between italy, japan, and spain are required to explain the similar age distribution of mortality but different basic reproduction numbers (r(0)). variation of susceptibility by age itself cannot explain the robust age distribution in mortality by covid-19 infections in those three countries, however it does suggest that the age-dependencies of (i) the mortality rate and (ii) the fraction of symptomatic infections among all covid-19 cases determine the age distribution of mortality by covid-19. since its emergence, coronavirus disease 2019 (covid-19) has resulted in a pandemic and has produced a huge number of cases worldwide 1 . as of may 29, 2020, the number of confirmed cases in italy was 382.3 (per 100,000 population), with 507.2 in spain, and 13.2 in japan 1 . of those infected, it has been reported that elderly individuals account for a large portion of fatal cases inducing a large heterogeneity in the age distribution of mortality [2] [3] [4] . the expected value of mortality (the number of deaths, hereafter referred to as mortality) is calculated as the product of the number of cases and the mortality rate among cases (hereafter referred to as morality rate). as the background mechanism of the heterogeneity of mortality by age, the association of two epidemiological factors with mortality can be considered: (i) the age-dependency of susceptibility to infection, which is related to the heterogeneity in the number of cases, and (ii) the age-dependency of severity, which is related to the heterogeneity in the mortality rate, e.g. the rate of becoming a symptomatic, severe, or fatal case among infected individuals. for the first factor, a high susceptibility for infection will generate a larger number of infections and result in an increase in fatal cases. the possibility of heterogeneity in susceptibility by age was pointed out by the analysis of epidemiological data reported from wuhan, china 4-6 and from iceland 7 . for the second factor, an increase in severity will result in a higher mortality rate and subsequently a rise in the number of fatal cases. this assumption is also reasonable because elder age as well as the existence of comorbidities, which are likely with aging, have been reported as risk factors for severe covid-19 infections [8] [9] [10] [11] [12] [13] . although not yet shown in relation to severe acute respiratory syndrome coronavirus 2 (sars cov-2), which is the causal agent of covid-19, the presence of age-dependent enhancement of severity has been suggested in sars coronavirus by the analysis of the innate immune responses in the balb/c mouse model [14] [15] [16] . additionally, it has been suggested that antibody-dependent enhancement (ade) can contribute to the formation of the observed age-dependency of severity, as suggested in sars and middle east respiratory syndrome (mers) cases [17] [18] [19] [20] [21] [22] . interestingly, the age distribution of mortality by covid-19 (the distribution of the proportion of deaths per age group among all deaths), is similar between italy, japan, and spain, even though the number of deaths are quite different among them [23] [24] [25] (fig. 1) . the reported number of deaths was 3 in 0-9 years old (yo), 0 in 10-19 yo, 11 in 20-29 yo, 58 in 30-39 yo, 257 in 40-49 yo, 1,051 in 50-59 yo, 3,107 in 60-69 yo, and 25,038 in 70 + yo in italy as of may 13, 2020. in japan, that was 0 in 0-9 yo, 0 in 10-19 yo, 0 in 20-29 yo, 2 in 30-39 yo, 8 in 40-49 yo, 16 in 50-59 yo, 44 in 60-69 yo, and 330 in over 70 + yo as of may 7, 2020. in spain, that was 2 in age 0-9 yo, 5 in 10-19 yo, 23 in 20-29 yo, 61 in 30-39 yo, 198 in 40-49 yo, 607 in 50-59 yo, 1669 in 60-69 yo, and 16,253 in over 70 + yo as of may 12, 2020. according to projections by the united nations 26 , the population size for 2020 per 1,000,000 was 4.99 in 0-9 yo, 5.73 in 10-19 yo, 6.10 in 20-29 yo, 7.00 in 30-39 yo, 9. 40-49 yo, 7 .05 in 50-59 yo, 5.34 in 60-69 yo, and 6.94 in 70 + yo. the large difference in the number of deaths between the countries suggests a large difference in their basic reproduction numbers, r 0 s. an independency between age distribution of mortality by covid-19 and r 0 is suggested. from this independency of age distributions of mortality from r 0 , it can be expected that the contribution of heterogeneity in susceptibility by age to forming the age distribution of mortality is small. that is because, as we will show in this paper, though the age-dependency of severity will naturally produce a proportional effect on the distribution of mortality and result in the formation of robust distributions, when the age-dependency of susceptibility forms the age distribution of mortality, the age distribution of mortality highly depends on r 0 and shows variability. to understand the background of robust age distribution of mortality with varied r 0 , we constructed a mathematical model describing the transmission dynamics of covid-19 and analyzed the impact of age-dependent susceptibility on the age distribution of mortality. the heterogeneity in social contacts by age may also contribute to the age distribution of mortality. our model took into account the heterogeneity in social contacts by age and country, and the effect of behavioral change outside of the household during the outbreak. we also estimated and compared the age-dependent susceptibility in japan, italy, and spain to argue the existence of heterogeneity in susceptibility among age groups. our result shows variation of susceptibility among age groups measured by the exponent parameter φ can explain the age distribution of mortality by covid-19 (fig. 2a) . however, the age distribution of mortality formed by the age-dependency of susceptibility is influenced by the value of r 0 (fig. 2b) , which cannot explain the similarity in age distributions of mortality among italy, japan, and spain. on the other hand, if susceptibility is constant among age groups, the impact of r 0 is quite small on the age distribution of mortality (fig. 3) . assuming that the age-dependency of mortality by covid-19 is determined by only age-dependent susceptibility (model 1), i.e., the mortality rate does not depend on age, the exponent parameter, φ, describing the variation of susceptibility among age groups for each country, italy, japan, and spain, was estimated as shown in fig. 4 . from the difference of the r 0 value and country, the estimated value of φ is largely varied. the impact of reductions in contacts outside of the household on the estimated value of φ was small. the estimate of φ in italy, assuming a range of r 0 = 2.4-3.3 27,28 was 15.0 (95% ci 14.0-16.0), 16.3 (95% ci 14.9-17.7), and 16.9 (95% ci 15.4-18.4) for 80%, 40%, and no reduction in contacts outside of the household. for japan, the estimate of φ assuming r 0 = 1.7 29 was 4.2 (95% ci 3.7-4.9), 5.5 (95% ci 4.9-6.3), and 6.1 (95% ci 5.4-6.9) for 80%, 40%, and no reduction in contacts outside of the household. when it comes to spain, the estimate of φ assuming an r 0 = 2.9 30 was 10.5 (95% ci 10.4-10.6), 11.7 (95% ci 11.6-11.9), and 12.3 (95% ci 12.2-12.5) for 80%, 40%, and no reduction in contacts outside of the household. www.nature.com/scientificreports/ the estimates of φ, assuming that the mortality by covid-19 infections depends on age but the fraction of infections becoming symptomatic does not depend on age (model 2), were also varied by the value of r 0 and by country (fig. 5, s1 and s2 ). employing the same assumptions of r 0 value, the estimate of φ in italy was 5.2 (95% ci 4.7-5.7), 5.9 (95% ci 5.3-6.4), and 6.1 (95% ci 5.5-6.6) for 80%, 40%, and no reduction in contacts outside of the household. for japan, the estimate of φ was 0.0 (95% ci 0.0-1.0), 0.0 (95% ci 0.0-1.2), and 0.0 (95% ci 0.0-1.4) for 80%, 40%, and no reduction in contacts outside of the household. for spain, the estimate of φ was 4.1 (95% ci 2.5-5.0), 4.8 (95% ci 2.6-5.8), and 5.1 (95% ci 2.6-6.2) for 80%, 40%, and no reduction in contacts outside of the household. in the present study, we explored the role of susceptibility to covid-19 in explaining the age distribution of mortality by covid-19. interestingly, the age distributions of mortality from covid-19 are quite similar between italy, japan, and spain ( fig. 1) . when comparing the age distributions of mortality, only the comparison between italy and spain is significant (p < 0.05 in wilcoxon rank sum test with bonferroni correction). on the other hand, the numbers of deaths are quite different (29, 525 for italy, 400 for japan, 18,818 for spain). indeed, r 0 values are largely different: 2.4-3.3 for italy 27,28 , 1.7 for japan 29 , and 2.9 for spain 30 . if the variation of mortality by age is determined by only the age-dependency of susceptibility, the age distribution of mortality is affected by r 0 as shown in fig. 2b . however, we observed a similarity in age distributions of mortalities between italy, japan, figure 3 . the sensitivity of transmission coefficient β against age distribution of mortality when it was assumed that age-dependent mortality was proportional to ccfr per age group. all parameters were fixed and parameterized as the setting for spain except the transmission coefficient β. www.nature.com/scientificreports/ and spain where their r 0 s are quite different. indeed, unrealistically different φs among these three countries are required to explain their age distribution of mortality for both settings, (i) age-independent mortality, and, (ii) the fraction of infections that becomes symptomatic among all covid-19 cases, f s , does not depend on age. although we cannot fully reject the existence of age-dependency in susceptibility, our results suggest that it does not largely depend on age, but rather that age-dependency in severity highly contributes to the formation of the observed age distribution in mortality. the estimates of φs assuming age independency in symptomatic infections were smaller than those that assumed age independency in mortality. this suggests that the age-dependency of the confirmed case fatality rate (ccfr), which can be biased by the age-dependent difference of the fraction of symptomatic infections among all cases, partially explains the age distribution in mortality. indeed, when we assumed that the fraction of symptomatic infections was not dependent on age, the estimate of φ in japan was close to zero in all scenarios regarding the fraction of symptomatic infections, meaning that susceptibility is constant among age groups (fig. 5) . although we observed φs not close to zero in italy and spain, this does not mean straightforwardly that susceptibility is age dependent because there is room for an alternative explanation: not susceptibility, but an age-dependent fraction of symptomatic infections can explain this age-dependency. unfortunately, as we do not yet have detailed data regarding the age-dependent fraction of symptomatic infections and the rate of diagnosis in covid-19, we cannot conclude which factors (i.e., susceptibility or the fraction of symptomatic infection among all cases) contributed to the observed age-dependency. wu et al. 4 showed variation of susceptibility to symptomatic infection by age. this susceptibility can be expressed as the product of the susceptibility and the fraction of symptomatic infection among all cases. to accurately understand susceptibility (i.e., without the constraint of the symptom onset), estimates of the agedependent fraction of symptomatic infections is required. to understand the mechanism of age-dependency of mortality by covid-19, an accurate age-dependent mortality rate is required. the data of mortality by covid-19 infections used in this study might not cover all mortalities by covid-19 infections. to estimate the age-dependent mortality rate, an accurate estimate of the case fatality rate is required. however, the number of cases, which is the denominator of the case fatality rate, is www.nature.com/scientificreports/ difficult to estimate for covid-19 due to changes in the testing rate [31] [32] [33] , the change of case definition 34 , selection biases 35 , and the delay between the onset of symptoms and death 12,36-38 as were the cases we experienced in the surveillance of other emerging diseases 39, 40 . to address this problem, implementation of active epidemiological surveillances, such as a large-scale cohort study including real-time detection of infections, should be considered. from the modelling perspective on mortality by covid-19, age-dependency of severity should be carefully taken into consideration. in particular, in the mathematical models of ade, previous models employed three types of assumptions 41 , the assumption of: increasing susceptibility to infection 42, 43 , increasing transmissibility once infection occurred 42, 44, 45 , and increasing severity and/or mortality associated with infection 46 . based on our results and from the biological/epidemiological observations of past sars and mers cases, the "increasing severity" assumption should be taken into account when analyzing sars cov-2 epidemics. we modelled the age-specific susceptibility as a power law function based on the monotonic increase of mortality by covid-19 over age as seen in fig. 1 . the power law function is widely used to model heterogeneity, e.g., the heterogeneity in risks of sexually transmitted infections 47 . although our model for age-specific susceptibility covers a wide variation of monotonic changes, our results might be biased by this formulation if the susceptibility changes over age in non-monotonic fashion. the increase in width of the confidence interval for the estimate of φ by increasing r 0 values were observed in fig. 5 . to explain with the "left-skewed" age-distribution of mortality with high r 0 , a large φ is required since the higher r 0 value decreased the heterogeneity of mortality by age (fig. 2b ) and the large φ increased the heterogeneity of mortality (fig. 2a) . the sensitivity of φ to the age-distribution of mortality becomes smaller when φ is larger (fig. 2a) , the large widths of the confidence intervals for the estimate of φ is necessary to explain the age-distribution of mortality when r 0 is high. in conclusion, the contribution of age-dependency to susceptibility is difficult to use to explain the robust age distribution in mortalities by covid-19, and it suggests that the age-dependencies of the mortality rate and the fraction of symptomatic infections among all covid-19 cases determine the age distribution in mortality from www.nature.com/scientificreports/ covid-19. further investigations regarding age-dependency on the fraction of infections becoming symptomatic is required to understand the mechanism behind the mortality by covid-19 infections. data. we analyzed the number of mortalities caused by covid-19 in italy reported on 13th may 2020, japan reported on 7th may 2020, and spain reported on 12th may 2020. the data were collected from public data sources in each country 23-25 . model. a simple seird model taking into account mixing between age groups (model 1). to understand the background of robust age distribution of mortality with varied r 0 , we employed a mathematical model describing transmissions of covid-19. clinical observations suggest that both asymptomatic and symptomatic cases are infectious after the latent period 48,49 , we used a simple age-structured seird (susceptible-exposedinfectious-recovered-dead) model, which can be written as; where s n , e n , i n , r n and d n represent the proportion of susceptible, latent, infectious, recovered and dead among the entire population, and the subscript index n denotes age group. we stratified the entire population by into eight groups, n = 1, 2, 3, 4, 5, 6, 7, and 8 for < 10 yo, 10-19 yo, 20-29 yo, 30-39 yo, 40-49 yo, 50-59 yo, 60-69 yo, and 70 + yo. β, k n,m , ε, γ and δ represent a transmission coefficient, an element of the contact matrix between age group n and m, the progression rate from latent to infectious, recovery rate and mortality rate by covid-19 infections, respectively. σ n denotes the susceptibility of age group n. for the sake of simplicity, based on the short study duration of covid-19 epidemics compared to the length of a human lifespan, births and deaths from causes other than covid-19 were ignored. to take into account the effect of behavioral changes outside of the household during the outbreak, k n,m is decomposed by a matrix for contacts within household k in,n,m and that for contacts outside the household k out,n,m ; where α denotes the reduced fraction of contacts outside of the household. we modelled age specific susceptibility as where c is susceptibility among age group 1 and a constant among all age groups, φ denotes the exponent parameter describing the variation of susceptibility among age groups. an increase in φ means an increase in the variation of susceptibility among age groups, and φ = 0 means that susceptibility is equal among all age groups. seird model taking into account mixing between age groups, asymptomatic/symptomatic, and age-dependency of mortality by . model 1 does not classify the cases into asymptomatic and symptomatic cases explicitly. if the progression of disease is largely different between asymptomatic and symptomatic cases, the estimates using model 1 can be biased. in addition, the age-dependency of mortality by covid-19 infections is not taken into account. model 2 takes into account both the different progression of disease between asymptomatic and symptomatic cases and the age-dependency of mortality by covid-19 infections; (1) s ′ n = −βσ n s n m k n,m i m , www.nature.com/scientificreports/ where i s,n and i a,n represent the proportion of symptomatic and asymptomatic cases among age group n. other compartments are the same as model 1. f s represents the fraction of symptomatic infections among all covid-19 cases and δ n represents the mortality rate by covid-19 infection among age group n. γ s and γ a denote the recovery rates among symptomatic and asymptomatic cases. other parameters are the same as model 1. we parameterized ε and γ using values from a previous modelling study of 50, 51 . the average length of the latent period (i.e., 1/ε) was set to 6.4 days 48, 50 , assuming that the latent period is equal to the incubation period, and the average length of the infectious period (i.e., 1/γ) was 7 days 48,51 for model 1. in model 2, to take into account the different infectious period between symptomatic and asymptomatic infections, we set an average length of infectious period among asymptomatic cases (i.e., 1/γ a ) as 9 days 49 and an average length of infectious period among symptomatic cases (i.e., 1/γ s ) as 7 days. we referred to the contact matrices for italy, japan, and spain from prem et al. 52 . β and c were controlled such that the basic reproduction number, r 0 , becomes arbitral values. r 0 was calculated by constructing a next generation matrix 53, 54 using each country's demographic data obtained from a public data source 26 . in terms of parameterization for mortality rate by covid-19 infection, a reliable estimate of δ n for covid-19 is difficult to obtain. due to the uncertainty of the fraction of symptomatic infections per age group, δ n is difficult to estimate from observed data, i.e., the confirmed case fatality rate among age group n (ccfr n ). since an estimate of δ n is difficult to obtain, we employed two different settings (i) δ n is assumed to be a constant among all age groups as assumed in the model 1, i.e., δ n = δ for any age group n, or, (ii) δ n is calculated from ccfr n assuming that the fraction of symptomatic infections among all covid-19 cases (f s ) is not dependent on age as assumed in model 2. in the setting for model 1, the value of δ is not required to estimate d n once the value of r 0 is given. we calculated d n by calculating the proportions of recovered persons per age group among all recovered persons r n (∞)/ n r n (∞) instead of d n (∞)/ n d n (∞) . in our model, shown in eq. (1-5), r n (∞)/ n r n (∞) is determined by the value of r 0 completely when all parameter values other than β and δ are fixed, and d n (∞)/ n d n (∞) = r n (∞)/ n r n (∞) if δ n = 0 . the proof can be found in the supplemental text. the assumption in model 1, δ n is constant among all age groups, may be too strong for the covid-19 epidemic. to take into account the age-dependency of mortality by covid-19, δ n was calculated from the ccfr n assuming that f s is not dependent with age. for the setting in model 2, assuming three scenarios; f s = 0.05, 0.25, and 0.5, δ n for each country were calculated using ccfr n in each country. we obtained δ n by solving ccfr n = δ n / (δ n + γ s ). fitting. we calculated the proportions of deaths in the age group n among all deaths, d n ( = d n (∞)/ n d n (∞) ), and fitted them to the observed data in each country. we solved model 1 shown in eqs. (1) (2) (3) (4) (5) and model 2 shown in eqs. (8) (9) (10) (11) (12) (13) numerically, and d n was calculated after sufficient time was given to finish the epidemics. we estimated φ using a log likelihood function describing the multinomial sampling process of deaths per age group; maximum likelihood estimates of φ with given r 0 were obtained by maximizing eq. (14) and the profile likelihood-based confidence intervals were computed. all data collected and analyzed during this study are included in this published article and its supplementary information files. www.nature.com/scientificreports/ situation report -130, coronavirus disease 2019 (covid-2019) 29 demographic science aids in understanding the spread and fatality rates of covid-19 case-fatality rate and characteristics of patients dying in relation to covid-19 in italy estimating clinical severity of covid-19 from the transmission dynamics in wuhan, china are children less susceptible to covid-19? clinical characteristics of 140 patients infected with sars-cov-2 in wuhan spread of sars-cov-2 in the icelandic population the effect of age on mortality in patients with covid-19: a meta-analysis with 611,583 subjects china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china clinical features of covid-19 in elderly patients: a comparison with young and middle-aged patients host susceptibility to severe covid-19 and establishment of a host risk score: findings of 487 cases outside wuhan estimates of the severity of coronavirus disease 2019: a model-based analysis clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study genomic analysis reveals age-dependent innate immune responses to severe acute respiratory syndrome coronavirus cellular immune responses to severe acute respiratory syndrome coronavirus (sars-cov) infection in senescent balb/c mice: cd4+ t cells are important in control of sars-cov infection aged balb/c mice as a model for increased severity of severe acute respiratory syndrome in elderly humans feasibility of using convalescent plasma immunotherapy for mers-cov infection, saudi arabia transmission of mers-coronavirus in household contacts the trinity of covid-19: immunity, inflammation and intervention is covid-19 receiving ade from other coronaviruses molecular mechanism for antibody-dependent enhancement of coronavirus entry evasion of antibody neutralization in emerging severe acute respiratory syndrome coronaviruses documents for press release infographic available in english -13 may 2020 update in covid-19 integrated surveillance: key national data enfermedad por el coronavirus (covid-19) annual population indicators in standard projections preliminary estimates of the reproduction number of the coronavirus disease (covid-19) outbreak in republic of korea and italy by 5 assessment of the sars-cov-2 basic reproduction number, r 0 , based on the early phase of covid-19 outbreak in italy the minutes of the fifth meeting effective reproductive number estimation for initial stage of covid-19 pandemic in latin american countries effectiveness of traveller screening for emerging pathogens is shaped by epidemiology and natural history of infection estimated effectiveness of symptom and risk screening to prevent the spread of covid-19 changes in testing rates could mask the novel coronavirus disease (covid-19) growth rate effect of changing case definitions for covid-19 on the epidemic curve and transmission parameters in mainland china: a modelling study sarscov-2 (covid-19) by the numbers incubation period and other epidemiological characteristics of 2019 novel coronavirus infections with right truncation: a statistical analysis of publicly available case data transmission potential and severity of covid-19 in south korea early epidemiological analysis of the coronavirus disease 2019 outbreak based on crowdsourced data: a population-level observational study methods for estimating the case fatality ratio for a novel, emerging infectious disease assessing the severity of the novel influenza a/h1n1 pandemic partial cross-enhancement in models for dengue epidemiology immunological serotype interactions and their effect on the epidemiological pattern of dengue a conceptual model for optimizing vaccine coverage to reduce vector-borne infections in the presence of antibody-dependent enhancement the effect of antibody-dependent enhancement on the transmission dynamics and persistence of multiple-strain pathogens the influence of different forms of cross-protective immunity on the population dynamics of antigenically diverse populations why are dengue virus serotypes so distantly related? enhancement and limiting serotype similarity between dengue virus strains could there have been substantial declines in sexual risk behavior across sub-saharan africa in the mid-1990s the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study natural history of asymptomatic sars-cov-2 infection incubation period of 2019 novel coronavirus (2019-ncov) infections among travellers from wuhan clinical presentation and virological assessment of hospitalized cases of coronavirus disease 2019 in a travelassociated transmission cluster projecting social contact matrices in 152 countries using contact surveys and demographic data mathematical epidemiology of infectious diseases: model building, analysis and interpretation social contacts and mixing patterns relevant to the spread of infectious diseases the authors gratefully acknowledge the manuscript language review of dr. heidi l. gurung. r.o. acknowledges support from the japan society for the promotion of science (jsps) (website: https ://www.jsps.go.jp/engli sh/ index .html) grant-in-aid for young scientists 19k20393. y.n. was supported by jsps grant-in-aid for young scientists (b) 16k20976. the funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. the authors declare no competing interests. supplementary information is available for this paper at https ://doi.org/10.1038/s4159 8-020-73777 -8.correspondence and requests for materials should be addressed to r.o.reprints and permissions information is available at www.nature.com/reprints.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/4.0/. key: cord-344653-to7571tw authors: whatley, mary c.; siegel, alexander l. m.; schwartz, shawn t.; silaj, katie m.; castel, alan d. title: younger and older adults’ mood and expectations regarding aging during covid-19 date: 2020-09-16 journal: gerontol geriatr med doi: 10.1177/2333721420960259 sha: doc_id: 344653 cord_uid: to7571tw the 2019 novel coronavirus disease (covid-19) has broadly impacted our daily lives. here, we used a longitudinal approach to investigate older adults’ mood and expectations regarding aging before and during the global pandemic (study 1). we also examined age differences in mood, expectations regarding aging, covid-19 attitudes, and loneliness using a cross-sectional approach (study 2). in study 1, older adults completed a mood and expectations regarding aging survey up to 2 years prior to the pandemic and again in april, 2020 (during the pandemic). participants also completed surveys regarding covid-19 attitudes and loneliness. in study 2, a united states sample of younger and older adults completed these surveys during the pandemic. older adults’ mood and expectations regarding aging remained fairly constant, and younger adults showed lower mood and expectations regarding aging than did older adults, despite older adults showing greater concern about covid-19. overall, we find that some older adults seem to be resilient with respect to their mood and expectations regarding aging. these findings reveal important preliminary implications for how older adults may be impacted as a result of lifestyle changes necessary for well-being and the well-being of society. the families, caregivers, when the world health organization declared the 2019 novel coronavirus disease (covid-19) a pandemic in march 2020, people were urged to "social distance" by limiting their activity in public spaces, refraining from in-person visits with family and friends, and maintaining a distance of 6 feet from others when engaging in essential activities. as a consequence, many older adults who had active social lives likely experienced major changes in their routines, leading them to feel isolated, lonely, or have decreased mood. further, almost one third of older adults live alone (administration on aging, 2018), many already experience loneliness (gerst-emerson & jayawardhana, 2015) , and increased loneliness may lead to a multitude of negative mental and physical health outcomes in both younger adults (jaremka et al., 2014) and older adults (ong et al., 2016) . some work has investigated older adults' worries about covid-19 (barber & kim, 2020) , but it is unclear whether covid-19 has influenced older adults' overall mood. covid-19 can be dangerous for people of any age, but mortality rates are higher for those aged 65 and older (cdc, 2020; hauser et al., 2020) . at the onset of the pandemic, older adults (aged 65+) made up 43.4% of covid-19-related hospitalizations, and the rate of hospitalization for this group was almost double that of those aged 50 to 64 years, which was three times higher than for 18 to 49 year-olds, demonstrating the striking increase in covid-19-related health risks with increasing age (garg, 2020) . widespread media focus on the impact of covid-19 on older adults as a fragile population could also lead older adults to feel more vulnerable and affect attitudes about aging (ayalon et al., 2020) . some work has shown that older adults' physical and mental health can be influenced by societal attitudes about aging (chang et al., 2020) . swift et al. (2017) describe the risks of ageism model (ram), which posits that societal ageism (e.g., economic, social, and psychological factors) contributes to both negative self-perceptions of age stereotypes and an increased likelihood of being a target of ageism in older adults. these experiences, in turn, serve as barriers to experiencing independence, autonomy, and higher quality of life. thus, a widespread focus on the fragility of older populations during the pandemic could have negative effects on older adults' attitudes or expectations about aging. unfortunately, negative attitudes about aging are related to a variety of health outcomes in older adults, including lower survival rates and physical and mental health issues (breda & watts, 2017; han & richardson, 2014) . anxiety about aging can even explain some of the relationship between one's environment and loneliness (ayalon, 2018) , suggesting that negative aging attitudes could exacerbate feelings of loneliness (see also shiovitz-ezra et al., 2018) . on the other hand, positive attitudes about aging have been associated with more new friends in older adulthood (menkin et al., 2017) , which could prevent loneliness. given the increased risk of hospitalization or death due to covid-19, older adults may take greater preventive measures and hold more serious attitudes toward covid-19 than younger adults. it is unclear, however, how attitudes about covid-19 relate to outcomes like mood or attitudes about aging, or whether this relationship is different between younger and older adults. those with more serious attitudes about covid-19 may experience greater loneliness or decreased mood if they are isolating to a greater extent, but people may also feel safer and thus more positive if they are taking the recommended precautions. in the current studies, we examined mood, expectations regarding aging, coronavirus attitudes, and loneliness in younger and older adults. in the first study, we examined mood and expectations regarding aging before and during the coronavirus pandemic. a sample of older adults who provided responses to surveys from january 2018 to december 2019 completed follow-up surveys during the course of the pandemic, and response differences were analyzed. participants. eighty-six older adults who completed the expectations regarding aging (era) and brief mood introspection scale (bmis) between january 2018 and december 2019 (time 1) were contacted to participate. forty-nine participants (m age = 73.90 years, sd age = 7.50 years) provided responses between april 7 and may 2, 2020 (time 2). two participants did not respond to the bmis at time 1 but did respond to all surveys at time 2. all participants reported residing in the united states at the time of data collection, and all other demographic information is presented in table 1 . of those who did not respond at time 2, 17 never responded to outreach, 12 were contacted and interested but did not participate before the deadline, three were unreachable, and five were reached but were not interested. to examine whether those who responded were demographically different from those who did not, we conducted chi-square tests for independence and found that older adults who participated at time 2 and those who did not showed no significantly different makeup of gender, χ 2 (1, n = 86) = 0.16, p = .69, ethnicity, χ 2 (2, n = 86) = 1.17, p = .34, race, χ 2 (4, n = 86) = 4.93, p = .29, nor education, χ 2 (3, n = 86) = 4.41, p = .22. there was also no difference in age, t(84) = 1.08, p = .29, nor in self-reported health, t(84) = 0.24, p = .81, between participants who responded at time 2 and those who did not. materials and procedures. this study used a longitudinal approach to examine differences in outcomes across two time points. participants were contacted by email, but given the option of completing the surveys over the phone if they were uncomfortable with computers or if it was easier for them. most (n = 41) chose to complete the surveys online. all procedures were approved by the university of california, los angeles institutional review board, and informed consent was obtained. after self-reporting health on a 1 (poor) to 10 (excellent) scale, participants completed the bmis (mayer & gaschke, 1988) , which contains 16 adjectives rated on a 1 (definitely do not feel) to 7 (definitely feel) likert scale, as well as an overall mood item rated from −10 (very unpleasant) to 10 (very pleasant). the bmis assesses four constructs related to participants' mood. first, the pleasant-unpleasant scale, which includes responses from all items, indicates a participant's overall mood valence, with higher scores indicating more pleasant mood. the arousal-calm subscale provides a measure of how aroused (i.e., jittery, excited, nervous) participants are, independent of the valence of those emotions, with lower scores indicating less aroused or more calm mood. the positive-tired subscale assesses positive mood, with lower scores indicating less positive or more tired mood, and the negative-relaxed subscale measures negative mood, with lower scores indicating less negative or more calm mood. participants also completed the 12-item era scale (sarkisian et al., 2005) , which measures attitudes about aging. participants rated statements about older age that apply both personally (e.g., "i expect that as i get older, i will become more forgetful.") and more broadly (e.g., "having more aches and pains is an accepted part of aging."). the era is composed of three subscales: cognitive function, physical health, and mental health, all rated from 1 (definitely true) to 4 (definitely false), and then converted to a 0 to 100 scale. lower scores indicate expectations of decline in older age, while higher scores represent higher expectations, including expecting achievement and high functioning in older age. note. study 1 participants' data from time 2. self-reported health was provided on a scale from 1 (poor) to 10 (excellent). participants then completed the attitudes and prevention subscales of a new covid-19 pandemic scale (priniski, 2020) , which measures participants' attitudes and opinions about the impact of covid-19. the scale was modeled after a scale measuring vaccine skepticism and beliefs about diseases like measles and mumps (powell et al., 2018) . after reading a brief definition of covid-19, participants provided responses on a likert scale from 1 (strongly disagree) to 7 (strongly agree) to a series of statements such as "covid-19, commonly referred to as coronavirus, is no more severe than the flu." lower scores indicate more serious attitudes and prevention intentions. after responding to a few open-ended questions about their behavior during the pandemic, participants then completed a 3-item version of the ucla loneliness scale (hughs et al., 2004) . the items (e.g., "how often do you feel that you lack companionship?") were rated on a scale of 1 (hardly ever) to 3 (often), with higher scores indicating greater feelings of loneliness. expectations regarding aging. we conducted dependentsamples t-tests on each of the era subscales and on the total era score. all means and standard deviations are reported in table 2 to determine the validity of the null effects between time points, we calculated a bayes factor for each test, which gives a measure of the strength of the evidence for the null or alternative hypotheses based on a priori hypotheses and the data (see kruschke, 2013; wagenmakers et al., 2017 for discussions of the benefits of using bayes factors). as interpreted by guidelines in lee and wagenmakers (2013) , the bayesian paired-samples t-tests using default cauchy priors indicated "moderate" evidence in favor of the null hypothesis (i.e., no difference between time 1 and 2) on the physical health (bf 01 = 5.26), cognitive function (bf 01 = 6.36), and total era (bf 01 = 6.40) scores, but only "anecdotal" evidence on the mental health score (bf 01 = 2.53). these values indicate that the data for the physical health measure were 5.26 times more likely to occur under the null relative to the alternative model, the data for cognitive health were 6.36 times more likely under the null model, and so on. thus, the results provide moderate evidence of consistent era physical, cognitive, and total scores between time 1 and 2, with inconclusive evidence on mental health scores. in subsequent analyses, we report bayes factors for null effects. mood. we scored the bmis according to mayer (2018) to obtain subscale scores on the following dimensions: pleasant-unpleasant (ranging from 16 to 112), arousalcalm (ranging from 12 to 84), positive-tired (ranging from 7 to 49), and negative-relaxed (ranging from 6 to 42). there were no differences between time 1 and time 2 on overall mood ratings, t(46) = 0.23, p = .82, d = 0.03, bf 01 = 6.16, or overall pleasant-unpleasant ratings, t(46) = 1.77, p = .08, d = 0.26, bf 01 = 1.50. in addition, there were no significant differences in the positive-tired subscale at time 1 and time 2, t(46) = 0.71, p = .48, d = 0.10, bf 01 = 4.97. however, scores on the arousal-calm subscale were significantly higher at time 2 than time 1, t(46) = 3.06, p = .004, d = 0.45, as were scores on the negative-relaxed subscale, t(46) = 3.35, p = .002, d = 0.49. the bayes factors for the null effects here support moderate evidence for the lack of change in positive mood, but only anecdotal evidence for the lack of change in pleasant mood. thus, while mood did not become less positive, participants were more aroused and had more negative (less calm) mood at time 2 than at time 1. correlations between expectations, mood, and covid-19. the means for the covid-19 and loneliness scales are displayed in table 2 . relevant pearson's correlations are discussed here, and all correlations between measures at time 2 are shown in figure 1 . in all analyses, correlation matrices were computed in r (version 4.0.1, r core team, 2020) using the stats (version 4.0.1, r core team, 2020) package, and p-values were computed using the "cor_pmat" function in the ggcorrplot (version 0.1.3, kassambara, 2019) package; correlation matrix figures were generated using the corrplot (version 0.84, wei & simko, 2017) package with rcolorbrewer (version 1.1-2, neuwirth, 2014) . the correlations revealed that those with higher expectations about aging had more pleasant mood, r(47) = 0.50, p < .001. in addition, higher loneliness scores were associated with significantly lower era scores, r(47) = −.33, p = .02, and bmis scores, r(47) = −.43, p = .003. higher health ratings were associated with higher era scores, r(47) = .37, p = .01, and bmis scores, r(47) = .36, p = .01. lastly, covid-19 scores were not associated with health, r(47) = .02, p = .89, era scores, r(47) = .08, p = .58, or bmis scores, r(47) = .18, p = .24, but were associated with loneliness scores, r(47) = −.30, p = .04, such that taking covid-19 more seriously was associated with greater loneliness. in study 1, we found that overall, our sample of older adults was maintaining positive mood and expectations about aging during the covid-19 pandemic, but that they reported more negative arousal. in addition, loneliness was negatively related to both attitudes about aging and mood pleasantness. thus, while older adults do not seem to be entirely unaffected by the covid-19 pandemic, this sample of older adults seemed to maintain positive mood and attitudes about aging overall. in study 2, we attempted to replicate findings from study 1 regarding loneliness, covid-19 attitudes, mood, and expectations regarding aging in a larger sample of older adults. we also examined age-related differences in mood, expectations about aging, loneliness, and attitudes toward covid-19 in a national sample of older and younger adults. participants. the participants in study 2 were younger and older adults recruited using prime panels on cloudresearch (formerly known as turkprime; www. cloudresearch.com). similar to other online data collection platforms like amazon mechanical turk (mturk), cloudresearch's prime panels allows for researchers to target and collect large, diverse samples of participants. prime panels participants have been shown to produce similar rates of passing attention checks and similar effect sizes as other online and in-lab samples, while being more representative of the u.s. population (chandler et al., 2019). prime panels also has a larger proportion of older adults, with over 23% of participants over the age of 60 relative to 3.3% of mturk participants meeting the same criterion (chandler et al., 2019; huff & tingley, 2015) . as such, despite obvious limitations inherent to online data collection, prime panels is a useful tool to efficiently obtain quality older adult data. participants were restricted to be ages 18 to 30 or 60+ and to reside in the united states. the older adult age range was restricted so as to match that of study 1, and the younger adult range is consistent with recent similar research (e.g., barber & kim, 2020) . to ensure participants were paying attention, we used a measure of participants' focus (i.e., the proportion of time in which a participant's computer mouse was present on the browser page), and participants were excluded from the experiment if they had less than 0.75 (out of 1.00) focus for the duration of the survey. participants were also excluded if they selected the incorrect response on an attention check question. the survey was completed in median time of 9.59 min (iqr = 6.46-13.25 min). the final sample consisted of 115 younger adults (m age = 25.15 years, sd age = 3.63 years) and 115 older adults (m age = 69.70 years, sd age = 6.16 years) who were compensated $2.00 for their participation. other relevant demographic information is presented in table 1 . materials and procedure. the same materials used in study 1 were also used in study 2. participants completed a demographics form and the era, bmis, covid-19 pandemic, and loneliness surveys. this study used a cross-sectional design to examine age differences in outcomes. expectations regarding aging. we conducted independent samples t-tests on each of the era subscales and the total era score. 1 means for all measures are shown in table 2 . older adults had higher scores on the physical health, t(228) = 3.29, p = .001, d = 0.43, mental health, t(219.2) = 7.31, p < .001, d = 0.96, and cognitive function, t(228) = 4.73, p < .001, d = 0.62 subscales than did younger adults. additionally, older adults provided higher total era ratings than did younger adults, t(221.6) = 6.15, p < .001, d = 0.81. mood. on average, there was no difference between older and younger adults' overall mood, t(228) = 1.25, p = .21, d = 0.17, bf 01 = 3.40. however, older adults scored significantly higher than younger adults on the pleasant-unpleasant scale, t(228) = 6.05, p < .001, d = 0.80, and on the positive-tired subscale, t(228) = 4.72, p < .001, d = 0.62. conversely, younger adults scored significantly higher than older adults on the arousal-calm subscale, t(228) = 2.76, p = .01, d = 0.36, and on the negative-relaxed subscale, t(222.3) = 6.14, p < .001, d = 0.81. younger adults were also significantly lonelier than older adults, t(228) = 3.37, p < .001, d = 0.44. overall, younger adults had less positive and more negative mood and reported experiencing greater arousal than older adults. we calculated attitude and prevention subscale scores for the covid-19 survey. older adults had more positive attitudes about the covid-19 pandemic than younger adults, t(210) = 7.88, p < .001, d = 1.04. older adults also reported more concern about covid-19 prevention than younger adults, t(195) = 6.58, p < .001, d = 0.87. overall scores on the covid-19 scale were higher in younger adults than in older adults, t(202) = 8.06, p < .001, d = 1.06. thus, older adults reported taking the covid-19 pandemic more seriously and engaging in preventative behaviors to a greater extent than younger adults. pearson's correlations were conducted within each age group to examine associations between overall era score, bmis pleasant-unpleasant mood, covid-19 score, loneliness rating, and relevant demographic factors like age, gender, education, income, and overall health. significant correlations of interest are discussed here (with additional correlations presented in figure 1 ). for older adults, higher era scores were associated with more pleasant mood, r(113) = .40, p < .001, lower loneliness ratings, r(113) = −.25, p = .006, higher health ratings, r(113) = .34, p < .001, and gender, r(113) = .22, p = .02. in addition, greater loneliness was associated with more unpleasant mood, r(113) = −.48, p < .001, lower health ratings, r(113) = −.20, p = .03, lower income, r(113) = −.21, p = .03, and being female, r(113) = .29, p = .002. more pleasant mood was also associated with better health, r(113) = .37, p < .001, and higher income, r(113) = .25, p = .01. lastly, covid-19 scores were not significantly correlated with era, r(113) = −.02, p = .87, bmis, r(113) = .03, p = .78, loneliness, r(113) = −.17, p = .07, nor health, r(113) = .06, p = .50, but were correlated with gender, r(113) = −.34, p < .001, such that females expressed more serious attitudes and prevention toward covid-19 than males. in younger adults, lower expectations regarding aging were associated with more unpleasant mood, r(113) = .27, p = .004, higher loneliness, r(113) = −.20, p = .03, higher age, r(113) = −.25, p = .01, higher income, r(113) = −.19, p = .04, higher education, r(113) = −.30, p = .001, and being male, r(113) = .28, p = .002. more unpleasant mood was associated with less covid-19 concern and prevention intent, r(113) = −.21, p = .02, higher loneliness, r(113) = −.43, p < .001, and lower health ratings, r(113) = .26, p = .01. similar to older adults, female younger adults reported higher covid-19 concern, r(113) = −.31, p < .001. in study 2, we found that older adults reported more positive mood and higher expectations about aging than younger adults did, supporting the finding that older adults, in general, were maintaining positivity following the onset of the covid-19 pandemic. we also replicated in both younger and older adults the finding that more frequent feelings of loneliness were related to lower expectations regarding aging and more unpleasant mood. in addition, females were taking covid-19 more seriously, reported higher expectations regarding aging, and were in better health, but female older adults were lonelier than males. lastly, older adults expressed greater concern for covid-19 than younger adults did, suggesting that they are taking it more seriously. the current findings suggest older adults are, in general, maintaining their expectations about aging and mood amidst a global pandemic, showing similar ratings of pleasant mood, positive mood, and expectations regarding aging before and during the pandemic and rating mood and expectations about aging more positively than younger adults, despite being more concerned with the virus and its prevention. in general, older adults tend to have more positive attitudes toward aging than younger adults (chopik & giasson, 2017; kornadt et al., 2017) , and these findings suggest that this is also true during a global pandemic even when there is increased societal focus on older adults' vulnerability. some recent work suggests that positive attitudes about aging can act as a protective factor against stress (bellingtier & neupert, 2018; levy et al., 2016) , which could potentially explain why these older adults are maintaining positive attitudes. in addition, our sample of older adults initially rated their mood as fairly positive and pleasant, but their positivity in mood was not reduced by the pandemic. both younger and older adults with higher expectations regarding aging tended to have higher mood, better health, and experience less loneliness, suggesting that maintaining high expectations regarding aging is related to positive outcomes like health and mood, consistent with prior work (e.g., pietrzak et al., 2014) . although we cannot make claims about the direction of these constructs in the current study, the stereotype embodiment theory (levy, 2009 ) posits that older adults may internalize attitudes about aging, leading to influences on their health and everyday behaviors. in addition, positive attitudes have been shown to protect against cognitive decline and stress (levy et al., 2016 (levy et al., , 2018 , which may affect health status and mood. however, older adults did report more negative mood and greater arousal during the pandemic than before, despite maintaining positive mood, suggesting that the pandemic may have some influence on older adults' mood, but that overall older adults are demonstrating resilience. additionally, covid-19 attitudes and behaviors did not seem to be related to mood or expectations in older adults (and were related to loneliness in study 1 only), but were related to mood in younger adults, such that those who took covid-19 less seriously reported more unpleasant mood. this finding suggests that older adults' mood may be less affected by their opinions about the pandemic than younger adults' and further suggests that older adults are resilient during this global pandemic, despite being more at-risk for serious complications. although these findings suggest some older adults are resilient during a global pandemic, it is important to interpret the results in light of sample demographics. in general, our samples were overwhelmingly white and educated. in addition, older adults in study 1 were mostly high-income, though participants in study 2 did have greater variation in income. this limitation in study 1 was inherently present due to the nature of our local older adult subject pool and collecting these follow-up data during the covid-19 pandemic was not an event we anticipated. this motivated the collection of a more diverse, nationally-representative sample of participants through the cloudresearch platform in study 2, and this sample is similar in demographics to recent studies on covid-19 and aging (e.g., barber & kim, 2020) . these findings have implications for both future research and practice. we find that some older adults are resilient and maintaining positive attitudes, and future research may seek to determine what factors contribute to this resilience, such as positive attitudes about aging (e.g., bellingtier & neupert, 2018; levy et al., 2016) , an increase in focus on close friends and family during challenging times, consistent with socioemotional selectivity theory (e.g., fung & carstensen, 2006) , and/or demographic factors. in addition, younger adults do not seem to be as resilient (although we do not have data from these measures prior to the onset of the pandemic). thus, future work can examine why younger adults are less resilient, and clinical practice may focus on improving mood and resiliency in younger adults. finally, males reported less serious attitudes and prevention intent toward covid-19 than females, consistent with other recent work (e.g., capraro & barcelo, 2020; galasso et al., 2020) , and this was true for both older and younger adults. however, males make up a larger portion of hospitalizations and deaths (jin et al., 2020) , so it is important to target this demographic to prevent the spread of covid-19 and increase preventive behaviors. in sum, despite imposed social distancing measures that may have reduced typical levels of social interaction and financial stability, older adults in the current studies maintained their overall mood and expectations regarding aging compared to before the onset of the pandemic, while younger adults reported lower expectations about aging and mood compared to older adults, suggesting some older adults may be steadfast in the face of a global pandemic. the author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was supported in part by the national institutes of health (national institute on aging), award number r01ag044335. 2017 profile of older americans loneliness and anxiety about aging in adult day care centers and continuing care retirement communities aging in times of the covid-19 pandemic: avoiding ageism and fostering intergenerational solidarity covid-19 worries and behavior changes in older and younger men and women negative aging attitudes predict greater reactivity to daily stressors in older adults expectations regarding aging, physical activity, and physical function in older adults the effect of messaging and gender on intentions to wear a face covering to slow down covid-19 transmission online panels in social science research: expanding sampling methods beyond mechanical turk global reach of ageism on older persons' health: a systematic review age differences in explicit and implicit age attitudes across the lifespan goals change when life's fragility is primed: lessons learned from older adults, the september 11 attacks and sars gender differences in covid-19 related attitudes and behavior: evidence from a panel survey in eight oecd countries (nber working paper 27359) hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease 2019-covid-net, 14 states loneliness as a public health issue: the impact of loneliness on health care utilization among older adults the relationships among perceived discrimination, self-perceptions of aging, and depressive symptoms: a longitudinal examination of age discrimination estimation of sars-cov-2 mortality during the early stages of an epidemic: a modelling study in hubei, china and northern italy evaluating the demographic characteristics and political preferences of mturk survey respondents a short scale for measuring loneliness in large surveys pain, depression, and fatigue: loneliness as a longitudinal risk factor gender differences in patients with covid-19: focus on severity and mortality ggcorrplot: visualization of a correlation matrix using 'ggplot2 age stereotypes and self-views revisited: patterns of internalization and projection processes across the lifespan bayesian estimation supersedes the t test bayesian cognitive modeling: a practical course stereotype embodiment: a psychosocial approach to aging buffer against cumulative stress: positive age self-stereotypes predict lower cortisol across 30 years positive age beliefs protect against dementia even among elders with high-risk gene brief mood introspection scale (bmis): technical and scoring manual the experience and meta-experience of mood positive expectations regarding aging linked to more new friends in later life rcolorbrewer: colorbrewer palettes loneliness and health in older adults: a mini-review and synthesis successful aging among older veterans in the united states articulating lay theories through graphical models: a study of beliefs surrounding vaccination decisions shifting and politically diverging attitudes towards covid-19 development of the 12-item expectations regarding aging survey pathways from ageism to loneliness the risks of ageism model: how ageism and negative attitudes toward age can be a barrier to active aging psychological science under scrutiny: recent challenges and proposed solutions r package "corrplot": visualization of a correlation matrix (version 0 mary c. whatley https://orcid.org/0000-0003-3609-5630shawn t. schwartz https://orcid.org/0000-0001-6444-8451 note 1. in these and all following similar analyses, when equal variance assumptions were violated, welch's unequal variances t-tests were used. key: cord-318977-4ng6gxpv authors: zittoun, tania; baucal, aleksandar title: the relevance of a sociocultural perspective for understanding learning and development in older age date: 2020-09-26 journal: learn cult soc interact doi: 10.1016/j.lcsi.2020.100453 sha: doc_id: 318977 cord_uid: 4ng6gxpv this paper proposes a sociocultural psychology approach to ageing in the lifecourse. it proposes to consider sociogenetic, microgenetic and ontogenetic transformations when studying older age. on this basis, it considers that older people's lives have two specificities: a longer life experience, and a unique view of historical transformation. the paper calls for a closer understanding of the specific and evolving conditions of ageing, and for more inclusion of older citizens in public debate and policy making. finally, while this paper was being reviewed, the covid-19 hit the world, with important consequences for the life of older persons; we conclude the paper with a short reflexion on the implications of our proposal. we aim at defining an approach to development in older age which is grounded on four assumptions. first, we examine the developing person all life-long, and not development as an outcome; development is thus understood in an open-systemic and relational way. second, and in order to do so, life-long developing persons need to be understood in their sociocultural environments, these also being in transformation. third, the approach needs to adequately account for the specificities of developing as an older person -older than others. finally, we thus attempt to show how people can develop and maintain meaningful engagements in society (elder & giele, 2009; hviid & villadsen, 2015; teo, 2015; valsiner, 2008; valsiner et al., 2009; zittoun et al., 2013) . on this basis, we will deliberately turn our back on individualistic approaches focused on the ageing person in isolation, as well as on approaches focused on the evolution, or rather decline, of specific functions (such as cognition or memory), or on studies that consider older age independently of the life-long of the person, or even, that start with normative assumptions about what may be a successful or positive ageing, − approaches which develop widely since the mid-1950's and are still exponentially growing (for recent synthesis, see anderson & craik, 2017; biggs, 2005; li, 2015; park & festini, 2017; tournier, this issue) . to develop such a theoretical frame, we draw on a sociocultural psychology of learning and development, which so far has been mainly focused on children, young adults and adults, as well as on the growing field of anthropological (droz-mendelzweig, 2013; lieblich, 2014; sarason, 2011) , critical gerontology, sociological and narrative approaches (freeman, 2011; gubrium, 1995 gubrium, , 2011 , and clinical studies of the lives of older people (aumont & coconnier, 2016; bergeret-amselek, 2016; gutton, 2016; quinodoz, 2008; villa, 2010) . sociocultural psychology is a theoretical approach to human experience and development that considers the mutual constitution of the person and their social and cultural world, as these dynamics are located in time and space; it also gives a central role to human experience and sense-making (cole, 1996; rosa & valsiner, 2018; valsiner, 2012; wertsch, 1998) . inspired by american pragmatism (dewey, 1938; james, 2007; peirce, 1974) and russian psychology (vygotsky, 1986 (vygotsky, , 1997 , it is now a flourishing field. some of its current sub-orientations such as narrative cultural psychology (bruner, 2003; daiute, 2014) , historico-cultural psychology (hedegaard et al., 2008) , and semiotic cultural psychology (valsiner, 2014; wagoner et al., 2014) meet in their dialogical epistemologies, and their interest for formal and informal learning as well as for human development (césar & kumpulainen, 2009; mäkitalo et al., 2017; zittoun et al., 2013) . in these conditions, it is surprising that sociocultural psychology has very little addressed psychology of ageing -it is hardly surprising for vygotsky, one of the main inspirations in the field who died aged 34 (zavershneva & van der veer, 2018) , but more so for more recent studies. indeed, such silence reproduces a tendency visible in mainstream psychology, that is, a strong divide between psychology of the life-course-ending somewhere in mid-adulthood-and gerontology, considering older age mainly as it is accompanied by illnesses and other ailments (jeppson grassman & whitaker, 2013) . there are however a couple of recent sociocultural studies of the older person, such as that of manuti et al. (2016) , who propose a dialogical perspective that "implies the acknowledgement of elderly subjectivity inside social discourses and, as a consequence, the need for catching what they can say" (manuti et al., 2016, p. 4) , of authors focusing on the materiality of people's lives and can therefore adopt a mediated activity approach (e.g., engeström & sannino, 2016; woll & bratteteig, 2018) which examines care (boll et al., 2018) . why has sociocultural psychology not studied ageing more? it may be that it has been privileging an analysis of the cultural conditions of growth which appeared more clearly in childhood; or perhaps it is due to the fact that, as a discipline, it has to be accountable for its existence, and thus studying learning and work in youth and adults can have more direct implications for practice. more generally, sociocultural psychology may also simply reflect a global tendency, both sociocultural and theoretical-an avoidance of thinking ageing and death: beyond a classic interest for ageing in ancient greece, modern psychology has long avoided the topic. indeed, the preoccupation of the "fathers of psychology", such as piaget or watson, did not find ageing relevant for their enquiry (birren & schroots, 2001) ; in addition, studying ageing raises specific methodological challenges (säljö, this issue). here we aim at developing a more systematic and thorough definition of a sociocultural perspective on age. for this, we propose to approach developing ageing persons through an understanding of sociogenetic, microgenetic, and ontogenetic dynamics (duveen, 2013; gillespie & cornish, 2010; zittoun, 2016) . ageing cannot be approached today without an understanding of societies and their historical changes-beyond the obvious fact that older people have a very different status in communities where age is associated with wisdom than in industrialized societies. this includes three aspects that have been documented in ageing studies and critical gerontology, and that are linked to practices of social inclusion and boundary work, practical arrangements and affordances, and social representations. first, one has to examine how various groups (nation states, region, and communities), as social collectives, explicitly or implicitly include, marginalize, or exclude their oldest members (de beauvoir, 1970) . such dynamics of exclusion for instance take place when older people are ignored in public debates about the role of older citizens or the future of society, or by a subtle logic of suspicion (e.g., in many countries people after a certain age have to test their driving capacities every year, independently of their actual state of health). moreover, "age" as social category has to be understood in articulation with other categories: ageing poor or rich, ageing migrant, or ageing hetero-or homosexual might create specific dynamics of social inclusion and exclusion, recently addressed in terms of cross-sectionality (machat-from, 2017; rosenberg et al., 2018) . second, societies and their historical transformations have to be understood in terms of their institutions, and in industrialized societies, the policies that create the financial, symbolic and material conditions of living of the older citizens, and their related various affordances. institutions define who is "retired" and when, what guarantees and rights people have after they have finished a working life (or, for non-working people, when they reach the same age). it is thus important to note that the consensus considering the "third age" starting at around 65 is aligned on the age of the pension (stuart-hamilton, 2011). institutions also define modes of housing for older citizens, urban arrangements and transports, allocations for home care, cultural offers such as universities of third age, or cheaper museum entrance, etc. developing as older person is thus radically different if one has a pension that covers 70% of the person's former salary and enables them to maintain their lifestyle, or if the pension falls beyond the 50% and demands the person to radically limit their expenses; if one lives in a town with low-buses or with no public transports, etc. (abramson, 2015; aneshensel et al., 2016; bengston, 2016; quesnel-vallée et al., 2016) . however, it is important to note that older people still may define their lives, and create margins of freedom beyond the local institutional possibilities and constraints, as we will see. third, societies produce and are shaped by social representations and discourses on ageing and what "older people" are, and what they are expected to do or not to do. important attention has been paid to "ageism" as the negative social representation of older age in societies that privilege youth and its appearance in terms of beauty, strength and performances (angus & reeve, 2006; casas, 2014; nelson, 2005) . in turn, older people have been said to develop resistance to their "mask of age" and become alienated (humberstone & cutler-riddick, 2015) . also, the emphasis on "successful", "active" or "positive" ageing, both in psychology (since the 1960s) and in institutional and public discourses (balard, 2015; havighurst, 1961; rowe & cosco, 2016 ), mostly individualizing "success" and ignoring sociocultural and economic conditions facilitating or impeding such modes of lives (bülow & söderqvist, 2014) , has brought some people to experience their own less-active older age as failure, even though it may be meaningful to them (stenner et al., 2011) . however, with the development of critical perspectives on these categories, and also probably with the growing population of older active people, there is currently an increasing transformation of social representations of becoming older. this change can for instance be observed in a growing number of films depicting the realities of living with age (haneke, 2012; sorrentino, 2015) , an increased market of products targeting ageing persons (whether cosmetics, insurance, travel packages, clothing, etc.) or with fashion movement valorising the beauties of older people (campone, 2018) . hence, at a sociogenetic level, we call for a careful analysis of the historical evolution and local specificities of the dominant discourses on ageing persons, the institutional arrangements setting conditions for older people's lives, and the differentiated dynamics of social inclusion and exclusion of elderly persons. research needs to examine how older people meet these discourses, arrangements and dynamics in their everyday lives, and how they can negotiate, resist or accept them, for instance as empowering and supportive social scaffoldings for pursuing meaningful ageing. in this rapidly changing field, older people play an active role themselves, for instance through specific forms of political involvement (recently, the swiss "grand-parents for the climate", 1 or the danish "grand-parents for asylum" [hviid, 2020] ). a sociocultural psychological perspective also demands an understanding of the person in her context and along her life-course. in other words, it requires understanding the person in time, in a dynamic moment of their life: how the present is related to the past and how it is oriented toward the future. to move out of a negative representation of ageing as decline, a first step would be to abandon classic models of development that consider the lifecourse as a staircase or as a curve where ageing is designated by a declining slope (e.g., sato et al., 2007; sato et al., 2013; zittoun et al., 2013) . drawing on recent theorisation, we propose to consider the course of life as constantly changing, and to conceptualize it as dynamic assemblage of spheres of experience (zittoun & gillespie, 2015) . drawing on phenomenology on the one hand, and on more psychosocial descriptions of the frames of living on the other, the notion of "sphere of experience" describes an experiential unit that a person can recognize as "the same" over time, place, and relationships, and usually includes specific activities, modes of relating to others, range of feelings, aspects of one's identity or positioning, and certain specific knowledge or know-how. spheres of experience can, for instance, include eating-with-good-friends, or gardening, or remembering one's childhood, or participate in a scientific inquiry as citizen scientist. each occurrence of "eating-with-good-friends" may be located in different places and include different foods and conversations; yet it may be the overall "same" range of experience. these spheres may be "proximal" (they take in the here-and-now of specific material and social affordances) or "distal", when they are achieved through a loop of imagining, such as "remembering one's childhood". over the day, people pass from one sphere to another through a "mild shock" (schuetz, 1944) . however, new experiences may demand a radical reconfiguration of some spheres of experiences (such as an illness that prevents some type of food) or their destruction, as when a good friend dies and all the possibilities of joined experience disappear. new spheres of experience can also be created, such as when one moves to a new place-liminal experiences that we have coined as transitions (zittoun & gillespie, 2015; zittoun et al., this issue) . in line with the main assumptions of lifecourse research, we assume of course the historical and social embeddedness of peoples' course of life, the fact that people's lives are interrelated, and that the results and timing of past event may constitute, enable or constrain current and future developments (elder, 1994; janet zollinger giele & elder, 1998) . however, we are also very sensitive to people's capacities to "rewrite" their course of life, to find or create alternative developmental trajectories, and to live not only from what has been actually achieved or failed, but also, from what has been dreamed or anticipated, or from what has not come to be actualized but is still relevant (zittoun & gillespie, 2016; zittoun & valsiner, 2016) . it is also worth noticing that we conceptualize the persons' capacities not only as individual characteristics, but as capacities emerging from the relationship between individual capacities and sociocultural conditions, policies, institutions, discourses, and tools that enhance or limit, empower or disempower, support or prevent personal navigation and capacities during a lifecourse. altogether, the approach we propose brings us to highlight the fact that development occurs if, and only if, people can maintain a sense of continuity and integrity across their spheres of experience (erikson, 1959) , and confer meaningfulness to their lives and future perspectives. the idea of meaningfulness may be described in several ways, but here we put emphasis on two main components. on the one hand, it implies "sense-making" of one's experience (bruner, 2003; freeman, 2011) , or "engagement" in significant activities (hviid, 2020; hviid & villadsen, 2015; lido et al., 2016) . it also entails a minimal orientation to the future, that has been called "creativity" of living (gutton, 2016; winnicott, 2001; zittoun & de saint-laurent, 2015) , or "desire for life" (quinodoz, 2008; villa, 2010) , or "imagination" as way to go beyond the here-and-now and as existential tension to what has-to-come or could possibly occur (zittoun & gillespie, 2016) . on the other hand, meaningfulness can be related to meaningful interpersonal relationships, social recognition, and more generally, social inclusion (sarason, 2011b) . in this sense, meaningfulness or orientation to the future engage one's fundamental dialogicality (marková, 2016) with self and society, past and future, real and imaginary others, that is, an intention of living. a sociocultural psychology perspective on ageing proposes to explore the making of the person and the social as a meeting between sociogenetic and ontogenetic dynamics precisely in specific activities and interactions, that is, at the level of microgenesis. it thus proposes to identify and examine socially situated experiences and practices in the making, in all kind of real and imaginary situations that constitute everyday life. microgenetic dynamics take place in a wide range of situations and relationships, and have been studied with various focuses: in older people's daily interactions with neighbours, family members, or objects, or with objects mediating interpersonal interactions (aarsand, 2007; iannaccone, 2015) ; as part of promenades in the urban, countryside, or institutional environment (badey-rodriguez, 2003; guglielmetti, 2015; mallon, 2005; meijering & lager, 2014) ; as activities of learning, working, gardening, exercising (humberstone & cutler-riddick, 2015; stenner et al., 2012) ; or as encounters with representatives of institutions, such as doctors or care practitioners (meijering & lager, 2014; mortenson et al., 2016; sarason, 2011; wapner et al., 1990) . hence, most aspects of daily life, from walking on the beach to remembering one's childhood, have been approached microgenetically (butler, 1963; gubrium & holstein, 1999; lieblich, 2014) . studies have recently proposed to consider these socio-material environments as part of the conditions or the arrangements enabling life, such as for instance in studies on the "landscape of care" (milligan & wiles, 2010) . more generally, the invitation is to pay a close attention to the actual social, material, technical, spatial environments or "ecologies" of older people's lives, and to study the dynamic of their mutual co-constitution (säljö, this issue) . from the perspective proposed here, the socio-materiel environments are thus the settings in which people may support, or develop their spheres of experiences. these microgenetic dynamics are, we believe, key-elements to document and understand the experience of becoming and being older; but we also claim that a sociocultural psychology of growing older can only be achieved by combining these dynamics with an understanding of the sociogenetic movement involved, and by preserving the unique perspective and experience of the person unfolding in time through ontogenesis. considering ageing as part of people's lifecourses from a triple socio-, onto-and microgenetic perspectives has the advantage of being integrative, but is not specific to older people's life. our main theoretical innovation lies in the identification of the specificities of development in the life of older people, first in a rapidly changing environment, and second, as a result of life experiencing. the evolutions noted above create new life conditions for older people; as the generation of baby-boomers becomes older, we observe the making of new societal configurations. on the one hand, the societal and institutional conditions of living when growing older may differ across places. life settings may radically vary, depending on local socioeconomic living conditions (abramson, 2015) , or at the scale of nation-states. a recent international comparison thus shows that location (i.e., specific region/state) is the best explanation for variations in factual conditions of living and in the self-evaluated quality of life in older people, all others variables being controlled (stewart et al., 2018) . some national retirement systems make life difficult; others systems, which may appear better, have however for long privileged sending older people to retirement homes located at the periphery of cities or in the countryside, de facto marginalizing and excluding older citizens from the social arena. on the other hand, however, these social and geographical inequalities are themselves in transformation. institutional movements start to develop measures to fight against this tendency, for instance by rearrangements of the urban space to facilitate the mobility of frailer people, by developing intergenerational housing options (for instance in many swiss cities) or by creating new city spaces to support meaningful engagement of older citizens (e.g., "the old people's playground project" in london [perry & blason, 2016] ). as these conditions are rapidly growing, we have to keep a special attention on these: first, the existing or newly designed conditions may not correspond to what people getting older use to expect for their older age when they were younger. for instance, in many eastern european countries, people grew up in three-generation houses with a grand-parent, and may have expected the same for themselves when they would reach the same age. however, with the rapid urbanization and professional mobility, this expectation is often not met, adding thus to the solitude of older people the disappointment of betrayed expectations. in contrast, in urban centres, people who may have feared growing old alone may now find new shared housing for older citizens, beneficiating from new and unexpected options. second, the social categories of "older people" are also rapidly diversifying, some of them being the object of public discourses: there is currently a heightened sensitivity to gender inequalities, due to fact that former baby-boomers who may have had unconventional lifestyles now access older age; there is also an increased presence of an ageing migrant population. these "new olds", unequally social and geographically located, encounter national and institutional evolutions that were frequently designed without their active participation and that are currently evolving. not only does society try to render meaningful the increase of older citizens, but older people have also a need to make sense of becoming older in this rapidly changing society, and to take part in reshaping it, with or without the younger generation. as the younger generations shape their own present and future living conditions, society would have everything to gain if they could do so in an inclusive, participative and dialogical way. older people have the specificities of having a longer life experience and often of being released from engaging daily activities. this has some implications. first, having lived longer lives, older people are more likely to have lived through more spheres of experiences, and more reconfiguration of spheres of experiences than younger people: many family or friend-related experiences, numerous professional situations, situations related to social life, events related to leisure activities, diverse cultural events. they may have witnessed the slow transformation of some of their spheres of experience and their relatedness with social changes, for instance through technological, economic, political, and cultural changes; they may have lived many ruptures, as some spheres disappeared, and others appeared. going through these many experiences and changes, people may have learned from experience something valuable not only for them as individual persons, but for other related persons, and for the society in which they are engaged. for example, they may have developed more nuanced ways to address loss and newness, to handle the daily life and exceptional events, to deal with emotions and make sense of it. this may be called "learning from experience" (bion, 1989) , or also, the development of personal life philosophies (valsiner, 2007; van der veer & valsiner, 1993, p. 16; zittoun et al., 2013 ) (comparable intuitions have been addressed by the notion of "wisdom" in psychology [baltes, 2004; baltes & kunzmann, 2004] ). this may thus become people's life motives (thomae, 1968) , "practical wisdom" and engagements (hviid, 2020) , or "melodies of living" (zittoun et al., 2013) . second, as people lived their lives, they may precisely have had the opportunity to experience many and diverse social changes and transformations as well: they lived through wars, economic crises, massive population movements, radical innovations, or political transformations. experiencing first-hand sociogenetic dynamics as they were themselves developing may have brought them to identify historical or societal patterns of change, evolutions, or on the contrary, to radically change their views on the world. they may thus have developed "personal world philosophies" colouring their interpretation of social histories as well as their understanding and participation in social life (de saint-laurent, 2017) . depending on these two aspects (the development of personal life, and world philosophies) people becoming older may diversely engage in, or maintain activities that are meaningful to them and society. if we try to develop more general understandings of ageing, we thus need to consider the tensions between the developing persons and their evolving environment (and not only the person's functions or psyche), and to account for the diversity of dynamics taking place. at one extreme, we may hypothesize that some older people have strong engagements within their spheres of experiences, to which they confer sense, and a clear orientation to the future; they also may have learned to read patterns in the social world. as a result, they may actively engage in, and create activities in which they find sense, inclusion and purpose, and feel that they can participate to societal changes. this is for instance the case of older people engaging in political action (caissie, 2011) , as also exemplified in the case-study reported by pernille hviid (2020) . at another extreme, older people may have developed negative representations of institutions and the social world, which, they feel, have closed down their opportunities to participate; excluded from social life, with spheres of experience that may be less satisfying, the may have very little occasions to produce meaningful activities and therefore to develop imaginations of their future. this is for instance the case of retiree in serbia for which socioeconomic conditions are de facto marginalizing. finally, somewhere in between, people may be more or less satisfied with their social world, while having a set of good-enough engagements; thus, they may maintain a sense of orientation toward the future and create new sphere of experience even in relatively constraining situations. such position is exemplified by the cases of people living in the retirement home who may find spaces of imagining and creating in the relatively limited zone of free movement left to them (zittoun et al., this issue) . identifying how older people's development emerges out of specific sociocultural environment may thus invite us to reflect on the condition that may facilitate life engagements and meaningfulness. our societies are largely changing in terms of structure of the population and economical balances, at a period where ecological and political challenges are everyday more present. the reality of the ageing of the population is undeniable, and societies expect a rapid increase of the proportion of older people in good health, ready to engage in meaningful living, even though they are excluded (or liberated) from active professional life. older age thus constitutes the future of most of us. it is therefore not only a theoretical imperative, but an ethical one as well, to include older persons in our society. we need to empower them and secure their involvement and voice in (re)shaping institutions and policies that have significant implications for their quality of life, as well as for the future courses of lives of others. this imperative is based on two key arguments. on the one hand, older people have the right to keep developing and live meaningful lives. on the other hand, and more specifically, they are also de facto the ones with the longest life experience, and are likely to remember the past, to have learned from the changing world, and from their own course of life. they may have much to contribute to our current and future situations, and it may be essential for our societies to rely on their experiences and philosophies as well. as a consequence, as social scientists and educational researchers, as well as citizens, it is necessary to create conditions of participation, in which people can pursue meaningful lives, manifest, use and share their life experience, and become producers of the institutional conditions of their living. while we have been finalizing this paper, the covid-19 pandemic has transformed the everyday life of almost all people in the world, both in terms of their activities and their social relationships. it is especially true for the persons of older age since they have been recognized as sensitive group of citizens in many countries. consequently, they have been the object of various sets of policies and practices related to the covid-19 pandemic. in order to protect them, sanitary measures have resulted in social isolation, and interdiction to engage in the daily activities and social relationships through which their main engagements take place. most older people had to question their projects and modes of lives; some were dramatically touched in their physical and mental health. in addition, in many countries, intergenerational resentment has been observed. one way or another, the great majority of older people have mostly been excluded from the debate and discussions related to their place and status during the crises -only the boldest have intervened in the media. at this point in time (august 2020), it is hard to predict how the covid-19 pandemic will transform ageing in many societies. however, this dramatic situation provides a strong case for the main thesis of our paper, illustrating how the three processes of social transformation, everyday interaction and the courses of life are intertwined, creating a knot of unique experiences demanding new forms of learning and development for many elderly persons around the world. computer and video games in family life. the digital divide as a resource in intergenerational interactions the end game: how inequality shapes our final years 50 years of cognitive aging theory aging, neighborhoods, and the built environment. handbook of aging and the social sciences ageism: a threat to "aging well" in the 21st century un portrait vivant d'octogénaires d'aujourd'hui la vie en maison de retraite: comprendre les résidents, leurs proches et les soignants old age: definitions, theory, and history of the concept wisdom as orchestration of mind and virtue. unpublished manuscriptberlin the two faces of wisdom: wisdom as a general theory of knowledge and judgment about excellence in mind and virtue vs. wisdom as everyday realization in people and products how theories of aging became social: emergence of the sociology of aging qui sont ces nouveaux analysants de plus de 70 ans? quel est leur désir beyond appearances: perspectives on identity in later life and some implications for method learning from experience handbook of the psychology of aging cultures of care in aging making stories: law, literature, life successful ageing: a historical overview and critical analysis of a successful concept the life review: an interpretation of reminiscence in the aged storying later life: issues, investigations, and interventions in narrative gerontology la nouvelle vague argentée age discrimination. encyclopedia of quality of life and well-being research social interactions in multicultural settings cultural psychology. a once and future discipline narrative inquiry: a dynamic approach trajectories of resistance and historical reflections logic: the theory of inquiry performances et défaillances du sujet âgé: étude anthropologique des recherches sur le vieillissement cérébral psychological development as social process time, human agency, and social change: perspectives on the life course the craft of life course research expansive learning on the move: insights from ongoing research/el aprendizaje expansivo en movimiento: aportaciones de la investigación en curso identity and the life cycle storying later life: issues, investigations, and interventions in narrative gerontology life course research. development of a field what can be said? identity as a constraint on knowledge production the culture of long term care: nursing home ethnography storying later life: issues, investigations, and interventions in narrative gerontology the nursing home as a discursive anchor for the ageing body enquête ethnographique auprès d'une maison de retraite du canton du tessin. unpublished master's thesis. switzerland: university of neuchâtel, neuchâtel (old stories of objects and people. an ethnographic study of a retirement home in the canton of ticino) travail d'adolescence, travail du vieillir ménégoz, m. (productor) (2012). amour. [motion picture]. france and austria: les films du losange successful aging studying children: a cultural-historical approach older women, embodiment and yoga practice aged experience -a cultural developmental investigation. learning, culture and social interactionarticle 100386 ruptures and repairs in the course of living: challenges to developmental psychology les plus de 65 ans pianotent, eux aussi, sur les claviers|canal alpha [canal alpha the principles of psychology ageing with disability. a lifecourse perspective aging mind: facets and levels of analysis older learning engagement in the modern city narratives of positive aging: seaside stories identity, old(er) age and migrancy: a social constructionist lens memory practices and learning: interactional, institutional, and sociocultural perspectives vivre en maison de retraite : le dernier chez-soi me, myself, and god: religion as a psychocultural resource of meaning in later life the dialogical mind: common sense and ethics home-making of older antillean migrants in the netherlands landscapes of care no place like home? surveillance and what home means in old age theories of memory and aging: a look at the past and a glimpse of the future collected papers of charles sanders peirce never too old to play: playgrounds for the elderly -in pictures. the guardian health inequalities among older adults in developed countries: reconciling theories and policy approaches vieillir: une découverte the cambridge handbook of sociocultural psychology lgbq-specific elderly housing as a "sparkling sanctuary": boundary work on lgbq identity and community in relationship to potential lgbq-specific elderly housing in sweden handbook of theories of aging development, ageing and hybrid minds: growth and decline and ecologies of human functioning in a sociocultural perspective centers for ending. the coming crisis in the care of aged people from describing to reconstructing life trajectories: how the tea (trajectory equifinality approach) explicates context-dependent human phenomena sampling reconsidered: idiographic science and the analysis of personal trajectories the stranger: an essay in social psychology human-landscape relations and the occupation of space: experiencing and expressing domestic gardens older people and 'active ageing': subjective aspects of ageing actively comparison of self-rated and objective successful ageing in an international cohort an introduction to gerontology critical psychology: a geography of intellectual engagement and resistance das individuum und seine welt life-span psychology: research findings and development on aging. learning human development as migration. striving towards the unknown open intransitivity cycles in development and education: pathways to synthesis the oxford handbook of culture and psychology an invitation to cultural psychology dynamic process methodology in the social and developmental sciences la puissance du vieillir thought and language the collected works of l cultural psychology and its future: complementarity in a new key cherished possessions and adaptation of older people to nursing homes mind as action playing and reality activity theory as a framework to analyze technology-mediated elderly care vygotsky's notebooks. a selection a sociocultural psychology of the life-course life-creativity: imagining one's life integrating experiences: body and mind moving between contexts imagination in human and cultural development creativity, imagination and self-continuity in the transition into a nursing home. learning making of the future: the trajectory equifinality approach in cultural psychology human development in the lifecourse. melodies of living this article has been written thanks to an earli e-cir grant, called agile (ages for learning and growth: sociocultural perspectives) which could meet for three years. key: cord-331065-tzvkj2rm authors: terracciano, antonio; stephan, yannick; aschwanden, damaris; lee, ji hyun; sesker, amanda a; strickhouser, jason e; luchetti, martina; sutin, angelina r title: changes in subjective age during covid-19 date: 2020-08-07 journal: gerontologist doi: 10.1093/geront/gnaa104 sha: doc_id: 331065 cord_uid: tzvkj2rm background and objectives: to examine change in subjective age with the emergence of coronavirus disease 2019 (covid-19). two competing hypotheses were tested: (a) people felt increasingly older due to the stress generated by the pandemic; (b) people felt increasingly younger due to psychological distancing from older age, a vulnerability to covid-19. research design and methods: an age and sex stratified sample of adults from across the united states (baseline n = 3,738) was assessed on three occasions: before the covid-19 outbreak in late-january/early-february and during the outbreak in late-march and again in late-april. multilevel modeling analysis examined change in subjective age and tested potential moderators of individual differences in the trajectory of subjective age. results: the average trajectory of subjective age followed a concave curve, with a nadir (feeling younger) during the second assessment in late-march. older age, negative expectations about aging, absence of pre-existing conditions, and less stress during covid-19 were associated with feeling younger but did not predict the rate of change. the only significant predictor of change in subjective age was the belief that the “coronavirus is only a threat to older adults”: the more individuals agreed with this statement, the more likely it was that they felt increasingly younger at follow-up. discussion and implications: subjective age changed during a global health crisis, with people feeling younger with the emergence covid-19. the findings support the hypothesis that subjective age partly reflects a coping process of psychological distancing from older age, the age group most vulnerable to covid-19. the impact of the coronavirus disease 2019 pandemic (world health organization, 2020) is evident in all age groups and at every age there are large individual differences, but the risk of severe health consequences and death from covid-19 has been particularly high for older adults, as well as individuals with underlying health conditions, males, and people from racial and ethnic minorities and low-income communities (garg et al., 2020; onder, rezza, & brusaferro, 2020; richardson et al., 2020) . in the united states, for example, the centers for disease control and prevention (cdc) reports that the rate of hospitalizations and fatality from covid-19 increase dramatically with age and are highest among adults older than 85 years (cdc covid-19, 2020; garg et al., 2020) . further, the white house "15 days to slow the spread" guidelines explicitly recommended that "if you are an older american, stay home and away from other people" (white house, 2020) . as such, discussions about age have been at the forefront during the covid-19 pandemic. the present study examined changes in how people perceived their own aging in the context of the covid-19 pandemic. specifically, we tested whether subjective age, that is how old or young individuals feel relative to their chronological age, changed with the emergence of the covid-19 crisis in the united states. examining potential changes in age identity is particularly relevant during this global health disaster because covid-19 poses disproportionate risks for older adults and because gerontologists have raised the alarm that "with the pandemic there has been a parallel outbreak of ageism" (ayalon et al., 2020) . subjective age is conceptualized as a biopsychosocial marker of aging that is sensitive to biological, clinical, and psychological changes (barrett & gumber, 2020; bellingtier, neupert, & kotter-grühn, 2017; stephan, sutin, & terracciano, 2015a; thyagarajan et al., 2019) . a growing literature indicates that individuals who report feeling younger tend to a c c e p t e d m a n u s c r i p t 5 perform better on physical and cognitive measures, have fewer depressive symptoms and less negative affect, have more favorable ratings of health and functional status, and live longer (barrett & gumber, 2020; bellingtier et al., 2017; rippon & steptoe, 2018; thyagarajan et al., 2019) . a younger felt age may also reflect a self-protective strategy that is used to distance and protect oneself from negative information and stereotypes about aging (kornadt, hess, voss, & rothermund, 2018; montepare & lachman, 1989; weiss & lang, 2012) . the dynamic, developmental processes that determine one's felt age are likely to incorporate external societal influences with internal evaluations of one"s aging (barrett & montepare, 2015; hess et al., 2017; westerhof, whitbourne, & freeman, 2012) . while there is a growing literature on the factors that moderate how old individuals feel, there has been relatively less experimental work or natural experiments, such as changes in the trajectory of subjective age with the exposure to a major stressor. there is, however, evidence on the malleability of subjective age. subjective age, for example, has been found to change in the short term in experimental studies (hughes, geraci, & de forrest, 2013; stephan, chalabaev, kotter-grühn, & jaconelli, 2013) , as well as over long periods in longitudinal observational studies (kornadt et al., 2018; ward, 2013) . to our knowledge, there are no published studies that have examined changes in subjective age with the emergence of a health disaster that is lifethreatening and has brought significant social and economic changes. we had two competing theoretically-informed hypotheses for how subjective age might change with the emergence of covid-19. first, a stress-related hypothesis predicts that individuals will feel older over time in response to the stress and losses due to covid-19. even on a day-to-day basis, research based on daily diary design indicates that older adults report feeling older on days when they experience more stressors or negative affect (kotter-grühn, neupert, & stephan, 2015) . over m a n u s c r i p t 6 time, family adversity and health-related stressors can erode psychological resources, increase psychological distress, and contribute to an older subjective age (bellingtier et al., 2017; foster, hagan, & brooks-gunn, 2008; keyes & westerhof, 2012; schafer & shippee, 2010) . prolonged exposure to stressful conditions or traumatic experiences have also been associated with accelerated subjective aging (avidor, benyamini, & solomon, 2016; kotter-grühn, kornadt, & stephan, 2016; palgi et al., 2019) . building upon the "weathering" hypothesis (geronimus, 1992) , palgi (2016) has argued that an older subjective age may emerge when exposure to stressful or traumatic conditions demand cognitive, social, physical, and mental resources that are beyond the person"s current resources. for example, research on individuals living in areas exposed to ongoing rocket attacks found that posttraumatic stress syndrome is related to an older subjective age (avidor et al., 2016; palgi et al., 2019) . second, a distancing hypothesis predicts that people will feel younger over time because they may psychologically distance themselves from older adulthood, an age group at higher risk of covid-19. this hypothesis is based on a conceptualization of a younger subjective age as a self-protective strategy that defends against the risks and stigma associated with growing older (kornadt et al., 2018; weiss & lang, 2012) . experimental research found that when individuals are exposed to negative age-related information, they react by distancing themselves from their age-group and their chronological age, resulting in a younger subjective age (weiss & freund, 2012; weiss & lang, 2012 the primary scope of the study was to examine the trajectory of subjective age in the context of covid-19 with longitudinal data from a nation-wide sample of americans aged 18 to 100 years. we assessed participants before and during the outbreak of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) in the united states with three waves of data collection from late january to late april. we tested two competing hypotheses (a) that the covid-19 related stress will lead people to feel older, and (b) that the distancing from aging as a vulnerability to covid-19 will lead people to feel younger. to further understand the impact of covid-19 and test the two competing hypotheses, we examined five individual-level predictors that may moderate the direction and rate of change in subjective age. the first moderator was a measure of stress during the pandemic. consistent with the stress-related hypothesis (avidor et al., 2016; kotter-grühn et al., 2016; kotter-grühn et al., 2015; palgi et al., 2019) , we expected that individuals who reported more stress would experience larger changes in the direction of feeling older compared to people who report less stress. the second and third moderators were negative expectations about aging and the belief that the coronavirus is only a threat to older adults. consistent with the distancing hypothesis (weiss & freund, 2012; weiss & lang, 2012) we expected that more negative views of aging and belief that threat of covid-19 was limited to older adults would lead to greater distancing and therefore larger changes in the direction of a younger subjective age. because federal guidelines indicate that older adults and individuals with pre-existing conditions are at higher risk for covid-19, we tested chronological age and disease burden as two additional moderators. in terms of magnitude, we expected changes in subjective age will be larger in older and less healthy participants. regarding the direction of change, being a member of a group identified as having increased vulnerability to covid-19 (cdc covid-19, 2020; garg et al., 2020) could lead to either heightened stress and an older subjective age or to greater distancing and a younger subjective age. besides testing chronological age as a a c c e p t e d m a n u s c r i p t 8 potential moderator, we conducted a sensitivity analysis by excluding individuals younger than 50 years because subjective age could be less salient for some younger individuals and they may confound the pattern of changes in older adults. while covid-19 could have more detrimental effect on older adults, a recent systematic review indicates that older adults do as well as younger populations on health outcomes after disaster exposure (bell, horowitz, & iwashyna, 2019). participants were adults aged 18 years or older living in the united states. they were recruited through dynata (www.dynata.com) and asked to complete an online qualtrics survey administered by florida state university. the sample was stratified for age and sex and included individuals across all 50 states as well as washington dc and puerto rico. respondents were compensated for their participation, with an additional incentive of 50% and 75% at wave 2 and 3, respectively, to enhance retention. respondents were excluded from the analyses if they did not consent to the study, took less than 5 minutes to complete the survey (the overall survey took approximately 25 minutes), for evidence of careless responding (e.g., demographics did not match across assessments or gave the same answers across all items of questionnaires), had missing data on subjective age, or had answers more than three standard deviations above and below the mean on subjective age. pre-registration of data collection can be found at https://osf.io/vqnh8. the preregistration did not include the wave 3 assessment or the analyses reported in this manuscript. a c c e p t e d m a n u s c r i p t 9 the longitudinal study design consisted of three assessment waves. the aim of the first wave of data collection was unrelated to covid-19. the second and third waves sought to address covid-19 research questions. the first wave of data collection occurred between january 31 and february 10, 2020 when the known spread of sars-cov-2 in the united states was limited. the second wave occurred between march 18 and march 29, 2020 when the number of sars-cov-2 positive cases increased exponentially. our wave 2 assessment was also during the white house"s "15 days to slow the spread" (white house, 2020) campaign that aimed to reduce the spread of sars-cov-2, especially among vulnerable groups. our wave 3 assessment occurred between april 23 and april 29, when the number of sars-cov-2 positive cases appeared to have reached a plateau in the united states (cdc, 2020a). during wave 3, the federal guidelines were still in effect and most states and local governments had issued stay-at-home orders. subjective age. at each wave, individuals were asked to indicate how old they feel in years ("many people feel older or younger than they actually are. what age do you feel?"). participants could select an age from a scroll down list. a proportional discrepancy score was computed as (felt age -chronological age)/chronological age (rubin & berntsen, 2006; stephan, sutin, caudroit, & terracciano, 2016) . to provide more precise coefficient estimates, we multiplied the proportional discrepancy by 100. a negative value indicated a younger subjective age, whereas a positive value indicated an older subjective age. a c c e p t e d m a n u s c r i p t coronavirus is only a threat to older adults" were assessed on a scale from 1= strongly disagree to 5 = strongly agree. at wave 2, negative expectations about aging were assessed using four items from the expectations regarding aging survey (sarkisian, steers, hays, & mangione, 2005) . the instructions stated: "the following questions are about what you expect about aging. please select the response below that best corresponds with how you feel about each statement" with the following items: "when people get older, they need to lower their expectations of how healthy they can be", "i expect that as i get older, i will spend less time with friends and family", "being lonely is just something that happens when people get old", and "as people get older, they worry more". response options were 1 = definitely true to 4 = definitely false; the alpha was 0.71. disease burden was assessed at wave 1. participants were asked (yes/no) "has a doctor ever told you that you have: asthma, chronic respiratory disease, diabetes, high blood pressure, heart conditions, kidney disease, liver disease". participants also reported their weight and height, which was used to derive body mass index (bmi) and obesity (bmi ≥ 30). consistent with cdc reports, having one or more of these conditions increases risk for severe complications of covid-19 (cdc, 2020b) . those with 1+ condition(s) were compared to those with no conditions. demographic covariates. the demographic covariates included age in years and gender coded as -.5 for male and .5 for female. education was assessed on a scale from "less than high school" to "phd or equivalent" and was coded into years of education. self-identified race and ethnicity were coded with three dummy variables for african americans, latinx, and others (others included asian and pacific islanders, individuals who reported other race, "prefer not to answer", or had missing data); white respondents were the reference group. means and percentages were used to provide basic descriptive statistics. for attrition analyses, we used t-tests or ancova for continuous variables and χ 2 for categorical variables to compare individuals with and without follow-up data. multilevel modeling (mlm), also known as hierarchical linear modeling or mixed-effects models (grimm, ram, & estabrook, 2016; raudenbush, bryk, & congdon, 2004) , was used to determine the trajectory of subjective age across the three waves. mlm is a flexible approach for longitudinal analyses that uses all available data. the mlm analytic framework uses the full information maximum likelihood (fiml) estimation procedure. instead of imputing missing data, fiml estimates population parameters that maximizes the likelihood function based on the incomplete longitudinal data. for instance, participants with data from less than three waves were included in the analyses. continuous variables were grand mean centered. the models estimated both fixed effects (sample means) and random effects (individual deviations from the means). we tested both a linear and a quadratic model to identify the overall trajectory of subjective age. we then tested the moderators as predictors of individual differences in the intercept and slope of subjective age, accounting for demographic covariates. all predictors were entered simultaneously. in sensitivity analyses we excluded individuals younger than 50. in an additional sensitivity analysis, we used inverse probability weighting to examine the impact of attrition, which is particularly likely in a sample that was not originally recruited for a longitudinal study. the probability of being a complete case (those with follow-up data) was generated from a logistic regression using the demographic variables as predictors. the inverse of the probability was then used as a weight in mlm, so that individuals who were likely to drop out were weighted more and individuals who a c c e p t e d m a n u s c r i p t 12 provided follow-up data were weighted less. the analyses were performed using linear mixed models in spss 26. the sample characteristics at each wave are shown in table 1 . a total of 3,738 participants had valid subjective age data at baseline and 2,064 and 1,715 provided valid data again at waves 2 and 3, respectively, for a total of 7,517 observations. attrition analyses the basic descriptive statistics are reported in table 1 and the correlations between baseline subjective age and the five moderators assessed at either wave 1 or 2 are reported in table 2 . the mean values reported in table 1 indicated a decline in subjective age discrepancy between wave 1 and 2 (i.e., a younger subjective age at wave 2); there was little difference between wave 2 and 3. a decline in subjective age was also found in the basic that 68% of the total variance in subjective age was between persons. next, we added a quadratic term to the model (-2 log likelihood = 66,272) and found that time (β = -4.10, se = 0.75, p < .001) and time*time (β = 1.62, se = 0.38, p < .001) were both significant predictors (random effects: within-subject variance = 176.13, se = 4.21, p < .001; betweensubject variance = 382.20, se = 11.93, p < .001). these coefficients indicate that subjective age followed a concave curve (figure 1) , with an estimated subjective age discrepancy of -9.32 at wave 1 (january/february), -11.80 at wave 2 (late-march), and -11.03 at wave 3 (late-april). as reported in table 3 (model 1), the linear and quadratic terms remained significant after including the demographic covariates in the model (-2 log likelihood = 65,894). among the covariates, older age, higher education, and african american race were associated with feeling younger. the random effects (within-subject variance = 176.04, se = 4.20, p < .001; between-subject variance = 336.34, se = 10.83, p < .001) remained significant and a comparison between the models [(382.2-336.34)/382.2] indicate that the demographic variables explained 12% of the between subject variance in subjective age. we repeated the analysis by restricting the sample to adults older than 50 and found that the linear and quadratic terms remained significant. the sensitivity analysis with inverse probability weighting also found that the linear and quadratic terms remained significant. overall, the basic descriptive statistics and the mlm model indicate a concave curve with a nadir at wave 2 (feeling the youngest during the covid-19 crisis in late-march), followed by a slight change toward the baseline level at wave 3. we next examined potential predictors of individual differences in the trajectory of subjective age. given that the largest changes occurred between the first two waves, we focused the analysis on change between wave 1 and wave 2. we tested the five moderators (age, disease burden, negative expectations about aging, "coronavirus is only a threat to older adults", and stress) in one model that included data from the first two waves, the a c c e p t e d m a n u s c r i p t 14 demographic covariates, and the main effects and interactions with time of the six variables. table 3 (model 2, -2 log likelihood = 35,744), the only significant predictor of change in subjective age was the question the "coronavirus is only a threat to older adults": the more individuals agreed with this statement, the more likely it was that they felt increasingly younger at wave 2 compared to wave 1. although no other variable predicted the rate of change (i.e., the interactions between time and the moderators) in subjective age, significant main effects indicated that on average individuals who were older and with more negative expectations about aging were more likely to feel younger, whereas respondents who reported at least one health condition or more stress were more likely to feel older. compared to a model without moderators, the model with moderators accounted for 19% of the variance of the slope parameter (i.e., explained 19% of individual differences in the subjective aging trajectory). because of overlap among the moderators, we repeated the analyses and found that the association of "coronavirus is only a threat to older adults" with the slope of subjective age was confirmed in a model with no other moderators. this study tested competing hypotheses on the trajectory of subjective age in the context of the covid-19 pandemic. compared to an assessment conducted before the outbreak in the united states, we found that respondents felt younger in the midst of the covid-19 crisis. specifically, we found a concave trajectory with a nadir (people felt youngest) in late-march, during the acute phase of the covid-19 crisis and partially revert toward the baseline level in late-april. we had two hypotheses for how subjective age would change with the pandemic: either people would feel older due to the stress of the pandemic or people would feel younger as a psychological defense mechanism against old age because it is a risk factor for a c c e p t e d m a n u s c r i p t 15 complications of covid-19. the results are more consistent with the distancing hypothesis than the stress-related hypothesis. at the time of the second assessment, there was consistent and pervasive messaging from the media (garfin, silver, & holman, 2020) , the cdc (2020b), other public health authorities (united nations, 2020), and by government guidelines (white house, 2020) that advanced age was a major risk factor for hospitalization and death due to covid-19. the changes in subjective age may represent a defense mechanism, a self-protective process of psychologically distancing oneself from the vulnerability associated with older age during covid-19. this interpretation is consistent with past experimental work (weiss & freund, 2012; weiss & lang, 2012) and was further supported by the finding that the changes were larger for people who believed that the coronavirus was only a threat for older adults. furthermore, the precautions taken to reduce the risk of covid-19 could lead to a more age-segregated society with fewer opportunities for intergenerational contacts. following the recommendations from authorities (white house, 2020) , some older adults could be especially isolated, even from friends and family members who want to avoid the risk of infecting their older friends and relatives. while phone or video calls are potentially helpful (noone et al., 2020) , social distancing is likely to reduce the in-person interactions across generations. as suggested by the intergroup contact theory (allport, 1954) , such reduced intergroup contact could result in worse intergroup attitudes and more ageism (drury, hutchison, & abrams, 2016; lytle & levy, 2019 ) that could lead to even more distancing. it is also worth observing that this hypothesized process of psychological distancing was occurring at a time when physical (or social) distancing was an emblematic and crucial component of the covid-19 response. in contrast, our findings were not consistent with the competing hypothesis that the covid-19 related stress would induce people to feel increasingly older during the pandemic. at the individual level, we found that higher stress was associated with an older subjective a c c e p t e d m a n u s c r i p t 16 age, but the level of stress during the covid-19 crisis was unrelated to change in subjective age. while there are numerous differences between the current and past studies that make comparisons difficult, our findings were generally not consistent with studies that linked post-traumatic experiences to an older subjective age (avidor et al., 2016; palgi et al., 2019) . cross-sectional evidence, however, also suggests no significant association between major life events, such as death of a friend or a close family member, and subjective age (bellingtier et al., 2017; schafer & shippee, 2010) . more research is clearly needed to fully understand the similarity and differences on the impact of personal, health-related, and conflict-related stressors and traumas on subjective aging. we considered two specific hypotheses, but it is likely that other factors may have contributed to our findings, such as social comparison processes. more favorable assessments of one"s health relative to others, for example, is related to a younger subjective age over time (hughes & lachman, 2018) . it is possible that individuals may have felt younger during the pandemic because they may have more favorably re-evaluated their health compared to people affected by covid-19. note, however, that we found disease burden related to the intercept but unrelated to the rate of change in subjective age. the life changes brought by the physical distancing measures and stay-at-home orders could be another potential factor that contributes to the trajectory of subjective age. for example, some students had to move back in with their parents, many adults had to work from home in less formal settings, some were suddenly unemployed, and parents had to spend more time with their kids instead of other adults. all these experiences could contribute to feeling younger. the group-level pattern of changes should be considered along with the heterogeneity of responses to the pandemic, which may vary according to individual differences and the level of exposure to covid-19 (aschwanden et al., 2020; luchetti et al., 2020) . regarding individual differences, we found that the belief of coronavirus being only a threat for older a c c e p t e d m a n u s c r i p t 17 adults was a significant moderator of the change in subjective age, but other relevant factors were not significant predictors of the slope. still, and consistent with the broader literature (e.g., avidor et al., 2016; rubin & berntsen, 2006; weiss & freund, 2012) , we found an older chronological age, more negative age expectations, less stress, and the absence of disease were associated with feeling relatively younger (i.e., effect on intercept). of course, there are other potential variables that could explain how different groups react to similar situations. regarding the level of exposure, while the covid-19 crisis had an impact on the entire population, some people were more directly impacted compared to others, which could contribute to significant differences on the direction and magnitude of the changes in subjective age. for example, people ill with covid-19 may feel older. given that subjective age is relatively stable and that many factors contribute to a person"s age identity, change in subjective age during the covid-19 crisis should be relatively modest. it is of note then, that the changes we found over a few weeks were comparable to changes observed over three (wurm, wiest, wolff, beyer, & spuling, 2019 ) to ten years (stephan, sutin, & terracciano, 2015b) . the present study has several strengths, including the longitudinal assessment of subjective age before and during a major health crisis that provides a prospective test of the study hypotheses. while not necessarily representative of the us population, the nation-wide sample was large and stratified by age and sex and oversampled for african americans. however, like for many longitudinal studies, the attrition may reduce generalizability of the findings. individuals with follow-up data were more likely to be older, white men with higher education. we cannot exclude that the pattern of change in subjective age during covid-19 could be different for the groups that were more likely to drop out of the present study, including younger individuals, women, and persons with lower education or from racial and ethnic minorities. however, while we lost to follow-up mostly younger adults, age did not a c c e p t e d m a n u s c r i p t 18 moderate the rate of change in subjective age. furthermore, the results were similar in a sensitivity analysis with inverse probability weighting. the findings are also limited to the united states and it remains to be tested whether the response to this pandemic varies across cultures (krendl & pescosolido, 2020; weiss & zhang, 2020) . we used a common measure of subjective age, but age identity is a multidimensional construct (kastenbaum, derbin, sabatini, & artt, 1972; kornadt et al., 2018) , and response to covid-19 could be stronger for some facets, such as physical subjective age or subjective age in the health domain. the use of single item measures or a brief scale for the moderators was another limitation of the study. while we focused on the changes in subjective age with the emergence of the pandemic, it is likely that a younger subjective age could function as a "buffer" against the threat of sars-cov-2 and reduce the risk for adverse psychological and health outcomes. in conclusion, the present research provided a rare population-wide test of the effect of a life-threatening crisis on age identity. we found a shift toward a younger subjective age with the outbreak of coronavirus in the united states. in addition to identifying a psychological reaction to the pandemic, the study has implications for gerontological research on the antecedents of age identity (barak & stern, 1986; kotter-grühn et al., 2016; stephan et al., 2015a) and extends the evidence that subjective age reflects, in part, a self-protective strategy from negative aging information and stereotypical representation of older adults (weiss & lang, 2012) . during the early response to the pandemic, feeling younger may reflect a process of distancing from information depicting older adults as vulnerable to a c c e p t e d m a n u s c r i p t m a n u s c r i p t m a n u s c r i p t a c c e p t e d m a n u s c r i p t m a n u s c r i p t 27 m a n u s c r i p t 29 the nature of prejudice psychological and behavioral responses to covid-19: the role of personality subjective age and health in later life: the role of posttraumatic symptoms aging in times of the covid-19 pandemic: avoiding ageism and fostering intergenerational solidarity subjective age correlates: a research note feeling old, body and soul: the effect of aging body reminders on age identity it's about time": applying life span and life course perspectives to the study of subjective age the combined effects of daily stressors and major life events on daily subjective ages coronavirus disease 2019 (covid-19). cases, data, & surveillance people who need to take extra precautions severe outcomes among patients with coronavirus disease 2019 (covid-19) -united states direct and extended intergenerational contact and young people's attitudes towards older adults growing up fast: stress exposure and subjective "weathering" in emerging adulthood the novel coronavirus (covid-2019) outbreak: amplification of public health consequences by media exposure. health psychology hospitalization rates and characteristics of patients looking beyond chronological age: current knowledge and future directions in the study of subjective age feeling old today? daily health, stressors, and affect explain day-to-day variability in subjective age countries and cultural differences in the stigma of mental illness: the east-west divide the trajectory of loneliness in response to covid-19 reducing ageism: education about aging and extended contact with older adults you're only as old as you feel": selfperceptions of age, fears of aging, and life satisfaction from adolescence to old age video calls for reducing social isolation and loneliness in older people: a rapid review patients dying in relation to covid-19 in italy subjective age and perceived distance-to-death moderate the association between posttraumatic stress symptoms and posttraumatic growth among older adults understanding the long-term connections between posttraumatic stress, subjective age, and successful aging among midlife and older adults hlm (version 6) presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area is the relationship between subjective age, depressive symptoms and activities of daily living bidirectional? people over forty feel 20% younger than their age: subjective age across the lifespan development of the 12-item expectations regarding aging survey age identity in context: stress and the subjective side of aging feeling younger, being stronger": an experimental study of subjective age and physical functioning among older adults subjective age and changes in memory in older adults how old do you feel? the role of age discrimination and biological aging in subjective age subjective age and personality development: a 10-year study feeling older and risk of hospitalization: evidence from three longitudinal cohorts how does subjective age get "under the skin"? the association between feeling older or younger than one"s age: the health and retirement study policy brief: the impact of covid-19 on older persons change in perceived age in middle and later life still young at heart: negative age-related information motivates distancing from same-aged people they" are old but "i" feel younger: age-group dissociation as a self-protective strategy in old age multiple sources of aging attitudes: perceptions of age groups and generations from adolescence to old age across china, germany, and the united states the aging self in a cultural context: the relation of conceptions of aging to identity processes and self-esteem in the united states and the netherlands the president's coronavirus guidelines for america: 15 days to slow the spread changes in views on aging in later adulthood: the role of cardiovascular events note: the values in the table are means and standard deviations, if not specified as numbers and percentages. at wave 1, the sample included 552 individuals aged 18-20, 512 aged 21-30 a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord-309885-6sjxi2et authors: maremanda, krishna p.; sundar, isaac k.; li, dongmei; rahman, irfan title: age-dependent assessment of genes involved in cellular senescence, telomere, and mitochondrial pathways in human lung tissue of smokers, copd, and ipf: associations with sars-cov-2 covid-19 ace2-tmprss2-furin-dpp4 axis date: 2020-09-09 journal: front pharmacol doi: 10.3389/fphar.2020.584637 sha: doc_id: 309885 cord_uid: 6sjxi2et background: aging is one of the key contributing factors for chronic obstructive pulmonary diseases (copd) and other chronic inflammatory lung diseases. here, we determined how aging contributes to the altered gene expression related to mitochondrial function, cellular senescence, and telomeric length processes that play an important role in the progression of copd and idiopathic pulmonary fibrosis (ipf). methods: total rna from the human lung tissues of non-smokers, smokers, and patients with copd and ipf were processed and analyzed using a nanostring platform based on their ages (younger: <55 years and older: >55 years). results: several genes were differentially expressed in younger and older smokers, and patients with copd and ipf compared to non-smokers which were part of the mitochondrial biogenesis/function (hspd1, fen1, cox18, cox10, ucp2 & 3), cellular senescence (pcna, pten, klotho, cdkn1c, tnks2, nfatc1 & 2, gadd45a), and telomere replication/maintenance (parp1, sirt6, nbn, tert, rad17, slx4, hat1) target genes. interestingly, nox4 and tnks2 were increased in the young ipf as compared to the young copd patients. genes in the mitochondrial dynamics and quality control mechanisms like fis1 and rhot2 were decreased in young ipf compared to their age matched copd subjects. ercc1 and gadd45b were higher in young copd as compared to ipf. aging plays an important role in various infectious diseases including the sars-cov-2 infection. lung immunoblot analysis of smokers, copd and ipf subjects revealed increased abundance of proteases and receptor/spike protein like tmprss2, furin, and dpp4 in association with a slight increase in severe acute respiratory syndrome coronavirus 2 (sars-cov-2) receptor ace2 levels. conclusions: overall, these findings suggest that altered transcription of target genes that regulate mitochondrial function, cellular senescence, and telomere attrition in the pathobiology of lung aging in copd and ipf is associated with alterations in sars-cov-2 ace2-tmprss2-furin-dpp4 axis as pharmacological targets for covid-19. aging is an important factor influencing the overall lung health and function (wahba, 1983; skloot, 2017) . lung function declines with age after lung maturation. evidences suggest that a significant contribution of various environmental factors influence the aging lung (rojas et al., 2015) . according to the behavioral risk factor surveillance system (brfss) data from 2017, 6.2% (age-adjusted) us adults were reported to have chronic obstructive pulmonary disease (copd) (wheaton et al., 2019) . further, there has been an increasing reports of young copd population visiting for different hospital services (gershon et al. 2019) . aging influences many chronic lung diseases, such as copd, idiopathic pulmonary fibrosis (ipf), and asthma. also chronic lung diseases like asthma and ipf share some of the common yet distinct features compared to copd (maghsoudloo et al., 2020) . environmental stress factors like smoking remains a common influencing factor for the disease progression in all these three cases. cigarette smoke (cs) is one of the strongest contributing risk factors in the pathogenesis of copd along with the decline in lung function (rahman and adcock, 2006) . cellular senescence is a process of irreversible cell cycle arrest, having both beneficial and harmful effects depending on the cell state (birch et al., 2018) . cs plays a role in advancing the lung aging by altering the process of cellular senescence (nyunoya et al., 2006) . several factors including oxidative stress influence the process of cellular senescence. telomeres and mitochondria play a major role in influencing the process of cellular senescence and are often associated with maintaining the lung cellular health (liu et al., 2002; passos and von zglinicki, 2005; birch et al., 2018) . earlier reports from our laboratory and others have shown that smoking and copd is associated with the mitochondrial damage and dysfunction, altering the process of cellular metabolism and function (ahmad et al., 2015; lerner et al., 2016) . similarly, telomere dysfunction was also associated with smoking and copd (morla et al., 2006; de-torres et al., 2017) . mitochondrial and telomere dysfunction also play a causative role in the progression of ipf (povedano et al., 2015; molina-molina and borie, 2018; zank et al., 2018) . several molecular mechanisms were identified in relation to cs causing copd pathogenesis and associated complications (putcha et al., 2015) . cs alters several key cellular functions, among them the crucial genes related to mitochondrial function, cellular senescence, and telomeric length were selected in the current study to observe for any differential changes among young and old age groups categorized as non-smokers, smokers, and copd groups. our previous studies showed independent contributions of these canonical signaling pathways and how they contribute toward the development of premature lung aging in chronic lung diseases, such as copd/emphysema yao and rahman, 2012; ahmad et al., 2017; rashid et al., 2018) . accumulating evidence suggest the close relationship of all these three pathways in influencing lung aging and disease (lee et al., 1998; saretzki et al., 2003; passos and von zglinicki, 2005) . senescent cells are found in many age-related/chronic diseases (tchkonia and kirkland, 2018) . studies from our laboratory showed that mice from different age group when exposed to chronic air and cs influence the process of lung inflammation and senescence. chronic cs exposure in lung epithelial cells and mice increases several markers of cellular senescence (nyunoya et al., 2006; fujii et al., 2012) . recently, it was reported that serum from copd patients can induce senescence in lung epithelial cells (kuznar-kaminska et al., 2018) , giving strength to the importance of this area that needs to be explored further. several dna damaging agents present in smoke, which may activate the dna damage response, thereby influencing telomere function leading to accumulation of senesced cells. however, recent meta-analysis suggests that even though smokers are associated with shorter telomere length, the study implicates that smoking does not accelerate the telomere attrition in leucocytes (bateson et al., 2019) . smoking and copd conditions altered the expressions of many key genes involved in the above three crucial pathways of cellular maintenance. the current study was undertaken to determine the changes in genes related to mitochondrial biogenesis and function, telomere function, and cellular senescence with respect to their age in human lungs. this study is important in unraveling some of the potential biomarkers to differentiate and follow the course of aging in copd. keeping in view the importance of these genes in both copd and ipf, we have also made comparisons between the similar age grouped copd and ipf subjects, using the same set of gene panels. aging is one of the key components, which decides the subject's susceptibility to various diseases and infections presumably due to inflammaging (gardner, 1980) . the recent pandemic of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) was thought to affect more elderly people especially men (bonafe et al., 2020; koff and williams, 2020; sargiacomo et al., 2020) . men with age-related comorbidities have a higher coronavirus disease 2019 (covid-19) mortality rate (zhao et al., 2020) . comorbidities like cardiovascular disease, diabetes, and chronic respiratory diseases present a high mortality rate (emami et al., 2020) . studies involving the role of lung aging and senescence play an important role in understanding the role of the multiple players involved in combating sars-cov-2 infection and can discover potential druggable targets. considering the important role played by some of the crucial receptors and targets in covid-19 (hoffmann et al., 2020) , we determined the protein expression of sars-cov-2 receptor angiotensin converting enzyme 2 (ace2) and aiding proteases like transmembrane protease serine protease-2 (tmprss-2) and spike protein convertase furin in lung homogenates of non-smokers, smokers, copd, and ipf subjects. we also examined the levels of dipeptidyl peptidase 4 (dpp4), the receptor for the middle east respiratory syndrome coronavirus, (mers-cov) (seys et al., 2018) . rigorous and unbiased approaches were used to ensure full and detailed reporting of both methods and analyzed data. the current study was approved for the procurement of the human lung tissues as de-identified tissues by the materials transfer agreement and procurement (institutional review board, irb), and laboratory protocols by the institutional biosafety committee, ibc of the university of rochester medical center, rochester, ny, with project code: drai1 001 protocol: 004, date of approval and irb/ibc approvals 2/11/2017 and 2/7/2018, and 9/29/2017 and 2/ 10/2017, university material transfer agreement (mta) signed on the above dates as well. patients' data or patients are not directly involved in this study as the lung tissues were procured from several agencies (see below). all patients/subjects were of age 21 and above. all methods were carried out in accordance with relevant guidelines and regulations of the university of rochester, rochester, ny. the human peripheral lung tissues from non-smokers, smokers, and copd/ipf were procured/obtained from the ndri (national disease research interchange; the samples were collected from patients with various cause of deaths reported such as cardiac arrest or trauma/accidents, for most of the samples lower peripheral lung lobes were used or as supplied), ltrc (lung tissue research consortium of the national heart lung blood institute, nhlbi), and department of medicine and pathology, and of the university of helsinki hospital, finland as described in our previous reports . the clinical characteristics of the subjects used in the current study are given in table 1 . the subjects were broadly classified into two age groups: young age (≤55 years) group, old age (>55 years) group, as per previous studies (sanchez-salcedo et al., 2014) . although there were some co-morbid conditions reported for the specimens from copd patients (which were on various medications), the tissues were assigned to different groups based on the age, smoking status (current/ex-smokers), and lung disease status (normal vs. smoker's, normal vs. copd) reported during the procurements of the specimens. as described in the above samples, the following samples were obtained in the same way for further disease-wise comparison. additional comparisons were made between copd (8 additional samples from above groups were added in addition to the 24 samples mentioned in table 1 ) and ipf lung samples (3 in young ipf, 13 in old ipf) based on their age to determine for the changes in the same custom gene panel (supplementary table 1 ). total rna was extracted from the human lung tissues stored at −80°c or in rnalater, using direct-zol rna miniprep plus kit (zymo research, r2071) according to the manufacturer's instructions. rna concentration was measured using a nanodrop 1000 (thermo fisher scientific, usa). various genes involved in mitochondrial biogenesis and function, telomere replication and maintenance, and cellular senescence pathways were included in the custom code sets (supplementary table 2 ). the code set contained a total of 112 genes including 6 reference genes (abcf1, hprt, polr1b, rplp0, ldha, gusb) for gene normalization (supplementary table 3 ). the code sets were identified by overlapping the existing panels of the above cellular pathways and the distinct genes were used as described in the code sets. the samples were sent for analysis and processed through the nanostring ncounter system (nanostring technologies seattle, wa, usa). a total of 400-ng rna was submitted after adjusting the samples to a minimum of 20 µg/µl as per the requirements. selected mrna (prepared as mentioned above), which were found to be significantly and differentially altered were further validated for their expression using qpcr (three samples per group, run in duplicates) used in the study as described earlier (maremanda et al., 2019) . the primers were obtained from bio-rad as described below with catalog numbers along with pcr conditions (initial denaturation at 95°c 10 min followed by 40 cylces at 95°c 15 s and 60°c 1 min, fluorescence intensity was measured during the end of 60°c incubation, melting curve analysis was performed after this reaction (65°c for 5 s, and then 0.5°c for 5 s until 95°c total protein assayed by bicinchoninic acid (bca) method were isolated from the lung homogenates of non-smokers, smokers, copd, and ipf in ripa buffer with protease inhibitors, which were reduced and separated using the pre-made polyacrylamide gels (bio-rad) (maremanda et al., 2019) . the transferred membranes were probed for some of the important protein involved in the covid-19, like tmprss2 (ab92323), furin (ab183495), dpp4 (ab28340), and ace2 (ab108252). all the antibodies used in the current study were procured from the abcam and were used at 1:1000 dilution in blocking buffer. the relative expression and equal loading as assessed using the ponceau s staining or b-actin after stripping of the blots. imaging was done using bio-rad chemidoc and blots were analysed using image lab densitometry. nanostring mrna counts were first normalized using the nanostringnorm function in the statistical analysis software r (version 3.6.1) on log2 transformed data. geometric mean of reference genes was used to remove the technical variation and background expression. differential analysis was conducted using linear models in the limma (version 3.44.3) package (r/bioconductor) after adjusting for the gender difference. comparison among different experimental groups were performed using linear contrasts within the linear model framework; moderated t statistics was used to determine the differences in the gene expression levels between groups with empirical bayes approach. the benjamini-hochberg procedure was used to adjust the p values to control the false discovery rates at 5%. the analyzed data was represented in the graphs as y-axis showing the negative log10 p-value and x-axis representing log2 fold change across each pairwise comparisons as described previously . the significantly altered gene data were shown as dot plot representation. four random samples from each age group were used for comparisons among non-smokers, smokers, and copd groups (as given in supplementary table 2) . comparisons with ipf includes all the samples as mentioned in the table 1 and supplementary table 3 . overall, the study consisted of 24 lung tissue samples from different sources as mentioned above. the collected tissues were classified into six different groups based on age, the smoking and disease status. further, comparative gene analysis was also done based on the smoking and disease status irrespective of the age. there were no genes in common that were changed in any of the comparisons involving all the three groups, i.e., non-smokers, smokers, and copd. first, we analyzed differentially expressed transcript levels among young non-smokers vs. young smokers, young smokers vs. young copd and young non-smokers vs. young copd (figure 1) . we found five genes were differentially expressed in young non-smokers vs. young smokers' pairwise comparison. out of five genes, the transcript levels of four genes (nfatc1, nfatc2, gadd45a, and cdkn1a) were decreased and one gene (parp1) was increased in the young smokers as compared to young non-smokers group (figures 2 and 3a ). next, we compared genes differentially expressed in young smokers vs. young copd pairwise comparison. out of five genes, transcript levels of one gene (sirt6) was decreased and the remaining four genes (rad17, cdkn1c, cox10, and klotho) were significantly increased in young smokers as compared to the young copd group (figures 2a and 3b) . finally, we found six genes differentially expressed among young non-smokers vs. young copd group pairwise comparison. out of six genes, the transcript levels of two genes cdkn1c and klotho that belong to cellular senescence panel were decreased in the young copd as compared to young nonsmokers group. while the transcript levels of the remaining four genes parp1, sirt6, tert, and slx4 were increased in the young copd as compared to the young non-smokers group (figures 2a and 3c) . overall, four genes parp1, sirt6, klotho, and cdkn1c were among the common target genes that were differentially expressed in the young copd group as compared to young non-smokers and young smokers groups. here, we analyzed differentially expressed transcript levels among old non-smokers vs. old smokers, old smokers vs. old copd, and old non-smokers vs. old copd groups. out of seven genes, we found three genes igf1, cox18, and rif1 were decreased and the remaining four genes nfatc1, nfatc2, rad17, and pcna were increased in old smokers as compared to old non-smokers group ( figures 2b and 4a) . the transcript levels of igf1, parp1, pten, nbn, hspd1, and rif1 were decreased and gar1 was increased in old smokers as compared to old copd group ( figures 2b and 4b ). only two genes were affected among old nonsmokers and old copd group; rpa2 and pcna were increased in old copd as compared to the old non-smokers group ( figures 2b and 4c) . overall, a total of three genes as mentioned above (igf1, rif1, and pcna) were among the common targets that were found to be differentially expressed in old smokers as compared to old non-smokers and the old copd groups. we then analyzed differentially expressed genes among young non-smokers vs. old non-smokers, young smokers vs. old smokers, and young copd vs. old copd pairwise comparisons. transcript levels across different age groups were performed to better understand, whether age influences the measured outcomes in the current study. accordingly, we found that nine genes were significantly elevated in young non-smokers as compared to old non-smokers group (pcna, nfatc2, acd, gsk3b, hat1, ucp2, cdkn1a, cdkn1c, and sirt1; figures 2c and 5a) . although, young smokers show increased transcript levels of parp1, ucp3, and e2f1 genes but decreased levels of nfatc1, nfatc2, myc, and gadd45a as compared to the old smokers group as seen in figures 2c and 5b . additionally, two genes (tnsk2 and pten) were decreased in the young copd group as compared to the old copd group. the transcript levels of gar1, tert, h2ax, and fen1 tend to increase in the younger copd group as compared to the old copd group (figures 2c and 5c) . interestingly, we noted that transcript levels of nfatc2 was decreased in lungs of old nonsmokers, but increased in lungs of old smokers. we performed grouped analysis of differentially expressed transcripts (comparisons without considering the age factor (young or old) among non-smokers, smokers and patients with copd groups (e.g., young non-smokers with old non-smokers group, young smokers with old smokers group, and young copd and old copd group; n = 8/group; figures 6 and 7a) . results indicated that smokers show decreased foxo1 and increased rad17 levels as compared to non-smokers group ( figure 8a ). while decreased parp1 and increased rad17 levels were observed in smokers as compared to copd group ( figure 8b ). in patients with copd klotho was decreased and parp1 and slx4 genes were increased as compared to nonsmokers group ( figure 8c) . furthermore, these comparisons revealed that smokers have significantly higher levels of rad17 expression compared to both non-smokers and copd groups. whereas, copd patients showed significantly higher levels of parp1 as compared to both non-smokers and smokers groups. pairwise analysis of young non-smokers vs. young ipf showed 25 significantly altered genes, which were given in table 2 . comparisons between old non-smokers and old ipf showed 13 significantly altered genes, as listed in table 3 along with their observed level of significance. the gene comparisons among these groups were given in figure 7b . as detailed above both copd and ipf are chronic age related diseases that severely alter lung function and share certain common features for the disease occurrence and progression. here, we compared the altered gene levels related to the same pathways among copd and ipf subjects as detailed above. there was no change in any of the genes analyzed in comparisons between young ipf (n = 3) and old ipf (n = 13). while, 16 genes were found to be altered in the comparisons between young copd vs. young ipf, as indicated in table 4 . a total of 6 genes were altered in comparisons between old copd vs. old ipf as shown in table 5 . some of the differentially expressed mrna targets predicted using nanostring were selected for qpcr analysis. the expression trends of these selected genes matches with the trend observed using the nanostring mrna analysis with varied levels of fold changes (figure 9 ). combined gene analysis for parp1 which matches with the trend as given in figure 8 . the results clearly indicate that the genes validated using qpcr are in agreement and significant across all the pairwise comparisons made. western blots analysis (figures 10 and 11 , and supplementary figures 1 and 2) revealed a significant increase in the protein levels of tmprss2 protease (which plays a crucial role in the processing of the sars-cov-2 proteins) in copd subjects as compared to smokers and non-smokers. similarly, the levels of another important protease/convertase furin, which cleaves the spike protein of sars-cov-2, was also increased in smokers and copd subjects, with a significant expression in copd subjects. ace2, cellular receptor for sars-cov-2 binding, was found to be increased in smokers as compared to the rest of the groups. the samples were also further probed for the expression of dpp4, another crucial protein which plays an important role in mers-cov binding. the dpp4 expression was found to be significantly higher in smokers as compared to copd and nonsmokers. these results indicate that the levels of proteases, which aid in the processing and binding of the viral spike proteins were highly expressed in copd and smokers. the expression results showed varied protein intensities in smokers and copd for tmprss2 and dpp4 in the lungs, which may suggest a varied aging is associated with the decline in lung function, and copd is a disease of aging (rojas et al., 2015; wheaton et al., 2019) . nonetheless, there is growing evidence of copd in younger subjects, which needs thorough and careful phenotypic characterization for potential markers to understand the cause and progression of disease. the current study examined the changes in gene expression in the lungs of non-smokers and smokers and patients with copd/ipf. the study included age as an influencing factor independent of lung disease status. the extracted rna was processed and analyzed using the sophisticated nanostring ncounter analysis platform. nanostring has several advantages in simultaneous estimation of the several gene levels in a single sample with low amounts of sample input (eastel et al., 2019; goytain and ng, 2020) . we have successfully used this platform to report changes in gene expression using different gene set panels in our earlier studies sundar et al., 2018 ). in the current study, the custom designed panel included genes from three different pathways addressing the mitochondrial biogenesis and function, telomere function, and cellular senescence, which play a major role in the lung inflammation and copd development. most chronic diseases, like copd, are associated with the mitochondrial dysfunctions. several reports claim the causal role of mitochondrial dysfunctions in the initiation and progression of smoking associated copd (bialas et al., 2016; ryter et al., 2018; zhang et al., 2020) . we have previously reported the presence of mitochondrial dysfunctions in cs-induced lung damage models and in human lungs (ahmad et al., 2015) . further, we along with others have reported that telomere dysfunction is also seen in copd patients and smoking plays a crucial role in influencing telomere genes (liu et al., 2002; morla et al., 2006; ahmad et al., 2017) . assessment of all these three pathway related genes in the same subjects throws light on the involvement and coordination of complex processes in smoking-related chronic lung disease such as copd. pairwise comparisons revealed that a total of 21 genes were altered among the young and old subjects. cdkn1a (p21), a cyclin-dependent kinase (cdk), plays a vital role in cellular senescence and proliferation and was reported to be increased in smokers and copd subjects (chiappara et al., 2013) . further, p21 disruption attenuated cs-induced lung inflammation in mice (yao et al., 2008) . in the current study, there was a figure 9 | quantitative pcr validation of the selected genes, which were found to significantly and differentially altered across various pairwise comparisons. the values were deduced based on 2-ddct method. the genes represented were found to be significant in their pairwise comparisons (p < 0.05). student t-test was used to compare the level of significance in pairwise comparisons, while anova was used for multiple comparisons. reduced expression in the p21 levels in the young smokers compared to non-smokersin accordance with the previous reports, where cdkn1c (p57), along with p21 was decreased in aging lungs of mice (park and chung, 2001) . among the other important targets klotho, sirt6, parp1, and pcna were altered in the current study. copd patients has reduced klotho expression as compared to non-smokers, in accordance with previous reports (gao et al., 2015) . in similar lines, parp1 was also elevated in the copd subjects compared to smokers and non-smokers, as reported earlier (hwang et al., 2010; dharwal and naura, 2018) . we have reported that tert levels were altered in mice (young and old) exposed to chronic cs . accordingly, the current results demonstrates that tert levels were significantly increased in copd patients, but this gene may be influenced in a different way in humans, as younger copd patients has higher tert levels compared to older ones. nuclear factor of activated t cells c2 (nfatc2) levels were significantly higher in aged smokers as compared to younger ones. earlier reports claim that nfatc2 levels were increased by nicotine/smoking (frazer-abel et al., 2004) . it was also reported that nfatc2 enhances tumor-initiating phenotypes in lung adenocarcinoma (xiao et al., 2017) . these observations were opposite in non-smokers, as they age the levels of nfatc2 decreased. this suggests that nfatc2 may be used as a potential marker related to cs-induced lung damage. among the other important genes that were altered and are crucial in the maintenance of these three pathways are acd, which is related to tpp1 gene and coordinates with its function was elevated in copd (else et al., 2007; ahmad et al., 2017) . fen1 could be a novel biomarker for copd which was increased in the young copd group as compared to the old copd group. prior studies showed mutation in fen1 linking lung cancer progression in an age-dependent manner in mice exposed to benzo[a]pyrene which is present in tobacco smoke (wu et al., 2012; ahmad et al., 2017) . pairwise comparisons between non-smokers and ipf subjects revealed changes in some important genes like parp1, pcna, fen1, cdkn1b, nfatc2, and gadd45b, as discussed in the above comparisons. however, the directionality of the changes varied between groups, which may be attributed to the small sample size in the study and the heterogeneity in the samples used. further comparisons were also made between the expression profiles of the young ipf and old ipf with their age matched copd subjects. interestingly, some of the well characterized genes in ipf like nox4 and tnks2 were increased in the young ipf as compared to the young copd patients (hecker et al., 2014) . mitophagy is a well-known phenomenon occurring in both copd and ipf and regulates the mitochondrial related damage response toward the disease figure 10 | western blot analysis of the crucial targets involved in covid19 in non-smokers, smokers, and copd subjects. five samples per groups were used to probe for the tmprss2, furin, ace2, and dpp4. data were shown as mean ± sem (n = 5/group). level of significance were indicated as **p < 0.01 and ***p < 0.001 across the groups. (hara et al., 2018; ryter et al., 2018) . genes participating in the mitochondrial dynamics and other quality control mechanisms like fis1 and rhot2 were found to be decreased in young ipf compared to their age matched copd subjects. ercc1 (excision repair cross-complementation group 1) was also found to be high in young copd as compared to ipf. earlier reports claim that ercc1 gene is strongly associated with copd subjects (de andrade et al., 2012) . some of the common gene targets like gadd45b needs further attention and characterization especially in the chronic lung diseases like copd and ipf. recent biomarker identification study indicated gadd45b in their list of genes that can be targeted in chronic diseases like asthma, ipf, and copd (maghsoudloo et al., 2020) . several studies indicate that the patients with underlying chronic disease conditions like diabetes, hypertension, and copd are more prone to covid-19 infections and have higher chances of the hospitalization rates and mortality (emami et al., 2020; koff and williams, 2020; zhao et al., 2020) . several crucial mechanisms and targets were reported to increase this susceptibility in these patients (hoffmann et al., 2020 ). in the current study, we have determined the expression of four such important protein targets reported to play an important role in sars-cov-2 covid-19. as anticipated, copd and ipf patients in our study have higher levels of tmprss2 proteins in the lungs, suggesting the ideal condition for the processing of the viral protein and attachment to its receptor ace2. ace2 receptor abundance expression was slightly increased in smokers, copd, and ipf subjects (leung et al., 2020) . furin, another crucial protease in covid-19 infection, was also found to be higher in smokers, copd, and ipf as compared to the non-smokers. we have also assessed the levels of dpp4 in the same samples and found that dpp4 was significantly higher in the smokers as compared to non-smokers and copd. dpp4 was found to play an important role in the entry of mers-cov, acts as its receptor (belonging to the similar class of beta coronaviruses) in humans, and was also suggested to play an important role in covid-19 infections (bassendine et al., 2020) . in agreement with recent reports (seys et al., 2018) , suggesting that smokers and copd have higher dpp4, our findings suggest increase in dpp4 in smokers, but to our surprise we didn't find any increase in copd subjects. this may suggest a different mechanism in smokers and copd, which required further studies. nevertheless, the varied abundance of different sars-cov-2 covid-19 proteins suggest cell-specific effects for viral entry in smokers and copd/ipf subjects. this may be used as pharmacological targets in attenuating covid-19 infections. figure 11 | western blot analysis of the crucial targets involved in covid19 in non-smokers and ipf subjects. five samples per groups were used to probe for the tmprss2, furin, and ace2. data were shown as mean ± sem (n = 5/group). level of significance were indicated as *p < 0.05 and ***p < 0.001 across the groups. in conclusion, our study provides a novel direction showing a crucial and interdependent association with different cellular pathways, e.g., mitochondrial, telomere, and cellular senescence in association with sars-cov-2 covid-19 proteins. whilst the study provides several differential gene expression patterns in non-smokers, smokers, and copd/ipf, there is a limitation regarding the small sample size and past smoking history in terms of their stratifications for further analyzing the data and their interpretations. it remains to be seen the alterations seen in various genes will have direct bearing on susceptibility to covid-19 infections in smokers, and patients with copd and ipf. nonetheless, this human study provides useful and valuable information in terms of approach and identifying targets involved in various cellular processes linking with age and copd and ipf disease progression with pharmacological targets in covid-19 infections. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation, to any qualified researcher. the current study was approved for the procurement of the human lung tissues as de-identified tissues by the materials transfer agreement and procurement (institutional review board, irbc), and laboratory protocols by the institutional biosafety committee, ibc of the university of rochester medical center, rochester, ny, with project code: drai1 001 protocol: 004, date of approval and irb/ibc approvals 2/11/ 2017 and 2/7/2018, and 9/29/2017 and 2/10/2017, university material transfer agreement (mta) agreements signed on the above dates as well. written informed consent was not provided because the human peripheral lung tissues from non-smokers, smokers, and copd/ipf were procured/obtained from the ndri (national disease research interchange) and ltrc [lung tissue research consortium of the national heart lung blood institute (nhlbi)]. km: experiments, data analyses, writing, and editing the manuscript. is: data analyses and editing the manuscript. dl: data analyses and editing the manuscript. ir: concept, design, obtained funding, writing, and editing the manuscript. this study was supported by the nih r01 hl1377380, r01 hl135613, and r01 es 029177 (all ir). dl is supported in part by the university of rochester ctsa ul1 tr002001 of the nih. this manuscript has been released as a pre-print at the following pre-print servers medrxiv with https://www.medrxiv.org/ content/10.1101/2020.06.14.20129957v1 and researchsquare with https://www.researchsquare. com/article/rs-35347/v1 . the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/10.3389/fphar.2020. 584637/full#supplementary-material supplementary table 1 | pre-selected genes belonging to the mitochondrial biogenesis and function pathway with their annotations. supplementary table 2 | determined genes with raw and normalized counts based on nano string analysis for non-smokers, smokers, and copd comparisons. supplementary table 3 | determined genes with raw and normalized counts based on nano string analysis for non-smokers, smokers, copd and ipf comparisons. impaired mitophagy leads to cigarette smoke stress-induced cellular senescence: implications for chronic obstructive pulmonary disease shelterin telomere protection protein 1 reduction causes telomere attrition and cellular senescence via sirtuin 1 deacetylase in chronic obstructive pulmonary disease covid-19 and co-morbidities: a role for dipeptidyl peptidase 4 (dpp4) in disease severity? smoking does not accelerate leucocyte telomere attrition: a metaanalysis of 18 longitudinal cohorts the role of mitochondria and oxidative/antioxidative imbalance in pathobiology of chronic obstructive pulmonary disease mitochondria, telomeres and cell senescence: implications for lung ageing and disease inflamm-aging: why older men are the most susceptible to sars-cov-2 complicated outcomes the role of p21 waf1/cip1 in large airway epithelium in smokers with and without copd age-dependent of transcriptomics in smokers, copd, and ipf copd as a disease of immunosenescence genetic variants associated with the risk of chronic obstructive pulmonary disease with and without lung cancer telomere length, copd and emphysema as risk factors for lung cancer parp-1 inhibition ameliorates elastase induced lung inflammation and emphysema in mice application of nanostring technologies in companion diagnostic development tpp1/acd maintains genomic stability through a complex role in telomere protection prevalence of underlying diseases in hospitalized patients with covid-19: a systematic review and meta-analysis nicotine activates nuclear factor of activated t cells c2 (nfatc2) and prevents cell cycle entry in t cells insufficient autophagy promotes bronchial epithelial cell senescence in chronic obstructive pulmonary disease klotho expression is reduced in copd airway epithelial cells: effects on inflammation and oxidant injury the effect of aging on susceptibility to infection trends in copd prevalence, incidence and health services use in younger adultsp nanostring ncounter technology: high-throughput rna validation mitochondrial quality control in copd and ipf. cells reversal of persistent fibrosis in aging by targeting nox4-nrf2 redox imbalance sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor cigarette smoke-induced autophagy is regulated by sirt1-parp-1-dependent mechanism: implication in pathogenesis of copd covid-19 and immunity in aging populations -a new research agenda serum from patients with chronic obstructive pulmonary disease induces senescence-related phenotype in bronchial epithelial cells aging-and smokingassociated alteration in the relative content of mitochondrial dna in human lung mitochondrial redox system, dynamics, and dysfunction in lung inflammaging and copd ace-2 expression in the small airway epithelia of smokers and copd patients: implications for covid-19 scaffold hopping approach on the route to selective tankyrase inhibitors mitochondrial dysfunction leads to telomere attrition and genomic instability identification of biomarkers in common chronic lung diseases by coexpression networks and drug-target interactions analysis age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, copd and ipf: associations with sars-cov-2 covid-19 ace2-tmprss2-furin-dpp4 axis age-dependent assessment of genes involved in cellular senescence, telomere and mitochondrial pathways in human lung tissue of smokers, copd and ipf: associations with sars-cov-2 covid-19 ace2-tmprss2-furin-dpp4 axis protective role of mesenchymal stem cells and mesenchymal stem cell-derived exosomes in cigarette smoke-induced mitochondrial dysfunction in mice clinical implications of telomere dysfunction in lung fibrosis telomere shortening in smokers with and without copd cigarette smoke induces cellular senescence age-dependent changes of p57(kip2) and p21(cip1/waf1) expression in skeletal muscle and lung of mice mitochondria, telomeres and cell senescence mice with pulmonary fibrosis driven by telomere dysfunction comorbidities and chronic obstructive pulmonary disease: prevalence, influence on outcomes, and management oxidative stress and redox regulation of lung inflammation in copd lung cellular senescence is independent of aging in a mouse model of copd/emphysema aging and lung disease. clinical impact and cellular and molecular pathways mitochondrial dysfunction as a pathogenic mediator of chronic obstructive pulmonary disease and idiopathic pulmonary fibrosis disease progression in young patients with copd: rethinking the fletcher and peto model mitoq counteracts telomere shortening and elongates lifespan of fibroblasts under mild oxidative stress covid-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? dpp4, the middle east respiratory syndrome coronavirus receptor, is upregulated in lungs of smokers and chronic obstructive pulmonary disease patients the effects of aging on lung structure and function dna methylation profiling in peripheral lung tissues of smokers and patients with copd genetic ablation of histone deacetylase 2 leads to lung cellular senescence and lymphoid follicle formation in copd/emphysema aging, cell senescence, and chronic disease: emerging therapeutic strategies influence of aging on lung function-clinical significance of changes from age twenty chronic obstructive pulmonary disease and smoking status -united states high risk of benzo [alpha]pyrene-induced lung cancer in e160d fen1 mutant mice nfatc2 enhances tumor-initiating phenotypes through the nfatc2/sox2/aldh axis in lung adenocarcinoma role of histone deacetylase 2 in epigenetics and cellular senescence: implications in lung inflammaging and copd disruption of p21 attenuates lung inflammation induced by cigarette smoke, lps, and fmlp in mice sirt1 protects against emphysema via foxo3-mediated reduction of premature senescence in mice idiopathic pulmonary fibrosis: aging, mitochondrial dysfunction, and cellular bioenergetics association of urine mitochondrial dna with clinical measures of copd in the spiromics cohort the impact of copd and smoking history on the severity of covid-19: a systemic review and meta-analysis key: cord-340285-mq9x12nw authors: blagosklonny, mikhail v. title: from causes of aging to death from covid-19 date: 2020-06-12 journal: aging (albany ny) doi: 10.18632/aging.103493 sha: doc_id: 340285 cord_uid: mq9x12nw covid-19 is not deadly early in life, but mortality increases exponentially with age, which is the strongest predictor of mortality. mortality is higher in men than in women, because men age faster, and it is especially high in patients with age-related diseases, such as diabetes and hypertension, because these diseases are manifestations of aging and a measure of biological age. at its deepest level, aging (a program-like continuation of developmental growth) is driven by inappropriately high cellular functioning. the hyperfunction theory of quasi-programmed aging explains why covid-19 vulnerability (lethality) is an age-dependent syndrome, linking it to other age-related diseases. it also explains inflammaging and immunosenescence, hyperinflammation, hyperthrombosis, and cytokine storms, all of which are associated with covid-19 vulnerability. anti-aging interventions, such as rapamycin, may slow aging and age-related diseases, potentially decreasing covid-19 vulnerability. humans and other animals (including the worm [30] and the fly [31] ) do not die from aging itself but from agerelated diseases such as ischemic heart disease (ihd), hypertension, diabetes, cancer, alzheimer's and parkinson's diseases, age-related macular degeneration, osteoporosis and sarcopenia (as we will discuss, even seemingly non-deadly diseases such as osteoporosis can lead to deadly complications). the incidence of these diseases increases exponentially with age. some diseases such as obesity, hypertension and diabetes develop earlier in the course of aging. other diseases, such as alzheimer's disease and macular degeneration, are usually diagnosed later [32, 33] . age-related diseases may also occur in younger people with genetic predisposition and environmental exposure hazards. but even without these factors, diseases develop because they are quasi-programmed (see "quasi-programmed aging section"). these diseases are not diseases of civilization, as it may seem. humans simply now live long enough to develop them. of course, "hazards of civilization" can accelerate them at a younger age. aging and its diseases cannot be separated. healthy aging, or aging without diseases, is merely a slow aging, when biological age is less than chronological age. during a period of seemingly healthy aging, pre-pre-diseases and pre-diseases are progressing until they eventually reach clinical manifestations. thus, healthy aging progress to unhealthy and pre-diseases become diseases [34] . age-related diseases and covid-19 vulnerability are highly intertwined. patients, who die from covid-19, otherwise would die from age-related diseases such as heart disease, cancer, diabetes, hypertension, just a year later. covid-19 approximately doubles a patient's aging-dependent risk of dying during one year. for example, (numbers are very approximate), a sixty year old woman has 1% chance to die from aging before her 61st birthday. at that age, if infected, the death rate from covid-19 is around 1% for females. if infected, a patient has approximately doubled chances to die compared with usual age-related mortality during one year. as david spiegelhalter put it: "getting covid-19 is like packing a year's worth of risk into a week or two". https://medium.com/wintoncentre/how-much-normalrisk-does-covid-represent-4539118e1196. children and young adults have a very low risk of death from aging-related diseases, so that risk remains extremely low even when doubled. although natural mortality is relatively high in the youngest age group, especially in infants, they do not die from age-related diseases of course. instead, infants are vulnerable to bacterial infections and candida infections due to underdeveloped immune system [35] . low covid-19 mortality in the pediatric age group [11] is consistent with the notion that covid-19 vulnerability is not due to a "weak" immune system. in contrast, as we will discuss in the next section, it is hyper-functional immune response that leads to death from covid-19 in the elderly by causing cytokine storm. aging severe covid-19 is characterized by hyperinflammation, cytokine storm, acute respiratory distress syndrome (ards), damage to the lung, heart and kidneys [36] [37] [38] [39] . in response to viral replication, hyperfunctional monocytes and macrophages infiltrate the lung, causing hyper-inflammation and hyper-secretion of cytokines such as interleukin (il)-6, il-2, il-7, il-1ra, interferon-γ inducible protein (ip)-10, tumor necrosis factor (tnf)-α, ferritin, monocyte chemoattractant protein (mcp)-1, macrophage inflammatory protein (mip) 1-α, granulocyte-colony stimulating factor (g-csf), c-reactive protein (crp) and procalcitonin. [22, [36] [37] [38] [39] [40] [41] [42] . this leads to leukocyte recruitment, vascular permeability, edema and further pulmonary damage in vicious cycle [37, 38, 41, 43, 44] . hyper-inflammation becomes systemic, in turn causing hyper-coagulation and thrombosis, disseminated intravascular coagulation [45] . this causes injury of distant organs such as the kidneys. pre-existing organ damage (late stages of agerelated diseases) exacerbates organ damage caused by cytokine storm [42, 43, 46] . in addition, cellular hyperfunctions and systemic hyper-inflammation may lead to cellular exhaustion, such as exhaustion of lymphocytes (lymphopenia) [47] [48] [49] . hypercoagulation is associated with hyperactive fibrinolysis and increased d-dimer blood levels [23] . cytokine storm is a systemic hyperfunctional response ( figure 1 ). of course, age-related hyperfunctional response, such as cytokine storm, is not caused by lifelong accumulation of molecular damage. aging is not caused by molecular damage after all. instead it's a continuation of developmental/growth programs that lead to hyperfunctions and in turn eventually to dysfunctions. hyperfunction theory of quasi-programmed aging "quasi" means "resembling" or "seemingly, but not really." quasi-program of aging is not a program but a continuation of developmental programs that were not switched off upon their completion [24, 50] . they purposelessly unfold, leading to age-related diseases, secondary organ failure and death. quasi-programmed (program-like) aging is associated with higher than optimal cellular and systemic functions, which eventually, via cellular exhaustion and organ damage, lead to functional decline ( figure 2 ). for example, starting from birth, blood pressure increases and continues to increase after organismal growth is completed. therefore, hypertension is the most prevalent age-related disease. in turn, hypertension can cause organ damage: stroke, infarction and renal failure. similarly, obesity develops in post-development as a continuation of growth (yet, it can be prevented by low caloric diets, illustrating that quasi-program of aging can be decelerated). hyperfunction is an excessive normal cellular function: contraction by smooth muscle cells (smc), adhesion and aggregation by blood platelets, insulin secretion by beta-cells, lipid accumulation by adipocytes, secretion by stromal and immune cells, oxidative burst by leukocytes, just to name a few. when higher than optimal, they cause vasoconstriction and hypertension, thrombosis, hyperinsulinemia, hypertrophy, hyperplasia, obesity, hyper-secretory phenotype or senescence-associated secretory phenotype (sasp), hyper-inflammation and so on. hyper-function is not necessarily an absolutely increased function. it may be also insufficiently decreased function (relative hyperfunction). levels of igf-1 and growth hormone decrease during lifespan. despite this decrease, igf-1 levels are still higher than optimal (relative hyper-function) because further genetic decrease in igf-1 levels (by genetic means) extends health span and lifespan in mammals [51] [52] [53] . cellular hyperfunctions may eventually switch to cellular exhaustion and loss of functions at late stages. during the course of type ii diabetes, mtor overactivation and hyperinsulinemia eventually lead to beta-cell exhaustion and insulin insufficiency, from prediabetes to diabetes [54, 55] . as another example, after puberty, hyperstimulation of the ovary eventually leads to oocyte exhaustion and menopause (see figure 3 in ref. [29] ). depletion of naïve lymphocytes is another example, as reviewed here later. age-related alterations are mostly noticed when they switch to functional decline, which is a late event. in some cases, functional decline can be primary and programmed. for example, thymus involution (replacement of t cells by adipocytes) starts early in life, accelerates at puberty and continues later. still loss of thymocytes and their niches may be in part due to adipocyte hyperplasia and hypertrophy [56] . in fact, obesity accelerates involution, whereas calorie restriction decelerates it [57, 58] . furthermore, the oblation of sex hormones decelerates or even reverses thymus involution [59] . thus, involution is triggered by adipocyte hyperplasia and increased production of sex hormones during puberty [56] . quasi-programmed aging is not driven by molecular damage. it is driven by nutrient/hormone/cytokinesensing and growth-promoting signaling pathways such as target of rapamycin (tor; mtor), which are involved in developmental growth and later cause hyperfunctional aging and its diseases [24, 26] . what is the cause-effect relationship between age-related diseases and covid-19 lethality? do patients die from age-related diseases, complicated by covid-19? or, in contrast, do these various diseases make covid-19 infection lethal? both scenarios take place to some extent. however, the relationship is mostly indirect. both age-related diseases and covid-vulnerability result from the same underlying cause (figure 3 ). this is why they are highly correlated. the cause is aging itself. aging is manifested by a sum of deadly -and not so deadly -diseases and conditions ranging from cancer to grey hair. although not all diseases seem to be deadly, they can cause complications such as stroke, ventricular fibrillation, renal failure, lung edema. even sarcopenia and osteoporosis lead to falls and broken bones culminating in a deadly sequence of events. cosmetic manifestations such as aging spots and wrinkles, while not deadly by themselves, can be manifestations of other diseases. for example, baldness correlates with prostate enlargement [60] , and the later can lead to urinary obstruction and renal failure. diseases occur together. for example, chronic obstructive pulmonary disease (copd) is associated with diabetes, cardiovascular disease and hypertension [61] . if a person has one disease (e.g., diabetes), this patient has higher chances of having other diseases (e.g., hypertension, ihd, cancer) or conditions, including covid-19 vulnerability, which is revealed only during infection but can be predicted by pre-existing diseases. aging is initially driven by an increase in cellular and systemic functions (hyperfunction), leading to age-related conditions. for example, hypertension is a systemic hyperfunction due to hyperfunction of multiple cell types such as arterial smooth muscle cells (asmc). similarly, covid-19-vulnerability is associated with hyperfunction of inflammatory cells that, in response to covid-19 infection, causes cytokine storm, hypercoagulation and damage of the lung and distant organs. the covid-19 vulnerability syndrome is an agingrelated disease, strictly dependent on biological age, associated with other age-related diseases, and exemplified by hyper-functional response to infection. with hundreds of cell types acting in concert, the immune system is so complex that we cannot discuss age-related alterations without oversimplification. the most noticeable alteration is that memory t and b cells replace naive t and b cells [62] . (this seems natural since life-long exposure to pathogens replaces naïve cells by memory cells). replacement of naïve immune cells decreases adaptive responses to novel antigens such as sars-cov-2. in contrast, immune protection by memory t cells from viral re-infection with known pathogens is usually increased with age [62] . immune responses are roughly divided into (a) innate responses, carried mostly by neutrophils, macrophages and nk cells, which react to pathogen rapidly and nonspecifically, and (b) adaptive responses, carried by t and b lymphocytes, which are delayed, slower and specific (e.g., antigen-specific clonal expansion of t and b lymphocytes and antibody production by b lymphocytes) [63] [64] [65] . in the elderly, immune responses to sars-cov-1/2 are "stuck in innate immunity," with insufficient progression to adaptive immunity [37]. however, decline in adaptive response, such as antibody production, plays little role in covid-19 mortality. it is hyper-functional innate immunity, hyper-inflammation, cytokine storm and hyper-coagulation that lead to organ failure and death. in agreement, hyper inflammatory response rather than high virus numbers leads to death of sars-cov-infected old nonhuman primates [66] . aging is associated with diseases of immune hyperfunction such as autoimmune disorders with paradoxical increase in certain signaling pathways and cytokine levels [67] [68] [69] . in the elderly, innate immune cells are in a state of sustained activation, producing pro-inflammatory cytokines [67, [70] [71] [72] . increased pro-inflammatory activity by the innate immune system, especially by monocytes/ macrophages, is a state of alertness and hyper-reactivity on the cost of potential age-related inflammatory diseases [67, [70] [71] [72] . whereas some functions are decreased, others are increased. according to the inflamm-aging concept, innate immune system overtakes adaptive immune system in aging. cause-effect relationships are bi-directional: immunosenescence (namely, a decrease in adaptive response) is a cause and consequence of inflamm-aging [67, [70] [71] [72] . we can consider inflamm-aging as an example of hyper-function. while some functions are decreased, others are increased. hyper-function is damaging. (in analogy, increased electric power, without an adaptor, would damage a laptop). damaging hyper-functions can lead to loss of function and cellular exhaustion. and vice versa, loss of function may cause compensatory hyper-functions of another components. cellular senescence is a continuation of cellular growth, when actual growth is completed [73, 74] . in proliferating cells, cellular mass growth is balanced by cell division. cells grow in size and then divide. when the cell cycle is blocked (e.g., p21 and p16), then growth-promoting pathways such as mtor and mapk drive conversion to senescence (geroconversion) [24, 74, 75] . during geroconversion, cells become hypertrophic and "fat". cellular functions increase: hyper-secretion and lysosomal hyper-function are manifested by sasp and beta-gal staining. hyper-activated growthpromoting pathways cause compensatory resistance to growth factors/insulin, permanent loss of re-proliferative potential [74] . rapamycin, everolimus, pan-mtor and mapk inhibitors slows down geroconversion, maintaining reversible quiescence instead of senescence [73, [76] [77] [78] [79] [80] [81] [82] [83] [84] [85] [86] [87] [88] . geroconversion is a continuation of cellular growth [73, 74] . similarly, aging is a continuation of developmental growth (see figure 1 in ref. [89] ). when the developmental program is completed, it becomes a quasi-program of aging. as discussed in detail, chronically activated nutrient-sensing and growth-promoting pathways drive age-related diseases, culminating in organismal death [24, 26] . age-related diseases are quasi-programmed. aging is a common cause of age-related diseases, a sum of all agerelated diseases. they are diseases of hyper-function, secondary hypo-function and compensation reactions [25] ; they are deadly manifestations of aging. from activation of cellular functions to systemic hyperfunctions, from diseases to organ damage and death, hyperfunction theory of quasi-programmed aging describes the sequence of events [26] . and as discussed in 2006, suppression of aging by gero-suppressants, such as rapamycin, will prevent and treat all age-related diseases [24] . this point of view is becoming widely accepted and, in recent literature, quasi-programmed model of diseases (2006) is called "geroscience hypothesis" [2, 90] . if aging were functional decline due to accumulation of molecular damage, then it would be near to impossible to restore functions and rejuvenate the immune system. in contrast, if functional decline is secondary to hyperfunctions (see figure 2 in ref. [89] ), these hyperfunctions can be suppressed pharmacologically to restore lost functions. typical drugs are inhibitors of their targets, rather than activators, so they decrease functions of their targets. by decreasing hyper-functions, which otherwise lead to secondary loss of functions, rapamycin may restore "lost" functions ( figure 4 ). rapamycin improves vaccination against viruses such as influenza in old mice, monkeys and humans [92] [93] [94] [95] [96] [97] [98] [99] [100] . importantly, rapamycin increases pathogenspecific but not graft-reactive cd8+ t cell responses [95, 101] . therefore, rapamycin and everolimus can both be used to prevent donor organ rejection and improve adaptive immunity against new pathogens [96] . differentiation is an increase of tissue-specific cellular functions. terminally differentiated b, t, and nk cells can rapidly react to already known pathogens [102] . decrease in naïve t and b lymphocytes (and thus diminished response to novel antigens) results in part from cellular hyper-differentiation in the immune system [64, 103] . hyper-functional differentiation can be counteracted by rapamycin [98] . as another example, age-related exhaustion of stem cells is partially due to loss of quiescence caused by growth over-stimulation [92, [104] [105] [106] . in general, senescent cells characterized by hyper-proliferative drive coupled with cell cycle arrest [77] . in young mice, mtor hyperactivation causes senescence of hematopoietic stem cells (hsc) and decreases lymphopoiesis [92] . in old mice, rapamycin rejuvenates hematopoiesis, and improves vaccination against influenza virus [92] . third, production of lymphoid cells may be decreased because of disruption of hypoxic niches due to adipocytes hyperplasia [56, 107] . hypoxic niches can preserve hsc [108, 109] probably because hypoxia inhibits mtor and cellular senescence [110] . in agreement, rapamycin preserves hscs [92, 98, 111, 112] reduces the proportion of memory cells and maintains a pool of naïve t cells [92, 98] . aging fourth, growth factor (gf)-and insulin-resistance is loss of function because cells cannot respond to gf/insulin. but it may be caused by over-activated mtor, which via s6k/irs feedback loop blocks insulin and gf signaling. rapamycin abrogates the loop restoring signaling [113] [114] [115] [116] [117] [118] . a high prevalence of age-related diseases, often called "diseases of civilization," is a success story of modern medicine. in the past, most people did not live long enough to develop age-related diseases and those who developed them died soon after. due to medical advances, people survive to 85 on average, despite suffering from age-related diseases. standard medicine preferentially extends life span, without necessarily affecting health span (see figure 3 in ref. [119] ). for example, defibrillation and coronary stenting can save life but not cure heart disease. it is anti-aging interventions that extend health span, delaying diseases, thus extending lifespan. aging is a common cause of all age-related diseases. by suppressing aging, anti-aging interventions may delay all age-related diseases [119] . as a well-known example, low calorie diets such as calorie restriction, intermittent fasting, and low carbohydrate diets extend both health and lifespan. figuratively, low calorie diets prolong life by improving health. nutrients and obesity activate growth-promoting pathways (e.g., mtor), thus accelerating development of quasi-programmed (age-related) diseases. obesity is associated with all age-related diseases from cancer to alzheimer's and from diabetes to sarcopenia. covid-19 vulnerability is also associated with obesity [9, 19, 20, 22] . according to hyperfunction theory, obesity accelerates aging and all age-related conditions including covid-19 vulnerability. diabetes is one of main risk factors of death in covid-19 [5, 6, 12, 13, 15, 21] . can type 2 diabetes, an agerelated disease, be reversed? in remarkable studies, it was shown that a brief course (6-8 weeks) of very low calorie diets (vlcds) can reverse type ii diabetes. in one study, vlcd reversed diabetes in 46% of patients with up to a 6-year history of diabetes [120] . vlcd is most effective for its prevention and at early stages of diabetes [121] . this anti-aging modality is so simple that remission can be achieved at home by healthmotivated individuals [122] . simultaneously, it treats other age-related diseases such hypertension [123] . obesity is associated with other diseases of hyperfunction from diabetes and sarcopenia to cancer and alzheimer's' disease. since age-related diseases are predictors of covid-19 mortality, vlcd in theory may decrease covid-19 vulnerability. in the soil of easter island, a complex bacteria produces anti-fungal antibiotic rapamycin to suppress yeast growth but, as a by-product, it also suppresses yeast aging (quasi-programed aging is a continuation of growth). approved for human use in 1999, rapamycin (sirolimus) and its close analog everolimus are widely used in several diseases including cancer and organ transplantation. hundreds of clinical trials (and twenty years of clinical practice) have ensured their safety and good tolerability especially in healthy older adults [119] . currently, several anti-aging clinics prescribe rapamycin out of label to prevent age-related diseases and slow aging. hundreds of recent reviews discussed rapamycin and everolimus in detail, so i will just emphasize a few points: 1. crucial prediction of hyper-function theory of quasi-programmed aging in 2006 was that rapamycin will slow aging, extend healthspan and lifespan and decrease all age-related [124] . it has been confirmed: it extends lifespan in animals from worm to mammals. in some strains of short-lived mutant mice, it extends life span two fold [98, 125] . 2. rapamycin slows geroconversion to cellular senescence in cell culture [74] . 3. mtor is a potential therapeutic target in chronic obstructive pulmonary disease copd [126] , [127] . rapamycin (sirolimus) is already approved and successfully used in lymphangioleiomyomatosis (lam), a progressive, cystic lung disease, associated with inappropriate activation of mtor [128] . longterm daily use of rapamycin improves lung function without causing serious side effects (and of course no even minor side effects in the lung, given that rapamycin improves lung function) [128] . 4. despite widespread misunderstanding, rapamycin and everolimus do not cause diabetes. in contrast, they prevent diabetic complications in animals with diabetes (see for references [129] ). in rodents, in some conditions they may cause symptoms of starvation pseudo-diabetes similar to prolong fasting and ketogenic diet [129] . although, the johnson study found a slight but significant correlation between medicare billing for insulin and the use of rapamycin in renal transplant patients, this correlation was mechanistically explained by interaction of rapamycin with two other drugs used in the same patients [130, 131] . in cancer patients, everolimus may cause reversible hyperglycemia as a mild, infrequent and reversible side effect after several weeks of daily high doses of everolimus and rapamycin [132] . mechanistically, everolimus decrease insulin production, not causing insulin resistance [132] . if anything, everolimus and rapamycin can be considered to treat complications of type ii diabetes and prevent hyperinsulinemia and obesity ( [129] and references within). what actually contributes to type 2 diabetes is excess of nutrients (and especially carbohydrates), which activate mtor and cause hyperinsulinemia and insulin resistance. as soon as covid-19 epidemic started, it become clear that covid-19 vulnerability is an aging-dependent condition and the use of rapamycin (sirolimus) was immediately suggested by independent researchers [1, 3, [133] [134] [135] [136] [137] . these proposals were based on a mixture of several rationales, which need to be clearly distinguished. in theory, there are at least three independent applications of rapamycin and everolimus for covid-19. currently, they all are still hypothetical. 1. anti-aging effect ( figure 5 ). by decreasing biological age and preventing age-related diseases, a long-term rapamycin therapy may in theory decrease covid-19 mortality rate in the elderly. anti-aging application is especially important because it is beneficial regardless of covid-19. after all, mortality rate from aging and its diseases is 100%, causing more than 2 million deaths in the usa annually. continuous use of rapamycin is expected to improve health, decrease age-related diseases and extend healthy lifespan, rendering individuals less vulnerable, when infected with the virus. 19 vulnerability (log scale) increases exponentially with age (blue line). the line ends at age 120, a maximum recorded age for humans. in theory, a continuous rapamycin treatment would slow down an increase of the vulnerability with age (red line). the increase is still logarithmic but at a different slope, because rapamycin slows the aging process. the maximum lifespan, in the absence of covid-19, is extended because the 100% natural death threshold is achieved later. 2. rejuvenating immunity. as we discussed in section "figuratively, rapamycin rejuvenates immunity" [91] , mtor inhibitors can improve immunity to viral infections, improve immunization and vaccination to some viruses such as flu [92-100, 111, 112, 138] . in addition, viruses such as flu [139] and coronavirus (mers-cov) [140] depend on mtor activity for replication. currently, however, there are no data regarding covid-19. although aimed to evaluate safety, phase 1 clinical trial "sirolimus in covid-19 phase 1 (sirco-1)" may reveal anti-viral effects too https://clinicaltrials.gov/ct2/show/nct04371640. 3. potential suppression of cytokine storm and hyperinflammation ( figure 1 ). as we discussed in the section "cytokine storm is a hyperfunction", cytokine storm and hyper-inflammation is a main cause of death in covid-19 pneumonia [36-40, 42, 45, 135, 141-143] rapamycin, an antiinflammatory agent, inhibits hyper-functions, cellular senescence and decrease secretion of cytokines ( [74, 81, 144] . rapamycin inhibits the jak2/stat4 signaling pathway [145] and reduces ifγ and tnf-α levels [112] . rapamycin (sirolimus) treatment improves outcomes in patients with severe h1n1 pneumonia and acute respiratory failure and was associated with improvement in virus clearance, and shortened ventilator days [146] . clinical trial "sirolimus treatment in hospitalized patients with covid-19 pneumonia (scope)" has been started https://clinicaltrials.gov/ct2/show/nct04341675. this review is intended for a professional audience, to stimulate new ideas and to aid the global efforts to develop effective treatments for covid-19 disease. this article does not represent medical advice or recommendations to patients. the media should exercise caution and seek expert medical advice for interpretation, when referring to this article. the author declares no conflicts of interest. geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections a geroscience perspective on covid-19 mortality covid-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection? aging (albany ny) risk factors for predicting mortality in elderly patients with covid-19: a review of clinical data in china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in wuhan, china biomarkers of biological age as predictors of covid-19 disease severity predictors of mortality for patients with covid-19 pneumonia caused by sars-cov-2: a prospective cohort study severe obesity, increasing age and male sex are independently associated with worse in-hospital outcomes, and higher in-hospital mortality, in a cohort of patients with covid-19 in the bronx, new york estimating excess 1-year mortality associated with the covid-19 pandemic according to underlying conditions and age: a population-based cohort study coronavirus disease (covid-19) and neonate: what neonatologist need to know covid-19 and diabetes: knowledge in progress diabetes mellitus is associated with increased mortality and severity of disease in covid-19 pneumonia -a systematic review, meta-analysis, and meta-regression cardiovascular disease, drug therapy, and mortality in covid-19 clinical characteristics and outcomes of patients with severe covid-19 with diabetes covid-19 and the cardiovascular system: implications for risk assessment, diagnosis, and treatment options covid-19 patients with hypertension have more severity condition, and acei/arb treatment have no infulence on the clinical severity and outcome association of hypertension with the severity and fatality of sars-cov-2 infection: a metaanalysis obesity and its implications for covid-19 mortality obesity predisposes to the risk of higher mortality in young covid-19 patients does comorbidity increase the risk of patients with covid-19: evidence from meta-analysis obesity and covid-19: immune and metabolic derangement as a possible link to adverse clinical outcomes elevated plasmin(ogen) as a common risk factor for covid-19 susceptibility aging and immortality: quasiprogrammed senescence and its pharmacologic inhibition validation of anti-aging drugs by treating age-related diseases prospective treatment of agerelated diseases by slowing down aging impact of sex and gender on covid-19 gender differences in patients with covid-19: focus on severity and mortality. front public health why men age faster but reproduce longer than women: mtor and evolutionary perspectives monsters in the uterus: teratoma-like tumors in senescent c. elegans result from a parthenogenetic quasi-program the torc1 inhibitor nprl2 protects age-related digestive function in drosophila answering the ultimate question "what is the proximal cause of aging dementia incidence continues to increase with age in the oldest old: the 90+ study disease or not, aging is easily treatable the changing profile of infant mortality from bacterial, viral and fungal infection over two decades sars-cov-2 and covid-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes the pathogenesis and treatment of the 'cytokine storm' in covid-19 on the alert for cytokine storm: immunopathology in covid-19 immune environment modulation in pneumonia patients caused by coronavirus: sars-cov, mers-cov and sars-cov-2 plasma ip-10 and mcp-3 levels are highly associated with disease severity and predict the progression of covid-19 the role of cytokines including interleukin-6 in covid-19 induced pneumonia and macrophage activation syndrome-like disease in the eye of the covid-19 cytokine storm the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak pathological evidence of pulmonary thrombotic phenomena in severe covid-19 covid-19 illness in native and immunosuppressed states: a clinical-therapeutic staging proposal lymphopenia in covid-19: therapeutic opportunities covid-19: immunopathology and its implications for therapy lymphopenia predicts disease severity of covid-19: a descriptive and predictive study aging is not programmed: genetic pseudo-program is a shadow of developmental growth the gh/igf-1 axis in ageing and longevity the somatotropic axis and aging: benefits of endocrine defects disruption of the gh receptor gene in adult mice increases maximal lifespan in females mtorc1 overactivation as a key aging factor in the progression to type 2 diabetes mellitus. front endocrinol (lausanne) reciprocal regulation of mtor complexes in pancreatic islets from humans with type 2 diabetes changes in primary lymphoid organs with aging obesity accelerates thymic aging inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution the role of sex steroids and gonadectomy in the control of thymic involution an observational study of the association between androgenetic alopecia and size of the prostate prevalence and outcomes of diabetes, hypertension and cardiovascular disease in copd aging boosts antiviral cd8+t cell memory through improved engagement of diversified recall response determinants trained immunity: a program of innate immune memory in health and disease convergence of innate and adaptive immunity during human aging the twilight of immunity: emerging concepts in aging of the immune system exacerbated innate host response to sars-cov in aged non-human primates from inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation paradoxical changes in innate immunity in aging: recent progress and new directions mtor signaling pathway as a master regulator of memory cd8 + t-cells, th17, and nk cells development and their functional properties inflamm-aging. an evolutionary perspective on immunosenescence immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front immunol chronic inflammation (inflammaging) and its potential contribution to ageassociated diseases growth stimulation leads to cellular senescence when the cell cycle is blocked rapamycin, proliferation and geroconversion to senescence cell senescence and hypermitogenic arrest pharmacologic inhibition of mek and pi-3k converges on the mtor/s6 pathway to decelerate cellular senescence mek drives cyclin d1 hyperelevation during geroconversion dual mtorc1/c2 inhibitors: gerosuppressors with potential anti-aging effect gerosuppression by pan-mtor inhibitors reversal of phenotypes of cellular senescence by pan-mtor inhibition rapamycin inhibits the secretory phenotype of senescent cells by a nrf2-independent mechanism rapamycin reverses the senescent phenotype and improves immunoregulation of mesenchymal stem cells from mrl/lpr mice and systemic lupus erythematosus patients through inhibition of the mtor signaling pathway targeted elimination of senescent ras-transformed cells by suppression of mek/erk pathway attenuation of torc1 signaling delays replicative and oncogenic ras-induced senescence paradoxical suppression of cellular senescence by p53 contact inhibition and high cell density deactivate the mammalian target of rapamycin pathway, thus suppressing the senescence program rapamycin retards epigenetic ageing of keratinocytes independently of its effects on replicative senescence, proliferation and differentiation status of mtor activity may phenotypically differentiate senescence and quiescence does rapamycin slow down time? geroscience: linking aging to chronic disease rejuvenating immunity: "anti-aging drug today" eight years later mtor regulation and therapeutic rejuvenation of aging hematopoietic stem cells rapamycin-induced enhancement of vaccine efficacy in mice immunostimulatory activity of lifespan-extending agents mtor regulates memory cd8 t-cell differentiation paradoxical aspects of rapamycin immunobiology in transplantation sirolimus enhances the magnitude and quality of viralspecific cd8+ t-cell responses to vaccinia virus vaccination in rhesus macaques chronic mtor inhibition in mice with rapamycin alters t, b, myeloid, and innate lymphoid cells and gut flora and prolongs life of immune-deficient mice mtor inhibition improves immune function in the elderly torc1 inhibition enhances immune function and reduces infections in the elderly cutting edge: rapamycin augments pathogen-specific but not graft-reactive cd8+ t cell responses aging, obesity, and inflammatory age-related diseases immunosenescence in aging: between immune cells depletion and cytokines up-regulation mtorc1 signaling governs hematopoietic stem cell quiescence aging, stem cells, and mammalian target of rapamycin: a prospect of pharmacologic rejuvenation of aging stem cells geroconversion of aged muscle stem cells under regenerative pressure microenvironmental contributions to hematopoietic stem cell aging long-term adaptation to hypoxia preserves hematopoietic stem cell function regulation of the hif-1alpha level is essential for hematopoietic stem cells hypoxia suppresses conversion from proliferative arrest to cellular senescence rapamycin enhances long-term hematopoietic reconstitution of ex vivo expanded mouse hematopoietic stem cells by inhibiting senescence rapamycin is highly effective in murine models of immune-mediated bone marrow failure amino acid and insulin signaling via the mtor/p70 s6 kinase pathway. a negative feedback mechanism leading to insulin resistance in skeletal muscle cells balancing akt with s6k: implications for both metabolic diseases and tumorigenesis tor signaling in growth and metabolism the mammalian target of rapamycin pathway regulates nutrient-sensitive glucose uptake in man rapamycin reverses insulin resistance (ir) in highglucose medium without causing ir in normoglycemic www.aging-us.com medium increased activation of the mammalian target of rapamycin pathway in liver and skeletal muscle of obese rats: possible involvement in obesity-linked insulin resistance rapamycin for longevity: opinion article remission of human type 2 diabetes requires decrease in liver and pancreas fat content but is dependent upon capacity for β cell recovery restoring normoglycaemia by use of a very low calorie diet in long-and short-duration type 2 diabetes population response to information on reversibility of type 2 diabetes caloric restriction and its effect on blood pressure, heart rate variability and arterial stiffness and dilatation: a review of the evidence rapamycin and quasi-programmed aging: four years later mtor inhibition alleviates mitochondrial disease in a mouse model of leigh syndrome mtor pathway activation drives lung cell senescence and emphysema restoration of corticosteroid sensitivity in chronic obstructive pulmonary disease by inhibition of mammalian target of rapamycin national institutes of health rare lung diseases consortium, and miles trial group. efficacy and safety of sirolimus in lymphangioleiomyomatosis fasting and rapamycin: diabetes versus benevolent glucose intolerance diabetes after transplantation and sirolimus: what's the connection? conversion to sirolimus therapy in kidney transplant recipients with new onset diabetes mellitus after transplantation the clinical course and potential underlying mechanisms of everolimus-induced hyperglycemia network-based drug repurposing for novel coronavirus 2019-ncov/sars-cov-2 targeting t-cell senescence and cytokine storm with rapamycin to prevent severe progression in covid-19 immunoregulation with mtor inhibitors to prevent covid-19 severity: a novel intervention strategy beyond vaccines and specific antiviral medicines the mechanistic target of rapamycin (mtor): novel considerations as an antiviral treatment inhaled biguanides and mtor inhibition for influenza and coronavirus (review) inhibition of p38 mapk activity promotes ex vivo expansion of human cord blood hematopoietic stem cells comprehending a killer: the akt/mtor signaling pathways are temporally high-jacked by the highly pathogenic 1918 influenza virus. ebiomedicine antiviral potential of erk/mapk and pi3k/akt/mtor signaling modulation for middle east respiratory syndrome coronavirus infection as identified by temporal kinome analysis matteo pavia task force. sars cov-2 infection in a renal-transplanted patient: a case report uk. covid-19: consider cytokine storm syndromes and immunosuppression the cytokine storm in covid-19: an overview of the involvement of the chemokine/chemokine-receptor system optimisation of a screening platform for determining il-6 inflammatory signalling in the senescence-associated secretory phenotype (sasp) mechanistic insights into impaired dendritic cell function by rapamycin: inhibition of jak2/stat4 signaling pathway adjuvant treatment with a mammalian target of rapamycin inhibitor, sirolimus, and steroids improves outcomes in patients with severe h1n1 pneumonia and acute respiratory failure supplementary key: cord-306504-0wq7rc6s authors: barakovic husic, jasmina; melero, francisco josé; barakovic, sabina; lameski, petre; zdravevski, eftim; maresova, petra; krejcar, ondrej; chorbev, ivan; garcia, nuno m.; trajkovik, vladimir title: aging at work: a review of recent trends and future directions date: 2020-10-20 journal: int j environ res public health doi: 10.3390/ijerph17207659 sha: doc_id: 306504 cord_uid: 0wq7rc6s demographic data suggest a rapid aging trend in the active workforce. the concept of aging at work comes from the urgent requirement to help the aging workforce of the contemporary industries to maintain productivity while achieving a work and private life balance. while there is plenty of research focusing on the aging population, current research activities on policies covering the concept of aging at work are limited and conceptually different. this paper aims to review publications on aging at work, which could lead to the creation of a framework that targets governmental decision-makers, the non-governmental sector, the private sector, and all of those who are responsible for the formulation of policies on aging at work. in august 2019 we searched for peer-reviewed articles in english that were indexed in pubmed, ieee xplore, and springer and published between 2008 and 2019. the keywords included the following phrases: “successful aging at work”, “active aging at work”, “healthy aging at work”, “productive aging at work”, and “older adults at work”. a total of 47,330 publications were found through database searching, and 25,187 publications were screened. afterwards, 7756 screened publications were excluded from the further analysis, and a total of 17,431 article abstracts were evaluated for inclusion. finally, further qualitative analysis included 1375 articles, of which about 24 are discussed in this article. the most prominent works suggest policies that encourage life-long learning, and a workforce that comprises both younger and older workers, as well as gradual retirement. the older population is growing rapidly. in 2019, approximately 700 million people were aged 65 years or more in the world population. it is anticipated that this number will be doubled to 1.5 billion in order to answer the research questions, we examined studies on the aging labour force that were published between january 2008 and august 2019, to recognize the trends in the literature written in english with respect to motivation issues and potential solutions. we focused on the trends starting from the recession in 2008, when, although the economic growth slowed, the employment rate of older people remained strong, thus basically changing the position of older workers [24] . an additional motivation for focusing on this time period was because in the last decade, many assistive technologies have emerged that can aid older adults in different environments. at the same time, many jobs are transforming and can be successfully performed from home, which has recently become evident with the covid-19 pandemic. considering these two observations, the goal of this research is to investigate whether there is an underlying trend that reveals opportunities for aging at work. we adopted the preferred reporting items for systematic review and meta-analysis (prisma) methodology [25] to review the literature on aging at work policies. the prisma flow distinguishes separate stages of systematic reviews. these stages are the collection of papers, scanning of papers' text, evaluation of eligibility of papers, and meta-analysis. the collected papers on aging at work policies exceeded the capacity that would allow articles to be searched manually. thus, we used natural language processing (nlp) algorithms to perform an efficient search of the identified literature. the nlp toolkit [26] was designed to automate the literature search by using different search phrases, scanning, and evaluating eligibility within the prisma framework while generating visualizations of aggregate results. the nlp toolkit provides increased efficiency of the review process by screening the title and abstract while using the predetermined properties and their synonyms to determine the literature search phrases. it should be noted that the nlp toolkit does not understand the context and, therefore, categorizes more articles as relevant than a human reader would. however, it is a valuable resource that increases the efficiency of the review process, as demonstrated in a scoping review [27] that focused on wearable technology for connected health. the adopted prisma information flow is shown in figure 1 . since the nlp toolkit automates the review process of publications that are indexed in only three digital libraries and because we have not taken into account the nonindexed publishers, some relevant publications (e.g., reference [28] ) have been omitted from the analysis. this one and a few other papers were manually identified, and those publications originated from different digital libraries. they were used to confirm the findings of this review. however, we did not use these papers from other digital libraries to identify trends because the size of the searched digital libraries is sufficient for the purpose of the analysis. the nlp search strategy was applied in order to automatically screen irrelevant articles that have a low correlation with the topics of interest in the study. additionally, it helped in consolidating the collected articles by automatically merging results from multiple digital libraries as well as removing duplicate entries. moreover, it allowed us to iteratively fine-tune and modify the search phrases in the hope of identifying more relevant articles. finally, the nlp toolkit automatically generated charts (such as that highlight the trends of publications for certain topics. for more details about the inner workings of the nlp-based toolkit, we refer interested readers to [26] , and also to [27] , which applied it to review wearable technology for connected health. by using yearly graphs, we were able to analyze and report the potential trends in data by investigating articles in each property group (i.e., theme) separately. the nlp toolkit input parameters are a collection of phrases. keywords, together with their synonyms, are applied as search terms for the digital libraries used in the literature search. the input can be further expanded by nlp toolkit properties. properties are phrases that are being searched within the title, abstract, or keywords section of the articles identified from the previous keywords search. property groups are sets of properties that can be used for a more comprehensive presentation of search results. the input parameters used in this study are shown in table 1 . these keywords, property groups and properties are the final versions after an iterative process in which all authors participated and considered different alternatives of keywords and properties, and analyzed the preliminary results. in the process of selecting articles to be included in the quantitative synthesis, four authors participated, of which at least two had to be in agreement. table 1 . the nlp toolkit input parameters: keywords, property groups and properties. "active aging at work", "older adults at work", "successful aging at work", "healthy aging at work", "productive aging at work" motivations "deficit", "discrimination", "growth" solutions "eu policy", "assistance schemes", "eligibility criteria", "legislation", "national policy" active aging at work healthy aging at work older adults at work productive aging at work successful aging at work . solutions-related properties: "eu policy", "assistance schemes", "eligibility criteria", "legislation", and "national policy". the trends apply to the period from 2008 to 2019. the titles and abstracts retrieved by the nlp-based search strategy were evaluated by two independent researchers. they compared their opinions in order to select articles that satisfied the inclusion and exclusion criteria. the inclusion criteria were as follows: 1. articles that consider the concept of aging at work, i.e., the aging labour force. (a) articles that discuss any of three motivation factors, i.e., discrimination, growth, and deficit; articles that support any of three solution pillars, i.e., assistance, policies, and legislation. 2. articles that use research methodology with any results. the exclusion criteria were as follows: 1. articles that are about aging and older people in general that do not consider the concept of aging at work; 2. articles that cover any of three motivation factors, i.e., discrimination, growth, and deficit, in a context other than the aging labour force; 3. articles that cover any of three solution pillars, i.e., assistance, policies, and legislation, in the context other than the aging labour force; 4. articles that do not provide sufficient information for classification. when researchers differed in their opinions about an article's suitability, the article was selected for further consideration. this resulted in an initial selection of 70 articles. furthermore, the full texts of the chosen articles were reviewed in order to determine their suitability for further discussion. after the data abstraction of the final selected articles, two additional researchers separately reviewed 20% of randomly chosen articles. in the case of any disagreement on the suitability of articles, a third researcher was consulted for recommendation and assessment of the given article. this researcher was a specialist who drew a final conclusion regarding the article selection process. for the selection of the final 24 articles, two of three authors needed to be in agreement, considering the completeness of the methods, relevance to the study goal, details about the population, and impact of the study. we used the inductive approach for the article review and analysis. the selected articles were systematically organized into two groups: 1. articles that focused on motivation factors (i.e., discrimination, growth, and deficit); 2. articles that focused on solution pillars (i.e., assistance, policies, and legislation). we generated a detailed summary of each article and extracted the following items: objective, methods, main findings, limitations, and keywords. the extracted items provided the input data for discussion and conclusions. after searching pubmed, ieee xplore, and springer, we identified 47,330 potentially articles. after performing the prisma steps shown in figure 1 , the number of articles was reduced. specifically, the removal of duplicates reduced the number to 25,187 studies. the first screening process eliminated an additional 7756 studies with an out-of-scope publication year, or other parsing issues (no title, abstract, etc.). then, 17,431 papers were subject to the eligibility estimate using the automated nlp toolkit, which removed articles without any of the required properties. eventually, 1375 papers remained as potentially relevant and eligible for further manual inspection. a total of 70 articles were initially selected to analyze the trends on the aging labour force, while 24 articles were used to explore the motivation issues and solutions in the given context. the selected keywords aimed to show different aspects on the literature corpus on aging at work. figure 2 presents the number of potentially relevant papers that contained the defined keywords and that were additionally filtered manually based on their relevance to the defined properties per year. a relatively similar number of identified articles can be observed in the evaluated time period. "active aging at work" is the keyword with the smallest number of occurrences. the most frequent keyword phrase in the identified publications is "older adults at work". the number of research articles did not grow in the period of interest, but articles that address the associated keywords seem to be distributed more evenly over time. findings related to property groups show that the number of papers related to "motivation" of the adult workforce is relatively constant, with a small decline in the last two years, while the papers focused on the "solutions" property group seems to be slightly more predominant in the last few years ( figure 3) . a more granular analysis was carried out on the property groups data at the properties level, and the chart reveals that "growth" is the primary topic within the motivation group of papers, followed by "discrimination". the papers related to the topic of "deficit" appeared only in recent years ( figure 4 ). the focus of papers within the "solutions" property group ( figure 5 ) seems to move from "national policy" based to "legislation", while "assistant schemes" and "eu policies" seem to be of smaller interest for the scientific community. there was only one paper that addressed "eligibility criteria", which makes this topic interesting for further research. a total of 12 articles out of 24 were selected for the further analysis of motivations that drive the research on the aging labour force. the selected articles were organized into three focus groups according to the considered terms related to motivation, i.e., "discrimination", "growth", and "deficit". a more detailed analysis of these articles is presented in table 2 . the remaining 12 articles out of 24 were used for a more detailed analysis of solutions for the aging labour force. the selected articles were organized into three focus groups according to the considered solutions, i.e., assistance, policy, and legislation. table 3 shows results of the analysis. the ageing labour force could represent a risk both for society and economy unless it is well managed. therefore, the attention that researchers, governments and other stakeholders have devoted to this issue has grown over the time. according to analysis of motivations ( table 2 ) and solutions ( table 3 ) for ageing at work, possible policy implications have been identified and split into five parts: extend the length of work ability. different organizations implement changes by creating common policies and strategies, but they are not oriented toward the older workforce. intentionally interrupting the existing age-graded logic and its replacement with age-neutral logic are proposed in [16] . the authors in [29] found that the expected decline in employment could be partially offset by public policies that encourage the employment of older people. this causes problems for public finances due to expenditures on health, long-term care, pensions, etc. [3] . in order to encourage policies to maintain work ability at an old age, it is necessary to invest in decreasing of both work stress and social inequalities in health care [30] . however, extending the length of work ability does not just pose issues, but provides social and economic opportunities. avoid the age-based discrimination. the labour market will have to adapt working positions and eliminate the attitude of age-based discrimination, since it will have to fight for a working force older than 65 because it is lacking. when facing age-based discrimination at work, the organizational help and friends and family support were found to be significant in achieving better health and adaptability [31] . on the other hand, older workers with high job satisfaction without age-based discrimination remained longer in the labour market [32] . finally, the authors in [10] found that experiences of discrimination were rare and reduced with age among men, whereas almost no age differences were noticed among women. this indicates that age-based discrimination is possibly overstated, and age-related obstacles could have been miscomprehended. therefore, the flexibility of older workers can be seen as an opportunity for the active global aging trend [33] . older workers with high job satisfaction, development possibilities, affirmative relations to management, and no age discrimination stayed longer in the work market. positive relations with colleagues did not affect older workers decisions on early pension. the measures were self-evaluated. the psychosocial factors were measured at single time point. successive changes in the psychosocial work conditions could cause early pension that would be missed by the study. early pension, work conditions, management quality, job satisfaction [31] to examine the relation between successful aging and stress sources at work among older workers in china questionnaire study. study sample-242 workers aged >40 years. method variance. harman's one-factor test. factor analysis. perception of institutional support and social help from family and friends significantly corresponds to efficient aging at work. participants were surveyed at a single time point. the study relied on participants self-reports. successful aging, work stressor, social help, institutional support [10] to improve comprehension of the discrimination at work, with a focus on age and gender challenges. survey study. study sample-3203 workers with mean age 43 years. computer-aided telephone interview. binary logistic regression. daily discrimination was unusual. it appears with age among men, and not among women. the nature of work market age obstacles is not understood correctly, and the degree of aging discrimination is overstated. there was a small number of workers who faced daily discrimination. the degree of daily discrimination has to be further investigated. ageism, employment discrimination, gender, work [33] to investigate the age-related connection between job stress, extreme tiredness, prosperity, and associated personal, institutional, and community factors. survey study. study sample-1298 participants aged 18 years or older. descriptive statistics. linear regression. one-way analysis of variance. job stress was associated with several types of extreme tiredness and prosperity. personal work style, institutional and community factors were associated with prosperity. old age was connected to a poor perception of health. the study did not compare work differences. the data were cross-sectional and the causal relation of the work conditions and style with job stress, extreme tiredness, and prosperity could not be confirmed. age difference, exhaustion, prosperity, work stress, work condition growth [30] to investigate the connection of social, demographic, economic and job related factors with disability. a decrease in job stress and sociable disproportion in healthcare is appropriate for the development of policies that support aging at work. the disability indices were not formulated based on functional testing. the evaluation of stressful work was performed by abbreviated scales. position, aging workforce, work stress, work ability, social disproportion [16] to examine organizational work disrupting age-graded policies. interview study. study sample-23 organizations with employees aged 50-69 years. qualitative content analysis. organizations implement changes by creating common policies and strategies, but not those oriented toward an aging workforce. they propose to intentionally interrupt the existing age-graded logic and replace it with age-neutral logic. creative, high-tech, or communications organizations were not studied. sample size was small, so broader claims about minnesota or u.s. workers cannot be made. organizational logic, older workers, pension, flexibility [29] to examine the influence of demographic trends on the economic growth and employment level that japan is expected to face in the next 20 years the expected decline in employment could be partially offset by public policies that encourage the employment of older people. not reported. low fertility, population decline, population aging [3] to provide a literature review on the need for the senior workforce and recognize main directions for research on this topic. there is a negative association between salary and employment outcomes for the senior workforce. the connection between efficiency and salary is defined by governmental conditions and motivation to take early pension. the variations in micro-, macro-, and meso-level factors were not captured, simultaneously. there is a need for improvements in the analysis of the impact of age-based discrimination on the employing of older workers. work market, employment protection, regulation, legislation deficit [17] to examine the influence of organizational factors on work ability. cross-sectional study (online survey). study sample-306 employees. path analysis modeling. maximum likelihood estimation. organizational culture and professional effort indirectly enabled the prediction of work ability, with job satisfaction mediating these relations. the sample included mostly younger and female workers. the cross-sectional design of the study did not provide the possibility to understand causes and effects related to work ability. work ability, organizational culture [34] to recognize professions prevailed by an older workforce and evaluate their vulnerability to hazards in these professions. survey study (interviews). study sample-6502 workers aged 55 or more. chi-squared test. work-related hazards should be decreased to inhibit professional disturbance in professions prevailed by an older workforce. self-informed data were included in the study. health issues, hazards, profession, musculoskeletal disorders [35] to investigate job discrimination related to age and disability. integrated mission system data from 1993 to 2007. descriptive statistics. job discrimination of aged or disabled workers is focused on challenges involving seating, revenge, and cancellation. data do not contain supplemental information regarding a secondary cause for each filed allegation. job/age/disability discrimination [36] to investigate the relation between psychosocial factors and pension intention of older employees, while considering healthiness and work ability. survey study. study sample-3122 workers aged 50 years or older. pearson correlation. ordinal logistic regression. ageism and the absence of acknowledgement and growth opportunities are connected to older male workers' pension intention. work ability is strongly related to the pension intention of both genders. the pension age could depend on unfamiliar alternations in the worker's environment or health status. psychosocial factors, pension intention, healthiness, work ability table 3 . detailed analysis of articles that focus on solutions. assistance [37] to critically review the literature on older farmers in canada and the usa and describe how musculoskeletal disorders influence their ability to work. literature review. twelve articles analyzed in detail. musculoskeletal disturbance can lead to trauma or loss of ability to farm. it is necessary to develop safer work practices and encourage healthiness, efficiency, and professional longevity. some related articles may have been excluded from the study due to the specificity of the search strings. older farmers, work-related musculoskeletal disorders, pension age [8] to investigate the action plans that workers use to acquire skills in software and complete assignments exploratory study (interviews, surveys). study sample-10 administrative assistants. grounded theory. non-parametric statistics. administrative assistants are regularly communicating and sharing knowledge. exclusion of workers from different organizations, lack of extensive investigation on behavior at work, and creation of software tool design instructions. workplace, generations, collaboration [38] to collect information to direct the preparation of programs for returning older adults to work survey study (questionnaires). study sample-37 jobless participants aged 51-76 years. anova. chi-square test. participants who felt discriminated indicated the preference to acquire technological skills and get classroom-based education. work obstacles could not be generalized. older workers, absence of technological skills, work conditions, work experiences policy [39] to investigate factors related to perceived work ability in a sample of brazilians sample aged 50 years and more longitudinal study (surveys). study sample-8903 workers aged 50 years and over. multivariate analysis. poisson regression. work ability in old age depends on the life course, i.e., academic level, health conditions in younger and older age, minimum working age, etc. policies aiming to extend longevity in the work market must consider these factors. the collection of self-reported data associated with past experiences might have been affected by the preference to demonstrate an acceptable image, causing information bias. establishment of temporal relations for the variable related to current conditions is limited. work ability, health, socioeconomic factors [40] to review the documentation about the influence of psychological health on staying at work after pension and discuss consequences of public health policies. systematic literature review. ten articles analyzed in detail. staying at work after pension can be positive for psychological health. pension action plans are required to provide national policies that will increase the pension age and not exacerbate any disproportion in the older population. only cross-sectional and longitudinal studies investigating the impact of unexpected variables on psychological health were involved in the review. pension, job status, psychological health, social policy [7] to analyze the literature on workplace health promotion (whp) aimed at older workers systematic literature review. eighteen articles analyzed in detail. existing documentation does not demonstrate that whp enhance work ability, retention, efficiency, lifestyle, health, or prosperity of the senior workforce. the heterogeneity and low quality of the studies makes it difficult to synthesize the literature and draw the conclusions. workplace health promotion, senior workforce, health, lifestyle [41] to investigate the results of unfulfilled expectations of staying at work after age 62 on life satisfaction. longitudinal survey. study sample-1684 workers aged 51 and over. growth mixture modeling. descriptive statistics. linear regression. multi-nominal logistic regression. majority of men and almost no women expected to stay at work after age 62. the subjective prosperity of older adults is affected by unmet expectations of staying longer at work . the significance of different job options before full pension was not assessed. work expectations, pension, life satisfaction, subjective prosperity [42] to find out whether the workers' ages determine the evaluation of their work-life balance. survey study. study sample-500 workers aged from 21 to 70 years. kruskal-wallis test. spearman's r correlation analysis. the maintenance of work-life balance will be indicated by older workers. all employees do not have the same possibilities to take advantage of solutions that provide the support of work-life balance. the diversity of the answers given by the participants according to the type and state of particpants affiliation was not analyzed. work-life balance, workers'assessment, aging workforce legislation [13] to estimate the impact on the efficiency of the reduction of assortment mechanisms among senior employees. italian national institute of statistics data from 2009 to 2013. descriptive statistics. multivariate regression analysis. the growth of pension age, as well as limitations on early pension intention, kept older workers at the work without a positive influence on efficiency. more efficient older employees are mroe likely to stay at work in comparison with those who are not as efficient. the number of employees kept at the work was underestimated. the reform's influence on the employees' structure is an additional issue. aging workforce, pension reforms, labor productivity [43] to investigate the workforce participation and absence among older adults in sweden. data from the swedish population register. study sample-workers aged 55-64 years. descriptive statistics. the alternation in regulations affected the share of workers associated with illness and disability pension programs. simultaneously, the share of workers going to early pension has grown. this study noticed no alternation related to the difference in working-life exit patterns associated with hierarchical and academic positions in the organization. workforce participation, older worker, pension, illness benefits [20] to review the expert way of thinking in relation to policies influencing the employment of older adults. survey study. study sample-89 participants aged 50 years or older. descriptive statistics. a broad range of policies recommend possibilities for innovation. there is a sampling bias related to the language and review method. there were no participants from south america, while a few participants from africa demonstrated about limited internet access. aging workforce, older workers, employment policy, mandatory pension, government answers [44] to investigate whether age and mental capabilities mitigate the connection between job stress and negative affect survey study. study sample-139 workers aged 25-69 years. descriptive statistics. correlation and regression analysis. johnson-neyman technique. cognition mitigated the connection between job stress and negative affect. crystallized cognition had a large influence on the connection between job stress and negative affect for senior workers. the mitigating influence of fluid cognition was unchanging. the study did not permit a setup of directionality among variables. better evaluation of professional features and job requirements is needed. job stress, negative affect, older workers improve the well-being of older workers. difficulties that older people experience at work indicates a need for healthcare strategies to adjust the work conditions so that they are suitable for older workforce with decreased physical ability. the authors in [34] identified professions that are dominated by older workers and suggested that work-related hazards (e.g., noise, vibrations, etc.) should be reduced to prevent health problems. older workers and workers with disabilities can be used as the sources of required skills. such unutilized workers need to be recruited and well-managed to ensure that their skills are retained [35] . in order to improve the well-being of older workers, the authors in [17] considered the influence of organizational factors, whereas those in [36] examined psychosocial factors at workplace. unfulfilled prospects for work in old age influenced the prosperity of older workers [41] . therefore, it is necessary to perform workplace health promotion activities [7] . promote the lifelong learning. the growth of the aging labour force and emerging technologies change the work environment, generating a need to train older workers to improve their skills. older workers gain benefits when well-designed training approaches are used. therefore, the authors in [38] studied the training requirements and work experience, as well as the perception of ideal job features. to encourage technology adoption in the work environment, there is a need to understand how workers study software tools and complete assignments [8] . therefore, further research should concentrate on developing safer work practices and supporting worker's productivity and professional longevity [37] . encourage the late retirement. in order to achieve more successful inclusion of older people into labour market, there is a need for more comprehensive policies and harmonized all-age legislation. this is indicated by the fact that the overall decrease in the share of individuals in pension and disability programs is caused by changes in regulations [43] . in this regard, the authors in [20] studied the factors that affect the aging labour force and the range of current policies that suggest the possible opportunities for innovation. the implications for older workers are related to lifespan earnings, job retention, retirement savings, the possibility of changing jobs, or employment assurance [13, 44] . increasing the pension age should not exacerbate social and health disproportion in the older workers [40] . this is important since many older workers report unequal options to take advantage of solutions for supporting the balance between work and private life [42] . the abovementioned policy implications may be useful from policy making perspective. they could lead to the creation of framework that targets government, the non-governmental sector, private sectors and other stakeholders. however, the creation of such policy framework should take into account many other contributing factors [28] that can be the subject for future research activities. furthermore, a future research agenda should consider the concept of ageing at work at national level and intensify collaboration at international level. nevertheless, the following recommendations for governments and other stakeholders can be drawn from this research study: 1. encourage incentives to extend the working ability in old age; 2. eliminate age-based discrimination at work along with promotion of gender equality; 3. invest in education, lifelong learning, health and well-being while increasing the productivity; 4. improve the working conditions to increase the safety at work and health of workers; 5. support late retirement along with the increase of life expectancy; 6. reduce the use of early retirement if workers' health and work ability are satisfactory. this study provides a systematic review of articles related to the aging labour force in terms of recent trends and future directions. additionally, it identifies and evaluates the motivations that drive research on the aging labour force and potential solutions that address the issues related to the aging at work. sustainable growth and age-based discrimination are recognized as the main motivations to perform the research activities in the given context. on the other hand, policies that stimulate life-long learning are identified as a potential solution for the aging labour force. the additional value of this study lies in its identification of policy implications and recommendations for governments and other stakeholders. furthermore, along with this paper, we also provide a supplementary materials of all identified relevant articles that can be filtered in terms of different fields to recognize articles for further analysis in a particular subfield. this initial search for a systematic review design may provide useful results on the relevance, practicability, and time needed to carry out a systematic review. despite the valuable insights in this study, it suffers from several limitations as well. first, this study took into consideration only three digital libraries, so some relevant articles could be unintentionally omitted from the study because of the specificity of the search strings and the fact that we have not taken into account the non-indexed publishers. however, the size of the searched digital libraries is sufficient, so the obtained results are suitable for the purpose of the study. additionally, the articles obtained for this study are the results of a search query sent to different search engines with different retrieving and formatting rules from those that are used in the considered libraries. however, we are convinced that the specificities of the publishers' search engines had no influence on the findings of this study, taking into the account the number of analyzed articles. finally, the articles are categorized to provide the quantitative results that show the recent trends and future directions of aging at work, whereas the qualitative results are manually covered to a limited extent to describe the motivation issues and solutions for the aging labour force. the aging of the population raises many issues and provides many opportunities. it intensifies the requirement for long-term care, healthcare, and a better-skilled workforce, and increases the demand for age-friendly environments. on the other hand, it enables the contributions of older people to their family, local community, or broader society. in order to review articles related to the ageing at work in terms of recent trends and future directions, we performed a scoping literature review using an nlp-based framework to automate some of the steps in the prisma methodology and quickly identify potentially relevant articles. as a result, starting from over 70 thousand potentially relevant articles, we analyzed in detail about 70 of the most relevant approaches and discussed 24 of them. we identified that the most prominent works suggest policies and practices that support life-long learning, a workforce that comprises both younger and older workers, and gradual retirement. approaches like these could be the best response to the globalization issues, reduction of workforce, maintenance of financial independence of the aging workforce, and other social benefits. future work could be focused on standardizing approaches to this problem across different countries, supported by different policymakers. the goal should not be to end up with the same approaches in different environments, as this would hardly encompass all cultural, sociological, and economic factors. instead, we believe that systematically documented and well-thought-out approaches will facilitate the measurement of the results and analysis of causality when investigating benefits and drawbacks. funding: v.t., e.z., i.c. and p.l. acknowledge the support of faculty of computer science and engineering, ss. cyril and methodius university in skopje, north macedonia. in addition, this manuscript is funded by fct/mec through portuguese national funds and when applicable co-funded by feder-pt2020 partnership agreement under the project uidb/eea/50008/2020 (este trabalho é financiado pela fct/mec através de fundos nacionais e quando aplicável cofinanciado pelo feder, no âmbito do acordo de parceria pt2020 no âmbito do projeto uidb/eea/50008/2020). this manuscript is based upon work from cost action ic1303-aapele-architectures, algorithms, and protocols for enhanced living environments and cost action ca16226-sheld-on-indoor living space improvement: smart habitat for the elderly, supported by cost (european cooperation in science and technology). cost is a funding agency for research and innovation networks. our actions help connect research initiatives across europe and enable scientists to grow their ideas by sharing them with their peers. this boosts their research, career and innovation. more information in www.cost.eu. based on ca16226 project, ltc18035 inter cost was proposed for national funding support of cost action framework by meys, czech republic. this work was also supported in part by the project (2020/2206), grant agency of excellence, university of hradec kralove, faculty of informatics and management, czech republic. the demand for older workers. in ageing, health and pensions in europe: an economic and social policy perspective healthy ageing and well-being at work ageing europe: looking at the lives of older people in the eu quality of life framework for personalised ageing: a systematic review of ict solutions workplace health promotion for older workers: a systematic literature review generations in the workplace: an exploratory study with administrative assistants joint report on towards age-friendly work in europe: a life-course perspective on work and ageing from eu agencies; publications office of the european union everyday discrimination in the australian workplace: assessing its prevalence and age and gender differences older women's responses and decisions after a fall: the work of getting "back to normal". health care women int transition from the labor market: older workers and retirement ageing workforce and productivity: the unintended effects of retirement regulation in italy understanding the psychology of diversity organizational change around an older workforce primary-and secondary-level organizational predictors of work ability population aging: opportunity for business expansion, an invitational paper presented at the asia-pacific economic cooperation (apec) international workshop on adaptation sustaining work participation across the life course supporting the labor force participation of older adults: an international survey of policy options accessibility and new technology mooc-disability and active aging: technological support one size does not fit all: uncovering older entrepreneur diversity through motivations, emotions and mentoring needs aging and work: an overview employers' use of older workers in the recession preferred reporting items for systematic reviews and meta-analyses: the prisma statement automation in systematic, scoping and rapid reviews by an nlp toolkit: a case study in enhanced living environments literature on wearable technology for connected health: scoping review of research trends, advances, and barriers the sage handbook of aging, work and society population decline, labor force stability, and the future of the japanese economy socioeconomic position, psychosocial work environment and disability in an ageing workforce: a longitudinal analysis of share data from 11 european countries an investigation of predictors of successful aging in the workplace among hong kong chinese older workers psychosocial work environment and retirement age: a prospective study of 1876 senior employees age differences in work stress, exhaustion, well-being, and related factors from an ecological perspective hazards and health problems in occupations dominated by aged workers in south korea age and disability employment discrimination: occupational rehabilitation implications the association between psychosocial work environment, attitudes towards older workers (ageism) and planned retirement work-related musculoskeletal disorders in senior farmers: safety and health considerations. workplace health saf training older workers for technology-based employment life course and work ability among older adults: elsi-brazil the impact of working beyond traditional retirement ages on mental health: implications for public health and welfare policy unexpected retirement from full time work after age 62: consequences for life satisfaction in older americans work-life balance: does age matter? work has the participation of older employees in the workforce increased? study of the total swedish population regarding exit from working life the moderating effects of aging and cognitive abilities on the association between work stress and negative affect this article is an open access article distributed under the terms and conditions of the creative commons attribution the authors declare no conflict of interest. the founders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. key: cord-311029-x0lk4110 authors: palermo, sara title: covid-19 pandemic: maximizing future vaccination treatments considering aging and frailty date: 2020-09-18 journal: front med (lausanne) doi: 10.3389/fmed.2020.558835 sha: doc_id: 311029 cord_uid: x0lk4110 the covid-19 pandemic is proving to be a multiplier of inequalities. especially toward the elderly population. a voiceless scream that comes from geriatrics, nursing homes, hospices from all over italy. they call it the silent massacre: from north to south, the bulletin of coronavirus positive—or already deceased—elderly people continues to grow exponentially without a chance to counter it. population aging and chronicity are a question that needs to be addressed. frailty is the most challenging expression of population aging, with major consequences for public health and clinical practice. it is a geriatric syndrome which consists in a state of higher vulnerability to stressors attributed to a lower homeostatic reserve due to an age-related multisystem physiological change. people over 60, and especially over 80, are particularly vulnerable to severe or fatal infection. moreover, the age-related dysregulation of the immune system in the elderly (i.e., immunosenescence and inflammaging) results in poorer responses to vaccination. physical frailty is an effective health indicator and it has previously shown to predict the response to the seasonal flu vaccine. these findings suggest that assessing frailty in the elderly may identify those who are less likely to respond to immunization and be at higher risk for covid-19 and its complications. moreover, cognitive frailty and neurocognitive disorders, mental health and reduced awareness of illness negatively impact on adherence to complex medication regimens among elderly patients. a worldwide research and development blueprint have been initiated to accelerate the development of vaccines and therapeutics for the covid-19 outbreak. considered the above, i suggest the importance to consider aging in thinking about future civud-19 vaccination and treatment, focusing on the possible impact of physical and cognitive frailty. covid-19 had such a high transmission rate in italian nursing homes-even in the regions least affected by the virus-that they were considered "contagion multipliers" from the beginning of the pandemic. to shed light on the matter is the "national survey on covid-19 contagion in residential and social-health facilities" by the "istituto superiore di sanità" (iss, https://www.iss.it/ en/home), which is the main center for research, control and technical-scientific advice on public health in italy. iss reports 3,859 deaths since 1 february, with 133 patients tested positive for covid-19 and 1,310 elderly with fluesimilar symptoms (1) . despite the drama of these data, national epidemiological data need to be considered to understand how devastating the impact of infection on the elderly is. the iss report -based on available data on april 13th, 2020 (18,641 deaths)-warned that the mean age of patients dying for sars-cov-2 infection was 79 years (median 80, range 5-100, . women dying for sars-cov-2 infection had an older age than men (median age women 83-median age men 79 ). an increase in lethality is observed with increasing age. lethality is higher in male subjects in all age groups, except for the age group over 90 years old. moreover, pre-existing conditions were usually observed in sars-cov-2 positive deceased patients. this information is not complete. there is the gray number of patients never screened to which is added the number of elderlies for whom the potential infection has never been reported. probably, many domestic deaths could be the consequence of the virus. this is not just an italian problem. covid-19 is causing "hidden deaths" -elders left to die in their beds or hidden from official death statistics-across europe. over 95% of people who died of sars-cov-2 in europe were over 60, according to who. more than four in five of those people had at least one other chronic underlying condition. half of coronavirus deaths happen in care homes. snapshot data on april 12th from 5 european countries suggest that care home residents have so far accounted for between 42 and 57% of all deaths related to covid-19, according to the london school of economics. this general framework imposes a reasoning about the impact of the various types of aging not only on the possibility of incurring the infection but also on the prognosis and efficacy of potential treatments. at the beginning of may, europe decided to do its part by accepting the who's invitation to join the "access to covid-19 tools (act) accelerator" initiative and investing in the development of diagnostic tests, drugs and vaccines against coronavirus. the proposed perspective article can stimulate further interest about frailty implications for the development of new vaccine formulations and vaccination protocols in case of pandemic emergencies within the reader audience. i presented here a different take on an existing issue that has important clinical implications but has been neglected in the early stages of the pandemic. the world's population is aging. in 2018, people aged 65 and over exceeded children under the age of five. in 2019, one in 11 people was over 65 (9%). this ratio could move to 1 in 6 people (16%) by 2050. an even more important fact: the number of people aged 80 and over is expected to triple from 143 million in 2019 to 426 million in 2050 (2) . to date, the european union consists of the over 500 million people, of whom about 100 million are elderly people (3) . while increasing life expectancy is considered a major achievement, it has a significant impact on public health since the expense to be incurred depend on the interaction between individual determinants (age, mortality, disability, and health) and social determinants (national income, technology, and wages) (4) . progressively there has been an epidemiological transition from infectious and disabling diseases to chronic-degenerative diseases (5) . indeed, population aging strongly increases expenditures on long-term care (6) . elderly people are also large medicines consumers, while a lot of older adults end up suffering from problems related to medication. the european medicine agency (ema) ensures that the medicines used by older people are of high quality and are studied appropriately in the older population, throughout the medicinal product lifecycle. for that reason, the clinical trials regulation (ec) no. 536/2014 states that "in order to improve treatments available for vulnerable groups such as frail or older people, people suffering from multiple chronic conditions, and people affected by mental health disorders, medicinal products which are likely to be of significant clinical value should be fully and appropriately studied for their effects in these specific groups, including as regards requirements related to their specific characteristics and the protection of the health and well-being of subjects belonging to these groups." indeed, ema develops scientific guidelines to help medicine developers address the specific requirements of older people in their medicine development programs, including in the design and conduct of clinical trials. ema disclosed a reflection paper on "physical frailty: instruments for baseline characterization of older populations in clinical trials" (7), actively recognizing the importance of considering the various types of aging when experimenting and developing new pharmacological treatments. the value of vaccines for the elderly should be based on efficacy, the capacity to confer protection against a specific infection; effectiveness, the capacity to generally improve health by avoiding other related diseases. to enhance both parameters, it is necessary to better understand aging. there is no single way of aging, but there are as many different aging processes as there are humans. however, some main directions can be identified. aging is a gradual and continuous process of natural mutation that begins in early adulthood. during the first year of middle age, many bodily functions begin a gradual decline. the life-span perspective recognizes changes in the functional state as characteristic of the human being aging process (8) . such changes are considered normal and are sometimes called pure aging. (9) . successful aging refers to the postponement or reduction of the unwanted effects related to advancing age. the main features of successful aging are the maintenance of physical health, an active and autonomous life; a full and satisfying emotional-relational life; prevention of ailments and disabilities. this perspective also applies to the neuropsychological domain: successful cognitive aging refers to people whose physical health may or may not be good, but whose cognitive profile remains exceptional; typical cognitive aging refers to people who experience a slow loss of cognitive efficiency that does not result in a neurocognitive disorder and whose distinctive feature is the reduction of mental processing speed (8) . it is a common opinion that aging is the main risk factor for many chronic diseases. recently, different types of aging patterns (the so-called "ageotypes") have been identified, based on the molecular pathways that changed over time (10) . four distinct biological pathways seem to be possible: metabolic (relating to the build-up and breakdown of substances in the body), immune (relating to immune responses), hepatic (relating to liver function), and nephrotic (relating to kidney function) (10) . therefore, ageotype may provide a molecular assessment of individual aging, reflective of personal lifestyle and medical history; it can help people focus on health risk factors and find areas where they are most likely to encounter problems down the line; it may ultimately be useful in monitoring and intervening in the aging process (10) . multimorbidity and polypharmacotherapy weakens the body and can predispose to accelerated aging, with an increase in disability, hospitalization, institutionalization, and mortality rate. frailty is certainly the most problematic expression of the aging population (11) . it can be defined as a dynamic condition of increased vulnerability, which reflects age-related multi-systemic pathophysiological changes, associated with an increased risk of negative outcomes, such as institutionalization, hospitalization, and death (12) . frailty in the elderly is an integrated (13) and multidimensional (14) condition in which biological, functional, psychological, and social assets interact with each other, determining and characterizing fragility (15) . to date, there is no unequivocal and recognized operational definition of frailty. eip-aha experts have identified two main approaches: the first concerns physical determinants (biomedical approach), while the second considers biological, cognitive, psychological, and socioeconomic factors (bio-psycho-social approach). indeed, a reliable assessment cannot be separated from the analysis of the affective, cognitive, and relational components (11) . in support of this interpretation, the sunfrail project (16) has defined frailty as a dynamic state that concerns the loss in one or more domains: • physical: weight loss, slowness, reduced physical activity, strength, and endurance. • psychological: cognition, mood, coping strategies. • socio-economic: social relationships, social support, income capacity. some scientific societies are recommending assessing frailty in patients with covid-19 infection to guide their triage and the results seem to be promising (17) . considering scientific literature, frailty was only investigated regarding its association with overall mortality, hospital contagion, intensive care unit admission rates, and disease phenotypes (18) . according to a recent systematic scoping review, specific interventions in relation to frailty or its impact on covid-19 treatments have not been evaluated yet (18) . aging leads to a progressive declining competence of the immune system, resulting in increased susceptibility to infectious diseases. flu is among the main causes of infectious death-and the most important agent of respiratory disease outbreaks-among the elderly (19) . indeed, morbidity and mortality due to respiratory infections increase in subjects ≥65-years old (20) . often subtle clinical manifestations may not be recognized initially in the elderly, preventing timely administration of antiviral treatment (19) (20) (21) . to compound the situation, the effectiveness of vaccination is often reduced due to immunosenescence (21) . aging results in a weakening in immune competence, which is characterized by increased autoimmunity, inability to maintain immunity to latent infections, increased risk of chronic inflammatory diseases and infections; disfavored vaccine efficacy (21) . frailty afflicts the immune system, more than would be expected because of aging (22) . a dysregulated immune systemcharacterized by amplified immunological markers of t-cell senescence and intensified inflammation-has been identified in frailty elderly (22) . immunosenescence and frailty are commonly described in older adults and appear to share common inflammatory factors (23) . it is unclear whether they are separate entities that occur due to coincident or potentially confounding factors, or if they are connected by the same underlying cellular mechanisms (23). however, it is possible that they support each other, triggering a deteriorating process that profoundly affects health and the ability to adapt to viral infections in the elderly. aging has been associated with an increase of inflammatory biomarkers (24) . this age-related fluctuation of the inflammatory mediators is referred to as "inflammaging." this concept refers to the connection between the aging process and a type of chronic low-intensity inflammation that has no visible (latent) symptoms but that produces systemic effects on the whole organism (25, 26) . inflammaging is considered a major immunological characteristic of the elderly and an etiological agent for agerelated pathologies (25) (26) (27) (28) . elevated levels of inflammatory cytokines in older adults are suggestive of inflammaging (29) . inflammation plays a central role in physical frailty. not only changes in hormone and inflammatory cytokine levels may mediate frailty among postmenopausal women (30) , but a mouse model of frailty and chronic inflammatory pathway activation demonstrated the upregulation of numerous proinflammatory cytokines (31) . the hypothesis that inflammation affects multimorbidity and frailty by increasing catabolism, inhibiting growth factors, and interfering with homeostatic signaling is being considered by researchers (32) . although pending further confirmation, inflammatory biomarkers could support diagnosis, prognosis, and therapeutic decisions in frail elderly (24) . it is important to note that inflammaging causes profound changes in crucial components of the innate immune system, which are related to an increased risk of infection and increased infection-related mortality (33) . in addition, the importance of molecules that contain damage-associated molecular patterns is emerging to activate innate immune cells and maintain the state of inflammaging (34) . between immunosenescence and inflammaging there is a mutually maintained state where immunosenescence is induced by inflammaging and viceversa (34) . increased production of inflammatory mediators contributes to the decrease of the adaptive immune response and, eventually, to immunosenescence (34) . in contrast, the decrease of the adaptive immune response reinforces the stimulation of the innate immune response leading to inflammaging (34) . frailty and multimorbidity are not synonyms (35) . quoting villacampa-fernández and colleagues [(35), p. 31]: "frailty identifies the increased vulnerability to stressors due to a dynamic, non-linear, and multidimensional depletion of physiological reserve and redundancy, whereas multimorbidity refers to the coexistence of two or more clinically manifest chronic diseases." elevated blood levels of pro-inflammatory markers are a powerful risk factor for multimorbidity and predict its future rates of change (32) . moreover, multiple chronic conditions are a significant contributor to pre-existing frailty (36) . a recent metaanalysis found that the prevalence of multimorbidity in frailty elderly was 72% and the prevalence of frailty among multimorbid individuals was 16% (37) . moreover, the number of chronic diseases mediates the relationship between sex and the number of frailty components, and the latter mediate the relationship between the number of diseases and disability (38) . considering vaccination, increasing frailty or the coexistence of multiple chronic conditions contributes to the loss of vaccine effectiveness (39) . much of the research literature on frailty has focused on physical health. however, mental health including cognition, personal well-being, and social interactions are as important as those related to physical illness and disability (40) . frailty may be relevant in identifying older people at risk of deteriorating mental health (41) . indeed, for each additional deficit-defining frailty, odds of psychiatric illness increased (42) . moreover, while an association with increased emotional distress has been found at the earliest stage of pre-frailty, once frailty develops there is a higher likelihood of clinically significant depression and anxiety (41) . frail elderly individuals were significantly more likely to have cognitive decline, memory decline, and sarcopenia (43) . cognitive frailty specifically refers to the co-occurrence of mild cognitive impairment and physical frailty in the absence of a major neurocognitive disorder diagnosis (44) . interestingly, individual indicators of frailty have been independently associated with cognitive function (45) . processing speed, executive function, and attention have been associated with weak grip strength and slow walking speed (45) . moreover, researchers found that frailty was directly associated with poorer executive function and worse sleep quality, which was also associated with worse processing speed (40) . the presence of physical and/or cognitive frailty in the elderly increases the risk of negative outcomes and leads to greater use of health and care services (11) . the interaction between mental health and the immune system is the subject of study in psychoneuroimmunology, which highlights the overcoming of brain-mind-body trichonomy (46) . not only the immune and emotional systems mirror each other, but both the immunological and emotional responses are dynamic and continuously changing (47) . clinical studies point to roles for the immune system in psychiatric diseases, while basic science has revealed that the brain has an active and multi-cellular resident immune system that interacts with peripheral immunity and impacts behavior (48) . conversely, mental health disorders can affect the immune system. indeed, relatively intense, or chronic stressors can produce immunosuppression (49) . pathogens of different nature, changes in environmental conditions, and significant life events cause an exacerbated or dysfunctional compensatory immune or emotional response in patients suffering from emotional or immunological disorders (47) . for example, major depressive disorder (mdd) has a marked effect on the immune system (50) . indeed, serum levels of interleukin-5 are elevated in persons with mdd. interleukin-5 has been previously associated with immune system t helper cells and conditions such as allergy. a higher risk of depression and of prevalence of underdiagnosed major neurocognitive disorders have been found in older frail outpatients (51). vaccines are one of the most effective therapeutic interventions against infectious diseases (52) . nonetheless, the most widely used vaccines would appear to be less immunogenic in the elderly than in young adults (53) . a useful example in the current pandemic context: the ability of the flu vaccine to induce protection is age-related, with an efficacy between 70 and 90% in children and adults (53) . these percentages drop to 30-50% at best for subjects ≥65-years old (53) . the estimated vaccine efficacy was of 23% in volunteers aged 70 years or older (54) . elderly are less responsive to vaccination prevention, probably due to the combined effect of immunosenescence and inflammaging. both are associated with frailty, however the impact of frailty on vaccine efficacy and effectiveness is uncertain. hypothetically lower efficacy among vaccinated frail elderly has been suggested, as proven by increasing all-cause mortality rates with increasingly impaired functional status (55) . frailty has been associated with impairment in tiv-induced strain-specific immunity to influenza, increased rates of influenza-like illness and laboratory-confirmed influenza infections (56) . a more recent study found that pre-vaccination strain-specific immunity is strongly associated with post-vaccination responses in frailty, with the highest associations in microneutralization titers in robust elderly (57) . vaccine efficacy seems to be remarkably figure 1 | aging is influenced by multifaceted extrinsic and intrinsic factors leading to several elderly phenotypes that must be recognized and clustered to specifically design vaccine formulations, including adjuvants. the immunobiography approach could inform the stratification of elderly subjects and guide the implementation of vaccination strategies designed for specific elderly population clusters. importantly, vaccines should be created to optimally balance immune stimulation and inflammation. frontiers in medicine | www.frontiersin.org 5 september 2020 | volume 7 | article 558835 distinctive across levels of frailty (58) . it has been found to be optimal among robust elderly, lower among prefrail and frail subjects, and not recognizable in the frailest ones (58) . these findings suggest the importance of accounting for frailty when assessing the impact of influenza vaccines (58) . the search for formulations of new vaccines should consider the intrinsic (secondary to pure aging) and extrinsic factors that influence deterioration in immune response (59) . understanding their contributions can reveal the mechanisms that lead to the progressive decline of immune competence with age and to identify the "immunobiography" of each subject (52) . follow this approach could allow developing novel and improved vaccines for the older adults. specifically, it can help identify different aging clusters would allow to develop vaccines according to the geriatric phenotype, facilitating inflammation reduction and improving vaccine response (figure 1 ). it is of primary importance to design vaccine formulations and vaccination protocols specifically tailored on the elderly (60). it is therefore necessary to consider possible aging clusters, immunosenescence, and inflammaging. this priority seems to be appropriate for the european vaccine development roadmap promoted by the innovation partnership for a vaccine roadmap in europe (iprove) (60) . promising research routes to improve the value of vaccines should consist of: (a) the inclusion of a comprehensive geriatric approach to aging; (b) the valorization of peculiar aging phenotypes and immunobiographies; (c) the integration of geriatric, immunological, clinical, and omics data according to a systems vaccinology approach to guide the design piof next generation vaccines and adjuvants specifically tailored for the elderly (27) (figure 2) . the pathogenic middle east respiratory syndrome coronavirus (mers-cov), severe acute respiratory syndrome coronavirus (sars-cov-1), and covid-19 coronavirus (sars-cov-2) have all emerged into the human population over the last two decades and resulted in substantial numbers of deaths. the genome of covid-19 partially resembled sars-cov-1 and mers-cov and indicated a bat origin (61) . all three are enveloped, positive-sense, single-stranded rna viruses that belong to the family coronavirdiae, and are known to cause acute respiratory, hepatic, and neurological diseases with varying severity. the most common presenting symptom is fever, followed by cough, sore throat and dyspnoea (62) . although related to sars-cov-1 and mers-cov, covid-19 shows some peculiar pathogenetic, epidemiological and clinical features which to date are not completely understood (62) . covid-19 generally has a less severe clinical picture, and thus it can spread in the community more easily than mers and sars, which have frequently been reported in the nosocomial setting. consistent with its clinical manifestations, covid-19 has a fatality rate of 2.3%, lower than that of sars (9.5%) and much lower than that of mers (34.4%). to date, no specific antiviral treatment or vaccine is available for treatment of covid-19. previous therapies targeting sars-cov and mers-cov may accelerate the development of covid-19 treatment because of their structural and genomic similarities (61) . those coronaviruses make use of a large envelope protein called spike (s) to engage host cell receptors and catalyze membrane fusion. because of the vital role that these s proteins play, they represent a vulnerable target for the development of treatments (63) . due to the indispensable role of the s-protein, therapies and vaccine exploration targeting s-protein-ace2 interaction may be very promising (61) . previous experience from sars-cov-1 and mers-cov treatments development have targeted angiotensin receptor blockers, gene silencing technologies, glycoprotein epitopes, and monoclonal antibodies, which may be useful for covid-19 too (64) . in the context of coronavirus, vaccine development started seriously after the sars-cov and mers-cov outbreaks, providing alternative approaches of applying subunit vaccines, whole inactivated virus, vectored, and live attenuated virus vaccines (64) . indeed, if any cross-reactive epitopes were identified between covid-19 and sars-cov, previous vaccine for sars-cov might be re-utilized to facilitate covid-19 vaccine development (65) . all viruses evolve over time, accumulating mutations that replicate imperfectly within the cells of a host in huge numbers and then spread into a population, with some of these mutations persisting through natural selection. sars-cov-2 is a single-stranded rna virus. such viruses are notorious for high mutation rates. one variable shaping covid-19 immunotherapy efficacy is how quickly the coronavirus mutates. a faster rate of mutation would increase the likelihood that the vaccine would not generate an effective immune response. only as an example, 149 sites of mutations were identified across the genome of 103 sequenced strains of sars-cov-2 in in wuhan (china), and the virus had evolved into two subtypes, termed l and s subtype (66) . the two subtypes showed great differences in geographical distribution, figure 2 | the improvement of vaccination strategies for the elderly should consider mechanism of action specifically suited to act in the context of immunosenescence/inflammaging and taking in consideration different clusters of elderly and individual immunobiography. with this aim, geriatric, immunological, clinical, and omics data (generated from clinical studies of vaccination in the elderly) should be integrated using a systems vaccinology approach to guide the design of next generation vaccines specifically tailored for the elderly population. transmission ability, and severity of disease. the l type is more prevalent than the s type (70 vs. 30%) and it might be more aggressive and spread more quickly. type s, which is evolutionally older and less aggressive, has increased in relative frequency over time probably due to weaker selective pressure (66) . this and similar scenarios add up more obstacles for vaccine design. nevertheless, evidence seems to show that sars-cov-2 may have a relatively slow mutation rate for an rna virus, increasing the chances that a vaccine would offer long-term protection (67) . currently, there are six strains of covid-19. the original one is the l strain, that appeared in wuhan in december 2019. its first mutationthe s strain-appeared at the beginning of 2020, while, since mid-january 2020, we have had strains v and g. to date strain g is the most widespread: it mutated into strains gr and gh at the end of february 2020 (67) . the small number of genetic differences between the original strain of the covid-19 from wuhan and those currently circulating indicates that a vaccine may likely offer lasting immunity (67) . to be successful in reducing the prevalence and incidence of a disease, vaccination programs rely on a high uptake level. some of the elderly population remain reluctant to take advantage of the offer of vaccination (68) . compliance with vaccine recommendations lowers getting older and the burden of vaccine-preventable diseases remains high in the elderly and the oldest old (26) . adherence rates have been shown to be related to age, race, sex, illness perceptions, and geographic residence (69) . moreover, depression, social exclusion, and low quality of life have a negative impact (70) . also, polypharmacy is associated with poorer adherence to treatment (71) . several other factors have been identified as contributors to low vaccine coverage in the elderly, including logistic factors such as ease of access and convenience, cultural attitudes, health literacy, and vaccine hesitancy (72) . hesitancy was defined by the who as the delay or refusal of vaccination despite the availability of vaccine services. vaccination uptake has been associated also with perceived vaccination effectiveness, and the perceived likelihood or severity of vaccination side effects (73) . for older adults, additional factors influencing vaccination uptake were underlying chronic diseases, and recent advice through physician consultation (73) . higher level of frailty in the elderly has been proposed to be a determinant of lower adherence (74) . a decrease in physical activity and difficulty in walking negatively affect adherence (71, 75) . additionally, some psychosocial frailty determinants have a strong influence: mourning and loneliness, a serious illness of some evidence argues that cognitive frailty (traditionally referred to as cognitive impairment) may also negatively affect adherence to treatment protocols and medication regimes in the elderly (76) (77) (78) (79) . indeed, poor adherence in cognitive frailty patients seems to range from 10.7 to 38% (80) . mild cognitive impairment (that it means cognitive frailty) has been recently associated with lower adherence (45, 81) . cognitive deficits related with physical frailty (attention/mental flexibility, working memory, and executive functions) (82-84) seem to be able to predict poor adherence to treatment (41) . a further factor-associated with the previous ones-which significantly impacts on adherence to treatment is a reduction in self-awareness (85, 86) . reduced self-awareness has been found to be associated with a decline in help-seeking behavior and compliance with medical treatment, presumably because of a reduction in motivation (85) . in particular, the uptake of influenza vaccines has been found to be largely driven by the risk perception of the disease (87). getting vaccinated is therefore the result of a complex series of behaviors, all of which are contingent on an interlocking system of thoughts and beliefs, people, funding, policies, and permissions (88) . this complex interlocking system is vulnerable to mental illness and neuropsychological disorders. particularly impacting are executive-metacognitive dysfunctions and alterations in mood (anxiety, apathy, and depression). a comprehensive appreciation of the physical, neuropsychiatric, and neuropsychological profile of the patient influence on non-adherence is necessary for clinicians to improve the quality of care. according to ecarnot et al. [(72) , p. 234], "strategies to improve vaccine uptake can target all the components underpinning low coverage, and include technology and communication-based strategies, physician-centered approaches, targeting healthcare workers for influenza vaccination, systembased factors, improved vaccine efficacy, and above all, political will and leadership." each elder reflects the uniqueness of his/her own life, therefore requiring personalized assessment and management tools, pharmacological treatments, and care. to face the challenge of an aging population, public health must consider the existence of several aging patterns and promptly adapt to the current needs, especially in the event of emergency situations such as covid-19 pandemic. a vaccine would offer lasting protection. the entire scientific community is working on a vaccine against covid-19. over 100 projects are under development. an incredible result if you think that only 3 months have passed since the exact sequence of sars-cov-2 was known. nevertheless, the rate of coronavirus mutation hinders the vaccination program. even vaccine might work against infectious disease, the efficacy was not certain because of its mutation rate of rna virus. these mutations, however, do not impinge on the process of developing effective vaccines or weaken protection from a vaccine (67) . starting next autumn, the possible return of sars-cov-2 will add to the seasonal flu. vaccinating elderly people will be essential to have fewer people hospitalized for flu complications, to easily distinguish the latter from covid-19 and to prevent effectively covid-19 infections. however, vaccines being designed today are not going to be effective enough for the people who need them most: older adults. this perspective article aims to stimulate research to demonstrate whether the assessment of frailty in the elderly and targeted vaccination treatment will contribute to improve individual health and the sustainability of health-care systems. indeed, vaccinations must be considered a fundamental medical, social, and economic intervention. with this aim, some promising routes that research can take to improve the efficacy and effectiveness of vaccinations in the elderly are shortly presented. the focus is given to the association among ageotypes, frailty, comorbidity, mental illness, immune system, and implications for vaccination. although crucial advancement has been made in recognizing the mechanisms underlying age-related immune response decline to infections (and vaccinations), some knowledge gaps remain in basic and translational research and clinical practice. the progressive increase of the elderly population imposes new strategies to guarantee sustained health and well-being. the development of better and/or new vaccines against pathogens affecting the elderly is a fundamental intervention to achieve this goal. the covid-19 epidemic presents itself as an opportunity to rethink the strategies applied so far. ongoing initiatives are expected to improve knowledge of covid-19 interaction with frailty and to promote patient-centered approaches, also in the field of vaccine testing. the original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author. sp conceived the content of this perspective article, wrote the manuscript, and produced infographics. survey nazionale sul contagio covid-19 nelle strutture residenziali e sociosanitarie united nation -department of economics and social affair population structure and ageing the effect of population aging on health expenditure growth: a critical review global burden of disease and risk factors editorial: global population aging -health care, social and economic consequences reflection paper on physical frailty: instruments for baseline characterisation of older populations in clinical trials mild cognitive impairment and dementia: definitions, diagnosis, and treatment analyses in the economics of aging personal aging markers and ageotypes revealed by deep longitudinal profiling vulnerability and social exclusion: risk in adolescence and old age hazzard's geriatric medicine and gerontology in search of an integral conceptual definition of frailty: opinions of experts a correspondence analysis revealed frailty deficits aggregate and are multidimensional determinants of frailty proactive interception and care of frailty and multimorbidity in older persons: the experience of the european innovation partnership on active and healthy ageing and the response of parma local health trust and lab through european projects covid-19 monza team members. frailty index predicts poor outcome in covid-19 patients frailty and covid-19: a systematic scoping review influenza in the elderly: a mini-review the world report on ageing and health: a policy framework for healthy ageing major features of immunesenescence, including reduced thymic output, are ameliorated by high levels of physical activity in adulthood immunologic changes in frail older adults frailty and sarcopenia: the potential role of an aged immune system inflammatory biomarkers of frailty inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans health relevance of the modification of low grade inflammation in ageing (inflammaging) and the role of nutrition vaccination in the elderly: the challenge of immune changes with aging inflammaging: a new immune-metabolic viewpoint for age-related diseases classical and lectin complement pathways and markers of inflammation for investigation of susceptibility to infections among healthy older adults menopause and frailty: a scoping review targeted deletion of interleukin-6 in a mouse model of chronic inflammation demonstrates opposing roles in aging: benefit and harm inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty aging of the immune system: focus on inflammation and vaccination circulating mitochondrial dna increases with age and is a familiar trait: implications for "inflamm-aging" frailty and multimorbidity: two related yet different concepts frailty and subsequent disability and mortality among patients with critical illness frailty and multimorbidity: a systematic review and meta-analysis multimorbidity, frailty and functional disability in octogenarians: a structural equation analysis of relationship the immune response to influenza in older humans: beyond immune senescence frailty and mental health: association with cognition, sleep, and well-being in older adults frailty, depression, and anxiety in later life psychiatric illness in relation to frailty in community-dwelling elderly people without dementia: a report from the canadian study of health and aging differential association of frailty with cognitive decline and sarcopenia in community-dwelling older adults cognitive frailty: rational and definition from an cognitive function in the prefrailty and frailty syndrome neuroscience, mental health and the immune system: overcoming the brain-mind-body trichotomy affective immunology: where emotions and the immune response converge the immune system and psychiatric disease: a basic science perspective stress and immunity elevated levels of serum il-5 are associated with an increased likelihood of major depressive disorder social vulnerability, mental health and correlates of frailty in older outpatients living alone in the community in italy vaccines, new opportunities for a new society efficacy and effectiveness of influenza vaccines: a systematic review and metaanalysis the efficacy of influenza vaccination in elderly individuals. a randomized double-blind placebo-controlled trial functional status of older nursing home residents can affect the efficacy of influenza vaccination frailty is associated with impairment of vaccine-induced antibody response and increase in post-vaccination influenza infection in community-dwelling older adults preexisting immunity, not frailty phenotype, predicts influenza postvaccination titers among older veterans the importance of frailty in the assessment of influenza vaccine effectiveness against influenza-related hospitalization in elderly people fighting against a protean enemy: immunosenescence, vaccines, and healthy aging innovation partnership for a roadmap on vaccines in europe (iprove): a vision for the vaccines of tomorrow insight into 2019 novel coronavirus -an updated interim review and lessons from sars-cov and mers-cov covid-19, sars and mers: are they closely related? structural basis for potent neutralization of betacoronaviruses by single-domain camelid antibodies coronavirus pandemic-therapy and vaccines identification of potential cross-protective epitope between a new type of coronavirus (2019-ncov) and severe acute respiratory syndrome virus on the origin and continuing evolution of sars-cov-2 geographic and genomic distribution of sars-cov-2 mutations a review of the factors involved in older people's decision making with regard to influenza vaccination: a literature review the influence of illness acceptance on the adherence to pharmacological and nonpharmacological therapy in patients with hypertension sex differences in barriers to antihypertensive medication adherence: findings from the cohort study of medication adherence among older adults geriatric syndromes are potential determinants of the medication adherence status in prevalent dialysis patients strategies to improve vaccine uptake throughout adulthood why are older adults and individuals with underlying chronic diseases in germany not vaccinated against flu? a population-based study the influence of frailty syndrome on medication adherence among elderly patients with hypertension a higher adherence to a mediterranean-style diet is inversely associated with the development of frailty in community-dwelling elderly men and women the impact of cognitive function on medication management: three studies ability of older people with dementia or cognitive impairment to manage medicine regimens: a narrative review association between poorer cognitive function and reduced objectively monitored medication adherence in patients with heart failure relation between cognitive impairment and treatment adherence in elderly hypertensive patients a systematic review of medication non-adherence in persons with dementia or cognitive impairment predictors of medication adherence in the elderly: the role of mental health cognitive function in individuals with physical frailty but without dementia or cognitive complaints: results from the i-lan longitudinal aging study global performance of executive function is predictor of risk of frailty and disability in older adults reduced self-awareness across pathologies: involvement of the anterior cingulate cortex commentary: metacognition and perspectivetaking in alzheimer's disease: a mini-review frailty: implications for clinical practice and public health socio-psychological factors driving adult vaccination: a qualitative study increasing vaccination: putting psychological science into action the author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 palermo. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-352737-3ttrx3lf authors: cunha, lucas leite; perazzio, sandro felix; azzi, jamil; cravedi, paolo; riella, leonardo vidal title: remodeling of the immune response with aging: immunosenescence and its potential impact on covid-19 immune response date: 2020-08-07 journal: front immunol doi: 10.3389/fimmu.2020.01748 sha: doc_id: 352737 cord_uid: 3ttrx3lf elderly individuals are the most susceptible to an aggressive form of coronavirus disease (covid-19), caused by sars-cov-2. the remodeling of immune response that is observed among the elderly could explain, at least in part, the age gradient in lethality of covid-19. in this review, we will discuss the phenomenon of immunosenescence, which entails changes that occur in both innate and adaptive immunity with aging. furthermore, we will discuss inflamm-aging, a low-grade inflammatory state triggered by continuous antigenic stimulation, which may ultimately increase all-cause mortality. in general, the elderly are less capable of responding to neo-antigens, because of lower naïve t cell frequency. furthermore, they have an expansion of memory t cells with a shrinkage of the t cell diversity repertoire. when infected by sars-cov-2, young people present with a milder disease as they frequently clear the virus through an efficient adaptive immune response. indeed, antibody-secreting cells and follicular helper t cells are thought to be effectively activated in young patients that present a favorable prognosis. in contrast, the elderly are more prone to an uncontrolled activation of innate immune response that leads to cytokine release syndrome and tissue damage. the failure to trigger an effective adaptive immune response in combination with a higher pro-inflammatory tonus may explain why the elderly do not appropriately control viral replication and the potential clinical consequences triggered by a cytokine storm, endothelial injury, and disseminated organ injury. enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe covid-19. elderly individuals are the most susceptible to an aggressive form of coronavirus disease , caused by sars-cov-2. the remodeling of immune response that is observed among the elderly could explain, at least in part, the age gradient in lethality of in this review, we will discuss the phenomenon of immunosenescence, which entails changes that occur in both innate and adaptive immunity with aging. furthermore, we will discuss inflamm-aging, a low-grade inflammatory state triggered by continuous antigenic stimulation, which may ultimately increase all-cause mortality. in general, the elderly are less capable of responding to neo-antigens, because of lower naïve t cell frequency. furthermore, they have an expansion of memory t cells with a shrinkage of the t cell diversity repertoire. when infected by sars-cov-2, young people present with a milder disease as they frequently clear the virus through an efficient adaptive immune response. indeed, antibody-secreting cells and follicular helper t cells are thought to be effectively activated in young patients that present a favorable prognosis. in contrast, the elderly are more prone to an uncontrolled activation of innate immune response that leads to cytokine release syndrome and tissue damage. the failure to trigger an effective adaptive immune response in combination with a higher pro-inflammatory tonus may explain why the elderly do not appropriately control viral replication and the potential clinical consequences triggered by a cytokine storm, endothelial injury, and disseminated organ injury. enhancing the efficacy of the adaptive immune response may be an important issue both for infection resolution as well as for the appropriate generation of immunity upon vaccination, while inhibiting inflamm-aging will likely emerge as a potential complementary therapeutic approach in the management of patients with severe covid-19. in december 2019, a novel coronavirus, severe acute respiratory syndrome coronavirus-2 (sars-cov-2), was discovered as the causative agent of an outbreak of viral lower-respiratory tract infections centered in wuhan (china) (1) . since then, sars-cov-2 has caused a widespread outbreak of severe acute respiratory syndrome throughout china, with exported cases occurring in other continents, including the united states, in a worldwide pandemic (1) . interestingly, a strong age gradient in the risk of death was observed among patients with coronavirus disease (covid-19) (2) . in this scenario, the remodeling of immune response that is observed among the elderly could be a possible explanation for the higher lethality of covid-19 noted on this population. the immune response is dynamically remodeled with aging, a phenomenon denominated as immunosenescence. this phenomenon increases susceptibility to a myriad of clinical conditions such as infections, autoimmune disorders, and malignancies. recent data had shed light on the physiological aspects of immunosenescence, which is now considered an immune adaptation to the aged microenvironment rather than merely a collapse of the system (3). both the innate and adaptive immunity is affected by aging. some individuals experience a sustained innate immune system activation, inducing proinflammatory cytokines secretion and innate immune cells' recruitment (4). innate immunity hyperactivation may be detrimental and impair global functionality, causing a clinical phenotype known as frailty syndrome. frailty syndrome is defined as a state of cumulative decline in several physiological systems with a disproportionate vulnerability to stressor events (5) . frailty syndrome prevalence increases with age, it is multifactorial in etiology, and the physical component of frailty can be objectively assessed by the fried frailty score (phenotype score) and the frailty index (deficit accumulation index) (6) . likewise, adaptive immunity remarkably changes as age increases, which can be summarized into two main topics: (1) bone marrow reorganization and hematopoietic stem cell pool differentiation into myeloid lineage, outnumbering lymphoid compartment; and (2) physiological thymic involution, compromising naïve t cells generation. the sum of these two factors can help explain the prior known impairment of the regenerative capacity of lymphocytes compared to myeloidderived cells in the elderly (7) . infectious diseases are more prevalent among the elderly. when compared to younger counterparts, the elderly more frequently present with respiratory and urinary tract infections, and those patients usually have a worse prognosis (8, 9) . it is possible that the impaired barrier function of mucosae and diminished adaptive immune response (both cellular and humoral) are the reasons for the increased susceptibility to infectious microorganisms among the elderly (10) . in addition, the natural killer (nk) cell senescence may affect the homeostasis of the immune system in the elderly, leading to an increased risk of cancer and additional risk of viral infections (11) . lastly, age-related cell dysfunctions leading to an exhausted phenotype are also an important characteristic of the immune system remodeling with aging, which might accelerate tissue damage and disable modulatory mechanisms (12) . herein, we review the state of the art research on senescence-induced immune dysregulation, focusing on innate and adaptive cell functional analysis and its potential impact in viral immune responses, such as in covid-19. currently, the concept of immunosenescence refers to a comprehensive remodeling of the immune system and its microenvironment, involving both innate and adaptive compartments that occur with aging (13, 14) . many physiological phenomena have been proposed to explain the immune response remodeling over time, including chronic exposure to antigens, impaired telomerase activity, mitochondrial dysfunction, defective autophagy, endoplasmic reticulum stress, defective ubiquitin/proteasome system, and age-related changes in the composition of gut microbiota (15) (16) (17) (18) . probably, a melting pot of diverse factors differently contributes to the final phenotype of the adapted and experienced immune system, named immunosenescence. aging of the immune system is characterized by an imbalance between stimulatory and regulatory mediators, such as cytokines and acute phase reactants, toward a sub-clinical chronic proinflammatory state called inflamm-aging. inflamm-aging is thought to be caused by a low-grade inflammation secondary to continuous antigenic stimulation (19) , whose source may be exogenous, like a pathogenic microorganism infection (20, 21) , or endogenous (15) (16) (17) (18) , like post-translational-modified macromolecules (15) . population studies incorporate the notion that the immune response depends on environmental exposure and how it interacts with endogenous variables. in fact, diet, exercise, xenobiotic exposure, and other environmental factors may epigenetically affect the metabolic health of immune cells (22) . lifestyle factors, such as exercise and favorable dietary habits, positively affect the immune system (22) , while poor nutrition and reduced muscle mass may predispose an individual to a proinflammatory condition (23) . age-related remodeling of innate immunity modifies the homeostasis of nk cells, neutrophils, and monocytes/macrophages (24) . nk cells from the elderly exhibit impaired perforin release upon stimulation and granule exocytosis (25, 26) . it reduces the elimination of senescent cells, which, in turn, promotes senescent cell accumulation in aged tissue. moreover, aging reduces the frequency of circulating nk p46 + cells, a modulatory cell subset involved in the resolution of inflammation and elimination of effector cells (27, 28) . neutrophils and macrophages are classically classified as part of innate immunity and possibly comprise the most important effector cells against bacterial infections. it is thought that age is accompanied by a decline in production and secretion of most chemokines, including those responsible for neutrophil and monocyte chemoattraction (29) . the absolute number of neutrophils seems to be maintained while the number of monocytes increase with age (30, 31) . however, the function of these cells may be impaired among the elderly (32) . the final consequence is that the delayed resolution of inflammation may be associated with age-related remodeling of neutrophils and macrophages (29) . in addition to their phagocytosis' capabilities, neutrophils are capable of releasing a mesh-like structure under specific circumstances, called neutrophil extracellular traps (net), in an attempt to physically delimitate the pathogenic agent, mainly microorganisms, and facilitate its contact with microbicidal peptides and enzymes (33) . net is composed of a decondensed chromatin meshwork imbedded with granule proteins with antimicrobial properties. net may also work as a physical path for immune cell migration to the inflammatory site (34) . neutrophil function is impaired in both animal models and humans with aging. hazeldine et al. (35) observed that older adults have less il-8 production, lps-induced net release, and cell migration compared to younger counterparts, probably secondary to an impaired signal transduction. microbicidal killing, phagocytic activity (36) , and degranulation capacity (37) of neutrophils are also reduced in the elderly. in addition, the same group investigated the migration pattern of neutrophils obtained from older compared to young adults. they observed that neutrophils from older subjects migrated with less accuracy than those from younger subjects. by inaccurately meandering among healthy tissues, neutrophils from the elderly inadvertently release more neutrophil proteinase that may contribute to tissue damage and systemic inflammation. reactive oxygen species (ros) are free radicals produced after oxidative bursts in phagosomes, which are pivotal for the microbicidal function of phagocytes (38) . in fact, ros do not just directly contribute to the bacterial clearance, but additionally can trigger net formation. the free radical ros production by neutrophils in older adults is decreased (39, 40) . interestingly, polymorphonuclear leucocytes from the elderly are less capable of modulating the triggering receptor expressed on myeloid cell-1 (trem-1)-induced oxidative bursts, suggesting that trem-1 signal transduction altered with aging may be one of the mediators of the decrease in microbicidal potential of innate immune cells in older adults (41) . animal models of premature immunosenescence have also shed some light into age-related remodeling of the immune system. guayerbas et al. (42) described a mouse model of premature immunosenescence based on the demonstration of early decline of immune parameters and behavioral tests in swiss outbred mice. mouse model-derived peritoneal leukocytes exhibited reduced proliferative response, impaired nk activity, and increased in vitro tnf-alpha production compared to control mice (42) . in addition, mouse modelderived macrophages of premature models were less functional with a striking loss of microbicidal activity (43) . the mice model of premature immunosenescence was refined and new models were developed as well (44, 45) . apparently, the key phenomenon are the oxidative and inflammatory stresses, which, not without reason, are associated with several non-communicable chronic diseases prevalent among the elderly (44, 46) . in fact, spleen and thymus cells from prematurely immunosenescent mice models have decreased antioxidant defenses and significantly increased oxidants and pro-inflammatory cytokines production (44) (45) (46) . interestingly, the antioxidant vs. oxidant imbalance observed in prematurely immunosenescent mice was similar to the one observed in old wild-type animals (44, 47) . hence, lab tests determining the oxidative burst profile of phagocytes (e.g., nitro blue tetrazolium test, dihydrorhodamine oxidation, o − 2 and h 2 o − 2 production by chemoluminescence, etc.) may be useful for assessing inflammaging features (4) . the state of chronic inflammation has to be counter-balanced by anti-inflammatory molecules (48) . when not under control, the low-grade inflammation loses its defense role and turns into a damaging state to the whole organism (49) . the practical consequence is that inflamm-aging is deleterious to human health, predicts frailty, and is associated with higher mortality rates (50) (51) (52) . remodeling of the adaptive immune response also occurs with aging. thymic involution and hematopoietic stem cell insufficiency play important roles in immunosenescence of adaptive immunity (53) . in general, elderly individuals are less able to respond to neo-antigens, due to the reduction of new thymus-emergent t cells, though homeostatic proliferation can partially sustain the richness of the tcr repertoire (54, 55) . moreover, peripheral t cells usually present a reduced absolute number in aged individuals with an inverted cd4:cd8 ratio and expansion of terminally differentiated effector memory t cells (56, 57) , associated with impaired proliferation ability, telomerase activity, and intracellular signaling (58, 59) . furthermore, most adult regulatory t lymphocytes are a terminally differentiated highly suppressive apoptosis-prone population with a limited capacity for self-renewal (60). this finding might explain, at least in part, the occurrence of agerelated autoimmune conditions. in addition, the imbalance between innate and adaptive immunity may disturb the fine regulation of the effector immune response, leading to a severe acute pro-inflammatory state that may lead to organ rejection in transplanted patients (61, 62) . while naïve t and b cells become dysfunctional with aging, memory t and b cells' function is relatively maintained (63) (64) (65) . in fact, naïve t lymphocytes obtained from the elderly present impaired cell binding of the immune synapse (66), reduced signal transduction (67), dysregulation of cytoskeletal function (68), defective protein glycosylation and activation (69) , and insufficient il-2 production (70). some authors advocate that age-related t-cell dysfunction is different from t cell exhaustion, a state of low cell responsiveness mediated by chronic conditions, such as viral infections and malignancies (figure 1 ) (71) . constant antigen stimulation figure 1 | t cell exhaustion vs. t cell senescence. in conceptual terms, the t-cell dysfunction observed in the elderly is different to the one reported as t-cell exhaustion. persistent viral and cancer stimulation leads to the remodeling of many t cells, which upregulate the expression of co-inhibitory receptors (e.g., pd-1, ctla-4, lag-3, icos, tim-3, and klrg-1), all of them hallmarks of t cell exhaustion. the co-inhibitory receptors downregulate the tcr-stimulated intracellular signal, and t-cells become hyporesponsive and develop responsiveness impairment. however, the immunosenescence is marked by similar levels of pd-1 and tim-3 and tiny elevations of ctla-4 and lag-3 in t cells from the elderly compared to those in younger groups. t-cell immunoglobulin and immunoreceptor tyrosine-based inhibitory motif (itim) domain (tigit) is a co-inhibitory receptor that is expressed on senescent t cells, which exhibited a marked terminal differentiated phenotype. interestingly, tigit-positive t cells from the elderly seems to retain some proliferative capacity, but produced significantly lower amounts of tnf-alpha, ifn-gamma, and il-2. progressively exhausts t cells by gradually upregulating the expression of inhibitory checkpoint receptors (e.g., pd-1, ctla-4, lag-3, icos, tim-3, and klrg-1) on cd4 + t cells (72) , which, in turn, downmodulate tcr-induced intracellular signaling (73) . interestingly, despite this conceptual difference between immunosenescence and t cell exhaustion, most of those cell exhaustion surface hallmarks are observed on dysfunctional immunosenescent cells, suggesting that these two phenomena share many mechanisms (54) . exhausted t-cells accumulate over time (67, (74) (75) (76) (77) . shimada et al. (74) demonstrated both gene and protein hyper expression of pd-1 and ctla-4 in cells from old male c57bl/6 mice compared to young controls. most pd-1 + t cells were quiescent and presented an anergic effector memory phenotype with impaired proliferative response to mitogens (74) . similarly, lee et al. (76) reported the accumulation of tim-3 + murine t cells with impaired proliferative capacity with aging. literature discussing t cell exhaustion and immunosenescence in humans is scarce, though. song et al. (77) described an elevated number of tigit + cd8 + t cells from old adults, another hallmark of cell exhaustion apparently associated with immunosuppressant features in neoplasm or chronic infection mouse models (78, 79) . tigit + cd8 + t cells from old individuals seem to retain a proliferative capacity, although they impaired tnf-alpha, ifn-gamma, and il-2 in vitro production and increased susceptibility to apoptosis (77) . therefore, we hypothesize that evaluation of the proliferative response to mitogens and in vitro cytokine production may be indirect ways to assess age-related remodeling of the immune system. in regards to b cell compartment, vaccine trials suggest that b cell repertoire abridge over time, foremost observed in frail patients (80, 81) . in addition, b cells from the elderly present both impaired antibody production and class switch recombination (82) . class switch recombination and immunoglobulin somatic hypermutation are crucial for humoral immune response and occur in mature b cells mediated by activation-induced cytidine deaminase, amongst other mediators (82, 83) . similarly, activated b cells from old mice have less activation-induced cytidine frontiers in immunology | www.frontiersin.org deaminase expression and reduction of class switched antibodies (84, 85) . interestingly, in vivo activated cd4 + t cells from oldaged individuals showed increased dual-specific phosphatase 4 (dusp4) transcription, which, in turn, negatively correlated with antigen-specific b cells' expansion. silencing of dusp4 restored cd4 + t cell-induced b-cell differentiation, suggesting that b cell dysfunction observed with aging is t cell-dependent. table 1 summarizes the main physiologic modifications of the immune system in the elderly. coronaviruses are a large family of viruses that cause upper and lower-respiratory tract illnesses in humans. sars-cov-2 is transmitted predominantly via respiratory droplets. clinically, patients frequently present with fever, cough, myalgia, and fatigue (95) . in a subset of patients, mainly elderly individuals, sars-cov-2 was shown to lead to bilateral pulmonary diffuse alveolar damage that may progress to acute respiratory distress syndrome (96, 97) . following the pulmonary phase, patients with poor outcome frequently evolve a life-threatening cytokine storm syndrome, characterized by bursts of proinflammatory cytokines and chemokines in the serum (96, 98) . the uncontrolled systemic inflammation causes endothelial injury and activation of coagulation cascade. the consequence is an explosive process of disseminated intravascular coagulation and consumption of coagulation factors that leads to organ damage and death. the innate immune response is the first level of response in the detection and clearance of a viral infection. in sars-cov-2, the spike protein (s) mediates the attachment, fusion, and entry of the virus in human cells (99) . the protein s strongly binds to angiotensin-converting enzyme 2 receptor leading to the attachment of the virus to the host cell (99) . the successful entry needs the priming of the s protein by tmprss2, a human cellular serine protease (100) . once in the host cell, sars-cov-2 can be detected by macrophages, which orchestrate the production of a pro-inflammatory microenvironment that inhibits viral replication, stimulates adaptive immunity, and recruits other immune cells to the site of infection. macrophages from elderly lungs may have a more pronounced production of il-6 and other pro-inflammatory cytokines in response to stimuli (101) . it is possible that il-6 has a critical role in the immune response of the elderly that mounts against sars-cov-2 (102). il-6 helps the differentiation of th17 lymphocytes, but inhibits the production of interferon-γ, which is necessary for the activation of cd8+ cells (102) . in addition, il-6 contributes to a pro-inflammatory microenvironment at the lung that impacts the integrity of the air-blood barrier (103) . patients with severe covid-19 have a higher il-6/interferon-γ ratio than those who present with a moderate disease, which could be related to the cytokine storm leading to lung injury (104) (105) (106) (107) . indeed, patients with severe covid-19 frequently have lower absolute numbers of interferon-γ producing cd4+ t cells compared to patients with moderate disease (108) . then, when patients with covid-19 enter the immune dysregulation phase, the increase in il-6 leads to a relative immunoparalysis that may impair the clearance of sars-cov-2 (98). elderly patients with covid-19 often present with a severe dysregulation of proinflammatory cytokines, such as il-6 and il-1 β, which may result in worse outcome (105) . drugs that uncouple il-1β/il-1r signaling (anakinra) or il-6/il-6r signaling (tocilizumab) may have an immunomodulatory potential and are hypothesized to attenuate the dysfunctional immune response during the hyperinflammatory phase of covid19 (98, 109) . in fact, some reports suggest that infusion of anakinra (109, 110) and tocilizumab (111) may improve the disease course in patients with severe covid-19 presentation. neutrophils have traditionally been considered the primary immune cells active in the defense against bacterial infections. more recently, neutrophils' role in viral infection has emerged based on observations of its correlation with viral infection severity and neutrophils' biological ability to recognize viruses (via viral pamps) and respond to them with specific effector functions (112) . patients with severe covid-19 more frequently present with a high neutrophil-to-lymphocyte ratio (113) , in part driven by the relative lymphopenia or lymphocyte exhaustion. in addition, patients with severe covid-19 are more susceptible to a greater burst of systemic inflammation and secondary bacterial infection that can lead to the increment of neutrophils. it is unclear if changes in neutrophils are only a reflection of the overall immune activation in covid-19 or if they play a direct pathogenic role. lastly, nk cells are less functional in the elderly, and studies have shown that severe covid-19 patients have further depleted peripheral nk cell counts in comparison with mild cases and healthy controls (114) (115) (116) . generally, nk cells are capable of recognizing infected cells and of triggering direct cell toxicity. further studies are needed to clarify how sars-cov2infected cells interact with nk cells and if any apoptosis or downmodulation occurs and prevents the effective elimination of infected cells. the airway epithelium is a physical barrier to pathogens (117) . the integrity of the air-blood barrier is essential for the maintenance of lung homeostasis and represents an important branch of innate immunity (118) . the invasion of the airway epithelial by sars-cov-2 may break the barrier integrity, triggering a vicious cycle of inflammation and tissue injury that is more pronounced among the elderly (119) . presumably, the same remodeling process that occurs in the immune system also happens at the lung microenvironment with aging (120). data from animal models suggest that senescent lungs are more susceptible to settle a pro-inflammatory response when injured (121) . in fact, bronchoalveolar lavage obtained from elderly patients with acute respiratory distress syndrome present with higher pro-inflammatory cytokine levels when compared to younger counterparts, suggesting that the lung may represent a small fraction of the inflamm-aging that occurs at the systemic level (122) . this local phenomenon may help to explain why elderly patients with covid-19 are more susceptible to a more severe lung injury that implies loss of lung function and respiratory failure (123) . the initial inflammation in covid-19 is propitious to the activation and differentiation of cd4+ and cd8+ t cells. the ideal final output is the development of an effective and specific immune response, involving both the production of anti-sars-cov-2 antibodies and the deployment of a large number of viral-specific cytotoxic lymphocytes that will ultimately eliminate the virus and achieve clinical recovery. in fact, when compared to severe h7n9 disease, reduced pro-inflammatory cytokines and chemokines were found in covid-19 patients with good prognosis, reinforcing the idea that adaptive immunity is a key factor for a favorable outcome (124) . thevarajan et al. (124) described a kinetic of the immune response in a 47-year-old woman with covid-19 who presented a favorable outcome. they evidenced a persistent increase in antibody-secreting cells, follicular helper t cells, activated cd4+ and cd8+ t cells, and immunoglobulin m (igm) and igg antibodies that bound to sars-cov-2. the peak of both antibody-secreting cells and follicular helper t cells was markedly higher in the patient compared to healthy controls and both cell subsets were persistently increased during convalescence (day 20). the experience from the sars epidemic of 2003 showed that convalescent sars patients present with neutralizing antibodies against s protein (125) . the sera stored from convalescent patients from the sars epidemic of 2003 can cross-neutralize the s protein-mediated sars-cov-2 entry in patients with . this data raises the possibility that the s protein could be an important antigen to vaccine protocols. in fact, in analogy to the sars epidemic of 2003, convalescent patients with sars may present igg and neutralizing antibodies peaking at 4 months after the disease and detectable up to 2 years afterwards, suggesting that memory b cells can be elicited during coronavirus infection (125) . cellular immune response may play a critical role in the adaptive immune response in patients with covid-19. thevarajan et al. (124) observed the emergence and rapid increase in activated cd8+ t cells at days 7-9 after infection preceded the resolution of symptoms of one young patient with a good prognosis. conversely, elderly patients and those requiring intensive care unit support presented a dramatically reduced number of cd4+ and cd8+ t cells (126) . lower total amounts of t cells, cd4+, and cd8+ t cells negatively correlated with patient survival (126) . diao et al. (126) noted that t cell absolute counting were negatively correlated to serum il-6, il-10, and tnf-α concentration in patients with covid-19, suggesting that the failure of the adaptive immune response and the increase of pro-inflammatory cytokine may be associated with worse survival. it is also possible that increased il-6 leads to a reduction in cd4 + t cells and nk cells in patients with covid-19 and immune dysregulation (98). in fact, some proinflammatory cytokines, such as il-6, may block the antiviral immune response by favoring t cells' exhaustion (102). diao et al. further characterized the exhaustion status of 14 patients with covid-19. they noted an increasing pd-1 and tim-3 expression on t cells as patients progressed from prodromal to overtly symptomatic stages (126) . whether this reflects the emergence of exhaustive t cells with a defective capacity to eliminate the virus or a normal evolution of the immune response against the virus remains to be determined. if greater severity of disease is seen in patients with a higher frequency of exhausted t cells, a potential therapeutic approach could be attempted to block those inhibitory receptors, unleashing the t cell response against the virus. among children, a mild-symptom disease usually occurs. they frequently crush the viral infection through an effective adaptive immune response. however, the remodeling of the immune system that happens with aging may lead to modifications in both adaptive and innate immunity. the final result of these changes may trigger a maladaptive immune response against sars-cov-2. in fact, the elderly are an at-risk group to a more aggressive disease that includes cytokine release syndrome, disruption of intrinsic lung defense, secondary bacterial pneumonia, endothelial injury, and end organ damage. the diminished naïve t cell repository observed among the elderly may dramatically affect the adaptive immune response against sars-cov-2, since fewer naïve t cells will be capable of responding to new infections (127, 128) . furthermore, there is also a reduction in the number of regulatory t cells with aging, which help keep the immune system under tighter control (129) . since the elderly frequently present with a remodeled adaptive immune response, they may fail to enhance antibody production. instead, a proinflammatory tone characteristic of inflamm-aging may convert the immune response of patients with covid-19 in a lifethreatening cytokine storm. on the contrary, young patients usually present with an enormous number of naïve t cells that had never encountered a virus. then, naïve t lymphocytes are rapidly primed and innate immunity does not overwhelm the adaptive immune response. this may explain, at least in part, the favorable prognosis observed among young subjects. figure 2 shows the possible relationship between immune response in patients with covid-19 and the remodeling process that takes place in the immune system with aging. the immune system faces a complex adaptation over time, culminating in functional and phenotyping alterations. the influence of age-related remodeling of the immune system is clinically observed within elderly features (e.g., frailty syndrome) that can be assessed by lab tests. despite several promising experimental methods, none are clinically validated so far, but certainly shed some light on the pathophysiology of immunosenescence. novel mechanisms of inflamm-aging may rise in the near future, leading to new potential therapeutic targets for age-related disorders. different from the chronological age, the "immune age" obtained by population studies may accurately reflect the molecular and cellular changes that occur over time (130) . immunosenescence may explain the lethality amongst the elderly with covid-19 with a combination of ineffective t cell response, failed antibody production against sars-cov-2, and inflamm-aging that terribly collapses the homeostasis, leading to severe organ dysfunction. the biomarkers that are hallmarks of the remodeled immune response have been raised as new potential targets in patients with covid-19. more studies are warranted to investigate how to help the elderly to elicit a functional adaptive immune response, as well as to diminish the harmful pro-inflammatory state of the disease. lc: conception and design, review of the literature, composition of the manuscript and final approval. sp, ja, and pc: design, critical review of the literature, composition of the manuscript, and final approval. lr: conception and design, selection of notable articles for review, critical review of the literature, composition of the manuscript, clinical, and translational orientation and final approval. all authors contributed to the article and approved the submitted version. national institutes of health (2020) estimates of the severity of coronavirus disease 2019: a model-based analysis aging of the immune system: how much can the adaptive immune system adapt? immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front immunol aging and the immune system: an overview epidemiology of frailty in older people inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment association of diagnostic coding with trends in hospitalizations and mortality of patients with pneumonia predictors of in-hospital mortality in elderly patients with bacteraemia admitted to an internal medicine ward innate immunesenescence: underlying mechanisms and clinical relevance the impact of ageing on natural killer cell function and potential consequences for health in older adults immunosenescence and its hallmarks: how to oppose aging strategically? a review of potential options for therapeutic intervention ageing of lymphocytes and lymphocytes in the aged immunosenescence: impact in the young as well as the old? from cell senescence to age-related diseases: differential mechanisms of action of senescenceassociated secretory phenotypes aging of the human metaorganism: the microbial counterpart the role of oxidative and inflammatory stress and persistent viral infections in immunosenescence inflammaging and 'garb-aging telomere dynamics in immune senescence and exhaustion triggered by chronic viral infection effect of ageing on cmv-specific cd8 t cells from cmv seropositive healthy donors t-cell dysregulation caused by chronic antigenic stress: the role of cmv in immunosenescence? physical activity and diet shape the immune system during aging can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? reduced neutrophil chemotaxis and infiltration contributes to delayed resolution of cutaneous wound infection with advanced age granule exocytosis mediates immune surveillance of senescent cells reduced release and binding of perforin at the immunological synapse underlies the age-related decline in natural killer cell cytotoxicity age-related changes in natural killer cell receptors from childhood through old age phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence age-related alterations in the inflammatory response to dermal injury functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion peripheral blood dendritic cells and monocytes are differently regulated in the elderly aging of the innate immune system neutrophil extracellular traps kill bacteria deficiency of adenosine deaminase 2 triggers adenosinemediated netosis and tnf production in patients with dada2 impaired neutrophil extracellular trap formation: a novel defect in the innate immune system of aged individuals senescence in innate immune responses: reduced neutrophil phagocytic capacity and cd16 expression in elderly humans effect of age on human neutrophil function neutrophil ageing and immunesenescence cellular signaling in the aging immune system signal transduction and functional changes in neutrophils with aging effects of aging on triggering receptor expressed on myeloid cells (trem)-1-induced pmn functions leukocyte function and life span in a murine model of premature immunosenescence relation of behaviour and macrophage function to life span in a murine model of premature immunosenescence oxidativeinflammatory stress in immune cells from adult mice with premature aging premature aging in behavior and immune functions in tyrosine hydroxylase haploinsufficient female mice. a longitudinal study nrf2 as a potential mediator of cardiovascular risk in metabolic diseases a model of premature aging in mice based on altered stress-related behavioral response and immunosenescence inflammaging and human longevity in the omics era the role of immunosenescence in the development of age-related diseases immune-endocrine biomarkers as predictors of frailty and mortality: a 10-year longitudinal study in community-dwelling older people predicting death from tumour necrosis factor-alpha and interleukin-6 in 80-year-old people associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly hallmarks of human "immunosenescence": adaptation or dysregulation? naive t cell maintenance and function in human aging impact of age, sex and cmv-infection on peripheral t cell phenotypes: results from the berlin base-ii study age-related change in peripheral blood t-lymphocyte subpopulations and cytomegalovirus infection in the very old: the swedish longitudinal octo immune study the inverted cd4/cd8 ratio and associated parameters in 66-year-old individuals: the swedish hexa immune study the loss of telomerase activity in highly differentiated cd8+cd28-cd27-t cells is associated with decreased akt (ser473) phosphorylation differential role of lipid rafts in the functions of cd4+ and cd8+ human t lymphocytes with aging human anergic/suppressive cd4(+)cd25(+) t cells: a highly differentiated and apoptosis-prone population immunosenescence and immune response in organ transplantation immunosenescence in renal transplantation: a changing balance of innate and adaptive immunity age-related deficiencies in antigen-specific cd4 t cell responses: lessons from mouse models functional cd8 t cell memory responding to persistent latent infection is maintained for life signal transduction in the aging immune system linking molecular and cellular events in t-cell activation and synapse formation defective cd8 t cell responses in aged mice are due to quantitative and qualitative changes in virus-specific precursors age-dependent defects in tcr-triggered cytoskeletal rearrangement in cd4+ t cells age-related defects in cd4+ t cell activation reversed by glycoprotein endopeptidase interleukin 2, but not other common gamma chain-binding cytokines, can reverse the defect in generation of cd4 effector t cells from naive t cells of aged mice molecular and cellular insights into t cell exhaustion lag-3, tim-3, and tigit: co-inhibitory receptors with specialized functions in immune regulation ctla-4 and pd-1 receptors inhibit t-cell activation by distinct mechanisms age-associated up-regulation of a negative co-stimulatory receptor pd-1 in mouse cd4+ t cells advancing age leads to predominance of inhibitory receptor expressing cd4 t cells characterization of age-associated exhausted cd8 + t cells defined by increased expression of tim-3 and pd-1 t-cell immunoglobulin and itim domain contributes to cd8 the immunoreceptor tigit regulates antitumor and antiviral cd8(+) t cell effector function tigit marks exhausted t cells, correlates with disease progression, and serves as a target for immune restoration in hiv and siv infection lineage structure of the human antibody repertoire in response to influenza vaccination bcell diversity decreases in old age and is correlated with poor health status aging affects human b cell responses mechanism and regulation of class switch recombination aging down-regulates the transcription factor e2a, activation-induced cytidine deaminase, and ig class switch in human b cells intrinsic defects in b cell response to seasonal influenza vaccination in elderly humans aging reduces the functionality of anti-pneumococcal antibodies and the killing of streptococcus pneumoniae by neutrophil phagocytosis regulatory role of extracellular matrix proteins in neutrophil respiratory burst during aging skin reactivity, basophil degranulation and ige levels in ageing defective in vivo induction of functional type 2 cytokine responses in aged mice impaired basophil induction leads to an age-dependent innate defect in type 2 immunity during helminth infection in mice age-related changes in eosinophil function in human subjects effect of age on surface molecules and cytokine expression in human dendritic cells mucosal immunosenescence: new developments and vaccines to control infectious diseases role of dendritic cells in innate and adaptive immune response in human aging clinical features of patients infected with 2019 novel coronavirus in wuhan virology, epidemiology, pathogenesis, and control of covid-19 pathological findings of covid-19 associated with acute respiratory distress syndrome covid-19 patients with severe respiratory failure characterization of the receptor-binding domain (rbd) of 2019 novel coronavirus: implication for development of rbd protein as a viral attachment inhibitor and vaccine sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor characterization of lung inflammation and its impact on macrophage function in aging the role of interleukin 6 during viral infections cx3cr1+ lung mononuclear phagocytes spatially confined to the interstitium produce tnf-α and il-6 and promote cigarette smoke-induced emphysema high il-6/ifn-γ ratio could be associated with severe disease in covid-19 patients the laboratory tests and host immunity of covid-19 patients with different severity of illness profiling serum cytokines in covid-19 patients reveals il-6 and il-10 are disease severity predictors dynamics of peripheral immune cells and their hla-g and receptor expressions in a patient suffering from critical covid-19 pneumonia to convalescence clinical and immunological features of severe and moderate coronavirus disease 2019 il-1 blockade with anakinra in acute leukaemia patients with severe covid-19 pneumonia appears safe and may result in clinical improvement safety and efficacy of early high-dose iv anakinra in severe covid-19 lung disease effective treatment of severe covid-19 patients with tocilizumab a role for neutrophils in viral respiratory disease. front immunol immune phenotyping based on neutrophil-to-lymphocyte ratio and igg predicts disease severity and outcome for patients with covid-19. medrxiv immune cell profiling of covid-19 patients in the recovery stageby single-cell sequencing a single-cell atlas of the peripheral immune response in patients with severe covid-19 functional exhaustion of antiviral lymphocytes in covid-19 patients the airway epithelium: more than just a structural barrier respiratory epithelial cells orchestrate pulmonary innate immunity cell host response to infection with novel human coronavirus emc predicts potential antivirals and important differences with sars coronavirus the role of pulmonary and systemic immunosenescence in acute lung injury aging exacerbates acute lung injury-induced changes of the air-blood barrier, lung function, and inflammation in the mouse age-dependent differences in pulmonary host responses in ards: a prospective observational cohort study clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study breadth of concomitant immune responses prior to patient recovery: a case report of non-severe covid-19 twoyear prospective study of the humoral immune response of patients with severe acute respiratory syndrome reduction and functional exhaustion of t cells in patients with coronavirus disease ageing and life-long maintenance of t-cell subsets in the face of latent persistent infections the aged lymphoid tissue environment fails to support naïve t cell homeostasis the impact of aging on regulatory t-cells a clinically meaningful metric of immune age derived from high-dimensional longitudinal monitoring the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 cunha, perazzio, azzi, cravedi and riella. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-325722-ixozph19 authors: yip, paul; chen, mengni; so, bing kwan; lam, kwok fai; wat, kam pui title: optimal strategies for reducing number of people in the social security system date: 2020-02-18 journal: int j environ res public health doi: 10.3390/ijerph17041305 sha: doc_id: 325722 cord_uid: ixozph19 providing social security to the population in need has become a major expenditure for many governments. reducing the number of dependents in the social security system and maintaining a dynamic economically active population is a high priority concern for policymakers. a good understanding of the dynamics of the social security system—specifically, who enters and who exits the system—would be helpful for formulating effective interventions. here, we made use of the data of hong kong’s comprehensive social security assistance (cssa), which is currently a basic welfare scheme in hong kong that provides supplementary payments to households that cannot support themselves financially. we proposed a stochastic model to examine the inand outmovement in the cssa scheme and conducted elasticity analyses. the elasticity analyses allowed us to identify the potential target groups of people that would lead to the largest reduction in the number of the cssa recipients in the system. this analytical method can also reveal whether policies would be more effective in preventing people from entering the cssa system or helping them leave the cssa scheme. our analyses suggest that targeting those aged 30–49 with children would have the largest impact. additionally, we found that policies that aim to prevent this group from entering the cssa system would be more effective in reducing the number of cssa recipients compared with policies that aim to help them exit. in contrast, for the younger age group of 10–29, policies that help them leave cssa would be more effective than policies that prevent them from entering cssa. providing employment for those unemployed in this younger group would be more effective. the results indicate that by tailoring measures to specific subgroups, the overall number of cssa recipients would be reduced, thereby improving the efficiency of hong kong’s social security system, which has accounted for more than 16.5% of hong kong government expenditure in 2018, amounting to more than hkd 92 billion. "leave no one behind" is the overarching principle of the united nations' 2030 sustainable development goals [1] . ending poverty everywhere, in all its forms, is the first of the sustainable development goals (sdg). in signing the sdg agenda 2030, governments around the world have committed to achieving this goal over the coming years. hong kong is one of the richest cities in the world with an impressive gdp of usd 46,000, but with a large gini coefficient of 0.537, and thus the issue of poverty deserves special attention. the poverty line in hong kong is set at 50% of the median until 1997, hong kong was a british colony for more than 150 years (since 1842). the social security system in hong kong was shaped by the laissez-faire philosophy under the previous colonial regime. the concept of self-reliance via employment is deeply rooted in the psyche of the hong kong population, and the so-called hong kong "lion rock spirit" captures an ethic of hard working and mutually helping one another in the community. only the very needy and vulnerable families would receive support by the government. thus, hong kong's welfare system was perceived as a typical example of the residual model of welfare, which views the government welfare provision only as a last resort. the laissez-faire philosophy and residual welfare model were also compatible with chinese confucian values, which emphasize filial piety, respect for older people, love for one's family, self-restraint, shouldering collective responsibility, mutual help, and so on. chiu and wong (2005) [11] have argued that confucian ideology has been used by the hong kong government as "a means to contain social welfare costs", as well as to justify the residual welfare model. on july 1st of 1997, the sovereignty over hong kong was returned back to mainland china and the city has become a special administrative region of the people's republic of china (hksar). under the principle of "one country, two systems", hong kong has enjoyed a high degree of autonomy and is responsible for its domestic affairs including tax system. the hksar government does not have to contribute any revenue towards the central government. since 1997, the social policies in hong kong have been not only shaped by the laissez-faire philosophy that were "inherited" from the colonial regime, but also constrained by the basic law that was issued after the handover to china [10] . according to the basic law, the hong kong government can only increase its public expenditure on social welfare within the limits of the budget surplus [12] . thus, social policies have become sensitive to the government budget. since 1997, the government experienced 6 years of budget deficit, from 1998-1999 to [2004] [2005] , which was related to the 1997 asian financial crisis and the 2003 severe acute respiratory syndrome (sars) epidemic. during this period, the low-income group suffered most from the two economic shocks. the rising social welfare needs of low-income families greatly increased government spending, and consequently new social policies to expand and diversify the social welfare system had to be suspended [10] . the comprehensive social security assistance (cssa) is the most important welfare program in hong kong. previously, this social security was called "public assistance", which was introduced in 1971 and modified from the british national assistance act. public assistance aimed to help the aged and the sick to maintain a basic living standard with a minimal allowance. it was in 1993 that public assistance was renamed cssa. the applications of cssa have to go through income and assets means tests. in the first year (i.e., 1993), the number of cssa cases was 91,362 and the number of cssa recipients was 121,060. there can be more than one recipient in one case, as the household is treated as a case unit and all the members within the household can be recipients. figure 1 shows the trends of cssa cases and recipients over the period of 1993-2017. the number of cases rapidly increased and reached a peak in the year 2005 (of 298,011); since then, it has steadily declined to 232,134 in 2017. the number of recipients had a similar trend, with a dramatic increase in the years of 1997 of , 1998 of , 2002 of , and 2003 of . in 1997 of and 1998 on july 1st of 1997, the sovereignty over hong kong was returned back to mainland china and the city has become a special administrative region of the people's republic of china (hksar). under the principle of "one country, two systems", hong kong has enjoyed a high degree of autonomy and is responsible for its domestic affairs including tax system. the hksar government does not have to contribute any revenue towards the central government. since 1997, the social policies in hong kong have been not only shaped by the laissez-faire philosophy that were "inherited" from the colonial regime, but also constrained by the basic law that was issued after the handover to china [10] . according to the basic law, the hong kong government can only increase its public expenditure on social welfare within the limits of the budget surplus [12] . thus, social policies have become sensitive to the government budget. since 1997, the government experienced 6 years of budget deficit, from 1998-1999 to 2004-2005, which was related to the 1997 asian financial crisis and the 2003 severe acute respiratory syndrome (sars) epidemic. during this period, the low-income group suffered most from the two economic shocks. the rising social welfare needs of low-income families greatly increased government spending, and consequently new social policies to expand and diversify the social welfare system had to be suspended [10] . the comprehensive social security assistance (cssa) is the most important welfare program in hong kong. previously, this social security was called "public assistance", which was introduced in 1971 and modified from the british national assistance act. public assistance aimed to help the aged and the sick to maintain a basic living standard with a minimal allowance. it was in 1993 that public assistance was renamed cssa. the applications of cssa have to go through income and assets means tests. in the first year (i.e., 1993), the number of cssa cases was 91,362 and the number of cssa recipients was 121,060. there can be more than one recipient in one case, as the household is treated as a case unit and all the members within the household can be recipients. figure 1 shows the trends of cssa cases and recipients over the period of 1993-2017. the number of cases rapidly increased and reached a peak in the year 2005 (of 298,011); since then, it has steadily declined to 232,134 in 2017. the number of recipients had a similar trend, with a dramatic increase in the years of 1997 of , 1998 of , 2002 of , and 2003 of . in 1997 of and 1998 , when the asian financial crisis struck hong kong, the number of recipients had increased by 59,239 and 86,000, respectively. 1993 1994 1995 1996 1997 1998 1999 2000 2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011 2012 2013 2014 2015 2016 2017 number of cssa cases and recipients year case recipients figure 2 shows the age composition of the recipients. as shown, in 1993, those aged 60 and above accounted for almost 60% of recipients, whereas those aged 15-59 and under 15 occupied about 25% and 15%, respectively. the proportion of recipients aged 0-59 initially rose continuously, reaching about 66% in 2004; since then, it has started to decline and the proportion was about 50% in 2017. as the population continues to age rapidly due to low fertility and long life expectancy, the proportion of recipients aged 60 and above is expected to increase. int. j. environ. res. public health 2020, 17, 1305 4 of 15 figure 2 shows the age composition of the recipients. as shown, in 1993, those aged 60 and above accounted for almost 60% of recipients, whereas those aged 15-59 and under 15 occupied about 25% and 15%, respectively. the proportion of recipients aged 0-59 initially rose continuously, reaching about 66% in 2004; since then, it has started to decline and the proportion was about 50% in 2017. as the population continues to age rapidly due to low fertility and long life expectancy, the proportion of recipients aged 60 and above is expected to increase. such a large share of spending on cssa and its rate of increase have become a concern for the hong kong government, especially in the years of the asian financial crisis and sars epidemic, such a large share of spending on cssa and its rate of increase have become a concern for the hong kong government, especially in the years of the asian financial crisis and sars epidemic, such a large share of spending on cssa and its rate of increase have become a concern for the hong kong government, especially in the years of the asian financial crisis and sars epidemic, when the budget turned to a deficit. the government did take steps to control the expenditure on cssa and balance their budget by reducing the value of cssa payments and the number of recipients. theoretically, reducing the number of recipients can be achieved either by preventing people from entering the cssa system or helping them leave the system. the "entering approach" often influences a relatively larger number of the population at risk of poverty, preventing "potential candidates" from falling into cssa with more universal measures. the universal measures often include minimum wage, universal health insurance, subsidized education, public housing, and so on, from which both cssa recipients and non-cssa people can benefit [13] . in particular, the universal cash handout scheme in hong kong is a very typical example. the hong kong government introduced scheme hkd 6000 and scheme hkd 4000 in 2011 and 2019, respectively. under these schemes, any hong kong permanent resident aged 18 and above was eligible to get a lump-sum payment of hkd 6000 and hkd 4000 in 2011 and 2019, respectively. in contrast, the "leaving approach" is more likely to affect a relative smaller group of people that are unemployed, in low-paid work, or single parents, helping them get out of the system with more focused measures. the focused measures include single parent allowance, transportation subsidy for low-income families, job training programs for the unemployed, and so on [13] . the hong kong government seemed to have adopted an "entering approach" in the 2000s, but the specific means of preventing people from entering was controversial. before 2004, hong kong residents could apply for cssa if they had lived in hong kong for at least 1 year. in 2004, the requirement for residence was then raised up to 7 years, effective from 2004 until 2013. this revision was mainly driven by concerns about the budget shortfall [14] . scholars also think that the government pursued the "entering approach" by blaming the poor for their laziness using the media, so that they were discouraged to apply for cssa [8, 9] . this created a psychological hurdle for those physically able adults and made them turn away from cssa voluntarily. wong (2000) [9] argued that the image of "laziness" and "dependency" constructed (whether intentionally or unintentionally) for the cssa recipients actually reflected "a failure rather than a success in fighting against poverty". the cssa is meant to provide timely help for those needy families such that they still can receive the necessary financial support while looking for employment. it does not mean to create some dependence on the system, and those seeking help should not be stigmatized. furthermore, it is always the children from cssa families who would need more support to break up intergenerational poverty. meanwhile, it should be emphasized that "welfare dependency" is a very common problem that many social security systems would face or try to avoid [15] [16] [17] . when the incentives to take and sustain jobs are not strong enough, people would continue claiming benefits from the social security system as they are often more secure and attractive than employment; thus, it would create a culture of "dependency", "laziness", or "worklessness", leading to "excessive and ineffective public expenditure", as well as "persistent and prevalent poverty" [17] . to reduce such "welfare dependency", an effective "leaving approach" may help to incentivize cssa recipients to return to and survive in the labor market. the poverty commission in hong kong has advocated social enterprises to play a role in poverty alleviation, particularly helping welfare dependents become self-sufficient, as social enterprises would provide more opportunities to the disadvantaged, as well as improve their skills and employability [18] . it is important to consider whether the "entering approach" is indeed more effective than the "leaving approach" in reducing the number of cssa recipients in hong kong. very few studies have provided evidence for the "entering approach". furthermore, without reducing the cssa payment and restricting the eligibility, is there any better way to control the expenditure on cssa? which group of people and in what approach should the government intervene so that the number of recipients can be effectively reduced? this paper tries to answer these mostly unexplored questions. specifically, by modelling the dynamics of the cssa system in a markov chain process and performing an elasticity analysis, we aimed to identify the potential target group and the group-specific approaches. the findings can shed some light on how to enhance and optimize the social security system in hong kong. the data required for the analysis included (1) the age-specific number of people who entered the cssa system during 2014-2015, (2) the age-specific number of people who left the system during 2014-2015, (3) the age-specific population in 2014, and (4) the number of births by mothers in terms of age group in 2014. on the basis of these data, we estimated the age-specific transition probabilities; that is, the probabilities of leaving cssa and the probability of entering cssa. all of the data are from the hong kong census and statistics department (hkc&sd). we modelled the dynamic of people moving in and out of the cssa system using a stochastic process (markov chain process). this method has been increasingly used in labor economics and demographic research, especially in evaluating social policies [19] [20] [21] [22] [23] . we first present a simplified model. suppose in a certain year, the probability of entering the system is p t and the probability of leaving the system is q t . let x t be the proportion of cssa recipients in the total population at time t. therefore, we can simply formulate the inflow and outflow of cssa recipients in equation (1). where a is a 2 × 2 matrix, the proportion of cssa recipients in the total population, x t+1 , can be reduced either through reducing the probability of entering cssa, p t , or through increasing the probability of leaving cssa, q t . to investigate whether the former or the latter approach is more effective in reducing the number of cssa recipients is of great importance to policymakers. in order to answer this question, we introduced the concept of elasticity. elasticity is originally a concept in economics. in economics, price elasticity, for instance, measures the impact on the demand of a product when its price changes, that is, percentage change in the quantity demanded of one product in response to percentage change in the price. very often, it is precisely interpreted as the percentage change of demand per 1% change in the price [24] . the concept of elasticity has recently been adopted by some scholars to evaluate the targeting of policies, for example the targeting of family polices in singapore, taiwan, and australia [21] [22] [23] . analogously, here we define the elasticity as the ratio of percentage change of x t+1 to the percentage change of any of the parameters (p t or q t ). the larger the elasticity, the more influential the parameter to x t+1 . the elasticity with respect to p t and q t can be formulated as follows: (2) by comparing the absolute values of δ p t and δ q t , we will know whether the "entering" or "leaving" approach is more effective in reducing the number of cssa recipients in a certain year. in reality, the probability of leaving or entering the cssa system often varies across different age and socioeconomic groups. as the data of cssa recipients by socioeconomic status is not available, we cannot include the socioeconomic groups in our analysis. thus, we further elaborated our model by considering age to better reflect the real dynamics of the cssa system in hong kong. let x in this study, we restricted our attention to those aged below 60, because those cssa recipients aged 60 and above have a high chance of leaving the cssa system due to death. the financial situation of older adults, and particularly those over the retirement age of 65, would also typically show little change due to the relatively low employability of older adults. on the basis of the data from hkc&sd, we estimated the transition parameters p (i) t and q (i) t for 10 year age-specific groups (covering the ages of 0-59). within the age group, those aged 0 deserve special attention. according to the rules under the cssa system, the newborns of a cssa recipient will become cssa recipients directly. on the basis of the assumptions that the birth rates of the cssa recipients and non-cssa people are the same, and that the births are from women aged 15-49, x (0) t and y (0) t can be formulated by equation (5). are the corresponding age-specific birth rates at time t. certainly, b (1) . the goal of our analysis was to investigate which group should be targeted and in which approach of "leaving" or "entering", so that the overall proportion of cssa recipients can have the largest reduction. let x denote the overall proportion of the cssa recipients in the population aged under 60, which can be calculated from the following formula: where w (i) t refers to the proportion of the age group i in the total population aged under 60 at time t, and 59 i=0 w t was estimated on the basis of the age-specific population in 2014 from hkc&sd. to achieve the goal, we estimated the elasticity with respect to p (i) t and q (i) t from the following formulae, which were modified from equations (2) and (3): moreover, to better understand the moving-in and -out of the cssa system, we calculated the probability of a cssa recipient aged i to first exit the system at or before the age of 60, as well as his/her mean time of staying in the system before the first exit. equations (9) and (10) were used to estimate the probability and the mean time. i) = 1 − 1 − q (i) t 1 − q (i+1) t · · · 1 − q (59) t (9) mean time = 1 × q (i) t + 2 × q (i+1) t × 1 − q (i) t + · · · +(60 − i) × q (59) t × 1 − q (58) t · · · 1 − q (i) t(10) the estimated age-specific probabilities of entering and leaving the cssa system are shown in table 1 . the probability of leaving was found to be much higher than the probability of entering across all the ages. the 20-29 age group has the highest probability of leaving and the lowest probability of entering the cssa system. except for the two youngest age groups, the probability of leaving cssa declines with the increase of age, indicating the increasing difficulty of raising their income above the level of the threshold. on one hand, this declining trend may be due to the fact that the family size will increase with people's age, and thus it would become more difficult to move all the family members out of the cssa system. on the other hand, previous research shows that in hong kong, as men and women get older, particularly after age 30, upward mobility of earnings declines while downward mobility of earnings increases [25] . workers in the lowest income quintile are more likely to be trapped at the bottom, experiencing no earning mobility [25, 26] . moreover, the declining probability of leaving for the two youngest age groups (i.e., ages of 0-9 and 10-19) is very much related to the parents' probability of leaving. parents of children aged 10-19 are more likely to be older, in the 40s and 50s, and that is probably why the leaving probability of the 10-19 age group is lower and very close to that of the 40-49 and 50-59 age groups. regarding the probability of entering cssa, the 0-9 and 10-19 age groups were found to be at the highest level-much higher than the other age groups. this was because these two groups are too young to participate in the labor market and their economic situation often depends on their parents. once their parents' incomes fall below the threshold level of cssa, they become cssa recipients directly. hence, these young people are indirectly entering the cssa system. thus, reducing their probability of entering should not directly aim at these young dependents but at improving incomes of their parents who are often in the age range of 30-49. maintaining the economic environment by keeping the unemployment rate low is important for middle-aged workers. table 2 shows the probability of a cssa recipient first exiting the system before age 60 and the mean duration of staying in the system. it is encouraging to see that the probabilities of first exit among those aged under 30 are higher than 0.99, implying that almost all of them will leave the cssa system before age 60. there was a significant decline in the probability of first exit after age 30. this is very consistent with the age pattern shown in table 1 . the probability dropped to 0.73 for those aged 50 and 0.48 for those aged 55. this is because there is much less time for them to leave the cssa before the cutoff age of 60. regarding the mean time of staying in the system, children under age 15 were found to have the longest duration. the mean time was found to decrease to about 4.8 years for those in their 20s and then starts to rise again in the age range of 30-40. those in their 50s have a much shorter duration of staying before they first leave the system. on the basis of the age-specific probability of entering and leaving cssa, we performed the elasticity analysis. the results (in absolute values) are shown in table 3 increased by 0.1, the overall proportion of cssa recipients would decrease by 0.0012 (= 0.012 × 0.1). from these results, it seems that preventing people aged 20-29 from entering the cssa system has a larger impact; that is, the "entering" approach would be more effective in reducing the number of cssa recipients in 2014. however, it should be noted that it is impossible and unrealistic to achieve a decrease of 0.1 in p is only 0.0015 and a decrease of 0.1 will make it negative. in reducing the number of cssa recipients; for the 10-19 and 20-29 age group, helping the cssa recipients leave the system will have a larger impact (see the last column in table 3 ). in sum, these results suggest that targeting the age group of 30-49 through the "entering approach" would lead to the greatest reduction in the number of cssa recipients, as aiming at this group would also effectively prevent those aged 0-9 from entering the cssa system. this study investigated the targeting of the social security system in hong kong by evaluating the cssa scheme, which is the fundamental welfare program. we have made use of the markov chain process to model the dynamics-the inflow and outflow-of the cssa system. we conducted elasticity analyses to identify the potential target group and the appropriate approaches for different subgroups classified by age. the results have revealed that the largest elasticity was in the 0-9 age group, meaning that targeting children at this age will lead to a largest decrease in the number of cssa recipients. currently, child poverty is a serious issue in hong kong. in 2017, before government intervention, the poverty rate among children aged below 18 was about 23.1%, much higher than many other developed societies [2,27]. as child poverty often results from parents' low income and unemployment, policies that support households with children would be desirable. more precisely speaking, the results suggest that targeting those aged 30-49 with children by decreasing the risk of entering cssa would have the largest impact on the number of cssa recipients. studies on child poverty in hong kong have found that family structure is a strong predictor. it was found that children from immigrant families are more likely to live below the poverty line in hong kong due to low education of parents, high unemployment rate of mothers, and low payment of parents' jobs [28] . moreover, children living with single parents have high risk of poverty; the poverty gap between children with single parents and children with two parents has been widening in recent decades [29] . the ethnic minority families such as pakistani, nepalese, and other south asian countries also have higher child poverty rates, as a result of discrimination in the education system and labor market due to the language barriers faced by their parents [30] . poverty is found to have a significant impact on children's psychological well-being-in hong kong, children in poverty have reported lower levels of self-esteem and more depressive symptoms, and they are more likely to live in public housing which is often more crowded, having poor hygiene and lack of facilities [31] . food insecurity, as well as limited educational opportunities and learning resources would have a therefore, compared to the rates of change, the elasticity that takes into account the feasibility of changing the parameter is preferable. as shown in table 3 , the elasticity to the probability of leaving in the 20-29 age group δ q (20−29) t was 0.109, meaning that given 1% increase in the probability of leaving (i.e., an increase of 1% × 0.2103), the proportion of cssa recipients would reduce by 0.109%. the elasticity to the probability of entering the group δ p (20−29) t × was 0.04, meaning that given a 1% decrease in the probability of entering (i.e., a decrease of 1% × 0.0015), the proportion of cssa recipients would reduce by 0.04%. thus, according to the elasticities, increasing the probability of leaving would have a greater impact, indicating that the "leaving approach" rather than the "entering approach" is more effective for the age group 20-29. as shown in figure 5 , the elasticities of the leaving probabilities decline with age, implying that the "leaving approach" is more effective in younger age groups than in older groups, as the employability of young people is much higher than their older counterparts and earning a salary through employment is the most effective way to leave the cssa system. the elasticities of entering probabilities also showed a decreasing trend over ages, although the 20-29 and 50-59 age groups had the lowest elasticities. this means that the "entering approach" for these two groups is relatively less effective than in other age groups. the age pattern of the elasticities showed that targeting younger age groups would make a larger difference than targeting older groups. therefore, intuitively, it may seem most effective to target the 0-9 age group. however, instead of focusing on these young dependents, attention should be paid to their parents who are often in the age group of 30-39 and 40-49. furthermore, elasticities of entering probabilities were larger than leaving probabilities in the 0-9, 30-39, and 40-49 age groups, whereas the opposite pattern was shown in the 10-19 and 20-29 age group. these findings inform us that for the 0-9, 30-39, and 40-49 age group, preventing them from entering the cssa system would be more effective in reducing the number of cssa recipients; for the 10-19 and 20-29 age group, helping the cssa recipients leave the system will have a larger impact (see the last column in table 3 ). in sum, these results suggest that targeting the age group of 30-49 through the "entering approach" would lead to the greatest reduction in the number of cssa recipients, as aiming at this group would also effectively prevent those aged 0-9 from entering the cssa system. this study investigated the targeting of the social security system in hong kong by evaluating the cssa scheme, which is the fundamental welfare program. we have made use of the markov chain process to model the dynamics-the inflow and outflow-of the cssa system. we conducted elasticity analyses to identify the potential target group and the appropriate approaches for different subgroups classified by age. the results have revealed that the largest elasticity was in the 0-9 age group, meaning that targeting children at this age will lead to a largest decrease in the number of cssa recipients. currently, child poverty is a serious issue in hong kong. in 2017, before government intervention, the poverty rate among children aged below 18 was about 23.1%, much higher than many other developed societies [2, 27] . as child poverty often results from parents' low income and unemployment, policies that support households with children would be desirable. more precisely speaking, the results suggest that targeting those aged 30-49 with children by decreasing the risk of entering cssa would have the largest impact on the number of cssa recipients. studies on child poverty in hong kong have found that family structure is a strong predictor. it was found that children from immigrant families are more likely to live below the poverty line in hong kong due to low education of parents, high unemployment rate of mothers, and low payment of parents' jobs [28] . moreover, children living with single parents have high risk of poverty; the poverty gap between children with single parents and children with two parents has been widening in recent decades [29] . the ethnic minority families such as pakistani, nepalese, and other south asian countries also have higher child poverty rates, as a result of discrimination in the education system and labor market due to the language barriers faced by their parents [30] . poverty is found to have a significant impact on children's psychological well-being-in hong kong, children in poverty have reported lower levels of self-esteem and more depressive symptoms, and they are more likely to live in public housing which is often more crowded, having poor hygiene and lack of facilities [31] . food insecurity, as well as limited educational opportunities and learning resources would have a negative impact on the development of children from poor families, creating intergenerational poverty in hong kong [32] . therefore, it is very important to identify the reasons of falling into the cssa system and barriers to exit among households with children. single parenthood, unemployment, and low-earnings are the major reasons for physically-able adults becoming cssa recipients. the latest poverty study in 2017 shows that poverty among those who are working was only 4.9% in comparison to 14.7% in the general community [2]. providing jobs and enhancing job earnings for the age group of 30-49 would effectively reduce the number of cssa recipients. the hong kong government has initiated the public transport fare subsidy scheme to enhance people's ability to look for employment across districts [33] . the government also provides additional support for families-especially single-parent families-to work part-time and look after their children after work. of course, the employment remuneration conditions should be improved so that working parents can earn enough to support the family without the need of cssa. the introduction of a minimum wage by the hong kong sar government in 2011 has helped to narrow the income gap, despite the fact that the minimum wage is still at a very low level of about hkd 37.5 (about usd 4.8) per hour. in many western countries, the minimum wage is substantially higher (e.g., usd 13.3 in australia, usd 10.3 in the united kingdom), despite the fact that hong kong's gdp per capita of usd 49,000 actually ranks higher. thus, it is important to examine the minimum wage structure, especially for those in low-skilled jobs, to improve their quality of life. meanwhile, different subgroups call for different approaches. the "entering approach" is not always most desirable for all the subgroups. it is found that for the 10-29 age groups, policies that aim to help people leave cssa will be more effective than policies that aim to prevent people from entering cssa. according to the hong kong poverty situation report 2017, the unemployment rate among the young people 15-29 is relatively higher than the general population. on the other hand, for those who are employed, young households have the highest proportion of high-skilled workers and the lowest poverty rate [2]. by upgrading working skills of young cssa recipients, young adults can enhance their employability and secure jobs with better earnings, so that they can support themselves without cssa. diversifying the economic and working opportunities is also of great importance in improving the employability of our young people. most of the economic activities in hong kong are in the professional, financial, and service sectors, and limited opportunities are available in other sectors, such as creative industries and local startups. the excessive rental cost in hong kong has been found to be a barrier for young people to start their own business. it is important for the government to provide initial support for these young entrepreneurs at the early stage of their career development. meanwhile, for the 30-59 age groups, policies that aim to prevent people from entering cssa will be more effective than policies that aim to help people leave cssa. people of these ages often have other family members to care for, either young children or old parents, and sometimes both. more often, they have jobs but the earnings are not adequate to cover the living expense of the whole family, and thus all members in the household become cssa recipients. in this case, policies that can increase the family income can prevent them from entering cssa. we should try to maintain or enhance the employability of these groups of people as a matter of importance. keeping them in the job is important for poverty alleviation. it will be difficult for the unemployed individuals to reenter to the workforce, especially for those who are not professionals. the bargaining power to aim for better working conditions would also be limited for the low-skilled workers as there are plenty in supply due to the current migration policy, with there being an influx of migrants of 150 per day from mainland china entering into hong kong. the wage of the low-skilled worker has been lagging behind the economic growth. hong kong still has one of the largest poverty gaps among the high income societies with a gini coefficient of 0.54 [2] . it is important to improve the wage level, especially for the low-skilled workers in hong kong. the minimum hourly wage is hkd 37.5 (usd 4.8), which is one of the lowest in comparison to other oecd (i.e., the organization for economic co-operation and development) countries. currently, the individual-based work incentive transport subsidy (i-wits), to some extent, can help middle-aged adults broaden their horizons for better job opportunities across the whole territory [33] . in addition, the working family allowance can provide extra income to households with children. the results have provided insights into the improvement of the cssa system in terms of accurate targeting. it should be emphasized that the probability of entering and leaving cssa, as well the elasticities with respect to these probabilities, should be monitored frequently and closely so that a more timely response can be in place to improve the efficiency of cssa. in spite of the positives, there are some limitations in this study. first, due to data limitations, we were only able to investigate the targeting groups by age, and did not include the subpopulations by socioeconomic status (e.g., education, employment, occupation). future research can assess the role of different socioeconomic subgroups in reducing the number of cssa recipients, with better data access. apparently, the young graduates from universities have less financial responsibility towards their parents and they can afford to have some gap years before graduation and employment. for the young professionals, once they work, it would be easier for them to leave poverty. second, we did not take into account gender difference. the number of female cssa recipients was found to often be larger than male recipients, which is mainly the contribution of women's overrepresentation in the "single-parent" case under cssa [34] . for example, in 2017, 87.6% of single-parent recipients were female, most of whom were divorced or separated, in the age of 30-49 [35] . however, due to a lack of gender-specific data, we were unable to examine whether the elasticities were different between men and women, and how big the difference was. third, we only restricted our analysis to those under age 60 and did not consider the elderly population due to limited information of the elderly people leaving cssa because of death. fourth, the markov chain and elasticity analyses were based on several assumptions (e.g., assumption of the same birth rates between cssa recipients and non-cssa people), and consequently they did not fully model the exact dynamics of the cssa system. fifth, we did not take into consideration the differential cost in achieving the same unit of the entering and exiting approach. however, this method is still a very useful tool to assess the targeting of the social security system and it can be further elaborated if more information about the cssa recipients and employment data is available. the propose model provides empirical evidence to identify the potential target groups of people that would lead to the largest reduction in the number of the cssa recipients in the hong kong social security system. this analytical method has also revealed whether policies would be more effective in preventing people from entering the cssa system or helping them leave the cssa scheme. despite the limitations of the stochastic model, it helps to improve the effectiveness of the social security system in hong kong. poverty and income inequality have become one of the major causes of the recent months of social unrest in hong kong in 2019-2020. the government has been increasing its expenditure on welfare spending. sometimes, the improvement is still quite limited. our model can be used as a tool to examine its effectiveness of any poverty program with the aim to reduce the number of cssa recipients. author contributions: manuscript preparation and data analysis-m.c., b.k.s., k.f.l. and k.p.w.; leading the investigation as the pi for the project, critical review and final approval of the paper-p.y. all authors have read and agreed to the published version of the manuscript. funding: this research was funded by the hong kong government: sppr-12. the common welfare: hong kong's social services social security inequality and the third world the 2018-2019 budget the basic law of the hong kong special administrative region of the people's republic of china; the constitutional and mainland affairs bureau speech by the chief executive in delivering "the chief executive's 2017 policy address" to the legislative council the social security system in hong kong: establishment and readjustment of the liberal welfare model the failure of social security in alleviating poverty in hong kong changes in social policy in hong kong since 1997: old wine in new bottles? from familistic to confucian welfare local policy in global politics: the limit of anti-poverty policy in hong kong nations. family-oriented policies for poverty reduction, work-family balance and intergenerational solidarity social mobilization, blame avoidance, and welfare restructuring in hong kong resisting the neo-liberal poverty discourse: on constructing deadbeat dads and welfare queens workfare in the world's freest economy telling stories of 21st century welfare: the uk coalition government and the neo-liberal discourse of worklessness and dependency the social impact of work-integration social enterprise in hong kong for whom are permanent jobs off limits? a markov-chain-based analysis of individual labor market dynamics comparative analysis of labor market dynamics using markov processes: an application to informality a new method of identifying target groups for pronatalist policy applied to australia identifying the most influential groups in determining singapore's fertility an elasticity analysis of the effectiveness of pronatalist measures in taiwan principles of microeconomics; south-western cengage learning special topic enquiry on earnings mobility; school of economics and finance social mobility in hong kong how to break the cycle of child poverty in hong kong, where one in five children are poor. south china morning post familial effect on child poverty in hong kong immigrant families child poverty in hong kong single-parent families the effect of poverty and income disparity on the psychological well-being of hong kong children social assistance programs and child poverty alleviation-a comparison between hong kong and mainland china associations between commuting and well-being in the context of a compact city with a well-developed public transport system women's commission. hong kong women in figures hkcsd. statistics on comprehensive social security assistance scheme this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors are grateful for data supplied by the social work department and the census and statistics department of the hong kong sar government and the many useful comments from the reviewers. the research is supported by the chief executive community project for poverty alleviation and the hong kong charities trust. the authors declare no conflict of interest. the funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results. key: cord-340028-6oicmeam authors: zhavoronkov, alex title: geroprotective and senoremediative strategies to reduce the comorbidity, infection rates, severity, and lethality in gerophilic and gerolavic infections date: 2020-03-31 journal: aging (albany ny) doi: 10.18632/aging.102988 sha: doc_id: 340028 cord_uid: 6oicmeam the recently identified sars-cov-2 betacoronavirus responsible for the covid-19 pandemic has uncovered the age-associated vulnerability in the burden of disease and put aging research in the spotlight. the limited data available indicates that covid-19 should be referred to as a gerolavic (from greek, géros “old man” and epilavís, “harmful”) infection because the infection rates, severity, and lethality are substantially higher in the population aged 60 and older. this is primarily due to comorbidity but may be partially due to immunosenescence, decreased immune function in the elderly, and general loss of function, fitness, and increased frailty associated with aging. immunosenescence is a major factor affecting vaccination response, as well as the severity and lethality of infectious diseases. while vaccination reduces infection rates, and therapeutic interventions reduce the severity and lethality of infections, these interventions have limitations. previous studies showed that postulated geroprotectors, such as sirolimus (rapamycin) and its close derivative rapalog everolimus (rad001), decreased infection rates in a small sample of elderly patients. this article presents a review of the limited literature available on geroprotective and senoremediative interventions that may be investigated to decrease the disease burden of gerolavic infections. this article also highlights a need for rigorous clinical validation of deep aging clocks as surrogate markers of biological age. these could be used to assess the need for, and efficacy of, geroprotective and senoremediative interventions and provide better protection for elderly populations from gerolavic infections. this article does not represent medical advice and the medications described are not yet licensed or recommended as immune system boosters, as they have not undergone clinical evaluation for this purpose. aging is a complex, multifactorial process [1] that leads to loss of function and is the primary risk factor for major human pathologies including cancer, diabetes, cardiovascular disorders, and neurodegenerative diseases [1, 2] . although there is still much debate in the scientific community, proposals have been made to classify aging as a disease in order to develop therapeutic strategies to prevent or delay the onset of age-related illnessess [3] [4] [5] . increasing frailty with age leads to an increased risk of many diseases. these diseases are commonly referred to as age-related [6] . many pathogens are more infectious and prevalent in the elderly, [7] [8] [9] [10] and may be referred to as gerophilic (from greek, géros "old man" and philia, "love"). some infections, including covid-19, are not exclusively gerophilic, as younger people may also become infected. however, these individuals have mild symptoms or remain asymptomatic, while the elderly experience substantially more severe symptoms and lethality. the term gerolavic (from greek, géros "old man", and epilavís, "harmful") may more appropriately the online resources our world in data [16] and the lancet's global burden of disease [17] provide deep visual insight into the global burden of disease by cause and demographics. in 2017, there were 56 million deaths globally; over two-thirds of these (76%) were in people over 50 years of age. according to the online period life tables put out by the us social security administration [18] , the annual chance of death in 2015 (the probability of dying within one year) for a person over 80 was 5.2%, increasing to 14.8% by the age 89. according to estimates by the us centers for disease control [19] , approximately 5,945,690 individuals older than 65 had symptomatic influenza during the 2017-2018 season, resulting in 3,329,586 medical visits, 540,517 hospitalizations, and 50,903 deaths. hence, the death rate for those hospitalized with influenza was 9.4% for patients over 65. however, many of the covid-19 patients over 65 years have one or more comorbities [20] , and it is often difficult february 11, 2020 . the figures are adopted and generated from [12] (http://weekly.chinacdc.cn/en/article/id/e53946e2-c6c4-41e9-9a9b-fea8db1a8f51). to attribute the cause of death exclusively to the gerolavic coronavirus. currently, there are no accurate statistics linking smoking status, lifestyle, and behavior to the severity and lethality of covid-19. despite this, it is possible that these factors, as well as frailty and comorbidities, play a substantial role. gerolavic diseases such as covid-19 may not significantly increase the yearly death rates for each individual age group; however, these diseases substantially accelerate death from multiple conditions, and compress the process to less than two weeks. comorbidity is also the likely cause of the substantial differences in death rates among different countries due to differences in patient demographics, levels of preparedness, when the epidemic began locally, and reporting [13] . only the data available from china, where the epidemic has subsided, and the diamond princess cruise ship were used for this study. one of the possible causes of the age-associated increases in covid-19 infection rate, severity, and lethality is immunosenescence. immunosenescence is a well-known age-related process contributing to the global burden of disease [21] . it is among the major factors underlying the difference between younger and older populations in the response rate to vaccinations and the virulence of infectious diseases [22] [23] [24] . among the factors contributing to immunosenescence is the chronic involution of the thymus gland with increased age. indeed, the infection rates of covid-19, separated by age, are correlated with involution of the thymus [12] . the thymus gland is most active early in life, reaching maximum size within the first year. its activity then declines with age until an individual reaches 40 to 50, after which there are negligible traces of the thymus remaining, replaced by fibrotic tissue [25] . as a result of thymic involution, the number of naïve t cells exiting the thymus decreases significantly, with substantial declines in older age [26] . besides thymic involution, there are many other factors driving immunosenescence and the increase in multimorbidity that occurs during aging [22, 27, 28] . figure 2 illustrates the hypothesised reciprocal relationship between immunosenescence and infectious disease acquisition. in this model, age-associated immunosenescence leads to a reduced ability to resist infection, while infection produces biological damage and loss of homeostasis. this ultimately contributes to accelerated aging and the development of age-related diseases, and further accelerates immunosenescence. in support of this model, infections and other age-related diseases are among the main causes of death in the developed world and in developing countries. due to the gerolavic nature of covid-19, the classical preventative measures and treatment strategies used for targeting infectious diseases may not be as effective, and there is a need for alternative geroprotective and senoremediative strategies. there are multiple clinical trials in progress using established medical interventions to treat covid-19, with the number of studies rapidly increasing [23] . for a list of promising sars-cov-2/covid-19 targets and treatment approaches, please refer to the global health drug discovery institute's portal dedicated to covid-19 [29] . here we compare the expected benefit of treatments for elderly populations (60 years and older) that are currently in development, including standard preventative strategies such as vaccines and antivirals targeting sars-cov-2, and the potential added benefit of speculative geroprotective strategies such as rapalogs, nad+ boosters, senolytics, and stem cell treatment. these additional measures may be used in isolation or as adjuvant therapies to reduce infection risk, symptom severity, or improve vaccine efficacy. vaccine development is one of the most successful approaches for combating viral diseases globally, and is often regarded as one of the greatest advances in biomedical science and integrated healthcare. currently, there are around 60 active clinical trials related to a sars-cov-2 vaccine, most of them taking place in china [30] . broadly speaking, the success of a vaccine partly depends on the similarity of the vaccine strain with the viral pathogenic strain in question. in addition, an individual's immune response must be sufficiently strong to mount a reaction to the vaccine that can later confer protection against the pathogen, should exposure occur. our current strategy for targeting annual influenza viral outbreaks focuses on effective vaccination based on predictions of strain variants. people >60 years of age with chronic medical conditions, such as type 2 diabetes or cardiovascular disease, direct immunosuppression from hiv, posttransplant or biologic treatment, pregnant individuals, or those with bmi>40, are believed to be at higher risk for influenza infection due to a weakened immune response [31] . similarly, vaccines do not provide complete protection in older populations due to agerelated declines in immune function and accumulation of multi-morbidities. outbreaks can occur in elderly nursing homes even when vaccination rates reach 80-98% uptake [32] . thus, even when a successful vaccine for sars-cov-2 becomes available, a geroprotective agent might be used in combination with the vaccine to boost the immune response. currently in most countries, the influenza vaccine formulation is determined 6-9 months before the expected outbreak season and the strains are based on the precedent season's viruses. as a result, vaccine efficacy is expected to differ from season to season. thus, an ongoing additive geroprotective therapy is of high importance [33, 34] and is applicable beyond the current pandemic. while vaccines may be the best preventative strategy for reducing the infection rates, severity, and lethality of covid-19, the rates to vaccines in the elderly will likely be lower [35] and vaccine potentiation strategies [36] may be explored and evaluated in clinical trials. while chemoprophylaxis is not routinely indicated and is not considered a replacement for vaccination, using influenza as an example, prophylactic treatment prior to symptom onset in high-risk groups or after close contact exposure to the virus is an alternative preventative strategy against viral disease [31] . for influenza, the neuraminidase inhibitors oseltamivir and zanamivir are occasionally given prophylactically to high-risk individuals in long-term care facilities during outbreaks [37] . nevertheless, there is currently no definitive benefit proven for antiviral treatment outside of these specific circumstances, as it comes at a cost and may be associated with side effects; for example, zanamivir can induce bronchospasms in patients with chronic respiratory disease and asthma. pharmacotherapy for individuals with infection remains the cornerstone of clinical practice. the success of antiviral treatment is condition-specific, ranging from new, direct-acting antiviral drugs that offer a potential cure for hepatitis c [38] ; to the highly active antiretroviral drugs that enable hiv positive individuals the prospect of a healthy life expectancy while on treatment; to antiviral drugs for herpes simplex types 1 and 2 that lead to symptom alleviation but do not eradicate the latent infection; to antivirals for seasonal influenza that are believed to reduce symptom duration, and reduce complications and transmission risk. other anti-influenza medications licensed for treatment, aside from oseltamivir and zanamivir, consist of an intravenous neuraminidase inhibitor, peravamir, and a novel oral inhibitor of cap-dependent endonuclease, baloxavir. neuraminidase inhibitors are effective against both influenza a and b, while an additional class of antivirals that are no longer recommended for treatment of influenza due to reduced efficacy, neurological side effects, and widespread resistance, adamantanes (m2 inhibitors, amantadine and rimantadine), are only active against influenza a [31] . although many patients with influenza exhibit minimal clinical improvement upon treatment with these medications, they are currently recommended for treatment of all hospitalised patients, even prior to laboratory confirmation of influenza infection. evidence shows that the greatest benefit is seen when these drugs are administered 24-30 hours prior to symptom onset, in which case they reduce symptom duration by 0.5-3 days and reduce transmission risk [39] [40] [41] [42] . according to the recent covid-19 treatment guidelines in china [43] , symptomatic treatment for covid-19 patients is recommended for mild cases and consists of aging rest, isolation, adequate hydration, analgesia, and antipyretic medication. moderate and severe cases (mostly hospitalized) require additional measures, such as careful fluid balance, intravenous antibiotics for superinfections, oxygen supplementation, non-invasive ventilation with or without positive pulmonary pressure, and in some cases intubation and mechanical ventilation. although the projected global infection rates are variable, we share a common concern that outside of china there may be an insufficient number of beds for hospitalization and ventilation units if the disease spread does not slow down. even asymptomatic covid-19 infections can induce lung fibrosis, which may lead to reduced function of the respiratory system. further, severe cases are often complicated by bacterial infections and pneumonia, leading to fibrosis. therefore, covid-19 rehabilitation may include antifibrotic compounds, anti-copd, and regenerative medicine therapies. there are multiple interventions proposed in the academic literature to remedy age-associated increases in infection rates, severity, and lethality for a variety of infections. for example, regular increased physical activity has been proposed to reduce immunosenescence [44] . fahy et al. [45] and horvath [46] have suggested that a combination of the potentially geroprotective compound metformin, recombinant human growth hormone (rhgh), and dehydroepiandrosterone (dhea) may reverse biological age, as measured using the methylation aging clock, and immunosenescence [45] . geroprotectors were previously proposed to enhance human radioresistance in extreme conditions [47] . while there is no clinical evidence yet suggesting age reversal or improved immune function in the elderly, efforts are being made to identify new geroprotectors using human data and artificial intelligence [48] [49] [50] . further, the use of natural compounds that mimic the effects of known geroprotectors is generally recognized as safe [51] . however, attempts have been made to develop criteria for the evaluation of geroprotectors for clinical validation. there are multiple strategies proposed to restore immune function in the elderly [52] , and multiple databases of geroprotectors exist [53, 54] . however, to date the only known geroprotectors backed by promising clinical evidence of improved immune response to viral infection in the elderly, although still limited by a lack of large clinical trials, are sirolimus (rapamycin) and everolimus. these may be used as single agents in combination with other treatments (figure 3 ). sirolimus (rapamycin) is a well-known geroprotector, known to effectively increase lifespan and slow aging in many species, including yeast [55, 56] , drosophila [57, 58] , c. elegans [59] , and mice [60] [61] [62] [63] [64] . it also delays age-related diseases in humans [65] [66] [67] [68] , and blagosklonny proposed rapamycin for the prevention of multiple age-related diseases in humans [69] [70] [71] [72] . sirolimus and rapalogs are commonly used as immunosuppressants. rapalogs, the derivatives and mimetics of rapamycin, target critical factors in the rapamycin (tor) pathway. everolimus (rad001), another close structural derivative of sirolimus developed by novartis, acts as an immunosuppressant; but like sirolimus, it has many other properties beyond immunosuppression [73] . paradoxically, these compounds also exert immunostimulatory effects, such as boosting t cell responses in reaction to pathogen infection and vaccination [74] . nevertheless, this would not be the first case of a physiological paradox in clinical medicine. the administration of beta-blockers to heart failure patients at first seemed contradictory, as these compounds slow down an already failing heart, but proved to provide the most benefit for the treatment of heart failure patients. likewise, hormonal treatment of hormone-dependent cancers, such as testosteronedependent prostate cancer, seems incongruous. however, administration of a synthetic version of gonadotropin-releasing hormone (gnrh) in a different dosing regime from the cyclical secretion that occurs physiologically, which normally indirectly increases testosterone levels, actually reduces hormone levels. therefore, it might be possible that a drug that is known to be an immunosuppressant might in a different dosing regimen prove to be an immunostimulant. however, extremely cautious clinical validation is required as this treatment might carry significant risks; indeed, there is some indication that morbidity from coronavirus infections occurs from secondary overactive immune responses [75, 76] . in addition to rapamycin, other agents that inhibit mtor, such as torin1, torin2, azd8055, pp242, ku-006379 and gsk1059615, may act similarly to rapamycin in low-doses and may have a geroprotective effect [77] [78] [79] . substantial pre-clinical validation would be required to apply these compounds to specific age-associated diseases and to explore clinical applications of these compounds in human clinical trials. multiple clinical observations suggested that patients with cytomegalovirus (cmv) disease who were treated with rapamycin demonstrated better outcomes and were better able to control cmv viremia than patients treated with standard calcineurin inhibitor-based immunosuppression following transplantation [74, 80] . in 2009, two seminal studies of sirolimus demonstrated the immunostimulatory effects of rapamycin on the cd8+ memory t cell response following pathogen infection [74, 80] . later studies also showed that monkeys treated with sirolimus exhibited increased recall responses and enhanced differentiation of memory t cells following vaccination with modified vaccinia ankara [81] . additional clinical studies by mannick et al. [82, 83] demonstrated the immunostimulatory role of rapalogs in the elderly using the novartis rapalog everolimus (rad001), a close structural analog of sirolimus (rapamycin). administration of everolimus ameliorated immunosenescence in healthy elderly volunteers and enhanced the response to the influenza vaccine by around 20% at doses that were well tolerated [82] . further studies demonstrated enhanced immune function and reduced infection in elderly patients receiving tolerable doses of everolimus. mannick et al. also conducted a phase 2a randomized, placebo-controlled clinical trial which demonstrated that a low-dose combination of dactolisib (bez235) and everolimus in an elderly population was safe and associated with a significant (p=0.001) decrease in the rate of reported infections [83] . mannick and colleagues further conducted a phase 2a randomized, placebo-controlled clinical trial that demonstrated that a low-dose combination of dactolisib (bez235), a pi3k inhibitor [84] and catalytic mtor inhibitor, and everolimus in an elderly population was safe and associated with a significant (p=0.001) decrease in the rate of reported infections [83] . a follow-up trial of dactolisib alone (bez235 rebranded as rtb101) for prevention of respiratory tract infections in the elderly did not meet the primary endpoint and further trials were withdrawn [85] . in prior studies, everolimus (rad001) was used as a standalone agent or in combination with dactolisib, which may explain the phase 3 failure of bez235/rtb101. there are over 95 phase 3 and phase 4 studies for these agents [86] , and they are generally well tolerated even in high doses. even though it may not be commercially viable due to the patent expirations, clinical trials should be conducted to evaluate the effectiveness of these agents for protection against sars-cov-2 (covid-19) and other gerophilic and gerolavic infections. metformin is a drug approved to treat type 2 diabetes but appears to target a number of aging-related mechanisms, including decreasing igf-1 levels, inhibiting mtor, and inhibiting mitochondrial complex 1. metformin is currently in the first large-scale human aging clinical trial of aging, the targeting aging with metformin (tame) study, which is investigating its effect on time to a new occurrence of a composite outcome that includes cardiovascular events, cancer, dementia, and mortality [87] . metformin would likely still be contraindicated in elderly patients with advanced chronic kidney disease and egfr<15. a reduced dose would potentially be required for egfr<30 due to a risk of lactic acidosis. the effects on gerophilic and gerolavic infections should be carefully examined in the context of the tame study, and other clinical trials involving metformin. nicotine adenine dinucleotide (nad) is a cofactor of multiple fundamental enzymes. it is involved in metabolic regulation through the krebs (citric acid) cycle, oxidative phosphorylation, and cellular signaling, as well as cellular senescence and dna repair through the poly-adp-ribose polymerases (parps), sirtuins, and cd38. nad levels decrease with aging, and benefits of nad supplementation have been reported in multiple animal studies. although no proof of a similar effect in humans has been shown, several clinical trials are in progress [88] [89] [90] [91] . supplementation with nicotinamide riboside (nr) in one human study produced an improvement in exercise capacity in a population with a mean age of 71 [92] . this compound was also shown to reduce blood pressure in hypertensive patients [93] . nicotinic acid is another nad precursor that is converted in the body to nad by the enzymes naprt, nmnat, and nads. large-scale trials of nicotinic acid for cardiovascular disease [94, 95] showed some efficacy, but produced adverse side effects, such as headache, skin flushing, and dizziness [96] . nad acts at a cellular level and it is still unclear whether oral or intravenous supplementation with nad donors, such as nr and nicotinic acid, will increase nad levels and exert a clinical benefit in humans. however, covid-19 patients may benefit tremendously from these compounds, as sars-cov-2infected patients have increased levels of cd38+, and nad has been shown to enhance dna repair via parp pathways [97] . caution should be exercised when conducting any clinical trials for nad boosters against gerophilic and gerolavic infections, as the underlying biology of nas metabolism and viral infections is still poorly understood. recent studies in humans demonstrate that nr supplementation reduces the levels of circulating inflammatory cytokines [98] , while nicotinamide mononucleotide (nmn) may reduce the expression of these cytokines [99] . other studies implicate nad in increased cytokine production [100] and the nad+consuming enzyme cd38 in increased inflammation [101] . additional immunological studies of nad boosters must be performed before clinical trials may be conducted. however, considering the large consumer base of nr and nmn supplements, it may be possible to conduct metastudies on influenza and sars-cov-2 infectivity, severity, and lethality. senolytics are drugs that are postulated to selectively destroy senescent cells, which accumulate with aging and exhibit senescence-associated secretory phenotype (sasp), through senolysis, apoptosis, immunosurveillance, or other mechanisms of action [102] . sasp is now hypothesised to lead to nad depletion and thus initiate or perpetuate an increase in sterile chronic inflammation. many drug classes, ranging from fibrates to cardiac glycosides, have been reported to have senolytic properties in animal models [103] . however, recent promising human data have been reported with the tyrosine kinase inhibitor dasatinib in combination with the plant flavonol quercetin in a trial by the mayo clinic [104] ; flavonoid polyphenols have also proven beneficial. in addition, pre-clinical and clinical data suggest that flavonoids may be used for prophylaxis in upper respiratory tract infections [105] . although senolytic drugs would have a scientifically plausible role in biological age reversal and thus reduction of mortality from gerolavic viruses like sars-cov-2, it has not been shown that these classes of drugs would protect against infection or could be used as adjuncts to vaccination. in addition, there remains the risk that senolytics would not be sufficiently specific to discriminate between deleterious senescent cells and quiescent (dormant) cells, which might still differentiate into the mature cell types of a given tissue, and could thus deplete beneficial protective stem cell reserves. it has been shown in multiple studies that calorie restriction leads to increased lifespan and improved cardiometabolic markers, even when initiated in middle age [106] . caloric restriction should be considered as a preventive measure on a long-term basis and is indicated for younger individuals. some elderly patients already have frailty syndromes and evident sarcopenia/ osteopenia, which limits the suitability of intermittent caloric restriction. nevertheless, the aging benefits of time-restricted feeding and intermittent fasting go beyond simple caloric restriction due to the production of ketones. ketones are active signaling molecules that play a major role in the ppar, sirtuin, nad and cd38 pathways, encourage autophagy (the removal of damaged cellular materials), modulate the immune response, and have been explored in clinical trials as an adjuvant therapy for cancer treatments [107] . within 8-12 hours of food restriction, ketones are believed to rise to 0.2 to 0.5mm and continue to increase within the first 48 hours to 1 to 2mm [108] . under fasting conditions the major body ketone in the plasma, beta-hydroxybutyrate (bhb), increases. bhb is believed to confer the major metabolic benefit of fasting and is in development as an independent therapeutic supplement. an age-related decrease of thymic function consequently reduces the levels of specific t cell subsets [109] . foxp3+ regulatory t (treg) cells are critical in homeostasis of the immune system and are believed to start declining in numbers at around 50-60 years of age; this remains one of the fundamental drivers of immunosenescence. there are two known origins for treg cells: thymus-derived treg cells and peripherally-derived treg (ptreg) cells. thus, inducing a peripheral treg response in older individuals might be a feasible strategy for increasing treg cell levels until we have more plausible options for thymic rejuvenation. foxp3 transcription factor (tf) is the most important regulator of tregs and ageassociated immunosenescence. foxp3 tf expression is regulated by chemical modification by sirtuin (sirt) and histone deacetylases, in particular sirt1 and hdac9 [110, 111] . interestingly, nad is essential for sirtuin action. therefore, it is plausible that nad and nad-related compounds such as nr and nmn, which are under investigation as therapeutic interventions that increase serum and cellular nad levels, also act via sirt1 along the foxp3 and treg axis, and play a role in immunosenescence and "inflammaging". a brief summary of the conventional and geroprotective and senoremediative strategies for patients 60 or older is provided in table 1 . while there are decades of clinical evidence supporting the use of rapalogs, such as sirolimus, everolimus, and metformin, substantial meta-analysis and additional clinical trials must be conducted to understand the population-level and individual effects of these drugs taken as single agents and in combination in the context of gerolavic diseases. in this paper i propose conducting clinical trials on these known geroprotectors as a preventative measure before patients are exposed to disease (figure 4 ). in the case of covid-19 as the number of cases worldwide increases, meta-analysis of infection rates, severity, and lethality should be performed rapidly to evaluate the effects of geroprotectors, with particular focus on rapamycin. since covid-19 engages the immune system to damage the lungs, it may be entirely plausible that the immunomodulatory properties of rapamycin may go beyond prevention and may provide an effective treatment option. however, this hypothesis must be validated using meta-analysis before being proposed for a clinical trial. as covid-19 causes substantial lung damage, antifibrotics, senolytics and other geroprotectors may be explored in clinical trials to assist in patient recovery to prevent a reduction in respiratory function. since senescence varies among individuals, a person's chronological age is not as important as their biological age. for several years, scientists have sought accurate aging biomarkers that may predict an individuals' biological age and, independently of immunosenescence, their risk of morbidity and mortality. these biomarkers, or "clocks", could then be used to test for the effectiveness of proposed geroprotective treatments and as surrogate markers in anti-aging clinical trials. while there are no reliable aging clocks to evaluate immunosenescence and inflamaging [112] , these biomarkers may be rapidly developed using historical data. at present, age clocks trained on clinical blood tests [113] , transcriptomic [114] and proteomic data [115] , methylation clocks [46, 116] , microbiomic clocks [117] and other clocks have been described. recent advances in artificial intelligence have enabled the development of multimodal multi-omics age-predictors, able to learn complex non-linear patterns and extract the most important features [113, 118] . none of these currently have robust clinical validation and cannot yet serve as companion biomarkers for geroprotective and antiaging interventions intended to ameliorate the population-level effects of infectious diseases during flu seasons and pandemics. we call for rigorous clinical validation and further development of biological aging clocks that could, in the future, allow us to measure the effectiveness of the numerous speculative geroprotective and senoremediative interventions described herein. covid-19 is a gerolavic infection. efficacy of the vaccine will likely be significantly reduced due to immunosenescence and multimorbidity. possible immunogenicity and mild viral prodrome symptoms as a result of vaccination. antibodies for covid-19 antibodies of serum of recovered individuals. antibodies targeting specific sars-cov-2 proteins. successfully trialed in other viral diseases including ebola. reduction in disease severity and lethality in exposed individuals. risk of systemic immune reactions and certain blood borne infections. selective small molecule inhibitors targeting sars-cov-2 proteins such as 3c-like protease. multiple examples from influenza. neuraminidase and endonuclease inhibitors. reduction in disease duration, severity, and lethality in exposed individuals. mild side effects such as nausea, vomiting, diarrhea, etc. non-steroidal antiinflammatory drugs (nsaids), antibacterials, pain management. multiple clinical trials, common use. reduction in severity of disease. mild side effects such as nausea, vomiting, diarrhea, etc. [24] . theoretically, treatments found to be effective against sars and mers are the most promising starting points for treatments likely to be effective against sars-cov-2. the sars outbreak of 2002 was rapidly contained, and no new cases have been reported since 2004 [119] . since the scale of the outbreak did not provide any commercial benefit for the pharmaceutical industry to develop effective drugs for sars, much of the discovery efforts stopped after the epidemic. when the news of sars-cov-2/covid-19 emerged in early january 2020, it was difficult to justify a business case for small biotechnology companies to allocate resources to the effort. by january 28 th , however, insilico medicine allocated resources to generate and test small molecules against the sars-cov-2 3c-like protease [120, 121] . as the scale of the current covid-19 pandemic remains uncertain, it is still difficult to justify allocating scarce company resources to full-scale drug discovery and drug development programs, which may cost tens or even hundreds of millions of dollars [122] . multiple biotechnology companies are in the same situation and will not be able to proceed without substantial backing from government agencies, nonprofit organizations, or bigger pharmaceutical companies. however, given the gerophilic and gerolavic nature of covid-19, strategies targeting age-associated pathologies and immunosenescence, which could decrease the comorbidity, infection rates, severity, and lethality of the disease, will remain commercially-viable even when the pandemic subsides. in addition, respiratory infections are now the third leading cause of death in the world, following cardiac disease and stroke [123] , further justifying the need for these interventions. considering the gerolavic nature of covid-19, where the majority of the seriously affected population is older than 60, classical prevention and treatment strategies may not be effective. given the severity and lethality of the pandemic, even healthcare systems in developed countries will find it challenging to cope with the increased disease burden and hospital needs. conventional approaches to prevention such as vaccines are much needed, but even these do not offer complete protection in the elderly due to multi-morbidity and agerelated immune declines. therefore, interventions that enable immunocompromised elderly to mount an immune response to newly developed vaccines are necessary to help eradicate the disease and reduce the associated mortality. to avoid substantial loss of life and quality of life, primarily among the elderly and vulnerable populations, governments and healthcare systems should investigate preventative and intervention strategies stemming from recent advances in aging research. as discussed in this paper, small clinical studies have shown that several geroprotective and senoremediative interventions, such as treatment with aging sirolimus and rapalogs, can induce immunopotentiation, increase resistance to infection, and reduce disease severity in the elderly, without severe side effects. serendipitously, during the revision of this article, another group utilizing computational approaches proposed using melatonin and sirolimus (rapamycin) in combination to treat the covid-19 infection outside the context of geroprotection [124] . many of these predicted geroprotectors are available as supplements; however, no meta-analysis or metaclinical trials have been performed at scale to evaluate their effectiveness. the covid-19 pandemic highlights the paucity of clinical trials on the effects of dietary supplements and drugs on aging and immunosenescence. the existence of pseudoscience and anecdotal promotion in the supplement industry does not mean that protective compounds do not exist. dietary supplement vendors and pharmaceutical companies need to actively engage in preclinical and clinical research to evaluate the effectiveness of the currently available products on immunosenescence and aging. this paper is not intended to encourage the use of rapalogs or other potential geroprotectors during the covid-19 pandemic. it may be possible that some of the potential geroprotectors described in this paper are harmful to the elderly after infection, and may actually increase disease severity and lethality. however, it may be possible to conduct clinical trials on the efficacy of geroprotectors previously tested in human clinical trials in treating covid-19 and other gerophilic and gerolavic infections. to combat the growing covid-19 pandemic, researchers have united globally to tackle a disease that is impacting lives and healthcare systems around the world. after carefully analysing preliminary data, we suggest that covid-19 has a gerophilic and gerolavic profile, being more infectious and more severe in the elderly. in this paper, we review the current literature on speculative aging reversal treatments, such as experimental geroprotective strategies using everolimus (rad001) and sirolimus (rapamycin). we summarize the current possible interventions and identify the lack of clinical evidence to support their immediate use with the aim of encouraging further, more rigorous reviews of geroprotective compounds such as rapalogs, metformin, senolytics, and conventional and investigational nad+ boosters. we also suggest that further clinical studies should be carefully designed and adequately powered to determine if these interventions might provide clinical benefit as adjuncts to vaccines and antiviral treatments by acting as immune response potentiators. lastly, as with many other diseases, covid-19 is more common and severe in elderly populations, and we thus invite further research and clinical validation in the field of biological aging clocks. these markers could potentially be used in the future to measure and analyze immunosenescence and the efficacy of interventions claimed to slow down or reverse age-related immune decline. this perspective is of a highly speculative nature presented during the time of a global covid-19 pandemic. it is intended for a professional audience to stimulate ideas and aid the global efforts of the scientific community to develop effective new treatments for this disease. this article does not represent medical advice or recommendations to patients. there is no clinical evidence to support the use of the treatments described in this article for this indication and the authors do not advise anyone to self-administer these drugs as covid-19 prevention or treatment. furthermore, this perspective is based on the limited data from the first weeks of the covid-19 outbreak. the demographic distribution of the infected and diseased may change and differ in different countries with different social customs and different ethnicities. the media should exercise caution and seek expert medical advice for interpretation when referring to this article to avoid misinterpretation or unsafe messages being delivered to the community amidst exceptional coverage of this disease in the media at present. the author would like to thank dr. quentin vahaelen of insilico medicine, dr. evelyne bischof of the jiaotong and shanghai university of medicine and the university of basel, and mr. dara vakili of imperial college london for advice and valuable contributions. the author would like to thank dr. richard faragher for the valuable suggestions and comments on the new term "gerolavic" to describe the infections harmful to the elderly, which did not previously exist; and rachel stewart for edits, formatting, and reference management. no funding has been provided for this work. alex zhavoronkov is a co-founder of insilico medicine, a leading artificial intelligence company specializing in target discovery and small molecule generation, and deep longevity, a company specializing in deep aging clocks, multimodal age predictors built using deep learning. he has multiple granted patents and patent applications on deep aging clocks, geroprotective aging interventions, generative chemistry, generative biology, and artificial intelligence techniques. the hallmarks of aging methods for structuring scientific knowledge from many areas related to aging research to help aging populations, classify organismal senescence classifying aging as a disease in the context of icd-11 editorial: should we treat aging as a disease? academic, pharmaceutical, healthcare policy, and pension fund perspectives aging, frailty and age-related diseases infection in an aging population grubeck-loebenstein b. persistent viral infections and immune aging lung infections and aging epidemiology and unique aspects of aging and infectious diseases characteristics of covid-19 infection in beijing the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) covid-19 coronavirus outbreak analysis of coronavirus estimating the asymptomatic proportion of novel coronavirus onboard the princess cruises ship causes of death. our world in data estimated influenza illnesses, medical visits, hospitalizations, and deaths in the united states -2017-2018 influenza season for the china medical treatment expert group for covid-19*. clinical characteristics of coronavirus disease 2019 in china immunosenescence of ageing mechanisms of development of multimorbidity in the elderly coronavirus puts drug repurposing on the fast track research and development on therapeutic agents and vaccines for covid-19 and related human coronavirus diseases analysis of the human thymic perivascular space during aging the influence of age on t cell generation and tcr diversity prevalence and patterns of multimorbidity among the elderly in china: a cross-sectional study using national survey data measuring multimorbidity in older adults: comparing different data sources search of: recruiting, not yet recruiting, available studies | "coronavirus infections" -list results -clinicaltrials.gov centers for disease control and prevention. influenza antiviral medications: clinician summary. 2020 detection and control of influenza outbreaks in well-vaccinated nursing home populations influenza virus-related critical illness: prevention, diagnosis, treatment influenza: overview on prevention and therapy vaccine potentiation by combination adjuvants. vaccines (basel) immunosenescence and human vaccine immune responses long-term use of oseltamivir for the prophylaxis of influenza in a vaccinated frail older population overview of direct-acting antiviral drugs and drug resistance of hepatitis c virus oseltamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments zanamivir for influenza in adults and children: systematic review of clinical study reports and summary of regulatory comments oseltamivir treatment for influenza in adults: a metaanalysis of randomised controlled trials and baloxavir marboxil investigators group. baloxavir marboxil for uncomplicated influenza in adults and adolescents understanding covid-19 new diagnostic guidelines -a message of reassurance from an internal medicine doctor in shanghai can physical activity ameliorate immunosenescence and thereby reduce age-related multi-morbidity? reversal of epigenetic aging and immunosenescent trends in humans dna methylation age of human tissues and cell types vive la radiorésistance!: converging research in radiobiology and biogerontology to enhance human radioresistance for deep space exploration and colonization signaling pathway cloud regulation for in silico screening and ranking of the potential geroprotective drugs in search for geroprotectors: in silico screening and in vitro validation of signalome-level mimetics of young healthy state artificial intelligence for aging and longevity research: recent advances and perspectives towards natural mimetics of metformin and rapamycin interventions to restore appropriate immune function in the elderly the drugage database of aging-related drugs org: a new, structured and curated database of current therapeutic interventions in aging and age-related disease regulation of yeast replicative life span by tor and sch9 in response to nutrients extension of chronological life span in yeast by decreased tor pathway signaling regulation of lifespan in drosophila by modulation of genes in the tor signaling pathway target of rapamycin activation predicts lifespan in fruit flies tor signaling and rapamycin influence longevity by regulating skn-1/nrf and daf-16/foxo rapamycin fed late in life extends lifespan in genetically heterogeneous mice rapamycin increases lifespan and inhibits spontaneous tumorigenesis in inbred female mice rapamycin slows aging in mice new nanoformulation of rapamycin rapatar extends lifespan in homozygous p53-/-mice by delaying carcinogenesis rapamycin extends maximal lifespan in cancer-prone mice immunostimulatory activity of lifespan-extending agents sirolimus and secondary skin-cancer prevention in kidney transplantation sirolimus therapy after early cyclosporine withdrawal reduces the risk for cancer in adult renal transplantation rejuvenating immunity: "anti-aging drug today" eight years later validation of anti-aging drugs by treating age-related diseases prevention of cancer by inhibiting aging an anti-aging drug today: from senescence-promoting genes to anti-aging pill aging and immortality: quasiprogrammed senescence and its pharmacologic inhibition selective effects of mtor inhibitor sirolimus on naïve and cmv-specific t cells extending its applicable range beyond immunosuppression paradoxical aspects of rapamycin immunobiology in transplantation type 1 interferons and the virus-host relationship: a lesson in détente sars coronavirus and innate immunity inhibitors of mtor in aging and cancer gerosuppression in confluent cells dual mtorc1/c2 inhibitors suppress cellular geroconversion (a senescence program) decreased cytomegalovirus infection after antilymphocyte therapy in sirolimus-treated renal transplant patients sirolimus enhances the magnitude and quality of viralspecific cd8+ t-cell responses to vaccinia virus vaccination in rhesus macaques mtor inhibition improves immune function in the elderly torc1 inhibition enhances immune function and reduces infections in the elderly nvp-bez235, a novel dual phosphatidylinositol 3-kinase/mammalian target of rapamycin inhibitor, elicits multifaceted antitumor activities in human gliomas effect of rtb101 on illness associated with respiratory tract infections in the elderly search of: rad001, certican, rapamycin metformin as a tool to effect of "nicotinamide mononucleotide" (nmn) on cardiometabolic function effects of nicotinamide riboside on metabolism and vascular function nicotinamide riboside and metabolic health nicotinamide riboside in systolic heart failure acute nicotinamide riboside supplementation improves redox homeostasis and exercise performance in old individuals: a double-blind cross-over study chronic nicotinamide riboside supplementation is welltolerated and elevates nad + in healthy middle-aged and older adults plaque inflammation and dysfunctional hdl in aim-high treatment of hdl to reduce the incidence of vascular events hps2-thrive interacting nad + and cell senescence pathways complicate antiaging therapies molecular immune www.aging-us.com aging pathogenesis and diagnosis of covid-19 nicotinamide riboside augments the aged human skeletal muscle nad + metabolome and induces transcriptomic and anti-inflammatory signatures head to head comparison of short-term treatment with the nad(+) precursor nicotinamide mononucleotide (nmn) and 6 weeks of exercise in obese female mice pharmacological inhibition of nicotinamide phosphoribosyltransferase/ visfatin enzymatic activity identifies a new inflammatory pathway linked to nad cd38 is robustly induced in human macrophages and monocytes in inflammatory conditions the clinical potential of senolytic drugs cardiac glycosides are broad-spectrum senolytics senolytics decrease senescent cells in humans: preliminary report from a clinical trial of dasatinib plus quercetin in individuals with diabetic kidney disease effect of flavonoids on upper respiratory tract infections and immune function: a systematic review and meta-analysis 2 years of calorie restriction and cardiometabolic risk (calerie): exploratory outcomes of a multicentre, phase 2, randomised controlled trial the role of intermittent fasting and meal timing in weight management and metabolic health effects of intermittent fasting on health, aging, and disease regulatory t cells and foxp3 inhibition of hdac9 increases t regulatory cell function and prevents colitis in mice sirtuin-1 targeting promotes foxp3+ tregulatory cell function and prolongs allograft survival are there reliable biomarkers for immunosenescence and inflammaging deep biomarkers of human aging: application of deep neural networks to biomarker development machine learning on human muscle transcriptomic data for biomarker discovery and tissue-specific drug target identification deep learning enables rapid identification of potent ddr1 kinase inhibitors genome-wide methylation profiles reveal quantitative views of human aging rates human microbiome aging clocks based on deep learning and tandem of permutation feature importance and accumulated local effects. biorxiv deep aging clocks: the emergence of ai-based biomarkers of aging and longevity uk national health service. sars (severe acute respiratory syndrome) insilico medicine publishes molecular structures for the key protein target of 2019-ncov potential covid-2019 3c-like protease inhibitors designed using generative deep learning approaches how to improve r&d productivity: the pharmaceutical industry's grand challenge acute respiratory infections are world's third leading cause of death network-based drug repurposing for novel coronavirus 2019-ncov/sars-cov-2 key: cord-285546-5tjhdczt authors: green, manfred s.; peer, victoria; schwartz, naama; nitzan, dorit title: the confounded crude case-fatality rates (cfr) for covid-19 hide more than they reveal—a comparison of age-specific and age-adjusted cfrs between seven countries date: 2020-10-21 journal: plos one doi: 10.1371/journal.pone.0241031 sha: doc_id: 285546 cord_uid: 5tjhdczt background: crude case-fatality rates (cfrs) for covid-19 vary widely between countries. there are serious limitations in the cfrs when making comparisons. we examined how the age distribution of the cases is responsible for the covid-19 cfr differences between countries. methods: covid-19 cases and deaths, by ten-year age-groups, were available from the reports of seven countries. the overall and age-specific cfrs were computed for each country. the age-adjusted cfrs were computed by the direct method, using the combined number of cases in all seven countries in each age group as the standard population. a meta-analytic approach was used to obtain pooled age-specific cfrs. findings: the crude overall cfrs varied between 0.82% and 14.2% in the seven countries and the variation in the age-specific cfrs were much smaller. there was wide variation in the age distribution of the cases between countries. the ratio of the crude cfr for the country with the highest cfr to that with the lowest (6.28) was much lower for the age-adjusted cfrs rates (2.57). conclusions: the age structure of the cases explains much of differences in the crude cfrs between countries and adjusting for age substantially reduces this variation. other factors such as the definition of cases, coding of deaths and the standard of healthcare are likely to account for much of the residual variation. it is misleading to compare the crude covid-19 cfrs between countries and should be avoided. at the very least, age-specific and age-adjusted cfrs should be used for comparisons. , who declared covid-19 as a pandemic. by october, 2020, almost all countries had been affected, and globally there were reports of more than 37 million cases and more than a million deaths. early estimates indicated that the average proportion of deaths among the diagnosed cases, defined as the case-fatality rate (cfr), was around 2.3% [2] . however, subsequently, the reported crude covid-19 cfrs varied widely between countries [3, 4] . the limitations of comparing crude cfrs in general, has been evaluated previously [5] . the strong positive association between the covid-19 cfr and age has been demonstrated both in observational studies [6] and in a model-based analysis [7] , particularly over the age of 40. the interpretation of the cfr depends on the context in which it is used. in a single cohort of patients, it can indicate the severity of the disease at a single point in time. it can also be used to assess trends in the impact of changes in health care over time. in the current context of the covid-19 pandemic, cfrs are commonly compared between countries and that may lead to speculation on differences in healthcare. for example, it may be concluded that the cfrs somehow reflect the successes and failures of the different countries in the treatment of serious cases. in general a number of factors could impact on the both the numerator and denominator of the cfr. this is especially important for the cfr for covid-19. there could be misclassification of causes of death and there are likely to be variations in the definition of cases in the denominator. substantial confounding by age could impact on cfr comparisons between different groups. a related concept is the infection fatality rate (ifr) which includes asymptomatic cases in the denominator, which need to be identified by screening tests. since the ifr is rarely available for covid-19, in this paper we consider only the cfr. in this paper, we examined the contribution of the age distribution of the cases when comparing the covid-19 cfrs between seven countries, with widely varying cfrs. we studied published crude and age-specific cfrs in cohorts of cases of covid-19 in seven countries, with varying periods of follow-up. the countries chosen were based on the accessibility of the data. the first case covid-19 in israel was confirmed on 21 february 2020. the first case in south korea was announced on 20 january 2020.the covid-19 spread from hubei province, china, after december 2019.sars-cov-2 was confirmed to have reached spain, sweden, italy, and canada on end of january 2020. the data on cases and deaths by age group were available from china on february 11, 2020. for south korea cases and deaths were updated to the end of april. for spain, the cases and deaths were updated to mid-may 2020. the information for israel, italy, canada and sweden were updated during august 2020. the data for each country were not necessarily updated to the time of the study, and the cfr's may have changed over time. age-specific data on the cases and deaths by ten-year age groups (0-9, 10-19, . . ...80+), were available for seven countries: italy [8] , spain [9], sweden [10] , china [11] , s korea [12] , israel (ministry of health, personal communication) and canada [13] . the outcome variable was defined as the crude cfr defined as the number of deaths divided by the number of reported cases. the exposure variable was the individual country. age-group was considered as a confounding variable. age-adjustment was carried by the direct method, using the distribution of the combined cases of all six countries by age group as the standard population. 95% confidence intervals were computed for each age-adjusted rate using winpepi [version 11.65, aug, 2016]. open access aggregative and anonymous data were used and there was no need for ethics committee approval. the age-specific number of cases, number of deaths and the crude cfrs by country are given in table 1 . the distributions of the cases vary markedly between the countries. for example, israel and south korea are heavily weighted in the 20-39 age group, china has a more balanced distribution and italy, sweden and canada are heavily weighted in the over 70 age groups. the distributions of the cases for each country are shown in fig 1. it is clear that distributions vary widely and are not necessarily related to the age distribution of the population of the country. for example, for south korea, there is a relatively large number of cases in the age group 20-29, due to an outbreak affecting that age group in particular. the age-specific cfrs are shown in fig 2. while there are differences in the age-specific cfrs between countries, the trend of steeply increasing cfrs in the oldest age groups is evident. age groups 0-9 and 10-19 were excluded from the figure, since there were almost no deaths. the crude (%) and age-adjusted cfrs (%) are compared in table 2 . the crude cfrs varied from 0.82% for israel to 14.20% for italy and the ratios of the crude cfrs compared with lowest cfr, varied between 0.36 and 6.28. the age-adjusted cfrs varied between 4.20% for china to 10.80% for italy and the ratios of the age-adjusted cfrs for each country compared with the lowest cfr adjusted varied between 1.00 and 2.57. fig 3 shows graphically the marked reduction in the differences between the crude (%) and age-adjusted cfrs (%) for the seven countries. we used meta-analytic methods to obtain weighted pooled estimates of the cfr's by age group. the results of the meta-analysis are presented in the forest plot in fig 4, in our study, we examined crude, age-specific and age-adjusted cfrs for covid-19 in seven countries, with widely varying crude cfrs. the trends in the age-specific cfrs were remarkably similar in the seven countries, with the cfr's increasing steeply in those over 70. after adjusting for age, the marked differences in the crude cfrs were substantially reduced. these findings demonstrate the importance of accounting for age when comparing rates in general and cfrs in particular. the results of this study are strengthened by the use of national data or large datasets from a number of countries, with considerable differences in the extent of the pandemic in each country. it should be stressed that the age distribution of the cases was used to compute the age-adjusted cfrs and not the age distribution of the total population in each country. in addition to the age distribution of the cases, the use of the cfr for comparisons between countries has other important limitations. selection bias is clearly present when calculating the denominator on the basis of reported cases. as mentioned, the cfr must be distinguished from the ifr, which includes asymptomatic cases identified by deliberate or incidental screening with diagnostic tests. in addition, if only those with more severe symptoms are tested this will affect the denominator of the cfr and will depend on the testing strategy of each country. if more mild cases are identified, this is likely to reduce the cfr. there is a lag time between the reporting of the case and the death which can occur up to weeks later. in the country reports, cases and deaths are usually reported at the same time, so the cases in the denominator are usually an overestimate of the true denominator which should be the number of cases reported sometime earlier [14, 15] . this will have a more dramatic effect when the number of cases are rising rapidly. selection bias may also affect the numerator if only deaths occurring in hospital are reported. information bias can be present in both the numerator and denominator of the cfr. the definition of the cases may be biased due to the variability of the sensitivity and specificity of the diagnostic tests for covid-19. information bias in the numerator can occur when the cause of death is coded. this could be particularly problematic in elderly people with multiple co-morbidities. the purpose of this paper is to demonstrate the dramatic effect of confounding by the age distribution of the cases when using crude overall cfrs for country comparisons. this was shown in an earlier paper when comparing six countries, and we have extended it to a comparison of seven countries with widely different cfrs. the age structures of the population of the seven countries used in this study vary markedly. the percentage of the population age 65 and over is 12% in israel, 23% in italy 23%, 9.3% in s korea, 19.6% in spain, 20% in sweden, 11% in china and 17.6% in canada [16] . however, the main impact of confounding by age was due to the differences in the age distribution of the cases. this was largely due to the specific circumstances of exposure. for example, most of the cases in italy occurred in an area of a particularly old population [3] . in some countries, many of the cases were medical personnel, a large number of whom were relatively young women [17] . in south korea, a large percentage of the cases were young women associated with a specific religious group [18] . in germany, many of the cases were relatively young people returning from skiing holidays in austria and italy [19] . in israel, the largest outbreaks occurred in the ultra-orthodox jewish community, where the number of children per family is much higher than in the general population. other factors affecting the age distribution of the cases, depended on the frequency of outbreaks in homes for the elderly [20] . the results of this study once again demonstrate the pitfalls of comparing unadjusted rates. the assumption that differences between countries in testing policies or standard of treatment accounted for the wide discrepancies in cfrs, is not well-founded. this does not mean that there are no differences. for example, it is possible that where the health services were overloaded, younger patients were more likely to be admitted to intensive care units with better chances of survival. clearly, the data are incomplete and other factors affecting cfrs such as case definitions, use of different denominators, underlying health conditions and the standard of health services are likely to play important roles. in order to assess the impact of these factors, age-specific and age-adjusted cfrs must be used. in addition to the selection and information biases inherent in computing cfrs, the age structure of the cases dramatically impacts on the differences in the crude cfrs between countries. failure to account for this source of confounding markedly distorts the country comparisons. the substantial reduction in the differences in the age-adjusted cfrs suggest that differences in the standard of healthcare between these countries may not play as important a role in affecting the death rates, as some have hypothesized. crude covid-19 cfrs have no real use for between country comparisons and should be avoided. in general, for comparisons between groups and countries, age-adjusted cfrs can be used, but age-specific covid-19 cfrs are generally far more meaningful. similarity in case fatality rates (cfr) of covid-19/sars-cov-2 in italy and china case-fatality rate and characteristics of patients dying in relation to covid-19 in italy early estimation of the case fatality rate of covid-19 in mainland china: a data-driven analysis potential biases in estimating absolute and relative case-fatality risks during outbreaks covid-19: death rate is 0.66% and increases with age, study estimates estimates of the severity of coronavirus disease 2019: a model-based analysis aggiornamento nazionale the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19)-china, 2020. the novel coronavirus pneumonia emergency response epidemiology team a30501000000&bid = 0031&list_no = 367045&act = view coronavirus disease 2019 (covid-19): epidemiology update". public health agency of canada real estimates of mortality following covid-19 infection estimating case fatality rates of covid-19 impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the 2019 novel coronavirus disease outbreak: a cross-sectional study korean society of infectious diseases; korean society of pediatric infectious diseases report on the epidemiological features of coronavirus disease 2019 (covid-19) outbreak in the republic of korea from a german exception? why the country's coronavirus death rate is low we express our appreciation to the official institutions of all countries for the providing their data on covid-19. conceptualization: manfred s. green, dorit nitzan. key: cord-353600-5wo74ms4 authors: tyrrell, daniel j.; goldstein, daniel r. title: ageing and atherosclerosis: vascular intrinsic and extrinsic factors and potential role of il-6 date: 2020-09-11 journal: nat rev cardiol doi: 10.1038/s41569-020-0431-7 sha: doc_id: 353600 cord_uid: 5wo74ms4 the number of old people is rising worldwide, and advancing age is a major risk factor for atherosclerotic cardiovascular disease. however, the mechanisms underlying this phenomenon remain unclear. in this review, we discuss vascular intrinsic and extrinsic mechanisms of how ageing influences the pathology of atherosclerosis. first, we focus on factors that are extrinsic to the vasculature. we discuss how ageing affects the development of myeloid cells leading to the expansion of certain myeloid cell clones and induces changes in myeloid cell functions that promote atherosclerosis via inflammation, including a potential role for il-6. next, we describe vascular intrinsic factors by which ageing promotes atherogenesis — in particular, the effects on mitochondrial function. studies in mice and humans have shown that ageing leads to a decline in vascular mitochondrial function and impaired mitophagy. in mice, ageing is associated with an elevation in the levels of the inflammatory cytokine il-6 in the aorta, which participates in a positive feedback loop with the impaired vascular mitochondrial function to accelerate atherogenesis. we speculate that vascular and myeloid cell ageing synergize, via il-6 signalling, to accelerate atherosclerosis. finally, we propose future avenues of clinical investigation and potential therapeutic approaches to reduce the burden of atherosclerosis in old people. the number of old people (aged >65 years) is rising worldwide, and cardiovascular diseases are the largest contributor to morbidity and mortality in this popu lation 1, 2 . changes in diet and lifestyle contribute to the high cardiovascular morbidity and mortality in old indi viduals, but many biological processes that are altered with ageing also contribute to this increased cardio vascular risk. as a result, therapies for cardiovascular disease that are effective in young and middle aged peo ple might be less effective in older people. additionally, novel therapies might be required to improve disease management specifically in old people. deciphering the mechanisms by which ageing promotes atheroscle rotic cardiovascular disease will be fundamental for the development of novel therapies to reduce the burden of atherosclerosis with ageing. the development of new therapies is especially relevant with the coronavirus dis ease 2019 (covid19) pandemic, because old people and particularly those with cardiovascular diseases are at a substantially higher risk of morbidity and death 3, 4 . in this review, we describe two major areas by which ageing promotes atherosclerosis. first, we dis cuss age related factors that are extrinsic to the vascula ture, focusing on the effects of ageing on myeloid cells of the immune system. age related effects in the bone marrow skew the differentiation of haematopoietic cells towards the myeloid cell lineage. ageing also promotes the generation of clones of haematopoietic cells with out clear development of haematopoietic malignancy or other known clonal disorder, a phenomenon known as clonal haematopoiesis of indeterminate potential (chip) [5] [6] [7] [8] . clinical studies from the past decade have revealed that the presence of chip increases the risk of cardiovascular diseases 6, 7 . intriguingly, the increased risk of cardiovas cular disease associated with the presence of chip is abrogated in patients with a loss of function mutation in il6 (ref. 9 ). however, the precise mechanisms by which chip promotes the development of cardiovascular diseases are yet to be fully clarified. we next address vascular intrinsic factors, discussing how ageing impairs vascular bioenergetics by compro mising mitochondrial function and how this alteration connects with inflammatory pathways within the vascu lature to promote atherosclerosis 10, 11 . we describe studies in mice and humans showing that, in the aorta, ageing impairs both mitochondrial function and the removal of damaged mitochondria (mitophagy) 10, 11 . we describe experimental evidence reported in 2020 demonstrating that the age mediated increase in the levels of the plei otropic cytokine il6 in the aorta occurs in a positive clonal haematopoiesis of indeterminate potential (chip) . clonal expansion of haematopoietic stem cells that carry certain somatic mutations that confer a cell proliferation advantage. feedback loop with vascular mitochondrial dysfunction and that these alterations promote atherosclerosis 11 . the cantos study 12 demonstrated that il1β block ade reduces the risk of recurrent cardiovascular events in patients aged >60 years. importantly, the greatest bene fit of il1β blockade was seen in patients who had low plasma il6 levels 13 . this pivotal clinical study indicates that chronic inflammation, potentially via il6 signal ling, is a major contributor to age related atherosclerosis. given this observation, we speculate that increased ath erosclerosis with ageing could result from a synergy between myeloid cells of the immune system and the vasculature via il6 signalling (fig. 1 ). this mechanism is especially important because clinically approved agents targeting this pathway (such as anti il6 therapies) are already available and could reduce the risk of cardio vascular disease in old people. finally, we propose that future experimental and clinical investigation will be required to determine the contribution of this inflamma tory pathway in age related atherosclerosis. we acknowl edge that other inflammatory pathways and cytokines could contribute to age related atherosclerosis, and the source of these cytokines (including il6) could be senescent adipocytes. a detailed discussion of the con tribution of ageing to senescence and atherosclerosis has been published previously 14 . ageing affects the immune system in complex ways (as reviewed previously [15] [16] [17] , and various components of the immune system contribute to atherosclerosis 18, 19 . this review focuses on clones of myeloid cells that increase with ageing and how these clones contribute to athero sclerosis. we do not describe how ageing affects other cells of the immune system, which has been reviewed previously (for example, b cells 20 , t cells 21 , eosinophils or dendritic cells 22 ). in addition, we focus on vascular mito chondrial function and how mitochondrial dysfunction could influence inflammatory pathways within the vasculature. however, given that most of the available evidence indicates that oxidative stress is not a major driver of biological ageing [23] [24] [25] , and given the complex roles that oxidative stress has in atherosclerosis 26 , we do not describe in detail the contributions of oxidative stress in age related atherosclerosis. neither do we describe in detail how ageing affects other processes within the arte rial wall, such as extracellular matrix remodelling or pro duction of pro fibrotic and pro calcific factors, which can promote atherosclerosis indirectly via increasing arterial stiffness and hypertension 27, 28 , and which have been previously reviewed 29, 30 . effects of ageing on myeloid cell production. numerous subpopulations of immune cells of various lineages have been implicated in atherosclerosis, including macrophages 31 , dendritic cells 32 , t helper 1 (t h 1) cells 33 and b cells 34 (reviewed previously 18, 35 ), all of which are affected by ageing. immune cells are generated in the bone marrow via haematopoiesis from regenerative haematopoietic stem cells (hscs) 36, 37 . monocytes, mac rophages and neutrophils are derived from myeloid biased hscs. with ageing, although the absolute number of hscs increases 38 , hscs lose their regener ative capacity 39, 40 . this loss of regenerative potential is accompanied by an expansion of the number of hscs that are committed to the platelet (megakaryocytes) and myeloid lineages 38, 41 . competitive bone marrow transplantation studies in mice have demonstrated that aged hscs have a reduced repopulation capacity, with an imbalance towards myeloid cell differentiation, compared with young hscs 38, 42 . several major biological pathways contribute to ageing, including dna damage, mitochondrial dysfunction, cell senescence, impaired autophagy, epigenetic alterations and gene transcrip tion dysregulation 25 . transcriptomic studies in mice have shown that with ageing, hscs upregulate stress responses and inflammatory pathways and downregu late the expression of genes related to genetic stability 43 . with ageing, hscs exhibit an increase in epigenetic dysregulation, specifically downregulation in chroma tin remodelling and transcriptional silencing 43 , and increases in dna methylation (as reviewed previously 44 ). these epigenetic alterations are accompanied by func tional defects in hscs, including a reduction in hsc homing to the bone marrow and hsc proliferation 43, 45 . importantly, mutations in genes such as idh2, which alter epigenetic regulation, lead to impairments in hae matopoietic progenitors in mice 46 and are associated with t cell lymphomas in humans 47 , a malignancy that increases with ageing. although whether hscs, or stem cells in general, undergo senescence is questionable 48 , the clearance of senescent cells improves hsc engraft ment in bone marrow transplantation mouse models and reduces myeloid skewing 49 . autophagy deficient young mice have increased mitochondrial content and metabolism that lead to mitochondrial stress in hscs compared with wild type young mice 50 . these features are also observed in aged wild type mice and are asso ciated with a skewing towards the myeloid lineage and a reduced proliferative capacity of hscs 50, 51 . loss of microrna146a (mir146a) in hscs with ageing also promotes a myeloid bias 52 . furthermore, myeloid cells derived from mir146a deficient hscs have elevated levels of both il6 and tumour necrosis factor (tnf) 52 , which connects altered regulation of transcription in hscs to inflammation. overall, these studies indicate that ageing has effects on hscs via several complex pathways that lead to reduced hsc function. ageing also alters haematopoiesis by influencing the bone marrow niche independently of the direct effects • ageing-related alterations in the bone marrow increase the phenomenon of clonal haematopoiesis of indeterminate potential (chip) and promote a skewing towards myeloid cell differentiation, both of which can accelerate atherosclerosis. • the increased risk of atherosclerotic cardiovascular diseases associated with the presence of chip might be mediated by il-6 signalling and/or inflammasome activation. • ageing is associated with a decline in mitochondrial function and an increase in il-6 levels in the vasculature, and both effects probably accelerate atherosclerosis independently of chronic hyperlipidaemia. • the role of the vasculature and myeloid cells of the immune system in promoting age-related atherosclerosis might be mediated by shared inflammatory pathways, in particular il-6 signalling. senescence a state of permanent replicative arrest in normally proliferative cells. www.nature.com/nrcardio on hscs. the bone marrow niche provides a support ing environment for hsc function and includes mesen chymal cells and endothelial cells 53 . how ageing affects the bone marrow niche is not clear, but the presence of chronic systemic inflammation might contribute. ageing leads to a chronic systemic low grade inflammatory state 54, 55 , which might be mediated by cellular senescence that leads to the production of inflammatory mediators (termed the senescence-associated secretory phenotype (sasp)) 56,57 . one source of senescent inflammatory cells is the adipose tissue, which typically increases in size with ageing 58, 59 . the number of adipocytes also increases in the bone marrow with ageing, accompanied by an elevation in the levels of pro inflammatory cytokines, including il6 (refs 60,61 ). these cytokines promote a skewing towards myeloid cell differentiation and an increase in platelet production, the latter of which could contribute to thrombosis 60, 61 . importantly, adipocytes arising from leptin receptor positive progenitors in the bone marrow, but not within other fat depots, synthesize stem cell factor, which promotes hsc regeneration 62, 63 . senescent stromal cells in the bone marrow are another potential source of inflammation 64 . these cells can dif ferentiate into adipocytes in the ageing bone marrow 65 and further promote an inflammatory environment. the function of bone marrow endothelial cells also declines with ageing 66 . furthermore, the number of vascular niches in the bone marrow that support hsc regenera tion decreases with ageing, but can be restored in aged mice by activating notch signalling in endothelial cells 53 . activation of the innate immune receptor toll like receptor 4 (tlr4) induces myeloid differentiation in hscs in mice 67 . ageing is associated with alterations in gut microbiota 68 , which could act as a microbial source for tlr4 stimulation (for example, lipopolysaccharide (lps) from gram negative bacteria activates tlr4). tlr4 activation could then increase the imbalance of hsc differentiation towards the myeloid lineage. in a 2019 study in mice, β 2 adrenergic receptor signalling in the bone marrow niche was found to increase with ageing in association with increased generation of myeloid cells and platelets through an il6 dependent mechanism 60 . this study also demonstrated that the bone marrow niche switches from an endosteal to a non endosteal mutation show an increased production of il-6 and il-1β, which can contribute to accelerated atherosclerosis. ageing can also have pro-atherogenic effects directly on the vasculature. ageing is associated with an increase in the levels of il-6, possibly mediated by increased production by vascular smooth muscle cells (vsmcs), and mitochondrial genomic instability and with a decline in mitochondrial function in the vasculature. the reduced mitochondrial function alters mitophagy and increases il-6 levels, creating a positive feedback loop that accelerates atherogenesis. vascular ageing also leads to the production of chemoattractants that increase myeloid cell recruitment into the arterial wall, further promoting atherosclerosis. impaired mitochondrial function combined with reduced mitophagy might lead to increased levels of reactive oxygen species (ros). senescence-associated secretory phenotype (sasp). secretion of cytokines, chemokines, growth factors and proteases by senescent cells. nature reviews | cardiology niche with ageing, indicating that ageing shifts myeloid cell production away from the bone tissue to further within the bone marrow 60 . this study also found that a mouse model of hutchinson-gilford progeria syn drome, which is associated with accelerated ageing 69 , had an imbalance favouring myeloid cells over lymphoid cells in the peripheral blood 60 . this effect was mitigated by administration of a β 3 adrenergic receptor agonist 60 . overall, clear evidence indicates that ageing alters the bone marrow niche via multiple mechanisms to impair hsc function and promote myeloid cell differentiation. clonal haematopoiesis and cardiovascular disease: clinical correlation. the positive selection and expansion of clones of hscs carrying certain somatic mutations, known as clonal haematopoiesis, occurs commonly with ageing. approximately 10% of individuals aged >70 years carry mutations associated with clonal haemato poiesis, whereas these mutations are rare in individu als aged <40 years 7, 70, 71 . these clones of haematopoietic cells harbour single somatic mutations most commonly in genes associated with haematological malignan cies, such as dnmt3a, tet2 and asxl1. individuals with mutations in these genes have an increased risk of developing haematological malignancies (hr 11-12, depending on the study) 7, 70, 71 . all cause mortality is increased in individuals with any somatic mutation asso ciated with clonal haematopoiesis (hr 1-2) compared with those with no mutations 7 . interestingly, the cause of the increased mortality in these individuals is not only the higher rate of haematological malignancies but also a higher rate of adverse cardiovascular events 7,70-72 . the association between clonal haematopoiesis and the risk of adverse cardiovascular events remained even after adjustment for traditional cardiovascular risk fac tors, such as diabetes mellitus, hypertension, smoking and bmi, in multivariate analyses 6 . as a result of these studies, the term chip was coined to distinguish the phenomenon of clonal haematopoiesis without clear development of haematopoietic malignancy or other known clonal disorder from the pre malignant clonal haematopoiesis of clinical importance 73 . a follow up clinical study provided further evidence of the association between cardiovascular disease and chip 6 . in particular, old individuals (aged 60-70 years) with chip had an approximately twofold higher risk of incident coronary artery disease, a fourfold higher risk of early onset myocardial infarction and a three fold higher coronary artery calcium score than similarly aged individuals without chip 6 . importantly, the size of the chip clone, defined as the variant allele frequency (vaf), correlates with the risk of cardiovascular dis ease. specifically, individuals with a chip clone with a vaf of >10% have a 12 fold increased risk of cardi ovascular disease compared with individuals with no mutations, whereas the risk of cardiovascular disease is not significantly increased in chip carriers with a vaf of <10% 6 . this study has established that chip is associated with the risk of cardiovascular diseases and has developed a potential new paradigm that certain clones of haematopoietic cells accelerate atherogenesis 6 . however, to date, the presence of chip can be used only as a biomarker of atherosclerosis and is not therapeutically actionable. mutations in tet2 are the second most prevalent somatic mutations associated with chip after those in dnmt3a. mouse models have been used to elucidate the mechanistic contributions of tet2 mutations to ath erogenesis. in irradiated, atheroprone ldlr −/− mice, those reconstituted with either tet2 −/− or tet2 +/− bone marrow had increased atherosclerotic lesion size compared with mice receiving wild type bone marrow 6, 74 . these data imply that deletion of one copy of the tet2 gene is sufficient to increase atherosclerosis in mice. further studies in mice showed that myeloid cell specific tet2 deficiency increases atherosclerotic plaque size 74 . interestingly, tet2 deficiency in bone marrow derived macrophages leads to an elevated secretion of il6 and il1β (a signature cytokine produced by inflammasome activation) 75 in response to various stimuli (such as ldl, lps and ifnγ) in vitro 74 . furthermore, the increased atherogenic potential of tet2 −/− bone marrow cells is reduced when bone marrow transplantation recipients are treated with a small molecule inhibitor of the nlrp3 inflammasome 74 . the effect of tet2 deficiency might not be limited to vascular diseases, because experimen tal studies have demonstrated that transfer of tet2 −/− bone marrow cells into non irradiated mice accelerates the development of age related cardiac hypertrophy and fibrosis 76 , and tet2 deficiency in myeloid cells worsens the development of heart failure in mice after acute injury 77 . the contribution of il6 to the cardiovascular risk in individuals with large chip clones (vaf >10%) was evaluated in 35,416 individuals without prevalent cardi ovascular disease enrolled in the uk biobank registry 9 . the investigators examined whether an il6r coding mutation that leads to reduced il6 signalling alters the association between chip and the risk of adverse cardiovascular events (myocardial infarction, coronary artery disease revascularization, stroke or death). the study revealed that the presence of the il6r mutation mitigated the increased risk of adverse cardiovascular events in individuals with large chip clones but not in individuals without chip 9 . these data indicate that il6 signalling is causally linked to the increased risk of cardiovascular disease associated with chip. il6 is released following inflammasome activation 78 ; therefore, the observed link between il6 and chip suggests that inflammasome activation is a mecha nism by which chip promotes the development of cardiovascular diseases. this concept is compatible with the study in mice discussed above, showing that the nlrp3 inflammasome contributes to the increased atherosclerotic burden induced by tet2 −/− bone marrow transplantation 74 . the contribution of il1β to cardio vascular disease in humans was demonstrated in the cantos study 12, 13 , which showed that a monoclonal antibody against il1β reduces the risk of recurrent car diovascular events in patients with previous myocardial infarction. the effects of il1β blockade in the cantos trial were greater in patients who had lower circulating variant allele frequency (vaf) . the proportion of sequences that match a gene mutation divided by the overall coverage at that gene locus. www.nature.com/nrcardio il6 levels after il1β blockade than in those with higher circulating il6 levels 13 . however, the role of il1β and il6 in experimental models of atherosclerosis is not completely clear because data indicating that each of these cytokines has atheroprotective effects have been reported 79, 80 . however, these studies were performed in young mice, so these cytokines might have increasingly pathogenic roles with ageing. monocytes and macrophages contribute to both the initiation of the chronic inflammatory process of ath erosclerosis and the resolution of the chronic vascular inflammation 81 . ageing directly influences the function of monocytes and macrophages 16 . human monocytes have lower levels of tlrs and a reduction in tlr dependent pro inflammatory cytokine production with ageing 16 . a study comparing bone marrow derived monocytes from young and aged atheroprone ldlr −/− mice showed that ageing leads to a downregulation in the expression of tnf and il1b but monocyte chemotaxis is preserved 82 . aged (6 month old) atherosclerotic apoe −/− mice have a reduction in the number of vascular progenitor cells in the bone marrow compared with 1 month old atheroscle rotic apoe −/− mice 83 . furthermore, administration of bone marrow derived hscs from young non atherosclerotic mice to non irradiated 6 month old apoe −/− mice reduced atherogenesis after feeding a high fat diet 83 . this finding suggests that ageing is accompanied by a reduc tion in the number of atheroprotective progenitor cells in the bone marrow. aged (18-21 month old) mice with chronic or induced acute hyperlipidaemia have more macrophage infiltration into atherosclerotic lesions than young mice 11, 82 . furthermore, the aortas of aged athero sclerotic mice (12 months old) and rats (30 months old) have higher levels of macrophage attracting chemokines and il6 than the aortas of young atherosclerotic mice (2 months old) and rats(10 months old) 82, 84 . although macrophages and monocytes can have an increased basal secretion of inflammatory cytokines, such as il1β, il6 and il8, with ageing 85 (possibly owing to senescence) 57 , whether these cells are the major contributors to the increased vascular production of il6 with ageing during atherogenesis is unclear. vascular cells such as vascular smooth muscle cells (vsmcs) have been shown in animal models to have an elevated il6 production with ageing before any signs of atherosclerosis development 86, 87 . efferocytosis is a crucial mechanism for resolving plaque inflammation and reducing atherosclerosis progression 88 . in vivo and in vitro assays have indi cated that the phagocytic function of tissue alveolar macrophages to take up apoptotic neutrophils declines with ageing 89 and is associated with reduced expres sion of scavenger receptor cd204 (ref. 90 ). in a mouse model of peritonitis, ageing led to reduced resolution of acute inflammation and was associated with reduced levels of pro resolution lipid mediators, specifically resolvins 91 . resolution of inflammation was also delayed with ageing in a human model of skin blistering 92 . this phenotype is related to reduced expression of the effe rocytotic receptor tim4 in macrophages. reduced tim4 expression with ageing was caused by elevations in p38 mitogen activated protein kinase activity in macrophages, and treatment with an oral p38 inhibitor increased the resolution of blister inflammation in old individuals 92 . overall, macrophages show impaired inflammation resolution properties with ageing; how ever, whether this impaired macrophage function contributes to increased atherosclerosis is not yet clear. vascular mitochondrial dysfunction with ageing before atherogenesis initiation. ageing affects the vasculature before the development of atherosclerosis. generally, ageing is associated with remodelling of the arterial wall, with evidence of reduced endothelial cell function, increased collagen deposition, fibrosis and functionally stiffer vessels 28, 93, 94 . in addition, vsmcs acquire a more proliferative and synthetic function with ageing 86 . vsmcs also show an increased generation of reactive oxygen spe cies (ros) and high oxidative damage 95 . endothelial cells also have a dysregulated antioxidant capacity with ageing (mediated by the disruption of nuclear factor erythroid 2 related factor 2 signalling), thereby contributing to vas cular ageing 96, 97 . all these effects of ageing can contribute to the development of hypertension, a major risk factor for cardiovascular disease. most studies on vascular ageing in rodent models have been performed in normolipidaemic animals. these studies provide evidence that mitochondrial dysfunction, a known hallmark of ageing 25 , contrib utes to vascular ageing before the initiation of athero genesis. disease free, normolipidaemic mice develop mitochondrial dysfunction in the aorta as they age, first detected at 11 months of age (measured as a decline in oxygen consumption rate (ocr)) and becoming more evident as the mice reach 18 months of age 98 . the reduction in ocr is accompanied by an increase in mitochondrial dna (mtdna) damage 98 , a sign of mito chondrial genomic instability, which is another hallmark of ageing 25 . furthermore, reduced vascular mitochon drial function with ageing is accompanied by a decrease in the expression of the mtdna helicase twinkle 98 , an enzyme involved in preserving mtdna integrity. aged transgenic mice expressing high levels of twinkle show delayed vascular ageing; in particular, the decrease in aortic compliance and the increase in aortic stiffness are delayed in these mice compared with aged wild type mice 98 . overall, experimental evidence indicates that mitochondrial dysfunction and mitochondrial genomic instability contribute to vascular ageing. in humans, atherosclerotic plaques show evidence of damage to mtdna, which is associated with reduced mitochondrial function, specifically lower ocr in the fibrous cap and core regions of the atherosclerotic plaque than in the shoulder region of the plaque or in non overtly diseased regions of the aorta 10 . these findings are compatible with those of previous experimental work indicating that apoe −/− mice fed a low fat, standard chow diet have increased vascular mtdna damage but not nuclear dna damage as the mice age 99, 100 . furthermore, human atherosclerotic plaques have lower levels of mitochondrial complex i and complex ii than non diseased aortic regions 10 . similar findings are noted in efferocytosis phagocytosis of apoptotic cells by phagocytic cells. atherosclerotic apoe −/− mice fed a high fat diet 10 . apoe −/− mice overexpressing twinkle have a reduced necrotic core area in atherosclerotic plaques compared with con trol apoe −/− mice 10 . mitochondrial dysfunction probably has a central role in ros generation but the interaction between these two factors is complex. for example, low levels of ros might improve cell fitness and pro mote survival, a concept known as mitohormesis 25, 101 . however, higher levels of ros might contribute to age related chronic vascular diseases. the complex inter action between mitochondrial dysfunction and ros might explain why disruption of some mitochondrial enzymatic pathways (such as nadph oxidase 1 (nox1) and nox2 signalling) in atherosclerotic mice has no effect on age related atherosclerosis 102 , whereas partial deficiency of ros scavenging enzymes (such as super oxide dismutase) 103 in atherosclerotic mice contributes to atherosclerosis 99 . however, one study found that mtdna damage occurs in both vsmcs and monocytes and cor relates with atherosclerotic burden in humans but with out evidence of alterations in ros levels 100 . furthermore, clinical trials on antioxidants have yet to reveal a benefi cial effect in patients with atherosclerotic cardiovascular disease 104, 105 . overall, mitochondrial dysfunction occurs during chronic hyperlipidaemia and atherogenesis, and this mitochondrial dysfunction promotes atherosclero sis. however, the precise role of ros in this context is complex and requires further investigation. part of the challenge of using stand ard mouse models of atherosclerosis (such as ldlr −/− or apoe −/− mice) to understand the role of ageing on atherogenesis is that even when fed a standard low fat diet, these mice age with chronic hyperlipidaemia. therefore, the effects of ageing cannot be dissected from the effects of chronic hyperlipidaemia. a study in mice published in 2020 circumvented this issue by first examining mitochondrial function in the aortas of young and aged wild type mice without hyperlipidaemia or vascular diseases 11 . consistent with previous studies, aged mice had evidence of reduced ocr in the aortas compared with young mice 11 . this ocr reduction in the vasculature from aged mice was accompanied by increased expression of the mitophagy protein parkin and increased basal mitophagy (box 1), a macroau tophagy process to remove damaged mitochondria. altered mitochondrial quality control in the ageing vas culature without hyperlipidaemia is linked to arterial stiffening in mice 106 . the mitochondrial dysfunction and elevated parkin levels with ageing in the mouse aorta are accompanied by an increase in tlr9, myd88 and il6 levels 11 . importantly, blocking il6 in aged mouse aortas in vitro increased the ocr and reduced parkin levels. this study identified a positive feedback loop in which mitochondrial dysfunction and elevated il6 levels coexist and positively influence each other 11 . however, the exact identity of the il6 producing and il6 responsive cell(s) has yet to be identified, although evidence suggests that vsmcs secrete more il6 with ageing 87 . to study the link between the changes occurring with normolipidaemia in the aged aorta and atherogen esis, young and aged wild type mice were made acutely hyperlipidaemic by inducing a decrease in ldl recep tor levels with adeno associated virus vector mediated during homeostasis, damaged mitochondria are recycled via mitophagy, which is a specialized subset of macroautophagy (see the figure) . mitophagy reduces the production of mitochondrial damage-associated molecular patterns (mtdamps) and limits inflammation. mitochondrial depolarization results in the accumulation of the serine/threonine protein kinase pink1 at the outer mitochondrial membrane, leading to the recruitment of parkin, an e3 ubiquitin ligase that ubiquitylates mitochondrial membrane proteins including mitofusin 1 (mfn1), mfn2 and voltage-dependent anion-selective channel protein 1 (vdac1). this ubiquitylation primes the mitochondria for targeting by the autophagy machinery, including sequestosome 1 (p62) and microtubule-associated protein 1 light chain 3 (lc3), to package mitochondria in autophagosomes and deliver them to lysosomes for degradation. other mitophagy mechanisms involve the apoptotic bcl-2 family proteins bcl-2/ adenovirus e1b 19 kda protein-interacting protein 3 (bnip3) and nip3-like protein (nix; also known as bnip3l), which dimerize and bind directly to lc3 and function as adaptors between mitochondria and autophagosomes. bnip3 and nix can also facilitate apoptosis and cell death by participating in the release of mitochondrial cytochrome c and opening of the mitochondrial permeability transition pore. pgc1α, proliferator-activated receptorγ co-activator 1α; tf, transcription factor. release of mtdamps www.nature.com/nrcardio delivery of pcsk9 and by feeding the mice a high fat diet for 10 weeks 11 , which is an established technique 107 . with this protocol, young and aged mice had similar and durable levels of hyperlipidaemia; however, aged hyperlipidaemic mice had larger atherosclerotic lesions with larger necrotic cores than young hyperlipidaemic mice 11 . importantly, administering spermidine, an agent that increases macroautophagy and mitophagy, to aged hyperlipidaemic mice reduced the levels of both il6 and parkin in the aorta and reduced the size of ather osclerotic plaques 11 . this finding is consistent with pre vious studies showing that treatment with spermidine or trehalose, an agent that increases mitophagy, reduces stiffness in the aged vasculature in normolipidaemic, non atherosclerotic aged mice 106, 108 . the cantos study 12 showed that in old patients (aged >60 years) with cardiovascular disease, il1β blockade reduces the risk of recurrent cardiovascular events, indi cating that chronic inflammation is a major contribu tor to age related atherosclerosis. as described above, mitochondrial dysfunction might coexist in a positive feedback loop with il6 signalling 11 to increase chronic inflammation in vascular ageing. furthermore, mito chondrial components that are released to the cyto sol after mitochondrial damage can stimulate innate immune responses 109 . mitochondrial injury in turn can be induced by tlr stimulation leading to the activa tion of caspase 4 and caspase 5 in humans or caspase 11 in mice 110 . these inflammatory caspases cleave gasder min d, which enables gasdermin d to form pores in the outer mitochondrial membrane, leading to impaired mitochondrial membrane potential and further increas ing mitochondrial injury 110 . whether this pathway is activated during ageing and in particular vascular age ing is unclear. nevertheless, the involvement of such a pathway could explain why chronic tlr activation, via either microbial products or sterile inflammatory medi ators, could lead to a chronic basal inflammatory state and mitochondrial dysfunction in the vasculature with ageing. mitochondrial injury leads to the release of mito chondrial components, known a s m it oc ho nd rial damageassociated molecular patterns (mtdamps), including mtdna, that when in the cytosol, can activate intracel lular innate immune signalling pathways, such as the dna sensing receptor cyclic gmp-amp synthase and the inflammasome 75, [110] [111] [112] . transfer of mitochondrial components into endosomes also activates the tlr9 inflammatory pathway 111 , but the detailed mechanisms are not fully elucidated. mitochondria also contain n formylated peptides that induce inflammation via engaging the n formyl peptide receptor 1 to increase neutrophil chemoattraction 113 , arterial injury and ros release 114 . cardiolipin, a component of mitochondrial membranes, can directly bind to nlrp3 and activate the nlrp3 inflammasome 115 . if chronically activated, all these pathways could promote vascular ageing and also diminish mitochondrial function, although ascertain ing the definitive contributions of each pathway requires future investigation. age related atherosclerosis might be mediated by alterations in the vasculature and mye loid cells via a shared inflammatory pathway. a potential candidate pathway is il6 signalling because available evidence indicates that the level of il6 is elevated with ageing in both the immune system and the vasculature. in the bone marrow niche in mice, il6 levels increase with ageing, which is probably mediated by increased β 2 adrenergic receptor signalling and increased num bers of adipocytes 60 (fig. 1) . il6 directly acts on hscs to promote a bias towards myeloid cell differentiation 60 . in mouse macrophages, tet2 deficiency, which is one of the most common genetic alterations found in the age related condition chip, increases il6 secretion in vitro 74 . importantly, the atherosclerosis promoting effects of chip seem to be abrogated in individuals with a loss of function il6 genetic polymorphism 9 . in the vasculature, the level of il6 increases with ageing, which is at least in part mediated by il6 production by vsmcs 87 . il6 is associated with ageing in general and is part of the 'inflammageing' phenotype 15, 16, 116 . why ageing leads to elevated basal secretion of inflammatory cytokines (not solely il6 but also other inflammatory mediators such as tnf) is not clear but might be caused by alter ations in the microbiota 117 , increased adiposity 118 , and changes in the immune system 17 and the vasculature 29, 30 . elevated cytokine levels with ageing could also be a manifestation of chronic, latent infections such as with herpesviruses 119 , of cellular senescence 57, 86, 87 or, potentially, of mitochondrial dysfunction. the role of il6 in young animal models of ath erosclerosis remains unclear and might relate to the complexities of il6 signalling (box 2). specifically, signalling via the classic il6 pathway occurs in a restricted number of cells (such as hepatocytes and some immune cells) and involves il6 binding to the membrane bound il6 receptor (il6r), with subse quent association with the signal transducing il6r subunit β (also known as gp130). evidence indicates that classic il6 signalling is important for tissue home ostasis, regeneration and host defence (as reviewed previously 120 ). soluble il6r can also engage il6 in the circulation and activate a broader range of cells than the classic pathway, via membrane activation of gp130. this pathway is termed il6 trans signalling (box 2) and can result in chronic inflammation 120 . these different il6 signalling pathways might explain the pleiotropic effects of il6 in different tissues and cellular compartments and also the divergent role of il6 in experimental atherosclerotic models. for instance, one study in apoe −/− mice showed that admin istration of exogenous il6 worsens atherosclerosis 121 . by contrast, another study in apoe +/− mice showed that il6 deficiency worsens atherosclerosis 80 nature reviews | cardiology atherosclerotic ldlr −/− mice 122 . the study found that inhib iting il6 trans signalling reduced atherosclerosis 122 , indicating that il6 trans signalling might have a path ogenic role in atherosclerosis. therefore, clinical ther apeutics to reduce atherosclerosis should focus on this il6 pathway. whether il6 has a causal role in age related ather osclerosis is not known yet. the contribution of il6 to age related atherosclerosis should be investigated in the future and should determine the main il6 producing and il6 responding cells. furthermore, the iden tification of the major il6 producing cells (fig. 2) and whether il6 activation occurs via the classic or trans signalling pathway with ageing could lead to more targeted therapeutics for atherosclerosis, especially given the availability of clinically approved agents to target il6 (refs 123,124 ). importantly, the risk-benefit balance of targeting il6 in atherosclerosis will need to be deter mined, given that anti il6 therapies in human studies increased the risk of infections 120 , similar to other bio logical agents (such as anti il1β antibodies) that have been used to reduce atherosclerosis 12, 13 . however, other biological agents such as tnf inhibitors 125 might be ben eficial for the treatment of atherosclerotic cardiovascular disease and should be investigated in age related ather osclerosis. finally, other inflammatory cytokines (such as tnf, c c motif chemokine 2 and il18, which are all part of the sasp) 56 might have a pathogenic role in age related atherosclerosis and should be assessed in future studies. therapies that can mitigate some of the detrimental biological effects of ageing, such as removing senescent cells (including senescent adipocytes) 126, 127 , improving mitochondrial function (for example, with metformin therapy) 128 , or augmenting macroautophagy (for exam ple, with rapamycin therapy) 129 or mitophagy, might reduce the burden of atherosclerosis in old people and should be investigated in future clinical studies. agents that increase mitophagy, such as spermidine, have been shown in experimental studies to reduce atherosclero sis in both young 130 and aged 11 mice. some or all these agents might have pleiotropic effects, which could reduce inflammation. furthermore, these agents might synergize with specific anti inflammatory therapies to reduce atherosclerosis with ageing, which will require future clinical investigation. ageing influences atherogenesis via multiple complex pathways, and one sole factor is unlikely to be a domi nant pathophysiological mechanism. in this review, we provide an overview of how ageing affects two systems, myeloid cell haematopoiesis and the vasculature, to pro mote atherosclerosis. we lay a framework of a poten tial shared inflammatory pathway, mediated by il6 signalling, that connects the role of the two systems in box 2 | il-6 signalling il-6 can signal via a classic signalling pathway and a trans-signalling pathway (see the figure) . in the classic il-6 signalling pathway, il-6 engages the membrane-bound il-6 receptor (il-6r) and subsequently interacts with the il-6r subunitβ (also known as gp130). intracellular signalling mainly involves activation of the janus kinase (jak) and the signal transducer and activator of transcription 3 (stat3). the classic pathway is generally restricted to hepatocytes and immune cells such as myeloid cells and lymphocytes. the trans-signalling pathway is activated by il-6 binding to soluble il-6r (sil-6r) in the circulation and then binding of the il-6-sil-6r complex to membrane-bound gp130 on a broad range of cells. sil-6r is released by enzymatic cleavage of membrane-bound il-6r by disintegrin and metalloproteinase domain-containing protein 17 (adam17). activation of the il-6 trans-signalling pathway generally leads to chronic inflammation, whereas the il-6 classic signalling pathway is involved in cell growth, regeneration and host defence. age related atherosclerosis and propose future avenues of investigation to determine whether il6 and/or other inflammatory pathways are feasible and effective ther apeutic targets to reduce the burden of atherosclerosis in old people. anti inflammatory strategies should be considered in the context of other therapies that aim to reduce many of the detrimental biological effects of ageing. overall, we hope that with the pursuit of further clinical investigation and trials, therapeutic options will be available in the future to reduce the burden of ath erosclerosis in the increasing number of old people in our society. fig. 2 | il-6 as a potential therapeutic target in age-related atherosclerosis. il-6 is upregulated in multiple tissues that have important roles in the increase in atherogenesis with ageing. therefore, blockade of il-6 might be an effective therapeutic strategy to reduce atherosclerosis development and progression during ageing. blocking il-6 might interfere with the increased il-6 signalling in bone marrow adipocytes that occurs with ageing (which promotes a skewing towards myeloid cell differentiation), thereby reducing the risk of clonal haematopoiesis of indeterminate potential (chip). il-6 blockade might also reduce the inflammatory potential of clones of myeloid cells associated with chip. il-6 blockade might reduce atherosclerosis burden, although direct comparisons of efficacy and safety with il-1β inhibition requires future investigation. il-6 blockade might increase mitochondrial function and reduce the expression of parkin, a mitochondrial stress protein, which might also contribute to reducing atherogenesis during ageing. hsc, haematopoietic stem cell; vsmc, vascular smooth muscle cell. prevalence and determinants of carotid plaque in the cross-sectional refine-reykjavik study heart disease and stroke statistics-2019 update: a report from the clinical characteristics of 138 hospitalized patients with 2019 novel coronavirusinfected pneumonia in wuhan, china association of cardiac injury with mortality in hospitalized patients with covid-19 in wuhan somatic mutations and clonal hematopoiesis: unexpected potential new drivers of age-related cardiovascular disease clonal hematopoiesis and risk of atherosclerotic cardiovascular disease age-related clonal hematopoiesis associated with adverse outcomes clonal hematopoiesis, with and without candidate driver mutations, is common in the elderly genetic interleukin 6 signaling deficiency attenuates cardiovascular risk in clonal hematopoiesis mitochondrial respiration is reduced in atherosclerosis, promoting necrotic core formation and reducing relative fibrous cap thickness age-associated mitochondrial dysfunction accelerates atherogenesis antiinflammatory therapy with canakinumab for atherosclerotic disease modulation of the interleukin-6 signalling pathway and incidence rates of atherosclerotic events and all-cause mortality: analyses from the canakinumab anti-inflammatory thrombosis outcomes study (cantos) killing the old: cell senescence in atherosclerosis t-cell immunity to influenza in older adults: a pathophysiological framework for development of more effective vaccines age-dependent dysregulation of innate immunity the twilight of immunity: emerging concepts in aging of the immune system the immune response in atherosclerosis: a double-edged sword immunity and inflammation in atherosclerosis b cell dysfunction associated with aging and autoimmune diseases aging of the immune system. mechanisms and therapeutic targets immunosenescence in aging: between immune cells depletion and cytokines up-regulation is the oxidative stress theory of aging dead? overexpression of mn superoxide dismutase does not increase life span in mice the hallmarks of aging oxidative stress in atherosclerosis is pulse pressure useful in predicting risk for coronary heart disease? the framingham heart study endothelial dysfunction and low-grade inflammation are associated with greater arterial stiffness over a 6-year period mechanisms of dysfunction in the aging vasculature and role in age-related disease mechanisms of vascular aging ly-6chi monocytes dominate hypercholesterolemia-associated monocytosis and give rise to macrophages in atheromata s-100 positive cells in human arterial intima and in atherosclerotic lesions in vivo downregulation of t helper cell 1 immune responses reduces atherogenesis in apolipoprotein e-knockout mice detection of b cells and proinflammatory cytokines in atherosclerotic plaques of hypercholesterolaemic apolipoprotein e knockout mice inflammation and atherosclerosis causes and mechanisms of hematopoietic stem cell aging inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment functionally distinct hematopoietic stem cells modulate hematopoietic lineage potential during aging by a mechanism of clonal expansion cell intrinsic alterations underlie hematopoietic stem cell aging age-associated characteristics of murine hematopoietic stem cells human and murine hematopoietic stem cell aging is associated with functional impairments and intrinsic megakaryocytic/ erythroid bias genetic regulation of primitive hematopoietic stem cell senescence aging hematopoietic stem cells decline in function and exhibit epigenetic dysregulation the epigenetic basis of hematopoietic stem cell aging clonal analysis reveals multiple functional defects of aged murine hematopoietic stem cells idh1(r132h) mutation increases murine haematopoietic progenitors and alters epigenetics idh2r172 mutations define a unique subgroup of patients with angioimmunoblastic t-cell lymphoma hematopoietic stem cell ageing is uncoupled from p16 ink4a-mediated senescence clearance of senescent cells by abt263 rejuvenates aged hematopoietic stem cells in mice autophagy maintains the metabolism and function of young and old stem cells stem cell aging. a mitochondrial upr-mediated metabolic checkpoint regulates hematopoietic stem cell aging altered microrna expression links il6 and tnf-induced inflammaging with myeloid malignancy age-dependent modulation of vascular niches for haematopoietic stem cells inflamm-aging. an evolutionary perspective on immunosenescence associations of elevated interleukin-6 and c-reactive protein levels with mortality in the elderly cellular senescence: a translational perspective cellular senescence and the senescent secretory phenotype: therapeutic opportunities clearance of p16ink4a-positive senescent cells delays ageing-associated disorders sarcopenia, obesity, and inflammationresults from the trial of angiotensin converting enzyme inhibition and novel cardiovascular risk factors study remodeling of bone marrow hematopoietic stem cell niches promotes myeloid cell expansion during premature or physiological aging changes in human bone marrow fat content associated with changes in hematopoietic stem cell numbers and cytokine levels with aging bone marrow adipocytes promote the regeneration of stem cells and haematopoiesis by secreting scf leptin receptor promotes adipogenesis and reduces osteogenesis by regulating mesenchymal stromal cells in adult bone marrow an early-senescence state in aged mesenchymal stromal cells contributes to hematopoietic stem and progenitor cell clonogenic impairment through the activation of a pro-inflammatory program age-related marrow adipogenesis is linked to increased expression of rankl endothelial transplantation rejuvenates aged hematopoietic stem cell function chronic exposure to a tlr ligand injures hematopoietic stem cells gut microbiota composition correlates with diet and health in the elderly defective extracellular pyrophosphate metabolism promotes vascular calcification in a mouse model of hutchinson-gilford progeria syndrome that is ameliorated on pyrophosphate treatment clonal hematopoiesis and blood-cancer risk inferred from blood dna sequence age-related mutations associated with clonal hematopoietic expansion and malignancies age-related clonal hematopoiesis clonal hematopoiesis in human aging and disease clonal hematopoiesis associated with tet2 deficiency accelerates atherosclerosis development in mice inflammasomes: mechanism of action, role in disease, and therapeutics tet2-mediated clonal hematopoiesis in nonconditioned mice accelerates age-associated cardiac dysfunction tet2-mediated clonal hematopoiesis accelerates heart failure through a mechanism involving the il-1β/nlrp3 inflammasome il-6 biology: implications for clinical targeting in rheumatic disease interleukin-1β has atheroprotective effects in advanced atherosclerotic lesions of mice atheroprotective role of interleukin-6 in diet-and/or pathogen-associated atherosclerosis using an apoe heterozygote murine model macrophages in atherosclerosis: a dynamic balance age-associated vascular inflammation promotes monocytosis during atherogenesis aging, progenitor cell exhaustion, and atherosclerosis increased production of tumor necrosis factor and interleukin-6 by arterial wall of aged rats age-associated elevation in tlr5 leads to increased inflammatory responses in the elderly age-associated proinflammatory secretory phenotype in vascular smooth muscle cells from the non-human primate macaca mulatta: reversal by resveratrol treatment aging enhances the basal production of il-6 and ccl2 in vascular smooth muscle cells the role of macrophages and dendritic cells in the clearance of apoptotic cells in advanced atherosclerosis age-related defects in tlr2 signaling diminish the cytokine response by alveolar macrophages during murine pneumococcal pneumonia aging impairs alveolar macrophage phagocytosis and increases influenza-induced mortality in mice aging delays resolution of acute inflammation in mice: reprogramming the host response with novel nano-proresolving medicines blocking elevated p38 mapk restores efferocytosis and inflammatory resolution in the elderly origin of matrix-producing cells that contribute to aortic fibrosis in hypertension vascular calcification and aortic fibrosis: a bifunctional role for osteopontin in diabetic arteriosclerosis aging, oxidative responses, and proliferative capacity in cultured mouse aortic smooth muscle cells disruption of nrf2 signaling impairs angiogenic capacity of endothelial cells: implications for microvascular aging vascular oxidative stress in aging: a homeostatic failure due to dysregulation of nrf2-mediated antioxidant response restoring mitochondrial dna copy number preserves mitochondrial function and delays vascular aging in mice mitochondrial integrity and function in atherogenesis mitochondrial dna damage can promote atherosclerosis independently of reactive oxygen species through effects on smooth muscle cells and monocytes and correlates with higher-risk plaques in humans nox4 nadph oxidase-dependent mitochondrial oxidative stress in aging-associated cardiovascular disease attenuated superoxide dismutase 2 activity induces atherosclerotic plaque instability during aging in hyperlipidemic mice antioxidants in cardiovascular therapy: panacea or false hope? front role of antioxidants in atherosclerosis: epidemiological and clinical update mitochondrial quality control and age-associated arterial stiffening induction of atherosclerosis in mice and hamsters without germline genetic engineering the autophagy enhancer spermidine reverses arterial aging mitochondria in innate immune responses mtdna activates cgas signaling and suppresses the yap-mediated endothelial cell proliferation program to promote inflammatory injury inhibition of x-box binding protein 1 reduces tunicamycininduced apoptosis in aged murine macrophages pan-viral specificity of ifninduced genes reveals new roles for cgas in innate immunity f2l, a peptide derived from hemebinding protein, chemoattracts mouse neutrophils by specifically activating fpr2, the low-affinity n-formylpeptide receptor mitochondrial n-formyl peptides induce cardiovascular collapse and sepsislike syndrome mitochondrial cardiolipin is required for nlrp3 inflammasome activation understanding how we age: insights into inflammaging age-associated microbial dysbiosis promotes intestinal permeability, systemic inflammation, and macrophage dysfunction inflammation, aging, and adiposity: implications for physical therapists immunologic changes in frail older adults the role of il-6 in host defence against infections: immunobiology and clinical implications interleukin-6 exacerbates early atherosclerosis in mice transsignaling of interleukin-6 crucially contributes to atherosclerosis in mice tocilizumab: a review in rheumatoid arthritis targeting interleukin-6 signaling in clinic risk of serious infections in tocilizumab versus other biologic drugs in patients with rheumatoid arthritis: a multidatabase cohort study senolytics improve physical function and increase lifespan in old age chronic senolytic treatment alleviates established vasomotor dysfunction in aged or atherosclerotic mice metformin as antiaging therapy: is it for everyone? rapamycin, but not resveratrol or simvastatin, extends life span of genetically heterogeneous mice spermidine reduces lipid accumulation and necrotic core formation in atherosclerotic plaques via induction of autophagy acknowledgements d.j.t. is supported by nih award f32-hl1400728, and d.r.g. is supported by nih awards r01-hl127687, r01-ai138347 and k07-ag050096. both authors researched data for the article, discussed its content, wrote the manuscript, and reviewed and edited it before submission. the authors declare no competing interests. nature reviews cardiology thanks c. leeuwenburgh, h. oliveira, a. tedgui and the other, anonymous, reviewer(s) for their contribution to the peer review of this work. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-322913-sq9mq6f1 authors: ciabattini, annalisa; garagnani, paolo; santoro, francesco; rappuoli, rino; franceschi, claudio; medaglini, donata title: shelter from the cytokine storm: pitfalls and prospects in the development of sars-cov-2 vaccines for an elderly population date: 2020-11-06 journal: semin immunopathol doi: 10.1007/s00281-020-00821-0 sha: doc_id: 322913 cord_uid: sq9mq6f1 the sars-cov-2 pandemic urgently calls for the development of effective preventive tools. covid-19 hits greatly the elder and more fragile fraction of the population boosting the evergreen issue of the vaccination of older people. the development of a vaccine against sars-cov-2 tailored for the elderly population faces the challenge of the poor immune responsiveness of the older population due to immunosenescence, comorbidities, and pharmacological treatments. moreover, it is likely that the inflammaging phenotype associated with age could both influence vaccination efficacy and exacerbate the risk of covid-19-related “cytokine storm syndrome” with an overlap between the factors which impact vaccination effectiveness and those that boost virulence and worsen the prognosis of sars-cov-2 infection. the complex and still unclear immunopathological mechanisms of sars-cov-2 infection, together with the progressive age-related decline of immune responses, and the lack of clear correlates of protection, make the design of vaccination strategies for older people extremely challenging. in the ongoing effort in vaccine development, different sars-cov-2 vaccine candidates have been developed, tested in pre-clinical and clinical studies and are undergoing clinical testing, but only a small fraction of these are currently being tested in the older fraction of the population. recent advances in systems biology integrating clinical, immunologic, and omics data can help to identify stable and robust markers of vaccine response and move towards a better understanding of sars-cov-2 vaccine responses in the elderly. 0.86, while the m:f ratio of deaths is around 1.38, suggesting that, despite being more frequently infected, females are more capable of dealing with the infection [2, 3] . it is widely reported that most deaths occurred among patients with at least one underlying disease, such as hypertension [4] and diabetes mellitus [5] . a meta-analysis of seven clinical studies performed in china identified chronic obstructive pulmonary disease (copd), cardiovascular disease, and hypertension as risk factors for severe disease and intensity care unit (icu) admission [6] . analysis of risk factors associated with more than ten thousand deaths by covid-19 in the uk confirmed that age was linearly correlated with risk of death and that obesity, diabetes, severe asthma, respiratory disease, neurological disease (including stroke), recent (< 5 years) hematological malignancy, and recent (< 1 year) cancer diagnosis were all associated with higher death risk. as for hypertension, the hazard risk was higher only for the population < 70 years old, even if hypertension itself was strongly associated with other risk factors such as obesity and diabetes [7] . importantly, these epidemiological studies identify the categories of subjects who are at higher risk of developing severe sars-cov-2 infection and that should be prioritized in vaccine administration. the massive effort for the development of a vaccine against sars-cov-2 could be frustrated by the poor responsiveness to vaccination that characterizes a large proportion of the elderly population. in this rush against the time, we risk to pay a dear toll for the lack of knowledge in the response to vaccination of the elderly, a well-known issue, neglected notwithstanding its evident urgency and the annual reproposal through the seasonal influenza epidemic above all. interestingly, there is a consistent overlap between the factors hampering vaccination effectiveness in the elderly and those that boost the virulence and worsen the prognosis of sars-cov-2 infection. a common characteristic of the elderly people is the onset of a sterile low-grade increase of the basal inflammatory state named "inflammaging," which is considered a universal etiological agent of most of the age-related diseases [8] . it is likely that some specific components of the inflammaging phenotype could both influence vaccination efficacy and then increase the risk of the early massive production of inflammatory cytokines, termed the "cytokine storm syndrome." this is a condition reported in severe covid-19 cases during which the patient's immune system spins out of control and starts damaging healthy organs owing to the increased vascular permeability, vascular paralysis, and hypovolemic shock [9] . angiotensin-converting enzyme 2 (ace2) has been identified as the receptor for sars-cov-2, and it has been suggested that differential levels of ace2 in the cardiac and pulmonary tissues of younger versus older adults may be at least partially responsible for the spectrum of disease virulence observed among patients with covid-19 [10] . here, we analyze the different aspects that tackle sars-cov-2 vaccination in the elderly population, considering immunologic, genetic, and socio-economic factors that impact on the age-related changes of immune responses. a view of the current available vaccine platforms with a special focus on the clinical trials including older adults is reported. how the elderly condition can affect covid-19 disease progression and the response to vaccination immunosenescence for many reasons, it is difficult to clearly define what immunosenescence is: (i) immunosenescence is quite complex and involves cellular and molecular changes occurring lifelong (from newborns to centenarians) in both the innate and the adaptive immune systems; (ii) these changes can be at the same time detrimental and beneficial/adaptive [11] ; (iii) it is difficult to identify a unique common marker of immunosenescence, due to the overwhelming number of biological and non-biological factors that can impinge lifelong on the immune system of each individual; (iv) the changes occurring with age in the immune system are deeply correlated with the profound environmental, epidemiological, lifestyle, societal, medical, and public health changes, including vaccination policies and practices, that occurred in the last century. accordingly, immunosenescence is highly contextdependent [12] , different in different geographical and historical settings and in men and women, correlated to socioeconomic position, and sensitive to psychological stressors. indeed, both the adaptive and the innate immune systems have the capability of "remembering" all immunological stimuli a person has been exposed to lifelong. we have conceptualized this situation with the term immunobiography, which should help in understanding the enormous heterogeneity of the immune phenotype in old people. this is also the reason why there is a sort of imprinting in the immune responses favoring those towards antigens that have been experienced early in life [13] . the complex biological processes of aging are the result of alterations in gene regulation and protein expression, signaling pathways, and biological networks. complex changes, including pervasive epigenetic and metabolic modifications, affect most of the subsets of naïve, memory, regulatory effector t cells, and b cells [14] [15] [16] . despite the challenging complexity, a universally observed hallmark of immunosenescence is the decrease of naive t cells (particularly cd8+ t cells) in peripheral blood [17] consequent to thymic involution responsible for the early decline in the output of naïve t cells to the periphery and for the related shrinking of the t cell repertoire [18] [19] [20] . other important aging-related alterations are (i) the shift in the bone marrow maturation of hematopoietic cells towards myelocytic differentiation [21] , concomitant with a reduced lymphopoiesis, mainly due to changes in progenitor cells in the bone marrow [12, 22] ; (ii) the increased numbers of memory cells owing to large clonal expansion towards epitopes of persistent viral infections (cytomegalovirus [cmv] and epstein barr virus [ebv]) [23, 24] ; (iii) the compromised ability of cd4+ t cells to differentiate into functional subsets, resulting in a multitude of dysregulated responses, such as a reduced cognate help to b cells with consequent reduced humoral immunity, and the increased ratio of the proinflammatory th17 cells with respect to the immunosuppressive t regulatory cells, thus favoring a basal proinflammatory status [16, 25] ; (iv) accumulation of differentiated exhausted t cells, induced by a repeated pathogen encounter during chronological aging, and end-stage differentiated senescent t cells, characterized by a progressive reduction of telomere length leading to a state of proliferative arrest [26] . with aging, health conditions associated with immune senescence, comorbidities (particularly noncommunicable diseases such as heart disease, cancers, and metabolic and autoimmune diseases), and pharmacological treatments affect the immune responses to both vaccines and infectious diseases. overall, as a result of immunosenescence, the elderly population is more susceptible to infections, particularly to influenza, streptococcus pneumoniae rsv, and group b streptococcus but also to opportunistic, re-emergent chronic infections such as herpes zoster as well as antibiotic-resistant nosocomial pathogens. the reduced adaptive immune response, together with altered innate cell function, such as chemotaxis, phagocytosis, signaling pathways, and intracellular killing, prevents the appropriate control of the initial inflammatory response elicited upon viral infection. for rna virus, such as coronavirus, different pattern recognition receptors (prr) are triggered on the innate cells during the early phases of infection. these include the endosomic toll-like receptor 3 and 7 and the cytosolic rig-i/mda-5 molecules, which recognize viral rna [27] , and the cgas-sting pathway, which recognizes cytosolic dna [28] activated by cellular damage and mitochondrial dna release caused by viral infection [29] . the stimulation of these prr leads to the expression of type i ifn, a factor that limits viral replication through the stimulation of interferon-stimulated genes, and other inflammatory cytokines [30] . for middle east respiratory syndrome (mers)-cov, the timing of type i ifn production appears to dictate the outcome of infection in mouse models, and its administration within 1 day after infection was protective against lethal infection, while a delay in ifn production caused an inability to control viral replication, leading to cellular damage of airway epithelia and the lung parenchyma and an eventual lethal inflammatory cytokine storm [31] . the latter response often predominates in older individuals and in aged mouse models of sars-cov-1 infection [32, 33] . induction of innate immune responses is a crucial step in the pathophysiology of covid-19 disease (fig. 2) . on one hand, it triggers the anti-viral host defense mechanisms necessary for elimination of infection, but on the other hand, it may contribute to hyperinflammation and tissue damage during the later stages of the disease in a minority of patients [34] . this can be particularly relevant in the elderly population in which inflammaging, the state of chronic low-grade sterile inflammation [8] , characterized by high serum concentrations of c-reactive protein (crp), il-6, il-8, and tumor necrosis factor (tnf)-α, can be present. tissue damage in covid-19 is mainly mediated by an excess of immune response to the virus, which results in a cytokine storm, with activation of the il-6 signaling pathway. the pathophysiology of sars-cov-2 infection has strong similarities to other severe viral lung infections caused by sars-cov-1 and mers-cov. one of the first published studies on clinical features of covid patients hospitalized in wuhan showed that proinflammatory cytokines and chemokines, such as tnf-α, granulocyte-colony stimulating factor (g-csf), interferon g a m m a -i n d u c e d p r o t e i n -1 0 ( i p -1 0 ) , m o n o c y t e chemoattractant protein-1 (mcp-1), and macrophage inflammatory proteins 1-α (mip-1α), were significantly higher in patients admitted to the intensive care unit (icu) compared to those who were not in icu [35] . immune pathology in the form of vascular and cutaneous lesions has also been widely reported [36, 37] . the role of a dysregulated inflammatory response was proven in an animal model of sars-cov-1 infection using aged macaques. aged animals are more prone to develop severe disease and activate more readily the innate response, in particular the nf-kb pathway and proinflammatory cytokines such as il-8 and il-1β, while not inducing significantly ifn-β response. the innate immunity activation is not due to the viral load, which is comparable among young and aged macaques [38] . transcriptomic analysis performed in samples from subjects with severe covid-19 revealed the presence of low levels of type i and type iii interferon genes together with elevated levels of proinflammatory cytokines and chemokines, such as il-6, il1ra, ccl2, ccl8 cxcl2, cxcl8, cxcl9, and cxcl16 [39] . which type of cells elicits this cytokine storm and the virological mechanisms behind this inflammatory reaction are still unclear [40] . lung epithelial cells, alveolar macrophages, dendritic cells, and endothelial cells can effectively release the proinflammatory cytokines and chemokines, thus attracting monocytes, macrophages, and t cells to the site of infection [41] . the overproduction of proinflammatory cytokines in the lungs can damage the tissue infrastructure, recruit macrophages that infiltrate air spaces, and generate the respiratory failure from acute respiratory distress syndrome (ards), which is recognized as the leading cause of mortality. meanwhile, the direct attack on other organs by disseminated sars-cov-2, the immune pathogenesis caused by the systemic cytokine storm, and the microcirculation dysfunctions together may lead to multi-organ damage, even though whether sars-cov-2 can directly target organs other than the lung and how it can happen are aspects that need to be further investigated [40] (fig. 2) . together with the hyperinflammatory response, a significant lymphopenia, mainly related to cd4+ t and cd8+ t cells, which correlates with the severity of viral infection, was reported [42] [43] [44] . the causes of this adaptive immunity suppression are still unclear. pulmonary recruitment of immune cells from the blood and the infiltration of lymphocytes into the airways may explain the reduction in blood. the wellsystemic and local (lung) immune responses and their pathological role, following sars-cov-2 entry into the host are schematically represented. induction of innate immune responses is a crucial step in the pathophysiology of covid-19 disease, contributing to hyperinflammation and tissue damage during the later stages of the disease. infiltration of immune cells in the lungs causes overproduction of proinflammatory cytokines, which eventually damages the lung infrastructure, accumulation of macrophages in the air spaces and diffuse alveolar damage leading to acute respiratory distress syndrome (ards). furthermore, elevated levels of circulating proinflammatory cytokines can cause septic shock and multi-organ dysfunction. together with the hyperinflammatory response, overt disseminated intravascular coagulation has been reported and a significant lymphopenia, mainly related to cd4+ t and cd8+ t cells, has been observed, possibly due to pulmonary recruitment of lymphocytes from the blood. a possible immunopathological role can be mediated by non-neutralizing antibodies produced by b cells, which may enhance sars-cov-2 infection through antibody-dependent enhancement (ade), further exacerbating organ damage known age-related alteration of the immune function of t cell and b cells could lead to insufficient control of viral replication, thus increasing the macrophage infiltration and the lung injury (fig. 2) . finally, a possible immunopathological role can be mediated by non-neutralizing antibodies produced by b cells that may enhance sars-cov-2 infection through antibodydependent enhancement (ade), further exacerbating organ damage. it has recently been shown that sars-cov-1 and the mers-cov take advantage of non-or subneutralizing antibodies and enter cells via surface cd32a receptors, an fc receptor expressed on the surfaces of monocytes and alveolar macrophages. the antibody-cd32 interaction facilitates viral entry and infection, and activates intracellular signaling to upregulate proinflammatory cytokines [45] . the complex and still unclear immunopathological mechanisms of sars-cov-2 infection, together with the progressive age-related decline of innate and adaptive immune responses, and the lack of a clear correlate of protection, make the design of vaccination strategies for older people extremely challenging (fig. 3 ). an emerging class of instruments in the aging research is the development of markers capable of assessing the speed of the aging process. age is a major risk factor for a high number of diseases, and in general, it affects the fitness of each individual, including the capability of responding to vaccine administration and counteracting a severe infection [46] . however, it is also evident that the elderly population is extremely heterogeneous, so while chronological age is useful to identify macroscopic risk classes, it is poorly informative within age classes to get individual information. biological age is thus useful to evaluate clinical parameters and health risks on the basis of the individual aging pace, which tend to be more heterogeneous in the elderly population. several established biological age markers have been generated based on both classical anthropometric, clinical, and biochemical parameters as well as on innovative molecular characterizations such as dna methylation and the composition of the n-glycan shell of circulating proteins [47] . such biomarkers have shown in a number of studies that the aging pace is higher in the vast majority of the different elderly conditions, thus demonstrating that biological age assessment should be a critical information in a broad spectrum of clinical practices and in the development of strategies to tackle healthcare burden and emergencies. the detailed description of available biological age markers is out of the scope of the present manuscript, and an extensive overview is available in the review by jylhävä et al. [46] . to date, biological age has not been assessed in the sars-cov-2 clinical setting, but it is noteworthy that biological age has been associated with all the most important risk factors related to a poor prognosis of sars-cov-2 infection. the field of elderly vaccination could benefit from biological age information, but also in this case, the available data are rare. in a study from gensous et al. [48] , the whole genome methylation profile of pbmc was assessed in a group of volunteers of different ages who underwent influenza vaccination. the relationship between the vaccination response and the methylation profile was studied. while no difference in terms of biological age emerged in the study, an agedependent epigenetic remodeling emerged in elder non-responders. the study is limited owing to the very low number schematic interconnection between the main immune mechanisms elicited by the vaccination process, with the peculiarity of the elderly immune system-affected by both inflammaging and immunosenescence-and the still undefined correlates of protection from sars-cov-2 infection. the complex and still unclear immunopathological mechanisms of sars-cov-2 infection, together with the progressive agerelated decline of innate and adaptive immune responses, and the lack of a clear correlate of protection make the design of vaccination strategies for older people extremely challenging of analyzed subjects but confirmed that dna methylation is an informative instrument to be exploited in vaccination studies and strategies. immunobiography refers to the comprehensive immunological, clinical, socio-economic, and geographical history of each individual, and accounts for the large heterogeneity observed in the elderly regarding their health status, mirrored by their large individual variation in the responsiveness to vaccines. a major advantage of immunobiography is that it incorporates the most advanced conceptualization of immunosenescence which, according to the most recent literature [49] , has to be considered as a context-and population-dependent phenomenon. accordingly, in order to be properly interpreted, agerelated changes of immune parameters occurring in an elderly person necessitate a variety of other additional data regarding sex/gender, demographic cohort, population/country, individual immunological history, anthropometric parameters, socioeconomic status and education, cmv serostatus, morbidity and co-morbidity, among others. it is of critical importance taking in consideration the elderly vulnerability to direct the rational design of vaccines designed for this target population. gender is a critical issue in both vaccination of the elderly and in the sars-cov-2 pandemic. the pandemic epidemiological data show clearly that the risk of severe disease and mortality is sharply higher in men than in women. men's hospitalization exceeds women by about 50%, indicating a significantly higher susceptibility of men towards severe sars-cov-2 infection. available data show that men outnumber women 2 to 4 times in terms of icu admissions [50] [51] [52] . these numbers are concordant with the fatality rate that ranges between 1.2 and 1.4 men deaths for one women death. moreover, this unbalanced pattern is mirrored by the vaccine uptake, responses, and outcome in older-aged individuals. elderly women are indeed more responsive than men for several vaccine protocols recommended in older-aged individuals such as those against influenza, tetanus, pertussis, shingles, and pneumococcal infections [53] . on the other hand, an influenza vaccination study reported that aged men antibodies had higher affinity than those produced by women. moreover, men seem to respond better to pneumococcal vaccination in two independent studies [54, 55] . there is an impaired vaccination response in both old men and women with sex-specific weaknesses. the most striking data, however, is related to infection and all-cause mortality: indeed, in a number of reports, vaccine administration produces a sharper decrease of specific and all-cause mortality in vaccinated women compared to men, indicating that women have higher benefit from vaccination in the elderly [56] [57] [58] . these data indicate the need to consider sex-specific vaccination protocols for the elderly population [58, 59] and that the lack of such instruments could be critical in the sars-cov-2 pandemic since old men are both the most susceptible to severe sars-cov-2 infection and are those less likely protected by a possible sars-cov-2 vaccine [60] [61] [62] . another factor that could affect vaccine response is the intestinal microbiota that plays a crucial rule in the regulation of the immune system and is highly affected by age [63] [64] [65] [66] . microbial community composition indeed is influenced by age, environmental and socio-economic factors, diet, gender, chronic infections, immunosuppressive chemotherapy, antibiotic treatment, or probiotic use [64, [67] [68] [69] . the improvement in the nucleic acid sequencing obtained in the last 15 years hits massively the microbiological research and promotes the analysis of heterogeneous microbiological ecosystems such as those that reside in humans. the characterization of such ecological niches opens to the new conceptualization of humans as metaorganisms (organisms composed of different organisms) to stress the tight interdependencies between the host and the microbiological species residing in different anatomical districts. gut microbiota changes with age and that is likely an important contributor and modulator of the inflammaging phenotype [70, 71] . elderly people have less diverse gut microbiota and reduced beneficial microorganisms [72] . the general imbalance of gut microbiota, called "dysbiosis," is associated with both frailty, a geriatric syndrome leading to increased vulnerability for adverse health outcomes, and systemic inflammation. since a hyperinflammation status has been observed in most severe cases of sars-cov-2 infection, it is possible that gut dysbiosis may influence the clinical manifestation in covid-19 infection [73, 74] . interestingly, the gut microbiota has been shown to also affect pulmonary health through a bidirectional cross-talk between the gut microbiota and the lungs [75] . along this "gutlung axis," microbial products can reach the lung through blood and modulate pulmonary immune responses [76] , while inflammation processes occurring in the lung can impact on the gut microbiota [77] . some studies have demonstrated that respiratory infections are associated with a change in the composition of the gut microbiota [78] and the antibiotic treatment of mice for removing some gut bacteria has led to increased susceptibility to influenza virus infection in the lungs [79] . since one of the severe clinical manifestations of covid-19 is pneumonia and progression to acute respiratory distress syndrome (ards), especially in elderly and immunecompromised patients [80] , it can be speculated that sars-cov-2 infection can affect this gut-lung cross-talk which might influence the outcome of the clinical manifestation [81] . moreover, even though respiratory symptoms represent the principal clinical presentation of covid-19, clinical evidence suggests that the intestine may be another viral target organ. indeed, a high expression of ace2 has been observed in the brush border of intestinal enterocytes [82] and, using a human small intestinal organoid system, it has been demonstrated that sars-cov-2 readily replicates into the enterocytes, resulting in the production of large amounts of infective virus particles [83] . some reports show that sars-cov-2 rna can be detected in the stool of some patients of covid-19 [84, 85] , and patients often present gastrointestinal symptoms such as diarrhea, vomiting, and abdominal pain [86] . therefore, the characterization of the gut microbiota in patients with active sars-cov-2 intestinal infection could represent a striking aspect to investigate. these considerations on inflammaging, immunobiography, biological age, gender, and microbiota pertain to every vaccination strategy, but are particularly relevant for the development of vaccines against sars-cov-2 since it more seriously affects the elderly population and immunopathology is a crucial factor for the severity disease. need for the design of a sars-cov-2 vaccination strategies tailored for the elderly sars-cov-2 vaccines are urgently needed, and their design should take into consideration that the elderly population is the main target population for vaccination. while older adults are most likely to be severely affected by covid-19, they also may be less responsive to vaccination. efficacy of vaccination in the elderly is indeed strongly reduced compared to that of younger adults [87, 88] . sars-cov-2 vaccination strategies, tailored for the elderly, should take into consideration the delicate balance between immunosenescence/ inflammaging and the immunopathological aspects of the covid-19 disease (fig. 3) . vaccine adjuvants and vectors should be specifically designed for stimulating the elderly immune system without exacerbating the inflammatory status [87] . despite these considerations, the elderly are rarely included in vaccine clinical trials; in the last decades, the vast majority of randomized control trials did not include older adults and in particular frail older adults who are mostly at risk. we currently do not have full knowledge on the mechanisms of immunity to protect this population from sars-cov-2 [10] . the development of a sars-cov-2 vaccine is extremely challenging, since we are faced with a novel virus, just emerged in humans, and correlates of protection have not yet been fully identified, even though the induction of neutralizing antibodies is presumed to be a crucial target for an effective vaccination (fig. 3) . protection in older individuals against influenza virus appears to require higher neutralization titers than in younger individuals [89] , and this issue might need to be addressed for sars-cov-2. the knowledge obtained from the vaccine development efforts for mers and sars-cov-1 can be of high value for sars-cov-2, although no vaccines are licensed for these coronavirus strains [90] . memory cd4+ t cells, induced by infections with other coronavirus and capable of responding to sars-cov-2, have been detected in 20-50% of sars-cov-2 unexposed donors [91, 92] . the characterization of these cross-reactive t cells in the elderly and their impact on the immunogenicity of vaccine candidates should be taken into consideration in the ongoing covid-19 vaccination studies. sars-cov-2 vaccine candidates based on different vaccine platforms have been developed, and about 140 candidates have been tested in pre-clinical experiments, according to the who landscape documents of covid-19 candidate vaccines (https://www.who.int/publications/m/ item/draft-landscape-of-covid-19-candidate-vaccines) (fig. 4) . information on the specific sars-cov-2 molecules selected as vaccine antigens is limited, even though most candidates aim to elicit neutralizing antibodies against the spike (s) protein and its receptor-binding domain (rbd), as already performed with the sars and mers vaccines. a wide range of both innovative and traditional technology platforms has been deployed, including nucleic acid (dna and rna), recombinant viral vectors (replicating and non-replicating), recombinant protein combined with adjuvants, and live attenuated or inactivated virus [93] . some of these platforms were already tested in human studies for sars-cov-1 virus, such as inactivated virus, dna and soluble s proteins [94] [95] [96] , or for mers-cov [97] . the most advanced candidates for sars-cov-2 entered in human clinical testing with unprecedented rapidity employ nucleic acid (both mrna and dna), recombinant vaccine vectors (human or chimpanzee adenovirus vectors), subunit s protein combined or not with different adjuvants, and inactivated sars-cov-2 virus. other novel platforms based on the use of synthetic modified antigen presenting cells (apc) or cytotoxic t lymphocytes are also under study (fig. 4) . the platforms using mrna, nonreplicating viral vectors, and inactivated sars-cov-2 virus have already reached the clinical trial phase iii. some of the different platforms used may be tailored for specific population subtypes, such as the elderly, children, pregnant women, or immunocompromised patients [98] . in this regard, some of the ongoing clinical studies have specifically taken into consideration the older population, by including vaccination arms with people aged > 60 years. a schematic diagram of the ongoing phase i and ii clinical trials that have included older adults is reported in fig. 5 . enrolling older adult volunteers will help to better understand vaccination outcomes among the older population, who are most at risk of complications from covid-19. the ongoing clinical studies based on mrna technology (mrna-1273 from moderna n. nct04283461, and bnt162 from biontech se, n. nct04368728) aim to evaluate the safety, tolerability, immunogenicity, and potential efficacy of different sars-cov-2 rna vaccine candidates in the adult population, with a specific attention to older people (n.-n. releases. nih clinical trial of investigational vaccine for covid-19 begins. 2020. https://www.nih.gov/newsevents/news-releases/nih-clinical-trial-investigationalvaccine-covid-19-begins). the lipid nanoparticleencapsulated mrna-1273 vaccine, which encodes for the full-length s protein, is currently evaluated in a dose-ranging study in the adult population (18-55 years old), and in participants from 56 to 70 and > 71 years of age (fig. 5) . similarly, the large dose-finding study with the bnt162 biological component (7600 estimated participants) based on the administration of mrna coding for the full-length s protein, or for the two smaller receptor-binding domains, is going to test the immunogenicity in adults (18-55 years) and older adults (56-85 years) . an ongoing phase i/iia trial (n. nct04447781) is also aimed at evaluating the safety, tolerability, and immunological profile of the ino-4800 vaccine that, exploiting the dna technology, contains a plasmid encoding the full-length s glycoprotein. the ino-4800 vaccine is administered by intradermal injection followed by electroporation in healthy adults aged 19 to 64 years. another platform that is currently specifically tested in older people is based on the adenovirus type 5 vector that encodes the s protein from the sars-cov-2 strain (trials n. 2020-001228-32; pactr202006922165132; nct0439814; chictr2000031781 and nct04400838; fig. 5 ). different studies are ongoing, and one conducted in canada is a doseescalation designed study, from the younger adults (18 to < 55) to the older adults (65 to < 85). another huge phase 2/3 study (n. nct04400838) is aimed at determining the efficacy, safety, and immunogenicity of the candidate covid-19 vaccine based on the chimpanzee adenovirus vector (chadox1 ncov-19) in healthy uk volunteers, specifically divided in adults (18-55 years old), elderly (over the age of 56), and children (5-12 years old). the chadox1 platform has already been shown to be effective in the established rhesus macaque model of sars-cov-2 infection [99] . in this pre-clinical study, a single dose of chadox1 ncov-19 has protected six [100] . moreover, the chadox1 has been used to develop investigational vaccines against several pathogens, including the closely related coronavirus responsible for the mers [101] . adenovirus-based vectors are characterized by a broad range of tissue tropism that covers both respiratory and gastrointestinal epithelium, the two main sites that express the ace-2 receptor of sars-cov-2, even though a possible immunodominance mediated by vector genes rather than the transgenes should always be considered [102] . using the traditional recombinant protein technology to express the spike protein, a trial sponsored by clover biopharmaceuticals aus pty ltd. (n. nct04405908) is assessing the safety, reactogenicity, and immunogenicity of multiple doses of scb-2019 administered with as03 adjuvant, or with cpg 1018 plus alum adjuvants. data will be separately analyzed on adult (18 to 54 years of age) and elderly (55-75 years of age) healthy subjects enrolled in the study. in another study, the s protein has been administered with the advax adjuvant (n. nct04453852), a potent and safe immunopotentiator composed of delta inulin [103] . four trials are testing in the elderly population the inactivated sars-cov-2 virus (n. nct04456595; chictr2000031809; chictr2000032459), and one of these has been specifically performed only in people > 60 years (n nct04383574; fig. 5 ). numerous other vaccine developers have indicated plans to initiate human testing in 2020. despite the several vaccine candidates (fig. 4) , challenges including the need for optimizing antigen design and adjuvant formulation define the number of doses needed, induce the optimal immune response without exacerbating the inflammatory and antibody-dependent response involved in possible lung disease, and fully define correlates of protection and duration of immune responses have to be considered [104] . finally, a general consideration for the sars-cov-2 vaccine development regards safety issues that could arise with covid-19 vaccines developed under the strong pressure of the pandemic situation. animal studies on vaccines for sars-cov-1 and mers-cov report possible adverse effects mediated by vaccine-induced antibodies that have poor or no neutralizing activity [105] . safety and efficacy are two indissoluble properties of a vaccine to be administered to billions of people globally and need to be accurately evaluated for every sars-cov-2 candidate. the efforts in the development of covid-19 vaccines can benefit from the availability of most advanced tools and high-throughput technologies to decipher the effective immune responses in the older population and the correlates of protection. recent advances in systems biology integrating clinical, immunologic, and omics data can help to identify stable and robust markers of vaccine response and move towards a better understanding of sars-cov-2 vaccine responses in the elderly. machine/statistical learning applied to multi-omics data from clinical studies promises to revolutionize vaccine development by illuminating the mechanistic drivers of protective immunity. the high-performance data acquisition methods in molecular and cellular biology push the field of bioinformatics for the development and use application of the immunobiography approach could inform the stratification of elderly subjects and guide the implementation of vaccination strategies designed for specific elderly population clusters [87] . mathematical modeling allows the combination of different networks involved in biological aging such as epigenetic networks, cell-cell networks, and population genetics and can allow to generate hypothesis on response to treatment or vaccination [106] . recent progress in mathematical modeling can be utilized to generate biomarker models for prediction of disease and also response to vaccination taking into consideration biological age. currently, computational models have been applied to immunology data, for example, for the analysis of a high-dimensional dataset in vaccination studies [107, 108] , but these models are limited to particular aspects [109, 110] . there is the potential for these models to become more sophisticated and to predict how responses to pathogens and vaccines are affected by pre-disposing factors [111, 112] . the systems vaccinology approach has been applied to characterize the immune response to different vaccines providing the proof-of-concept evidence of the capacity of systems approaches to delineate "molecular signatures" predictive of vaccine responses [113] [114] [115] [116] [117] [118] [119] [120] [121] [122] [123] [124] [125] [126] [127] [128] [129] [130] [131] . this approach has also been applied to identify molecular signatures induced by immunization with the rvsv-zebov ebola vaccine, recently approved for human use. systems analysis has been conducted integrating clinical, immunologic, and omics data in clinical trials with different doses and in different continents (vianello et al. 2020 submitted, santoro et al. 2020 submitted). despite the great efforts made, unfortunately, many of the most useful clinical and multi-omics datasets are siloed in local databases to protect participant privacy and data confidentiality. creation of secure, faircompliant, federated learning databases in which predictive biological and mathematical models based on ai/ machine/statistical learning can be developed, refined, and tested on distributed datasets would have an enormous impact in supporting a rational vaccine development. sars-cov-2 vaccines are urgently needed, and their design should take into consideration that the elderly are the main target population for vaccination. the pandemic is stimulating the research on vaccine development, and this should be a tremendous opportunity to specifically include age and gender as critical factors for vaccination approaches and effectiveness. while older adults are most likely to be severely affected by covid-19, they also may be less responsive to vaccination. in the ongoing tremendous efforts for covid-19 vaccine development, only a limited number of clinical trials have included the older fraction of the population in the study design, and the platforms used are not specifically designed considering the peculiarity of the elderly immune system. indeed, vaccination strategies tailored for the sars-cov-2 infection in the elderly should take into consideration the delicate balance of immunosenescence and inflammaging with the immunopathological aspects of the sars-cov-2 infection, such as the cytokine storm reported in severe covid-19. therefore, the possible overlap between the factors hampering vaccination effectiveness in the elderly and those that boost the virulence and worsen the prognosis of sars-cov-2 infection should be carefully taken into consideration. thus, vaccine formulations, such as adjuvants and vectors, should be specifically designed for stimulating the elderly immune system without exacerbating the inflammatory status. the ongoing efforts in covid-19 vaccine development should fully exploit the availability of high-throughput technologies and recent advances in systems biology to decipher the effective immune responses in the older population and identify correlates of protection to guide towards sars-cov-2 vaccine strategies optimally designed to protect the older population. authors' contributions ac, pg, and dm, fs drafted the work; dm, rr, and cf revised it critically for important intellectual content; all the authors approved the version to be published. funding open access funding provided by università degli studi di siena within the crui-care agreement. this work was supported by commission of the european communities, horizon 2020 framework programme, grant number 730964 (transvac2), and russian ministry of science and education agreement no. 075-15-2020-808. conflict of interest the authors declare that they have no conflict of interest. consent for publication the authors are responsible for the correctness of the statements provided in the manuscript. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. estimates of the severity of coronavirus disease 2019: a model-based analysis sex differences in immune responses sexx matters in infectious disease pathogenesis covid-19 with different severities: a multicenter study of clinical features risk and predictors of in-hospital mortality from covid-19 in patients with diabetes and cardiovascular disease predictive symptoms and comorbidities for severe covid-19 and intensive care unit admission: a systematic review and meta-analysis. public health opensafely: factors associated with covid-19 death in 17 million patients inflamm-aging. an evolutionary perspective on immunosenescence covid-19 cytokine storm: the interplay between inflammation and coagulation covid-19 and immunity in aging populations -a new research agenda immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front immunol age-related changes of human bone marrow: a histometric estimation of proliferative cells, apoptotic cells, t cells, b cells and macrophages immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity senescence of t lymphocytes: implications for enhancing human immunity ageing, autoimmunity and arthritis: senescence of the b cell compartment -implications for humoral immunity the th17/treg balance is disturbed during aging shortage of circulating naive cd8(+) t cells provides new insights on immunodeficiency in aging successful and maladaptive t cell aging contributions of age-related thymic involution to immunosenescence and inflammaging age-related modifications of the human alphabeta t cell repertoire due to different clonal expansions in the cd4+ and cd8+ subsets inflamm-aging of hematopoiesis, hematopoietic stem cells, and the bone marrow microenvironment age-related changes in lymphocyte development and function mechanisms underlying t cell immunosenescence: aging and cytomegalovirus infection different contribution of ebv and cmv infections in very long-term carriers to agerelated alterations of cd8+ t cells human t cell immunosenescence and inflammation in aging 2020) t cells, aging and senescence ribose 2'-o-methylation provides a molecular signature for the distinction of self and non-semin immunopathol self mrna dependent on the rna sensor mda5 coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of sting-mediated signaling dengue virus activates cgas through the release of mitochondrial dna immune responses in covid-19 and potential vaccines: lessons learned from sars and mers epidemic. asian pac ifn-i response timing relative to virus replication determines mers coronavirus infection outcomes early upregulation of acute respiratory distress syndrome-associated cytokines promotes lethal disease in an aged-mouse model of severe acute respiratory syndrome coronavirus infection an interferon-gamma-related cytokine storm in sars patients trained immunity: a tool for reducing susceptibility to and the severity of sars-cov-2 infection clinical features of patients infected with 2019 novel coronavirus in an outbreak of severe kawasaki-like disease at the italian epicentre of the sars-cov-2 epidemic: an observational cohort study classification of the cutaneous manifestations of covid-19: a rapid prospective nationwide consensus study in spain with 375 cases exacerbated innate host response to sars-cov in aged nonhuman primates imbalanced host response to sars-cov-2 drives development of covid-19 sars-cov-2 and viral sepsis: observations and hypotheses the trinity of covid-19: immunity, inflammation and intervention clinical and pathological investigation of patients with severe covid-19 longitudinal characteristics of lymphocyte responses and cytokine profiles in the peripheral blood of sars-cov-2 infected patients hematological findings in coronavirus disease 2019: indications of progression of disease the potential danger of suboptimal antibody responses in covid-19 biological age predictors the continuum of aging and age-related diseases: common mechanisms but different rates responders and non-responders to influenza vaccination: a dna methylation approach on blood cells does the human immune system ever really become "senescent baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region baseline characteristics and outcomes of patients with covid-19 admitted to intensive care units in vancouver, canada: a case series presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area sex and gender impact immune responses to vaccines among the elderly persistence of antibody response to pneumococcal capsular polysaccharides in vaccinated long term-care residents in brazil the immunogenicity of 7-valent pneumococcal conjugate vaccine versus 23-valent polysaccharide vaccine in adults aged 50-80 years study of the effectiveness of influenza vaccination in the elderly in the epidemic of 1989-90 using a general practice database effectiveness of influenza vaccine in the community-dwelling elderly effect of influenza vaccine status on winter mortality in spanish community-dwelling elderly people during 2002-2005 influenza periods efficacy and costeffectiveness of influenza vaccination of the elderly in a densely populated and unvaccinated community systems analysis of sex differences reveals an immunosuppressive role for testosterone in the response to influenza vaccination a single dose of unadjuvanted novel 2009 h1n1 vaccine is immunogenic and well tolerated in young and elderly adults immune response following h1n1pdm09 vaccination: differences in antibody repertoire and avidity in young adults and elderly populations stratified by age and gender role of the microbiota in the modulation of vaccine immune responses the influence of the intestinal microbiome on vaccine responses antibiotics-driven gut microbiome perturbation alters immunity to vaccines in humans the impact of the microbiome on immunity to vaccination in humans the impact of diet and lifestyle on gut microbiota and human health antibiotic-induced changes in the intestinal microbiota and disease the microgenderome revealed: sex differences in bidirectional interactions between the microbiota, hormones, immunity and disease susceptibility inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty inflammaging: a new immune-metabolic viewpoint for agerelated diseases gut microbiome and aging: physiological and mechanistic insights diet, microbiota and gut-lung connection. front. microbiol 9 frailty syndrome: an overview pulmonary-intestinal cross-talk in mucosal inflammatory disease gut microbiota metabolism of dietary fiber influences allergic airway disease and hematopoiesis the role of the lung microbiota and the gut-lung axis in respiratory infectious diseases respiratory viral infection alters the gut microbiota by inducing inappetence collateral effects of antibiotics on mammalian gut microbiomes what we know so far: covid-19 current clinical knowledge and research gut microbiota and covid-19-possible link and implications single cell rna sequencing of 13 human tissues identify cell types and receptors of human coronaviruses sars-cov-2 productively infects human gut enterocytes prolonged presence of sars-cov-2 viral rna in faecal samples gastrointestinal manifestations of sars-cov-2 infection and virus load in fecal samples from a hong kong cohort: systematic review and metaanalysis covid-19: gastrointestinal manifestations and potential fecal-oral transmission vaccination in the elderly: the challenge of immune changes with aging efficacy and effectiveness of influenza vaccines: a systematic review and meta-analysis hemagglutination inhibition antibody titers as a correlate of protection against seasonal a/h3n2 influenza disease vaccines for sars-cov-2: lessons from other coronavirus strains selective and cross-reactive sars-cov-2 t cell epitopes in unexposed humans sars-cov-2-specific t cell immunity in cases of covid-19 and sars, and uninfected controls sars-cov-2 vaccines: status report safety and immunogenicity from a phase i trial of inactivated severe acute respiratory syndrome coronavirus vaccine vrc 301 study team, a sars dna vaccine induces neutralizing antibody and cellular immune responses in healthy adults in a phase i clinical trial nih clinical trial of investigational vaccine for covid-19 begins safety and immunogenicity of an anti-middle east respiratory syndrome coronavirus dna vaccine: a phase 1, open-label, single-arm, dose-escalation trial the covid-19 vaccine development landscape ) respiratory disease in rhesus macaques inoculated with sars-cov-2 chadox1 ncov-19 vaccination prevents sars-cov-2 pneumonia in rhesus macaques recent advances in the vaccine development against middle east respiratory syndrome-coronavirus a review of sars-cov-2 and the ongoing clinical trials advax adjuvant: a potent and safe immunopotentiator composed of delta inulin developing covid-19 vaccines at pandemic speed immunopathogenesis of coronavirus infections: implications for sars the human body as a super network: digital methods to analyze the propagation of aging. front from bivariate to multivariate analysis of cytometric data: overview of computational methods and their application in vaccination studies. vaccines computational analysis of multiparametric flow cytometric data to dissect b cell subsets in vaccine studies a perspective on the role of computational models in immunology computational modelling approaches to vaccinology sensitive detection of rare diseaseassociated cell subsets via representation learning multivariate models for prediction of human skin sensitization hazard systems biology approach predicts immunogenicity of the yellow fever vaccine in humans yellow fever vaccine induces integrated multilineage and polyfunctional immune responses systems biology of immunity to mf59-adjuvanted versus nonadjuvanted trivalent seasonal influenza vaccines in early childhood early patterns of gene expression correlate with the humoral immune response to influenza vaccination in humans apoptosis and other immune biomarkers predict influenza vaccine responsiveness systems analysis of immunity to influenza vaccination across multiple years and in diverse populations reveals shared molecular signatures molecular signatures of antibody responses derived from a systems biology study of five human vaccines metabolic phenotypes of response to vaccination in humans defective t memory cell differentiation after varicella zoster vaccination in older individuals predicting rts,s vaccine-mediated protection from transcriptomes in a malaria-challenge clinical trial systems analysis of protective immune responses to rts,s malaria vaccination in humans expression of genes associated with immunoproteasome processing of major histocompatibility complex peptides is indicative of protection with adjuvanted rts,s malaria vaccine integrated analysis of genetic and proteomic data identifies biomarkers associated with adverse events following smallpox vaccination immunomonitoring of human responses to the rvsv-zebov ebola vaccine ebola vaccine r&d: filling the knowledge gaps correlates of vaccineinduced protective immunity against ebola virus disease systems vaccinology identifies an early innate immune signature as a correlate of antibody responses to the ebola vaccine rvsv-zebov merck ad5/hiv induces broad innate immune activation that predicts cd8+ t-cell responses but is attenuated by preexisting ad5 immunity a cell-based systems biology assessment of human blood to monitor immune responses after influenza vaccination publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-344713-jisp238l authors: meyers, keith; thomasson, melissa a. title: can pandemics affect educational attainment? evidence from the polio epidemic of 1916 date: 2020-07-27 journal: cliometrica (berl) doi: 10.1007/s11698-020-00212-3 sha: doc_id: 344713 cord_uid: jisp238l we leverage the largest polio outbreak in us history, the 1916 polio epidemic, to study how epidemic-related school interruptions affect educational attainment. using polio morbidity as a proxy for epidemic exposure, we find that children aged 10 and under, and school-aged children of legal working age with greater exposure to the epidemic experienced reduced educational attainment compared to their slightly older peers. these reductions in observed educational attainment persist even after accounting for the influenza epidemic of 1918. the global covid-19 pandemic in early 2020 led to severe disruptions in nearly all aspects of life. stay-at-home orders closed schools and non-essential businesses, generating widespread unemployment and large declines in economic activity that cannot yet be fully assessed. the social and economic costs of this crisis have been widely felt. a united nations report suggests that global gdp could decline by 1% (united nations 2020), while the managing director of the international monetary fund stated that she anticipates that the pandemic will generate "...the worst economic fallout since the great depression," with global gdp contracting by 3% (gopinath 2020) . according to unesco, over 1.5 billion students, almost 90% of all learners, have had their schooling disrupted by this crisis. at least 189 countries have closed schools in response to the covid-19 threat, which may interrupt human capital accumulation in children and contributes to the social costs of the pandemic (unesco 2020). 1 while most people alive today have never witnessed this scale of the pandemic, research on other epidemics may provide insights into the possible magnitude of the disruption. 2 in this paper, we examine the 1916 polio epidemic to measure how it impacted the educational attainment of children during the outbreak. the 1916 epidemic is unique in that it was the first and largest major polio epidemic in the usa and was one of the first major public health crises many nascent public health departments faced. 3 the 1916 epidemic proved to be the first of many outbreaks that would continue until the advent of the salk vaccine in 1954, although trevelyan et al. (2005) suggest that the 1916 epidemic was more intense than subsequent outbreaks. 4 while smaller in magnitude than the more famous 1918-1919 spanish flu, the polio epidemic started in new york city and new jersey, but then spread across the usa, resulting in mass quarantines and prolonged school closures at the start of the 1916-1917 academic school year. the polio epidemic may have affected educational attainment in two ways. first, infected children may have missed school during the period of their illness and recovery. second, even children who did not have symptoms missed school during periods of closure or because their parents refused to send them to school. thus, we leverage geographic variation in the severity of the epidemic, as well as the fact that polio differentially affected children of different ages, to measure how the disease affected the educational attainment reported by these children as adults in the 1940 census. children living in areas with high polio morbidity were more likely to be infected and more likely to endure school closures than children in less-affected areas. children under 10 were more susceptible to polio, yet children aged 14 and older may have been more likely to quit school during a prolonged closure and join the labor force. 1 during the ebola outbreak, five million children in africa faced school closures (sifferlin 2014) . schools in sierra leone were closed for nine months, and schools in guinea and liberia were closed for six months (sifferlin 2014; paye-layleh 2015) . in nigeria, schools that were supposed to open in august remained closed until october (bbc news 2014). 2 studies examining the impact of the 2003 sars outbreak on the chinese economy show that it resulted in temporary negative shocks to tourism, retail sales and personal consumption, as well as a 0.5% reduction in gdp (siu and wong 2004; hanna and huang 2004) . more recent studies of the impact of ebola on the countries of guinea, liberia and sierra leone suggest that "aversion behavior"-the actions taken by people to avoid illness, and the actions taken by investors as they anticipate these behaviors-led to a loss of $1.6 billion in 2015, or about 12% of their combined gdp (thomas et al. 2015) . 3 prior to 1916, most of the us population had limited experience with the poliovirus. while minor and relatively isolated outbreaks occurred previously in the usa, the 1916 outbreak affected more than three times the number of people relative to previous years. in 1916, 28.5 cases of polio were reported per 100,000 people, compared to the 1909-1915 rate of 7.9 per 100,000 population (paul 1971; nathanson and kew 2010) . 4 the 1916 outbreak had greater rates of morbidity than later epidemics, and there is evidence that the 1916 epidemic may also have been under-reported (nathanson and kew 2010). our results show that children born in states with more reported polio cases had lower educational attainment compared to slightly older birth cohorts who would have already completed schooling before the 1916-1917 school year and that the decline in educational attainment varied depending on their age during the outbreak. we find that a one-standard-deviation increase in polio intensity reduced years of completed schooling by 0.07 years for children between the ages of 14 and 17 in 1916. for children who were 10 and under during the epidemic (and who were most susceptible to polio), a one-standard-deviation increase led to a 0.1 year reduction in years of completed education. these results are robust to controlling for 1918-1919 influenza intensity. polio is caused by the poliovirus, an enterovirus transmitted fecal-orally. evidence on egyptian stele (depicting an adult with a withered leg and crutch) dating from 1580-1350 bc suggests that polio has existed for thousands of years (nathanson and kew 2010) . although the existence of polio dates to antiquity, it was not until the late 19th century that epidemics began occurring in the usa and europe. the most plausible explanation for this pattern is that before the late 19th and early twentieth centuries, most people were probably exposed to polio during infancy when infants had circulating maternal antibodies that made the infection much less severe. over the next 100 years, improved public sanitation delayed exposure to the virus, thus increasing both the age of primary infection and the severity of the illness, since maternal antibodies were no longer circulating. as a result, epidemics that became increasingly severe were reported each summer and fall, and the average age of persons infected increased (nathanson and kew 2010; centers for disease control and prevention 2015) . 5 in 1916, there were over 5000 deaths and 23,000 more documented infections, numbers that eclipsed those of previous (and subsequent) epidemics (lavinder et al. 1918; trevelyan et al. 2005) . table 1 details the number of reported polio cases and deaths by state during the epidemic. nearly every state reported polio cases, with massachusetts, new york, new jersey, and connecticut reporting the highest numbers of reported polio infections. while much of the epidemic was in the northeastern usa, there were also sizable outbreaks in minnesota, montana and mississippi. it is important to note that while cities may be more heavily impacted by modern epidemics, polio was unusual in that it was precisely better hygiene that predisposed victims to a later, and more severe, onset. in places with poor sanitation, children would have been exposed at much younger ages (often infancy, without obvious symptoms) and be less likely to suffer a severe case. while many cities had improved sewer and sanitation (thus leading to the large flare of the epidemic in 1916), rural areas had traditionally been "healthier" places to live from a sanitation standpoint. lavinder et al. (1918) note that the epidemic was more prevalent and intense in small towns and the country than in large cities, and "...not due to mere chance but to some fundamental law" (p. 19). the outbreak generated substantial fear. commonly known as "infantile paralysis," polio often caused mild (or no) symptoms but could attack the nervous system and cause permanent paralysis. little was known about how the disease was spread, and no vaccine for polio would be available for another forty years. the disease transcended class lines and affected the poor and the rich alike. in new york city, for example, a large share of cases occurred among native-born children living in single-family dwellings with clean surroundings and indoor toilets (lavinder et al. 1918). 6 3 actions taken to curb the spread of polio public health officials struggled to contain the outbreak, which began in june and lasted until november. as the disease spread, officials became increasingly desperate. to prevent the spread of the epidemic and allay public fear, officials implemented various non-pharmaceutical interventions, such as strict quarantines. placards were also placed in front of homes of infected individuals to notify the community of the public health risk. in at least one case, a child suffering from polio was forcibly removed from his home to a hospital, against the wishes of his parents (emerson 1917) . in new york city, children ages 16 and under were prohibited from leaving new york city for travel unless they produced "... a certificate that the premises occupied by them were free from poliomyelitis, and had been free from this disease since january 1, 1916." this was supplemented by a medical examination of such travelers at the point of departure (emerson 1917) . in new york city and philadelphia, health officials ordered the city streets to be washed with millions of gallons of water each day (offit 2005; rogers 1992) . 7 government policy also called for a ban on public gatherings in areas where numerous cases were reported (emerson 1917) . in the summer of 1916, new york public health officials barred children from movie theaters and libraries, closed sunday schools and banned picnics (the new york times 1916c, e; rogers 1992) . fears that domesticated animals could spread the disease led to the extermination of 72,000 cats and 8000 dogs (the new york times 1916b). even though drastic measures were undertaken to control the spread of the disease, hundreds of new infections were reported every week. as autumn approached, fears that afflicted youths would infect their peers and a belief that quarantines could limit the virus' spread led many school districts to delay the start of the 1916 school year until the epidemic waned. as the new york department of health noted, "the unprecedented virulence and extent of the existing epidemic, and unfamiliarity with the disease, has engendered in the public such a state of mind that concession to public alarm seemed advisable" (emerson 1917) . the extent and nature of these closures varied across political and geographic divisions of the usa due to the decentralized structure of the nation's public health (the new york times 1916d) . newspaper accounts show numerous other cities nationwide joined new york in postponing the start of school. philadelphia delayed opening schools until september 18th (and then to october 2nd), and both washington, d.c., and fort wayne schools were not reopened until october 2nd (the washington times company 1916; evening public ledger 1916a, b) . schools closed across the nation even in states with small numbers of cases. for example, some schools closed in seattle, with only five cases reported (the tacoma times 1916) . but, even when schools may not have been officially closed, there is evidence that parents worried about sending their children to school. 9 for example, even after the delayed reopening in new york city, worried parents withheld their children from school; up to 200,000 students were absent the first few weeks after schools opened, and the district announced "leniency" for parents who failed to send their children to school (the new york times 1916a). to gain insight into the extent of school closures nationally and when they occurred, we searched newspaper records contained in the chronicling america newspaper archive (library of congress 2020). cities in the most heavily affected areas are most frequently mentioned, but newspaper accounts demonstrate that school closures tended to occur wherever an area experienced a breakout of polio. the epidemic started in june, accelerated in july and persisted through the start of the academic school year. these data most likely represent a subset of school closures, since not all newspapers are covered in the library of congress archive. moreover, our search procedure may have failed to reveal all closures. 10 many newspapers referred to school closures in different cities, or even in major cities in other states. although we found some articles in which a city expressly stated schools would remain open (including chicago, detroit and milwaukee), for most cities we could not ascertain with certainty that they did not close. in fig. 1 , we plot the frequency of school delay announcements in the chronicling america newspaper archive for all newspapers from july 1, 1916, to november 1, 10 the search used the entire chronicling america newspaper archive for the usa during the active epidemic. the search required either the word(s) "polio" or "poliomyelitis" or "infantile" or "paralysis" to be referenced on the same page as the words of "school" and "postpone". we allowed the words "school" and "postpone" to be within five words of each other. many articles even referred to the disease as the "baby plague" or "plague". searches for "school closures" also yielded similar results, but with a flatter distribution and wider tails because they often referred to sunday school closures. 1916. school postponement notifications in us newspapers began to increase in the weeks preceding the start of the academic school year (normally around september 5 or september 11), peaked during the two first weeks of september and gradually decreased until the first week of october. the latest public school start date we observe in the chronicling america newspaper archive (library of congress 2020) was october 2, 1916, although some new england preparatory schools advertised that they postponed their start dates into the middle of october. the newspaper articles also reveal that the persistence of the epidemic caused public health officials and school boards to repeatedly push back school start dates. washington, dc initially planned to start on time, then pushed back the start two weeks to september 25, and then finally postponed until october 2. boston, ma did the same. the entire state of pennsylvania also postponed school starts multiple times until the first week of october. to dig deeper into the relationship between city-level school closures and polio outbreaks, we further searched for announcements of school closures in 161 cities for which we have polio morbidity data digitized by van panhuis et al. (2018) . these were cities that voluntarily participated in the disease reporting system conducted by the us public health service, which published this information in its weekly bulletins. we were able to find newspaper accounts of school postponement for 38 of these cities. 11 table 10 in the appendix provides more detailed information on the city names, the dates of postponement, and the name of the newspaper in which we found the information. of these 38 cities, 84% opened over 2 weeks late, with 60.5% opening on october 2, 1916. only three (chicago, detroit, and milwaukee) opened on time. figure 2 presents the relationship between weekly polio morbidity in these 38 cities and the timing of school postponements using data from project tycho. 12 we highlight the relationship between the epidemic timing and school postponement by separating this information by the timing of the school starts: schools that started on time, schools that delayed their start dates to a later date in september, and schools that delayed school starts into october. a mass of polio outbreaks in august and september coincided with delayed school starts in many affected cities. polio outbreaks continued in these cities throughout october, and the epidemic ended in november. in fig. 3 , we focus in on a subset of the reported data for cases under 100 per week. for many cities with schools that opened in october there large numbers of reported weekly polio cases throughout september and well into october. schools that postponed only a few weeks into september generally had fewer reported cases of acute polio than either the schools that started in october. in the few schools that we confirmed opened on time, most city week observations report low numbers of polio infections. the exception to this pattern is the city of chicago, which opened schools on time even while polio still spread throughout the community. there is a broad and well-documented literature in economics and in economic history about the impact of early childhood health and economic shocks on later life outcomes (almond et al. 2018) . within this literature, there are a number of papers that demonstrate the long-run consequences of infectious disease shocks in childhood. beach et al. (2016) show that reduced early-life exposure to typhoid improved later life educational attainment, perhaps by improving cognitive functioning. 13 bhalotra and venkataramani (2013) also find that reduced infant exposure to waterborne disease is associated with improved test scores for girls and improved heights for boys. there is also evidence that individuals who do not contract infectious diseases during epidemics can also be affected. for example, parman (2015) examines the impact of the 1918 influenza pandemic on the siblings of those children born during the outbreak and finds that older siblings received an additional three months of education, while younger siblings received slightly less education relative to children who did not have a sibling born during the pandemic. to our knowledge, no one has examined the case of polio in the usa, which is unique in that educational attainment may have been affected even despite the fact that relatively small numbers of people contracted polio. the polio epidemic may have reduced educational attainment through two channels. children who contracted the disease may have missed school while ill, thus reducing educational attainment, although this might depend on whether they contracted a mild form of the disease or paralytic polio. gensowski et al. (2019) find that children who contracted paralytic polio in denmark in 1952 were more likely to earn a university degree than children who did not, suggesting that these children shifted investment into education as their comparative advantage moved from jobs requiring certain physical abilities to those requiring more cognitive skills. other children may have experienced reduced educational attainment if they missed school for short periods of time due to school closures or avoidance, or if they delayed entry into formal schooling (for example if the parents of a wouldbe kindergartner decided to wait until the fall of 1917 to send the child to school). younger children who have their schooling disrupted even for short periods of time may suffer negative effects. for example, marcotte and hemelt (2008) find that unscheduled school closings due to weather negatively affect student performance on third-grade state assessment examinations. middle-grade students may have lower educational attainment if their learning is disrupted during key periods of development (lloyd 1978; hernandez 2011) . whether these effects persist in the long run is less clear. card and krueger (1992) find that men educated in states with higher-quality schools (measured by term length, student-teacher ratio and teacher wage) have higher returns from their schooling. pischke (2007) uses data from a german school district that had a one-time shortening of the school year and finds that the short school year had no negative effect on earnings and employment later in life, although it did lead to more students repeating a grade and fewer students entering higher secondary school tracks. other research does suggest that interruptions in schooling at crucial points of development may have long-run impacts. hernandez (2011) suggests that children in third-grade experience a pedagogical shift from "learning to read" toward "reading to learn." a failure to develop this proficiency in reading on time appears to inhibit human capital accumulation of students and limits the potential to keep pace with their peers. lloyd (1978) suggests that students who perform at a lower level than their peers may be more likely to drop out of school, with third-grade academic performance accurately predicting whether an individual would drop out of school nearly 70% of the time. 14 in addition to the effect on younger children of missing school, prolonged school closures may have caused older children of legal working age to exit school and enter the labor force. a sizable literature on the effects of compulsory schooling laws suggests that educational attainment is affected by increases in the legal age of school exit, increases in the age at which children can legally work and decreases in the maximum age of school entrance. 15 in 1910, 22 states had legislated 14 as the minimum age for employment in manufacturing (moehling 1999) . 16 around 16.8% of males and 5.8% of females between the ages of 10 and 15 were active participants of the workforce in 1920, suggesting that many school-age individuals in 1916 would have possessed workforce alternatives to education (carter and sutch 1996) . together, this evidence implies that a notably large portion of youth ages 14 and older had viable and legal employment alternatives available to them in 1916. moreover, if worried parents delayed their youngest children's entry into school for a year, research by deming and dynarski (2008) suggests that these "redshirted" children may have less educational attainment than their non-redshirted peers since they reached a legal working age having acquired fewer years of formal schooling. using the 1916 polio epidemic as a natural experiment, this paper examines the effect of epidemics on the educational attainment of children. our primary identification strategy relies on interacting different age cohorts with polio morbidity rates in an individual's birth state. data on polio morbidity at the state level come from lavinder et al. (1918) , who provide comprehensive information pertaining to statelevel polio morbidity covering most of the continental usa. we use the data from lavinder et al because the us public health reports do not include areas with only a few cases (us surgeon general and us public health service 1917). in all specifications, we interact data on polio morbidity with dummy variables for an individual's age in 1916, since children of different ages may have been differently affected by polio. given that nearly 90% of children infected by polio before 1919 were under the age of 10, they may have been more likely to experience the effects of polio directly than children of older ages (nathanson and kew 2010) . on the other hand, children who were 14 and over may have been more likely to leave school for the workforce than children of younger ages. a priori, we expect children under 10 and children ages 14 or older to have their educational attainment impacted at a greater rate than those between the ages of 11 and 13. we use polio morbidity as our primary data for two reasons. first, complete data on school closures are not available, and state-level data on attendance is not reported for the 1916-17 school year. 17 second, polio morbidity data enable us to capture both the direct and indirect impacts of polio on children. polio may have directly affected school attendance for the children who contracted the disease. since do we not have information on whether specific individuals contracted polio, we instead rely on the polio case (notification) rate in an individual's birth state. in addition, the epidemic may have indirectly affected children who missed school either because schools closed, or because fearful parents kept them at home. schools in areas with higher rates of polio were more likely to close, and parents were more reluctant to send their children to school even when schools were open. relying on school closure data may fail to capture some of these "avoidance" behaviors. for example, data on average daily attendance for five boroughs in new york city 17 prior to 1916, information on enrollment, attendance and length of the school year was reported in the annual report of the us commissioner of education. however, in 1916, the office switched to reporting biennially, and the information was not reported in 1916/17 (u.s. bureau of education 1917). to try to disentangle the school closure effect from other effects, we did run regressions using a sample of 15 of the 38 cities we found specific closure dates for in our search of newspapers that also were big enough to be listed as a place of residence in the 1940 census. while statistically significant in one specification, results (available upon request) show the same general pattern we describe below. (available only between 1911 and 1917) indicate that average daily school attendance in new york city fell in the 1916-17 school year, as shown in fig. 4 . we measure 1916 polio epidemic exposure by reported infections at the statelevel so that our main identifying assumption is that people who were school age in 1916 would be exposed in their state of birth. this assumption would be violated if children and adolescents migrated between states prior to the 1916 epidemic. while we can only speculate as to the number of children who moved across states during childhood, we do know that in 1940, 77% of people were residing in the same state in which they were born. further, migration would bias the treatment effect toward zero if migration prior to the epidemic was not systematically correlated with polio morbidity. using data from the 1920 us census, we find that the difference between state of birth and state of residence in 1920 is less of a concern and that assigning polio virulence to state of birth is a reasonable proxy for exposure to the 1916 epidemic. in fig. 5 , we present the share of persons who were not observed in their state of birth in the 1920 decennial census. on average, 84% of people ages 0 to 21 in 1916 in states that reported polio still resided in their state of birth. to test whether the epidemic influenced the educational attainment of exposed cohorts, we match a sample of white males born between 1895 and 1916 with the 1916 polio morbidity rate in their state of birth, and the years of education they report having in the 1940 us census (ruggles et al. 2019). we restrict the sample to males since they entered the workforce as permanent participants. 18 we also exclude blacks, since margo (1986) finds that the highest grade of school reported in the 1940 census does not accurately represent years of schooling received for african americans. table 2 reports summary statistics for the primary sample. equation (1) represents the reduced form empirical regression used to study the effects of the 1916 epidemic on educational attainment: s,a denotes years of completed education for individual i, born in state b, residing in state s in 1940, and born in birth year cohort a. to compare the relationship between polio morbidity in 1916 and educational attainment, we compare the educational attainment of persons born between 1899 and 1916 (who were between the ages of 0 and 17 at the time of the epidemic) to those who were born between 1895 and 1898 (who were between the ages of 18 and 21). this allows us to compare the educational attainment of persons who plausibly could have been in school with those who would have already completed school. in order to test our hypothesis that children of different ages may have been deferentially impacted by the polio epidemic based on their labor market alternatives, we bin them into four age groups: ages 14-17 (born 1899-1902), ages 11-13 (born 1903-1905) , and children under age 10 (born 1906-1916) . we interact 1916 polio morbidity per 1000 population ( polio b ) in an individual's birth state with these age-specific cohort groups ( agebin a,j ). the omitted cohort is individuals aged 18 to 21 (born 1895-1898). the variables b , s , and a denote state of birth, state of residence in 1940, and age cohort fixed effects. the identification of polio morbidity's effect on educational attainment comes from comparing different age cohorts from the same birth state while controlling for current state of residence, and national shocks common across birth cohorts. state of birth fixed effects control for factors common across persons born in the same state, and state of residence fixed effects control for factors that are shared among persons residing in the same 1940 enumeration state. common shocks shared across birth year cohorts, such as wwi, are controlled for using birth year fixed effects. in the full specification, we also include state-level economic and demographic controls for 1916 by state of birth, and control for schooling laws that applied to each birth year cohort from each state. 19 these controls are denoted by x b and include doctors per capita in 1916, education expenditures per capita in 1916, the natural log of manufacturing wages per earner in 1916, and the natural log of population in 1916. interacting these controls with age cohort fixed effects allows the effect of these state-level characteristics on educational attainment to vary across different age cohorts. these interactions allow the state-level treatment effect of the epidemic to vary across birth year cohorts. the schooling laws, constructed by lleras-muney (2002), denote the ages of mandatory school entry, age of school exit and age at which children could obtain work permits for each birth year cohort from each state of birth. these laws proxy for idiosyncratic changes in schooling regulations for each state of birth by birth year cohort. 20 finally, i,b,s,a denotes a heteroskedastic error term clustered by state of birth. in our analysis, we run three different regressions, reported in table 3 . columns (1)-(3) report results from estimating equation (1) with the years of schooling as the dependent variable. column (1) includes fixed effects for state of residence in 1940, state of birth, and birth year. column (2) also includes the full set of fixed effects and birth state by age-cohort trends to control for potential underlying geographic trends common across cohorts born in different areas of the country, and column (3) 19 we thank adriana lleras-muney for providing these data. 20 the mandatory schooling law data start in 1915 and continue until 1939. we assign the cohort-specific law by subtracting the year the law was enacted from the age students can leave school. this identifies the birth year cohort to which the law plausibly applied. the laws are assigned for each year of birth by state of birth. in cases where there might be more than one applicable law, we assign the minimum age implied by the laws. in the case of missing values, we linearly interpolate if the missing value is between two birth years. in cases where we cannot linearly interpolate, we assign the schooling law from the closest birth year without a missing value in the state of birth, e.g., if values for birth years 1895 and 1896 are missing and we have values for 1897, the values for 1897 are assigned to the earlier cohorts. this process works for all states except for wyoming where we cannot assign variable values for 58 individuals. inclusion or exclusion of the schooling laws has little effect on estimated regression coefficients. replaces the trend variables with flexible state of birth economic and demographic controls for 1916 interacted with age cohort dummies, and adds schooling law controls. all coefficient results discussed refer to our preferred and most restrictive specification, (3), unless otherwise noted. results presented in table 3 confirm our hypothesis that the polio epidemic of 1916 had different effects on educational attainment for children of different ages. schoolaged children who were old enough to have labor market alternatives (i.e., those who were between ages 14 and 17 in 1916) and those who were living in areas more affected by the epidemic had lower educational attainment than similarly-aged children living in areas with lower polio morbidity rates. this result is robust even in our models with the most restrictive controls. a one-standard-deviation increase in the polio morbidity rate per 1000 persons (reported as 0.415 in table 2 ) results in persons ages 14-17 having around 0.066 fewer years of educational attainment on average. the reference cohort of persons ages 18-21 had, on average, nine years of education. a back-of-the-envelope calculation suggests that this effect is equivalent to every fifteenth individual completing one less year of education. there is also a statistically significant and negative relationship between polio morbidity and educational attainment for children 10 and under. the estimated coefficient suggests that a one-standard-deviation increase in polio morbidity decreases educational attainment by 0.111 years-the equivalent of one in ten people of the cohort completing one less year of education. 21 in contrast, state-level polio morbidity in 1916 does not have a statistically significant relationship with educational attainment in individuals who were over 10, but too young to legally work in most states. the estimated coefficients on the interaction between polio morbidity and persons ages 11 to 13 in 1916 are negative, although the standard errors are large and they are not precise zeros. relative to individuals born before 1898, the educational attainment of people born in those years do not appear to be strongly affected by polio morbidity rates. 22 we test whether our results are robust to using two-year age groupings. results (reported in 1902, 1903/1905 and 1906/1916 . the reference birth cohort is 1895/1898. standard errors are clustered by state of birth and are in parentheses. all specifications include state of birth fixed effects, fixed effects for state of residence in 1940, and birth year fe. 1916 economic controls are controls interacted with age cohort dummies. these variables include 1916 state-level doctors per capita, education expenditures per capita, log manufacturing wages per earner and log population. cohort schooling laws included proxies for the age of school entry, age of school exit and age of work permit that varies by state of birth and by year of birth * p < 0.10 , * * p < 0.05 , * * * p < 0.01 the appendix) are robust and confirm our main findings: that students with the ability to work legally, and children younger than 10 experienced reduced educational attainment relative to children in the middle grades. in addition to state-level data, we have county-level data on polio morbidity from lavinder et al. (1918) for a select set of states in the eastern usa, as shown in fig. 6 . these county data cover the northeastern part of the usa, which experienced much higher rates of polio cases and deaths than other regions. while we do not have data on county of birth, we can connect this county-level measure of polio intensity to county of residence in 1940 and restrict the sample to persons residing in the same state they were born in. essentially, we assume that people living in a particular county in 1940 (as long as it is in their birth state) were also born in this county. if we assume that migration within the usa between 1916 and 1940 is not systematically correlated with polio morbidity in 1916, then migration bias would just introduce classical measurement error in county-level exposure to the 1916 epidemic. 23 the results using the county-level polio morbidity in table 4 mirror the results using state-level data. while the estimated coefficients are smaller, the relationship between education and polio is negative and statistically significant for all cohorts ages 0 to 17 in 1916. these results suggest that children living in counties with greater polio cases in 1916, on average, had lower levels of educational attainment than slightly older persons. a one-standard-deviation increase in county-level polio cases reduced the educational attainment of persons born between ages 14 to 17 by 0.07 years relative to the reference cohort born a few years earlier. similarly, persons aged 11-13 also experienced reduced educational attainment; a one-standard-deviation increase in polio morbidity in this age group reduced educational attainment by 0.08 years. children under 10 during the polio epidemic had the largest reductions in educational attainment, with a one-standard-deviation increase in polio morbidity associated with a 0.13 year reduction in average educational attainment. 23 measurement error could occur, however, if people move between high-morbidity and low-morbidity areas for reasons related to education-for example, if people born in rural counties moved to more urban counties for jobs. in this case, we may be overstating the impact of polio morbidity on educational attainment at the county level. for this reason, we have more confidence in the state-level results that aggregate rural and urban counties and include state of residence in 1940 fixed effects that further control for migration. an alternative method would be to link individuals observed between the 1920 and 1940 censuses and assume that if they reside in the same county, they were likely born in that county. this could further reduce measurement error, but requires significant resource investment and is still not entirely free of measurement error. we also examine whether our results are robust to two alternative specifications. first, the 1916 polio outbreak primarily affected young children under the age of five. as sanitation improved, epidemics in later decades tended to infect older children more frequently. using age-specific infection rates for the 1916 polio epidemic from a study by dauer (1938) in boston, we substitute our interaction of the polio notification rate variable with age category bins with a new variable created by interacting the polio notification rate for 1916 and the age-specific polio infection rate from dauer (1938) . we assign infection risks of 68% for persons under age four in 1916, 20% for persons ages 5 to 9, 8% for persons ages 10 to 19, and 4% for anyone above the age of 19. in table 5 , we present the main regressions specifications using this alternative measure of polio epidemic exposure. the negative and statistically significant coefficients in specifications (1) and (3) are consistent with our main findings and are larger in magnitude. according to specification (3), for persons aged four and under, an increase in polio cases by one per 1000 people decreased educational attainment by 0.505 years. for persons between ages five and nine, the reduction in educational attainment was 0.06 years, while educational attainment fell by 0.024 years for people aged 10 to 19 during the epidemic. it is also plausible that persons exposed to the 1916 polio epidemic were also affected by the 1918 influenza pandemic, which killed over 500,000 people in the usa. the flu came in three waves. the first, with low mortality, came in the spring of 1918. a second wave associated with higher mortality came in fall/winter 1918, with a third wave arriving in early 1919. we include the 1918-19 flu mortality rates from garrett (2008), the united states bureau of the census (1921), and the united states bureau of the census (1922) into our analysis, since public health departments were not required to report influenza cases. table 6 provides state-level data on influenza deaths by state in 1918 and 1919. to control for the intensity of the 1918 influenza epidemic, we include the state-level 1918 influenza mortality rate interacted with age bins in our regression, even though the disease was most virulent and lethal in older populations than the children we focus on (i.e., adults of prime-working age). this exercise addresses potential concerns that the 1916 polio epidemic is spuriously correlated with 1918 influenza intensity. 24 we study the effects of influenza intensity on observed education in 1940 for a subset of states used in the main analysis (27 of 43). 25 results reported in table 7 show that including the influenza death rate and its interactions with age groups does not affect our finding that children of legal working age in states with greater numbers of polio cases had less educational attainment. it attenuates the statistical significance of the 1916 epidemic for children ages 0 to 10 in 1916 in specifications (1) and (2) but strengthens it in specification (3). the effect of influenza mortality itself on educational attainment is statistically insignificant in specifications (1) and (2). in specification (3), we find influenza mortality increases educational attainment for persons born between 1903 and 1916. this result is consistent with the findings in parman (2015) , who shows that families results reported are for white males. sample is restricted to individuals residing in the same state as their state of birth. years of education are top coded at 17 years. age cohorts interacted with polio correspond to birth years 1899/1902, 1903/1905, and 1906/1916 adjusted educational investments in children in response to reduced human capital caused by prenatal exposure to the 1918 flu: slightly older children with siblings who were prenatally exposed to the flu pandemic experienced increased educational attainment. to further substantiate the main results, we also perform a placebo test comparing men ages 22 to 33 in 1916 to reference cohort of those ages 18 to 21. results, reported in table 8 , indicate that there is not a consistent pattern between reported polio morbidity and educational attainment. there is a small, negative and statistically significant relationship between polio intensity and the level of education observed for the age 22 to 24 cohort at the 10% level in specification (3). however, this relationship is not consistent across all specifications, suggesting that polio morbidity at the state level is relatively uncorrelated with unobserved factors that could affect observed educational attainment in 1940. in the appendix, we include an additional specification test using two-year birth cohorts, which do not substantively change our results. our primary results focus on men because they had more workforce opportunities and may have responded differently to polio than women. table 9 reports results from our primary specification on a sample of women in 1940. we find that the polio epidemic affected girls under age 10 in a similar way to men. girls aged 14-17 also reported reduced educational attainment in high-polio areas, although not in our most saturated model. in our male sample, we find that boys aged 11-13 living in areas with higher polio did not have a statistically significant lower educational attainment than boys living in areas less affected by polio, although the standard errors are large and the results are an imprecise zero. for girls aged 11-13, the adj r 2 0.084 0.085 0.084 estimated coefficients are negative and statistically significant. we are not sure why. in general, males and females had different returns to education, and it might have been that girls, for whatever reason, did not return to school in the same numbers as their male counterparts. the first major polio epidemic in the united states struck in the summer of 1916 and persisted into the fall. with over 23,000 cases of polio diagnosed, the epidemic tested the nascent system of public health departments. officials engaged in a variety of measures to stem the outbreak, including quarantines, washing streets, and closing public schools. in this paper, we focus on the effect of the epidemic on years of schooling reported by individuals in the 1940 us census. educational attainment could have been reduced for infected children, or for children who spent less time in school because their schools were closed or because their parents refused to send them. while we do not have data on school closures, we leverage geographical variation in polio morbidity as a proxy and focus on whether children of differential ages were differently affected. younger children were more likely to have the virus, and older children may have opted to join the workforce instead of stay in school. our results show that children of legal working age living in areas with higher rates of polio infection had diminished educational attainment than similarly aged children living in states with lower infection rates. this result, which is robust and consistent across specifications, does not hold for age groups who were not of legal working age, nor does it hold for slightly older children who had already completed their secondary schooling. we find stronger negative educational effects for children who were most susceptible to the virus and who were age 10 and under during the epidemic. table 9 women: effect of 1916 polio notification rate per 1000 on educational attainment of age cohorts specifications 1 to 3 are the same specifications presented in the main analysis in table 3 , except these results are for white women. years of education are top coded at 17 years. age cohorts interacted with polio correspond to birth years 1899/1902, 1903/1905, and 1906/1916 our results suggest that a one-standard-deviation increase in polio intensity during the 1916 epidemic reduced educational attainment by 0.07 years for the age 14-17 cohort and 0.11 years for the cohort age 10 and younger. based on the average reported days in the school year, these numbers suggest that annual attendance declined by roughly 11 days in the age 14-17 group and 17 days among children et al. (1918) aged 10 and under. these numbers are not trivial; they are within the range of lleras-muney's (2002) finding that compulsory attendance and child labor laws increased educational attainment by about 18 days. another way of looking at the impact is to look at the aggregate effect in the cohort. for the cohort of children aged 14-17 during the epidemic, these numbers suggest that on average, about 1 out of 15 of them had one year less of educational attainment in their lifetime. the impact is even larger among younger children, with one out of every 10 children attaining one less year of education. these cohort-wide reductions in educational attainment suggest that public quarantines, school closures, and parental fear magnified the social cost of the 1916 poliomyelitis epidemic, and may shed light on how epidemics can affect even people who do not contract the illness. clearly, school closures, even for short times, may reduce educational attainment among affected children. today, with virtual instruction, it is likely that these effects may be smaller. it is also likely that the impact on high-school completion will be mitigated because many jobs require high school diplomas. nevertheless, greater numbers of students are now enrolled in college. these results suggest that if these students leave school (either because they do not like virtual learning, or have a negative financial shock), they may be less likely to return and suffer from lower overall educational attainment as a result. 1900, 1901/1902, 1903/1904, 1905/1906, 1907/1908, 1909/1910, 1911/1912, 1913/1914, and 1915/1916 1900, 1901/1902, 1903/1904, 1905/1906, 1907/1908, 1909/1910, 1911/1912, 1913/1914, and 1915/1916 we test sensitivity of our main analysis using alternative reference cohorts. the main analysis uses persons who would have been between 18 and 21 during the polio epidemic. we prefer using multiple birth year age bins study the polio epidemic. this is because our age variable is constructed from year of birth, there is some imprecision in lining up school attendance and age in 1916. in particular, some persons who reach the age of 18 in 1916 may have started the school year as 17 year olds. we find a relatively negative and consistent relationship between polio virulence and the age someone was in 1916. we redo the main regressions using persons aged 19-21, 20-21, 21, 18-20, 18-19 , and 18 as reference cohorts. we include an additional interaction between polio and the age cohorts removed from the reference cohort as a "placebo cohort." we find results consistent with our main analysis. using single year reference or falsification cohort in a specification using multiple year bins can alter the statistical significance of our results. potential issues arise from using either 18 year olds alone as a reference cohort or using 18 year olds alone as a falsification cohort. our preferred specifications using 1916 economic controls attenuate these effects, the regressions with these controls present negative and statistically significant results consistent with the main regression specification (tables 13, 14) . table 13 alternative reference cohort specification with falsification, part 1 specifications 1 to 3 are the specifications presented in the main analysis and use the reference birth cohort is ages 18 to 21 in 1916 (birth years 1895/1898). specifications 4 to 6 use a reference cohort ages 19 to 21 and persons aged 18 in 1916 are in the "placebo cohort." results reported are for white males. years of education are top coded at 17 years. age cohorts interacted with polio correspond to birth years 1899/1902, 1903/1905, and 1906/1916 . standard errors are clustered by state of birth and are in parentheses. 1916 economic controls are controls interacted with age cohort dummies. these variables include 1916 state level doctors per capita, education expenditures per capita, log manufacturing wages per earner, and log population. cohort schooling laws included proxies for the age of school entry, age of school exit, and age of work permit that varies by state of birth and by year of birth. * p < 0.10 , * * p < 0.05 , * * * p < 0.01 table 14 alternative reference cohort specification with falsification, part 2 specifications 1 to 3 are the specifications that use ages 20 to 21 in 1916 as the reference birth cohort and persons aged 18 to 19 are in the "placebo cohort." specifications 4 to 6 use a reference cohort age 21 and persons aged 18 to 20 in 1916 are in the "placebo cohort." results reported are for white males. years of education are top coded at 17 years. age cohorts interacted with polio correspond to birth years 1899/1902, 1903/1905, and 1906/1916 . standard errors are clustered by state of birth and are in parentheses. 1916 economic controls are controls interacted with age cohort dummies. these variables include 1916 state level doctors per capita, education expenditures per capita, log manufacturing wages per earner, and log population. cohort schooling laws included proxies for the age of school entry, age of school exit, and age of work permit that varies by state of birth and by year of birth. * p < 0.10 , * * p < 0.05 , * * * p < 0.01 childhood circumstances and adult outcomes: act ii is the 1918 influenza pandemic over? long-term effects of in utero influenza exposure in the post-1940 u.s. population the effect of age at school entry on educational attainment: an application of instrumental variables with moments from two samples cognitive development and infectious disease: gender differences in investments and outcomes does school quality matter? returns to education and the characteristics of public schools in the united states fixing the facts: editing of the 1880 u.s. census of occupations with implications for long-term trends and the sociology of official statistics early life health and cognitive function in old age epidemiology and prevention of vaccine-preventable diseases public reaction to a severe polio outbreak in three massachusetts communities studies on the epidemiology of poliomyelitis symposia: investment in children: the lengthening of childhood a monograph on the epidemic of poliomyelitis evening public ledger, p 2 evening public ledger (1916b) school opening postponed childhood health shocks, comparative advantage, and long-term outcomes: evidence from the last danish polio epidemic human capital and social capital: the rise of secondary schooling in america, 1910-1940 the great lockdown: worst economic downturn since the great depression the impact of sars on asian economies published: the annie e casey foundation lavinder ch, freeman aw, frost wh (1918) epidemiologic studies of poliomyelitis in new york city and the northeastern united states during the year 1916 chronicling america: historic american newspapers were compulsory education and child labor laws effective? an analysis from 1915 to 1939 in the u.s prediction of school failure from third-grade data unscheduled school closings and student performance race, educational attainment, and the 1940 census compulsory schooling legislation and school attendance in turn-of-the century america: a 'natural experiment' approach state child labor laws and the decline of child labor from emergence to eradication: the epidemiology of poliomyelitis deconstructed the cutter incident: how america's first polio vaccine led to the growing vaccine crisis childhood health and sibling outcomes: nurture reinforcing nature during the 1918 influenza pandemic the impact of length of the school year on student performance and earnings: evidence from the german short school years weekly reports for dirt and disease: polio before fdr million kids aren't in school because of ebola acknowledgements thomasson acknowledges support from the julian lange professorship. we thank see tables 10, 11 and 12. the economic impact of ebola on sub-saharan africa: updated estimates for 2015. technical report. world bank group trevelyan b, raynor-smallman m, cliff ad (2005) key: cord-292024-ae7rauc6 authors: fulop, t.; larbi, a.; hirokawa, k.; cohen, a. a.; witkowski, j. m. title: immunosenescence is both functional/adaptive and dysfunctional/maladaptive date: 2020-09-15 journal: semin immunopathol doi: 10.1007/s00281-020-00818-9 sha: doc_id: 292024 cord_uid: ae7rauc6 alterations in the immune system with aging are considered to underlie many age-related diseases. however, many elderly individuals remain healthy until even a very advanced age. there is also an increase in numbers of centenarians and their apparent fitness. we should therefore change our unilaterally detrimental consideration of age-related immune changes. recent data taking into consideration the immunobiography concept may allow for meaningful distinctions among various aging trajectories. this implies that the aging immune system has a homeodynamic characteristic balanced between adaptive and maladaptive aspects. the survival and health of an individual depends from the equilibrium of this balance. in this article, we highlight which parts of the aging of the immune system may be considered adaptive in contrast to those that may be maladaptive. due to the current covid-19 pandemic, there is much interest in the immune system of older individuals, who are at highest risk of severe disease and death [1] [2] [3] [4] [5] . it seems to be common knowledge that infections and diseases are increased in the elderly and may be considered associated with the aging process itself [6] [7] [8] [9] . in the meantime, there is an unprecedented increase both in life expectancy and in the number of centenarians and semi-supercentenarians (several "blue zones" where these oldest old individuals are "enriched" compared with the general population exist on earth) [10, 11] . many changes have been described in the innate and adaptive immune systems with aging [12] [13] [14] [15] [16] [17] [18] [19] [20] . these contentions seem to represent completely contradictory trends which may be difficult to reconcile. interestingly, two decades ago a common denominator of aging and age-related diseases called inflammaging was described by franceschi et al. [9, [21] [22] [23] , a concept that was largely based on the previously described age-related immune changes called as immunosenescence [24, 25] . as a corollary, this became for geroscience and the nine hallmarks of aging one of the basic underlying mechanisms of aging designated as "intercellular communication" [26] [27] [28] . however, a new appreciation of the data found in older adults suggests that not all changes in the immune system generally considered detrimental are actually harmful, and concomitantly the immune system of the elderly is able to perform better than it was previously suspected when adequately challenged [29, 30] . as mentioned, the common paradigm is that age-related diseases (ards) and the decreased vaccine response are somehow linked to immune alterations with aging, commonly called immunosenescence [16, 20] . however, several recent observations challenge this idea. first, the elderly are in fact able to sustain an adequate vaccine response compared with young subjects [30] . second, for semi-supercentenarians the most important survival factor was proposed to be inflammation [31] [32] [33] . third, the immune checkpoint inhibitors are as efficient in elderly as in young [34, 35] . lastly, most infections are not fatal in the elderly, including covid-19, and not all older adults suffer from numerous age-related diseases [36, 37] . therefore, it could be conceptualized that the age-related immune changes may be a mix of adaptation/resilience and maladaptation/allostatic load, which are closely related to what was called the immunobiography or immunoadaptation, in line with the well-known physiological concepts hormesis and homeodynamics [25, [38] [39] [40] . in this article, we propose a framework to understand adaptation and maladaptation of the immune system and their consequences for elderly. thus, we will describe a holistic conceptualization of the immune system changes during aging, called the "adaptage theory." the main role of the immune response is the protection of the organism from all external and internal challenges in the form of pathogenic microorganisms as well as transformed (neoplastic) or damaged (injured) cells [7, 23] . the immune system is fully equipped to perform this complex task. however, many reports state that with aging there is not a single part of this response which would not undergo changes, and these changes were uniformly conceptualized as being only "bad," deteriorative changes, and their consequences could be only detrimental for elderly [41] [42] [43] . this notion generated the concept of removing the problem by the rejuvenation of the immune system of the aged individuals to the level of young subjects [44, 45] , however in the physiological environment of an otherwise old organism. usually, the aging-associated changes in the immune system are described separately for its innate and adaptive compartments. here we will try to describe the unified concept of these age-related changes. when we consider aging, we consider time. so, the immune system today is not the same as yesterday, neither in young nor in elderly persons. this means that at every moment challenges are arising in our external and internal environment which should be dealt with by the immune system [38] and that these challenges build on the previous state. this implies that every event occurring during life will consequently change or sculpt the immune response [25] . so, during life, we have many aggressions which can be halted by the innate immune system alone, or if they are more serious, they will need the involvement of the adaptive immune system [46, 47] . thus, in any case, the first encounter of an external or internal pathogen is with the cells of innate immune system [48] . this system is fully equipped to deal with all aggressors in a very fast time frame starting from minutes to days. this system is composed of neutrophils, monocytes/macrophages, dendritic cells (dc) and nk cells, and numerous soluble mediators secreted by these cells, including cytokines and chemokines [49] . by itself, this system is powerful enough to clear an aggression without harm [50, 51] but also in special circumstances to turn against its own by sustaining inflammation, over time leading to chronic inflammatory diseases [52] [53] [54] . among these are, for example, rheumatoid diseases, atherosclerosis, cancer, or asthma, the precursory stages of which may be arising very early in life [55, 56] . acute inflammation is meant to eliminate everything which is harmful for the organism and ends with a (near) complete return to the original state. however, if the aggression is chronic, or if the innate immune system is not set back because the regulatory mechanisms are overwhelmed, the inflammatory process can become chronic and potentially harmful. when we think about a chronic process, we suppose that time plays a role; thus, aging (occurring with time) is a relevant factor [57] . this means that all these pathologies are considered ards. nevertheless, we should mention that the chronic nature of such stimulation has already somehow elucidated the occurrence (explained the beginnings) of these diseases early in life [57] . the concept of trained innate immune memory sheds some light how the innate immune system may orchestrate the eventual alertness or chronicity of the innate immune response. at each aggression, innate immune cells such as monocytes are activated [58] [59] [60] [61] [62] . "trained" at each occasion by intracellular immunometabolic changes/reprogramming as well as by subsequent epigenetic imprint, these cells will increase their inflammatory response [63] [64] [65] . however, this process may take two different paths. one path is the controlled, wellorchestrated innate immune memory, which helps to resolve aggressions rapidly and stop the inflammatory process, but nonetheless remains at a higher activation/readiness state [58] [59] [60] [61] [62] . the other pathway is less controlled, which can lead to what has been called "immune paralysis" [66] . not only will the response not be adequate, but these cells are already overstimulated, so a new stimulus may not trigger an efficient response and the functionality of the innate immune cells will decrease when it should increase. this has been shown also for some specific phagocytic cells' functions with aging [67] . a basal state of activation of the innate cells was demonstrated with aging, which may lead to a preparedness and readiness of the system [68] [69] [70] [71] . this may help the innate immune system to be reactive more quickly and at a higher level. interestingly, many tissue-resident and blood-born innate immune cells, including neutrophils and microglia, display hyperactivation phenotypes with aging [72, 73] . however, it was also shown that this may lead to a relative immune paralysis state resulting in the blunting of the innate cells functionality when specifically challenged. it should be mentioned that this does not mean that these phagocytic cells may not enhance their functions, but not in all elderly and not to the level as would be expected in case of young. this is corroborated by the findings that most elderly subjects may efficiently clear an infection, such as influenza or even sars-cov-2 [14, 16, 37, 74] . certainly, this happens in fewer cases than in young subjects, but it is not impossible. thus, this is a perfect example of the adaptation/maladaptation concept of the aged immune system. moreover, the innate immune response can also determine how the adaptive immune system will react [75, 76] . cells have evolved which seem to be intermediate between the innate and the adaptive immune system and may react faster than standard adaptive immune system but keep its characteristics [76] [77] [78] . these innate lymphoid cells (ilc) are broadly classified into three main subsets: ilc1 (ifn-γ producing), ilc2 (il-4, il-5, and il-13 producing), and ilc3 (il-17 or il-22 producing or both) [79, 80] . ilcs are either present in the tissues or in the circulation. they can rapidly react to microbial and cytokine signals. they also rapidly induce the cxcl13 chemokine, which is the ligand of cxcr5 playing a role in the tissue accumulation of these ilcs [81, 82] . by their rapid response, these cells also contribute to the eradication of the microbes constantly invading the human organism and permanently threatening its overall health. the innate-like t cells comprise the cells displaying a γδtcr, mucosa-associated invariant t (mait), inkt (invariant natural killer t), gemt (germline-encoded mycolyl lipid-reactive), and innate-like b cells [83] . these cells recognize foreign/self-lipid presented by nonclassical mhc molecules, such as cd1d, mr1, and cd1a [84] . they are activated during the early stages of bacterial infection and act as a bridge between the innate and adaptive immune systems. unlike their conventional counterparts, innate t cells rapidly recognize foreign pathogen signals and manifest immediate effector functions after activation [85] . these innate t cells are implicated in immune responses to viral infections such as cmv, are able to recognize a broad range of cancer cells, and react to stress-induced molecules, such as mhc class i-related chains a and b (mica and micb) that are expressed on virus-infected cells and also participate in the general antimicrobial defense [86] [87] [88] . the nature of the antigens recognized by innate t cells is also diverse and broadly non-overlapping, involving metabolites, bacterial products, and lipids. inkt cells have been principally shown to respond to glycolipids, γδ t cells are potently activated by (e)-4-hydroxy-3-methyl-but-2-enylpyrophosphate (hmbpp) [89] , and mait cells can be activated by riboflavin metabolitesreduced 6-hydroxy methyl-8-δ-ribitylumazine (rrl-6-c h 2 o h ) , a s w e l l a s f o l i c a c i d m e t a b o l i t e , 6formylpterin(6fp) [90] . so, they have some characteristics of the innate immunity such as rapid effector functions but also adaptive immunity because of the rearrangement of their tcr and thymic selection. this allows innate t cells to perform effector immune responses much earlier than conventional t cells and act as an additional "bridge" between innate and adaptive immune responses. studies demonstrate that unconventional t cells do indeed contribute to the ability of host organisms to clear and control certain bacterial infections. these cells are able to efficiently travel to the sites of inflammation and initiate rapid responses by means of cytokine production and cytotoxic activities. in the description of immune changes with aging, there are a few places for these essential cells. larbi and his group devoted a lot of work to understand how these cells work during aging [91, 92] . they have shown that vδ2+ t cells composition and functionality are not altered in older adults. they have further shown that peripheral vδ2+ phenotype, functional capacity (cytokines, cytotoxicity, proliferation), and gene expression profile are specific to this subset when compared against all other αβ and γδ t cells in aging. also, hallmarks of senescence including telomere length, epigenetic profile, and dna damage response of vδ2+ differ from all other αβ and γδ t cells. finally, they have shown that vδ2+ are resistant to cellular aging due to their unique epigenetic and transcriptomic signatures. these findings constitute another type of adaptation in view to compensate/complement the changes observed in adaptative t cells during aging. future work should unravel whether this potential of being resilient to stressors in vδ2+ could be promoted in other cell type and consequently exploited to lead to better response to infections and in the field of cancer immunotherapy or designing a vaccine utilizing vδ2+ properties for the elderly. group 2 ilc (ilc2) respond to the alarmin cytokine il-33 and are potent producers of il-5 and il-13 as well as a variety of other effector molecules in vitro and in vivo [93] . tissueresident ilc2 are implicated in tissue repair, tissue remodeling, and metabolic homeostasis [94] . recently, it was shown in the choroid plexus of the brain that ilc2 in the aged brain are long-lived and capable of reversibly switching between cell cycle dormancy and proliferation [95] . they are relatively resistant to cellular senescence and exhaustion under replication stress, leading to enhanced self-renewal capability. when activated in vitro and transferred intracerebroventricularly, they revitalized the aged brains and enhanced cognitive function of aged mice. these results suggest that aging may expand a unique population of brain-resident ilc2 with enhanced cellular fitness and potent neuroprotective capability, by decreasing neuroinflammation, cellular senescence, and exhaustion and moreover capable of self-renewing. it is still unclear whether similar ilc2 cells may be found elsewhere in aging organism, but this is another cell type which may resist the "detrimental" effect of aging and show adaptative traits even if is occurring locally. the subsets of memory or memory-like t and b cells with innate-like properties have been observed to accumulate with aging [42, [96] [97] [98] [99] [100] . the increased numbers and activity of certain innate or innate-like immune cell subsets with aging might be considered host responses to compensate for the drastic decline in adaptive immune cell development and function [95] . these cells mirror the findings in vδ2+ t cells as described above and show the plasticity and adaptability of the innate and innate-like cells with aging, probably maintaining some physiologically important functions when the other part of the system is fainting [91] . thus, we can say that the effects of aging on the immune system are much more complicated than a commonly preached generalized decline in immune cell development, phenotype, and function. once an aggression occurs and the innate response is inefficient or insufficient to clear it, the innate system should drive the adaptive immune system to react [75, 76] . this is carried out by coordinated and efficient actions by the cells and the soluble mediators of the innate immune system. the antigens should be efficiently presented, and the mediators should prime the adaptive immunity. it has often been stated that antigen presentation is altered with aging; however, this is still controversial and probably depends on the strength of the innate stimulation [101] [102] [103] [104] [105] [106] [107] . dendritic cells (dcs) are one type of innate immune cell known for antigen presentation, being key components linking innate and adaptive immunity through priming of naïve t cells and shaping adaptive t cell responses [108, 109] . there are two major dc subsets in human peripheral blood: conventional dcs (cdcs) and plasmacytoid dcs (pdcs). these dc subsets recognize different pathogen-associated molecular patterns by expressing distinct repertoires of toll-like receptors (tlrs) and other receptors [110, 111] . engagement of specific dc subset tlrs in turn triggers distinct immune response pathways. for example, pdcs produce a large amount of interferon alpha (ifn-a) in response to virus infection [112] . as mentioned, age effect studies of human dcs have been controversial [107] . while some studies demonstrated agedependent declines, others have shown no difference in the number of circulating dcs [113, 114] . several studies have also indicated age-related functional changes in dcs, such as impaired expression of tlrs [115] ; decreased production of cytokines, chemokines, and ifn-a after tlr stimulation [112] [113] [114] [115] [116] ; and increased responses to self-antigen [117] . an earlier study has shown that the b cell and monocyte antigen presentation in the frame of mhc did not change with age. however, what was interesting in the data reported in one study is that among the 11 elderly even if the monocyte antigen presentation was homogenously maintained, there were 4 elderly with less bcr antigen presentation [106] . even if most of the results suggest a change in antigen presentation, the various steps leading to it are differentially affected by age from the number of dcs through the immunoproteasome processing and the final mhc dependent presentation like in b cells. interestingly, almost a quarter century ago, one of us (jmw) had demonstrated that the level of expression of mhc class i (h-2) molecules on spleen t cells of old mice is higher than on the surface of young splenic t cells; this effect was concomitant with the significant (homeostatic?) decrease of the level of transporter of antigenic peptides (tap)-1 in the same cells [118] . these observations were later supported by assounga et al. [119] . contrarily, expression of mhc class ii on macrophages derived from old mice was reported to be decreased compared with young animals [120] . these data even if contradictory may also illustrate that in the immune system, the changes are not uniform, and the system is self-adapted to compensate eventual failure of some part of the whole system. however, other non-antigen processing and presentation functions of apc, such as ability to become activated, costimulation, or cytokine/chemokine production, may play a role in the difficulties of the immune response to progress to the adaptive immune response [121] . more human studies are needed to clearly elucidate which processes are conserved and which are not in the antigen presentation process. however, once the innate immune response is able to present the antigens, the adaptive immune response takes over with b and t lymphocytes' activation [75] . these main cell types executing the adaptive immune response have many different subpopulations [122] . this part of the immune system has been extensively studied in human aging [123] [124] [125] [126] . there is a very broad consensus considering the adaptive immune system as the "devil" which is responsible for all the misfortunes of the immune system with age [25, 28] . the most important changes are the decrease in the naïve immune cell compartment of the cd4 + and cd8 + t lymphocytes, however being more important in the latter [12, 16, 96, 97] . concomitantly, the tcr repertoire variability is also drastically decreased [127, 128] . in contrast, there is a concomitant increase in memory t and b cells which represent the subpopulation which already encountered antigens [129] [130] [131] . this quickens the adaptive response to cognate antigens, which is evolutionarily beneficial for the survival of an (older) individual, provided he/she stays in the general area where they spent their childhood and where meeting new, previously unknown pathogens is normally infrequent. the contrary would be quite strange if we consider from an evolutionary perspective that the immune system should react to all internal and external stimulation. this state of the adaptive immune system only reflects what we called earlier as immunobiography or immune history [38, 132] . so, in this case, it should be considered neither bad nor good; it reflects only the reality of the role of the immune system. this is simply a life-long adaptation to life. certainly, the decrease of naïve cells in the elderly may not be advantageous for the survival of the individual when an encounter occurs with a completely new antigen such as the sars-cov-2 causing current (2020) pandemics of covid-19 [15] . as we already know, these individuals may die in proportions significantly higher than young covid-19 patients [1, 2] . the cause of this decrease of naïve t cells is the involution of the thymus which starts early in life [13] . this also should have some adaptative reasons in the life of an individual. the maintenance of such an organ (with one of the highest proportions of concurrently dividing cells) is very costly in terms of metabolic energy; so, as most of the naïve t cells have been generated early in life, there is no need for its full function later in life. also, if it is maintained, some errors in the regulatory mechanisms may occur with time, and some diseases such as autoimmune disease may increase. on the other hand, it should be stated that once more nature has foreseen a compensatory mechanism for lack of naïve t cells of thymic origin, which is their homeostatic proliferation in the periphery [133] . there is an unsettled debate among researchers as to whether this phenomenon fully replaces the lost tcr repertoire expressed by the thymus-generated naïve t cells. however, long survival of centenarians demonstrates that it should be an efficient compensatory mechanism. it is of note that many nonagenarians and centenarians recovered form covid-19 despite the apparent lack of naïve t cells [134] . the increase of the memory (mainly cd8 + ) t cells is also considered quite damaging for old individuals [135, 136] . the reason is that their numerous proliferation cycles have led to what is called a senescent state or senescence [137] [138] [139] . this senescent state precludes their capacity to proliferate, mainly due to decreased cd28 expression resulting in slower and weaker activation during a known antigenic encounter, leading to decreased protection [18, 140] . in the meantime, senescent t cells, analogously to other senescent cells arising with age in the body, produce large amounts of proinflammatory cytokines (a phenomenon called senescence-associated secretory phenotype, sasp) as stated by the inflammaging characteristics of the human immune system [141, 142] . this could substantially impede the response to recall antigens in specific cases, but in the meantime, the clinical and experimental evidence both point to the fact that even in the elderly, this part of the adaptive immune system may function efficiently. in the meantime, these cells are also able to contribute to the maintenance of innate immune preparedness. the sasp phenotype elicits an autocrine role on senescent cells, but it is also involved in the recruitment of immune cells, such as macrophages, neutrophils, and natural killer (nk) cells in order to eliminate the senescent cells themselves [143] . concomitantly, upon accumulation of senescent cells, the production of cytokines is enhanced, along with the recruitment of immune cells, jointly paving the way towards the installation of inflammaging [14, 57] . the cytomegalovirus (cmv) infection was considered one of the most important triggers of accumulation of senescent t cells [144, 145] . this consideration generated many studies to evaluate whether senescence of the immune cells could be considered detrimental or beneficial. certainly, the accumulation of senescent cells has numerous maladaptive aspects [146, 147] ; but, as many recent studies have shown, it also has adaptive aspects [148] . finally, the exact percentage of the senescent/exhausted t cells at different ages and what role they may play physiologically is not clearly settled in this context. it may be that they (mainly exhausted t cells) are like the reserve in the army which can awaken when the well-trained t cells are not able to combat pathologies like cancer [149] [150] [151] . in view of the continuous production of immune cells, it seems likely that part of accumulated memory immune cells is not truly irreversibly senescent but rather exhausted, exhibiting reduced functional capabilities which can possibly be reversed when the circumstances may necessitate it [152] . with aging, not only phenotypic changes but also functional changes occur in the adaptive system, which may or may not be always related to the t cell subpopulations but may be due directly to the immunobiography [38] . there are documented changes in the main signaling pathways in t cells, including the tcr, costimulatory receptors, and cytokine receptors, which lead to the decrease of cytokine production, proliferation, cytotoxicity, and differentiation [153] [154] [155] [156] . moreover, the metabolism of these cells is also affected because of the changes in the mtor pathway either favoring the autophagy or the anabolic effects of its stimulation [157] . the changes from oxphos in the resting state to aerobic glycolysis characterizing activated t cells are delayed and less intense in aging t cells [158, 159] . these changes in the functioning may arise from the membrane changes with aging altering the immune synapse formation and consequently the cognate signaling pathways [160, 161] . the changes either in the feedforward or feedback pathways are very complex-as the experimental results suggest-but together, we can say that they may decrease the efficiency of the t and b cell responses with age in certain circumstances which can really have detrimental consequences for the individual [162] [163] [164] . there are also new data that some pathways (precisely the jak-stat pathway [165] ) in the resting t cells are activated with age. to summarize the immune changes in the continuity from the innate to the adaptive immune response, it can be concluded that the immune response in old individuals is complex and heterogenous and probably is more dependent on the type of challenge than from the age of the subjects [166, 167] . furthermore, many compensatory and redundant mechanisms are inbuilt to assure an adequate immune response even in the very elderly. thus, there is an equilibrium between adaptation and maladaptation, and this balance may be disrupted depending on the type, the degree, and the acuteness of aggression (fig. 1 ). the performance of the immune system cannot be completely evaluated without discussing the role of the inbuilt immune suppressor mechanisms which may also be affected by age [168] [169] [170] . first, the role of tregs is double; on the one hand, they should control the extent of the inflammation, and on the other hand, they should avoid the autoimmune processes arising continuously in the body and assure the attrition of the immune response once the danger has been eradicated [168, 171] . given the central role of treg cells in immune homeostasis, age-related loss of treg function would be predicted to render the host susceptible to excessive immunity, encountered in elderly humans as a syndrome of chronic low-grade inflammation [172] . conversely, age-dependent gain of treg activity would expose the host to greater risk of immune failure, such as the rising risk of malignancies and infections in the aging population [171] . emerging data suggest that some treg populations, specifically naturally occurring tregs (ntreg), seem to accumulate with advancing age, whereas inducible tregs (itreg) appear to be less available in the older host, though this is controversial [118] . human studies assessing peripheral blood of aged versus young individuals seem to concur that the percentage of cd4 + tregs is increased in older individuals [173, 174] . all these data indicate that the cd4 + treg compartment expands with age, relative to the total cd4 + t cells. human cd4 + foxp3 + tregs from older individuals show enhanced foxp3 expression compared with tregs from young individuals, while the remainder of their fig. 1 . the balance between the adaptive/maladaptive patterns of an individual's aging immune system. adaptive and maladaptive immune changes can be found simultaneously in the same individual and in the same arms of the immune response (innate or adaptive). concurrent (also balanced or imbalanced) changes in other body systems will affect the immune system. complex integrated immunobiography over time will determine which state (balanced/adapted or imbalanced/maladapted) will predominate and towards which destiny (resilience and longevity, or aging-related diseases, frailty and earlier death) the organism will be pushed phenotypic makeup (gitr, ctla-4, cd127 low ) is unchanged [175] . the implication of this finding is that although tregs retain most of their functional properties, which would be responsible for suppressing immune activation against infection and tumors, while in the meantime, they may fail to control autoimmune inflammation. however, autoimmune diseases are relatively rare in elderly [176] . such an abnormality suggests that an apparent paradox is observed during aging as an aberrant inflammation coexists with immune hyporesponsiveness to infection, vaccination, and tumors [9] . like cd4 + tregs, the percentage of cd8 + foxp3 + tregs has been shown to be significantly increased in the blood of older individuals [177] . given the critical role of tregs in immune homeostasis, any decline in treg competence would inevitably lead to a disbalance of protective and pathogenic immunity and would favor chronic, relentless, and possibly tissuedamaging inflammation [171] . in reality, as already discussed above, aging is indeed associated with a low-grade but clinically not manifest inflammation (inflammaging) which is not out of control. this indicates that the increased treg number sufficiently control inflammaging, in contrast to what it is commonly stated. in contrast, increased numbers of tregs could be considered detrimental in the suppression for the specific adaptive immune responses, mainly in infections and eventually in cancer [168] . it is of note that in cancer tregs were demonstrated to be immunosuppressive directly in the tumor microenvironment [178] . it is also questionable whether their role in the specific immune response is detrimental or regulatory, as the age-related inflammatory diseases start at middle age and not in old age. the well-regulated treg activity may also prevent a hyperreactivity of the immune system, as is seen in the present covid-19 infection in a form of cytokine storm. there is another major immunoregulatory/suppressor cell type, namely, myeloid derived suppressor cells (mdscs) [170, 179] . the mdscs are specialized immunosuppressors which can control the functions of all other immune cells, thus preventing excessive inflammatory responses [180] . there is convincing evidence that the aging process increases the frequencies of circulating mdscs in humans [181] . verschoor et al. [182] revealed that the levels of the cd11b + cd15 + and granulocytic mdscs were increased in the blood of community-dwelling seniors (61-76 years) and especially in frail elderly people (67-99 years). furthermore, it was shown that the mdscs induce the increase of tregs [170, 183] . in this way, there is an immunosuppressive network which is created as individuals are aging as coined by salminen et al. [184] . it seems that tgf-β, il-10, and no, secreted by mdscs, are the major soluble mediators maintaining the functions of this age-related immunosuppressive network [185] . there is an abundant literature indicating that tgf-β signaling suppresses the functions of cd4 + [186] and cd8 + [187] t cells as well as dcs [188] and nk cells [189] . in particular, tgf-β inhibits the signaling pathways of cd28 and mtor kinase [190] . il-10 also inhibits the cd28mediated signaling in t cells by activating shp-1 tyrosine phosphatase-1 [191] . together, the immunosuppressive network increase with aging may have several pathological consequences [184, 185] , but however, in the spirit of immunobiography, this can also be considered an adaptation to decrease the lifelong activation process of the innate immune system (innate immune memory) but unfortunately in the meantime downregulate adaptive immune activation. among the elderly, the number of centenarians and semisupercentenarians is steadily increasing, especially in the blue zones [192] . there is a debate as to whether centenarians and semi-supercentenarians are the result of selection or whether they represent the way that humans should physiologically age, with others simply having risk factors that preclude them from attaining this age even if we consider their genetic specificities. centenarians are a category of exceptionally aged individuals that succeed in preventing or delaying the onset of age-related disorders such as cv disease, type 2 diabetes mellitus (t2dm), alzheimer's disease, or cancer [193, 194] . it is also well-known that these centenarians do not avoid major diseases but are able to counteract their deleterious effects, which most of the other elderly are not capable of. probably the advantage that they have is what we could call the "adaptage," which during their immunobiography resulted in the development of resilience which could overcome the many dysfunctions and lead to a maintained functionality [192] . the centenarians have adapted their immune responses which maintain an adequate functionality and, in the meantime, control inflammaging [31, 32, 195] . this means that they have an efficient anti-inflammaging machinery which may be constituted from immunosuppressive cells and soluble mediators like circulating gp130 to compensate for their increased il-6 level [32] . in this context, pawelec's group has shown a positive correlation between increased frequency of tregs and survival in the elderly, which suggests the increasing importance of maintaining a balance between the adaptation and the maladaptation of immune responses and inflammation as we grew old [196] . one example of this adaptation/maladaptation is the microbiome largely influencing/shaping the functioning of all physiological systems, particularly that of the immune system in centenarians [193, [197] [198] [199] . extreme longevity seems also to be associated with a unique shift of the gut microbiome c h a r a c t e r i z e d b y e n r i c h m e n t i n a k k e r m a n s i a , bifidobacterium, and christensenellaceae [200] . on one hand, microbiota in centenarians show more diversity than in young old, resembling more that found in young subjects [201] . here, certain aspects of the changes in centenarians and semi-supercentenarians are proinflammatory, such as the decline in the abundance of the putative butyrate producers like faecalibacterium (phylum firmicutes), while on the other hand within the bacteroidetes phylum, rikenellaceae (alistipes) and porphyromonaceae (parabacteroides, odoribacter, porphyromonas), also butyrate producers, were found to be increased in all centenarians [201] with the concomitant decrease of prevotella (phylum bacteroidetes) richness, sustaining the changes in microbiota holding strong antiinflammatory activity [202, 203] . thus, the dysbiosis, proinflammatory change in microbiota composition in the oldest old, is compensated by the increase of anti-inflammatory bacteria which are metabolically more active than the former [204] . thus, the microbiota of centenarians support both the increase in the inflammatory load found in the sera but also a compensatory mechanism which is maintaining a fine balance, nevertheless favoring longevity. we should also mention that not all centenarians are made equal. a recent study by tedone et al. [192] studied telomere length and telomerase activity in t cells from low-and highperforming centenarians. they identified several parameters that are different between high-and low-performing centenarians: (a) the amount of proliferation following in vitro stimulation is dramatically greater in high-performing centenarians compared with 67-to 83-year-old controls and lowperforming centenarians; (b) telomere length is greater in the high-performing centenarians; and (c) telomerase activity following stimulation is greater in the high-performing centenarians. in addition, this study has validated a number of genes whose expression was directly related to telomere length which may influence the risk and progression of multiple aging-associated conditions. together, centenarians have better resilience and biological reserves to effectively cope with multiple issues originated from their immunobiography. they can also better cope with inflammaging as they are able to mount a powerful antiinflammaging response neutralizing the overall presence of inflammatory processes [32, 205] . it was clearly demonstrated in case of the semi-supercentenarians in whom the most powerful determinant of longevity was the presence of controlled inflammation [33] . they are the perfect example of hormesis and homeodynamic balance, as they have all the described supposed detrimental effect of aging on the immune system, but they have a powerful compensatory mechanism, a perfect demonstration of the "adaptage" concept of the immune changes. the understanding of adaptation/maladaptation of the immune system with aging was never more relevant than during the covid-19 pandemic. it is widely stated that the old individuals are more susceptible [6, 9, 206, 207] . this should help us to better understand the immune changes with aging which may be detrimental and which may be beneficial. as mentioned, not all elderly who are infected will progress to the severe stage and will not die either [208] [209] [210] [211] . the sars-cov-2 infection is a two-step inducer of the immune response. at the beginning, a functional immune system could contain the infection even in elderly [212, 213] . an effective innate and adaptive immunity is required to try to advance the response until efficient antibody production begins. most of the elderly can fight the infection but perhaps will not establish protective immunity with ab. in those where the immune system is less efficient, the virus will propagate, and a massive destruction of the tissues, especially those possessing abundant ace2 receptors, will ensue [214, 215] . damaged cells will induce massive inflammation via the stimulation of macrophages producing the cytokine storm. as the lung is the main acute target for sars-cov-2, it could be that the lung epithelial cells may also participate in the inflammatory mediators' production [216] . this is not far from resembling the pathomechanism of sepsis [217, 218] . it is debatable whether good health is an advantage or not for the course of sars-cov-2 infection, as the huge immune response during the second phase may be a strong disadvantage [219, 220] . it is also of note that among the elderly who died in the hospitals, only 1% had comorbidities [221] . in the nursing homes, the situation is different as the old persons living in these institutions are not only comorbid but very ill; otherwise they would not be in these institutions [222] [223] [224] [225] . in their cases, already the first step is deficient, so they die as in the case of influenza from the immunosuppressive effect of the virus and the following increased infection by bacteria or fungi [226, 227] . these differences in the elderly reflect their heterogeneity and also the differences of the immune status in each individual. what would it take to move from the "damn-age" concept to the "adaptage" concept? first of all, biology of aging research should dissociate itself from what can be called ageism. the idea that young individuals are by definition in a better state is a cultural belief, not a biological fact [227] . thus, perhaps not all data should be interpreted as detrimental, but considered from an evolutionary and immunobiographic perspective, including the concepts of balanced adaptation/maladaptation as the norm. it should also move from the "good versus bad" concept that biology does not recognize, as these are moral concepts. furthermore, researchers should not derive unequivocal conclusions from mouse data applied to humans, as they do not always follow the same path. in fact, the majority of the immune system-related data refer to mouse data without sufficient warning about the profound difference between murine biology and human biology. these data are highly misleading and lead to many failures when applied to humans. one recent example is the failure of vaccination and use of monoclonal antibodies for treating alzheimer's disease [228] . one of the most important criticisms of human studies is the heterogeneity of humans, which increases with age. this is absolutely true, but this is not a disadvantage but a wealth. this is the only way to unravel how the immune and other related physiological systems age. the immune system and physiology more generally are canonical examples of complex adaptive systems [229, 230] , and it is well-known that linear, cause-and-effect models perform poorly for understanding such systems [231] ; nonetheless, much of the research in these fields has applied methodology based on controlled experiments, which assume that results in a tightly controlled environment (e.g., lab mice) are easily extrapolatable, rather than methodologies that embrace heterogeneity and complexity. undoubtedly, the latter are challenging, but they are also essential if we want to arrive at robust conclusions. this is more and more emphasized in research papers when they deal with aging. the one mentioned for centenarians is a bright example of this necessity if we want to understand what is occurring during aging [192] . another example is a study published a few years ago, which has shown how to identify the drivers of the interindividual diversity of the human immune system, which is crucial to understand their consequences for immune-mediated diseases. by examining the transcriptional responses of 1000 individuals to various microbial challenges, they have shown that age and sex influence the expression of many immunerelated genes, but their effects were overall moderate, whereas genetic factors affect a smaller gene set but with a stronger effect. these results enable us to understand the regulatory role of interindividual variants in the pathogenesis of immune-related diseases and improve our understanding of the respective effects of age, sex, and genetics on immune response variation [166] . furthermore, better understanding not only of the changes in the adaptive t cell compartment but also in the innate compartment occurring with aging will help to better understand how the inflammaging concept may also have some adaptive characteristics and not only be considered the driver of agerelated diseases [14] . it is of paramount importance to assess the role of the trained immune memory in aging humans [38, 67] . furthermore, this would help also to design better vaccines. this is demonstrated by the success of shingrix a vaccine designed for elderly to prevent herpes zoster reactivation, which uses a special adjuvant to help boost the innate immune stimulation toward an effective adaptive immune response in 80 to 90% of old individuals [29] . this would perhaps end the misleading concept that elderly do not respond to vaccination. as we have already stated, this is not the fault of the immune changes with aging but the use of inadequate vaccines, such as in the case of the influenza vaccines, and in particular vaccines that were designed for the immune systems of younger individuals. the increased success of the quadrivalent vaccine is the proof that elderly can built efficient and protective responses [232] [233] [234] . finally, the understanding of the holistic nature as well as the step by step progression of the immune system should lead not to the "single pill" intervention model but to the multimodal/multistep intervention model. aging is a natural process which ultimately results in death. however, the aging process should not be defined only by the perspective of death, which is inevitable. concomitantly, it is often conceptualized that aging is the major underlying cause of all alterations occurring with aging and leading to agerelated diseases, forgetting that these disease processes started long before the beginning of old age. however, the aging process is very different for each individual, which means that aging is not occurring uniformly in every human being. this underlies the plasticity of the physiological functions' changes accompanying aging, including those of the immune system. the immune system has evolved to protect us from aggressions and challenges. it is well established that its dysfunction can lead to pathologies in the elderly. however, not all elderly will suffer from these diseases: more and more are reaching a very old age, with centenarians and semi-supercentenarians having a relatively well-functioning immune system. so, the immune system during life is depending on its individual, unique immunobiography, consequently developing concomitantly adaptative and maladaptive aspects of its functioning. the balance between these functions will determine how the person will age (fig. 1) . it is possible that the effect of age may only be detrimental, as the most common paradigm is stating. however, a more positive and balanced consideration of the immune response with aging will permit us to intervene in a judicious manner. still, many studies are needed to learn how to not intervene when it is not necessary and how to intervene in a multimodal/multistep way where it is needed. better lifestyle, vaccines, and microbiome modulation will help to increase the adaptaging part of the immune system for a healthier life of old individuals. epidemiology working group for ncip epidemic response, chinese center for disease control and prevention (2020) the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china severe outcomes among patients with coronavirus disease 2019 (covid-19) -united states characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention casefatality risk estimates for covid-19 calculated by using a lag time for fatality care for critically ill patients with covid-19 the role of immunosenescence in the development of age-related diseases the immune system and its dysregulation with aging aging of the immune system. mechanisms and therapeutic targets inflamm-aging. an evolutionary perspective on immunosenescence blue zones: lessons from the world's longest lived identification of a blue zone in a typical chinese longevity region the twilight of immunity: emerging concepts in aging of the immune system contributions of age-related thymic involution to immunosenescence and inflammaging human inflammaging immunosenescence in aging: between immune cells depletion and cytokines up-regulation immunosenescence and its hallmarks: how to oppose aging strategically? a review of potential options for therapeutic intervention macrophages in age-related chronic inflammatory diseases markers of t cell senescence in humans does the human immune system ever really become "senescent inflammaging and 'garb-aging inflammaging: a new immune-metabolic viewpoint for agerelated diseases inflammaging and human longevity in the omics era immunity and inflammation: from jekyll to hyde immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? front immunol geroscience: linking aging to chronic disease the emergence of geroscience as an interdisciplinary approach to the enhancement of health span and life span the hallmarks of aging efficacy of an adjuvanted herpes zoster subunit vaccine in older adults persistence of immune response to an adjuvanted varicella-zoster virus subunit vaccine for up to year nine in older adults inflammation, not cholesterol, is a cause of chronic disease inflammaging and anti-inflammaging: the role of cytokines in extreme longevity inflammation, but not telomere length, predicts successful ageing at extr eme old age: a longitudinal study of semisupercentenarians immune checkpoint inhibitors and elderly people: a review does patient age influence anti-cancer immunity? the first 75 days of novel coronavirus (sars-cov-2) outbreak: recent advances, prevention, and treatment benign covid-19 in an immunocompromised cancer patient -the case of a married couple immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity vaccination in the elderly: the challenge of immune changes with aging inflammation, genetic background and longevity immunosenescence: implications for response to infection and vaccination in older people the impact of senescence-associated t cells on immunosenescence and agerelated disorders immune system dysfunction in the elderly immunosenescence and vaccine failure in the elderly: strategies for improving response a sestrindependent erk-jnk-p38 mapk activation complex inhibits immunity during aging innate immunity: impact on the adaptive immune response a brief review of the basics of immunology: the innate and adaptive response a brief journey through the immune system a brief outline of the immune system introduction to the immune system macrophage polarization in chronic inflammatory diseases: killers or builders? how the innate immune system senses trouble and causes trouble the immune system in atherosclerosis inflammation and cancer role of the peripheral innate immune system in the development of alzheimer's disease the integration of inflammaging in age-related diseases bacille calmette-guerin induces nod2-dependent nonspecific protection from reinfection via epigenetic reprogramming of monocytes innate immune memory: an evolutionary perspective trained immunity: an ancient way of remembering innate immune memory: the latest frontier of adjuvanticity bcg vaccination protects against experimental viral infection in humans through the induction of cytokines associated with trained tmmunity epigenetic programming of monocyte-to-macrophage differentiation and trained innate immunity ) mtor-and hif-1α-mediated aerobic glycolysis as metabolic basis for trained immunity epigenetics and trained immunity the itaconate pathway is a central regulatory node linking innate immune tolerance and trained immunity from inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation phosphoinositide 3-kinase inhibition restores neutrophil accuracy in the elderly: toward targeted treatments for immunosenescence host resistance and immune aging signal transduction and functional changes in neutrophils with aging impairment of shp-1 down-regulation in the lipid rafts of human neutrophils under gm-csf stimulation contributes to their agerelated, altered functions aging, microglial cell priming, and the discordant central inflammatory response to signals from the peripheral immune system aging microglia-phenotypes, functions and implications for age-related neurodegenerative diseases immunosenescence: a systems-level overview of immune cell biology and strategies for improving vaccine responses adaptive immunity the biology of innate lymphoid cells the roles for innate lymphoid cells in the human immune system spatial and temporal mapping of human innate lymphoid cells reveals elements of tissue specificity innate lymphoid cells (ilcs): cytokine hubs regulating immunity and tissue homeostasis innate lymphoid cells: major players in inflammatory diseases group 3 innate lymphoid cells mediate early protective immunity against tuberculosis human nkp44+ group 3 innate lymphoid cells associate with tumorassociated tertiary lymphoid structures in colorectal cancer why innate lymphoid cells? cd1d restriction and th1/th2/th17 cytokine secretion by human vδ3 t cells cd1d-lipid antigen recognition by the γδ tcr ) γ/δ t cell subsets in human aging using the classical α/β t cell model histone deacetylase inhibitor modulates nkg2d receptor expression and memory phenotype of human gamma/delta t cells upon interaction with tumor cells nkg2d-and t-cell receptor-dependent lysis of malignant glioma cell lines by human γδ t cells: modulation by temozolomide and a disintegrin and metalloproteases 10 and 17 inhibitors the vγ9vδ2 t cell antigen receptor and butyrophilin-3 a1: models of interaction, the possibility of co-evolution, and the case of dendritic epidermal t cells an overview on the identification of mait cell antigens mapping of γ/δ t cells reveals vδ2+ t cells resistance to senescence vδ2+ and α/ß t cells show divergent trajectories during human aging the development of adult innate lymphoid cells innate lymphoid cells: 10 years on activation of group 2 innate lymphoid cells alleviates aging-associated cognitive decline n g immunosenescence to improve responses to vaccines a b-cell subset uniquely responsive to innate stimuli accumulates in aged mice riley rl in senescence, age-associated b cells secrete tnfα and inhibit survival of b-cell precursors toll-like receptor 7 (tlr7)-driven accumulation of a novel cd11c + b-cell population is important for the development of autoimmunity ageassociated b cells: a t-bet-dependent effector with roles in protective and pathogenic immunity impact of aging on antigen presentation cell function of dendritic cells systems-level analysis of innate immunity innate immunosenescence: effect of aging on cells and receptors of the innate immune system in humans aging of the innate immune system inflammation and neutrophil immunosenescence in health and disease: targeted treatments to improve clinical outcomes in the elderly characterization of mhc-ii antigen presentation by b cells and monocytes from older individuals radiation-and age-associated changes in peripheral blood dendritic cell populations among aging atomic bomb survivors in japan dendritic cells and the control of immunity monocyte-derived dendritic cells as antigenpresenting cells in t-cell proliferation and cytokine production toll-like receptor signaling and its inducible proteins tlr signalling and the function of dendritic cells circulating, interferon-producing plasmacytoid dendritic cells decline during human ageing peripheral blood dendritic cells and monocytes are differently regulated in the elderly aging is associated with a numerical and functional decline in plasmacytoid dendritic cells, whereas myeloid dendritic cells are relatively unaltered in human peripheral blood age-associated decrease in tlr function in primary human dendritic cells predicts influenza vaccine response dendritic cells in human aging increased reactivity of dendritic cells from aged subjects to self-antigen, the human dna reciprocal expression of p-glycoprotein and tap1 accompanied by higher expression of mhc class i antigens in t cells of old mice winter) memory lymphocytes of young and old c57bl/6 mice express high levels of class i major histocompatibility complex (h-2 kb) protein immunosenescence of macrophages: reduced mhc class ii gene expression global analyses revealed age-related alterations in innate immune responses after stimulation of pathogen recognition receptors from "truly naïve" to "exhausted senescent" t cells: when markers predict functionality immunosenescence: participation of t lymphocytes and myeloid-derived suppressor cells in agingrelated immune response changes human t cell immunosenescence and inflammation in aging t cells and immune functions of plasma extracellular vesicles are differentially modulated from adults to centenarians diversity and clonal selection in the human t-cell repertoire age-related decrease in tcr repertoire diversity measured with deep and normalized sequence profiling similar but different: virtual memory cd8 t cells as a memory-like cell population aging of antiviral cd8(+) memory t cells fosters increased survival, metabolic adaptations, and lymphoid tissue homing activation of mir-21-regulated pathways in immune aging selects against signatures characteristic of memory t cells cutting edge: synapse propensity of human memory cd8 t cells confers competitive advantage over naive counterparts successful and maladaptive t cell aging covid-19 and immunity in aging populations -a new research agenda the impact of aging on memory t cell phenotype and function in the human bone marrow aging and cytomegalovirus infection differentially and jointly affect distinct circulating t cell subsets in humans memory t cell homeostasis and senescence during aging memory t-cell homeostasis and senescence during aging t cell replicative senescence in human aging senescence of t lymphocytes: implications for enhancing human immunity divergent mechanisms of metabolic dysfunction drive fibroblast and t-cell senescence human cd8(+) emra t cells display a senescence-associated secretory phenotype regulated by p38 mapk immunosurveillance of senescent cells: the bright side of the senescence program impact of cmv upon immune aging: facts and fiction cmv seropositivity and t-cell senescence predict increased cardiovascular mortality in octogenarians: results from the newcastle 85+ study the reserve-capacity hypothesis: evolutionary origins and modern implications of the trade-off between tumor-suppression and tissue-repair age and age-related diseases: role of inflammation triggers and cytokines. front immunol dissecting aging and senescence-current concepts and open lessons defining 't cell exhaustion overcoming t cell exhaustion in infection and cancer molecular and cellular insights into t cell exhaustion is there a positive side to t cell exhaustion? front immunol signal transduction changes in cd4(+) and cd8(+) t cell subpopulations with aging signaling pathways in aged t cells -a reflection of t cell differentiation, cell senescence and host environment membrane signal transduction in t cells in aging humans cellular signaling in the aging immune system longitudinal study of leukocyte dna methylation and biomarkers for cancer risk in older adults does metabolic reprogramming underpin age-associated changes in t cell phenotype and function? free radic biol med metabolic reprogramming in memory cd4 t cell responses of old adults age-associated decline in effective immune synapse formation of cd4(+) t cells is reversed by vitamin e supplementation aging, immunosenescence and membrane rafts: the lipid connection signal inhibition by the dual-specific phosphatase 4 impairs t cell-dependent b-cell responses with age decline in mir-181a expression with age impairs t cell receptor sensitivity by increasing dusp6 activity downregulation of inhibitory src homology 2 domain-containing phosphatase-1 (shp-1) leads to recovery of t cell responses in elderly defective signaling in the jak-stat pathway tracks with chronic inflammation and cardiovascular risk in aging humans distinctive roles of age, sex, and genetics in shaping transcriptional variation of human immune responses to microbial challenges personal aging markers and ageotypes revealed by deep longitudinal profiling regulatory t cells and the immune aging process: a mini-review an association between immunosenescence and cd4(+)cd25(+) regulatory t cells: a systematic review immunosenescence: the potential role of myeloid-derived suppressor cells (mdsc) in age-related immune deficiency homeostasis and function of regulatory t cells in aging immune aging and autoimmunity functional regulatory t cells accumulate in aged hosts and promote chronic infectious disease reactivation cd4 cd25high regulatory t cells are not impaired in patients with primary sjögren's syndrome the number of human peripheral blood cd4+ cd25high regulatory t cells increases with age aging of the immune system: a risk factor for autoimmunity? the frequency of regulatory cd3+cd8+cd28-cd25+ t lymphocytes in human peripheral blood increases with age tumorinfiltrating regulatory t cells: phenotype, role, mechanism of expansion in situ and clinical significance myeloid-derived suppressor cells as regulators of the immune system the immunobiology of myeloidderived suppressor cells in cancer parameters of the immune system and vitamin d levels in old individuals. front immunol blood cd33(+)hla-dr(-) myeloid-derived suppressor cells are increased with age and a history of cancer correlation between mdsc and immune tolerance in transplantation: cytokines, pathways and cell-cell interaction er stress activates immunosuppressive network: implications for aging and alzheimer's disease activation of immunosuppressive network in the aging process the tgf-β-smad3 pathway inhibits cd28-dependent cell growth and proliferation of cd4 t cells cellintrinsic transforming growth factor-β signaling mediates virusspecific cd8+ t cell deletion and viral persistence in vivo the role of tgf-β signaling in dendritic cell tolerance canonical tgf-β signaling pathway represses human nk cell metabolism tgf-β inhibits the activation and functions of nk cells by repressing the mtor pathway il-10 inhibits cd28 and icos costimulations of t cells via src homology 2 domain-containing protein tyrosine phosphatase 1 telomere length and telomerase activity in t cells are biomarkers of highperforming centenarians the gut microbiota of centenarians: signatures of longevity in the gut microbiota profile gut microbiota changes in the extreme decades of human life: a focus on centenarians cellular immune activation in sardinian middle-aged, older adults and centenarians ccr4+ regulatory t cells accumulate in the very elderly and correlate with superior 8-year survival the interaction of intestinal microbiota and innate lymphoid cells in health and disease throughout life gut microbiota and aging through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians comparison of the gut microbiota of centenarians in longevity villages of south korea with those of other age groups comparative analysis of the gut microbiota in centenarians and young adults shows a common signature across genotypically non-related populations recognition of commensal microflora by toll-like receptors is required for intestinal homeostasis gut microbiota signatures of longevity pérez-martínez p (1866) gut microbiota and aging-a focus on centenarians inflammaging and antiinflammaging: a systemic perspective on aging and longevity emerged from studies in humans inflamm-aging: why older men are the most susceptible to sars-cov-2 complicated outcomes. reprints (www.preprints. org) sars-cov-2 and covid-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes china medical treatment expert group for covid-19. clinical characteristics of coronavirus disease 2019 in china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study clinical characteristics of patients who died of coronavirus disease 2019 in china risk factors for severity and mortality in adult covid-19 inpatients in wuhan 1) the many faces of the anti-covid immune response imbalanced host response to sars-cov-2 drives development of covid-19 organ-protective effect of angiotensin-converting enzyme 2 and its effect on the prognosis of covid-19 a hypothesis for pathobiology and treatment of covid-19: the centrality of ace1/ace2 imbalance severe acute respiratory syndrome coronavirus 2 (sars-cov-2): an overview of viral structure and host response the immune system regulation in sepsis: from innate to adaptive sepsis and immunosenescence in the elderly patient: a review immune response to sars-cov-2 and mechanisms of immunopathological changes in covid-19 the first, holistic immunological model of covid-19: implications for prevention, diagnosis, and public health measures immune-epidemiological parameters of the novel coronavirus -a perspective covid-19 pandemic: palliative care for elderly and frail patients at home and in residential and nursing homes editorial: covid-19 and older adults the coronavirus and the risks to the elderly in long-term care covid-19 and older adults: what we know invasive pulmonary aspergillosis complicating severe influenza: epidemiology, diagnosis and treatment is aging biology ageist? anti-amyloid-β monoclonal antibodies for alzheimer's disease: pitfalls and promise systems immunology: just getting started complex adaptive systems complex systems dynamics in aging: new evidence, continuing questions vaccines to prevent infectious diseases in the older population: immunological challenges and future perspectives control of adaptive immunity by the innate immune system influenza and bacterial superinfection: illuminating the immunologic mechanisms of disease publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-329626-lsbny5to authors: losada-baltar, andrés; jiménez-gonzalo, lucía; gallego-alberto, laura; pedroso-chaparro, maría del sequeros; fernandes-pires, josé; márquez-gonzález, maría title: “we’re staying at home”. association of self-perceptions of aging, personal and family resources and loneliness with psychological distress during the lock-down period of covid-19 date: 2020-04-13 journal: j gerontol b psychol sci soc sci doi: 10.1093/geronb/gbaa048 sha: doc_id: 329626 cord_uid: lsbny5to objectives: families are going through a very stressful time because of the covid-19 outbreak, with age being a risk factor for this illness. negative self-perceptions of aging, among other personal and relational variables may be associated with loneliness and distress caused by the pandemic crisis. method: participants are 1310 spanish people (age range: 18-88 years) during a lock-down period at home. in addition to specific questions about risk for covid-19, self-perceptions of aging, family and personal resources, loneliness and psychological distress were measured. hierarchical regression analyses were done for assessing the correlates of loneliness and psychological distress. results: the measured variables allow for an explanation of 48% and 33% of the variance of distress and loneliness, respectively. being female, younger, having negative self-perceptions about aging, more time exposed to news about covid-19, more contact with relatives different to those that co-reside, fewer positive emotions, less perceived self-efficacy, lower quality of sleep, higher expressed emotion and higher loneliness were associated with higher distress. being female, younger, having negative self-perceptions about aging, more time exposed to news about covid-19, lower contact with relatives, higher self-perception as a burden, fewer positive emotions, lower resources for entertaining oneself, lower quality of sleep and higher expressed emotion were associated with higher loneliness. the outbreak of the covid-19 pandemic is having a strong impact among individuals and families, who are going through a very stressful period (zhang, wang, rauch, & wei, 2020) . countries such as spain are requiring lock-downs of their citizens. epidemiological data indicate that age is clearly associated with the risk of developing critical health problems and mortality related to this illness (remuzzi & remuzzi, 2020) . beyond chronological age, negative self-perceptions of aging may be related to negative outcomes for older adults and play a significant role in this context, considering previous findings linking negative selfperceptions of aging to less engagement in health behaviors (levy & myers, 2004) . the risk of getting infected by covid-19 through personal contact, together with the lock-down scenario, may contribute to feelings of loneliness and psychological distress. the prolonged exposure to stress due to the lock-down scenario may also contribute to an increase in psychological distress by reducing sources of support (e.g., family), increasing the importance of personal resources such as self-efficacy and relational variables. these issues may have a strong impact on perceived loneliness, a factor widely associated with psychological distress as well as an outcome in itself (cacioppo & cacioppo, 2018) . drawing upon the stress and coping model (lazarus & folkman, 1984) , which highlights the relevance of personal or social resources for understanding the differences in distress between individuals, the objective of this study is to analyze the capacity of variables related to the outbreak of covid-19 to explain loneliness and distress in people exposed to covid-19 lock-down scenario, controlling for sociodemographic variables (including age and selfperceptions of aging), and personal and family resources. a c c e p t e d m a n u s c r i p t 5 participants and procedure participants were people older than 18 years living in spain and experiencing the required (mandatory) situation of lock-down at home, beginning on monday 16 th of march after the government's decision. participation in this study was requested through social networks and all the options available for the researchers to contact potential participants. the same description and request for participation was sent to associations or institutions that frequently collaborate with the research team, as well as to other potential associations or institutions contacted through social networks such as whatsapp, facebook or linkedin. the data presented here were gathered from saturday 21 st of march (at 19:00 hours) to thursday 24 th of march (at 21:00 hours). all participants provided their consent to participate in the study and during the first week of lock-down answered a survey that was developed using google forms. the study was approved by the ethics committee of the hospital universitario fundación alcorcón. in addition to age, gender, and marital status, self-perceptions of aging were measured through the same procedure used by levy, slade, kunkel and kasl (2002) , with the liang and bollen (1983) attitudes toward own aging subscale. this is a 5-item scale (e.g., "things keep getting worse as i get older"), with higher scores indicating more negative selfperceptions of aging. cronbach's alpha of this scale in the current sample was .60. stressors. considering sources of stress that have been identified as related with covid-19, such as the risk to clinicians' physical health (dewey, hingle, & linzer, 2020) , fear about own health (brooks et al., 2020) , and massive quantities of information about the pandemic a c c e p t e d m a n u s c r i p t 6 (van bavel et al., 2020), the following questions were included: "do you have a profession or vital situation that puts you in a risk situation?" (answers: "no" and "yes") and "do you consider yourself to be at risk of serious health outcomes if getting covid-19?" (answers: "no", "yes", and "i don't know). the item "how much time do you devote to looking for and processing information related to covid-19 and the current situation? (e.g., news, radio or tv, internet, others)" was included (answers ranging from 0 "not at all" to 10 "i am attentive to all the possible information"). family resources. the items "i am satisfied with the support that i receive from my family" (adapted from the apgar questionnaire (smilkstein, 1978) , with answers ranging from 0 "almost never" to 2 "always"), "i feel that i am a burden to my family" (from the self-perceived burden scale (cousineau et al., 2003) ; answers from 0 "never or almost never" to "4 "almost always"), and "how much contact do you have with relatives different to those you reside with?" (answers from 0 "no contact at all" to 10 "i have all the contact that i need") were included. in addition, participants were requested to report how many people (different from themselves) they were co-residing with. personal resources. ad hoc questions were included to measure diverse personal resources related with emotion regulation, behavioral, cognitive and social coping strategies selected among the many and diverse potential resource variables analyzed in the stress and coping literature. specifically, questions were included to measure daily positive emotions ("how many moments of happiness, humor, laughter, or positive emotions do you have per day?"; answers from 0, "no moment at all" to 10 "i have many moments per day"); entertainment resources ("to what extent do you feel that you have resources for entertaining yourself at home?"; answers from 0 "i have nothing to entertain myself with" to 10 "i have all the things i need"); and self-efficacy ("to what extent do you feel capable of coping effectively with the current situation?"; answers from 0 "not at all capable" to 10 "totally capable"). daily a c c e p t e d m a n u s c r i p t 7 time devoted to exercise was reported in a scale from 0 "no time at all" to 4 "more than one hour and a half"). quality of sleep was rated in a scale ranging from 0 "very bad" to 3 "very good". finally, as an indicator of expressed emotion, the following items based on the family attitude scale (kavanagh et al., 1997) were included: "to what extent do you like to have people around?", "i feel that people living with me are driving me crazy", "i lose my temper with those living with me", and "i shout at people living with me". cronbach's alpha for these 4 items in this sample is .87. loneliness. perceived loneliness was measured using the same procedure as kool and geenen (2012) , through the item "how much loneliness do you feel?", with answers ranging from 0 "i do not feel lonely at all" to 10 "i feel absolutely lonely". psychological distress. a wide array of psychological responses to covid-19 have been described, including anxiety and depression (wang et al., 2020), anger or fear (brooks et al., 2020) . with the aim of providing a brief measure of these diverse emotions, and drawing on research providing support for the use of single-item measures of emotional problems (e.g., zimmerman et al., 2006) , an ad-hoc 5-item scale was developed that measured, respectively, anxiety, anger, sadness, fear and hope (e.g., "how much sadness do you feel"). answers ranged from 0 "i do not feel _____ at all" to 10 "i feel totally _____", except for the item measuring hope, which was reversed. cronbach's alpha for this scale with the current sample is .80. in addition to descriptive and correlational analyses, two hierarchical regression analyses were conducted to examine the association between the assessed variables and loneliness and psychological distress, using the spss software (version 22.0). drawing upon the stress and a c c e p t e d m a n u s c r i p t 8 coping model, sociodemographic variables were included in the first step, followed by stressors, family resources, personal resources, and loneliness. participants were 1310 people (71.1% female) with an age range from 18 to 88 (mean = 42.36; sd: = 16.20). of these, 408 (31.1%) were aged between 18 and 29 years, 300 (22.9%) between 30 and 44, 375 (28.6) between 45 and 59, and 227 (17.3%) were older than 60 years. regarding measures of risk of contracting covid-19, 273 (20.8%) people reported being professionals at risk, and 309 (23.6%) reported perceiving themselves as at risk for covid-19. the descriptive characteristics of the remaining variables and correlations between the assessed variables can be found in the supplemental material. regarding the results of the hierarchical regression for explaining psychological distress (table 1) , the inclusion of variables at each step contributed significantly to the explained variance of psychological distress, with steps 1 (sociodemographic characteristics and negative self-perceptions of aging) and 4 (personal resources) yielding the highest contributions to the variance. the variables with a significant contribution to explaining distress in the final model were: being female, of lower chronological age, higher negative self-perceptions about aging, more time devoted to covid-19 information, more contact with other relatives different to those that co-reside, fewer daily positive emotions, less perceived self-efficacy, lower reported quality of sleep, higher expressed emotion and higher loneliness. regarding the results of the hierarchical regression for explaining loneliness (table 2) , the inclusion of variables at each step (except step 2, stressors) contributed significantly to the explained variance of loneliness, with step 1 (sociodemographic characteristics and negative self-perceptions of aging) yielding the highest contribution to the variance. the variables a c c e p t e d m a n u s c r i p t 9 with a significant contribution to explaining loneliness in the final model were the same that contributed to the explanation of psychological distress (except for perceived self-efficacy), plus a lower number of people (different from themselves) co-residing, a higher selfperception as a burden, and lower reported resources for entertaining oneself at home. contrary to our hypothesis, an inverse association was found between chronological age and both loneliness and distress. consistent with these results, previous studies have found a lower reactivity to stress in older adults (e.g., birditt, fingerman, & almeida, 2005) , that may be related to resilience (ong, bergeman, bisconti, & wallace, 2006) , or to a more effective emotion regulation ability, involving more use of preventive and emotion-focused strategies (e.g., charles & carstensen, 2007) . however, as expected, negative self-perceptions of aging were found to be strongly associated with emotional outcomes. this central role of negative self-perceptions of aging in the explanation of loneliness and distress identified in this study provides additional support for its importance as a dimension associated with negative outcomes, and supports an interesting combination of both the embodiment theory (levy, 2009 ) and the stress and coping model (lazarus & folkman, 1984) . the fact that the strength of association between negative self-perception of aging and loneliness and distress decreases (although still significant) in the fourth step of the model (when personal resources are included) could be suggesting an interesting mediation role of personal resources in the relationship between negative self-perceptions of aging with loneliness and psychological distress. these findings seem to support previous results reported by levy and myers (2004) , who found that positive self-perceptions of aging were related to engagement in more preventive health behaviors, and by bellingtier and neupert (2018) , who found that older a c c e p t e d m a n u s c r i p t 10 adults with more negative attitudes toward own aging reported increased emotional reactivity to stressors. being female was found to be associated with reporting higher loneliness and distress and, among the assessed stressors, participants having a profession that put them at risk of being infected with covid-19 did not show higher distress scores. only time devoted to looking for and processing covid-19 information, a strategy that can increase psychological vulnerability (van bavel et al., 2020) , had a significant positive association with loneliness and psychological distress. regarding family resources, having contact with members of the family that do not reside in the same household was found to be related to more distress (but lower loneliness) in the final step of the regression analysis. the correlations of distress with lower satisfaction with family support and negative self-perception as a burden, and fewer resources for entertaining oneself at home, are no longer significant when personal resources are considered. possible mediation effects could explain these findings. for example, lower satisfaction with the support from the family may lead to higher expressed emotion attitudes (delvecchio, di riso, chessa, salcuni, mazzeschi, & laghezza, 2014) . in summary, in addition to gender, chronological age, self-perceptions of aging, and time devoted to covid-10 information, family and personal resources, seem to be relevant for explaining loneliness and psychological well-being during a critical stressful period. a c c e p t e d m a n u s c r i p t 11 years old, in our study most of the participants were women. in addition, although the percentage of participants from the age ranges of 30 to 44, and 45 to 59 is similar to the general population distribution, a higher proportion of participants was obtained for the age range of 18 to 29, and a lower proportion for the range of 60 and older. also, older adults who participate in this study are users of online technologies and may not therefore be representative of the general older adult population, something that may be acting as a confounding variable in this study (as well as in similar studies done in the context of covid-19; zhong et al., 2020) . even though studies exist that provide support for the use of single-items in surveys and even clinical contexts (e.g., zimmerman et al., 2006) , the use of single-items for measuring the wide-ranging effects of the lock-down situation in the context of individuals and families through a brief and easy to answer measure is a limitation of the study. the internal consistency of the self-perceptions of aging scale, although similar to that reported in other studies (e.g., siebert, wahl, degen, & schröder, 2018) , is low. regarding the psychological distress measure, even though a good internal consistency was found, future studies are needed to support the validity and reliability of the measure. despite the fact that the obtained percentage of explained variance of loneliness and psychological distress is high, other variables that can also contribute to distress in this scenario were not measured, such as perceived susceptibility and confusion about information reliability (qian et al., 2020) , knowledge, attitudes and practices towards covid-19 (zhong et al., 2020) , or uncertainty about the future (including potential health or economic issues). in spite of these limitations, we believe that the findings of this study, obtained at a unique moment, with a large sample of participants during the first stage (first week) of the lockdown period linked to the covid-19 outbreak, provide important information regarding the effect of psychosocial variables on loneliness and psychological distress. loneliness and psychological distress seem to be related to family and personal resources that may have to a c c e p t e d m a n u s c r i p t 12 do with a negative view of aging, such as perceiving oneself as less capable of facing stressful situations adaptively, or maladaptive ways of communicating with other relatives. the data from this study suggest that it is not chronological age itself but having negative self-perceptions of aging that is related to loneliness and psychological distress in people during a lock-down at home during the covid-19 crisis. older adults with positive selfperceptions of aging seem to be more resilient to loneliness and distress during the covid-19 outbreak. m a n u s c r i p t 13 acknowledgements. the authors thank all the participants in the study. special thanks to cristina segura and javier yanguas (departamento de gent gran de la fundación bancaria la caixa) and pilar rodríguez from fundación pilares, and all the institutions that contributed to the sample recruitment. data collection was not pre-registered. the study materials, analytic methods and data are available upon request from the corresponding author on reasonable request. a c c e p t e d m a n u s c r i p t table 1 . step 1 step 2 step 3 step 4 step a c c e p t e d m a n u s c r i p t 21 table 2 . step 1 step 2 step 3 step negative aging attitudes predict greater reactivity to daily stressors in older adults age differences in exposure and reactions to interpersonal tensions: a daily diary study the psychological impact of quarantine and how to reduce it: rapid review of the evidence the growing problem of loneliness emotion regulation and aging measuring chronic patients' feelings of being a burden to their caregivers: development and preliminary validation of a scale expressed emotion, parental stress, and family dysfunction among parents of nonclinical italian children supporting clinicians during the covid-19 pandemic population by age and gender the family attitude scale: reliability and validity of a new scale for measuring the emotional climate of families loneliness in patients with rheumatic diseases: the significance of invalidation and lack of social support stress, appraisal and coping stereotype embodiment: a psychosocial approach to aging. current directions in psychological science longevity increased by positive self-perceptions of aging the structure of the philadelphia geriatric center morale scale: a reinterpretation positive emotions, and successful adaptation to stress in later life psychological responses, behavioral changes and public perceptions during the early phase of covid-19 outbreak in china: a population based cross-sectional survey covid-19 and italy: what next longitudinal change of selfperceptions of aging and mortality attitude toward own aging as a risk factor for cognitive disorder in old age: 12-year evidence from the ilse study the family apgar: a proposal for a family function test and its use by physicians using social and behavioural science to support covid-19 pandemic response health, distress and life satisfaction of people in china one month into covid-19 outbreak knowledge, attitudes and practices towards covid-19 among chinese residents during the rapid rise period of covid-19 outbreak: a quick online cross-sectional survey a c c e p t e d m a n u s c r i p t key: cord-304365-al3p52uj authors: egenvall, a.; nødtvedt, a.; häggström, j.; ström holst, b.; möller, l.; bonnett, b.n. title: mortality of life‐insured swedish cats during 1999–2006: age, breed, sex, and diagnosis date: 2009-09-22 journal: j vet intern med doi: 10.1111/j.1939-1676.2009.0396.x sha: doc_id: 304365 cord_uid: al3p52uj background: a cat life insurance database can potentially be used to study feline mortality. hypothesis: the aim was to describe patterns of mortality in life‐insured swedish cats. cats: all cats (<13 years of age) with life insurance during the period 1999–2006 were included. methods: age‐standardized mortality rates (mr) were calculated with respect to sex (males and females), age, breed, and diagnosis. survival to various ages is presented by time period and breed. results: the total number of cats insured was 49,450 and the number of cat‐years at risk (cyar) was 142,049. during the period, 6,491 cats died and of these 4,591 cats (71%) had a diagnosis, ie, were claimed for life insurance. the average annual mr was 462 deaths per 10,000 cyar (95% confidence interval, 431–493). sex‐specific rates did not differ significantly. the overall mortality of the persian and the siamese groups was higher than that of several other breeds. overall and breed‐specific (for most breeds) survival increased with time when analyzed by 2‐year periods. the 6 most common diagnostic categories (ignoring cats recorded as dead with no diagnosis) were urinary, traumatic, neoplastic, infectious, cardiovascular, and gastrointestinal. the mr within diagnostic categories varied by age and breed. conclusions and clinical importance: in this mainly purebred, insured cat population, the overall mortality varied with age and breed but not with sex. the increase in survival over time is likely a reflection of willingness to keep pet cats longer and increased access to and sophistication of veterinary care. i nformation regarding the common causes of death in an animal species is useful to veterinary practitioners, owners, breeders, and other stakeholders. it is a cornerstone of informed clinical decision making, when planning breeding programs or for deciding on disease prevention measures in populations. valid populationbased statistics must include information both on the denominator (the animals in the background population) and the numerator (the cases of disease or death). population-based figures on cat mortality and morbidity are limited. in a large telephone survey of north american households, a crude yearly death rate of 8.3 cat deaths/100 cats was found in the (presumably) general owned cat population. 1 information on feline mortality also has been obtained from case series or case control studies, where measures of proportional mortality may be found. risk factors for mortality at 23 british adoption centers were analyzed in a case control study, reporting an overall mortality of 4.7%. cats o 7 weeks and 47 years were at increased risk of death in this population. 2 in a german case series, cause of death was reported for 4,561 cats based on postmortem investiga-tions from 1969 to 1982. infectious disease (dominated by feline panleukopenia) was the most common reason for mortality. 3 more recently, cause of death among cats admitted to a french incineration facility was reported, and accidental death, followed by infectious disease, was most common. 4 the swedish agria insurance a database has been utilized to study morbidity and mortality in dogs and horses insured for veterinary care and life, respectively. 5, 6 in general, veterinary care insurance reimburses the owner for the cost of veterinary treatments up to a certain limit when the costs are above the deductible (which is paid by the owner). life insurance reimburses the owner for a certain set value (life insurance value) if the animal dies or is euthanized. according to agria's market estimates, approximately one-third of the officially registered pure-bred cats in sweden were insured for life with agria (ib ahlen, personal communication). because of the large proportion, this database may provide a valid source of population-based mortality rates (mr) in purebred cats. because of the high number of individuals included, mortality can be stratified and presented by sex, age group, breed, and diagnosis. we are unaware of any other population-based feline mortality studies of a similar scale in the veterinary literature. the aim was to describe patterns of mortality in swedish cats covered by a life insurance plan between 1999 and 2006, with respect to sex, age, breed, and diagnosis and to present survival to various ages crudely, by breed and time period. in order to qualify for life insurance at agria, a cat must be vaccinated against feline panleukopenia and have a market value, which is the maximum sum for which the cat can be life-insured (a cat acquired for free may get a low-life insurance value, 1,000 swedish crowns [sek]). therefore, in general only purebred cats have life insurance, usually acquired at young age, even though cats can enter life insurance until 6 years of age (if 42 years a health certificate from a veterinarian must accompany the application). cats can be life-insured up to 13 years of age. life insurance is renewed annually but can be terminated by the owner at any time if he or she so wishes. when a life-insured cat dies, a claim is processed using forms completed by the attending veterinarian. information includes a summary of the cat's disease problems. the form may be accompanied by the complete medical record, if requested by the insurance company. veterinarians classify the cause of death using a standardized diagnostic registry as has been described. 5 the exception is in some cases of traumatic death, where the owner, with witnesses, can state that the cat was, for example, killed in a traffic accident. the insurance does not pay claims for lost cats. in general, only 1 diagnostic code is used per claim. the registry includes both specific and general codes. 7 data on all cats insured between 1999 and 2006 were downloaded from the agria insurance database. variables used in this study included cat identification, sex, date of birth, breed, life insurance coverage, and diagnostic codes for cause of death. dates of visits to veterinarians and when cats entered or left the insurance program and reasons for leaving insurance were included. cats were assigned to the age category they had january 1st of each year (0 o 1 years, 1 o 2, etc). sex was either male or female as recording and timing of neutering was not reliable in the database. in the insurance data, 41 breed codes were used to classify breeds. breeds that were considered closely related were combined. abyssinians and somalis were combined to abyssinians; persians, chinchilla, colorpoint persians, and exotic shorthairs to the persian group; and siamese, balinese, foreign white, javanese, oriental shorthair, and seychelliosis to the siamese group. data have been presented for individual breeds with at least 1,000 cat-years at risk (cyar). ''domestic'' cats included domestic shorthair and longhair cats. the ''other'' group included various breeds. diagnoses were amalgamated into broad diagnostic categories or problems: ascites, allergy, anorexia, behavior, cardiovascular, dead/no diagnosis, ears, eyes, gastrointestinal, hormonal/metabolic, infections, locomotor problems, lost, neoplastic, neurological, surgery/complications thereof, reproductive, respiratory, integumentary, symptomatic (eg, fever, pain, unspecified), traumatic, and urinary. diagnoses also were presented on a specific-diagnosis level (usually the original code or combination of extremely similar codes). a complete list of diagnoses is available from the 1st author (ae). descriptive statistics were calculated. cats were at risk from either the 1st of january 1999 or the start date of insurance (if later), and until the date of death or withdrawal from insurance. cats for which the owner either submitted a life claim or simply reported the animal as dead were used as the numerator for mortality. mr calculations were used with the exact time at risk as the denominator. age-standardized mrs (asmr, which adjusts for differences in age distributions across groups or categories) have been calculated both for the whole period and yearly and are expressed as deaths per 10,000 cyar (data on age category 9 o 10 years and over were amalgamated for standardization). ''age category-specific'' mrs were calculated directly. standard errors times 1.96 yielded 95% confidence intervals (95% ci) for asmrs 8 and age category-specific mrs. 9 age standardized mrs, and mrs, respectively, have been calculated crudely, yearly, by sex, breed group, breed, diagnostic category, diagnosis, and by combinations thereof as well as for withdrawal unrelated to death. mortality was calculated for breed groups and for specific breeds with at least 1,000 cyar. proportional mortality was calculated as percent of all deaths, both for diagnostic categories and for specific diagnoses. unusually high breed group-specific asmrs were examined in detail (original or amalgamated diagnosis) to provide additional insight into the specific types of health issues in those breeds (cis not presented). this was done when there were at least 10 cats in each breed or breed group. survival curves were constructed crudely, by sex, as well as by breed group and sex. the survival at 5, 7.5, 10, and 12. the total number of cats insured was 49,450. the total cyar was 142,049, varying from 15,576 cyar in 2001 to 21,916 cyar in 2006 and is shown by age category in figure 1 . the 10th, 50th, and 90th percentiles for the cyar contributed by an individual cat were 4 months, 2.2 years, and 6.7 years. the median age at enrollment average total mortality (mr) by age category, with 95% confidence intervals, and the total number cat-years at risk (cyar) per age category (the last category excluded). estimates are calculated for discrete age categories. was 3.5 months, and 80% of the cats had been enrolled before 1 year of age. the number of cyar was 74,094 for males and 67,955 for females. the mean and median age of the analyzed population progressed during the time analyzed. the mean age, described by the age category on january 1 of each year, decreased from 4.0 to 2.9 years (median, from 3 to 2) during the time period. the breeds with the highest cyar were the persian group, the birman, and the norwegian forest cat ( table 1 ). the overall average yearly withdrawal rate was 1,424 withdrawals per 10,000 cyar (averaged 95% ci, 1,375-1,474). in total, 6,491 cats died with no clear time trend across years for mortality. the minimum annual asmr was 423 (95% ci, 396-452) in 2003 and the maximum was 519 (95% ci, 485-552) in 2000; the average was 462 (95% ci, 431-493) deaths per 10,000 cyar. figure 1 shows mrs by age with 95% cis (omitting the oldest age category because of few cats). in total, 3,540 of the deaths were males and 2,951 were females. the asmr was 476 (95% ci, 433-520) and 447 (95% ci, 403-492) deaths per 10,000 cyar for males and females, respectively. for breeds with at least 1,000 cyar, mortality is presented in table 1 including cyar, number of deaths, the asmr with 95% ci, the risk percent and the percent of deaths for which a diagnosis was available. overall, 4,591 cats died and were given a diagnosis (specific or unspecific). therefore, 71% of the deaths were claimed and had a diagnosis. table 2 . for all breeds other than the ragdoll, survival to 10 years was considerably higher in the last half compared with the 1st half of the study period (most comparisons are statistically significant, based on nonoverlapping cis). omitting cats first insured after 18 months of age had almost no effect on the survival estimates (overall 0.6 percent difference of the point estimates at 10 years of age). table 3 shows category-specific asmrs for the 11 diagnostic categories with at least 80 deaths, and for the 31 specific diagnoses within these with at least 20 deaths each. by sex, there were no significant differences for any of the categories. figure 3 demonstrates the age-specific mrs for the 6 most common diagnostic categories, ignoring cats that were recorded as dead/no diagnosis. figure 4 shows diagnostic category-specific asmrs by breed group for the same 6 categories. although point estimates vary widely, cis often overlap. the following asmrs are based on at least 10 cases per breed or breed group. for the somewhat amalgamated diagnosis upper urinary problems, the asmrs, in deaths per 10,000 cyar, maine coon 20, persian group 16, ragdoll 12, and norwegian forest cat 6. for mammary tumors the asmrs, in deaths per 10,000 cyar, were siamese 51, norwegian forest cat 14, persian group 9, and birman 6. for the somewhat merged diagnosis lower urinary problems 2 breeds had at least 10 deaths in total: the persian with an asmr of 16 and the norwegian forest cat with 14 deaths per 10,000 cyar. for the code cystic kidneys an asmr of 19 deaths per 10,000 cyar was found in the persian group (74 cases), whereas point estimates below 4 were found in other breeds. the burmese had an asmr for diabetes mellitus of 16 deaths per 10,000 cyar, the domestic cat 8 deaths per 10,000 cyar, the norwegian forest cat 7 deaths per 10,000 cyar and persian groups 3 deaths per 10,000 cyar. the mr was (not surprisingly) low during the 1st 5 age categories ( o400 deaths per 10,000 cyar) and reaching over 1,600 deaths per 10,000 cyar in age category 11 o12 years. by diagnostic category, urinary, neoplastic, and cardiovascular (nonsignificantly [ns] judged by overlapping cis) and gastrointestinal (ns) increased with age whereas infections and traumatic causes (ns) decreased with age. most of these results are similar to clinical perceptions or, where relevant comparisons can be made, published results from dogs. case series based on pathology data show that infections and trauma are the most common causes of death in cats. 3, 4 traumatic road accidents have been shown to decrease in frequency with increasing age. 10 data from studies presenting proportional mortality figures suggest that young cats often die from infections, whereas this is less common for older animals. 3, 4, 11 no significant differences were found between sex for the overall asmrs. unfortunately, data on deaths in cats over 13 years were not recorded. cats can have veterinary care insurance until older ages and analysis of that data may shed some light on diseases affecting older cats. however, from the perspective of preventing premature death, the mortality in the ''youngest'' cats (ie, o13 years of age) is undoubtedly of the highest importance. at 5, 7.5, and 10 years of age, many breeds showed a decrease in mortality over time (based on nonoverlapping cis between time periods). however, in ragdolls there are no differences and in maine coons the cis clearly overlap. as none of the survival curves reach 50% even in the highest age category, it is evident that that median age of death in these life-insured cats is 412 years of age. 9 2 also shown is the proportional mortality (pm) in percent for each system (number of cases with a specific diagnosis divided by the total number of cases (n54,591) with a diagnosis). breed-specific mortality varied from 664 in the siamese to 285 deaths per 10,000 cyar in the bengalese (table 1 ). in particular for the breed-specific analysis, the mrs were age standardized to avoid the effect of differing age distributions, as caused by waxing and waning popularities for some breeds, or changes in insurance enrollment. domestic cats have an asmr just below the average mean. in this database, the domestic cats may differ from the total population of domestic cats in sweden. from the survival analysis of the more common breeds, siamese and ragdolls have the lowest survival to 10 years. population-based research on these insurance data is facilitated by the mandatory use of a standardized, hierarchical diagnostic registry by all contributing veterinarians. 7, 12 previous studies have validated the accuracy of the diagnostic information for dog and cat data. 13 in the cats, we found that both demographic (breed, sex, and year of birth) and diagnostic information was correctly coded in 89% of the cases. however, we are unable to determine the level of certainty of the veterinarians' diagnoses, or the amount of ancillary information that underlies the diagnosis (eg, whether specific-neoplasia diagnoses are based on histologic con-firmation or not). however, the use of diagnostic categories allows us to group the data at levels for which we are more confident in the validity of the information. ''dead no diagnosis'' has been shown to be one of the most common recorded ''causes'' of death in these cats, as has been seen in studies of dogs and horses. this likely is a reflection of the realities of veterinary practice where cautious veterinarians are unable or unwilling to commit to a specific diagnosis in the absence of a diagnostic evaluation. there might also be a tendency to use a nonspecific code for convenience. however, certain categories of disease (eg, heart failure) might be more likely to be ''missed'' and placed in the no diagnosis category because of lack of diagnostic evaluation or postmortem examination than cases of, for example, traumatic death. space does not allow a detailed discussion of all of the major diagnostic categories for deaths in these cats and we have chosen to highlight the 5 most common specific categories. although cis have been calculated, their interpretation is difficult. these data essentially represent a census of deaths in the complete population of life-insured cats. in the subsequent discussions we have therefore chosen to focus on the point estimates in discussing differences. extrapolation and generalization of these findings to other populations of cats should be done with extreme caution. in addition, readers may note that the cis for the asmrs become considerably wider than cis of raw rates (unpublished information). urinary disease was the most common cause of death in total and in the persians, british shorthair, and ragdolls. in the 8 breeds in figure 4 , only the ragdolls had a very high asmr for urinary problems. the main 2 categories within ''urinary'' are kidney/ureter and lower urinary problems, with the former, having an asmr approximately 3 times the latter. the persian group had a considerably higher asmr for urinary disease than the domestics. within this breed, polycystic kidney disease accounted for a proportional mortality within the diagnostic category urinary of 20% and the persian group actually does have a somewhat higher proportion of upper compared with lower urinary disease compared with the other breeds. accordingly, only a part of the high rate is likely because of the known predisposition for polycystic kidney disease. 14 as death because of urinary disease increases with age, it can be assumed that it will be a common cause of death in these breeds also after 12 years of age. traumatic causes of death were primarily traffic accidents and falls from a height, and were most common in domestic cats, norwegian forest cats, and maine coons. this may be a reflection of the degree to which these breeds have access to the outdoors, and be opposite to the situation postulated for urinary deaths 10 (ie, indoor cats tend to get obese or develop disease because of lack of exercise but are less at risk for severe trauma). in 25% of swedish breeding catteries, some or all of the cats had free access to outdoors. 15 neoplastic disorders are the 3rd most common cause, with considerable variation among breeds. for the maine coon and siamese groups, neoplastic disease, dominated by mammary tumors in the siamese, was the most common cause of death, even though these are relatively young cats. significant breed differences in cancer risk are described for dogs, and a genetic component exists for some cancers in dogs. studies have shown that siamese cats are at increased risk of developing mammary carcinoma, although the mechanism is unknown. 16 in the total population, infectious disease was the most common cause of death. this is probably because all cats must be vaccinated against feline panleukopenia before enrollment into life insurance. domestic and maine coon cats had low mrs attributed to infections compared with several other breeds. infections, dominated by fip, were the most common cause of death in birmans. fip is a sporadic disease caused by mutation of an endemic virus (feline coronavirus, fcov). 17 inheritance of susceptibility to fip previously has been described for persians and birmans, 17 and an overrepresentation of other breeds also has been described. 17 as cats would not be covered for death because of fip occurring within a year after the start of insurance, and because fip can be challenging to confirm, 17 the number of fip cases may be even higher than shown here. regardless, infections dominated by fip were the most common diseases in birmans up to 12 years of age. one contributing factor to the high incidence of infections in birmans may be that a number of cats with ascites or hydrothorax because of restrictive cardiomyopathy are falsely diagnosed as having exudative fip. death because of cardiovascular reasons was the 3rd most common cause in birmans, and these diagnoses can be difficult to differentiate without further clinical testing, such as echocardiography. 18 the most common specific diagnosis within the cardiovascular category was, not surprisingly, cardiomyopathy. however, feline cardiomyopathies are a heterogenous group of diagnoses. depending on the morphologic appearance and pathophysiology, cardiomyopathy in cats is frequently classified as hypertrophic, dilated, restrictive, arrhythmogenic, and ''unclassified'' cardiomyopathy. 18, 19 the specific-feline cardiomyopathy often was not specified in the database, but based on the literature and clinical experience, hypertrophic cardiomyopathy, was the most likely diagnosis in most of the cases in most of the breeds. this disease is well documented in almost all of the breed groups in this study as a major contributor to cardiovascular disease. 19, 20 the present study could not show a difference in sex, which is in agreement with previous studies. 20 the domestic cat group stands out as having a lower cardiovascular asmr than other breeds. this finding may not completely reflect the true incidence of cardiomyopathy in this population because domestic cat owners may not be as motivated as pure bred cat owners or breeders to establish an exact diagnosis or to treat chronic disease. we have closely considered whether the interesting result on survival (ie, the increase over this 8-year period for cats o13 years of age) could have arisen as a consequence of insurance policies or been a function of the research method. however, we found both of these unlikely to account for the magnitude of the differences seen. as regards statistics, given that the method is stratified on and uses the available information at each age span to calculate the statistics, if there were no cats or deaths in an interval (ie, ''young''), problems may arise at older ages, but this was not the case here. it is anecdotally assumed that owners are more willing to access veterinary care for their cats and to engage in treatment for chronic diseases (eg, diabetes) than was the case in the past. presumably, increased access to veterinary care would be facilitated by having health care insurance (which almost all life-insured cats have). a similar pattern of decreased mortality over time has been shown in dog data from the agria database (brenda bonnett, personal communication). the extent to which increased survival can be attributed to veterinary care per se or to the attitudes of owners with regard to willingness to treat older animals and those with chronic disease is impossible to determine based on our results. with regard to the whole population (however, not between breeds, see breed section above) the yearly mrs (data not shown) and the asmrs were similar. reasons for varying overall rates over the years include random variation, varying breed-age distributions (in the unadjusted rates) and undefined systematic variation relative to the insurance process or other factors. we believe the cats insured at agria are relatively representative of the purebred cat population in sweden, with the limitation that cats over 13 years of age are not included, and the median age of death is 412.5 years. the life-insured domestic cats are likely not representative of the total population of owned domestic cats in sweden. the overall mortality varied with age and breed but not with sex. cause-specific mortality varied with age and breed. urinary problems, trauma, neoplasia, infections, and cardiovascular problems were the 5 most common categories of causes of death. the fact that the overall survival increased with time period likely reflects both a willingness to keep pet cats longer and the increased level of veterinary care. the limitations of the diagnostic information have been discussed, but are reflective of veterinary practice and such issues are common in population-based research using secondary data. given the scarcity of population-level information on cats, these limitations do not outweigh the usefulness of the data. birth and death rates estimates of cats and dogs in us households and related factors a study of risk factors for cat mortality in adoption centres of a uk cat charity causes of death and disease in cats based on 1969-1982 post mortem statistics comparative study of causes of death and life expectancy in carnivorous pets (ii) gender, age, breed and geographic pattern of morbidity and mortality in insured dogs during mortality of swedish horses with complete life insurance between 1997 and 2000 variations with sex, age, breed and diagnosis diagnosregister fo¨r ha¨st, hund och katt (diagnostic registry for the horse, the dog and the cat) veterinary epidemiolog research, 1 st ed france: international agency for research on cancer; 1987, 59. 10. rochlitz i. study of factors that may predispose domestic cats to road traffic accidents: part 1 insurance data for research and clinical decision-making in companion animals: benefits and limitations validation of computerized swedish dog and cat insurance data against veterinary practice records prevalence of polycystic kidney disease in persian and persian related cats in france the swedish breeding cat: population description, infectious diseases and reproductive performance evaluated by a questionnaire epidemiological features of feline mammary carcinoma a review of feline infectious peritonitis virus infection: 1963-2008 feline myocardial disease 1: classification, pathophysiology and clinical presentation echocardiographic assessment of spontaneously occurring feline hypertrophic cardiomyopathy. an animal model of human disease this work has been supported by grants from the foundation for research, agria insurance.financial support: this study was supported by grants from the foundation for research, agria insurance. key: cord-322704-0suc6pt6 authors: riffe, t.; acosta, e.; coverage-db team, t. title: coveage-db: a database of age-structured covid-19 cases and deaths. date: 2020-09-23 journal: nan doi: 10.1101/2020.09.18.20197228 sha: doc_id: 322704 cord_uid: 0suc6pt6 coverage-db is an open access database including cumulative counts of confirmed covid-19 cases, deaths, and tests by age and sex. original data and sources are provided alongside data and measures in age-harmonized formats. the database is still in development, and at this writing, it includes 87 countries, and 195 subnational areas. cumulative counts of covid-19 ases, deaths, and tests are recorded daily (when possible) since january 2020. many time series thus fully capture the first pandemic wave and the beginning of later waves. an international team, composed of more than 60 researchers, contributed to the collection of data and metadata in coverage-db from governmental institutions, as well as to the design and implementation of the data processing and validation pipeline. we encourage researchers interested in supporting this project to send a message to the email: coverage-db@demogr.mpg.de information about pandemic dynamics is critical to understand the potential impacts on populations, design mitigation strategies, and evaluate the efficacy of their implementation. centralization, standardization, and harmonization of data is critical to enable comparisons of the demographic impact of covid-19 vis-à-vis differences in the age-compositions of confirmed infections and deaths. the international data landscape must keep pace with the global march of the pandemic, and researchers must work to triangulate the available data to create comparable measures to monitor and predict its demographic impacts. the covid age database (coverage-db) aims to provide global coverage of key demographic aspects of the covid-19 pandemic as it unfolds in an up-to-date, transparent, and open-access format. coverage-db offers data with standardized count measures and harmonized age groups to allow comparisons between populations at national and subnational scales. the database is currently under expansion through both the increase in coverage of national and subnational populations and the inclusion of more recent periods as the pandemic continues to unfold. at this writing, the database contai ns daily counts of covid-19 cases, deaths, and tests performed by age and sex for 87 national and 195 subnational populations around the world, depending on the available data for each source. the date range available for each country or subpopulation varies. in several country series, the database includes the earliest confirmed cases in january, 2020. for most populations the database includes daily time series, beginning from an initial starting date when the data were first released or collected by our team. fig. 1 displays a map of countries included in the database, indicating at least one subnational population from 12 co untries. a detailed overview of data availability is given in a searchable table [external link]( https://bit.ly/3kvdrld ) is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint data collected: collection: official counts of covid-19 cases, deaths, and tests are extracted from reports published by official governmental institutions, such as health ministries and statistical offices. depending on the source, data are collected in a variety of formats, including machine-readable files, pdf tables, html tables, interactive dashboards, press releases, official announcements via twitter, and in a few instances, from digitized graphics. a full list of data sources is available in a dashboard view ( https://bit.ly/2qg1mxl ). generally, covid-19 cases, deaths and tests are reported as counts in 10-year age groups, but some sources report data in other metrics (fractions, percents, ratios) or as summary indicators such as case fatality ratios by age. reported age intervals vary by source, ranging from single ages to 30-year or greater age bands, and sometimes reported age intervals change over time within sources. usually data are reported as cross-sectional snapshots of cumulative counts, but some sources give full time series of new cases or deaths, in which case we cumulate counts over time. we also collect standard metadata on each of the sources to capture various characteristics of the collected data, such as the primary collection channels, definitions used, and notes on major disruptions or events. an overview of key fields from this metadata is shared as a spreadsheet ( https://bit.ly/2famkfn ). is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . all source data is entered into standard spreadsheet templates hosted in a central folder on google drive. data entry into the templates is either manual or automatic depending on the source. r programs collect data from the source templates and compile the merged input database. the merged input file is then subject to a series of automatic validity checks. initial checks are carried out by the individual responsible for data collection and entry using an interactive application ( https://mpidr.shinyapps.io/cleaning_tracker/ ). data is then harmonized to standard metrics (counts), measures (cases, deaths, tests), and age bands (5and 10-year age intervals). harmonization procedures include various kinds of rescaling to ensure coherence in marginal sums. age group harmonization is done using the penalized composite link model, 1 which was designed for splitting histograms of count data. the complete details on all steps of production are available in the coverage-db method protocol, which is publicly available on the web ( https://osf.io/jcnw3/ ). a table listing which adjustments are applied to each population is available on the project website ( https://bit.ly/2e61bsv ). both the merged input database and the harmonized output files are uploaded daily as zipped csv files to an open science framework repository (osf) ( https://osf.io/mpwjq/ ). a github repository ( https://bit.ly/2ybtpcj ), which is linked to osf, contains all r scripts used in the complete production pipeline, including compilation, diagnostics, and harmonization. since collection efforts began for coverage-db in late march 2020, we are aware o f 6 studies using the data, many of which provide r code online and are fully reproducible. these studies aim t o: (i) explore country differences in the age distribution of covid-19 deaths, 2 (ii) assess the contributi on of infection case age-structure and age-specific fatality to between-and within-country differences in case fatality rates (cfr) associated with the covid-19, 3 (iii) produce a standard age-specific case fatality rate pattern for an indirect demographic method to estimate covid-19 total infections, 4 (iv) analyze the association between intergenerational relationships and covid-19 fatality rates, 5 (v) estimate years of life lost due to covid-19, 6 and (vi) calculate pooled sex ratios of age-specific cfrs of covid-19 in europe. 7 the database is also used to monitor covid-19 impacts in particular age ranges, for instance, unicef uses the database for monitoring the burden of the pandemic on the infant, child, and juvenile mortality around the world. as an example of the analyses that coverage-db enables, fig. 2 displays changes in the relation between age-specific deaths and cases in colombia, . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . inspired by fig. 1 of dudel et al. 3 we divide both cases and deaths in each age band by the respective population sizes. diagonal lines indicate implied age-specific case fatality rates. the graphic illustrates a sharp increase in cfr over age for each sex, and it also displays considerable sex differences. for instance, men aged 60-69 in colombia have almost the same case fatality rates (approximately 12% risk of death after covid-19 infection is diagnosed) as women aged 70-79. we repeat this exercise to compare colombia with mexico (see fig. 3) , where standardizing by population size is more justified. case fatality rates and death rates are much higher in mexico than in colombia in each age band -around 2-fold -, except for ages 80+, which show a substantial reduction in the case fatality rate difference, and much higher death rates for colombia. while we cannot separate the reasons for this with precision, it is clear that colombia has conducted about twice as many tests per positive case than has mexico, and positivity trends have been on the rise in both countries. 8 however, we do not know the age pattern of positivity in these two countries. on the other hand, both countries have excellent open data practices, allowing for construction of detailed series taking into account retrospective corrections. this highlights challenges in making such comparisons, but also the need to produce data with sufficient detail to adjust for biases. it is our view that researchers should 4 . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . triangulate creatively from all available data rather than avoiding difficult comparisons. relation between deaths and cases per 100,000 population by age group in mexico and colombia, until 22 august 2020. diagonal lines indicate the case fatality rate. since the beginning of the pandemic, it has been evident that population characteristics are key to understanding the prevalence, spread and fatality of covid-19 across countries. however, data on cases, deaths, and tests disaggregated by age and sex are not easily comparable across countries, and sometimes not even accessible. the main strength of coverage-db is to provide a centralized, open-access, and fully reproducible repository of age-and sex-specific case, death, and test counts from covid-19, collected from official sources, and harmonized to standard output formats. the data harmonization process is transparent, following a strict protocol. 9 the initial input data is provided alongside the harmonized counts, as well as the code used to harmonize the different input measures, metrics, and age groups into comparable granular output metrics. all scripts are written in the open-source r programming language. 10 the data sources and limitations are documented for each country in a standard metadata framework. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . https://doi.org/10.1101/2020.09.18.20197228 doi: medrxiv preprint a limitation of the coverage-db is the heterogeneous and difficult-to-evaluate quality of the underlying data. no single data source can currently claim accurate estimates of covid-19 incidence or fatalities. age-specific case counts are highly dependent upon the testing capacity, 11 testing strategy, 12 and differences in the definition of cases across sources and over time. cases are underestimated everywhere, with underestimation expected to vary by age, given the relationship between age and case severity. 13 the accuracy of diagnostic rt-pcr tests used to confirm infections is also known to vary. 14 furthermore, at any given date, cumulative counts are underestimated because of the lag between infection and a positive test result. 15 death counts from covid-19 are also likely underestimated for similar reasons, but also due to various kinds of delays in death registration. media reports have circulated about intentional data manipulation in some of the official data covered in the database. 16 excess all-cause mortality has been observed across many regions. [17] [18] [19] [20] although some of these deaths are likely from postponing or foregoing treatment from non-covid-19 related causes, the magnitude of this excess is suggestive that numerous covid-19 related deaths are classified under different causes. populations also differ in whether deaths to suspected covid-19 cases are included in official statistics and in post-mortem practices when an infection is suspected. 21 some populations only report deaths occurring in hospitals, neglecting a potentially sizable proportion of deaths occurring in institutional settings and at home. 22 while most populations currently report all deaths to confirmed covid-19 infections as covid-19 deaths for this database, the underlying cause of death eventually reported on death certificates may differ in patients with severe comorbidities. to mitigate biases and misinterpretations due to different practices and definitions, such information is constantly updated and documented in the metadata of the database, which is freely accessible to users. all of these issues compromise the comparability of the data contained within the coverage-db, both across populations at any given time and within populations over time. for these reasons, infection fatality ratios, which include in the numerator detected and undetected covid-19 infections, should not be estimated from coverage-db data alone. proper estimation of incidence and fatality will likely require triangulating data across numerous sources as these become available. to this end, the coverage-db was designed to be easily merged with other databases such as the our world in data database on covid-19 testing, 8 the covid-19 dashboard of johns hopkins, 23 the world population prospects database, 24 and th e short term mortality fluctuations database. 20 moreover, given that we have near-complete time series capturing the whole pandemic curve in some places, careful modeling of the lag structures might allow some of these data-driven biases to be estimated. . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . https://doi.org/10.1101/2020.09.18.20197228 doi: medrxiv preprint both merged input and harmonized output files can be downloaded directly from the osf site ( https://osf.io/mpwjq , doi: 10.17605/osf.io/mpwjq), which contains a folder called data with three files of primary data. fi g 4 shows where to find the files in the osf repository. each of the main data files has a stable link (see tab. 1), which always points to the most recent version. each file is a zipped csv file by the same name. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . https://doi.org/10.1101/2020.09.18.20197228 doi: medrxiv preprint for stable links to download particular versions, click on the version number in the version column seen in fig. 4 . users can note versions either by referring to timestamps provided in the headers of data files or by referring to osf file version numbers, which increment with each daily update. a data dictionary is given in both the osf wiki ( https://osf.io/mpwjq/wiki/home/ ) and the method protocol. files are shared in csv format to be as universally accessible as possible. a guide to getting started using the data in r is also provided ( https://bit.ly/3g8nivu ), and tips for other statistical packages may also be added. users are encouraged to reach out for further information or advice on using the database, or to express interest in the project: coverage-db@demogr.mpg.de . . cc-by 4.0 international license it is made available under a perpetuity. is the author/funder, who has granted medrxiv a license to display the preprint in (which was not certified by peer review) preprint the copyright holder for this this version posted september 23, 2020. . https://doi.org/10.1101/2020.09.18.20197228 doi: medrxiv preprint efficient estimation of smooth distributions from coarsely grouped data population age structure only partially explains the large number of covid-19 deaths at the oldest ages. demographic research monitoring trends and differences in covid-19 case fatality rates using decomposition methods: contributions of age structure and age-specific fatality. medrxiv a demographic scaling model for estimating the total number of covid-19 infections. medrxiv no clear association emerges between intergenerational relationships and covid-19 fatality rates from macro-level analyses global years of life lost to covid-19 covid-19 in unequally ageing european regions. world development [internet]. forthcoming coronavirus pandemic (covid-19) method protocol for the coverage-db r: a language and environment for statistical computing austria: r foundation for statistical computing countries test tactics in 'war' against covid-19 epidemiology and transmission of covid-19 in 391 cases and 1286 of their close contacts in shenzhen, china: a retrospective cohort study. the lancet infectious diseases estimates of the severity of coronavirus disease 2019: a model-based analysis. the lancet infectious diseases laboratory diagnosis of covid-19: current issues and challenges incubation period of 2019 novel coronavirus (2019-ncov) infections among travellers from wuhan, china covid-19: a need for real-time monitoring of weekly excess deaths. the lancet 000 missing deaths: tracking the true toll of the coronavirus outbreak. the new york times the economist. tracking covid-19 excess deaths across countries. the economist european monitoring of excess mortality for public health action (euromomo)kåre mølbak short-term mortality fluctuations (stmf) data series the human mortality database demographics of covid-19 deaths institut national d'études démographiques 2020 comment la france compte-t-elle ses morts ? an interactive web-based dashboard to track covid-19 in real time. the lancet infectious diseases world population prospects -population division -united nations we gratefully acknowledge the hard work of health ministries and statistical offices around the world in preparing and disseminating the data included in coverage-db. the coverage-db project team is composed of more than 60 researchers that share in the authorship of this manuscript according to the credit authorship system (see contributions by author under the following link: https://docs.google.com/spreadsheets/d/1shygpjarbfinxlmfku6vr7lzlyg z00p1zkbapdanaiw/edit?usp=sharing ). key: cord-305475-lhi0hcki authors: risku, minna; kätkä, minna; lappalainen, suvi; räsänen, sirpa; vesikari, timo title: human bocavirus types 1, 2 and 3 in acute gastroenteritis of childhood date: 2012-05-24 journal: acta paediatr doi: 10.1111/j.1651-2227.2012.02727.x sha: doc_id: 305475 cord_uid: lhi0hcki aim: recently identified human bocavirus (hbov) types 2 and 3 have been associated with acute gastroenteritis in children. we studied 878 stool specimens from children with acute gastroenteritis and 112 controls (43 children with unspecified fever, 33 with respiratory tract infection and 36 healthy children) for known hbovs. the same specimens were previously studied for rotaviruses, noroviruses, sapoviruses, adenoviruses, coronaviruses and aichivirus. methods: hbovs were detected by pcr and positive amplicons were sequenced to identify hbov1, hbov2, hbov3 and hbov4. results: hbov of any type was found in 85 (9.7%) cases of acute gastroenteritis and in 6 (5.4%) controls. hbov1 was detected in 49 (5.6%) cases and 2 (1.8%) controls, hbov2 in 29 (3.3%) cases and 2 (1.8%) controls and hbov3 in 8 (0.9%) cases and 2 (1.8%) controls. no hbov4 was found. hbov as a single infection was found in 16 (1.8%) cases and in 6 (5.4%) controls; in the remaining cases, a known gastroenteritis virus was also found. among the single hbov infections, hbov2 was the most common type with 8 (50%) cases. conclusion: hbovs are rarely found alone in children with acute gastroenteritis. further studies are warranted to confirm a possible specific association of hbov2 with gastroenteritis. the first human bocavirus (hbov1) was described in 2005 by allander et al. (1) as a result of screening of nasopharyngeal aspirates of children with respiratory tract infection. since then, hbov1 has been connected to respiratory tract infections (2) (3) (4) , and the evidence for this has increased with the use of serological studies (5) . on the other hand, co-infections with other respiratory pathogens are common and hbov1 has also been found in asymptomatic subjects (6) (7) (8) . furthermore, several studies have shown that hbov1 may also be present in faecal samples of children with acute gastroenteritis (age) (9) (10) (11) (12) (13) , and to complicate matters, patients with hbov1 in respiratory tract samples have been reported to have diarrhoea (3) . as in the case of the respiratory tract, simultaneous presence of hbov1 with other, previously established gastroenteritis viruses is common in faecal specimens (10, 12, 13) , and no clear connection between hbov1 and age of children has been established (11, 13, 14) . since 2009, three new human bocaviruses have been identified (14) (15) (16) . hbov2 was found in a stool specimen of a pakistani child in 2009 (15) , and since then, hbov2 has been detected in several studies on children with age (14, (17) (18) (19) (20) (21) . again, co-infections with known human gastroenteritis viruses have commonly been found (18, 20) as well as shedding in stools of asymptomatic children (20) . therefore, the role of hbov2 as an enteric pathogen is still not confirmed. hbov2 has also been detected in stools of abbreviations age, acute gastroenteritis; hbov, human bocavirus; hbov1, human bocavirus 1; hbov2, human bocavirus 2; hbov3, human bocavirus 3; hbov4, human bocavirus 4; pcr, polymerase chain reaction key notes • we found human bocaviruses (hbovs) 1, 2 and 3 at respective rates 5.6%, 3.3% and 0.9% in children with acute gastroenteritis but mostly in combination with known gastroenteritis viruses. • of the cases with hbov as a single agent (1.8% of all age cases), hbov2 accounted for 50%. • further studies are warranted to confirm the possible role of hbov2 in acute gastroenteritis; otherwise, the role of human bocaviruses appears small. children with respiratory tract infection (22) but not at all (23) or rarely (24) in respiratory tract samples. hbov3 was also originally detected in a stool sample in 2009 (14) . several other studies have confirmed the presence of hbov3 in faecal samples of patients with gastroenteritis, but detection rates have been lower than those of hbov2 (19) (20) (21) . recently, hbov4 was found in faecal samples of children and adults (16) , but the significance of this virus may be regarded as unknown. to elucidate the role of different human bocaviruses in age of children, we tested stool specimens from 878 children seen in hospital because of age. the samples were collected in a 2-year prospective study from august 2006 to august 2008 (25) . this material had been tested previously for known gastroenteritis viruses including rotaviruses, noroviruses, sapoviruses, adenoviruses, coronaviruses and aichivirus (25) (26) (27) (28) (29) . (25) . children under 15 years of age with age admitted to the paediatric outpatient clinic or to the hospital ward, or those who came down with age during hospitalization were eligible for the study. informed consent was obtained from the guardians of all study subjects diagnosed with age by a paediatrician or included in the study as controls. a total of 878 stool specimens were obtained from children with age (one per subject) and 112 stool specimens were collected as controls including three different groups of patients: 43 specimens from children with fever of unknown origin (some of these also had vomiting but not diarrhoea), 33 specimens from children with respiratory tract infection and 36 specimens from healthy children admitted for examinations. because the study material was not originally collected for hbov studies, the selection of the control material was not optimal for hbovs. also, the number of control cases remained small causing some limitations for statistical analyses, as discussed later. rotaviruses, caliciviruses including norovirus genogroups i and ii and sapoviruses, and human coronaviruses (229e, oc43, hku1 and nl63) had previously been studied using the same material (25) (26) (27) . in addition, 516 stool specimens were previously tested for aichivirus and 724 for adenoviruses (28, 29) . all enteric viruses were tested using polymerase chain reaction (pcr) method, except for adenoviruses; either a pcr or prospect ò enzyme-linked immunosorbent assay-kit (oxoid, basingstoke, uk) was used. suspensions 10% w ⁄ v were made by diluting stool specimens in phosphate-buffered saline. viral nucleic acid was extracted using qiaamp viral rna mini kit (qiagen, hilden, germany) according to the manufacturer¢s protocol (this method was tested to be suitable for dna extraction). hbov dna was amplified by pcr, and a two-step pcr method was used to increase sensitivity. in the first pcr, reaction volume was 50 ll containing 5 ll of the sample dna, 1· green gotaq ò flexi buffer (promega, madison, wi, usa), 1.5 mmol ⁄ l of gotaq ò mgcl 2 (promega), 200 lmol ⁄ l of each dntp (promega), 2.5 u of gotaq dna polymerase (promega) and 0.5 lmol ⁄ l of hbov ns1 primers (sigma-aldrich, st louis, mo, usa). pcr programme was run as follows: denaturation at 94°c for 3 min, 35 cycles of amplification (40 sec at 94°c, 30 sec at 62°c, 65 sec at 72°c) and final extension at 72°c for 5 min. the first amplification produced a 960-bp amplicon of gene ns1 encoding for a non-structural protein (table 1 ). in the second pcr, there were two pools of primers, pool boca (30) and pool hbov, producing amplicons of 291 and 200 bp in size, respectively (table 1) . pool hbov-primers were designed to detect all hbovs, especially the newer ones, and pool boca primers already in use in our laboratory for hbov1 were included in the pcr. reaction volume was 50 ll containing 2 ll of the 1st pcr product, 150 lmol ⁄ l of each dntp and 0.5 lmol ⁄ l of hbov ns1 2nd primers or boca ns-1 primers, and the rest of the reaction conditions were as in the 1st pcr. pcr programme was run as follows: 3 min at 94°c, 30 cycles of amplification (30 sec at 94°c, 30 sec at 55°c, 30 sec at 72°c) and at 72°c for 5 min. pcr products were visualized in gel electrophoresis, and positive results were confirmed by sequencing using abi prismô 310 genetic analyzer (applied biosystems, foster city, ca, usa). sequences were analysed using sequen-cherô 4.8 program (gene codes corporation, ann arbor, mi, usa) and compared to reference strains by ncbi blast ò -program to determine hbov types. statistical analyses were conducted using pasw statistics 18 program (spss ò , chicago, il, usa). statistical significance was calculated using fisher¢s exact test, and p < 0.05 was considered significant. altogether, 878 stool specimens were collected from children with age and 112 specimens from control groups including 43 specimens from children with fever of unknown origin, some of whom also had vomiting, 33 specimens from children with respiratory tract infection, and 36 specimens from healthy children admitted for examinations. in 719 (81.9%) of the 878 stool specimens of children with age, one or more viruses, including rotaviruses, noroviruses, sapoviruses, adenoviruses, coronaviruses, aichivirus and human bocaviruses, were found. in the combined control groups, 22 (19.6%) of 112 specimens were positive for at least one of these viruses, excluding sapoviruses and aichivirus that were not detected from controls. human bocaviruses were detected in 91 (9.2%) cases of all stool samples, 85 (9.7%) of the 878 cases with age and 6 (5.4%) of the 112 (non-age) controls. there was not a statistically significant difference in the amount of hbovpositive cases between age group and combined controls (p = 0.165). hbov1 was detected in 49 (5.6%) cases of age. there was also one (2.3%) positive sample in the group of children with fever of unknown origin and one (3.0%) positive sample in the group of children with respiratory tract infection; in the healthy children, there were no positive samples. ( table 2 .) the differences in detection rates of hbov1 between age and the separate control groups were not statistically significant (p = 0.529). during the first season twenty-nine (3.3%) specimens in the age group were positive for hbov2. in the control groups, there was one (2.3%) positive sample in children with fever of unknown origin and one (2.8%) positive sample in the group of healthy children, but none in the children with respiratory tract infection. (table 2 .) the differences in detection rates of hbov2 between age and the separate control groups were not statistically significant (p = 0.949). numbers of hbov2-positive samples during the first and the second season were 18 and 13, respectively. hbov3 was detected in 8 (0.9%) cases of children with age, in one (2.3%) case of children with fever of unknown origin, and in one (3.0%) case of children with respiratory tract infection, and in none of the healthy children (table 2. ). the differences in detection rates of hbov3 between age and the separate control groups were not statistically significant (p = 0.260). all hbov3-positive cases were found during the first season. in this study, no hbov4 was detected. in 16 (1.8%) cases of age, human bocavirus was the only virus detected, whereas in the combined controls, all 6 (5.4% of all controls) cases were single infections with hbov. among the 16 cases of age in which hbov was the only virus detected in stool, hbov2 was the most common one with 8 (50.0% of all single infections) cases, followed by hbov1 with 7 (43.8%) cases and hbov3 with one (6.3%) case (table 3) . conversely, among the 69 cases of mixed infections, 42 (60.9% of the hbov-positive mixed infections) contained hbov1, 21 (30.4%) contained hbov2, and 7 (10.1%) cases contained hbov3. in one sample, both hbov1 and hbov2 were detected. the proportion of hbov2 was greater in the single infections than in mixed infections and vice versa for hbov1, but the differences in the proportions of different hbovs between mixed and single infections were not statistically significant (p = 0.428). forty-two (85.7%) of 49 hbov1-positive cases, 21 (72.4%) of 29 hbov2-positive cases and 7 (87.5%) of 8 hbov3-positive cases were mixed infections with known gastroenteritis viruses. proportion of mixed infections did not differ significantly between different hbovs (data not shown). in mixed infections, rotaviruses and noroviruses were the most common gastroenteritis viruses detected with bocaviruses (table 3. ). in six cases negative for rotaviruses and noroviruses, hbovs were detected together with adenovirus. fifty-six of the mixed infections contained two different viruses, and in 13 cases, there were more than two viruses. the one case with both hbov1 and hbov2 in the stool also had rotavirus in the same specimen. the seasonal distribution of hbov findings is shown in fig. 1 . most of the hbov-positive cases were detected from november to june. from november to march, over 10% of all stool samples collected per month were positive for some of the hbovs, exception being january 2008 with low detection rate of 1.9%. this study was set-up to examine whether hbovs in general and bocavirus types hbov2 and hbov3 in particular could be linked with age in childhood as aetiological agents. as a whole, we could not confirm such an aetiological role of any of the hbovs in age in children, although hbov2 appeared more common than the other types when hbov was found in stool without other viruses. in this study, human bocaviruses were detected in 9.7% of children with age. hbov1 was detected in 5.6% of all age cases, which concurs with previous studies of hbov1 in children with age (0.8-9.1%) (10, (12) (13) (14) . however, the differences in the rate of hbov1 in age and control groups were not statistically significant, and in very few cases, hbov1 was detected alone without well-established gastroenteritis viruses such as rotavirus or norovirus, which were likely to have a causative role in such cases. as a single infection, hbov1 was found in only 0.8% of age cases. as shown in fig. 1 , there is a peak in hbov1 findings during december 2007. this peak is most likely due to the waterborne age outbreak that occurred in nokia, a town near to tampere, and was caused by contamination of drinking water by sewage water (29) . during the outbreak, there was an unusual amount of mixed infections with severe gastrointestinal symptoms (29) . fifty stool samples from children connected to the nokia outbreak were tested during our study, and we found eight hbov1-positive cases (all of these were mixed infections) and two hbov2-positive cases (one was a mixed infection). even if all 'nokia cases' were excluded from the calculations, the differences between hbovs (separately for hbov1, hbov2 and hbov3) in age and control groups did not change outstandingly. hbov2 was detected in 3.3% of the samples of the children with age. this is a lower detection rate than those reported from australia (17.2%) (14) and china (20.4-24.6%) (17, 20) , but close to the 3.6% reported from south korea (18) . hbov2 was detected as a single virus in 0.9% of age cases. while we could not confirm a specific association of hbov2 with age in children, there were nevertheless numerically more 'pure' cases (eight in all) of hbov2 than other hbovs, leaving a small possibility of a specific association of hbov2 with gastroenteritis. arthur et al. (14) in their case-control study found a statistically significant association between hbov2 and age, but in other studies, despite the common findings in stool specimens, the causal association of hbov2 and age has been weak (17, 20) . in this study, hbov3 was found in 0.9% of the age samples over 2 years. hbov3 was not detected during the second season at all, and there was only one case of hbov3 as a single virus in specimen without other gastroenteritis viruses. in earlier studies, detection rates of hbov3 in children with age have been 0.9-2.7% (14, 20) , and in general, hbov3 has been less common than hbov2 in stool samples of children with age (19, 20) . we were unable to find any hbov4 in our study. this was also the case in several other recent studies (19) (20) (21) , and therefore, the role of this virus remains unclear. we did a thorough work-up of most of the established gastroenteritis viruses including rotaviruses, noroviruses, sapoviruses, enteric adenoviruses, coronaviruses and aichivirus (astroviruses or bacterial pathogens were not studied) and found co-infections in 81.2% of all bocavirus-positive age cases. similar rates (approximately 74-80%) have been detected in earlier studies in which other gastroenteritis viruses have been investigated using adequate methods (20, 21) . in such co-infections, it is reasonable to assume that the known gastroenteritis viruses actually have a causative role and hbov may be either shed from the respiratory tract or infecting the intestinal tract with no pathogenic role in age. in the future, simultaneous testing of respiratory and stool samples together with serologic testing should be carried out to clarify this assumption. the number of the 'pure' hbov-positive cases was small and could not be positively associated with age. nevertheless, it is noteworthy that in 50.0% of the single infections, hbov2 was the bocavirus detected, whereas in the mixed infections, its proportion was only 30.4%. in this study, most of the hbov-positive cases were detected from november to june. the highest proportional detections rates, comparing to number of collected samples per month, were in winter months (fig. 1) . there was no remarkable difference in seasonality between hbov1 and hbov2, but hbov3 was detected only from february 2007 to july 2007. in some previous studies, hbov1 was detected throughout the year, but some higher incidence during winter months was also seen (3, 11) . hbov2 was also detected throughout the year, and the highest incidences were detected from february to april (17) . the sizes of the control groups were a limitation in our study and also a limitation for a reliable statistical analysis of causative role of hbovs in age. in principle, using all three groups, that is, children with respiratory tract infection, children with fever and vomiting, and healthy children as controls, might be justified, but the size of each group remained too small, and some statistical comparison was made with pooled controls, which is not optimal. originally, this material was not collected for bocavirus studies. because of these limitations and because other viruses were frequently found in cases of age, we focused more on infections with hbov as a single pathogen indicating specific association with age. further studies are warranted, and a study with simultaneous collection of specimens from respiratory tract and stools is in progress to investigate the type-specific association of hbovs with respiratory or gastrointestinal tract, respectively. collection of the serum samples is also being carried out in our next studies for serological testing and the detection of hbov viraemia. in conclusion, we investigated stool samples from a large number of children with age and found human bocaviruses 1, 2 and 3 at respective rates of 5.6%, 3.3% and 0.9%, but bocaviruses were seldom detected alone without other viruses like rotaviruses and noroviruses. even those cases that appeared to be single hbov infections may actually have been co-infections if a more comprehensive work-up on viruses such as astroviruses had been performed and bacterial pathogens had also been investigated. in the total material, hbov2 and hbov3 did not stand out as having any stronger association with age than hbov1, but in the 'pure' hbov cases of age, hbov2 was slightly overrepresented. cloning of a human parvovirus by molecular screening of respiratory tract samples human bocavirus and acute wheezing in children human bocavirus infection in children with respiratory tract disease human bocavirus in children: mono-detection, high viral load and viraemia are associated with respiratory tract infection serodiagnosis of human bocavirus infection human bocavirus infections in hospitalized children and adults clinical and epidemiologic characteristics of human bocavirus in danish infants: results from a prospective birth cohort study frequent and prolonged shedding of bocavirus in young children attending daycare human bocavirus infection in children with acute gastroenteritis in japan and thailand human bocavirus, a respiratory and enteric virus human bocavirus infection in children hospitalized with acute gastroenteritis in china detection of human bocavirus in children hospitalized because of acute gastroenteritis human bocavirus in children hospitalized for acute gastroenteritis: a case-control study a novel bocavirus associated with acute gastroenteritis in australian children a newly identified bocavirus species in human stool human bocaviruses are highly diverse, dispersed, recombination prone, and prevalent in enteric infections development of a real-time pcr assay for detecting and quantifying human bocavirus 2 detection of human bocavirus-2 in children with acute gastroenteritis in south korea real-time quantitative pcr detection of four human bocaviruses high prevalence of human bocavirus 2 and its role in childhood acute gastroenteritis in china detection of human bocavirus 3 in china the first detection of human bocavirus 2 infections in china simmonds p. absence of detectable replication of human bocavirus species 2 in respiratory tract human bocavirus 2 in children rotavirus gastroenteritis in finnish children in 2006-2008, at the introduction of rotavirus vaccination noroviruses in children seen in a hospital for acute gastroenteritis in finland detection of human coronaviruses in children with acute gastroenteritis aichi virus infection in children with acute gastroenteritis in finland mixed viral infections causing acute gastroenteritis in children in a waterborne outbreak evidence of human coronavirus hku1 and human bocavirus in australian children we would like to thank study nurse marjo salonen, laboratory supervisor marjo salminen and our laboratory technicians, especially emilia halttunen, for excellent work in this project. we also thank heini huhtala for indispensable help with statistical analyses. no conflict of interest. no specific funding. key: cord-309809-zvh2k97q authors: knepple carney, amy; graf, allyson s; hudson, grace; wilson, ellen title: age moderates perceived covid-19 disruption on well-being date: 2020-08-18 journal: gerontologist doi: 10.1093/geront/gnaa106 sha: doc_id: 309809 cord_uid: zvh2k97q background and objectives: it is not fully understood how large-scale events affect well-being. older adults showed the highest levels of resilience following the september 11(th) (9/11) terrorist attacks, but during the severe acute respiratory syndrome (sars) outbreak there were no age-related differences in well-being. the current study examined the coronavirus disease 2019 (covid-19) disruption on well-being throughout adulthood. research design and methods: perceived stress and affect were examined in 166 community-dwelling adults (mage=35.65; sd=15.53; range=18-79) in relation to the perceived disruption of the covid-19 pandemic to their lives. results: a significant moderation was found for age and covid-19 disruption on perceived stress [f(5, 153) = 8.88, p & .05, r(2)= .22] and negative affect [f(5, 154) = 4.91, p & .05, r(2)= .14], but not for positive affect. for participants over 50, those who rated covid-19 as a low or high disruption had similar scores on stress and negative affect, but with younger aged participants, perceiving high disruption corresponded with higher levels of stress and negative affect. discussion and implications: findings are consistent with the strength and vulnerability integration (savi) model, wherein older adults try to maintain positive emotional well-being; with middle-aged and older adults in the current study having experienced less negative impact on well-being. middle-aged and older adults may be better able to regulate negative emotions, from covid-19, than younger adults. savi proposes a greater negative impact on older adults when they experience sustained stressors; as the challenges with covid-19 continue, further data will need to be examined. older adults, ethnic minorities, those with lower socioeconomic status, and those with underlying health conditions have disproportionality been affected by covid-19 (khunti, et al., 2020; li, et al., 2020) , through both higher rates of testing positive as well as greater mortality rates. there is a higher risk of infection for older adults living in nursing homes; over 40% of deaths attributed to covid-19 have been associated with residential care facilities (nytimes, 2020; lloyd-sherlock, et al., 2020) . with the onset of covid-19, older adults have experienced heightened ageism in public discourse as well as within institutional decision-making related to the allocation of medical resources and proposed distancing policies (colenda, et al., 2020) . with the unease of potentially contracting the disease, changes in routine, worries about money, and fear for family members, many people are facing challenges to their wellbeing. prime, wade, and browne (2020) suggest that the pandemic can have implications for the well-being of the whole family structure. covid-19 can cause social disruptions (e.g. job loss, social distancing, confinement), which in turn, can affect an individual's well-being, as well as the well-being of their family members. these disturbances can affect a person directly and indirectly. it is important to assess the impact that the disruption of covid-19 has on psychological well-being. of particular interest, during this health crisis, is to understand how the impact on well-being may differ by age. well-being is a multifaceted and multidimensional construct, which includes an array of dimensions, including positive emotions, engagement in meaningful activities, interpersonal relationships, purpose in life, and a sense of accomplishment (seligman, 2011) . these broader aspects sometimes differ in their importance and interrelations at different points in the lifespan (kern, et al., 2015) . emotional well-being has been shown to change over the lifespan, with an increase in positive affect and a decrease in negative affect as a c c e p t e d m a n u s c r i p t people age (carstensen, 1995) . the strength and vulnerability integration (savi) model posits that older adults are motivated to enhance positive well-being and possess both agerelated strengths and vulnerabilities in their pursuit of this goal (charles, 2010) . additionally, older adults are better at regulating their negative affect when exposed to daily stressors, compared to younger adults (scott, et al., 2013) . aging is related to an increase in strengths such as less reactivity to adverse events, a positivity bias with more focus on good rather than bad, and successful use of coping strategies, such as attentional focus and appraisal, with many of these changes slowly starting to take place in middle age. but, with increased age, it may also become more challenging to regulate sustained levels of arousal, making it harder to return to homeostasis when a long-term stressor is encountered (charles, 2010) . previous research examining well-being during crisis situations has provided mixed results on whether age groups are affected differently. it was found that older adults (65+) showed the highest levels of resilience to ptsd following the 9/11 terrorist attacks (bonanno, et al., 2006) . however, during the sars outbreak of 2003, in hong kong, it was found that there were no age-related differences in well-being between older and younger adults (lau, et al., 2008) . even in non-crisis situations, regardless of age, higher levels of global perceived stress heighten a person's negative affective response to stress (scott et al., 2013) ; although, older adults in another study reported less of an increase in negative affect when faced with a daily stressor, compared to younger adults (uchino, et al., 2006) . how a person interprets disruptions due to covid-19 may differ from other crises. the risk of severe illness or death from covid-19 increases with age, the greatest risk being for those over the age of 85 (cdc, 2020b). furthermore, individuals with underlying medical conditions, those with disabilities, and racial and ethnic minorities may be differentially impacted by the effects of the pandemic (lakhani, 2020; raifman & raifman, 2020; webb hooper, et al., 2020) . data from the national center for health statistics and the census a c c e p t e d m a n u s c r i p t bureau collected during the current pandemic has found that younger adults (age 18-29) are experiencing anxiety and depression at higher rates than any other age group, and less anxiety and depression with increased age (cdc, 2020a). although we are starting to learn about age-group differences in relation to covid-19 disruption, it is not fully understood how age and well-being are associated during a crisis such as a global pandemic. the current study examined the association among age and covid-19 disruption on stress and affect. based on savi (charles, 2010) and given trends in pathological well-being conditions (cdc, 2020a), it was anticipated that age would moderate the association between self-perceived disruption of covid-19 on stress and negative affect, such that older participants would experience lower levels of stress and negative affect compared to younger participants. participants were drawn from community-dwelling adults, with access to the internet, who responded to social media ads posted on various facebook groups (e.g. buy/sell groups, groups for promoting surveys, groups that provide local/state information). participants were invited to complete an online survey examining the effects of covid-19 disruption, wellbeing, and health. all participants were entered into a drawing to win one of thirty $10 gift cards. four participants were not included in analyses because they failed more than 2 attention checks (i.e. did not select "agree" when the question stated "select the agree option") within the survey. a total of 166 (74.1% from the mid-western united states) participants completed the survey (age range 18-79 years, m age = 35.65, sd = 15.53), with 81% of the sample being women (n = 135), and 94.5% of the sample being white (n = 160). the sample included 33.1% (n = 55) emerging adults (age range 18-24), 28.9% (n = 48) young adults (age range 25-39), 28.3% (n = 47) middle-aged adults (age range 40-59), 7.8% a c c e p t e d m a n u s c r i p t (n = 13) older adults (age range 60-79), and 1.8% (n = 3) did not answer the question. most (90%) reported that they were "currently following a stay-at-home order." all surveys were completed between march 30, 2020 and april 7, 2020. this research was approved through the university's institutional review board (protocol #e20-35), and informed consent was obtained from each participant. perceived stress. the perceived stress scale (cohen, et al., 1983; cohen & williamson, 1988) was used to index current evaluation of stress. the perceived stress scale included 10 items, where each item was scored on a 5-point likert scale (0 = never to 4 = very often), with a higher score representing greater perceived stress (m = 19.99, sd = 7.31, and α = .90). see table 1 for all means and standard deviations. negative affect scales were used (lawton, et al., 1992) . each item was rated on a 5-point likert scale, and participants were asked how much they agree with how they currently feel (1 = strongly disagree to 5 = strongly agree) with a higher score endorsing greater levels of a c c e p t e d m a n u s c r i p t with less than 2% of missing data from any variable, no imputations were conducted. a power analysis, using g*power (erdfelder, et al., 1996) , suggested that data from 109 adults would provide sufficient power (power =.80) to detect medium-sized effects (f 2 =.15) in a 3-variable regression equation (p < .05). because traditional approaches are not wellsuited for estimating power in moderated regression analyses (hayes, 2012) , process was adopted, to allow for 5,000 bias-corrected boot-strapping samples to increase the stability of the beta weights. process (hayes, 2012 ) was used to test whether age moderated the effect of covid-19 disruption on various types of well-being, with race (coded as white/poc) and gender as covariates. use of process allowed continuous variables to be automatically mean-centered; therefore, assumptions of generalized linear models were not violated. to ascertain the associations between age, covid-19 disruption, and well-being, pearson correlations were examined. age was not significantly associated with covid-19 disruption (r(161) = -.05, p = .55). a small but significant negative association between age and perceived stress (r(162) = -.22, p = .00) was observed. similarly, a significant positive association emerged between covid-19 disruption and perceived stress (r(163) = .34, p = .00), and between covid-19 disruption and negative affect (r(164) = .26, p = .010. however, age was not significantly correlated with affect, with coefficients ranging from -.04 to .11, nor was there a significant association between covid-19 disruption and positive affect. see table 1 this study investigated whether age of the participant altered the association between subjective covid-19 disruption and well-being. consistent with savi (charles, 2010) there was an overall moderating effect of age on the perceived disruption of covid-19 to wellbeing association. although, no differences in positive affect were found in the current study, perceived stress and negative affect were significantly affected. at younger ages, those reporting higher covid-19 disruption also reported greater impacts on their well-being. the results of this study indicate that covid-19 disruption appeared to have less of an effect on stress and negative affect with increased age. based on johnson-neyman analyses, it was found that the effect of covid-19 disruption on well-being doesn't vary between middleaged (starting around the age of 50) and older adults, even if they perceived greater disruption. these results are consistent with bonanno, et al. (2006) who found that older adults had the greatest resilience to ptsd following 9/11 and is consistent with the recent findings from the cdc (2020a) regarding clinical depression and anxiety. the current study adds to the literature by examining not just two age groups, but effects stemming multiple age periods. by including a representation of middle-aged adults, we were able to examine these associations through regression analyses. there are debates on the challenges and relevance of studying stress retrospectively (scott, et al. 2013 ). the current study adds to the body of research by examining stress and affect during the time of a, potentially, continuous stressor. consistent with previous findings on stress (uchino, et al., 2006) , the current study found that when faced with a stressor, in this case a global pandemic, middle-aged and older adults may be better at regulating their emotions even when they perceive the stressor as disruptive. when examining the negative aspects of well-being, middle-aged and older adults may be better at regulating their own a c c e p t e d m a n u s c r i p t emotional reaction to a major life stressor. this may be due, in part, to the fact that middleaged and older adults may have faced more cumulative stressors (e.g., war, recession), and have more personal resources to deal with stressors. emotional regulation exists within a larger framework of coping styles that can be enacted to manage situational responses (marroquin, et al., 2017) with age-related differences indicating more frequent use of positive appraisal with increased age (charles, 2010) . the current research has implications for understanding who may need emotional interventions or psychological counseling during a crisis experience. recognizing the differential effects of individual coping styles when situated within the context of the situational severity, compounding stressors, and age-related differences may aid in identifying possible mechanisms that explain the age-related moderation of well-being related to covid-19 disruption. middle-aged and older adults may be better at regulating negative emotions, during the onset of a continuous stressor, than younger adults. the current study points to the idea that if a person feels a crisis is disruptive to their lives, the younger a person is, the greater impact on their perceived stress and negative affect. although, the current study is consistent with savi, this theory also states that there may be a greater negative impact on older adults when they experience sustained stressors (charles, 2010) . the current results may change as the stressor continues, with profound implications on physical, psychological, and social well-being. as the covid-19 pandemic continues to be a stressor, further research will need to be conducted to examine the long-term effects on stress and affect. a c c e p t e d m a n u s c r i p t although representing all adult age periods is a strength of the current study because it fills gaps within previous research that only compared older and younger adults, it must be acknowledged that only 7.8% of the sample in this study represents older adults. by testing a limited number of older adults, the conclusions about older adults must be examined with caution. because data were collected through a convenience sample online and may have unintentionally targeted specific groups based on where ads were posted, the limited generalizability of the sample must be acknowledged as evidenced by the large proportion of women and white, non-hispanic, respondents. in future research, having a more diverse sample will help to clarify how the intersection of age, gender, and race affects perceptions of covid-19 disruption in relation to well-being. knowledge remains limited regarding disparities of the oldest adults. the intersection of age and race/ethnicity, and the moderating effects of age and covid-19 disruption on well-being over a longer time period need to be examined further. also, given the timing of the investigation in the progression of the covid-19 pandemic, in the u.s. sample, the current study opted to only focus on the strengths brought about by age within the savi framework. an examination of the vulnerabilities would be a purposeful pursuit as the covid-19 pandemic extends in time. lastly, by using a single item to examine disruption of covid-19, the current study is not able to capture the nuances of how disruption is experienced (e.g. loss of loved one, job changes, quarantine, etc.); as a subjective measure, differences in the interpretation of the rating scale might have also resulted. a multi-item, multi-faceted measure is recommended in future studies. a c c e p t e d m a n u s c r i p t despite the disruption of covid-19 across all ages and the greater susceptibility of older adults to serious health and social consequences, the current study suggests that middleaged and older adults experienced less distress than younger adults in response to their perceived disruptions. in the face of ageist media reports that paint aging adults as a vulnerable group, these are the type of strengths that can be highlighted to reframe ageist rhetoric. this finding suggests a protective advantage with increased age despite the profound effects of living through a time of global crisis, but also signals a potential cohort effect that may continually influence the lives and mental health needs of younger adults as they age. those effects remain to be seen although the pandemic provides everyone with the experience of navigating through a time of crisis, it has the potential to produce lasting strengths and vulnerabilities that are carried into the next crisis, strengths and vulnerabilities that will continue to be shaped by further experience and age-related change. m a n u s c r i p t table 1 psychological resilience after disaster: new york city in the aftermath of the september 11 th terrorist attack evidence for a life-span theory of socioemotional selectivity mental health: household pulse survey strength and vulnerability integration (savi): a model of emotional well-being across adulthood a global measure of perceived stress perceived stress in a probability sample of the united states covid-19 pandemic and ageism: a call for humanitarian care gpower: a general power analysis program process: a versatile computational tool for observed variable mediation, moderation, and conditional process modeling computational procedures for probing interaction in ols and logistic regression: spss and sas implementations a multidimensional approach to measuring well-being in students: application of the perma framework is ethnicity linked to incidence or outcomes of covid-19? which melbourne metropolitan areas are vulnerable to covid-19 based on age, disability, and access to health services? using spatial analysis to identify service gaps and inform delivery severe acute respiratory syndrome) pandemic in hong kong: effects on the subjective wellbeing of elderly and younger people the factorial generality of brief positive and negative affect measures bearing the brunt of covid-19: older people in low and middle income countries prevalence and impact of cardiovascular metabolic diseases on covid-19 in china coping, emotion regulation, and well-being: intrapersonal and interpersonal processes more than 40% of u.s. coronavirus deaths are linked to nursing homes risk and resilience in family well-being during the covid-19 pandemic disparities in the population at risk of severe illness from covid-19 by race/ethnicity and income age differences in emotional responses to daily stress: the role of timing, severity, and global perceived stress flourish age-related differences in ambulatory blood pressure during daily stress: evidence for greater blood pressure reactivity with age covid-19 and racial/ethnic disparities m a n u s c r i p t a c c e p t e d m a n u s c r i p t a c c e p t e d m a n u s c r i p t key: cord-294180-t5bncpo4 authors: neto, leônidas oliveira; tavares, vagner deuel de oliveira; galvão-coelho, nicole leite; schuch, felipe barreto; lima, kenio costa title: aging and coronavirus: exploring complementary therapies to avoid inflammatory overload date: 2020-06-26 journal: front med (lausanne) doi: 10.3389/fmed.2020.00354 sha: doc_id: 294180 cord_uid: t5bncpo4 nan acute respiratory distress syndrome (ards) is the main cause of death in covid-19 patients (1, 2) . in recent years the relationship between this respiratory syndrome and inflammatory system dysregulation has been discussed (3) . patients with ards could present distinct endophenotypes with respect to immune alterations: hyper-or hypo-inflammatory profiles (4, 5) . the identification of inflammatory endophenotypes of ards is important, as patients respond differently to clinical and hospital management (3) . in patients with a hyper-inflammatory profile, a pro-inflammatory storm is observed in the human body, with elevated rates of biomarkers such as c reactive protein (crp) (2, 6) and cytokines such as interleukins (il)-6 and tumoral necrosis factor (tnf)-α that are able to develop a systemic inflammatory response. the release of il-6 and tnf-α into the systemic circulation directly contributes to the increase in systemic inflammation levels and arteriosclerosis processes (7) . people with chronic clinical comorbidities (1) such as hypertension, diabetes (8) , and kidney disease (9) have a higher risk of becoming critically ill and dying from covid-19. for this reason, the older age population has a higher risk of mortality by covid-19, since they have many of these diseases (10, 11) . it is interesting to highlight that both aging and chronic diseases are linked to an increase in levels of systemic inflammation, which could explain a potential common pathway between these factors and covid-19. therefore, the acute and strong immune system dysregulation induced by the virus may be linked to ards and its complications, such as multiple organ failure, and finally lead to patient death (12) , mainly in those with previous inflammatory allostatic overload (13, 14) . in fact, people with covid-19 present high levels of systemic inflammatory biomarkers (15) , and the detection of these forms part of the preliminary guidelines for the diagnosis and treatment of sars-cov-2 (12) . accordingly, multiple experimental treatments with immune-suppressing or stimulating drugs have been tested, aiming to reduce the pro-inflammatory cascade and, thus, mortality (16) (17) (18) . while the search for effective treatments and vaccines is the top priority, non-pharmacological complementary therapies targeting reductions in baseline inflammatory load, mainly in the oldest population, should receive some attention. during aging, a natural and progressive deterioration in cells and impairment in organ functions occur due to metabolic, immunological, neuroendocrine, or oxidative stress (19) . at a molecular level, imbalance between the oxidant/antioxidant pathways (19) could be explained by malfunction in inflammatory/antiinflammatory homeostatic mechanisms, which result in a chronic low-grade pro-inflammatory state known as inflammaging (20). the inflammatory system is responsible for defending systemic functioning and repairing damages from infections and harmful environmental agents. aging is a process that all living organisms ages and corresponds to a reduction of defenses to the aggressor agents of living beings, and this we call immunosenescence. this process is gradual and differs between genders (21) . at ∼40 years of age, the first major reduction in immune functions occurs and occurs in a similar way between men and women. studies with covid-19 reveal that it is exactly in this age group that lethality doubles, from 0.2 to 0.4%. around the early post-60s, we have a new functional immune decline for men, which only occurs in the late 60s for women, which may partly explain the higher mortality of men worldwide (22) . several studies report that, with aging, both the innate and adaptive immune response suffer changes both in their cellular composition and in their function (23, 24) . in the case of covid-19, the innate immune response in the elderly would be activated, and there would be no satisfactory passage of the innate immune response to adaptive, maintaining a chronic activation of the former and preventing the elimination of sars-cov2 (23, 25) . in addition to maintaining the chronic immune response, which generates a chronic inflammatory state, there is an important decline in the performance of the adaptive system. yet, there is a reduction in the recognition of new antigens by adaptive immunity due to the reduction of naive cells and, moreover, a depletion of aging immune cells, which are already very stimulated and do not retain their functions. there are reports that immune cells of adaptive response also undergo changes in their functions and start to act as cells of the innate response (26) . during the covid-19 pandemic, two of the proinflammatory proteins were elevated in severe patients (27) , yet the inflammatory state may be associated with multiple diseases (25) . in this sense, the consequences are systemic and affect the elderly especially, causing changes in body composition and an imbalance between availability and energy demand that can affect the quality of life and functionality of the elderly (28) . in addition, the inflammation overload makes the elderly more susceptible to several other diseases, such as cardiovascular disease, diabetes, osteoporosis, and ostearthrosis (29) . in this context, lifestyle and nutraceuticals arise as important prophylactic interventions to reduce the burden of baseline inflammation in older adults and consequently improve quality of life, mobility, cognition, mood, and metabolic and immune balances, especially during the pandemic. it is possible that covid-19 will be a long pandemic, with multiple infection waves (30) ; therefore, these strategies are especially important since they can be adopted in the long term and under physical social isolation. the aim of this study is to discuss how diet and nutraceuticals and lifestyle as complementary therapies could help older adults during the covid-19 pandemic, reducing inflammaging. comfort foods are very palatable foods that are rich in saturated fats and carbohydrates, especially sugar, which can decrease stress and anxiety through activation of the dopaminergic pathways of the reward system (31, 32) . in times of lockdown, a rise in the intake of comfort foods is likely, and this behavior tends to strengthen each time the reward system is activated (33) . since comfort foods have a high caloric rate, they can lead to weight gain when the energy expenditure is lower than the caloric intake, resulting in obesity, which is recognized as an inflammatory disease (34) . in order to avoid weight gain, which adds load to inflammaging through an increase in the synthesis of harmful adipocytokines by white adipose tissue (35) , a diet should be prescribed by a specialist. for instance, some diets, such as the mediterranean diet, the low glycemic index diet, moderate carbohydrate intake, and vegetarian diets, should be adapted to the personal demands and preferences of older adults and prescribed in times of lockdown (36) . however, diets with severe restriction should be avoided, as they could lead to impulsive food behaviors (31) . besides adjustment in the diet, some specific nutrient supplementations can assist in health improvement, such as magnesium, zinc, s-adenosyl methionine, omega-3, and vitamin d, which are important for good maintenance of cognitive and physiological mechanisms (37, 38) . magnesium is fundamental for nervous system function and insulin sensitivity, helping in the prevention or management of diabetes mellitus type ii, characterized as a chronic and mild inflammatory disease (34, 39) . zinc also contributes to improving insulin sensitivity (40) and body metabolism (39) . vitamin d, or more specifically, 25hydroxyvitamin d [25 (oh) d], is an anti-inflammatory nutrient (41) , and reduces the activation of the renin-angiotensin system, preventing hypertension (42), besides its importance to bone and muscle, an inverse relationship is also observed between its levels and mortality risk in old adults (43) . omega-3 has an important role in cognition and as an anti-inflammatory agent; thus, it seems effective against age-related mood disorder (44, 45) . recently, 25-hydroxyvitamin d [25(oh)d] has been suggested as a nutraceutical alternative to reduce the risk of covid-19 infection due to improvement in the immune system, whereas vitamin d3 is pointed out as an adjunctive treatment in higher doses (1, 46) . in addition, vitamin c could be an alternative to treat respiratory tract infections. also, one study indicated that administration of ∼ 15 g/day of vitamin c for 4 days may decrease mortality in patients with ards (47). however, the vitamin c supplementation did not significantly improve organ dysfunction scores or alter biomarkers of inflammation and vascular injury. thus, controlled trials and large-population studies should be conducted to prove these hypotheses. moreover, it is important to highlight that the benefits of both diet and nutraceutical interventions are enhanced and the risks reduced when planned for a specific patient, through precisionbased approaches that consider nutritional macro/micronutrient deficiencies, levels of inflammatory cytokines, and genomic and microbiome analysis, among other factors (48) . this individual analysis is mainly relevant to elderly adults who usually show imbalances in many micro-and macronutrient levels as a result of aging or pharmacological treatments. although some of these approaches are low-cost, unhappily, they are not always applied. therefore, their use should be stimulated to has to help reduce the number of deaths around the world, mainly during the pandemic (49) . sedentary behaviors such as longer screen time and lower physical energy expenditure can aggravate physical and mental conditions (50) , especially in this period of social isolation. therefore, reducing the time spent in sedentary behavior at home is of great importance for maintaining health during lockdown (51) . furthermore, increasing the time spent engaging in exercise is essential. lifestyle therapy consists of adopting a health routine that includes a balanced diet, physical exercise, relaxation and meditation techniques, and good sleep (38, 48) . a robust body of evidence has demonstrated the benefits of these modifications of lifestyle for mental health, mainly for mood symptoms (52) (53) (54) (55) , indicating that lifestyle therapy is an effective strategy for preventing and treating some mental disorders (56-59), including in old adults (45) . it is natural that with aging, the frequency and intensity of physical activities will decrease (51) . however, there are further reasons for encouraging an increase in activity levels, such as for improving cardiorespiratory fitness (60) , which in turn reduces mortality risk (61) , and poor health (62) . furthermore, reducing sedentary behavior and engaging in exercise may increasing the production of systemic anti-inflammatory cytokines and help to combat inflammation (63, 64) by increasing innate immune function (65) and decreasing the chronic inflammation related to various diseases (66) . considering the high rate of risk factors being present in older adults as a risk group (67) , it is necessary to build tools directed at this group that aim to reduce sedentary behaviors and to keep them active during the covid-19 pandemic. as well as setting prescribed exercises and encouraging increased levels of daily physical activity, all movements should be stimulated, even simple routine activities such as those related to cleaning the house (68) . with respect to exercises, to reduce sedentary behavior, we recommend the practice of modest exercises that are popularly known as jumping jacks, going up and down stairs, pushups, sit and get up, and balance exercises. these exercises are options that can fit well into the lockdown situation and can be done with home objects such as chairs and benches. however, all exercise should be supervised and prescribed by a trained professional, considering the individual, social, and economic aspects of the subject. however, it is necessary that this orientation occurs using distance-oriented tools, such as internet-based strategies like apps or video calls or mobile telephone messages. group classes can also improve motivation and social support, which in turn reduces psychological stress levels, helping in homeostatic balance (69) . however, as some elderly adults have impaired motor skills, other alternatives have been used to reduce symptoms of mental disorders and reduction inflammation. for this, approaches with an integrative mind-body focus have been gaining ground in order to prevent or treat diseases such as chronic stress, anxiety, and depression (70) , which are known to induce a mildly proinflammatory profile (71) . these approaches use meditative practices as tools aimed at refining attention and promoting better emotional regulation and self-awareness (72) . one of the main components of mindfulness-based activities is the regulation of attention (73) . thus, attentional focus during the exercises proposed in mindfulness programs is directed to the observation of the experience of thoughts, body sensations, and emotions (74, 75) . in addition, the practice of relaxation and meditation also has an effect on reducing inflammation (76) . successful mind-body interventions in older adults have shown improvements in different aspects, such as pain control, sleep quality, attention, global cognition, and working memory (77) . additionally, positive results were recently presented for the reduction of depressive symptoms through internet mindfulness therapy in this population (78) . therefore, applying relaxation and meditation therapies is urgent, as these can improve mental and physical health in older people who are in isolation, following the guidelines of the who. social physical isolation due to covid-19 can bring serious risks to health if older adults continue with, or assume, a nonhealthy lifestyle, which includes a lack of physical activity and a diet low in nutrients and rich in comfort foods. therefore, strategies should be encouraged to promote and raise awareness among the older population about the application of lifestyle and nutraceutical tools. these interventions have great potential for insertion in public policies in different contexts due to their low cost, effectiveness, and simplicity. we are aware that it can be difficult to apply all of these suggestions, mainly in elderly adults, but every step is important and better than none. therefore, a healthy lifestyle should be encouraged as an intervention to prevent frailty among older people, and a multi-professional care system should act in this time of covid-19 to reduce risks and avoid damage related to inflammation overload in older adults. ln: conceptualization, project administration, and writingoriginal draft preparation. vt, ng-c, and fs: reviewing and editing. kl: conceptualization, project administration, and writing-original draft preparation. all authors contributed to the article and approved the submitted version. the authors declare that this study was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. ng-c was supported by the capes foundation of the brazilian ministry of education (research fellowship 88887.466701/2019-00) and the national science and technology institute for translational medicine (inct-tm fapesp 2014/50891-1; cnpq 465458/2014-9). a comprehensive literature review on the clinical presentation, and management of the pandemic coronavirus disease 2019 (covid-19) clinical features of patients infected with 2019 novel coronavirus in wuhan recent advances in understanding and treating acute respiratory distress syndrome latent class analysis of ards subphenotypes: analysis of data from two randomized controlled trials carolyn acute respiratory distress syndrome subphenotypes respond differently to randomized fluid management strategy the mercurial nature of neutrophils: still an enigma in ards? adipose tissue: immune function and alterations caused by obesity endocrine and metabolic link to coronavirus infection kidney disease is associated with in-hospital death of patients with covid-19 similarity in case fatality rates (cfr) of covid-19/sars-cov-2 in italy and china clinical predictors of mortality due to covid-19 based on an analysis of data of 150 patients from wuhan, china diagnosis and clinical management of severe acute respiratory syndrome coronavirus 2 (sars-cov-2) infection: an operational recommendation of peking union medical college hospital (v2.0): working group novel coronavirus, peking union medical colle interacting mediators of allostasis and allostatic load: towards an understanding of resilience in aging allostasis and allostatic load: expanding the discourse on stress and cardiovascular disease induction of pro-inflammatory cytokines (il-1 and il-6) and lung inflammation by coronavirus-19 (covi-19 or sars-cov-2): anti-inflammatory strategies associations between immune-suppressive and stimulating drugs and novel covid-19-a systematic review of current evidence metronidazole a potential novel addition to the covid-19 treatment regimen the use of antiinflammatory drugs in the treatment of people with severe coronavirus disease 2019 (covid-19): the experience of clinical immunologists from china the role of oxidative stress in the aging process inflammation, genetic background and longevity clinical advances in sex-and gender-informed medicine to improve the health of all: a review the lethal sex gap: covid-19 24. nikolich-žugich j. the twilight of immunity: emerging concepts in aging of the immune system review-article chronic inflammation in the etiology of disease across the life span sestrins induce natural killer function in senescent-like cd8+ t cells dysregulation of immune response in patients with covid-19 in wuhan, china age and age-related diseases: role of inflammation triggers and cytokines aging, inflammation and the environment projecting the transmission dynamics of sars-cov-2 through the postpandemic period stress, eating and the reward system minireview: glucocorticoids -food intake, abdominal obesity, and wealthy nations in 2004 shaping the stress response: interplay of palatable food choices, glucocorticoids, insulin and abdominal obesity obesity & inflammation: the linking mechanism & the complications the endocrine function of adipose tissues in health and cardiometabolic disease overweight, obesity, and outcomes: fat mass and beyond nutritional medicine as mainstream in psychiatry adjunctive nutraceuticals for depression: a systematic review and meta-analyses magnesium in prevention and therapy a comprehensive review on zinc(ii) complexes as anti-diabetic agents: the advances, scientific gaps and prospects vitamin d and the immune system interplay of vitamin d, erythropoiesis, and the renin-angiotensin system vitamin d and ageing the antiinflammatory role of omega-3 polyunsaturated fatty acids metabolites in preclinical models of psychiatric, neurodegenerative, and neurological disorders the role of physical exercise and omega-3 fatty acids in depressive illness in the elderly evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths effect of vitamin c infusion on organ failure and biomarkers of inflammation and vascular injury in patients with sepsis and severe acute respiratory failure: the citris-ali randomized clinical trial nutraceuticals for major depressive disorder-more is not merrier: an 8-week double-blind, randomised, controlled trial stress-mediated hormetic modulation of aging, wound healing, and angiogenesis in human cells physical activity can attenuate, but not eliminate, the negative relationships of high tv viewing with some chronic diseases: findings from a cohort of 60 202 brazilian adults associations of moderate to vigorous physical activity and sedentary behavior with depressive and anxiety symptoms in self-isolating people during the covid-19 pandemic: a cross-sectional survey in brazil epa guidance on physical activity as a treatment for severe mental illness: a meta-review of the evidence and position statement from the european psychiatric association (epa), supported by the international organization of physical therapists in mental the lancet psychiatry commission: a blueprint for protecting physical health in people with mental illness cardiorespiratory fitness in severe mental illness: a systematic review and meta-analysis aerobic exercise improves cognitive functioning in people with schizophrenia: a systematic review and meta-analysis exercise as medicine for mental and substance use disorders: a metareview of the benefits for neuropsychiatric and cognitive outcomes physical activity protects from incident anxiety: a meta-analysis of prospective cohort studies physical activity and incident depression: a metaanalysis of prospective cohort studies quantity and quality of exercise for developing and maintaining cardiorespiratory, musculoskeletal, and neuromotor fitness in apparently healthy adults: guidance for prescribing exercise impact of physical inactivity on the world's major non-communicable diseases is physical activity or physical fitness more important in defining health benefits? pro-and antiinflammatory cytokine balance in strenuous exercise in humans the anti-inflammatory effect of exercise can exercise training improve immune function in the aged? reversing age-associated immunosenescence via exercise covid-19 and the consequences of isolating the elderly #traininginhome -training at home during the covid-19 (sars-cov2) pandemic: physical exercise and behavior-based approach resposta ao estresse: ii. resiliência e vulnerabilidade effects of yoga on depressive symptoms in people with mental disorders: a systematic review and meta-analysis is depression an inflammatory disorder? the clinical use of mindfulness meditation for the self-regulation of chronic pain mindfulness: a proposed operational definition full catastrophe living: using the wisdom of your body and mind to face stress, pain, and illness how does mindfulness meditation work? proposing mechanisms of action from a conceptual and neural perspective mindfulness meditation and the immune system: a systematic review of randomized controlled trials mindfulness-based stress reduction for chronic insomnia in adults older than 75 years: a randomized, controlled, single-blind clinical trial internet mindfulness meditation intervention (immi) improves depression symptoms in older adults the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 neto, tavares, galvão-coelho, schuch and lima. this is an openaccess article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-267664-vahd59z8 authors: cesari, matteo; proietti, marco title: covid-19 in italy: ageism and decision-making in a pandemic date: 2020-04-01 journal: j am med dir assoc doi: 10.1016/j.jamda.2020.03.025 sha: doc_id: 267664 cord_uid: vahd59z8 nan the world health organization declared the covid-19 situation as a pandemic on march 11th, 2020. 1 to date, italy is the country after china at having been most severely hit by this humanitarian and public health tsunami. projections are even suggesting that the number of deaths due to sars-cov-2 in italy will continue to increase in the near future, leaving us the sad world record of casualties. what has happened in italy during these last few weeks? on february 22nd, a "red zone" was defined by the government to quarantine a group of several towns in the lombardy region, just a few hours after the diagnosis of the first case in italy. this area, where about 50,000 persons live, included codogno (where patient 1 was identified), castiglione d'adda, and casalpusterlengo. on march 8th, the red zone was extended to the entire region of lombardy (about 10 million people) and several surrounding provinces in a new attempt of preventing the uncontrolled diffusion of the virus to the rest of the country. the following day, the entire country was transformed into a "red zone". on march 21st, a complete lockdown of italy was ordered by the government as a drastic and unprecedented countermeasure against the coronavirus. behind this story of the italian crisis is the drama of a healthcare system close to collapse. the exponential increase of patients admitted to emergency departments with fever and/or respiratory symptoms resembled the mounting wave of a tsunami. it soon became evident how inadequate the availability of beds was to face the continuous flow of patients. the situation was aggravated by the need to isolate covid patients, given the high contagiousness of the virus. at the same time, intensive care units started to saturate, and the number of devices for ventilating patients suddenly appeared insufficient to address the growing demand. furthermore, healthcare professionals started falling sick (sometimes even dying) as consequence of their untiring willingness to serve the community, as well as the infrastructural unpreparedness for the enormity of the outbreak. our world was completely subverted by the emergency. no plans or protocols had the time to be tested and verified, at least on a large scale. the rapidity of the evolving scenario made it necessary to adopt easy and pragmatic solutions even for critical and delicate matters. not surprisingly, the usual, despicable age criterion started to be implicitly adopted in the decisional algorithm for the allocation of scarce resources to the mounting number of patients. it is noteworthy that during the early crisis, the società italiana di anestesia, analgesia, rianimazione e terapia intensiva (siaarti; italian society of anesthesia, analgesia, and intensive care) released clinical ethics recommendations for the allocation of treatment in exceptional resource-limited situations. 2 the document mentions the word "age" twice, in two critical paragraphs. they read as follows: "3. it might be needed to set an age limit for the admission to intensive care. it is not a mere choice related to values, but to spare resources that might be extremely scarce to those who have in primis the highest chance of survival and then to those who may have more years of life saved, in order to maximize benefits for the largest number of persons. 4. the presence of comorbidity and functional status must be carefully evaluated in addition to age. it is possible that a relatively short stay in healthy persons might potentially become longer and thus resource consuming over the healthcare system in case of persons with advanced age, frailty or severe comorbidity." it is important to consider that what the siaarti mentioned as a scenario of "extremely scarce" resources may correspond to the optimistic vision of the saturation that the lombardy region has been experiencing over the past weeks. persons with covid-19 often experience extremely rapid (and often unexpected) clinical changes, with sudden respiratory distress. clinicians often find themselves in the position of having to act quickly to move a patient from the acute care ward to the intensive care unit, to be placed on a ventilator. it is not rare to see that in 20-30 minutes, the patient turns from relatively stable to extremely critical. in this scenario, which is the risk factor for negative outcomes that is easier and quicker to obtain? of course, the patient's age… if we want to fight such an ageistic approach and replace the age criterion for the allocation of resources, we must have and propose a parameter more robust than age but equally easy-to-obtain, that can be used for critical and rapid decision-making. otherwise, geriatricians might be at risk of remaining too theoretical and disengaged from the real world. we must show that we understand why intensive care physicians are prioritizing the life of a 40 year-old person over that of a 90 year-old, and that this is the best decision. they have never been exposed to anything other than this approach. and the critical nature of the situation can further provide ground for justifying such arguable choices. "all is fair in love and war"-and we are indeed in war! the 2013 document referred by the siiarti recommendations was developed without the involvement of geriatricians. it discusses how to choose if a patient should undergo palliative versus intensive care. the criterion that is most frequently used is age. 3 however, the most recent recommendations seem to create some formal openings to geriatric concepts that are traditionally ignored, and therefore, to reconsider basing decisions only on the number of years lived. it is true that age is always at the beginning considerations that drive decisions; everything is still strongly designed to lead toward the exclusion of older persons. at the same time, one should not underestimate the statement that "the presence of comorbidity and functional status must be carefully evaluated in addition to age". the sentence might appear superficial to those who do not understand it, perhaps because this is not typically the case. at the same time, the statement potentially draws a first line in the sand for the future. it is a starting point to help discriminate what should be done and what should not be done, between good clinical practice and pure malpractice. implementation of these principles into decisional algorithms should, we believe, be part of pandemic preparation everywhere. in settings where rationing of resources becomes a necessity and such preparation has not been made, medical staff or oversight organizations should implement ad hoc guidelines that incorporate key prognostic factors beyond age -most notably frailty, comorbidity, and functional status. 4, 5 in this manner, a sentence about function and comorbidities in an ethics document underscores the need to operationalize the meaning of prognosis at advanced age, 6 and acknowledges the critical role that function and comorbidity play in the aging individual. 7 clinicians familiar with principles of geriatrics and gerontology could thus support the development of more contemporary recommendations by identifying valid, efficient ways of measuring comorbidities and function across different settings and specialties. we might suggest the use of simple tests and scales, such as the clinical frailty scale, 8 or the assessment of mobility independence, 9 that might optimally capture the pre-illness health status of the individual, mirroring his/her physiological reserve, and, by incorporating such tools into electronic records for rapid assessment, provide support for better clinical decisionmaking than the all-too-simplistic criterion of chronological age. we realize we might be too optimistic to think that ageism is going to soon be defeated among clinicians. age is still the first criterion mentioned. however, we get some hope reading that, unlike the past, it is not the only criterion being proposed. will comorbidities and functional status start to change how we think and act in times of crisis? it is probably still too early to see major changes. however, while continuing to push towards a less ageistic society and medical practice, we should take advantage of these openings that arise from non-geriatricians. these are indeed opportunities to build constructive exchanges. if the principles of geriatrics had been incorporated into pandemic planning before this crisis, perhaps we would today have more justification to counter the ageistic approach. while ageist attitudes cannot be justified, we who focus on the care of older persons must take some responsibility for what is not happening. we need to realize how much work we still have ahead of us in educating and reframing the thinking among our clinician colleagues and our society, and therefore roll up our sleeves and perhaps leave aside some of our ego. when we hear that the decision of using a ventilator for a person with respiratory distress is based on his/her birth date, we must admit our failure and realize how many problems modern medicine has -in particular, that without our input, modern medicine may be at risk of having lost the meaning and value of the human life. who director-general's opening remarks at the media briefing on covid-19 -11 clinical ethics recommendations for the allocation of intensive care treatments, in exceptional, resource-limited circumstances grandi insufficienze d'organo "end stage": cure intensive o cure palliative? documento condiviso per una pianificazione delle scelte di cura prognostic indices for older adults: a systematic review the central role of prognosis in clinical decision making frailty and multimorbidity: different ways of thinking about geriatrics evidence for the domains supporting the construct of intrinsic capacity a global clinical measure of fitness and frailty in elderly people a diagnosis of dismobility-giving mobility clinical visibility: a mobility working group recommendation a comparison of frailty indexes for the prediction of falls, disability, fractures, and mortality in older men prognostic indices for older adults: a systematic review the central role of prognosis in clinical decision making key: cord-317583-jhulvfev authors: blanchflower, david g. title: is happiness u-shaped everywhere? age and subjective well-being in 145 countries date: 2020-09-09 journal: j popul econ doi: 10.1007/s00148-020-00797-z sha: doc_id: 317583 cord_uid: jhulvfev a large empirical literature has debated the existence of a u-shaped happiness-age curve. this paper re-examines the relationship between various measures of well-being and age in 145 countries, including 109 developing countries, controlling for education and marital and labor force status, among others, on samples of individuals under the age of 70. the u-shape of the curve is forcefully confirmed, with an age minimum, or nadir, in midlife around age 50 in separate analyses for developing and advanced countries as well as for the continent of africa. the happiness curve seems to be everywhere. while panel data are largely unavailable for this issue, and the findings using such data largely confirm the cross-section results, the paper discusses insights on why cohort effects do not drive the findings. i find the age of the minima has risen over time in europe and the usa. in this paper, i report on the existence of a midlife nadir in well-being. the analysis is conducted mostly at the country level with happiness and life satisfaction variables, although a number of other measures are used that relate to a household's financial situation and their living standards, satisfaction with local services, and the macro economy. all produce u-shapes in age. using country-level data, i identify u-shapes in age in 145 advanced and developing countries. 1 this includes 138 of the 193 member countries of the united nations. i find this happiness curve (rauch 2019) for 109 developing 2 and thirty-six advanced countries based on an analysis where i control for gender, education, marital and labor force status, and time. i use data from fourteen different survey series. i use these data to estimate 477 separate country-level estimates that reach a minimum, on average, at age 48.3. 3 there are 241 estimates from developed countries with an average minimum at age 46.7 and 236 estimates from developing countries with an average minimum at 49.9. i examine cross-section time series data at the country level rather than examining panel data. longitudinal data files that have a long run of years are restricted to the uk (bhps and ncds), germany (gsoep), and australia (hilda). in part, the concern with these surveys is non-random attrition bias and hence missing values over time with the least happy dropping out or even dying, which may well introduce measurement error. there is a small literature looking at age effects using panel data that i interpret as largely supportive of u-shapes, although there are some technical issues that must be considered. my interest is to see whether there is evidence of a midlife zenith in other countries besides the uk, germany, and australia. i examine the importance of cohort effects to determine if younger and older age cohorts are different from those in the middle and find out that they are not. i examine the data over time and adjust for cohort effects and find remarkable consistency in the findings. i find that introducing cohort effects in the samples where i have a long time series, namely, the eu commission's eurobarometer series pre and post the great recession (2009) (2010) (2011) (2012) (2013) (2014) (2015) (2016) (2017) (2018) (2019) , has little impact on the results. i find the minima in europe have risen over time, from around age 40 in 1975 to over 50 in the most recent data. i also address the issue of possible differential response rates among older people, along with the concern that happy people live longer. to minimize that concern, i focus my analysis on people from early adulthood, which is usually age 18 but in some samples is as low as 15, to under the age of 70. i exclude older people. it makes sense to look at as many countries as possible given the evidence that in the raw data the usa looks different. in the raw us data, essentially however measured, happiness rises initially to a peak around age 30 and then declines into midlife and then rises again after age 70. this apparent m-shape disappears once controls are included and a well-defined u-shape appears. it also disappears when the sample is split into separate married and unmarried samples. these patterns are not found elsewhere in the world. this has led to a debate in the usa especially about the importance of including control variables, although less so outside the usa where it matters little. in other countries, the u-shape generally appears whether controls are included or not, although the point at which the function reaches a minimum may differ. it is also worth pursuing the possibility that the u-shape doesn't apply to poorer countries, where residents have shorter life expectancies. blanchflower and oswald (2008a) find a u-shape for 39 developing countries in world values survey sweeps 1-4 4 that averages out at a minimum around age 43 when including control variables. in this paper, i find there are u-shapes in age in developing countries with minima similar to those in advanced countries regardless of how well-being is measured. i examine the presence or not of u-shapes with and without controls in the usa and find the evidence is much stronger with controls. i then turn to examining data for the uk and 36 european countries and find there is evidence of a u-shape whether controls are included or not, with very little difference in the age minima. i then proceed to examine a series of multi-country data files. it is striking that the same finding holds across so many countries. the u-shape can be found in multiple data files and does not depend on what question is asked or how the responses are coded. i document clear patterns in the data. this paper is the mirror image of blanchflower (2020b) that examined unhappiness data and finds comparable evidence using twenty different measures for an unhappiness curve that maximized with controls at age 49 compared with a zenith of happiness estimated in this paper at age 48. yes, there is, despite what psychologists say. the background literature is large and there is some disagreement over whether u-shapes exist at all (see, for example, baird et al. (2010) , blanchflower (2009) , blanchflower and oswald (2004) , carstensen et al. (2011) , charles et al. (2001) , easterlin (2003 easterlin ( , 2006 , frey and stutzer (2002) , frijters and beaton (2012) , glenn (2009) , graham and pozuelo (2017) , hellevik (2017) , hudson et al. (2016) , lachman (2015) , leland (2018) , mroczek and kolanz (1998) , mroczek and spiro (2005) , rauch (2018) shields and price (2005) , stone et al. (2010) , steptoe et al. (2015) , wunder et al. (2013) , and schwandt (2016)). a recent review by ulloa et al. (2013) goes so far as to draw the conclusion that existing studies show either a u-shaped, inverted u-shaped, or linear relation between aging and subjective well-being. other studies, such as lachman (2015) , come close to arguing that there may be a midlife dip but that it is too small to be significant. many of the studies such claims were based on had very small samples sizes and in fact did show u-shapes despite claims they didn't. an early psychology literature suggested there was no age-happiness relationship (cantril, 1965, and palmore and luikart, 1972) . myers (2000, p. 58 ) argued that no time in life is notably happiest and most satisfying. in contrast, michael argyle concluded that studies of life satisfaction found that it increased with age (argyle, 1999 (argyle, , 2001 . a survey by diener et al. (1999, p. 291) concluded that life satisfaction often increases, or at least does not drop, with age. easterlin (2006) examined data from the general social surveys from 1972 to 1993 and claimed that "happiness is greatest at midlife but not by a great deal. on average it rises somewhat as people progress from age 18 to 51 and declines thereafter" (2003, p.471) . a survey by diener et al. (1999, p. 291) concluded that recent studies converge to show that life satisfaction often increases, or at least does not drop, with age. diener and suh (1998) examined world values survey data for 1994 and argued that the raw data on life satisfaction trended up slightly through age. deaton (2008) concluded that the u-shaped relation is present solely in rich, english-speaking countries in which the elderly is relatively satisfied with their lives. (ibid., p. 8). more recently, whitbourne (2018) has gone so far as to argue that the u-shape curve is a "myth." blanchflower and graham (2020a) examine the evidence that psychologists have cited claiming no u-shape exists over the life span and found that many of the studies cited had very small sample sizes. examples are helson and lohnen (1998) (n = 80), freund and baltes (1998) (n = 206) , and hamarat et al. 2002 (n = 95) to name but a few. it is hard to say much of anything about statistical differences in well-being by age with sample sizes that small. psychologists have also cited work by ingelhardt (1990) as not finding any u-shapes in age. for example, diener et al. (1999) citing ingelhardt (1990) argue that "international studies based on representative samples from multiple countries also show that life satisfaction does not decline with age." myers (1992) argued that ingelhardt showed that "age differences in well-being were trivial. does happiness then align itself more with any particular age? do young adults have more fun? surprisingly, and definitely, not" (p. 69). ingelhardt (1990) examined well-being across sixteen nations using data from eurobarometers #13-#26 (april 1980 -november 1986 and the world values survey on the usa, canada, hungary, and japan for 1981-1982 and argued that there was "little variation by age" in well-being (p. 224). it turns out the data he used in fact show otherwise. blanchflower and graham (2020a) went back to the 1990 ingelhardt book and observed he in fact reported u-shapes in the raw data in nine of the sixteen countries studied. blanchflower and graham examined the same data ingelhardt used and estimated a series of happiness equations and found there were u-shapes in age with controls in all the countries and variables ingelhardt examined. in addition, diener and suh (1998) cite work by okma and veenhoven (1996 ), also used eurobarometers, between 1980 and 1990 , and argued that the paper showed an almost flat line with age. from around age 18 to 90, they argued it showed there was almost no change in life satisfaction. it didn't. blanchflower and graham (2020a) went back to analyze these same eurobarometer files for the same years which are part of the publicly available mannheim trend file. across these nations, the average score for those under 20 was 3.14, reaching a low point of 2.97 at age 54 and then rising to 3.20 at age 90. so, it is true that life satisfaction scores at age 90 are not that different from age 18 but that ignores the midlife drop. without controls in a life satisfaction equation, there is a well-defined nadir in well-being in age controlling for year and nation that minimizes at age 48 and also one with controls-for gender, education, and marital and labor force status-that minimizes at age 43. i update and extend results in an earlier paper (blanchflower and oswald, 2008a) , where it was shown that a u-shape in age existed in well-being data across a number of countries. using data on 500,000 randomly sampled americans and west europeans, the paper found that holding other factors constant, a typical individual's happiness reaches its minimum on both sides of the atlantic for both males and females in middle age. 5 the minimum in age was broadly similar between advanced, east european, and developing nations. the function minimized on average in midlife. for example, in europe, for both men and women, it minimized at around 47 with controls including education and marital and labor force status. for developing countries from the wvs, sweeps 1-4, minima were 43 for men and 44 for women. a maximum in age in unhappiness data for europe was found at around age 47. some apparent exceptions, particularly in twenty developing nations along with a few western countries, mostly where there are small numbers of observations, to the u-shape were noted. 6 subsequently, glenn (2009) argued that it was inappropriate to include controls and what mattered was the raw data; blanchflower and oswald (2009) disagreed. glenn claimed that the appearance of this u-shaped curve of well-being is the result of the use of inappropriate and questionable control variables and especially marital status. it is worth rehearsing the arguments we used there again. in many countries around the world, and especially in europe, as i illustrate in detail below, the u-shape can be found 5 evidence for a u-shape was found in twenty-two advanced countries (australia, belgium, canada, denmark, finland, france, germany, greece, iceland, ireland, italy, japan, luxembourg, malta, netherlands, norway, portugal, spain, sweden, switzerland, uk, and usa) . second, evidence was provided for the existence of a similar u-shape through the life course in east european, latin american, and asian nations. evidence was found in fourteen ex-soviet republics (albania, bosnia, bulgaria, croatia, czech republic, estonia, hungary, latvia, lithuania, macedonia, poland, romania, serbia, slovakia) and thirty-eight developing countries (argentina, azerbaijan, belarus, brazil, brunei, brazil, brunei, cambodia, chile, china, colombia, costa rica, dominican republic, ecuador, el salvador, iraq, israel, honduras, kyrgyzstan, laos, mexico, myanmar, nicaragua, nigeria, paraguay, peru, puerto rico, philippines, russia, singapore, south africa, south korea, tanzania, turkey, ukraine, uruguay, uzbekistan, and zimbabwe. i find evidence of a u-shape in all of these countries also. 6 that included algeria, armenia, austria, bangladesh, chile, colombia, egypt, greece, india, indonesia, iran, jordan, luxembourg, moldova, morocco, new zealand, pakistan, saudi arabia, singapore, slovenia, taiwan, uganda, venezuela, and vietnam. in this paper, i report u-shapes for all but three of them-bangladesh, pakistan, and saudi arabia. without any control variables, and a major problem with glenn's analysis was that he focused too heavily on the usa. second, we disagreed with glenn's methodological position, which seems to be that social scientists should not hold constant other factors when they study the relationship between well-being and age. ultimately, in social science, the control variables that are included in multiple regression equations we noted have to be chosen with an eye on the intellectual or policy question being answered. the summary of our argument went as follows. if the aim is to describe the data, it is reasonable to leave out most or all control variables. "smokers die at rate z" is an acceptable statement to make. but that is not the same as "smoking changes your risk by z," which requires other confounding variables to be controlled for such as diet, education, income, and exercise. we argued that would be an error to use an equation without controls to tell the public what impact aging has on happiness without separating out the effects of other variables such as, say, education, marriage, or unemployment. if the aim is to understand relationships, we concluded, "it seems, it will rarely be desirable to stop at bivariate patterns." that seems right and i don't stop at bivariate patterns in this paper either. blanchflower and oswald (2019) examined the issue of differences between the well-being and age relationship with and without controls using seven pooled crosscountry data sets, covering 51 countries and 1.3 million randomly sampled people; the paper examines the cross-sectional pattern of psychological well-being from approximately age 20 to age 90. 7 the paper described the two conceptual approaches. one studies raw numbers on well-being and age which we termed the descriptive approach. the second studies the patterns in regression equations for well-being (that is, adjusting for other influences). this we termed the ceteris-paribus analytical approach. the paper applied each and compared the patterns of life satisfaction and happiness. using the first method, evidence of a midlife low was found in five of the seven data sets; the two that didn't were both for the usa. using the second method, all seven data sets produced evidence consistent with a midlife low. deaton (2018) reported only unadjusted estimates in part he argued because of the difficulty in applying consistent controls to the gallup data, not because the questions do not exist, but because their meaning varies so much across the globe, with different patterns of education, work, retirement, and health systems. deaton also suggested that a weightier argument is that many possible and potentially important controls are age dependent, including income and the presence of children but especially health, disability, and marital status. deaton notes that "different authors use different countries and different data sets with different swb questions, so it is possible that the age patterns in the gallup data are different from those that come from other questions and different survey protocols; it would be an important (if daunting) task to make systematic comparisons." this is what i try to do here. 8 some psychologist have even gone as far as to argue that even if there is a u-shape it is broadly irrelevant as any change is "trivial." jebb et al. usa, 1972 usa, -2014 and (g) latino barometer, 2013 and 2015. 8 in private communications, sir angus deaton suggested that he didn't have quite this in mind. he suggested, more just a look at the questions they ask, their response rates, and whether they are even grossly consistent. that "it is possible that the u-shaped (or other) curve exists but that it is so small that it is not practically meaningful. in other words, just because differences across age are statistically significant, that does not mean that these differences have practical significance. researchers in past studies have generally not taken effect size into account,â�¦ at some point, an effect size becomes so small that it is truly trivial and lacks practical significance. for our cantril ladder scale, respondents reported (and probably thought) in terms of the nearest whole scale point from 1 to 10. therefore, it seemed that differences below 1.00 should be considered quite small." as blanchflower and oswald (2019) note the claim that the size of the dip is tiny does not appear to be correct. in the seven data sets, they studied the size of the drop, in well-being to the low point in the late 40s is equivalent in magnitude to the influence of a major life event like unemployment or marital separation. the size of the fall in wellbeing from youth to midlife is large and likely highly consequential. i should also note that i know of no evidence in any well-being data involving a change anywhere approaching 1.00 for any life event. some have argued that no u-shape exists in longitudinal data (frijters and beatton 2012; kassenboehmer and haisken-denew 2012) . in contrast, cheng et al. (2017) drawing on four data sets, and only within-person changes in well-being, build on the work of van landeghem (2012) and document powerful support for a u-shape in longitudinal data. three of the data sets are nationally representative household surveys, namely the british household panel survey (bhps, 1991 (bhps, -2008 , the household income and labour dynamics in australia (hilda, 2001-10) , and the german socio-economic panel (soep, 1984 (soep, -2008 . the fourth data set comprises a relatively more homogenous sample of medical doctors from the medicine in australia balancing employment and life (mabel) longitudinal study. they measure the change in well-being of randomly selected individuals each year and then plot that against individuals' ages. on average, they find people's wellbeing gradually drops until individuals reach midlife. from then on, it picks up smoothly as people go on, in each of three countries and four data sets, to approach the age of 70. wunder et al. (2013) and ranjbar and sperlich (2019) both use semi-parametric methods on german soep panel data to examine the relation between age and well-being. they both get the same results. ranjbar and sperlich conclude "we find a clear, deep valley between the ages of 45 and 50, typically interpreted as a midlife crisis." bleischmann (2014) also uses the gsoep and finds "mean life satisfaction is steadily declining between 20 and 55. after this low, happiness increases strongly until the age of 70." de ree and alessi (2011) have examined that the gsoep 1986-2007 found that that "the data is indeed consistent with a u-shape in age over most of the life cycle" (p. 282) but have noted that age profiles are not identified without forcing arbitrary restrictions on the cohort/time profiles. there are clear issues though with the data they examine given they have to drop a quarter of households due to missing values. kroh (2011) notes that less than 50% of the original 1984 sample remains after 2007. ferrer-i-carbonelli and frijters (2004) also examine gsoep data find a u-shape with controls for west german workers. the authors find the result is the same whether estimated by ols, ordered logit, or ordered probit and include controls for time, household income, children, a steady partner, and health. when they re-estimate with fixed effect, the u-shape disappears. piper (2015) uses gmm dynamic panel estimation with 16 waves of the british household panel study on youngsters age 16-30 and found that happiness declined over that age range, a result found by comparing the coefficients of the age dummies: a result in line with the overall u-shape. furthermore, tests of the individual age group coefficients demonstrate that they are, in many cases, significantly different from each other. additionally, because the preferred model controls for the individual waves in the sample, this decline of life satisfaction with age is a life cycle effect. the life satisfaction of young people between 16 and 30 falls, and this seems to be something that everyone, on average, experiences. overall, his findings, piper argues, "are in line with the common u-shape finding." clark (2019) also finds, using the same data source and panel data methods controlling for fixed effects, that the data "continues to produce a u-shaped relationship between well-being and age." other commentators have expressed skepticism that the curve's trajectory holds true mainly in countries where the median wage is high and people tend to live longer or, alternatively, where the poor feel resentment more keenly during middle age and don't mind saying so. john briley in a recent op-ed argued that "the curve is not universaldata from economically struggling countries, for example, don't show the happiness rebound." 9 arthur krystal 10 , for example, has suggested that there may be a simpler explanation: "perhaps the people who participate in such surveys are those whose lives tend to follow the curve, while people who feel miserable at seventy or eighty, whose ennui is offset only by brooding over unrealized expectations, don't even bother to open such questionnaires." this critique of course could apply to any research based on surveys with a bias having nothing to do with age. there is zero evidence that the u-shape has anything to do with differential response bias by age especially under the age of 70. i have the u-shape in many data sets with various happiness measures including happiness itself and life satisfaction and cantril's ladder. it makes no difference if the dependent variable is scored, from 1 to 4 say or from 1 to 10; the results are essentially the same. the smaller numbers of observations for older age groups are an issue but that simply reflects the overall demographics in the country-there are fewer people age 80 than age 30 and especially so in countries with shorter life expectancy. 11 helliwell (2019) recently argued that "to use a single life satisfaction question in large population-based samples might represent the best use of survey resources." following helliwell's advice, where feasible, i use life satisfaction as my well-being measure, where i can. 3 data i examine the happiness curve using individual micro data from thirteen distinct micro survey series. these were chosen because well-being measures of various types were 9 john briley, "does happiness in your 50s signal the end of ambition?," the washington post, december 18, 2019. 10 arthur krystal, "why we can't tell the truth about aging? a long life is a gift. but will we really be grateful for it?," the new yorker, october 28, 2019. 11 according to the census bureau's international population database in 2018, there were 4,675,612 individuals age 30 in the us versus 1,483,523 age 80. in ldcs, the ratio is smaller-in venezuela, for example, the numbers are 519,040 and 65,319 respectively, so it is 8 times there versus 3 times in the us. https://www.census.gov/data-tools/demo/idb/region.php?t=10&rt=0&a=both&y=2019&c=us&r= available. mostly, the questions examined are on happiness or life satisfaction. the questions used vary a little as do the number of possible responses varying from three to eleven that i call steps. other sweeps (e.g., the brfss from 2010), for example, did not contain happiness measures although they do contain unhappiness measures (blanchflower, 2020a) . i also examine a broader set of questions on family life, health, trust, financial situations, living standards, and more. in most cases, i have to recode the variables such that a higher number means greater happiness. source: gallup usdt, 2008 brfss, 2005 brfss, -2010 and gss, 1974-2018 . t-statistics in parentheses. sample size changes when controls are added because of missing values to the control variables *labor force status not available in 2008, hence the smaller sample size 6) ten-step happiness using sweeps 1-9 of the european social surveys (ess) 2002-2016 (table 6 ) 7) ten-step life satisfaction (table 7) and 10-step step happiness from the european quality of life survey: 2003-2016 (table 8 ) 8) seven-step happiness from the 2012 (table 9 ) and 7-step life satisfaction from the 2017 sweeps of the international social survey program (table 10 ) 9) ten-step life satisfaction from waves 2-6 of the world values survey (wvs); 1990-2014 (table 11 ) 10) five-step happiness from the asia barometers of 2005 (table 12) 11) four-step life satisfaction from the latino barometers of 2016 and 2017 (table 13 ) 12) eleven-step cantril's life satisfaction ladder from the gallup world poll (2008-2017) (table 14 ) 13) three-step financial satisfaction from wave 6 of the wvs (table 15) (table 16 ) 15) five-step satisfaction with living standards in the afro barometers 2016 and 2019 (table 17) the issp and wvs both contain data from four large non-european englishspeaking advanced nations-australia, canada, new zealand, and the usa-plus japan. they all give u-shapes in happiness with and without controls. i use three methods to identify the u-shape. first, i run an ols regression with the dependent variable a measure of well-being, on a pooled sample of countries across all second, i then re-estimate for individual countries including the gender, education, and marital and labor force status control variables with the age of respondents limited to those under the age of 70. i do this for simplicity given very different life expectancies across countries and hence much smaller sample sizes for older age groups and likely variability at older ages. sample sizes are often quite small for these individual country regressions, and on average many are only around 1000 observations. i find for several advanced countries that there are insignificant results using, for example, issp data, but when using eb or ess when the samples are much larger, the significance of both age terms appears. i assume that there is a significant u-shape if there is a negative sign on the age coefficient and a positive sign on the square with the t-statistic of both above 1.5. finally, i re-estimate the well-being equation and replace the age and age squared term with a complete set of single year of age variables which i then plot in a series of figures. this is to ensure that the quadratic i fitted is not an inappropriate functional form. this way the form is freely estimated and then plotted, with the individual coefficients added to the constant. these figures show u-shapes. the well-being variables are always coded from low to high, so a positive coefficient means happier. sometimes i use happiness data and sometimes life satisfaction and the number of options available varies by survey and year. mostly there are four options that i call 4-step, or eleven options from 0 to 10 that i call 11-step, plus i also use 3-step, 5-step, 7-step, and 10-step. it doesn't seem that this makes much of a difference. sample size does seem to matter although it is surprising how many ushapes are identified even with sample sizes of less than a thousand. i am also able to identify u-shapes in age in both european and african nations using a broader set of attitudinal questions on living standards as well as on an individual's financial conditions as well as the state of the national economy. i focus in particular on questions about financial situations individuals find themselves in as well as on the general state of the economy. these questions are widely used in consumer confidence surveys. respondents are asked such questions in the eurobarometers, as well as in the monthly consumer surveys run by the european commission in every eu country since the 1980s. these surveys have started to move down sharply from march 2020 as the covid-19 shock hit (bell and blanchflower, 2020) . i also compare results of asking similar questions in europe and africa in relation to satisfaction with living standards. it seems the u-shape in age is more general than just in happiness and life satisfaction equations and applies to other attitudinal economic variables. this suggests the happiness curve has broader applicability to other attitudinal variables about the person and the economy. in this section, i report the results of estimating a series of ols well-being regressions. in each case, i report coefficients and t-statistics for the age and the age squared variables with and without controls for education, gender, marital and labor force status, country, and where appropriate where there are multiple survey years used a set of year dummies. the without controls equations include year and country dummies and in the case of the us and the uk state or region dummies when available. i calculate the minimum of the quadratic in age by differentiating with respect to age and solving which means dividing the age coefficient by the age 2 coefficient multiplied by 2. hence, on row 1 of table 1 , the age coefficient is â�� 0.0266 and the age 2 coefficient is + 0.00032 so the minimum is -1 ã� 0.0266/(2 ã� 0.00032) = 41. both are highly statistically significant with t-statistics of 70 and 92 respectively. i turn first to the two countries that have micro data files with many hundreds of thousands of observations-the usa and the uk. in this paper, i report 9 separate estimates each for the two countries, with controls and in both well-being is u-shaped and on average it minimizes in both at age 45 (footnote 1). q1. "please imagine a ladder, with steps numbered from 0 at the bottom to 10 at the top. the top represents the best possible life for you and the bottom of the ladder represents the worst possible life for you. on which step of the ladder would you say you personally feel you stand at this time?" in the gss, the happiness q1 is used. q2. "taken all together, how would you say things are these days? would you say that you are very happy = 3, pretty happy = 2, or not too happy = 1?" (my codes). in the brfss, respondents are asked the following 4-step question: q3. "in general, how satisfied are you with your life? very satisfied = 4; satisfied = 3; dissatisfied = 2 and very dissatisfied = 1." (all my codes). in table 1 , i report the results of estimating ols regressions which include an age and an age squared term plus year dummies and 50 state dummies for usdtp and the brfss and 8 region dummies with the gss as that is all that is available. i then repeat including controls for gender, labor force and marital status, and education. in the case of the gusdt, the age term is negative, and the age squared term is positive without and with controls implying a minimum at 41 and 48 respectively. 12 in the case of the brfss, without controls, the age term is negative, and the square term is positive, but the minimum is over 100. for the gss, the signs are reversed but are both significant suggesting an inverted u-shape. in both cases, when i add controls, there is a significant u-shape with a minimum of 41 and 40 respectively. 12 life satisfaction was included in a subset of the brfss for louisiana, minnesota, mississippi, rhode island, and tennessee in 2013-2017. i re-estimated the equation in table 1 using these data (n = 68,888), with controls for age and its square, state, year, education, gender, race, and marital and labor force status and found the quadratic minimized at age 43. the second part of the table restricts the sample to under 70 years of age. the major change is that the brfss data now gives a u-shape that minimizes at age 40 versus one that minimizes at age 43 with controls. in the case of the gss, with many fewer observations, the age squared term is insignificant and hence i don't report a minimum. it is important in the usa to look at the raw data to determine the appropriateness of fitting a quadratic to the data. fig 1 for the brfss, 2005-2010, plots the two quadratics with controls from table 1 for all ages and for ages under 70. it also plots the results of replacing the two age terms with single year of age dummy variables from equations with and without controls. in each case, the individual coefficients are added to the constant. it is clear that without controls, in the raw data, there are two hills: an early dip to the early twenties and a rise to the mid-thirties and then a fall through the mid-fifties and a rise again to the early seventies before the function dips again. adding controls produces a clean and highly significant u-shape which turns over after the age of seventy and remains broadly flat thereafter. the upward slope flattens after around age 60 and then starts turning down around age 70. 13 it is clear that the quadratic for those age under 70, with controls, seems to fit the data better, than the one on the full sample. fig 2 does the same with the usgdtp. the quadratic based on data under the age of 70 seems a close approximation. of note though is that there are marked differences in the raw data in the usa between the married and the non-married that is not true elsewhere. below i report 3step happiness equations for the gss and 4-step life satisfaction equations in the brfss with only year and region controls included as below with t-statistics in parentheses. in the case of the gss, the positive age and negative age term suggest it also should be noted that there is some evidence that the minimum of the u-shape has risen over time as life expectancy has climbed. in the usa, using data for those age under 70, it was 74 in 1980 versus 79 in 2017. the midpoint using the gss for the years 1975-1999 was 37 and for the years 2000-2018 was 47. as we show below, there is also evidence of a slightly bigger rise in europe, where life expectancy in many countries grew more. 14 i now turn to examine the data, for people under age 70, from the other major large cross-section survey of well-being from the most recent sweeps available for 2016-2018, from the annual population surveys for the uk. earlier sweeps were used in bell and blanchflower (2019) to examine the well-being of the underemployed and the unemployed. these surveys contain data three happiness measures and overall there are about 215,000 observations on each variable. the three questions i examine are as follows. q4. life satisfaction-"overall, how satisfied are you with your life nowadays, where nought is 'not at all satisfied' and 10 is 'completely satisfied'." q5. happiness-"overall, how happy did you feel yesterday, where nought is 'not at all happy' and 10 is "completely happy'?" q6. worthwhile-"overall, to what extent do you feel that the things you do in your life are worthwhile, where nought is 'not at all worthwhile' and 10 is 'completely worthwhile?'." table 2 shows that for all three variables, the age coefficient in all six specifications is significant and negative and the age squared term is significant and positive and all minimize in the forties. fig 3 plots the single year of age coefficients for each of the three variables with the full set of controls included in each case. the minima are a little higher at around age 50. i now move to looking at data files that cover multiple countries. for simplicity, going forward, i use a quadratic in age as a reasonable approximation to the age profiles in well-being and firstly restrict the sample to those age under 70 so that the estimated minima are not impacted by what happens in the older age groups especially as sample sizes can be small at higher ages. to report a minimum, i impose the second rule that both the coefficients on the age and age squared variables must have the right signs and t-statistics of at least 1.5. for each of the data files, i report a pooled regression with year dummies and the full set of controls are for gender; education, and marital and labor force status which are available in broadly the same form in all of the data sets. i also fit age quadratics to each sample pooled across countries with age unrestricted and then replace the quadratic with a more flexible form of single year of age dummies. i then plot the age coefficients, added to the constant, as a check on the quadratic. i start out using data from the eurobarometer surveys (eb). concern has recently been expressed over response rates to these surveys especially in relation to the questions on respondent's views on the eu, with the concern that eurosceptics do not respond to the surveys which then suggest higher levels of support than they should. the eurobarometer surveys differ from other surveys that use the mail or the telephone; the eu commission only conducts interviews with members of the public face-to-face at home. this makes it even more difficult to achieve high response rates. the eu commission on 5 december 2019 defended the methods of its public opinion surveys in response to criticism that the low rate of responses could lead to bias towards the eu. in the most recent eurobarometer survey for which response rates have been calculated, and obtained by the danish newspaper, the rate was 14% in finland, 15% in germany, 20% in luxembourg, 22% in italy, 27% in the uk, 28% in denmark, 31% in greece and france, 33% in ireland, 34% in spain, 38% in latvia, and 40% in portugal. erik gahner larsen from the university of kent in a blog 15 noted rightly that the response rate is informative but not sufficient or even necessary in order to obtain representative samples. he finds no evidence that countries with lower response rates are much more positive towards the eu in eurobarometer compared to the european social survey. of note is that there seems very little evidence that responses to questions on life satisfaction in the eb have been impacted over time by a rise in non-response rates. table 3 uses data on 4-step life satisfaction for over 1.2 million europeans from forty-two sweeps of the eb for the years 2009-2019 for those age under 70 with only year dummies. 16 the question asked is: q7. "on the whole, are you very satisfied, fairly satisfied, not very satisfied or not at all satisfied with the life you lead? not at all satisfied (= 1); not very satisfied (= 2); fairly satisfied (= 3) and very satisfied (= 4)". it establishes the facts in european countries, by which i mean the eu28 plus eight other countries (albania, iceland, norway, macedonia, montenegro, serbia, turkey, and turkish cyprus). there are six developing countries including four ex-soviet (albania, macedonia, montenegro, and serbia) that are not eu members plus turkey and turkish cyprus in that group, all of which are so-called candidate countries. 15 "eurobarometer and euroscepticism" https://erikgahner.dk/2019/eurobarometer-and-euroscepticism/ 16 information, "new data reveals serious problems with the eu's official public opinion polls", 3 december 2019. https://www.information.dk/udland/2019/12/new-data-reveals-serious-problems-with-the-eus-officialpublic-opinion-polls and eszter zalan, "eu commission defends eurobarometer methodology," eu observer, december 5, 2019. first, estimates are provided for pooled samples across all countries without controls. there is a minimum in midlife at age 63. separate estimates are provided by country and in all thirty-seven cases the age term is significant and negative and the squared term significantly positive. there is some variation with a low of 43 in luxembourg and a high of 158 for bulgaria. the average across the estimates is. table 4 repeats the exercise adding controls and the overall equation now has a minimum of fifty-four, and there are u-shapes for every country. a set of cohort q16. the situation in our country? q17. the situation of the national economy? q18. the employment situation in the country? q19. the presence of public services in our country? q20. at the present time, would you say that, in general, things are going in the right direction or in the wrong direction, in our country 1 = things are going in the wrong direction 2 = neither the one or the other 3 = things are going in the right direction? i am now going to read out different aspects of everyday life. for each, could you tell me if this aspect of your life is very satisfactory (= 4), fairly satisfactory (= 3), not very satisfactory (= 2) or not at all satisfactory (= 1)? q21. q28. in general, how would you describe your own present living conditions? possible responses include: 1 = very bad, 2 = fairly bad, 3 = neither good nor bad, 4 = fairly good, 5 = very good? dummies are added in the second row and the minimum is largely unchanged. there are u-shapes in every country with the minima ranging from 29 for luxembourg to 80 in montenegro. fig 4 uses single year of age plots with and without controls using these eb files from 2009 to 2019, and both show u-shapes. it shows an important point that in the eurobarometer files there is always a u-shape whether controls are included or not. there is an issue raised by morgan and o'connor (2017), henceforth mo, over whether there is an m-shape rather than a u-shape in eb data. however, in blanchflower (2020b) , i showed that this early bump arose because mo omitted students, who are young, and happy. once students are included, the m-shape disappears and the u-shape returns. table 5 significant u-shapes in every year, but over time the minimum has risen as we noted it did for the usa. the minimum rises from an average of 41 in 1975-1976 to over 50 since 2017. 17 life expectancy for most of these eu countries rises even more rapidly over these years than it does in the usa. for example, based on oecd data between 1980 and 2017 in both france and italy, life expectancy at birth rose from 74 to 83 and in both germany and the uk it increased from 73 to 81 (see footnote above). it is perhaps surprising that the estimates from developing countries that we examine below that have lower life expectancies have broadly similar minima to advanced countries. table 6 reports a series of happiness equations by country with controls and again restricted to age under 70, using eight sweeps of the european social surveys. there are over a third of a million observations overall and the question is an 11-step happiness variable. q8. "taking all things together, how happy would you say you are, from 0 to 10 with zero 'extremely unhappy' and 10 'extremely happy?'" the ess contains our first data on four developing countries-israel, russia, turkey, and ukraine-plus twenty-five eu countries, minus malta, latvia, and romania plus iceland, norway, and switzerland. there is a minimum again in every country equation that are also in the forties and fifties and average 52. all four of the developing countries have a u-shape and there are eight advanced countries with no ushape (denmark, estonia, finland, iceland, italy and lithuania, poland, and slovenia is happiness u-shaped everywhere? age and subjective well-being in... all six of these countries had significant u-shapes with larger samples with the eb data. the european quality of life surveys (eqls) includes the q8 happiness question above but also a 10-step life satisfaction equation. q9. all things considered, how satisfied would you say you are with your life these days? please tell me on a scale of 1 to 10, where 1 means very dissatisfied and 10 means very satisfied. table 7 makes use of 10-step life satisfaction data from four sweeps (2003, 2007, 2011, and 2016) of the eqls pooled together, with controls. table 9 now turns to look at 5-step happiness data in five sweeps of the asia barometers of 2003-2007. 18 the question asked is 18 blanchflower and oswald (2008a) q12. "all things considered would you say that you are happy these days? -very happy = 5; pretty happy = 4 neither happy nor unhappy = 3; not too happy = 2 and very unhappy = 1?" once again, the numbers refer to my codes. in each case, there is a well-defined ushape with controls and only without controls in two of the five sweeps. significant ushapes are found in fourteen asian developing countries-china, india, laos, maldives, mongolia, myanmar, philippines, singapore, south korea, sri lanka, taiwan, tajikistan, thailand, and uzbekistan. 1997, 2000, 2001, and 2003-2005 and found a u-shape at age 50 for men and age 43 for women with a full set of controls, so this updates that analysis. for both 2017 and 2018, there are well-defined u-shapes that minimize in the forties and fifties with controls. there are u-shapes for those under the age of 70 in twelve, for bolivia, brazil, columbia, costa rica, ecuador, honduras, mexico, panama, paraguay, peru, uruguay, and venezuela. 9 multi-country data-issp, wvs, and the gallup world poll 9.1 international social survey programme 2012 and 2017 table 11 now moves to using 7-step life satisfaction data from the 2012 issp which is not limited to europe; the sample size is only 60,000. the question asked is: q10. "if you were to consider your life in general, how happy or unhappy would you say you are, on the whole? completely happy = 7; very happy = 6; fairly happy = 5; neither happy nor unhappy = 4; fairly unhappy = 3; very unhappy = 2; completely unhappy = 1?" numbers are my coding to ensure a larger coefficient means more happiness. controls are included. all 31 countries have significant u-shapes, mostly in the forties and fifties again. table 12 does the same but with the 2017 issp with a 7-step life satisfaction question and a sample size of n = 43,775. q11. "all things considered, how satisfied are you with your life as a whole nowadays? completely satisfied = 7; very satisfied = 6; fairly satisfied = 5; neither satisfied nor dissatisfied = 4; fairly dissatisfied = 3; very dissatisfied = 2; completely dissatisfied = 1?" there are u-shapes everywhere once again. table 13 looks in turn at each of the five sweeps 2-6 of the world values survey in turn that all use the q9 10-step life satisfaction equation defined above. in each of the five sweeps, there is always a minimum between forty and fifty overall with controls, and only in wave 2 is there no u-shape without controls. in every one of the 137 reported country estimates, for advanced and developing countries, remarkably, given the small sample sizes, there are significant happiness curves. blanchflower and graham (2020b) examined data from the gallup world poll from 2008 to 2017 for fourteen countries. fourteen of those countries have significant and well-defined u-shapes in age and they are not available in any of the other data files, so in table 14 we report results for these developing countries using the q1 question above for cantril's life satisfaction ladder measure. 1) there are well-being u-shapes in advanced and developing countries. 2) these answers seem to be similar using happiness or life satisfaction data. 3) it doesn't seem to matter how many steps there are in the dependent variable; essentially, the same answer is found with a 4-step, 7-step, 10-step, or an 11-step measure. 4) the answers are broadly the same whichever data file is used. 5) adding cohort dummies does not remove the u-shape. 6) there is a minimum around age 50 with controls of the happiness curve in both advanced and developing countries, and a little higher than that without controls. 10 satisfaction with financial situation: macro happiness and living standards i now move away from looking at happiness and life satisfaction directly and extend my horizons by looking at other broader measures of well-being. it was already wellknown that there were similarities between happiness data and assessment of someone's financial situation and their living standards, but i find the similarities do not stop there. remarkably, this u-shape pattern emerges when i look at assessments of the national economy as well as the quality of local services. it emerges when respondents are asked about job opportunities and time to do things and the u-shape appears to have broad applicability to a wide class of qualitative measures. , 1973-2002 10.1 financial situation of the household i now turn to other ways of measuring satisfaction, which it turns out also show ushapes. all of the questions used are reported in the appendix. easterlin (2006) found evidence of a u-shape in age in the us general social survey for the years 1972-1993 in answers to q14 which relates to how an individual is doing financially. he finds that satisfaction with one's financial situation, "declines very slightly through age 36, but thereafter rises considerably, with the biggest increase late in life." this contrasts with his findings on happiness overall as well as happiness with the family that he found followed an inverted u-shape. 19 i took the data easterlin (2006) used and re-estimated, with and without controls, for a longer time period, from 1972 to 2018. t-statistics are in parentheses and i restricted the sample to those under age 70 for simplicity. without controls, year dummies are included, with controls adds controls for gender, marital status, years of education, race, and labor force status. sample size is with controls. i confirm easterlin's findings; both happiness and family situation without controls generate inverted u-shapes in age, whereas financial situation has a u-shape in age even without controls. all three though have u-shapes once controls for education, marital status, and work status are included. the minima are 41 for happiness, 55 for family situation, and 32 for financial situation with controls. it is apparent that a u-shape in these gss data seems more robust using the financial situation data than the other two measures of well-being. i explored the characteristics of this rather intriguing financial circumstance variable further as comparable data is available in wvs sweeps 5 and 6 for both developing and developed countries. in table 15 , i model responses in turn from waves 5 and 6 of the wvs that contains a 10-step question on how satisfied the respondent is with the financial situation of the household q14. we are interested in how people are getting along financially these days. so far as you and your family are concerned, would you say that you are pretty well satisfied (= 3) with your present financial situation, more or less satisfied (= 2), or not satisfied at all (= 1)? there are statistically significant u-shapes with controls in both developed and developing countries in both wave 5 and wave 6. with controls in the country 19 data for satisfaction with family life are only available for the years 1972-1993 hence the sample restriction but in what follows i used data for both happiness and financial situation for the years 1972-2018. the family situation question was satfam: "for each area of life i am going to name, tell me the number that shows how much satisfaction you get from that area. your family life (my codes) -7. a very great deal; 6. a great deal; 5. quite a bit; 4. a fair amount; 3. some; 2. a little; 1. none." equations with the sample restricted to those under 70 years of age, there are u-shapes in thirty-four developing countries from around the world. 20 table 16 uses data from four different european data files. the first part uses eurobarometer #91.5 for june-july 2019. the first question relates to the financial situation examined above and finds a u-shape also that minimizes at age 41. i then estimate six different attitudinal questions on the individual's views on the situation in the country (q15); the national economy (q16); the respondent's own job if working (q17); the respondent's own financial situation (q18); employment situation in the country (q19); and the presence of public services in their country (q20). in every case, the age term is significant and negative, and the square term is positive. each of the variables have well-defined and statistically significant u-shapes in age and the t-statistics on age and its square are everywhere above five. a 3-step question is also used on the direction of the country, which is often used in polling. the age minima vary from ages 41-54. a great deal of use is made in economics of survey responses from individuals on the general state of the economy, including in consumer confidence measures such as the michigan and conference board measures in the usa and conducted by the european commission monthly for every eu member state. for example, respondents in the eu commission survey are asked for their views on the "general situation of the economy over the next twelve months" that i have through march 2020. 21 these variables are then collapsed into a score. an equivalent survey from firms is available from his markit in the form of a much-watched composite pmi available monthly from 1998 through april 2020. 22 in fig 14, i plot both series for the eurozone that seem to track each other well. their decline in 2007 onwards gave early warnings as did other similar attitudinal variables that few spotted of the oncoming global recession in 2007 (blanchflower 2009 ). of note is their dramatic collapse in both in march and in april 2020 to new lows. 23 for example, the composite pmi hit a record low of 13.5, down from 29.5 in march and 51.6 in february. the low point in the great recession was 36.2 in february 2009. the general economic situation measure had the biggest collapse in the history of the series that runs back to 1985, beating the previous record collapse that occurred in august 1990 when iraq invaded kuwait. these macro happiness indicators provide a clear picture of the impact of the covid-19 shock in march and april 2020 that the official statistics do not (bell and blanchflower 2020 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 the final 5-step question in part 2 of the table relates to living standards which are also ushaped with a minimum at age 44. the third and fourth sections of table 16 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 94 age 4-step life satisfaction latinobarometers, 2017 with controls 18 20 22 24 26 28 30 32 34 36 38 40 42 44 46 48 50 52 54 56 58 60 62 64 66 68 70 72 74 76 78 80 82 84 86 88 90 92 age 7-step life satisfaction issp 2017 with controls very little analysis has been done on how well-being and age are treated in africa. 24 the afro barometers are a natural place to turn, but unfortunately, they don't contain any questions on happiness or life satisfaction. both the 2016 and 2019 surveys do though contain a question on living standards. this living standard, measure of wellbeing, has been widely used in the development literature for measuring well-being in africa. it was used by sulemana et al. (2019) for a study of well-being in sub-saharan africa. they justified its use arguing that "the question taps into the individual's evaluations of their life we used this construct as a suitable measure of subjective wellbeing." the authors argued that "many other studies have constructed well-being measures in the same way," which turns out to be correct. deutsch et al. (2016) used this variable from the 2008 afro barometer as did pokimica et al. (2012) and sulemana (2015b) in their studies of well-being in ghana. sulemana (2015a) in a study of the impact of crime on well-being in africa used data from the 4th sweep of the afro barometer for 2008. sulemana et al. (2017) used this measure with the afro barometer data in their study of the relationship between corruption and well-being in africa. others have been creative in their use of measures of well-being for africa. bookwalter et al. (2011) in a study of south africa use a household level life satisfaction variable. life satisfaction in both surveys was reported at the household level. the head of the household was asked a 5-step question q22 on living standards. q22. in general, how would you describe your own present living conditions? possible responses include: 1 = very bad, 2 = fairly bad, 3 = neither good nor bad, 4 = fairly good, 5 = very good? table 17 reports the results from estimating an ols equation with this living conditions variable as the dependent variable with and without controls by country. limiting age to less than 70, there are 22 countries with significant u-shapes in 2016 and seventeen in 2019. fig 15 plots the single year of age coefficients added to the constant for 2016 with controls and there are obvious u-shapes again, with minima mostly in the mid-fifties. there are u-shapes for thirty african countries using the afro barometer data for those under age 70. 25 the u-shape appears to have broad applicability to a range of attitudinal questions on the economy and an individual's personal economic situation as well as to their happiness and life satisfaction. there is a happiness curve. no ifs, no buts, well-being is u-shaped in age. the average age at which the u-shaped minimized across the 477 country-level estimates reported here is 48.3. it is in rich and poor countries. 24 or indeed of happiness in africa, for an exception, see helliwell et al. (2019) who found evidence over the years 2006-2018 that happiness in the middle east and north africa had dropped steadily while sub-saharan africa had no overall trend. the authors identify how much happiness has changed over the last decade and how low it is in africa. they note big declines in happiness in rwanda, malawi, tanzania, central african republic, and botswana (their figure 2.8 i found evidence of the nadir in happiness in one hundred and forty-five countries, including one hundred and nine developing and thirty-six developed. i found it in europe, asia, north and south america, australasia, and africa. i identified it in all but six of the fifty-one european countries. 26 i have a well-being u-shape for every one of the thirty-five member countries of the oecd. 27 i have it for 138/193 member countries of the united nations. i found the well-being u-shape in english-speaking countries and non-englishspeaking countries. a u-shape is revealed in countries ranked highly in the cia world factbook for countries with both high and low life expectancy at birth. 28 i found it in twelve countries ranked in the top twenty for life expectancy of 82 or more. 29 i also found a u-shape in ten countries in the bottom twenty for life expectancy of 223 countries in the world according to the cia. 30 the curve's trajectory holds true in countries where the median wage is high and where it is not and where people tend to live longer and where they don't. i found additional evidence from an array of attitudinal questions that were worded slightly differently. evidence of a u-shape was found across european countries in questions relating to an individual's finances as well as to the state of the economy and democracy and how public services work. in africa, i used a question that development scholars had used relating to living standards and found a u-shape for thirty african countries. this suggests the u-curve in age may have much broader applicability than just in well-being data. given the robustness of these findings, it remains a puzzle why so many psychologists continue to suggest that well-being is unrelated to age. people are struggling. in the usa, deaths of despair are most likely to occur in the middle-aged years, and the patterns are robustly associated with unhappiness and stress. across countries, chronic depression and suicide rates peak in midlife. those in middle age in the years since 2008 were most vulnerable to a once-in-a-generation financial shock especially if they were poor and with low levels of education. in the usa, the employment rate in 2020 was below that in 2008. in the uk, real wages were below pre-recession levels at the onset of the covid-19 crash in march 2020. the financial crisis did not suddenly create frailty in downtrodden communities but simply exposed underlying problems with deep roots in the long decades before. it seems it is normal to have a midlife dip in well-being, but for many, especially those with the least skills, with little social support and few if any savings, that was too much to bear when a giant downturn came along in 2008. the finding of a zenith in well-being in midlife likely adds important support to the notion that being in one's forties and fifties exacerbates vulnerability to disadvantages and shocks. 31 that is people with disabilities, less education, broken families, lost jobs, and so on are likely also to get hit hardest by the effects of aging. some might face downward spirals as age and life circumstances interact. many will not be getting the social/emotional support they need, because midlife is the worst time to present vulnerability. they will be dealing with shame and isolation, in addition to the firstorder effects of whatever they are coping with in normal times at a midlife low is tough. it is made much harder when combined with a deep downturn especially when the speed of recovery and the length of lockdown is uncertain. interdisciplinary research is clearly needed into how to stem the worst manifestations of the midlife nadir in well-being, such as depression, lack of sleep, suicide, and higher tendency to drug and alcohol abuse. the fact that the happiness zenith occurs in developed and developing countries and it has even been found in great apes (weiss et al. 2012) suggests there may be something deeply engrained perhaps in the genes. the pandemic is global. vulnerable individuals and communities around the world will be devastated by the shock, because of both job and income loss but also from bereavement. the prime aged with low levels of happiness already are especially at risk. the happiness curve is found in 145 countries. no myth. 31 i am grateful to jonathan rauch for these suggestions that he says create a "toxic brew." age minimum u-shape 4-step life satisfaction minima with controls by year, eurobarometers u-shape 4-step life satisfaction minima with controls by year, eurobarometers v10-step happiness with controls 10-step happiness with controls, ess 1-8 is happiness u-shaped everywhere? age and subjective well-being in kazakhstan was the only country i had data for and did not find a u-shape. the remaining five i had no data for were all tiny-andorra malta (11) eswatini (215) causes and correlates of happiness life satisfaction across the life span: findings from two nationally representative panel studies us and uk labour markets before and during the covid-19 crash the well-being of the overemployed and the underemployed and the rise in depression in the uk is happiness u-shaped everywhere? age and subjective well-being in 132 countries blanchflower dg (2020b) unhappiness and age international evidence on well-being in measuring the subjective well-being of nations: national accounts of time use and well-being the mid-life dip in well-being: economists (who find it) versus psychologists (who dont)! nber working paper #w26888 fig. 15 living standards with controls is happiness u-shaped everywhere? age and subjective well-being in subjective well-being around the world: trends and predictors across the life span: a response do modern humans suffer a psychological low in midlife? two approaches (with and without controls) in seven data sets the u-shape without controls: a response to glenn is well-being u-shaped over the life cycle? hypertension and happiness across nations well-being over time in britain and the usa heterogeneity in the relationship between happiness and age: evidence from the german socio-economic panel understanding life-satisfaction changes in postapartheid south africa emotional experience improves with age: evidence based on over 10 years of experience sampling age-related differences and change in positive and negative affect over 23 years longitudinal evidence for a midlife nadir: result from four data sets ed) the economics of happiness. how the easterlin paradox transformed our understanding of well-being and progress income, health, and well-being around the world: evidence from the gallup world poll what do self-reports of wellbeing say about life-cycle theory and policy? life satisfaction and age: dealing with under-identification inage-period-cohort model on the measurement of multidimensional well-being in some countries in eastern and southern subjective well-being and age: an international analysis subjective well-being: three decades of progress explaining happiness life cycle happiness and its sources: intersections of psychology, economics and demography how important is methodology for the estimates of the determinants of happiness? selection, optimization and compensation as strategies of life management: correlations with subjective indicators of successful aging the economics of happiness the mystery of the u-shaped relationship between happiness and age is the apparent u-shape of well-being over the life course a result of inappropriate use of control variables? happiness, stress, and age: how the u curve varies across people and places age differences in coping resources and satisfaction with life among middle-aged, young-old and oldest-old adults the u-shaped age-happiness relationship: real or methodological artifact? measuring and using happiness to support public policies changing world happiness affective coloring of personality from young adulthood to midlife getting older, feeling less? a cross-sectional and longitudinal investigation of developmental patterns in experiential well-being subjective well-being around the world: trends and predictors across the life span heresy or enlightenment? the well-being age u-shape effect is flat documentation of sample sizes and panel attrition in the german socio economic panel (soep) (1984 until 2010). data documentation 59 mind the gap in the middle: a call to study midlife happiness is a choice you make: lessons from a year among the oldest old the effect of age on positive and negative affect: a developmental perspective on happiness change in life satisfaction during adulthood: findings from the veterans affairs normative aging study the funds, friends, and faith of happy people is a longer life a better life? happiness of the very old in 8 eu countries health and social factors related to life satisfaction sliding down the u-shape? a dynamic panel investigation of the age-well-being relationship, focusing on young adults religion and subjective well-being in ghana a note on empirical studies of life-satisfaction: unhappy with semiparametrics? unmet aspirations as an explanation for the age u-shape in well-being the relationship between subjective well-being and work-life balance among labourers in pakistan exploring the economic and social determinants of psychological well-being and perceived social support in england subjective wellbeing, health, and ageing a snapshot of the age distribution of psychological wellbeing in the united states the effect of fear of crime and crime victimization on subjective well-being in africa an empirical investigation of the relationship between social capital and subjective wellbeing in ghana international remittances and subjective wellbeing in sub-saharan africa: a micro-level study a micro-level study of the relationship between experienced corruption and subjective wellbeing in africa how does subjective well-being evolve with age? a literature review is happiness u-shaped everywhere? age and subjective well-being in a test for the convexity of human well-being over the life cycle: longitudinal evidence from a 20-year panel evidence for a midlife crisis in great apes consistent with the u-shape in human well-being well-being over the life span: semi-parametric evidence from british and german longitudinal data publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgments i thank three referees and the editor, angus deaton, dick easterlin, carol graham, robson morgan, kelsey o'connor, andrew oswald, and jonathan rauch for the helpful comments. conflict of interest the author declares that he has no conflicts of interest. key: cord-259971-e3h8pr1v authors: nwachukwu, izu; nkire, nnamdi; shalaby, reham; hrabok, marianne; vuong, wesley; gusnowski, april; surood, shireen; urichuk, liana; greenshaw, andrew j.; agyapong, vincent i.o. title: covid-19 pandemic: age-related differences in measures of stress, anxiety and depression in canada date: 2020-09-01 journal: int j environ res public health doi: 10.3390/ijerph17176366 sha: doc_id: 259971 cord_uid: e3h8pr1v background: the spread of covid-19 along with strict public health measures have resulted in unintended adverse effects, including greater levels of distress, anxiety, and depression. this study examined relative presentations of these psychopathologies in different age groups in a canadian cohort during the covid-19 pandemic. methodology: participants were subscribers to the text4hope program, developed to support albertans during the covid-19 pandemic. a survey link was used to gather demographic information and responses on several self-report scales, such as perceived stress scale (pss), generalized anxiety disorder 7-item (gad-7) scale, and patient health questionnaire-9 (phq-9). results: there were 8267 individuals who completed the survey, giving a response rate of 19.4%. overall, 909 (11.0%) respondents identified as ≤25 years, 2939 (35.6%) identified as (26–40) years, 3431 (41.5%) identified as (41–60) years, 762 (9.2%) identified as over 60 years, and 226 (2.7%) did not identify their age. mean scores on the pss, gad-7, and phq-9 scales were highest among those aged ≤25 and lowest amongst those aged >60 years old. conclusions: the finding that the prevalence rates and the mean scores for stress, anxiety, and depression on standardized scales to decrease from younger to older subscribers is an interesting observation with potential implications for planning to meet mental health service needs during covid-19. with its discovery in wuhan, china, and its subsequent rapid spread around the world, the coronavirus disease (covid19) pandemic has caused palpable fear [1] [2] [3] to manage the illness in the absence of a proven cure or an effective vaccine, governments have adopted extreme public health measures including shutting down all but essential services and industries, promoting hand hygiene measures, restricting travel and closing borders, implementing social distancing, self-isolation, and quarantine measures [4] . typically, social distancing has been achieved through limiting the distance between individuals in public spaces, limiting the number of individuals who are allowed to gather together, self-isolation/quarantine for 14 days after travel or if individuals present with covid-19 like symptoms or have been in contact with potentially infected individuals. these measures have caused a widespread disruption of both the social fabric of society and economic activities [5] . these abrupt changes to the pattern of human activities have had indirect negative effects on the physical and mental health of individuals across the world. self-isolation measures and quarantine, despite their considerable clinical utility, often have unintended adverse effects [6] including greater levels of distress, anxiety, depression, and post-traumatic stress disorder (ptsd). for the current covid-19 pandemic, published studies examining rates of anxiety and depression are consistently reporting prevalence estimates of around 20% [7] [8] [9] . a recent meta-analysis reported rates of depression and anxiety that exceed 20% with differences in certain demographic variables such as gender and occupation [10] . in the severe acute respiratory syndrome (sars) outbreak in taiwan during late april to mid-may 2003, a relationship between age and the development of psychological symptoms was reported, with younger age groups at higher risk [11] . for the covid-19 pandemic, several studies have also reported a possible negative relationship between depression, anxiety, ptsd, and age [7, 12] . in an online survey of chinese subjects, prevalence of generalized anxiety disorder and depressive symptoms was significantly higher in participants younger than 35 years than in participants aged 35 years or older [13] with age and amount of time spent focusing on covid-19 identified as potential risk factors for psychological illness. individuals ≤35 years of age appear to be more likely to develop anxiety and depressive symptoms during the covid-19 pandemic [14] . in a nationwide survey examining psychological distress among chinese people in the covid-19 pandemic using a covid-19 peritraumatic distress index (cpdi) [15] ; the authors examined frequency of anxiety, depression, specific phobias, cognitive change, avoidance and compulsive behavior, physical symptoms, and loss of social functioning in the past week, with scores on the cpdi ranging from 0 to 100. a cpdi score between 28 and 51 indicates mild to moderate distress while a score ≥52 indicates severe distress. in that study, participants under 18 years had the lowest cpdi scores. individuals from 18-30 years or >60 years of age presented the highest cpdi scores, thus presenting a more nuanced view of the effect of the pandemic on psychological symptoms across the age spectrum. possible explanations for their finding include the idea that teenagers and children have shown relatively low morbidity and mortality in the pandemic and therefore may feel less stressed by it and, because of school closures and quarantine measures they may recognize that they have had limited exposure to the coronavirus. younger adults on the other hand may be exposed to more information about the virus via social media, a factor that has been shown to increase vulnerability [16] . in addition, their loss of social connections with friends may have further increased their vulnerability to mental distress. the highest mortality rates for the virus are reported among the elderly, thus potentially exposing this age group to be more adversely affected psychologically [15] . the majority of initial studies examining the impact of age on stress, anxiety, and depression levels in the current covid-19 pandemic arise from asia. this present study sets out to examine the evidence for the impact of age on stress, anxiety, and depression levels in the covid-19 pandemic from the perspective of a canadian cohort with the goal of informing policy planning in relation to age-appropriate mental health supports and resource allocations during this covid-19 pandemic period. this was a cross-sectional survey exploring the mean differences of perceived stress, anxiety, and depression symptom scores among subscribers of various age categories who enrolled in the text4hope program. the study recruitment procedures and statistical methods have been described in related papers [17] . in summary, the text4hope program is a daily supportive text message service, launched by alberta health services (alberta, edmonton), the provincial health authority on 23 march 2020 to support the mental health of albertans during the covid-19 pandemic. subscribers were sent an online survey link with an accompanying message: "to help us evaluate the text4hope program's effectiveness, please complete a short survey . . . ." the survey questions included demographic information such as gender, age, ethnicity, education, relationship status, employment status, and housing status. respondents also completed clinical self-assessments for stress, anxiety, and depression using the perceived stress scale (pss), the generalized anxiety disorder 7-item (gad-7) scale and the patient health questionnaire-9 (phq-9), respectively. participant consent was implied by submission of subscribers' survey responses. the survey link has no expiry date as enrollment to the text4hope program is ongoing. ethical approval for the research was obtained through the university of alberta health research ethics board (pro00086163). data analysis was undertaken using spss version 26 (ibm inc, endicott, ny, usa) [18] . demographic characteristics of respondents were summarized in absolute numbers and percentages, by age category. one-way analysis of variance (one-way anova) with two tailed significance (p-value < 0.05) was performed to assess the differences between the ethnic groupings and the corresponding mean scores for pss, gad-7, and phq-9, respectively. as all variables violated the homogeneity of variance assumption based on the levene statistic test of homogeneity, we determined statistically significant differences for the mean scores for the various clinical measures across age groups using the welch f test and a games-howell post hoc test. of the 44,992 subscribers who joined text4hope in the first 6 weeks, 8267 responded to the online survey invitation, yielding a 19.4% response rate. our sample size of 8267 indicates that any prevalence rate estimates for the entire sample of 44,992 subscribers would have a 99% confidence interval and a margin of error of only 1.28%. of the 8267 respondents, 909 (11.0%) identified as ≤25 years, 2939 (35.6%) identified as aged 26-40 years, 3431(41.5%) identified as aged 41-60 years, 762 (9.2%) identified as >60 years, and 226 (2.7%) did not identify their age. the mean age for our sample was 42.09 years (standard deviation = 13.44 years). additional demographic characteristics of the respondents are shown in table 1 , which indicates a majority of respondents self-identified as female, (n = 6991, 87.1%), caucasian (n = 6579, 82.3%), with post-secondary education (n = 6835, 85.2%), as employed (n = 5883 73.3%), as married, cohabiting, or partnered (n = 5706, 71.1%), and as home-owners (n = 5194, 65.9%). the data displayed in table 2 illustrate the prevalence rates for clinically meaningful stress, anxiety, and depression. these data suggest the prevalence of high/moderate stress, likely gad and likely mdd were highest in those aged 25 or under and lowest in those aged over 60 years. mean scores for all the respondents were 20.79 (sd = 6.83, n = 7589) on the pss, 9.68 (sd = 5.87, n = 6944) on the gad-7 scale, and 9.43 (sd = 6.29, n = 7082) on the phq-9 scale. the data displayed in table 3 indicate that the mean scores on the pss, gad-7, and phq-9 scales were highest among those aged 25 years and under and lowest amongst those who were over 60 years old. there is an observed trend for the mean scores for all three scales to decrease with a shift from a younger age bracket to an older age bracket. results from the levene test for homogeneity of variances suggested there was a violation of the assumption of equality of means for the pss, gad-7, and phq-9 scales (p > 0.05). because of this, it was appropriate to apply the welch f test and a games-howell post hoc test to determine mean score differences on the three scales between the different age groups. welsh f tests confirmed that the differences between the groups in terms of their mean pss, gad-7, and phq-9 scores were statistically significant. there were statistically significant differences between and within age groups for scores on the pss (f = 319.89, p < 0.001), gad-7 scale (f = 225.23, p < 0.001), and phq-9 (f = 195.82, p < 0.001). the results of the games-howell post hoc test are as presented in table 4 . the results displayed in table 4 confirm statistically significant differences in mean scores on the pss, gad-7, and phq-9 scales between each of the age categories and any other age category (p < 0.001 for each comparison). the mean scores for the pss, gad-7, and phq-9 scales declined significantly with a shift from a younger age to an older age group suggesting that older respondents had less stress, anxiety, and depression symptoms compared to younger respondents. for each of the three scales, the greatest mean differences were observed between respondents who were ≤25 years compared to those >60 years. for the pss and the gad-7, the respective mean differences in scores was 8.75, with a 95% ci of 7.89-9.61 and p < 0.001, and 6.41, with a 95% ci of 5.57-7.24 and p < 0.001. for the phq-9, the mean difference in the score between these age groups was 5.88, with a 95% ci of 5.14-6.63 and p < 0.001. overall, the results suggest a decrease in severity of stress, anxiety, and depression symptoms with increasing age during covid-19 in a canadian sample. our results indicate that about two-thirds of our respondents were aged between 26 and 60 years, and the remaining respondents were aged either 25 years and under or over 60 years. this contrasts with a study by gonzalez-sanguino et al. [7] where the majority of respondents were aged between 18-39 years (56.63%). the respondents in our sample were spread over a wider middle age range. furthermore, the average age of the sample population in the study by gonzalez-sanguino et al. [7] was lower than the average age for our study participants (37.92 vs. 42.09, respectively). our study results are, however, similar to those of other studies which have a lower representation of the elderly population [7, 8] ; and this underrepresentation of this important segment of the population may limit us in relation to inferences made for those over 60 years of age in this study. our results indicate that the prevalence rates for moderate/high stress, likely gad, and likely mdd as well as the mean scores on the pss, gad-7, and phq-9 scales were highest amongst those aged under 25 years, and lowest amongst those over 60 years. this finding is consistent with some previous studies that reported higher scores in stress, anxiety, and depressive symptoms in younger people compared to older ages [7, 11, 12] . the finding that people aged 60 years and above reported lower scores on our rating scales is both interesting and curious, given that covid-19 infections have been shown to cause significantly higher morbidity and mortality in this age group compared to the younger age group [19, 20] . since there was stronger emphasis of the need for people over 60 years to take more stringent measures with social distancing and they are also likely to have higher prevalence of underlying medical conditions, it may have been expected that they would be more distressed during the pandemic. on the other hand, older people tend to be less socially mobile than younger ones, thus possibly explaining their reported lower scores on rating scales for stress, anxiety, and depression during a pandemic lockdown. people above 60 years are also more likely to have experienced various major life events in the past, possibly including having lived through past epidemics or pandemics, hence their increased resilience as found in our study. additionally, younger people, especially those under 25 years, may have perceived their academic, social, occupational, and economic prospects to be more threatened by covid-19 compared to those over 60 years and this will likely, at least in part, explain their increased stress levels according to our study [13, 14] . as outlined in the introduction, several studies have reported lower rates of anxiety and depression in older age groups compared to younger ones [7, 11, 12] . another hypothesis that could be propounded to explain this finding include that younger people, especially those under 25 years of age, are known to spend more time on social media and other news outlets. for example, in a 2019 us study, 90% of people aged 18 to 29 were active on social media, compared to 45% of those aged over 65 years [21] . high consumption rates of news about the covid-19 pandemic have been associated with increased levels of distress [16] . having said this, one might also have expected that increased opportunities for social connection through social media outlets that are readily available to younger people would limit the impact of physical distancing on them, perhaps compared to older adults. one group particularly vulnerable to the effects of the covid-19 pandemic continues to be older adults in senior care homes [19] . at the time this survey was designed in the context of text4hope, that fact was not known. it is likely that the majority of seniors responding to the text4hope survey are not in care, and this limitation must be taken into account in interpreting these and similar results on decreased severity of mental health indices in the older population. more research directed specifically at understanding the impact of social connectedness with stress, anxiety, and depression is needed to shed more light in this area. according to the uk office for national statistics, a population-based survey found that people over seventy years of age reported feeling happier than those aged 16 to 69 years during the period before a national lockdown was imposed in the wake of covid-19 in the united kingdom (uk) [22] . interestingly, this gap in reported feelings of happiness between the groups decreased by the third week of the lockdown. again, the uk government recommended stricter social distancing measures for those over 70 years of age, possibly explaining why they would have become increasingly more anxious and distressed as the pandemic continued. in comparison, our study data were collected at a single point at the beginning of the lockdown when social distancing was imposed across the province of alberta, canada. the clinical and practical utility of our study derives mainly from the its potential to serve as a guide to healthcare planners in directing treatment and support services in a more targeted and age-appropriate way during this covid-19 pandemic and related crisis situations in the future. with the knowledge that younger people, including students [4], tend to suffer disproportionately higher levels of stress, anxiety, and depression, equitable attention must be paid to ensure that their needs are met in all relevant areas. for example, online platforms may be used to deliver psychotherapeutic interventions and support networks to young people in their homes so as to minimize the spread of the virus while mitigating their increased vulnerability to mental distress during the pandemic. educational institutions and authorities may also need to develop online platforms and portals to aid the delivery of lectures and other learning materials with a view to maintaining as much of their daily structure and routine as possible. our study was limited in being a snapshot of self-reported experiences of mental health signs and symptoms at the beginning of the alberta lockdown, as opposed to a more longitudinal evaluation, especially if administered by a trained clinician. it is possible therefore that data collected a few weeks further down the line from our original data set would reflect similar findings as did the aforementioned uk study [3] . furthermore, our study is not representative of the population in alberta either by age or gender [23] and so our findings may not be generalized to the entire population. in addition, although the anova analysis allowed for comparison of the stress, anxiety, and depression levels between all the age groups as a strength, it did not take into account potential confounding factors such as sex, ethnicity, relationship status, employment and education status, which is a limitation. age is likely to be one of the several factors upon which vulnerability to mental health effects of covid-19 would be based. in addition, other social determinants of health, along with co-morbid physical health conditions, are known to play significant parts in increasing vulnerability in times of crisis [10] . any interventions aimed at mitigating mental health effects of covid-19 must therefore take of all these various factors into account. finally, our survey did not ask participants about pre-existing stress, anxiety, and depression. it is possible that some respondents had these baseline stress, anxiety, and depression and so the reported scores on the standardized scales may not all be attributable to the covid-19 pandemic. our results also indicate that both the prevalence rates as well as the mean scores for stress, anxiety, and depression on standardized scales were highest amongst those under 25 years, and lowest amongst those over 60 years. the trend for mean scores across the stress, depression, and anxiety scales to decrease in severity from younger to older age has potential implications for planning to meet mental health service needs during covid-19. innovative and cost-effective interventions such as supportive text messaging which are independent of geographic location, are free to the end user, do not require expensive data plans, and can reach thousands of people simultaneously [24] [25] [26] [27] [28] [29] [30] [31] could be useful particularly to a younger age population who seem to be most impacted psychologically during the covid-19 pandemic. author contributions: i.n. participated in writing-original draft preparation, and writing-review and editing. n.n. participated in writing-original draft preparation, and writing-review and editing. r.s. participated in data curation, and writing-review and editing. a.g. participated in data curation, and writing-review and editing. w.v. participated in data curation, and writing-review and editing. s.s. participated in data curation, and writing-review and editing. m.h. participated in conceptualization, methodology, writing-review and editing. l.u. participated in writing-review and editing. a.j.g. participated in methodology, writing-review and editing. v.i.o.a. participated in conceptualization, methodology, validation, formal analysis, supervision, funding acquisition, writing-original draft preparation, data curation, and writing-review and editing. all authors have read and agreed to the published version of the manuscript. funding: this study was supported by grants from the mental health foundation, the calgary health trust, the university hospital foundation, the alberta children's hospital foundation, the royal alexandra hospital foundation, and the alberta cancer foundation. the sponsors had no role in the design, execution, interpretation, or writing of the study. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia progression of mental health services during the covid-19 outbreak in china a novel coronavirus from patients with pneumonia in china the socio-economic implications of the coronavirus pandemic (covid-19): a review the psychological impact of quarantine and how to reduce it: rapid review of the evidence mental health consequences during the initial stage of the 2020 coronavirus pandemic (covid-19) in spain immediate psychological responses and associated factors during the initial stage of the 2019 coronavirus disease (covid-19) epidemic among the general population in china impact on mental health and perceptions of psychological care among medical and nursing staff in wuhan during the 2019 novel coronavirus disease outbreak: a cross-sectional study prevalence of depression, anxiety, and insomnia among healthcare workers during the covid-19 pandemic: a systematic review and meta-analysis prevalence of psychiatric morbidity and psychological adaptation of the nurses in a structured sars caring unit during outbreak: a prospective and periodic assessment study in taiwan idoiaga-mondragon, n. stress, anxiety, and depression levels in the initial stage of the covid-19 outbreak in a population sample in the northern spain generalized anxiety disorder, depressive symptoms and sleep quality during covid-19 outbreak in china: a web-based cross-sectional survey study on the public psychological states and its related factors during the outbreak of coronavirus disease 2019 (covid-19) in some regions of china a nationwide survey of psychological distress among chinese people in the covid-19 epidemic: implications and policy recommendations mental health problems and social media exposure during covid-19 outbreak covid-19: closing the psychological treatment gap during the pandemic, a protocol for implementation and evaluation of text4hope (a supportive text message program) case-fatality rate and characteristics of patients dying in relation to covid-19 in italy epidemiology working group for ncip epidemic response. the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) in china population who currently use any social media from office for national statistics: personal and economic well-being in great britain population of alberta, by age and sex six-months outcomes of a randomised trial of supportive text messaging for depression and comorbid alcohol use disorder perception of patients with alcohol use disorder and comorbid depression about the usefulness of supportive text messages coronavirus disease 2019 pandemic: health system and community response to a text message (text4hope) program supporting mental health in alberta alcohol use disorder and comorbid depression: a randomized controlled trial investigating the effectiveness of supportive text messages in aiding recovery randomized controlled pilot trial of supportive text messaging for alcohol use disorder patients randomized controlled pilot trial of supportive text messages for patients with depression supportive text messages to reduce mood symptoms and problem drinking in patients with primary depression or alcohol use disorder: protocol for an implementation research study cross-sectional survey evaluating text4mood: mobile health program to reduce psychological treatment gap in mental healthcare in alberta through daily supportive text messages acknowledgments: support for the project was received from alberta health services and the university of alberta. the authors declare no conflict of interest. key: cord-315992-jxxio17w authors: borja-gonzalez, maria; casas-martinez, jose c.; mcdonagh, brian; goljanek-whysall, katarzyna title: aging science talks: the role of mir-181a in age-related loss of muscle mass and function date: 2020-07-08 journal: transl med aging doi: 10.1016/j.tma.2020.07.001 sha: doc_id: 315992 cord_uid: jxxio17w nan the outbreak of covid-19 was declared a public health emergency of international concern in january 2020, scientists all over the world found new ways of progressing scientific research and maintaining or even expanding collaboration in a virtual setting. "aging science talks" were one of the most successful initiatives that engaged scientists all over the world working in the field of aging and highly relevant in the context of the pandemic. aging is the biggest risk factor for developing chronic disorders such as heart disease, type 2 diabetes, chronic obstructive pulmonary disease (copd), stroke, neurodegenerative diseases, chronic kidney diseases (ckds) and cancer [1] , [2] . aging is a complex process with detrimental effects on cell and tissue homeostasis which ultimately effects organ function [3] . several mechanistic pathways have been associated with aging, such as an increase in inflammation, oxidative stress, dna mutations, mitochondrial dysfunction, accumulation of senescence cells and disrupted proteostasis [4] [5] [6] . although life expectancy has increased, this has not been accompanied by an increase in health span, that can subsequently result in a greater strain on healthcare systems [7] . the susceptibility of the aged population suffering chronic disorders has been recently highlighted due to the coronavirus disease (covid-19) caused by severe acute respiratory syndrome coronavirus-2 (sars-cov-2). emerging data show that older people and those with certain underlying medical conditions, such as obesity or diabetes, are particularly affected by sars-cov-2 [8][11] . aging and covid-19 are associated with changes in systemic inflammation and dysregulation of the immune system function [8] and it has been suggested that covid-19 survivors, especially those requiring mechanical assisted ventilation will suffer from frailty [12] . early studies have shown the existence of musculoskeletal deterioration in patients with covid-19, although long-term follow-up studies are needed [13] . frailty is largely associated with sarcopenia, aging-related loss of muscle mass and function, characterised by a progressive and degenerative loss of skeletal muscle mass, quality, and strength during aging [14] . sarcopenia affects 5-13% of 60-70 year olds and up to 50% of people over 80 [15] . currently, diet and exercise remain the only effective interventions, that aim to maintain muscle mass and force, however no therapeutic has been established to successfully treat sarcopenia [16] , [17] . the molecular mechanisms underlying sarcopenia are multifactorial [18] [19] [20] . nevertheless, the transcriptome and proteome changes, as well as epigenetic changes in skeletal muscle during aging have been identified [21] [22] [23] [24] [25] . the role of micrornas (mirnas, mirs) as epigenetic modifiers in regulating loss of muscle mass and function has become increasingly recognised (reviewed in [17] ). mirs are short, noncoding rnas which regulate the expression of approximately 2/3 human genes [26] . mirs bind to their targets, usually within the 3'utr region of mrnas, via sequence complementarity. this results in gene expression regulation at the post-transcriptional level, through the degradation of the target mrna(s) and/or translational block, ultimately resulting in decreased protein levels [26] . in skeletal muscle, mirs have been demonstrated to control multiple biological processes, including development, regeneration, and aging (reviewed in [27] , [28] ). a number of mirs are involved in the regulation of muscle protein synthesis, that target regulators involved maintaining the balance between muscle atrophy and hypertrophy, and including regeneration of skeletal muscle [29] [30] [31] [32] . early studies in humans demonstrated differential expression of mirs in skeletal muscle during aging [24] , [33] . we and others have demonstrated the role of mirs in aging-associated processes in skeletal muscle, such as satellite cell senescence and inflammation [30] , [34] , [35] . bioinformatic analyses of non-coding rnas and transcripts in human and rodent muscle during aging have identified mir-181a as a potentially key regulator of muscle mass and function during aging [25] , [36] . the mir-181 family of mirs includes four mirs in humans and rodents: mir-181a, b, c and d. mir-181a and b are clustered together at two genomic loci on chromosomes 1 and 9 and mir-181c and d are clustered on chromosome 19 in humans. interestingly, the two mir-181 clusters producing two members of mir-181 family each, have been shown to have divergent roles in myocardial function [37] . the mir-181 family is predicted to regulate over 1000 genes [38] . unsurprisingly, the mir-181 family has been shown to regulate multiple genes in many tissues, including genes associated with mitochondrial dynamics [37] , [39] [40] [41] [42] [43] [44] [45] [46] [47] [48] . in skeletal muscle, mir-181a appears to be the predominant mir-181 family member in skeletal muscle affected by aging and has been suggested as biomarker of muscular health [36] , [46] . mir-181 has also been demonstrated to be upregulated in muscle during exercise and predicted to regulate transcription factors and co-activators involved in the adaptive response of muscle to exercise [49] . based on computer simulation models, mir-181a was predicted to regulate muscle atrophy and hypertrophy through its target genes: hoxa11 by inhibiting myod, and sirt1, through regulating foxo3 signalling [50] . indeed, we and others confirmed these as mir-181a direct targets [25] , [50] . more recently, mir-181 family of mirs gained more attention due to their regulation of processes associated with mitochondrial dynamics and directly targets park2 and p62/sqstm1 [44] , [46] , [51] . mitochondrial dysfunction is one of the hallmarks of aging [5] . skeletal muscle is characterised by a loss of mitochondrial content [52] and disrupted mitochondrial turnover, particularly in sedentary individuals [46] , [53] [54] [55] [56] . a number of studies to date suggest that mir-181 may be a global regulator of mitochondrial dynamics, redox homeostasis and potentially energy balance of the whole organism [34] , [39] , [44] , [46] , [51] . for example, post-stroke treatment with antagomir-181a has been shown to reduce infarction size through regulating bcl-2 expression and nf-kb activation [57] . the regulation of bcl-1 by mir-181 has also been demonstrated in astrocytes [40] . in this study, reduction of mir-181 levels and concomitant upregulation of bcl-2 led to a controlled increase in oxidative stress and antioxidant defence. furthermore, inhibition of mir-181a was reported to protect the brain from stroke via regulation of grp78 and mir-181a/b downregulation has been proposed to protect retinal neurons from cell death through regulating mitochondrial homeostasis [44] , [58] . the role of mir-181 in regulating the response to oxidative stress has also been studied in the context of myocardial function [37] . mir-181c levels were shown to negatively correlate to those of cox1, whereas mir-181a/b were suggested to regulate the levels of pten [37] . the authors proposed that decreased levels of mir-181c resulted in cox1 upregulation and dysfunction of complex iv and increased ros production in vitro [59] . it therefore appears that mir-181 may play a critical role in regulating redox homeostasis and potentially mitochondrial dynamics in nervous and cardiac cells, with studies suggesting that inhibition of mir-181 may prevent cell death and improve antioxidant response via targeting bcl-1, bcl-2, grp78 and pten. interestingly, in other tissues mir-181 has been demonstrated to be a positive regulator of metabolism, mitochondrial function and redox homeostasis [60] . mir-181 has been proposed to function as the primary metabolic rheostat in immune cells trough targeting of pten and pi3k signaling [61] . loss of mir-181a1/b1 in thymocytes was demonstrated to result in major metabolic reprogramming: a dysregulated expression of key components of the glycolytic, pentose phosphate and nucleotide biosynthetic pathways and mir-181a1/b1-deficient cells failed to reach the biosynthetic potential of proliferating thymocytes [62] . this led to suboptimal glucose uptake, reduced glycolytic rates, and impaired metabolic fitness in mir-181-deficient cells [62] . moreover, mice lacking multiple mir-181 alleles display immune phenotypes in b-cell development and t-cell homeostatic proliferation [63] . interestingly, mir-181a1/b1; mir-181a2/b2 double knockout mice show reduced survival when compared to littermates and a significant reduction in body size [62] . furthermore, no data on triple knock-out mice exists, which may suggest that complete deficiency of the mir-181 family is lethal [61] . consistently, the role of mir-181 as a positive regulator of metabolism though regulation of pten, overexpression of the mir-181a/b-1 cluster was also demonstrated to enhance osteogenesis through protein synthesis and mitochondrial metabolism [51] . moreover, oxygen consumption rate and atp-linked respiration were increased by mir-181a/b-1 through its regulation of the pten/pi3k signalling [51] . in the context of cancer, mir-181a has been shown to have pro-but also anti-oncogenic role [39] , [41] , [64] [65] [66] . in cd8+ t cells, interferon-γ is regulated by mir-181a during differentiation [67] . in our study, using mir gain-and loss-of-function approaches, we have demonstrated that mir-181 regulates skeletal muscle size and function during aging through regulating mitochondrial dynamics [46] . specifically, we demonstrated that mir-181a prevents the accumulation of park2, dj-1 and p62 in muscle during aging. this accumulation could be associated with disrupted mitochondrial turnover observed during aging [46] . using the mitoqc reporter construct for the investigation of mitophagic flux [68] , we demonstrated that mir-181a overexpression promotes mitophagy. the increased mitophagic flux may be associated with activation of alternative pathways than pink/parkin pathway, such as receptormediated mitophagy via bnip3. mitochondrial turnover is regulated by a number of different pathways and the exact regulatory mechanisms have not yet been fully determined [69] , [70] . interestingly, we also observed a parallel increase in markers of mitochondrial biogenesis following mir-181a overexpression in skeletal muscle [46] . a coupling of mitochondrial biogenesis and mitophagy has been previously observed in c. elegans and proposed to be mediated via nrf2 pathway [71] . ultimately the overexpression of mir-181a resulted in increased mitochondrial content and increased myofibre size and muscle force in skeletal muscle from old mice [46] . interestingly, the positive effects of mir-181 on mitochondrial function have been demonstrated in other tissues such as chondrocytes [72] . whilst most data agree on the importance of mir-181 in regulation of mitochondrial dynamics, redox homeostasis and energy balance, it appears that the role of mir-181a could be contextdependent as has been reported for other mirs [30] , [73] . different members of mir-181 family were shown to have divergent function in myocardial function [37] , [38] , [42] , [43] . mir-181 family members are ubiquitously expressed and the dose dependent reduction in organism size and viability following reduction of levels of the mir-181 family members suggests the critical role of this mir family in metabolic fitness and proliferation [61] . moreover, mir-181 target genes such as parkin or pten are conserved among species and it has been suggested that this family of mirnas has evolved to provide anabolic robustness during development [61] . this may also suggest the important role of mir-181 family in a multitude of disorders associated with changes in mitochondrial dynamics and oxidative stress, such as sarcopenia or aging. the potential of mirs as novel therapeutics for various disorders has been proposed due to their implication in regulating multiple pathways and involvement in many disease states including aging and sarcopenia [25] , [27] , [35] . despite multiple mir-based therapies being in clinical trials, no mir-based drug has been yet approved for use [74] [75] [76] [77] [78] [79] . since the recent approval of the first rna drug for disease (2018) with no other treatment options, an interest in rna therapeutics has increased. onpattro (patisiran) infusion has been used to treat peripheral nerve disease (polyneuropathy) caused by hereditary transthyretin-mediated amyloidosis (hattr) in adult patients [80] . as mirs regulate the expression of multiple genes simultaneously, they are attractive therapeutic targets for disorders with a complex molecular background, such as sarcopenia. mirs are small, charged, and water-soluble molecules and can be injected intravascularly or subcutaneously [81] . moreover, synthetic mirs and their inhibitors can be efficiently delivered, into muscle without a systemic immune response [74] , [82] . furthermore, various mir-based therapies are undergoing clinical trials, mir mimics and inhibitors (antagomirs, antimirs) [74] . some of the remaining issues that remain to be resolved before mirs can enter the drug market are potential off-target effects and tissuespecific delivery. these would be of significance when designing a mir-based therapeutic for muscle disorders, as delivery would likely be via iv injection which could result in systemic expression. nevertheless, mir-based approaches have shown efficacy in diseases such as cancer, hepatitis c and heart abnormalities [75] , [83] . emerging data for mirs as therapeutic is encouraging and with emerging technologies, mir-based approaches may provide functional interventions for preventing aging-and disease-related loss of muscle mass and strength. the authors declare there is no conflict of interest. association between muscular strength and mortality in men: prospective cohort study shared molecular and cellular mechanisms of premature aging and aging-associated diseases impaired proteostasis during skeletal muscle aging weight stability masks sarcopenia in elderly men and women the hallmarks of aging systematic analysis of the gerontome reveals links between aging and age-related diseases dynamics of life expectancy and life span equality sars-cov-2 and covid-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes clinical features of covid-19 in elderly patients: a comparison with young and middle-aged patients why does covid-19 disproportionately affect the elderly? covid-19 in older people: a rapid clinical review age, comorbidity, frailty status: effects on disposition and resource allocation during the covid-19 pandemic musculoskeletal consequences of covid-19 sarcopenia: aging-related loss of muscle mass and function epidemiology and consequences of sarcopenia treatment of sarcopenia: the road to the future micrornas as potential therapeutic targets for muscle wasting during cancer cachexia aging in relation to skeletal muscle dysfunction: redox homoeostasis to regulation of gene expression sarcopenia: aging-related loss of muscle mass and function cellular and molecular mechanisms underlying age-related skeletal muscle wasting and weakness single muscle fiber proteomics reveals fiber-type-specific features of human muscle aging identification of a molecular signature of sarcopenia aging differentially affects human skeletal muscle microrna expression at rest and after an anabolic stimulus of resistance exercise and essential amino acids aging and microrna expression in human skeletal muscle: a microarray and bioinformatics analysis the functional consequences of age-related changes in microrna expression in skeletal muscle most mammalian mrnas are conserved targets of micrornas micrornas: modulators of the underlying pathophysiology of sarcopenia? micrornas in skeletal muscle differentiation and disease expression patterns of muscle-specific mir-133b and mir-206 correlate with nutritional status and sarcopenia involvement of micrornas in the regulation of muscle wasting during catabolic conditions mir-26a is required for skeletal muscle differentiation and regeneration in mice maintenance of muscle stem-cell quiescence by microrna-489 diminished skeletal muscle microrna expression with aging is associated with attenuated muscle plasticity and inhibition of igf-1 signaling age-related changes in mir-143-3p: igfbp5 interactions affect muscle regeneration inflamma-mir-21 negatively regulates myogenesis during aging using computer simulation models to investigate the most promising micrornas to improve muscle regeneration during aging divergent effects of mir-181 family members on myocardial function through protective cytosolic and detrimental mitochondrial microrna targets predicting effective microrna target sites in mammalian mrnas molecular mechanisms of pathogenesis in hepatocellular carcinoma revealed by rna-sequencing mir-181 targets multiple bcl-2 family members and influences apoptosis and mitochondrial function in astrocytes role of the microrna 181 family in glioma development echocardiography and vascular ultrasound: new developments and future directions il-6: a potential role in cardiac metabolic homeostasis mir-181a/b downregulation exerts a protective action on mitochondrial disease models the role of microrna-181a in myocardial fibrosis following myocardial infarction in a rat model mir-181a regulates p62/sqstm1, parkin, and protein dj-1 promoting mitochondrial dynamics in skeletal muscle aging mir-181a regulates inflammation responses in monocytes and macrophages mir-181a and inflammation: mirna homeostasis response to inflammatory stimuli in vivo mirna in the regulation of skeletal muscle adaptation to acute endurance exercise in c57bi/6j male mice the microrna mir-181 targets the homeobox protein hox-a11 during mammalian myoblast differentiation microrna-181a/b-1 overexpression enhances osteogenesis by modulating pten/pi3k/akt signaling and mitochondrial metabolism the impact of aging, physical activity, and pre-frailty on skeletal muscle phenotype, mitochondrial content, and intramyocellular lipids in men maintenance of skeletal muscle mitochondria in health, exercise, and aging age-associated loss of opa1 in muscle impacts muscle mass, metabolic homeostasis, systemic inflammation, and epithelial senescence drp1-mediated mitochondrial shape controls calcium homeostasis and muscle mass signalling pathways regulating muscle mass in aging skeletal muscle. the role of the igf1-akt-mtor-foxo pathway post-stroke treatment with mir-181 antagomir reduces injury and improves long-term behavioral recovery in mice after focal cerebral ischemia mir-181 regulates grp78 and influences outcome from cerebral ischemia in vitro and in vivo nuclear mirna regulates the mitochondrial genome in the heart microrna-181a suppresses parkin-mediated mitophagy and sensitizes neuroblastoma cells to mitochondrial uncoupler-induced apoptosis mir-181 and metabolic regulation in the immune system the microrna mir-181 is a critical cellular metabolic rheostat essential for nkt cell ontogenesis and lymphocyte development and homeostasis mirnas in b cell development and lymphomagenesis hsa-microrna-181a is a regulator of a number of cancer genes and a biomarker for endometrial carcinoma in patients: a bioinformatic and clinical study and the therapeutic implication the mir-181 family promotes cell cycle by targeting ctdspl, a phosphatase-like tumor suppressor in uveal melanoma microrna-181 serves as a dual-role regulator in the development of human cancers microrna-181a regulates ifn-γ expression in effector cd8+ t cell differentiation loss of iron triggers pink1/parkinindependent mitophagy outstanding questions in mitophagy: what we do and do not know mechanisms of mitophagy in cellular homeostasis, physiology and pathology interfacing mitochondrial biogenesis and elimination to enhance host pathogen defense and longevity circadian rhythms regulate amelogenesis widespread context dependency of microrna-mediated regulation therapeutic mirna and sirna: moving from bench to clinic as next generation medicine the potential for microrna therapeutics and clinical research development of mirnabased therapeutic approaches for cancer patients micrornas in cancer: biomarkers, functions and therapy microrna therapeutics: towards a new era for the management of cancer and other diseases treating cancer with microrna replacement therapy: a literature review patisiran: first global approval microrna therapeutics: the next magic bullet? modulating micrornas in cardiac surgery patients: novel therapeutic opportunities? scaffold-based microrna therapies in regenerative medicine and cancer key: cord-264811-xbeipob9 authors: choi, yongin; kim, james slghee; choi, heejin; lee, hyojung; lee, chang hyeong title: assessment of social distancing for controlling covid-19 in korea: an age-structured modeling approach date: 2020-10-14 journal: int j environ res public health doi: 10.3390/ijerph17207474 sha: doc_id: 264811 cord_uid: xbeipob9 the outbreak of the novel coronavirus disease 2019 (covid-19) occurred all over the world between 2019 and 2020. the first case of covid-19 was reported in december 2019 in wuhan, china. since then, there have been more than 21 million incidences and 761 thousand casualties worldwide as of 16 august 2020. one of the epidemiological characteristics of covid-19 is that its symptoms and fatality rates vary with the ages of the infected individuals. this study aims at assessing the impact of social distancing on the reduction of covid-19 infected cases by constructing a mathematical model and using epidemiological data of incidences in korea. we developed an age-structured mathematical model for describing the age-dependent dynamics of the spread of covid-19 in korea. we estimated the model parameters and computed the reproduction number using the actual epidemiological data reported from 1 february to 15 june 2020. we then divided the data into seven distinct periods depending on the intensity of social distancing implemented by the korean government. by using a contact matrix to describe the contact patterns between ages, we investigated the potential effect of social distancing under various scenarios. we discovered that when the intensity of social distancing is reduced, the number of covid-19 cases increases; the number of incidences among the age groups of people 60 and above increases significantly more than that of the age groups below the age of 60. this significant increase among the elderly groups poses a severe threat to public health because the incidence of severe cases and fatality rates of the elderly group are much higher than those of the younger groups. therefore, it is necessary to maintain strict social distancing rules to reduce infected cases. coronavirus disease 2019 (covid-19) is a novel viral disease that is currently threatening public health worldwide. the virus responsible for the disease was initially called novel coronavirus (2019-ncov) due to its novelty. analysis of the phylogeny and taxonomy of 2019-ncov have shown that the virus belongs to the subgenus sarbecovirus, which sars-cov belongs to [1], but is more closely related to bat sars-cov [2, 3] . thus, 2019-ncov was named "severe acute respiratory syndrome coronavirus 2" or "sars-cov-2" [4] . cases of sars-cov-2 display symptoms such as fever, dry cough, dyspnea, and diarrhea, which are similar to symptoms noted in mers-cov and sars-cov. however, the distribution of each symptom differs [5] . in this study, we use the outbreak data of covid-19 in the seoul and gyeonggi provinces between 1 february and 15 june 2020 [18, 19] . figure 1 shows the epidemic curve of confirmed cases of covid-19 over the date of illness onset. a total of 1577 covid-19 cases were reported. covid-19 incidences were divided into different age groups to capture the age-dependent transmission dynamics. figure 1a shows that the number of imported cases comprised about 39.6% infected cases before may but drastically diminished to about 4.0% afterward. figure 1b shows that about 55.2% of infected cases were among ages 20-49 throughout the whole outbreak, and from may 1 through 14, about 76.8% of infected cases were among ages 20-39. table 1 shows the incidence data by age group and the sources of infection in the target area during the period. the sample dataset used in this study is shown in table s1 in supplementary section a. int the transmission dynamics of covid-19 are greatly affected by governmental control policies such as social distancing, school closures, and lockdowns. the korean government has attempted to implement appropriate control policies in response to changes in the number of infected people. in korea, on 23 february, the increasing level of covid-19 cases raised the alert to its highest level of "red", thus strengthening the overall response system to possible epidemics [20] . as a result of this increase in the number of infected people, different levels of social distancing were implemented by the korean government [21] . a brief description of the four levels of social distancing in korea is shown in table 2 , and further details about the social distancing policies are given in table s3 in supplementary section b. the transmission dynamics of covid-19 are greatly affected by governmental control policies such as social distancing, school closures, and lockdowns. the korean government has attempted to implement appropriate control policies in response to changes in the number of infected people. in korea, on 23 february, the increasing level of covid-19 cases raised the alert to its highest level of "red", thus strengthening the overall response system to possible epidemics [20] . as a result of this increase in the number of infected people, different levels of social distancing were implemented by the korean government [21] . a brief description of the four levels of social distancing in korea is shown in table 2 , and further details about the social distancing policies are given in table s3 in supplementary section b. as seoul and gyeonggi provinces are densely populated with diverse people, to enhance the realism of our model, it is beneficial to consider the heterogeneity in contact networks. two of the most important heterogeneous aspects of a contact network are location and age since different locations are often visited by certain age groups, which leads to consistent contact with specific age groups. for instance, people tend to have contact with people of a similar age outside their households (i.e., schools and workplaces). since our age-structured model allows us to adjust the transmission rates among different age groups and since the location is closely linked to an individual's contact pattern with certain age groups, we applied these location-based contact patterns to the transmission rates. we divided the contact locations into four categories: school, workplace, household, and other locations. for each location category, we used the specific contact matrix of korea from [21] to build our model. each contact was defined by either physical or nonphysical contact; physical contact includes skin-to-skin contact like kissing, handshaking, etc., whereas nonphysical contact includes, as seoul and gyeonggi provinces are densely populated with diverse people, to enhance the realism of our model, it is beneficial to consider the heterogeneity in contact networks. two of the most important heterogeneous aspects of a contact network are location and age since different locations are often visited by certain age groups, which leads to consistent contact with specific age groups. for instance, people tend to have contact with people of a similar age outside their households (i.e., schools and workplaces). since our age-structured model allows us to adjust the transmission rates among different age groups and since the location is closely linked to an individual's contact pattern with certain age groups, we applied these location-based contact patterns to the transmission rates. we divided the contact locations into four categories: school, workplace, household, and other locations. for each location category, we used the specific contact matrix of korea from [21] to build our model. each contact was defined by either physical or nonphysical contact; physical contact includes skin-to-skin contact like kissing, handshaking, etc., whereas nonphysical contact includes, e.g., a two-way conversation with three or more words in the physical presence of another person but no skin-to-skin contact [24] . each location-specific contact matrix is a 16 × 16 square matrix, which represents the mean number of instances of contact between individuals of five-year age groups, such as 0-4, 5-9, 10-14, 15-19, 20-24, 25-29, 30-34, 35-39, 40-44, 45-49 , 50-54, 55-59, 60-64, 65-69, 70-74, and 75 and above. each element is the contact rate of an individual in one of the 16 age groups with people in the other 16 age groups at the specific locations. more precisely, the location-specific contact matrix m is written as [25] where each element m ij denotes the mean number of contacts an individual in age group i makes with individuals in age group j per day. note that contact matrix m is not necessarily symmetrical, which is a general feature that is also found in [26] [27] [28] . since the focus areas are seoul and gyeonggi province, and the location-specific matrices of the whole region of korea are only available in [25] , we estimated the location-specific matrices of the focus area by using the proportion of the population of the area compared to that of korea. we assumed the total population to be constant since the period of interest covers less than a year. we used the census data of korea from january 2020 throughout the simulations. a summary of the data can be found in figure s2 and table s2 in supplementary section b, which describe how to calculate the contact matrix of the focus area. the calculated location-specific matrices for seoul and gyeonggi province are shown in figure s4 in supplementary section b. a full contact matrix m is composed of a linear combination of the location-specific contact matrices [25] : where m w is the workplace contact matrix, m s is the school contact matrix, m h is the household contact matrix, and m o is the contact matrix for all other locations, except for the workplace, school, and household; c w , c s , and c o are constants, and c h is a 16 × 16 diagonal matrix, which are each multiplied by their respective matrices. based on the real policies of school closure and social distancing levels in korea, we composed five different contact matrices by adjusting c w , c s , c h , and c o as m o , m c , m c w , m c m , and m c s , which denote the contact matrices of the cases of school openings with no social distancing, school closures with no social distancing, school closures with weak social distancing, school closures with medium social distancing, and school closures with strong social distancing, respectively. when the school is closed, c s = 0 since there are no contacts made in the school. on the other hand, when the school is closed, c h = diag(1.5, 1.5, 1.5, 1.5, 1.1, 1.1, . . . , 1.1) 16 , where diag( ) n denotes the diagonal matrix with n diagonal entries, such that for age groups below the age of 20, contact rates increased by 50.0% and for age groups 20 and above, contact rates increased by 10.0% [29] . for social distancing, when there is no social distancing, weak social distancing, medium social distancing, or strong social distancing, we assumed c o = 1, 0.7, 0.5, 0.3, respectively, such that c o decreases under stronger social distancing. note that different types of c o levels were tested while decreasing the orders of c o for stronger social distancing, as shown in figures s12 and s13 in supplementary section d, but we present only one case due to the lack of a significant difference in the fitting and simulation results. an example of a scenario/policy-specific contact matrix of seoul and gyeonggi province-school closure with no social distancing, m c -is shown in figure 3 ; a comparison with the equivalent version for korea is provided in figure s3 in supplementary section b. table 3 shows a summary of the contact matrices for different policies. the contact matrices for each scenario/policy are shown in figure s5 . medium social distancing 1 * 0 * (1.5, 1.5, 1.5, 1.5, 1.1, 1.1, … , 1.1) 0.5 * school closing strong social distancing 1 * 0 * (1.5, 1.5, 1.5, 1.5, 1.1, 1.1, … , 1.1) 0.3 * * values with an asterisk (*) are assumed. ** i16 and diag(·)16 denote the 16 × 16 identity matrix and the diagonal matrix with diagonal entries, respectively. we developed a mathematical model to describe the transmission dynamics of covid-19 by employing an s-e-i-h-r compartment model with 16 age groups. in this model, , , , , and denote the susceptible, exposed, infectious, hospitalized, and recovered/removed population of age group , respectively. the diagram for the model is shown in figure 4 . we developed a mathematical model to describe the transmission dynamics of covid-19 by employing an s-e-i-h-r compartment model with 16 age groups. in this model, s i , e i , i i , h i , and r i denote the susceptible, exposed, infectious, hospitalized, and recovered/removed population of age group i, respectively. the diagram for the model is shown in figure 4 . we developed a mathematical model to describe the transmission dynamics of covid-19 by employing an s-e-i-h-r compartment model with 16 age groups. in this model, , , , , and denote the susceptible, exposed, infectious, hospitalized, and recovered/removed population of age group , respectively. the diagram for the model is shown in figure 4 . (3) are described in table 4 . b i infection probability of a person in age group i per contact in this model, the asymptomatic infectious population is excluded. although recent studies around the world suggest the presence and significance of an asymptomatic infectious population [31, 32] , we found that it is appropriate to apply the settings from our area of interest and the time period we are observing. hence, we refer to a recent antibody test for covid-19 for randomly selected subjects in korea [33] , which includes 1833 subjects from seoul and 278 subjects from gyeonggi province, where only 1 subject was found positive (a total of 3555 subjects were tested through a screening inspection and plague reduction neutralization test; 1555 serum samples were collected from 21 april through 19 june from 192 regions in korea, and 1500 hospitalized patients from seoul were tested from 25 may through 28 may). thus, the ratio of asymptomatic infected people to infected people was estimated to be very small in korea. for this reason, together with the difficulty in determining the proportion of asymptomatic infections accurately, we did not consider a compartment for asymptomatic infections in the mathematical model. the parameter 1/q is the median value computed from the data for each period, and its values are given in table 5 . we estimate the transmission rate β ij by utilizing the least squares method, lsqcurvefit, which is an embedded function in matlab. to measure the potential of the disease transmission in each period, we use the effective reproduction number r t , which is the average number of secondary cases infected by an index case in a population of both susceptible and nonsusceptible hosts. r t is computed as r t = ρ(g), where ρ is the spectral radius of the next generation matrix g [34] . the derivation of the value of r t is described in supplementary section c. this study used the data available in [18, 19] . the datasets were already fully anonymized and did not include any identity information. thus, ethical approval was not required for this analysis. the covid-19 data for gyeonggi province are accessible in [18] , and the data for seoul city are available upon request [19] . we estimated the transmission rate using the epidemiological data described in section 2. depending on each period, we estimated the transmission rates corresponding to the age group by applying the least squares method to the age-specific incidence data. we observed that the number of incidence data for each 5-year age group was not sufficient to estimate the transmission rate between age groups due to the absence of reported cases in some periods. thus, to clarify the different properties of transmission rates between age groups, we estimated the transmission rate for 10-year age groups, such as 0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, and 70 and above, by combining two 5-year age groups into one 10-year age group. figure 5 compares the observed and estimated covid-19 cases for (a) incidence and (b) cumulative incidence among all ages. the results of the data-fitting for each age group are shown in figures s6 and s7 in supplementary section d. in a population of both susceptible and nonsusceptible hosts. is computed as = ( ), where is the spectral radius of the next generation matrix g [34] . the derivation of the value of is described in supplementary section c. this study used the data available in [18, 19] . the datasets were already fully anonymized and did not include any identity information. thus, ethical approval was not required for this analysis. the covid-19 data for gyeonggi province are accessible in [18] , and the data for seoul city are available upon request [19] . we estimated the transmission rate using the epidemiological data described in section 2. depending on each period, we estimated the transmission rates corresponding to the age group by applying the least squares method to the age-specific incidence data. we observed that the number of incidence data for each 5-year age group was not sufficient to estimate the transmission rate between age groups due to the absence of reported cases in some periods. thus, to clarify the different properties of transmission rates between age groups, we estimated the transmission rate for 10-year age groups, such as 0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, and 70 and above, by combining two 5-year age groups into one 10-year age group. figure 5 compares the observed and estimated covid-19 cases for (a) incidence and (b) cumulative incidence among all ages. the results of the data-fitting for each age group are shown in figures s6 and s7 in supplementary section d. table 5 shows the values of the estimated infection probability and the effective reproduction number depending on the age group and period. here, is a vector consisting of the infection probability for eight age groups instead of sixteen age groups (i.e., = for ∈ {0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70+}), and each subsequent pair of equals (i.e., = = , = = , ⋯ , = = ). the value of was bigger than 2 in period 1, but after governmental control policies began in period 2, it decreased below 2. in particular, in periods 3 and 4, when medium and strong levels of social distancing were implemented, respectively, the value of became much less than 1. however, significant local infections have occurred since 24 april, when infected cases linked to club attendance among the table 5 shows the values of the estimated infection probabilityb and the effective reproduction number r t depending on the age group and period. here,b is a vector consisting of the infection probability for eight age groups instead of sixteen age groups (i.e.,b = b k for k ∈ {0-9, 10-19, 20-29, 30-39, 40-49, 50-59, 60-69, 70+}), and each subsequent pair of b i equalsb k (i.e.,b 0−9 = b 0−4 = b 5−9 , b 10−19 = b 10−14 = b 15−19 , · · · ,b 70+ = b 70−74 = b 75+ ). the value of r t was bigger than 2 in period 1, but after governmental control policies began in period 2, it decreased below 2. in particular, in periods 3 and 4, when medium and strong levels of social distancing were implemented, respectively, the value of r t became much less than 1. however, significant local infections have occurred since 24 april, when infected cases linked to club attendance among the young age groups were reported [23] . in the period between 24 april and 6 may, the r t value was estimated to be 2.4846, and the governmental control policies against local infections were implemented in period 7, which decreased the value of r t to 0.8047. in periods 1 and 2, the time taken to be diagnosed from symptom onset, 1/q, was estimated at 8 and 5 days, respectively, but decreased to 3-4 days since 29 february when social distancing began. in the transition from period 2 to period 3, medium social distancing was implemented, and the infection probabilityb for age groups 0-9, 10-19, 20-29, 30-39, and 40-49 decreased by 37.8%, 86.1%, 21.3%, 40.6%, and 17.8%, respectively, while that of the age groups 50-59, 60-69, and 70+ increased by more than 400.0%, which resulted in a decrease of r t of 0.6776. once the strong social distancing started in period 4,b either decreased or remained at similar level for almost all age groups, resulting in the r t decreasing by 0.1145. in period 5-2, theb for age groups 20-29 and 30-39 increased rapidly, resulting in an increase of r t of 2.4846. we investigated the potential effect of social distancing under various scenarios. in table 6 , between 24 april and 31 august, we created seven scenarios along the baseline considering the social distancing strengths described in section 2.2. these scenarios were designed to test the effects from the strongest case (scenario 1) to the weakest case (scenario 7). weak weak weak figure 6 shows (a) a comparison of the time-dependent cumulative incidences for the scenarios and (b) the age-specific cumulative incidences up to 31 august 2020. figure 6a illustrates the effects of different social distancing combinations under each scenario, and in figure 6b , we can observe how each scenario affects different age groups accordingly. the incidence plot corresponding to figure 6a is shown in figure s8a . the simulation results of the incidence and cumulative incidence for each age group are shown in figures s9 and s10 in supplementary section d, respectively. table 7 shows the cumulative incidence of each age group up to 31 august 2020. young age groups were reported [23] . in the period between 24 april and 6 may, the value was estimated to be 2.4846, and the governmental control policies against local infections were implemented in period 7, which decreased the value of to 0.8047. in periods 1 and 2, the time taken to be diagnosed from symptom onset, 1/q, was estimated at 8 and 5 days, respectively, but decreased to 3-4 days since 29 february when social distancing began. in the transition from period 2 to period 3, medium social distancing was implemented, and the infection probability for age groups 0-9, 10-19, 20-29, 30-39, and 40-49 decreased by 37.8%, 86.1%, 21.3%, 40.6%, and 17.8%, respectively, while that of the age groups 50-59, 60-69, and 70+ increased by more than 400.0%, which resulted in a decrease of of 0.6776. once the strong social distancing started in period 4, either decreased or remained at similar level for almost all age groups, resulting in the decreasing by 0.1145. in period 5-2, the for age groups 20-29 and 30-39 increased rapidly, resulting in an increase of of 2.4846. we investigated the potential effect of social distancing under various scenarios. in table 6 , between 24 april and 31 august, we created seven scenarios along the baseline considering the social distancing strengths described in section 2.2. these scenarios were designed to test the effects from the strongest case (scenario 1) to the weakest case (scenario 7). weak weak weak figure 6 shows (a) a comparison of the time-dependent cumulative incidences for the scenarios and (b) the age-specific cumulative incidences up to 31 august 2020. figure 6a illustrates the effects of different social distancing combinations under each scenario, and in figure 6b , we can observe how each scenario affects different age groups accordingly. the incidence plot corresponding to figure 6a is shown in figure s8a . the simulation results of the incidence and cumulative incidence for each age group are shown in figures s9 and s10 in supplementary section d, respectively. table 7 shows the cumulative incidence of each age group up to 31 august 2020. (a) (b) figure 6 . cumulative incidence for scenarios of social distancing: (a) the time-dependent cumulative incidence for the total age group and (b) the age-specific cumulative incidence from 1 february to 31 august 2020. strong, medium, and weak social distancing is denoted by s, m, and w, respectively, and w+ denotes weak social distancing+ defined in table 2 . table 7 show that if a strong level of social distancing had been maintained for all three periods, the number of infected people would have decreased by about 44.6%. on the other hand, if a weak level of social distancing was implemented for the three periods, the number of incidences would have increased by about 29.2%. however, when the intensity of social distancing is reduced in all the scenarios, the number of incidences increases in proportion with the degree of the intensity reduction. in particular, people who are between the ages of 0 and 19 present a minimum number of infected cases in all the scenarios of social distancing. in other words, the number of infected cases among those between the ages of 0 and 19 was the least affected by the strength of social distancing. for those between 50 and above, the number of infected cases increased drastically (28.4, 42.4 , and 42.0 percent increase for age groups 50-59, 60-69, and 70+, respectively) in scenario 7 compared to the baseline, showing that without sufficiently strong social distancing, the age groups of 50 and above became noticeably vulnerable compared to the younger age groups. scenarios 6 and 7 used the same weak social distancing strength from 24 april through 29 may. the only difference is in the social distancing strength during the longest period of 29 may-31 august, where scenario 6 uses strong social distancing, and scenario 7 uses weak social distancing. despite the strength differences for the period of approximately three months, the effects on ages 0-19 appear to be minimal compared to those for people aged 20 and above. moreover, the number of infected cases among those age 40 and above was effectively reduced even though social distancing was weak starting from 29 may. corresponding to figure 6b , the comparison of age for each scenario is shown in figure s11a in supplementary section d. figure 7 shows (a) the monthly incidence of cases for the total age group under all scenarios and (b) a comparison of the monthly incidence among the two age groups of 20-49 and 50 and above for the baseline (scenarios 1 and 7) . the monthly incidence of the other scenarios for these two age groups is shown in figure s11b ,c in supplementary section d. table 8 shows the monthly incidence of the total age group, the age groups of 20-49, and those of 50 years and above for all scenarios. in the four months of may through august, compared to the baseline, the total incidence increased by 43.9% under scenario 7 but decreased by 66.6% for scenario 1. table 8 . monthly incidence of the total age group, the age groups of 20-49, and those 50 years and older (50+) for all scenarios. the percentage below incidence represents the percentage increase or decrease from the baseline. may (a) (b) figure 7 . cumulative incidence based on scenarios: (a) the monthly incidence for the total age group and (b) the monthly incidence of the two age groups of 20-49 and 50 and older (50+) for the baseline (scenarios 1 and 7). in this study, we analyzed the epidemiological data of covid-19 cases in seoul and gyeonggi province between 1 february and 15 june 2020. the symptoms, transmission rates, and fatality rates of this disease differ by age, and the risks of severe symptoms and fatality rates are greater with an increase in age [13] . to take these aspects into account, we developed an age-structured model that describes the age-dependent dynamics of covid-19. in the age-structured model developed in this study, we estimated the transmission rate by applying the contact matrix obtained from [25] to the actual incidence and population data for seoul and gyeonggi province. since the control policies implemented by the governmental authorities affect the dynamics of infectious diseases [13, 35] , we divided the whole period between 1 february and 15 june into seven distinct periods following important changes in governmental control policies. we observed that the simulated incidence curve with the fitted transmission rate matches well with the actual incidence data of each age group over the whole period. using the developed age-structured model, we investigated the effect of social distancing under various scenarios in the focus area. for each of the seven distinct periods, we estimated the infection probabilityb for each age group and the effective reproduction number r t , which led to three interesting results. first, as the social distancing strength increased, r t decreased from 2.1971 to 0.0001 until 24 april. until the serious infections linked to clubs began to emerge, social distancing was effective in preventing local transmission. in period 5-2, the behavioral changes among those aged 20-39 [23] were suspected to be the primary cause of the escalating outbreaks after 24 april, among which the r t increased to 2.4846. secondly,b differed greatly depending on the age group. despite an increase in social distancing strength, the age groups 50 and above experienced an increase inb during period 3, while the transmission rates for the age groups younger than 50 decreased. this suggests that social distancing affects different age groups with different magnitudes, with younger age groups being more effective while under control. thirdly, in period 6 during the weak social distancing, age groups 50 and above showed a greater change inb than age groups 20-49. this resulted in critical situations featuring an elevated number of deaths since the fatality rate is generally greater for people age 50 and above [17] . the baseline scenario reflected the actual social distancing policies implemented by the korean governmental authorities between 1 february and 15 june 2020. in other scenarios, it was assumed that various levels of social distancing, different from the baseline scenario, were implemented in periods 5, 6, and 7. the simulation results in table 7 showed that if a strong level of social distancing has been implemented for all three periods, the number of infected people would have decreased by about 44.6%. on the other hand, if a weak level of social distancing was maintained for the three periods, the number of infected people would have increased by about 29.2%. for all the scenarios, the results showed that a reduction in the intensity of social distancing produced an increase in the number of infected persons. notably, the number of incidences in the age groups 60 years and above increased significantly compared to that of other age groups, which represents a very dangerous situation, as the fatality rate of the elderly groups is much higher than that of the younger groups [17] . therefore, it is necessary to properly maintain a high-level intensity of social distancing to lower the fatality rate and reduce medical expenses. however, the social and economic costs that may emerge from strengthening social distancing should also be considered. to investigate the effects of social distancing, we assumed that all schools were closed during the whole period of this study. we also reviewed some previous studies on the effects of school closures during different disease outbreaks [27, 36] . indeed, during the covid-19 pandemic, many of our sampled schools have been opened since mid-may, except when there were recorded incidences of infected people in a school or its nearby area. schools under such conditions were closed for a certain period, and quarantine policies were implemented differently for each school. however, it was difficult to provide an accurate reflection on the effects of schools opening/closing in this study since there are no reports on group infections in all schools over the whole period. therefore, we propose that our model is more suitable for analyzing the impact of fixed and clear-cut control policies like social distancing, rather than the impact of schools opening/closing on the transmission of covid-19. despite the limitations in our study, we successfully developed an age-structured model using the epidemiological data in seoul and gyeonggi province by implementing an age and location-based contact matrix, which is not a well-known model for covid-19. through this study, we analyzed the effects of different social distancing policies and further extended those effects to simulate different scenarios. as the social distancing strength was weakened, people age 50 and above were directly affected, showing a more significant increase in transmission rate than that among people age 20-49. strong social distancing can be very effective in reducing the number of infected cases, as shown in scenario 1, where the cumulative incidence was reduced by 44.6% compared to the baseline. in this paper, we developed an age-structured mathematical model for assessing the age-dependent transmission of covid-19 in korea. the target area was seoul and gyeonggi province, the most populated area in korea. we divided the total human population in the target area into different age groups. we estimated the transmission rate for each age group in seven distinct periods using the covid-19 data and contact matrix for each age group and investigated the effect of social distancing on the control of the disease in the age-structured model under various scenarios. in the most optimal scenario (scenario 1), the reduced cumulative incidence of 44.6% from the baseline established that social distancing strength can have a critical impact on the mitigation of transmission dynamics. our modeling approach for covid-19 has novelty in that we estimated the transmission rates of different age groups in seven distinct periods following government control policies. the modeling approach presented in this work can be applied to other target areas worldwide if sufficient epidemiological data and contact matrices for the various age groups are available. supplementary materials: the following are available online at http://www.mdpi.com/1660-4601/17/20/7474/s1, section a: data analysis (table s1 : dataset sample; figure s1 : cumulative incidence of seoul/gyeonggi province by (a) age group, (b) source of infection, and (c) region); section b: contact matrix and control policy ( figure s2 . population of south korea and seoul/gyeonggi province in january 2020 by age groups; table s2 estimation of transmission rate: incidence of each age groups. incidences by local transmission (local and imported transmission) are blue-colored estimation of transmission rate: cumulative incidence of each age groups. incidences by local transmission (local and imported transmission) are blue-colored scenario simulation: (a) incidence and (b) cumulative incidence of all ages. s, m, w denote strong, medium, weak social distancing, respectively, and w+ denotes weak social distancing+. black circles are actual incidence data scenario simulation: incidence of each age groups scenario simulation: cumulative incidence of each age groups; figure s11. other figures. (a) is scenario specific analysis on monthly incidence of two age groups of 20-49 and 50 or older (50+) for the baseline, scenario 1 and 7 on different types c o levels for strong, medium and weak social distancing: (a) c o monthly incidence of two age groups of 20-49 and 50 or older (50+) on different three types c o levels for strong, medium and weak social distancing: (a),(b) c o bat origin of a new human coronavirus: there and back again a pneumonia outbreak associated with a new coronavirus of probable bat origin a new coronavirus associated with human respiratory disease in china the species severe acute respiratory syndrome-related coronavirus: classifying 2019-ncov and naming it sars-cov-2 a novel coronavirus outbreak of global health concern world health organization. who director-general's opening remarks at the media briefing on covid-19-11 coronavirus disease 2019 (covid-19) situation report-51 coronavirus disease 2019 (covid-19) situation report-209 vaccines: status report. immunity draft landscape of covid-19 candidate vaccines coronavirus disease 2019 (covid-19) advice for the public cmmid covid-19 working group age-dependent effects in the transmission and control of covid-19 epidemics the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study age-structured modeling of covid-19 epidemic in the usa, uae and algeria korea centers for disease control & prevention. cases in korea by city/province gyeonggi infectious disease control center korea centers for disease control & prevention. the updates of covid-19 (23 februrary) in korea social contacts and mixing patterns relevant to the spread of infectious diseases projecting social contact matrices in 152 countries using contact surveys and demographic data projecting social contact matrices to different demographic structures measured dynamic social contact patterns explain the spread of h1n1v influenza inferring the structure of social contacts from demographic data in the analysis of infectious diseases spread impact of non-pharmaceutical interventions (npis) to reduce covid19 mortality and healthcare demand report 2: estimating the potential total number of novel coronavirus cases in wuhan city asymptomatic transmission, the achilles' heel of current strategies to control covid-19 presumed asymptomatic carrier transmission of covid-19 korea centers for disease control & prevention. updates on covid-19 in korea (as of 9 july). available online modelling the effective reproduction number of vector-borne diseases: the yellow fever outbreak in luanda stochastic methods for epidemic models: an application to the 2009 h1n1 influenza outbreak in korea a modeling study of school closure to reduce influenza transmission: a case study of an influenza a (h1n1) outbreak in a private thai school the data for seoul city used in this research were provided by a government-wide r&d funding project for infectious disease research (gfid) in the korea (grant no. hg18c0088). the authors declare no conflict of interest. the funders had no role in the study design, data collection and analysis, the decision to publish the results, or the preparation of the manuscript. key: cord-309556-xv3413k1 authors: chow, ryan d.; chen, sidi title: the aging transcriptome and cellular landscape of the human lung in relation to sars-cov-2 date: 2020-04-15 journal: biorxiv doi: 10.1101/2020.04.07.030684 sha: doc_id: 309556 cord_uid: xv3413k1 since the emergence of sars-cov-2 in december 2019, coronavirus disease-2019 (covid-19) has rapidly spread across the globe. epidemiologic studies have demonstrated that age is one of the strongest risk factors influencing the morbidity and mortality of covid-19. here, we interrogate the transcriptional features and cellular landscapes of the aging human lung through integrative analysis of bulk and single-cell transcriptomics. by intersecting these age-associated changes with experimental data on host interactions between sars-cov-2 or its relative sars-cov, we identify several age-associated factors that may contribute to the heightened severity of covid-19 in older populations. we observed that age-associated gene expression and cell populations are significantly linked to the heightened severity of covid-19 in older populations. the aging lung is characterized by increased vascular smooth muscle contraction, reduced mitochondrial activity, and decreased lipid metabolism. lung epithelial cells, macrophages, and th1 cells decrease in abundance with age, whereas fibroblasts, pericytes and cd4+ tcm cells increase in abundance with age. several age-associated genes have functional effects on sars-cov replication, and directly interact with the sars-cov-2 proteome. interestingly, age-associated genes are heavily enriched among those induced or suppressed by sars-cov-2 infection. these analyses illuminate potential avenues for further studies on the relationship between the aging lung and covid-19 pathogenesis, which may inform strategies to more effectively treat this disease. these data indicate that differential expression of sars-cov-2 host entry factors alone is unlikely to explain the relationship between age and severity of covid-19 illness. to discern the host cell types involved in covid-19 entry, we turned to a single cell rna-seq (scrna-seq) dataset of 57,020 human lung cells from the tissue stability cell atlas 19 . in agreement with prior reports, analysis of the single cell lung transcriptomes revealed that alveolar type 2 (at2) cells were comparatively enriched in ace2 and tmprss2-expressing cells 20, 21 ( supplementary figure 3a-b) . however, ace2-expressing cells represented only 1.69% of all at2 cells, while 47.52% of at2 cells expressed tmprss2. alveolar type 1 (at1) cells also showed detectable expression of ace2 and tmprss2, but at lower frequencies (0.39% and 26.70%). ctsl expression could be broadly detected in many different cell types including at2 cells, but its expression was particularly pronounced in macrophages (supplementary figure 3c) . since the expression of host entry factors ace2, tmprss2 and ctsl did not increase with age, we next sought to identify all age-associated genes expressed in the human lung (methods). using a likelihood-ratio test 22 , we pinpointed the genes for which age significantly impacts their expression. with a stringent cutoff of adjusted p < 0.0001, we identified two clusters of genes in which their expression progressively changes with age (figure 1d) . cluster 1 is composed of 643 genes that increase in expression with age, while cluster 2 contains 642 genes that decrease in expression with age. gene ontology and pathway analysis of cluster 1 genes (increasing with age) revealed significant enrichment for cell adhesion, vascular smooth muscle contraction, oxytocin signaling, and platelet activation, in addition to several other pathways (figure 1e) . these findings are consistent with known physiologic changes of aging, including decreased pulmonary compliance 23 , and heightened risk for thrombotic diseases 24 . of note, deregulation of the reninangiotensin system has been implicated in the pathogenesis of acute lung injury induced by sarschina and italy have found that patients with hypertension were more likely to develop ards 17 , require icu admission 31 , and die from the disease 32 , though we note that correlative epidemiologic studies do not necessarily demonstrate causality. cluster 2 genes (decreasing with age) were significantly enriched for mitochondrion, mitochondrial translation, metabolic pathways, and mitosis, among other pathways (figure 1f) , which is consistent with prior observations of progressive mitochondrial dysfunction with aging [33] [34] [35] . of note, cluster 2 was also enriched for genes involved in lipid metabolism, fatty acid metabolism, peroxisome, and lysosomal membranes. age-associated alterations in lipid metabolism could impact sars-cov-2 infection, as sars-cov can enter cells through cholesterol-rich lipid rafts [36] [37] [38] [39] . similarly, age-associated alterations in lysosomes could influence late endocytic viral entry, as the protease cathepsin l cleaves sars-cov spike proteins from within lysosomes 40, 41 . having compiled a high-confidence set of age-associated genes, we sought to identify the lung cell types that normally express these genes, using the human lung single cell transcriptomics dataset from the tissue stability cell atlas 19 . by examining the scaled percentage of expressing cells within each cell subset, we identified age-associated genes predominantly enriched in different cell types. cell types with highly enriched expression for certain cluster 1 genes (increasing with age) included fibroblasts, muscle cells, and lymph vessels (figure 2a) . in contrast, cell types with highly enriched expression for certain cluster 2 genes (decreasing with age) included macrophages, dividing dendritic cells (dcs)/monocytes, and at2 cells (figure 2b) . similar results were found using an independent human lung scrna-seq dataset from the human lung cell atlas (supplementary figure 4a-b) 42 . examining the muscle-enriched genes that increased in expression with age, gene ontology analysis revealed enrichment for vascular smooth muscle contraction, cgmp-pkg signaling, z-disc, and actin cytoskeleton, among other pathways ( figure 2c ). as for the at2-enriched genes that decreased in expression with age, gene ontology analysis revealed enrichment for metabolic pathways, biosynthesis of antibiotics, lipid metabolism, extracellular exosome, and mitochondrial matrix (figure 2d) . a subset of these enriched gene ontologies had also been identified by the bulk rna-seq analysis (figure 1e-f) . thus, integrative analysis of bulk and single-cell transcriptomes revealed that many of the age-associated transcriptional changes in human lung can be mapped to specific cell subpopulations, suggesting that the overall abundance of these cell types, their transcriptional status, or both, may be altered with aging. as the pathophysiology of viral-induced ards involves an intricate interplay of diverse cell types, most notably the immune system 43, 44 , aging-associated shifts in the lung cellular milieu 23 could contribute an important dimension to the relationship between age and risk of ards in patients with covid-19 31 . to investigate the cellular landscape of the aging lung, we applied a gene signature-based approach 45 to infer the enrichment of different cell types from the bulk rna-seq profiles. since bulk rna-seq measures the average expression of genes within a cell population, such datasets will reflect the relative proportions of the cell types that comprised the input population, though with the caveat that cell types can have overlapping expression profiles and such profiles may be altered in response to stimuli. using this approach, we identified ageassociated alterations in the enrichment scores of several cell types (figure 3a) . whereas epithelial cells decreased with age, fibroblasts increased with age (figure 3b ). this finding is consistent with the progressive loss of lung parenchyma due to reduced regenerative capacity of the aging lung 46 , as well as the increased risk for diseases such as chronic obstructive pulmonary disease and pulmonary fibrosis 47 . in addition, these results are concordant with the findings from analysis of human lung single-cell transcriptomes (figure 2a-b) . among the innate immune cell populations, the enrichment scores of total macrophages were inversely associated with age (figure 3c) . macrophages are major drivers of innate immune responses in the lung, acting as first-responders against diverse respiratory infections 48 . thus, the age-associated decrease in macrophage abundance may be a possible factor related to the greater severity of lung pathology in patients with covid-19. although macrophage accumulation is often associated with the pathologic inflammation of viral ards 49, 50 , pulmonary macrophages can act to limit the duration and severity of infection by efficiently phagocytosing dead infected cells and released virions [51] [52] [53] . notably, macrophages infected with sars-cov have been found to abort the replication cycle of the virus 54,55 , further supporting their role in antiviral responses. however, macrophages may suppress antiviral adaptive immune responses 48, 56 , inhibiting viral clearance in mouse models of sars-cov infection 57 . in aggregate, these prior reports suggest that the precise role of lung macrophages in sars-cov-2 pathophysiology is likely contextdependent. it is also plausible that the increased numbers of macrophages are not the primary distinction between young and old patients, but rather the functional status of the macrophages. in line with this, we observed that the age-associated changes in macrophages were specifically attributed to the pro-inflammatory m1 macrophage subset but not the immunoregulatory m2 subset 58 (figure 3c) , though this binary classification scheme represents an oversimplification of macrophage function. nevertheless, elucidating the consequences of age-associated changes in lung macrophages may reveal insights into the differential outcomes of older patients with covid-19. further studies are needed to investigate whether macrophages or other innate immune cells respond to sars-cov-2 infection, and how their numbers or function may change with aging. among the adaptive immune cell populations, we observed that th1 cells and cd4 + tcm cells trended in opposite directions with aging (figure 3d) . while the lungs of younger donors were enriched for th1 cells, they were comparatively depleted for cd4 + tcm cells; the inverse was true in the lungs of older donors. of note, mouse models of sars-cov infection have indicated important roles for cd4 + t cell responses in viral clearance 59, 60 . additionally, th1 cells are responsive to sars-cov vaccines 61 and promote macrophage activation against viruses 62 . it is therefore possible that age-associated shifts in cd4 + t cell subtypes within the lung may influence the subsequent host immune response in response to coronavirus infection. however, future studies will be needed to determine the role of th1 cells and other adaptive immune cells in the response to sars-cov-2, and how these dynamics may change with aging. we next explored the roles of lung age-associated genes in host responses to viral infection. since functional screening data with sars-cov-2 has not yet been described (as of march 30, 2020), we instead searched for data on sars-cov. while these two viruses belong to the same genus (betacoronaviridae) and are conserved to some extent 8 , they are nevertheless two distinct viruses with different epidemiological features, indicating unique virology and host biology. therefore, data from experiments performed with sars-cov must be interpreted with caution. we reassessed the results from a prior in vitro sirna screen of host factors involved in sars-cov infection 63 . in this kinase-focused screen, 130 factors were determined to have a significant effect on sars-cov replication. notably, 11 of the 130 factors exhibited age-associated gene expression patterns (figure 4a) , with 4 genes in cluster 1 (increasing with age) and 7 genes in cluster 2 (decreasing with age). the 4 genes in cluster 1 were all associated with increased sars infectivity upon sirna knockdown; these genes included clk1, akap6, alpk2, and itk. paradoxically, while knockdown of clk1 was associated with increased sars infectivity, cell viability was also found to be increased (figure 4b) . of the 7 genes in cluster 2, 6 were associated with increased sars infectivity and reduced cell viability upon sirna knockdown (aurkb, cdkl2, pdik1l, cdkn3, mst1r, and adk). age-related downregulation of these 6 factors could be related to the increased severity of illness in older patients. however, we emphasize that until rigorous follow-up experiments are performed with sars-cov-2, the therapeutic potential of targeting these factors in patients with covid-19 is unknown. using the human lung scrna-seq data, we then determined which cell types predominantly express these host factors. of the 4 genes in cluster 1 that had a significant impact on sars-cov replication, clk1 was universally expressed, while alpk2 expression was rarely detected (figure 4c, supplementary figure 5a) . itk was preferentially expressed in lymphocytic populations, and akap6 was most frequently expressed in ciliated cells and muscle cells. of the 7 overlapping genes in cluster 2, aurkb and cdkn3 were predominantly expressed in proliferating immune cell populations, such as macrophages, dcs/monocytes, t cells, and nk cells (figure 4d, supplementary figure 5b) . mst1r, pdik1l, and pskh1 were infrequently expressed, through their expression was detected in a portion of at2 cells (5.54%, 5.30%, and 5.47%, respectively). finally, adk and cdkl2 exhibited preferential enrichment in at2 cells (51.40% and 34.43%). in aggregate, these analyses showed that the age-associated genes with functional roles in sars-cov are expressed in specific cell types of the human lung. we then investigated whether age-associated genes in the human lung interact with proteins encoded by sars-cov-2. a recent study interrogated the human host factors that interact with 27 different sars-cov-2 proteins 64 , revealing the sars-cov-2 : human protein interactome in cell lines expressing recombinant sars-cov-2 proteins. by cross-referencing the interacting host factors with the set of age-associated genes, we identified 20 factors at the intersection ( figure 5a ). 4 of these genes showed an increase in expression with age (i.e. cluster 1 genes), while 16 decreased in expression with age (cluster 2 genes). mapping these factors to their interacting sars-cov-2 proteins, we noted that the age-associated host factors which interact with m, nsp13, nsp1, nsp7, nsp8, orf3a, orf8, orf9c, and orf10 proteins generally decrease in expression with aging (figure 5b) . however, a notable exception was nsp12, as the age-associated hostfactors that interact with nsp12 both showed increased expression with aging (crtc3 and mycbp2) (figure 5c ). nsp12 encodes for the primary rna-dependent rna polymerase (rdrp) of sars-cov-2, and is a prime target for developing therapies against covid-19. the observation that crtc3 and mycbp2 increase in expression with aging is intriguing, as these genes may be related to the activity of nsp12/rdrp in host cells. of note, mycbp2 is a known repressor of camp signaling 65, 66 , and camp signaling potently inhibits contraction of airway smooth muscle cells 67 . thus, age-associated increases in mycbp2 could promote smooth muscle contraction, which is concordant with our analyses on age-associated gene signatures in the lung (figure 1e) . mycbp2 might possibly contribute to covid-19 pathology by not only interacting with sars-cov-2 rdrp, but also through its normal physiologic role in promoting smooth muscle contraction. to assess the cell type-specific expression patterns of these various factors, we further analyzed the lung scrna-seq data. of the sars-cov-2 interacting genes that increase in expression with age, mycbp2 was frequently expressed across several populations, particularly proliferating immune populations (dc/monocyte, t cells, macrophages), muscle cells, fibroblasts, and lymph vessels (figure 5d) . mycbp2 was also expressed in 21.86% of at2 cells. cep68 was preferentially expressed in lymph vessels, while akap8l and crtc3 showed relatively uniform expression frequencies across cell types, including a fraction of at2 cells (8.53% and 9.07% expressing cells, respectively). of the sars-cov-2 interacting genes that decrease in expression age, npc2 and ndufb9 were broadly expressed in many cell types, including at2 cells (99.96% together, these analyses highlight specific age-associated factors that interact with the sars-cov-2 proteome, in the context of the lung cell types in which these factors are normally expressed. finally, we assessed whether sars-cov-2 infection directly alters the expression of lung ageassociated genes. a recent study profiled the in vitro transcriptional changes associated with sars-cov-2 infection in different human lung cell lines 68 . we specifically focused on the data from a549 lung cancer cells, a549 cells transduced with an ace2 expression vector (a549-ace2), and calu-3 lung cancer cells. several age-associated genes were found to be differentially expressed upon sars-cov-2 infection (figure 6a-c) . of note, the overlap between lung ageassociated genes and sars-cov-2 regulated genes was statistically significant across all 3 cell lines (figure 6d-f) , suggesting a degree of similarity between the transcriptional changes associated with aging and with sars-cov-2 infection. among the age-associated genes that were induced by sars-cov-2 infection, the majority of these genes increase in expression with age (cluster 1) (figure 6g-i) . conversely, among the age-associated genes that were repressed by sars-cov-2 infection, most of these genes decrease in expression with age (cluster 2). of note, the directionality of sars-cov-2 regulation (induced or repressed) and the directionality of ageassociation (increase or decrease with age) were significantly associated across all 3 cell lines (figure 6g-i) . to identify a consensus set of age-associated genes that are regulated by sars-cov-2 infection, we integrated the analyses from all 3 cell lines. 603 genes were consistently induced by sars-cov-2 infection (figure 7a ). of these, 20 genes are in cluster 1 (increase with age) and 2 genes are in cluster 2 (decrease with age). the 20 induced genes in cluster 1 include several factors involved in ras signaling (rab8b, rasa2, and rasgrp1) as well as clk1, which was shown to be involved in host responses to sars-cov infection (figure 4a-b) . on the other hand, 641 genes were concordantly repressed by sars-cov-2 infection (figure 7b here we systematically analyzed the transcriptome of the aging human lung and its relationship to sars-cov-2. we found that the aging lung is characterized by a wide array of changes that could contribute to the worse outcomes of older patients with covid-19. on the transcriptional level, we first identified 1,285 genes that exhibit age-associated expression patterns. we subsequently demonstrated that the aging lung is characterized by several gene signatures, including increased vascular smooth muscle contraction, reduced mitochondrial activity, and decreased lipid metabolism. by integrating these data with single cell transcriptomes of human lung tissue, we further pinpointed the specific cell types that normally express the age-associated genes. we showed that lung epithelial cells, macrophages, and th1 cells decrease in abundance with age, whereas fibroblasts and pericytes increase in abundance with age. these systematic changes in tissue composition and cell interactions can potentially propagate positive feedback loops that predispose the airways to pathological contraction 69 . we find that some of the age-associated genes have been previously identified as host factors with a functional role in sars-cov replication 63 , and a fraction of the age-associated factors have been shown to directly interact with the sars-cov-2 proteome 64 . furthermore, age-associated genes are significantly enriched among genes directly regulated by sars-cov-2 infection 68 , suggesting transcriptional parallels between the aging lung and sars-cov-2 infection. moreover, it is intriguing that the genes induced by sars-cov-2 infection tend to increase in expression with aging, and vice versa. whether any of these age-associated changes causally contribute to the heightened susceptibility of covid-19 in older populations remains to be experimentally tested. it is also important to note that the datasets analyzed here were not from patients with covid-19. given the limited data that is currently publicly available, we emphasize that the analyses presented here at this stage should not be used to guide clinical practice. these analyses resulted in a number of previously unnoted observations and phenomena that illuminate new directions for subsequent research efforts on sars-cov-2, generating genetically-tractable hypotheses for why advanced age is one of the strongest risk factors for covid-19 morbidity and mortality. ultimately, we hope such knowledge can help the field to sooner develop rational therapies for covid-19 that are rooted in concrete biological mechanisms. we thank akiko iwasaki, craig wilen, hongyu zhao, wei liu, wenxuan deng, andre levchenko, katie zhu, ruth montgomery, bram gerriten, steven kleinstein and a number of other colleagues for their critical comments and suggestions, which were incorporated into the analyses and manuscript. we thank antonio giraldez, andre levchenko, chris incarvito, mike crair, and scott strobel for their support on covid-19 research. we thank our colleagues in the chen lab, the genetics department, the systems biology institute and various yale entities. we also want to thank all of the healthcare workers who are risking their health on the frontlines to treat patients with this disease. rc and sc conceived and designed the study. rc developed the analysis approach, performed all data analyses, and created the figures. rc and sc prepared the manuscript. sc supervised the work. no competing interests related to this study. the authors have no competing interests as defined by nature research, or other interests that might be perceived to influence the interpretation of the article. the authors are committed to freely share all covid-19 related data, knowledge and resources to the community to facilitate the development of new treatment or prevention approaches against sars-cov-2 / covid-19 as soon as possible. as a note for full disclosure, sc is a co-founder, funding recipient and scientific advisor of evolveimmune therapeutics, which is not related to this study. c. david gene ontology and pathway analysis of cluster 1 age-associated genes that exhibit enriched expression in muscle cells. d. david gene ontology and pathway analysis of cluster 2 age-associated genes that exhibit enriched expression in alveolar type 2 (at2) cells. a. venn diagram of the intersection between age-associated genes in human lung and the sars-cov-2 : human protein interactome (gordon et al., 2020) . of the 20 age-associated genes that were found to also interact with sars-cov-2, 4 of them increased in expression with age, while 16 decreased with age. b. age-associated genes in human lung and their interaction with sars-cov-2 proteins, where each block contains a sars-cov-2 protein (underlined) and its interacting age-associated factors. blocks are colored by the dominant directionality of the age association (orange, decreasing with age; blue, increasing with age). gene targets with already approved drugs, investigational new drugs, or preclinical molecules are additionally denoted with an asterisk. the genotype-tissue expression (gtex) project was supported by the common fund of the office of the director of the national institutes of health, and by nci, nhgri, nhlbi, nida, nimh, and ninds 10, 11 . rna-seq raw counts and normalized tpm matrices were downloaded from the gtex portal (https://gtexportal.org/home/index.html) on march 18, 2020, release v8. all accessed data used in this study are publicly available on the web portal and have been deidentified, except for patient age range and gender. case-fatality rates in china and italy were from the chinese cdc and italian iss, for visualization of rna-seq expression data, the tpm values were log2 transformed and plotted in r (v3.6.1). all boxplots are tukey boxplots, with interquartile range (iqr) boxes and 1.5 ã� iqr whiskers. pairwise statistical comparisons in the plots were assessed by two-tailed mann-whitney test, while statistical comparisons across all age groups were performed by kruskal-wallis test. to identify age-associated genes, the raw counts values were analyzed by deseq2 (v1.24.0) 22 , using the likelihood ratio test (lrt). age-associated genes were determined at a significance threshold of adjusted p < 0.0001. genes passing the significance threshold were then scaled to z-scores and clustered using the degpatterns function from the r package degreport (v1.20.0). gene clusters with progressive and consistent trends with age were retained for downstream analysis. gene ontology and pathway enrichment analysis was performed using david (v6.8) 70 (https://david.ncifcrf.gov/), separating the age-associated genes into the two clusters (increasing or decreasing with age), as described above. scrna-seq data were analyzed in r (v3.6.1) using seurat 71,72 and custom scripts. of the 1285 age-associated genes identified from gtex bulk transcriptomes, 1049 genes were matched in the tissue stability cell atlas dataset and 1021 genes were matched in the human lung cell atlas dataset. to determine the percentage of cells expressing a given gene, the expression matrices were converted to binary matrices by setting a threshold of expression > 0. cell typespecific expression frequencies for each gene were then calculated using the provided cell type annotations. to identify genes preferentially expressed in a specific cell type, we further scaled the expression frequencies in r to obtain z-scores. data were visualized in r using the nmf package 73 . where applicable, gene ontology analysis was performed with david (v6.8) 70 , using genes with z-score > 2 in the cell type of interest for analysis. to infer the cellular composition of each lung sample, we analyzed the tpm expression matrices using the xcell algorithm 45 . the resultant cell type enrichment tables were analyzed in r. for data visualization, cell type enrichment scores were scaled to z-scores, and the median zscore for each age group was expressed as a heatmap, using the superheat package 74 . ageassociation was assessed across all age groups by kruskal-wallis test. to assess whether any age-associated genes affect host responses to sars-cov (a coronavirus related to sars-cov-2), we analyzed the data from a published sirna screen of host factors influencing sars-cov 63 (data set s1 in the publication; accessed on march 20, 2020). for data visualization, each point corresponding to a target gene was size-scaled and color-coded according to the age-association statistical analyses described above. to assess whether any lung age-associated genes encode proteins that interact with the sars-cov-2 proteome, we compiled the data from a preprint manuscript detailing the human host factors that interact with 27 different proteins in the sars-cov-2 proteome 64 (accessed on march 23, 2020). to assess whether the expression of lung age-associated genes is influenced by sars-cov-2 infection, we utilized the data from a preprint manuscript detailing the transcriptional response to sars-cov-2 infection 68 , from the gene expression omnibus (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=gse147507) (accessed on april 13, 2020). differentially expressed genes were determined using the wald test in deseq2 (v1.24.0) 22 comparing sars-cov-2 infected cells to batch-matched mock controls, with a significance threshold of adjusted p < 0.05. of the 1285 age-associated genes, 988 genes were matched to the rna-seq dataset. statistical significance of overlaps between the gene sets was assessed by hypergeometric test, assuming 21,797 total genes as annotated in the rna-seq dataset and 988 age-associated genes. statistical significance of the association between the directionality of sars-cov-2 regulation and the directionality of age-association was assessed by two-tailed fischer's exact test. gene ontology and pathway enrichment analysis was performed using david (v6.8) 70 (https://david.ncifcrf.gov/). comprehensive information on the statistical analyses used are included in various places, including the figures, figure legends and results, where the methods, significance, p-values and/or tails are described. all error bars have been defined in the figure legends or methods. codes used for data analysis or generation of the figures related to this study are available upon request to the corresponding author and will be deposited to github upon publication for free public access. all relevant processed data generated during this study are included in this article and its supplementary information files. raw data are from various sources as described above. all data and resources related to this study are freely available upon request to the corresponding author. tables table s1 : demographics of donors for gtex lung samples. (gordon et al., 2020) with age-association statistics from this study. table s22 : differential expression analysis in a549 cells, infected with sars-cov-2 vs mock control, with age-association annotations. table s23 : differential expression analysis in a549-ace2 cells, infected with sars-cov-2 vs mock control, with age-association annotations. table s24 : differential expression analysis in calu-3 cells, infected with sars-cov-2 vs mock control, with age-association annotations. cdkn1b gna13 rab8b n4bp3 rasgrp1 camsap2 mxi1 gem c1s rbm33 rasa2 brwd1 phc3 gatad2b pnrc1 arid4b atrx clk1 pnisr prtg h1f0 nckipsd cnn3 ptov1 cfd rhoc polr2f gnai2 tk1 tm4sf4 pskh1 ap1m2 msh2 atp6v0e2 pgam5 mvk aacs acaca acss2 nipsnap1 nsdhl aifm1 agr2 gipc1 mmab hadh qdpr ap1s1 ndufa7 poldip2 ahcy mrps28 samm50 prpf19 nup93 gba cln3 apeh atic arpc1b ppp1ca aprt atp6v0d1 akr1a1 phb c1qbp parp1 cbr1 acat1 pdhb ndufa9 mrpl27 prdx3 mtch2 ormdl2 ndufs3 a t p 1 b 1 a l g 5 n e u 1 p r i m 1 c e n p f h o o k 1 g c c 1 p i g o n a r s 2 a a r 2 a t p 6 v 1 a n d u f a f 1 a g p s n p c 2 p p t 1 n d u f b 9 -log 10 (adj. p-value) gem c1s gna13 rab8b brwd1 cnot6l cdkn1b camsap2 mxi1 rasa2 rbm33 gatad2b phc3 clk1 arid4b atrx pnisr pnrc1 prtg h1f0 nckipsd cnn3 gnai2 rhoc cfd ptov1 polr2f ap1m2 agr2 tk1 tm4sf4 gba pgam5 pskh1 acss2 acaca aacs mvk msh2 atp6v0e2 nup93 nipsnap1 nsdhl aifm1 acat1 cbr1 gipc1 mmab hadh mrps28 ap1s1 poldip2 qdpr ahcy atic apeh cln3 prpf19 samm50 arpc1b ppp1ca aprt parp1 pdhb mtch2 ndufa9 mrpl27 asna1 ndufs3 c1qbp ndufa7 phb ormdl2 atp6v0d1 akr1a1 prdx3 estimating clinical severity of covid-19 from the transmission dynamics in wuhan, china adjusted age-specific case fatality ratio during the covid-19 epidemic in hubei, china case-fatality rate and characteristics of patients dying in relation to covid-19 in italy coronavirus disease 2019 (covid-19) in italy severe outcomes among patients with coronavirus disease 2019 (covid-19) -united states a novel coronavirus from patients with pneumonia in china genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding a pneumonia outbreak associated with a new coronavirus of probable bat origin epidemiological characteristics of 2143 pediatric patients with coronavirus disease in china the genotype-tissue expression (gtex) project a novel approach to high-quality postmortem tissue procurement: the gtex project cryo-em structure of the 2019-ncov spike in the prefusion conformation receptor recognition by the novel coronavirus from wuhan: an analysis based on decade-long structural studies of sars coronavirus sars-cov-2 cell entry depends on ace2 and tmprss2 and is blocked by a clinically proven protease inhibitor structure, function, and antigenicity of the sars-cov-2 spike glycoprotein covid-19 and italy: what next? the lancet 0 risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease the epidemiological characteristics of an outbreak of 2019 novel coronavirus diseases (covid-19) -china scrna-seq assessment of the human lung, spleen, and esophagus tissue stability after cold preservation single-cell rna expression profiling of ace2, the putative receptor of wuhan single cell rna sequencing of 13 human tissues identify cell types and receptors of human coronaviruses moderated estimation of fold change and dispersion for rna-seq data with deseq2 effect of aging on respiratory system physiology and immunology alterations in platelet functions during aging: clinical correlations with thrombo-inflammatory disease in older adults a crucial role of angiotensin converting enzyme 2 (ace2) in sars coronavirus-induced lung injury angiotensin-converting enzyme 2 protects from severe acute lung failure identification of a novel coronavirus in patients with severe acute respiratory syndrome a novel angiotensin-converting enzyme-related carboxypeptidase (ace2) converts angiotensin i to angiotensin 1-9 a human homolog of angiotensin-converting enzyme cloning and functional expression as a captopril-insensitive angiotensin-converting enzyme 2 is an essential regulator of heart function clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in wuhan, china baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region the mitochondrial basis of aging and age-related disorders the mitochondrial basis of aging mitochondrial dysfunction in the elderly: possible role in insulin resistance lipid rafts are involved in sars-cov entry into vero e6 cells sars coronavirus entry into host cells through a novel clathrin-and caveolaeindependent endocytic pathway lipid rafts play an important role in the early stage of severe acute respiratory syndrome-coronavirus life cycle lipid rafts: heterogeneity on the high seas sars coronavirus, but not human coronavirus nl63, utilizes cathepsin l to infect ace2-expressing cells inhibitors of cathepsin l prevent severe acute respiratory syndrome coronavirus entry a molecular cell atlas of the human lung from single cell rna sequencing molecular pathology of emerging coronavirus infections clinical progression and viral load in a community outbreak of coronavirus-associated sars pneumonia: a prospective study xcell: digitally portraying the tissue cellular heterogeneity landscape regeneration of the aging lung: a mini-review the aging lung pulmonary macrophages: key players in the innate defence of the airways the clinical pathology of severe acute respiratory syndrome (sars): a report from evolution of pulmonary pathology in severe acute respiratory syndrome regulating the adaptive immune response to respiratory virus infection regulation of immunological homeostasis in the respiratory tract alveolar macrophages in the resolution of inflammation, tissue repair, and tolerance to infection antibody-dependent infection of human macrophages by severe acute respiratory syndrome coronavirus cytokine responses in severe acute respiratory syndrome coronavirus-infected macrophages in vitro: possible relevance to pathogenesis alveolar macrophage elimination in vivo is associated with an increase in pulmonary immune response in mice evasion by stealth: inefficient immune activation underlies poor t cell response and severe disease in sars-cov macrophage plasticity, polarization, and function in health and disease t cell responses are required for protection from clinical disease and for virus clearance in severe acute respiratory syndrome coronavirus-infected mice cellular immune responses to severe acute respiratory syndrome coronavirus (sars-cov) infection in senescent balb/c mice: cd4+ t cells are important in control of sars-cov infection induction of th1 type response by dna vaccinations with n, m, and e genes against sars-cov in mice expanding roles for cd4+ t cells in immunity to viruses a kinome-wide small interfering rna screen identifies proviral and antiviral host factors in severe acute respiratory syndrome coronavirus replication, including double-stranded rna-activated protein kinase and early secretory pathway proteins a sars-cov-2-human protein-protein interaction map reveals drug targets and potential drug-repurposing protein associated with myc (pam) is a potent inhibitor of adenylyl cyclases pam mediates sustained inhibition of camp signaling by sphingosine-1-phosphate camp regulation of airway smooth muscle function sars-cov-2 launches a unique transcriptional signature from in vitro, ex vivo, and in vivo systems a microphysiological model of the bronchial airways reveals the interplay of mechanical and biochemical signals in bronchospasm systematic and integrative analysis of large gene lists using david bioinformatics resources integrating single-cell transcriptomic data across different conditions, technologies, and species comprehensive integration of single-cell data a flexible r package for nonnegative matrix factorization superheat: an r package for creating beautiful and extendable heatmaps for visualizing complex data key: cord-274546-jswt3pun authors: griette, q.; magal, p.; seydi, o. title: unreported cases for age dependent covid-19 outbreak in japan date: 2020-05-12 journal: nan doi: 10.1101/2020.05.07.20093807 sha: doc_id: 274546 cord_uid: jswt3pun we investigate the age structured data for the covid-19 outbreak in japan. we consider epidemic mathematical model with unreported infectious patient with and without age structure. in particular, we build a new mathematical model which allows to take into account differences in the response of patients to the disease according to their age. this model also allows for a heterogeneous response of the population to the social distancing measures taken by the local government. we fit this model to the observed data and obtain a snapshot of the effective transmissions occurring inside the population at different times, which indicates where and among whom the disease propagates after the start of the public measures. covid-19 disease caused by the corona virus sars-cov-2 first appeared in wuhan, china on december 31, 2019. beginning in wuhan as an epidemic, it then spreads very quickly around the world to become a global pandemic within a month. symptoms of this disease include fever, shortness of breath, cough, and a non-negligible proportion of infected individuals may develop severe forms of the symptoms leading to their transfer to intensive care units and, in some cases, death. however it is also worth noting that symptomatic and asymptomatic individuals are both infectious [19, 23, 26] making challenging the control of the disease. the virus is characterized by its rapid progression among individuals, most often exponential in the first phase, but also a marked heterogeneity in populations and geographic areas. the number of reported cases worldwide exceeded 3 millions as of may 3, 2020 [28] . the heterogeneity of the number of cases and the severity according to the age groups, especially for children and elderly people, aroused the interest of several researchers [3, 17, 14, 20, 21] . indeed, several studies have shown that the severity of the disease increases with the age and co-morbidity of hospitalized patients [21, 25] . let us mention that wu et al. [24] have shown that the risk of developing symptoms increases by 4% by age in adults aged between 30 and 60 years old while davies et al. [4] found that there is a strong correlation between chronological age and the likelihood of developing symptoms. however let us mention that a higher probability of developing symptoms does not necessarily imply greater infectiousness as completely asymptomatic individuals can also be contagious. in fact in [26] it has been found that the viral load in the asymptomatic patient was similar to that in the symptomatic patients. moreover while adults are more likely to develop symptoms, it has been shown in [7] that the viral loads in infected children do not differ significantly from those of adults. these findings suggest that a study of the dynamics of inter-generational spread is fundamental to better understand the spread of the corona virus and most importantly to efficiently fight the covid-19 pandemic. to this end the distribution of contacts between age groups in society (home, workplace, school ...) is an important factor to take into account when modeling the spread of the epidemic. to account for these facts, some mathematical models have been developed in [1, 2, 4, 17, 20] . in [1] the authors studied the dependence of the covid-19 epidemic on the demographic structures in several countries but did not focus on the contacts distribution of the populations. in [2, 4, 17, 20] a focus on the social contact patterns with respect to the chronological age has been made by using the contact matrices provided in [16] . while [1, 4] used the example of japan in their study, their approach is significantly different from ours. in this article we focus on an epidemic model with unreported infectious symptomatic patients (i.e. with mild or no symptoms). our goal is to investigate the age structured data of the covid-19 outbreak in japan. in section 2 we present the age structured data and the mathematical models (with and without age structure). one of the difficulties in fitting the model to the data is that the growth rate of the epidemic is different in each age class, which lead us to adapt our early method presented in [9] . the new method is presented in the appendix a. in section 3 we present the comparison of the model with the data. in the last section we discuss our results. patient data in japan have been made public since the early stages of the epidemic with the quarantine of the diamond princess in the haven of yokohama. we used data from [29] which is based on reports from national and regional authorities. patients are labeled "confirmed" when tested positive to covid-19 by pcr. interestingly, the age class of the patient is provided for 13 660 out of 13970 confirmed patients (97.8% of the confirmed population) as of april 29. the age distribution of the infected population is represented in figure 1 and compared to the total population per age class (data from the statistics bureau of japan estimate for october 1, 2019). both datasets are given in table 1 and a statistical summary is provided by table 2 . note that the high proportion of 20-60 years old confirmed patients may indicate that the severity of the disease is lower for those age classes than for older patients, and therefore the disease transmits more easily in those age classes because of a higher number of asymptomatic individuals. elderly infected individuals might transmit less because they are identified more easily. the cumulative number of death ( figure 4 ) is another argument in favor of this explanation. we also reconstructed the time evolution of the reported cases in figure 2 and figure 3 . note that the steepest curves precisely concern the 20-60-years old, probably because they are economically active and therefore have a high contact rate with the population. figure 1 : in this figure we plot in blue the age distribution of the japanese population for 10 000 people and we plot in orange the age distribution of the number of reported cases of sars-cov-2 for 13660 patients on april 29. we observe that 77% of the confirmed patients belong to the 20-60 years age class. 2 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. figure 4 : cumulated number of sars-cov-2-induced deaths per age class. we observe that 83% of death occur in between 70 and 100 years old. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. the model consists of the following system of ordinary differential equations: (2.1) this system is supplemented by initial data here t ≥ t 0 is time in days, t 0 is the starting date of the epidemic in the model, s(t) is the number of individuals susceptible to infection at time t, i(t) is the number of asymptomatic infectious individuals at time t, r(t) is the number of reported symptomatic infectious individuals at time t, and u (t) is the number of unreported symptomatic infectious individuals at time t. asymptomatic infectious individuals i(t) are infectious for an average period of 1/ν days. reported symptomatic individuals r(t) are infectious for an average period of 1/η days, as are unreported symptomatic individuals u (t). we assume that reported symptomatic infectious individuals r(t) are reported and isolated immediately, and cause no further infections. the asymptomatic individuals i(t) can also be viewed as having a low-level symptomatic state. all infections are acquired from either i(t) or u (t) individuals. our study begins in the second phase of the epidemics, i.e. after the pathogen has succeeded in surviving in the population. during this second phase τ (t) ≡ τ 0 is constant. when strong government measures such as isolation, quarantine, and public closings are implemented, the third phase begins. the actual effects of these measures are complex, and we use a time-dependent decreasing transmission rate τ (t) to incorporate these effects. the formula for τ (t) during the third phase is the date d is the first day of public intervention and µ characterises the intensity of the public intervention. a similar model has been used by [6, 9, 10, 11, 12, 13] to describe the epidemics in mainland china, south korea, italy, and other countries, and predict the future evolution of the epidemic based on actual data. interpretation method t 0 time at which the epidemic started fitted s 0 number of susceptible at time t 0 fixed i 0 number of asymptomatic infectious at time t 0 fitted u 0 number of unreported symptomatic infectious at time t 0 fitted τ (t) transmission rate at time t fitted n first day of public intervention fitted µ intensity of the public intervention fitted 1/ν average time during which asymptomatic infectious are asymptomatic fixed f fraction of asymptomatic infectious that become reported symptomatic infectious fixed ν 1 = f ν rate at which asymptomatic infectious become reported symptomatic fixed rate at which asymptomatic infectious become unreported symptomatic fixed 1/η average time symptomatic infectious have symptoms fixed table 3 : parameters of the model. at the early stages of the epidemic, the infectious components of the model i(t), u (t) and r(t) must be exponentially growing. therefore, we can assume that the cumulative number of reported symptomatic infectious cases at time t, denoted by cr(t), is since i(t) is an exponential function and cr(t 0 ) = 0 it is natural to assume that cr(t) has the following special form: as in our early articles [9, 10, 11, 12, 13] , we fix χ 3 = 1 and we evaluate the parameters χ 1 and χ 2 by using an exponential fit to we use only early data for this part, from day t = d 1 until day t = d 2 , because we want to catch the exponential growth of the early epidemic and avoid the influence of saturation arising at later stages. the estimated parameters χ 1 and χ 2 will vary if we change the interval [d 1 , d 2 ]. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093807 doi: medrxiv preprint once χ 1 , χ 2 , χ 3 are known, we can compute the starting time of the epidemic t 0 from (2.5) as : we fix s 0 = 126.8 × 10 6 , which corresponds to the total population of japan. we fix the fraction f of symptomatic infectious cases that are reported. we assume that between 80% and 100% of infectious cases are reported. thus, f varies between 0.8 and 1. we assume that the average time during which the patients are asymptomatic infectious 1/ν varies between 1 day and 7 days. we assume that the average time during which a patient is symptomatic infectious 1/η varies between 1 day and 7 days. in other words we fix the parameters f , ν, η. since f and ν are known, we can compute computing further (see below for more details), we should have (2.10) by using the approach described in [5, 22] the basic reproductive number for model (2.1) is given by by using (2.8) we obtain (2.11) in what follows we will denote n 1 , . . . , n 10 the number of individuals respectively for the age classes (2.12) the model for the number of asymptomatic infectious individuals i 1 (t), . . . , i 10 (t), respectively for the age classes [0, 10[, . . . , [90, 100[, is the following . . . (2.13) the model for the number of reported symptomatic infectious individuals r 1 (t), . . . , r 10 (t), respectively for the age classes [0, 10[, . . . , [90, 100[, is (2.14) 6 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. in their survey [16] , prem and co-authors present a way to reconstruct contact matrices from existing data and provide such contact matrices for a number of countries including japan. based on the data provided by prem et al. [16] for japan we construct the contact probability matrix φ. more precisely, we inferred contact data for the missing age classes [80, 90[ and [90, 100 [. the precise method used to construct the contact matrix γ is detailed in appendix b. the precise contact matrix γ we used is the following 17) where the i th line of the matrix γ ij is the average number of contact made by an individuals in the age class i with an individual in the age class j during one day. notice that the higher number of contacts are achieved within the same age class. the matrix of conditional probability φ of contact between age classes is the following . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. figure 6 : cumulative number of cases. we plot the cumulative data (reds dots) and the best fits of the model cr(t) (black curve) and cu (t) (green curve). we fix f = 0.8, 1/η = 7 days and 1/ν = 7 and we apply the method described in [13] . the best fit is d 1 = april 2, d 2 = april 5, n = april 27, µ = 0.6, χ 1 = 179, χ 2 = 0.085, χ 3 = 1 and t 0 = january 13. figure 7 : daily number of cases. we plot the daily data (black dots) with dr(t) (blue curve). we fix f = 0.8, 1/η = 7 days and 1/ν = 7 and we apply the method described in [13] . the best fit is d 1 = april 2, d 2 = april 5, n = april 27, µ = 0.6, χ 1 = 179, χ 2 = 0.085, χ 3 = 1 and t 0 = january 13. the daily number of reported cases from the model can be obtained by computing the solution of the following equation: the model to compute the cumulative number of death from the reported individuals is the following where η d is the death rate of reported infectious symptomatic individuals and p is the case fatality rate (namely the fraction of death per reported infectious individuals). in the simulation we chose 1/η d = 6 days and the case fatality rate p = 0.286 is computed by using the cumulative number of confirmed cases and the cumulative number of deaths (as of april 29) as follows p = cumulated number of deaths cumulated number of reported cases = 393 13744 . 8 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. in order to describe the confinement for the age structured model (2.12)-(2.15) we will use for each age class i = 1, . . . , 10 a different transmission rate having the following form the date d i is the first day of public intervention for the age class i and µ i is the intensity of the public intervention for each age class. in figure 9 we combine the method described in the appendix a to estimate the parameters τ i from the data. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. in order to understand the role of transmission network between age groups in this epidemic, we plot in figure 10 the transmission matrices computed at different times. the transmission matrix is the following where the matrix φ describes contacts and is given in (2.18) , and the transmission rates are the ones fitted to the data as in figure 9 τ during the early stages of the epidemic, the transmission seems to be evenly distributed among age classes, with a little bias towards younger age classes (figure 10 (a) ). younger age classes seem to react more quickly to social distancing policies than older classes, therefore their transmission rate drops rapidly (figure 10 (b) and (c)); one month after the start of social distancing measures, the transmission mostly occurs within elderly classes (60-100 years, figure 10 (d) ). the recent covid-19 pandemic has lead many local governments to enforce drastic control measures in an effort to stop its progression. those control measures were often taken in a state of emergency and without any real visibility concerning the later development of the epidemics, to prevent the collapse of the health systems under the pressure of severe cases. mathematical models can precisely help see more clearly what could be the future of the pandemic provided that the particularities of the pathogen under 10 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . consideration are correctly identified. in the case of covid-19, one of the features of the pathogen which makes it particularly dangerous is the existence of a high contingent of unidentified infectious individuals who spread the disease without notice. this makes non-intensive containment strategies such as quarantine and contact-tracing relatively inefficient but also renders predictions by mathematical models particularly challenging. early attempts to reconstruct the epidemics by using siur models were performed in [6, 9, 10, 11, 12] , who used them to fit the behavior of the epidemics in many countries, by including undetected cases into the mathematical model. here we extend our modeling effort by adding the time series of deaths into the equation. in section 3 we present an additional fit of the number of disease-induced deaths coming from symptomatic (reported) individuals (see figure 8 ). in order to fit properly the data, we were forced to reduce the length of stay in the r-compartment to 6 days (on average), meaning that death induced by the disease should occur on average faster than recovery. the major improvement in this article is to combine our early siur model with chronological age. early results using age structured sir models were obtained by kucharski et al. [8] but no unreported individuals were considered and no comparison with chronological data were performed. indeed in this article we provide a new method to fit the data and the model. the method extends our previous method for the siur model without age (see appendix a). the data presented in section 2 suggests that the chronological age plays a very important role in the expression of the symptoms. the largest part of the reported patients are between 20 and 60 years old (see figure 1 ), while the largest part of the deceased are between 60 and 90 years old (see figure 4 ). this suggests that the symptoms associated with covid-19 infection are more severe in elderly patients, which has been reported in the literature several times [14, 25] . in particular, the probability of being asymptomatic (our parameter f ) should in fact depend on the age class. indeed, the best match for our model (see figure 9 ) was obtained under the assumption that the proportion of symptomatic individual among the infected increases with the age of the patient. moreover, our model reveals the fact that the policies used by the government to reduce contacts between individuals have strongly heterogeneous effects depending on the age classes. plotting the transmission matrix at different times (see figure 10 ) shows that younger age classes react more quickly and more efficiently than older classes. this may be due to the fact that the number of contacts in a typical day is higher among younger individuals. as a consequence, we predict that one month after the effective start of public measures, the new transmissions will almost exclusively occur in elderly classes. a appendix: method to fit of the age structured model to the data we first choose two days d 1 and d 2 between which each cumulative age group grows like an exponential. by fitting the cumulative age classes [0, 10[, [10, 20[, . . . and [90, 100 [ between d 1 and d 2 , for each age class j = 1, . . . 10 we can find χ j 1 and χ j we choose a starting time t 0 ≤ d 1 and we fix and we obtain where χ i j ≥ 0, ∀i = 1, . . . , n, ∀j = 1, 2, 3. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. figure 11 : we plot an exponential fit for each age classes using the data from japan. we assume that cr 1 (t) = ν 1 1 i 1 (t), . . . where by assuming that the number of susceptible individuals remains constant we have . . . and u n (t) = ν n 2 i n (t) − ηu n (t). (a.5) . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. if we assume that the u j (t) have the following form u j (t) = u j e χ j 2 t , (a. 6) then by substituting in (a.5) we obtain (a.7) we define the error between the data and the model as follows . . . let the matrix φ be fixed. we look for the vector τ = (τ 1 , . . . , τ n ) which minimizes of define for each j = 1, . . . , n k j (t) := χ j 2 + ν i j e χ j 2 t and h j (t) := s j φ j1 hence for each j = 1, . . . , n d2 d1 and by setting we deduce that 13 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. the copyright holder for this preprint this version posted may 12, 2020. . whenever φ is diagonal. therefore the optimum is reached for any diagonal matrix. moreover by using similar considerations, if several χ 2 j are equal, we can find a multiplicity of optima (possibly with φ not diagonal). this means that trying to optimize by using the matrix φ does not yield significant and reliable information. in the figure 12 below, we present an example of application of our method to fit the japanese data. we use the period going from march 20 to april 15. the survey [16] presents reconstructed contact matrices for a number of countries including japan for the 5-years age classes [0, 5), [5, 10) , ..., [75, 80) at various locations (work, school, home, and other locations) and a compilation of those contact matrices to account for all locations. the precise description of the compilation is presented in the paper. note that this paper is a follow-up of mossong et al. [15] where the survey procedure is described (including the data collection protocol) for several european countries participating in the polymod study. the data is publicly available online [32] and is presented in the formed of a zipped collection of spreadsheets, containing the data for several countries in columns x1 x2 ... x16. the columns stand for the average number of contact of one individual of the corresponding age class (0-5 years for x1, 5-10 years for x2, etc...), with an individual of the age class indicated by the row (first row is 0-5 years, second is 5-10 years etc...). since the age span covered by the study stops at 80, we had to infer the number of contacts for people over the age of 80. we postulated that most people aged 80 or more are retired and that their behaviour does not significantly differs (statistically speaking) from the behaviour 14 . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) of people in the age class [75, 80). therefore we completed the missing columns by copying the last available information and shifting it to the bottom. we repeated the procedure for lines. we believe that the introduced bias is kept to a minimum since the numerical values are relatively low compared to the diagonal. because we use 10-years ages classes and the data is given in 5-years age classes, we had to combine adjacent columns to recover the average number of contacts. to combine columns together, we used the following formula c i = n 2(i−1)+1 c 2(i−1)+1 + n 2(i−1)+2 c 2(i−1)+2 n 2(i−1)+1 + n 2(i−1)+2 , where the column c i corresponds to the average number of contacts of an individual taken at random in the [10(i − 1), 10i) and c i is the average number of contacts of an individual taken at random in the age class [5(i − 1), 5i). to combine two lines, we simply use the sum of the data l i = l 2(i−1)+1 + l 2(i−1)+2 . the matrix γ in (2.17) is the transpose of the array obtained by the former procedure applied to the "all locations" dataset. then φ is obtained by scaling the lines of γ to 1, i.e. . cc-by-nc-nd 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) the copyright holder for this preprint this version posted may 12, 2020. . https://doi.org/10.1101/2020.05.07.20093807 doi: medrxiv preprint age could be driving variable sars-cov-2 epidemic trajectories worldwide, medrxiv modeling strict age-targeted mitigation strategies for covid-19, arxiv sars-cov-2 infection in children: transmission dynamics and clinical characteristics age-dependent effects in the transmission and control of covid-19 epidemics on the definition and the computation of the basic reproduction ratio r 0 in models for infectious diseases in heterogeneous populations estimating the last day for covid-19 outbreak in mainland china an analysis of sars-cov-2 viral load by patient age, online preprint early dynamics of transmission and control of covid-19: a mathematical modelling study understanding unreported cases in the 2019-ncov epidemic outbreak in wuhan, china, and the importance of major public health interventions predicting the cumulative number of cases for the covid-19 epidemic in china from early data a covid-19 epidemic model with latency period a model to predict covid-19 epidemics with applications to south korea predicting the number of reported and unreported cases for the covid-19 epidemic in china sars-cov-2 infection in children social contacts and mixing patterns relevant to the spread of infectious diseases projecting social contact matrices in 152 countries using contact surveys and demographic data the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study effect of a one-month lockdown on the epidemic dynamics of covid-19 in france, medrxiv preprint transmission of 2019-ncov infection from an asymptomatic contact in germany age-structured impact of social distancing on the covid-19 epidemic in india temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov-2: an observational cohort study reproduction numbers and subthreshold endemic equilibria for compartmental models of disease transmission presymptomatic transmission of sars-cov-2-singapore estimating clinical severity of covid-19 from the transmission dynamics in wuhan, china clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study report of the who-china joint mission on coronavirus disease who coronavirus disease (covid-19) situation report number 104 acknowledgements: data from covid19japan.com. funding: q.g. and p.m. acknowledge the support of anr flash covid-19 mpcuii.keywords: corona virus, age-structured data, reported and unreported cases, isolation, quarantine, public closings; epidemic mathematical model key: cord-103337-a1yidr4y authors: aleta, a.; moreno, y. title: age differential analysis of covid-19 second wave in europe reveals highest incidence among young adults date: 2020-11-13 journal: nan doi: 10.1101/2020.11.11.20230177 sha: doc_id: 103337 cord_uid: a1yidr4y most of the western nations have been unable to suppress the covid-19 and are currently experiencing second or third surges of the pandemic. here, we analyze data of incidence by age groups in 25 european countries, revealing that the highest incidence of the current second wave is observed for the group comprising young adults (aged 18-29 years old) in all but 3 of the countries analyzed. we discuss the public health implications of our findings. europe is experiencing a second wave of the covid-19 pandemic, with incidence levels rising across all european countries. authorities have already begun to enforce non-pharmaceutical interventions (npis) to avoid the collapse of the healthcare system, which will likely induce further drops in the estimated 2020 gross domestic product due to additional slowdowns of the economy in many sectors. whether we are able to tailor our response to this second wave in such a way that npis minimize social impact and economical losses is key for the future of europe and its rapid recovery after the pandemic is brought under full control. this fundamentally depends on understanding better how the current surge of covid-19 is unfolding and affecting the different strata of the population, which will eventually make it possible to adapt public policy responses and implement targeted measures on the fly. to understand the evolution of the ongoing wave, one should trace it back to its origin in the summer, when the incidence started to grow again after the effects of the strict restrictions that were imposed in the spring faded out, which resulted in an increased number of local outbreaks and community transmission of covid-19 in most of europe. for instance, it has been reported that a variant of sars-cov-2 emerged in early summer 2020 in spain and spread to multiple european countries since then [1] . the source of the outbreak that spain experienced in the summer can be related to outbreaks that started among agricultural workers in the north-east of the country -particularly in aragon and catalonia. these outbreaks then moved to the local population and replicated through the rest of the country. an analysis of the incidence by age group in one of these regions -aragon, see figure 1 -shows that in early summer the disease spread mainly within the 15-24 and 25-34 age groups. however, coinciding with the end of the summer and the start of the academic year, the disease spread mostly in the 15-24 age group. to elucidate if this pattern is characteristic of this region or if it is more general, we have collected data on the covid19 incidence in 25 european countries aggregated by age groups during the period from 1 september to 27 october. figure 2 shows the fraction of new cases in a given age bracket relative to the population of that age group. the horizontal line represents the situation in which the disease propagates homogeneously through the different age strata. several features of the data are worth highlighting. first, in all countries but three (czechia, romania, and slovenia), the maximum ratio of accumulated incidence in the period analyzed corresponds to the age bracket of young adults -mainly between 18-29 years old. secondly, the incidence curves are not markedly peaked for the elderly as it happened in march-april during the first wave [2, 3] . third, the overall ratio of infected to population size of a given age group is below one for children in all countries. these very robust and regular patterns of the incidence of the current second wave are a remarkable observation given that countries in europe responded distinctly and at different times during the early stages of the pandemic. the fact that the age-differential incidence is common to most countries in europe points to common causes and similar transmission routes. noticeably, a similar pattern has also been observed in the united states [4] . a . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; figure 2 : total number of new cases since 1 september to 27 october in each age bracket, divided by the size of the group. in red, the age bracket with the largest deviation from 1. several hypotheses could be advanced as most likely explanations for the striking regularity in age differential patterns across european countries. the higher incidence in young adults could result from interventions such as reopening of universities and other educational centers across europe [5] . nonetheless, it could also be rooted in behavioral factors associated with this age group [6] , rather than from demographic or cultural causes specific to each european country or to differences in public interventions. these behavioral determinants could be the perception of low risk in this group and youngers' social mixing and lifestyle -this is arguably the age group with the largest mobility and contact heterogeneity. the latter hypothesis is also consistent with the observation that the high incidence in younger people does not propagate to other age groups. from a public health perspective, these data could prove fundamental to understand which factors impact the evolution of the current surge of covid-19 and to adapt our response to the present unfolding of the covid-19 pandemic. first, more efforts should be devoted to communicating with young adults to induce a change that reduces the incidence among them. reporting data of incidence by age group to the general public could help to raise scienceswitzerland . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; rooted awareness among the targeted age group. secondly and important for the current debate regarding the role of schools, children seem to be infected less often than what would be expected if the transmission of sars-cov-2 would be homogeneously distributed across age groups. this points to the success of policies aimed at protecting this group [7, 8] . we note that it is also possible that the observed pattern for the children is either because they could be less susceptible to be infected or that they might be less likely to be tested as they are mostly asymptomatic. data however seems to indicate that the main reason is the former rather than the latter. admittedly, if a large fraction of children were transmitting the disease, a surge in the age groups of their parents -those in close contact with them-should be expected, which is not a feature of the data in most countries. likewise, the results suggest that schools for under 16-18 years old could remain unsheltered given that the benefits of keeping them open seem to overcome the social cost of a closure [9, 10] . these results could help understand what are the main drivers of the second wave and to better design and adapt public health interventions during this stage of the pandemic. furthermore, the previous findings highlight the need for more research in relation to tracing and identification of transmission chains, which will disambiguate what are the sources of contagion by age-strata. we also urge authorities to make available as much epidemiological data by age, sex, and other traits as possible to enable analyses like the one discussed here. funding: aa and ym acknowledge partial support from intesa sanpaolo innovation center. ym acknowledges partial support from the government of aragon and feder funds, spain through grant e36-20r (fenol) and 17030/5423/440189/91019, and by mineco and feder funds (fis2017-87519-p). the funders had no role in study design, data collection, and analysis, decision to publish, or preparation of the manuscript. . cc-by-nc 4.0 international license it is made available under a is the author/funder, who has granted medrxiv a license to display the preprint in perpetuity. (which was not certified by peer review) preprint the copyright holder for this this version posted november 13, 2020. ; https://doi.org/10.1101/2020.11.11.20230177 doi: medrxiv preprint emergence and spread of a sars-cov-2 variant through europe in the summer of covid-19 cases and case fatality rate by age -knowledge for policy european commission the changing demographics of covid-19 recent increase in covid-19 cases reported among adults european commission/eacea/eurydice, 2020. the organisation of the academic year in europe -2020/21. eurydice facts and figures risk attitudes across the life course surveillance of covid-19 school outbreaks no evidence of secondary transmission of covid-19 from children attending school in ireland impact of school closures for covid-19 on the us healthcare workforce and net mortality: a modelling study covid-19, school closures, and child poverty: a social crisis in the making key: cord-291184-uza4orb8 authors: lyra, wladimir; do nascimento, jose dias; belkhiria, jaber; de almeida, leandro; chrispim, pedro paulo; de andrade, ion title: covid-19 pandemics modeling with seir(+caqh), social distancing, and age stratification. the effect of vertical confinement and release in brazil. date: 2020-04-14 journal: nan doi: 10.1101/2020.04.09.20060053 sha: doc_id: 291184 cord_uid: uza4orb8 the ongoing covid-19 epidemics poses a particular challenge to low and middle income countries, making some of them consider the strategy of vertical confinement. in this strategy, contact is reduced only to specific groups (like age groups) that are at increased risk of severe disease following sars-cov-2 infection. we aim to assess the feasibility of this scenario as an exit strategy for the current lockdown in terms of its ability to keep the number of cases under the health care system capacity. we developed a modified seir model, including confinement, asymptomatic transmission, quarantine and hospitalization. the population is subdivided into 9 age groups, resulting in a system of 72 coupled nonlinear differential equations. the rate of transmission is dynamic and derived from the observed delayed fatality rate; the parameters of the epidemics are derived with a markov chain monte carlo algorithm. we used brazil as an example of middle income country, but the results are easily generalizable to other countries considering a similar strategy. we find that starting from 60% horizontal confinement, an exit strategy on may 1st of confinement of individuals older than 60 years old and full release of the younger population results in 400 000 hospitalizations, 50 000 icu cases, and 120 000 deaths in the 50-60 years old age group alone. the health care system avoids collapse if the 50-60 years old are also confined, but our model assumes an idealized lockdown where the confined are perfectly insulated from contamination, so our numbers are a conservative lower bound. our results discourage confinement by age as an exit strategy. the severe acute respiratory syndrome coronavirus 2 (sars-cov-2) outbreak has been 2 ongoing for 5 months now [1] . since it was first reported in dec 2019 in china [2] , the 3 virus rapidly made its way to other parts of the world taking pandemic proportions [3] . influenza [13] , contributing to the understanding of the dynamics of disease and 23 providing useful predictions about the potential transmission of a disease and the 24 effectiveness of possible control measures, which can provide valuable information for 25 public health policy makers [14] . sir-type models, also known as kermack-mckendrick 26 model [15] , consists of a set of differential equations and has been applied to a variety of 27 infectious diseases. although considered as simple, sir models have been of great help 28 to stop epidemics in the past such as putting in place effective vaccination protocols [16] . 29 here we develop an sir type compartmental models for covid-19 including both 30 symptomatic and asymptomatic, quarantined, and hospitalized while taking into 31 consideration differences by age groups. we also analysed at the effect of confinement that is actually in confinement. however, it is estimated to be around is 56% according 46 to satellite data 1 , given socio-economic consequences of a lockdown, particularly on a middle income 48 country, decision makers are considering a vertical confinement as an exit strategy to 49 the regular lockdown. vertical confinement is understood as reducing contact to a 50 specific age group that is more at risk of contracting and developing sars-cov-2 [18] , 51 as opposed to horizontal (or general) confinement that does not discriminate between 52 age groups. throughout this manuscript, we will present the model which we validated 53 with data on other countries. we then applied the model to the specific sars-cov-2 54 scenario in brazil. we finally tested the effect of both general confinement and the causalities. the model 60 we used a modified version of an sir-type deterministic compartmental model to trace 61 covid-19 epidemic evolution in an isolated population of n individuals 2 . we assumed 62 that a population could be subdivided into the following compartments: we split that the population in subcategories by age (range, 0-10, 10-20, 20-30, 30-40, 75 40-50, 50-60, 60-70, 70-80, and 80+ years old) and that rates should vary with age [18] . 76 taking into consideration the 8 compartments and the 9 age groups, the model is the software is written in python 3.7, and is made public at https://github.com/wlyra/covid19 april 9, 2020 3/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . for each compartment x the age sub-bins add up to x = i x i and compartments 79 are such that s + c + e + a + i + q + h + r = n , with n = i n i being the total 80 population; n i is the population in each age bin. eqs. (1)-(8) describe a compartmentalization of the population and the flow between 82 the compartments. contact with infected individuals removes a fraction of the 83 susceptible (s) population at a rate given by λ, referred to as infection force, making 84 them exposed (e) to (sars-cov-2) . exposed (e) becomes infectious at the rate σ; a 85 fraction p of them becoming symptomatic (i) and (1 − p) asymptomatic (a). the the timescales corresponding to σ, γ, θ, ξ, and η are the incubation time t σ = σ −1 92 the infectious interval t γ = γ −1 , the remission time t θ = θ −1 , the time to hospitalization 93 t ξ = ξ −1 , and the average length of hospital stay t η = η −1 . the infection force is driven by the infected, both symptomatic (i) and where we use the shorthand notation and β is the infection rate, related to the reproduction number lock-down consists of having a fraction of the susceptible population removed from 99 the epidemic dynamic by moving them from s i to c i at a rate ψ i .similarly, lifting the 100 lock-down is done by placing c i into s i at the rate φ i . we consider these functions to 101 be dirac deltas 102 april 9, 2020 4/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint fatality rate as a function of median age. the fatality rate by age bins is taken from [18] and the population pyramids from un data. where t lock and t lift are the time (in days) of lock-down and of lifting of the lock-down, 103 respectively. to allow for partial demographic lock-downs (e.g., 80% lock-down of the 104 population are in complete lock-down ), a i and b i are allowed to vary by age (e.g., 80% 105 lock-down of the 40's age group population are in complete lock-down ). the flow chart 106 between compartments is shown in fig. 1 . other diagnostic quantities are the numbers u i of people in need of an intensive care 108 unit (icu) bed where ζ i is the fraction of hospitalized patients that need critical care. both ζ i and the 110 hospitalization fraction q i are age-stratified. for integration, we use a standard runge-kutta algorithm, with timesteps in this section we present details about the model validation and strategies to verify 114 characteristic timescales and other parameters. april 9, 2020 5/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. research on covid-19 [19] . the age-dependent parameters fatality rate µ i , fraction of 120 infectious that are hospitalized q i , and fraction of hospitalized that need critical care are 121 shown in table 2 . [18] . because all these timescales are much smaller than a human lifetime, aging of the 123 population is ignored and no upward flow between the age sub-compartments 124 (i → i + 1) is considered. population pyramids are taken from un data 3 , and split into 125 the pre-defined age bins. 126 we derive r(t) from the available statistics since knowledge on the real number of 127 infected is not clear. the most reliable indicator in this situation is the number of 128 deaths. given a fatality rate µ and an average time τ between exposure and death, the 129 number of dead at a time t + τ will equal the fatality rate times the number of people 130 that got exposed at time t. assuming that confinement dynamics do not play a role 131 (although it is trivial to include it), the equation is the following: taking the continuous limit and substituting eq. (1) where we also write t r = t + τ for the retarded time. summing over all age bins 134 d = i d i we have the cumulative death rate on the lhs, which is an observable and µs = i µ i s i . we can then substitute eq. (9) and solve for r(t) as a function of 136 time 137 since death occurs an average of τ days after infections, we setup the integration to 138 start τ days before the first reported covid-19 death, i.e., t = 0 means t r = τ . finally, 139 to start the integration we need to define the initial number of exposed individuals. this should be where t 0 is the time of the first death and µ = n −1 i µ i n i is the age-weighted fatality 142 rate. according to current knowledge of the epidemics, τ ≈ 14 days [18] . 143 we compared our model predictions with official data on cases and deaths for rate for a number of countries, which corresponds to the left hand side of eq. (18) . we 147 apply eq. (19) to convert this data into r(t), feeding this value into eq. (1)-eq. (8) to 148 start the seir evolution. the populations i(t) and s(t) that enter in eq. (19) are then 149 calculated to update r(t). the resulting values are plotted in the right-hand-side of the timescales σ, γ, θ, and ξ, as well as the fractions p and w, are found by markov 152 chain monte carlo (mcmc) fitting, with priors as given in table 1 fig. 4a shows the evolution of the compartments of exposed (e), asymptomatic (a), 166 symptomatic (i), and hospitalized (h), in linear scale. fig. 4b shows the same curve of 167 h but also the fraction of hospitalizations needing icu (u ), in log scale. the epidemic 168 is starting at march 1st and number of symptomatic is predicted to end at july 1st. to not overwhelm the health care system capacity (≈ 3 × 10 4 ) icu beds, the level of social distancing should be over 70%. brazil is managing 56%. april 9, 2020 9/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . fig. 6 . the other rows explore vertical confinement. in the second column 60% of 202 the population under 40 is confined, but the population older than 40 is confined to a 203 april 9, 2020 10/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . higher degree, at 90% (solid blue line) and 99% (dashed blue line). the cyan line marks 204 the same model as the upper plots, where 60% of the population is confined, irrespective 205 of age. the 3rd, 4th, and 5th row of plots show the same analysis but confining 60% up 206 50, 60, and 70 years old, respectively. as seen in the cyan line, the number of 207 hospitalized rises from 30-60 and falls for 70 onwards. that is because even though 70+ 208 are more likely to be hospitalized, the number of 30-60 is much higher in the population. 209 fig. 8 shows the same results for the fraction of hospitalized that needs icu. fig. 9 210 shows results from the same suite of models but for the number of fatalities. for the 211 number of icu cases, there is no significant difference past age 60, with only a minor 212 uptick at the 70-80 age range. collapse of health care system can be avoided if vertical 213 confinement is instored on people who are 60 or older, but at the expense of a significant 214 number of extra icu cases for the 50-60 age bin. at 60% confinement, hundred of 215 thousands of deaths are seen in the 60-70, 70-80, and 80+ age bins. the number lowers 216 to 50 000 in the 90% confinement. as noted before, vertical confinement for 60 years old 217 and older, leads to a significant number of deaths for the 50-60 age bin (over 50 000). vertical confinement at 50 years old leads to much lower death rate for this age segment. 219 finally, we look at vertical confinement as an exit strategy. in fig. 10 we model a our model estimate hundreds of thousands of infected people in brazil at april 1st. 247 this is more than the number of expected cases in the country while we write this 248 article, considering the estimated under notification of cases [20] and do nothing to 249 control the infection. it is possible that the actual number be less than that although it 250 is also important to notice brazil has not done a real lockdown so far. the model also ignores mobility, in the sense that it does consider travel to and from 252 the country. given that right now we are the stage of community tranmission, this limitation should not be of significance to the results. 254 conversely, and more importantly, the model assumes that the confined population 255 is completely safe from infection, whereas in reality a vertical lockdown may not be 256 feasible to implement as the elderly are not adequately distanced from the younger in 257 their family and/or social circle, and infection cannot be avoided if the younger is 258 exposed to finally, the analysis assumes that the data on fatalities is accurate. underreported 260 deaths should lead to an unknown source of error in the present study. also, the 261 mcmc produces error bars in the parameters that we did not take into account in the 262 forward modeling. is this study we examine the strategy of vertical confinement as currently debated in 265 brazil. since the fatality rate of covid-19 is disproportionate among the elderly, the 266 federal government has suggested confining only the at-risk age groups. such a strategy 267 would limit the economic impact of the pandemic while at the same time minimizing an exit strategy of vertical confinement of individuals older than 60 year old by may 279 1st would see a second wave disproportionally affect the 50-60 age bin. the icu cases 280 in this age range alone would bring the health care system to collapse and result in over 281 100 000 deaths. if vertical confinement is contemplated, it should be of the population 282 over 50 years old. however, this age range, 50-60, is also a part of the workforce, and 283 thus defeats the purpose of a vertical confinement. moreover, we emphasize that our 284 model assumes an idealized lockdown where the confined are perfectly insulated from 285 contamination, while in reality there would be several practical barriers to it as the 286 confined elderly would depend on the young for most essential activities, and a perfect 287 lockdown would not be achieved in a multi-generational household, especially in close 288 quarters such as found in the low and even middle income neighborhoods common in 289 brazil. our results therefore discourage vertical confinement as an exit strategy and 290 point toward enforcing a higher degree of horizontal confinement than currently 291 practiced. we urge brazilian authorities to take action to prevent virus dissemination in 292 the critical coming weeks. markov chain monte carlo. to fit the best value to w and p, and to better 295 constrain σ −1 , γ −1 , θ −1 , ξ −1 , we use the affine-invariant ensemble sampler for markov 296 chain monte carlo (mcmc) [21] to sample the parameter space around the solutions 297 and evaluation of the parameter uncertainties. for the priors input, we use the values 298 taken from the [18] . to search for the minimization of cumulative hospitalization h c , 299 we generated a cumulative error c err on the reported confirmed cases c c . 300 april 9, 2020 14/17 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20060053 doi: medrxiv preprint as the jhu-csse reports on the confirmed cases are given daily with some 301 fluctuations, we need to take this into account while weighing all solutions by adding a 302 1-day error matrix together with the confirmed cases (being conservative). in an ideal 303 scenario, the cumulative number of hospitalization would be the same as the number of 304 confirmed cases. in real life, not all confirmed cases are hospitalized so we do not expect 305 to fit the h c with c c . rather, we weigh the c c array with the h c array using: h c is the weighed cumulative hospitalizations and n is the length of the data. following we get the residual between c c and h c , and we used the negative binomial 308 distribution to calculate each likelihood [22] : (10 20 ) to discard as a bad fit. 312 we limit each parameter using a range cutoff in when feeding the probability 313 function to restrict parameter space. that way, we do not run models with unrealistic 314 physical parameters (such as e.g. symptomatic going to the hospital in −2 days), and 315 also constrain the known range for the other parameters. the mcmc function feeds on 316 6 free parameters, 4 fixed parameters and 2 predetermined arrays as presented in 317 . cc-by-nc-nd 4.0 international license it is made available under a author/funder, who has granted medrxiv a license to display the preprint in perpetuity. is the (which was not peer-reviewed) the copyright holder for this preprint . https://doi.org/10.1101/2020.04.09.20060053 doi: medrxiv preprint covid-19) situation report -75. world health organization characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72314 cases from the chinese center for disease control and prevention covid-19: towards controlling of a pandemic the ebola epidemic in west africa: challenges, opportunities, and policy priority areas the next epidemic -lessons from ebola major issues and challenges of influenza pandemic preparedness in developing countries. emerging infectious diseases covid-19 and italy: what next? the lancet covid-19) situation report -79. world health organization covid-19) situation report -72. world health organization mathematical modeling of the west africa ebola epidemic modeling the spatiotemporal transmission of ebola disease and optimal control: a regional approach a modified sir model to study on physical behaviour among smallpox infective population in bangladesh simulating sars: small-world epidemiological modeling and public health policy assessments a contribution to the mathematical theory of epidemics a simple vaccination model with multiple endemic states nacional do estabelecimentos de saúde impact of non-pharmaceutical interventions (npis) to reduce covid19 mortality and healthcare demand early dynamics of transmission and control of covid-19: a mathematical modelling study. the lancet infectious diseases substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov2) bayesian data analysis key: cord-254896-e6k1bp9n authors: posch, martin; bauer, peter; posch, alexander; könig, franz title: analysis of austrian covid-19 deaths by age and sex date: 2020-07-03 journal: wien klin wochenschr doi: 10.1007/s00508-020-01707-9 sha: doc_id: 254896 cord_uid: e6k1bp9n we analyze the age and sex distribution of the reported covid-19 deaths in austria. in accordance with international studies, the austrian data also suggests that the risk of death increases substantially with age. the observed age dependency of the proportions of registered covid-19 deaths in relation to the population sizes in the age groups is approximately exponential, similar to the age dependency of the general age specific mortality rate. furthermore, we compare the general age specific mortality rate in austria with the estimates of the sars-cov‑2 infection fatality rate by ferguson et al. (2020). the parallels to the general age specific mortality rates do not imply that covid-19 does not pose an additional risk. on the contrary, it follows from the structure and magnitude of the infection fatality rate that it is substantial, especially for higher age groups. however, since in many cases persons with severe pre-existing conditions are affected, it is not yet possible to estimate what effects covid-19 will have on life expectancy. on 31 march 2020 (of the total 128 deaths by that time) [1] . in addition, the current marginal age distribution and marginal gender distribution (but not the gender distribution per age group) of deaths is continuously published on the dashboard of the ministry of health [2] . for this analysis we used both the data set from march 31, as well as data from the dashboard including 439 deaths reported by 11:00 on 21 april 2020. in both data sets, the majority of the deceased are men (61% men by 31 march and 58% by 21 april). most of the deceased are over 60 and 55 years of age, respectively ( fig. 1a and b) . when comparing the graphs, the different age categories and total number of deaths should be taken into account. however, the absolute figures must be related to the size of the population in each age group. then they can be interpreted as current covid-19 mortality per 10,000 people in each age group in austria ( fig. 1c and d) accounting for all cases reported to the epidemiological reporting system by 31 march and 21 april, respectively. this illustration shows a clear age trend and the gender difference is even more pronounced (since women are in the majority in the upper age groups of the population). it should be noted that the graphs do not show the infection fatality rate, defined as the proportion of fatalities among infected persons, but the proportion of registered covid-19 deaths in relation to the general population. the age dependency of mortality rates is not unusual. also, the normal mortality risk depends strongly on age. the mortality tables show for each age and sex the number of people who die in the next year of life (fig. 2a , red and blue lines) per 10,000 people in that age and sex group. the risk of mortality is high at birth, but then drops below 0.01% by age 7. after that, it increases again, especially among the more risk-taking young men. the risk of men remains higher than that of women until old march 2020) and 95% confidence intervals. 2018 population size data from [9] . d as c but with other age categories, sex groups pooled, and including deaths reported until 21 april age and only approaches that of women at the end of the curve. if we compare this normal mortality risk with the covid-19 mortality until 31 march or 21 april, respectively ( fig. 2a and b) , we see a similar increase (although the number of covid-19 deaths registered by the respective survey date scaled to the population size is orders of magnitude lower than the annual mortality rates). the proportion of austrians who die from covid-19 by a given date depends on how many people are infected and the risk of death among those infected, the so-called infection fatality rate. however, estimating infection fatality rates is complex [4, 5] . a simple, but not very reliable estimator is the proportion of observed deaths among those who tested positive. however, the positively tested are only a part of all infected persons and it is difficult to quantify the dark figure of undetected infections that are analysis of austrian covid-19 deaths by age and sex mild or even without symptoms. it is difficult to determine the number of undetected cases of infected persons, as it depends heavily on the number of tests and the testing strategy. only representative antibody tests will provide reliable estimates. therefore, instead of infection fatality rates, case fatality rates (the number of deaths per registered cases) are often considered instead. but these are also difficult to estimate during an outbreak of an epidemic because many of those who test positive are still ill when the data is collected and may die within the next few days. the case fatality rates however, depend sensitively on the number of undetected cases, which explains part of the differences between the numbers reported in different countries. an indication for the infection fatality rate is provided by the cases on the diamond princess, the cruise ship on which all passengers were tested and a mortality rate of 1.5% (11 out of 712 tested positive) was observed. however, the risk of death is strongly age dependent. scientists at imperial college london [3] used a model-based approach to estimate the age-dependent risk for infected persons to die from covid-19. sir david spiegelhalter, professor of risk communication at the university of cambridge, observed that these estimated infection fatality rates were roughly similar to the normal annual mortality risk in the united kingdom [6, 7] . comparing the infection fatality rate estimates reported in [3] with the normal annual mortality rates for austria, we see parallels as well -the estimated risk of death with covid-19 is for the majority of age groups roughly as high as the normal risk of dying within 1-2 years (fig. 3 , black dots). however, the risk is not spread over the entire period, but concentrated on a much shorter interval. we also observe that the number of those who have died in austria with covid-19 per population size in the respective age and sex group have a similar exponential age dependency as the estimated infection fatality rates (fig. 2a, b and 3) . on closer inspection, one sees that the increase of the former is somewhat steeper. this could still be consistent with the infection fatality rate estimates if infection rates are higher in the upper age groups. in fact, if the number of people who tested positive are put in relation to the population size, the current data of the ministry of health show that the group of people over 85 years of age is overrepresented. a misinterpretation would be to conclude from these considerations that the risk of death is not increased. on the contrary, it follows from the structure and magnitude of infection fatality rate that it is substantial, especially for higher age groups. although it is unclear how many people would have died in the course of the year even without covid-19 disease, it can be assumed that the risk of dying from covid-19 is to a substantial extent an additional risk. it is red and blue lines as in fig. 2a and b . black dots: estimated infection fatality rates per age group according to [3] plotted at the mean ages of the age groups for which the estimates were reported. due to the exponential increase of the risk with age, this gives a slightly positively biased estimate of the number of deaths at the mean age not yet known, however, how many years of life (on average) one loses through a sars-cov-2 infection. since many seriously ill patients with already shortened life expectancy are affected, the additional effect on the general life expectancy could be less than it would be derived from mortality alone. although in the long run the loss of years of life may be a more relevant figure than mortality itself, in the short run, especially to assess the social impact, mortality is of greater importance. such risk comparisons put the danger of covid-19 disease into perspective, but it is doubtful whether this pandemic can be perceived as less drastic. these mortality estimates do not take into account the possible overloading of the healthcare system and the associated indirect effects on mortality of other diseases, such as heart attacks, strokes, or cancer, which can no longer be treated appropriately. according to estimates by imperial college london [3] , 5% of infected 40-to 50-year-old people need hospital treatment, a figure that rises to over 25% for those over 80. of those treated in hospital, about 6% of 40-to 50-yearold people need intensive care and over 70% of those over 80. in order to comprehensively evaluate the effects of the disease, it is also necessary to consider in which state of health, for example, older patients who did not die leave the hospital after intensive care treatment. the long-term consequences of the disease are also not yet known. therefore, comprehensive measures to control the spread of the epidemic are essential to prevent the collapse of the health sys-tem. it is difficult to include the social and economic consequences of the measures, which can also have medical consequences. even if deaths are easier to collect than the number of people infected, these figures are not without controversy. firstly, it is often difficult to determine whether a patient dies from covid-19 (i.e., the virus is the cause of death) or dies with the virus (i.e., is infected but the cause of death is different). two figures are currently reported by the ministry of health: those of the deceased who tested positive (regardless of the actual cause of death) and those who died from covid-19. on the other hand, there may also be an unrecorded number, since covid-19 deaths may not always be recognized as such. more reliable than the number of deaths due to covid-19 is the total number of deaths. reports from several countries with stronger outbreaks of the epidemic indicate that the death figures in recent weeks are significantly higher than the long-term averages. but also in austria, increased death rates, especially among the elderly, have been reported recently [8] . the extent to which the deaths affect people who would have died this year even without covid-19 may become apparent in the annual statistics. funding open access funding provided by medical university of vienna. posch, and franz könig declare that they have no competing interests. open access this article is licensed under a creative commons attribution 4.0 international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. amtliches dashboard covid19. 2020 impact of nonpharmaceutical interventions (npis) to reduce covid-19 mortality and healthcare demand globalcovid-19casefatalityrates,centre for evidence-based medicine the many estimates of the covid-19 case fatality rate does covid raise everyone's relative risk of dying by a similar amount? more evidence how much 'normal' risk does covid represent? sterbefälle älterer menschen im zeitraum vom 16.3. bis 5.4.2020 überdurchschnittlich hoch. 2020 max planck institute for demographic research (germany). the human mortality database key: cord-260797-tc3pueow authors: aleta, alberto; ferraz de arruda, guilherme; moreno, yamir title: data-driven contact structures: from homogeneous mixing to multilayer networks date: 2020-07-16 journal: plos comput biol doi: 10.1371/journal.pcbi.1008035 sha: doc_id: 260797 cord_uid: tc3pueow the modeling of the spreading of communicable diseases has experienced significant advances in the last two decades or so. this has been possible due to the proliferation of data and the development of new methods to gather, mine and analyze it. a key role has also been played by the latest advances in new disciplines like network science. nonetheless, current models still lack a faithful representation of all possible heterogeneities and features that can be extracted from data. here, we bridge a current gap in the mathematical modeling of infectious diseases and develop a framework that allows to account simultaneously for both the connectivity of individuals and the age-structure of the population. we compare different scenarios, namely, i) the homogeneous mixing setting, ii) one in which only the social mixing is taken into account, iii) a setting that considers the connectivity of individuals alone, and finally, iv) a multilayer representation in which both the social mixing and the number of contacts are included in the model. we analytically show that the thresholds obtained for these four scenarios are different. in addition, we conduct extensive numerical simulations and conclude that heterogeneities in the contact network are important for a proper determination of the epidemic threshold, whereas the age-structure plays a bigger role beyond the onset of the outbreak. altogether, when it comes to evaluate interventions such as vaccination, both sources of individual heterogeneity are important and should be concurrently considered. our results also provide an indication of the errors incurred in situations in which one cannot access all needed information in terms of connectivity and age of the population. the average. within a network perspective, this is just a consequence of the higher number of contacts, or degree, that some individuals have in the network [17, 18, 20] . this individual heterogeneity also signaled that outbreaks could be really large if key individuals become infected and, at the same time, gave a new target for efficient control strategies such as vaccinating highly connected individuals [21, 22] . however, despite the many advantages of this approach, determining the complete contact network of a large population is almost infeasible, especially for infections transmitted by respiratory droplets or close contacts. hence, it is common to use idealized networks built using some empirical data of the population, such as the degree distribution [23] . lastly, there are high-resolution approaches that rely on lots of statistical data to build agent-based models in which the behavior of every single individual is taken into account [24] [25] [26] [27] [28] [29] . note, however, that in agent-based models, individuals are usually assigned to certain mixing groups (i.e., their household, school, or workplace), and that inside those groups homogeneous mixing is used, due to the lack of data for all these settings at a country scale [30] . an important step to create more realistic models in this direction is to collect high-resolution data on individual contacts using wearable sensors [21] , that can be used to build timevarying networks in which not only the information about who contacts who is contained but also the duration and frequency of contacts [31] . several settings have been monitored, such as schools and workplaces [32, 33] , or even conferences and museums [34, 35] . although the data is still too rare to be used in large scale simulations, it has already been shown that the heterogeneity induced by the time-varying networks inside each mixing group produces a different outcome than the one obtained assuming homogeneous mixing within each group [30] . our goal in this paper is to analyze the role of one particular type of heterogeneity in disease dynamics, namely, the age structure of the population. originally, age was introduced into the models to study childhood diseases [5] . the classical approach consists of dividing the population into different groups, one for each age bracket under consideration, and establishing an age-dependent transmission rate. this transmission rate can be arranged in a matrix in which each element encodes the transmission probability between groups i and j (this matrix is also known as the who acquired infection from whom matrix [36, 37] ). it is also possible to separate the effect of the transmission itself in a common parameter and encode the number of contacts between each group in the matrix [38] . note that this procedure falls into the second category described previously. that is, it takes into account the heterogeneity induced by having different classes of individuals but hides the individual variability under a homogeneous mixing approach within each group, as in models of sexually transmitted diseases with groups with different activity levels. nevertheless, this approach is widely used today and has yielded outstanding results for many diseases such as chickenpox [39] , herpes zoster [40] , measles [41] [42] [43] , pertussis [44] and tuberculosis [45] . in fact, even though the theoretical basis of this method is relatively old, data on the contact patterns of the general population as a function of their age have been available only recently. the first large-scale study on the contact patterns between and within groups in the context of infections spread by respiratory droplets or close contact took place in 2008 and was focused in europe [14] . since then, a number of studies covering different countries have appeared, although data on africa and asia are still scarce [46] . various methods have been developed to infer the contact patterns in the absence of direct data [47] [48] [49] , and to project them into the future [50] . and yet, most studies that use this data disregard the whole distribution of contacts and use only the average number of contacts between groups, completely neglecting the individual heterogeneity (with few exceptions [51] ). as a consequence, in these studies, superspreading events cannot occur naturally, unless the model is modified, contrary to network models in which the large connectivity of some individuals can result in the appearance of such events. similarly, the virtual absence of an epidemic threshold for certain types of contact networks cannot be observed with these simplified contact patterns [52] . to bridge this gap, in this paper, we focus on analyzing the role that disease-independent heterogeneity in host contact rates plays in the spreading of epidemics in large populations under several scenarios, both numerically and analytically. furthermore, in contrast to previous approaches to this problem [53] [54] [55] [56] , we use a data-driven approach to highlight not only the role of those heterogeneities but also to explore the validity of the conclusions that one can derive when only limited information about the population is available. there are multiple ways of modeling the contact patterns of the population, depending on the availability of data and the characteristics of the disease. in this work, we consider that diseases have the same outcome on all individuals regardless of their condition and that individuals do not change their behavior as a consequence of the disease. this way, we can focus on the effect of adding different characteristics to the population contact patterns. to be more specific, we use the information from the survey that was carried out in italy for the polymod project [14] . in this project, over 7,000 participants from eight european countries were asked to record the characteristics of their contacts with different individuals during one day, including age, sex, location, etc. since that pioneering work, the number of countries where this type of study has been conducted has been increasing steadily, but data on africa and asia are still scarce. besides, the resolution and amount of information vary from study to study [46] . as such, we build four different models of interaction, assuming that only partial information about the population is available, see fig 1. the simplest formulation is the homogeneous mixing approach (model h), suitable when very limited information about the population is available. in this model, all individuals are able to contact each other with equal probability. the number of such interactions, hki, can be extracted from contact surveys simply by calculating the average number of contacts per individual. note, however, that this formulation is very simplistic since all individuals are completely equivalent. a slightly better approximation is to divide the population into agegroups, given the demographic structure of the population, fig 1b, and establish a different number of contacts between and within them (model m), which is the common approach currently used in the epidemic literature to model age-mixing patterns. in this case, the necessary information includes knowing the age of both individuals participating in each contact, although this information can be easily summarized in an age-contact matrix, m, where each entry m αβ represents the average number of contacts from an individual in age group α to individuals in age group β. note that in both models only the average number of contacts is used, in one case the average over the whole population and in the other over each age-group. another possibility is to use the whole contact distribution, fig 1d, to build the contact network of the population. this formulation is commonly found in the network science literature since it highlights the role that the disproportionate number of contacts of some individuals have in the dynamics of the disease. a simple way of creating these networks is to represent each individual i as a node and extract its degree (number of contacts) from the distribution. then, the expected number of edges between nodes i and j is ha ij i ¼ k i k j = p l k l (model c). to obtain this expression, we can consider that each node i has k i stubs associated. next, if these stubs are matched together randomly, the probability that each stub from node i ends up at one of the k j stubs of node j is k j over the total number of stubs, ∑ l k l . this method is known as the configuration model. lastly, we can combine both ingredients, the mixing patterns, and the contact distribution of the population in a network representation. to do so, we propose to arrange nodes in a multilayer network, in which each layer represents an age-group. as such, the first step to create this network is to extract the age associated to each node from the demographic structure of the population, fig 1b, and assign them to their corresponding layer (since we are working with 15 age-groups, our system is composed by that same amount of layers). then, the degree of each node should be extracted from the desired distribution. to incorporate the mixing patterns into the configuration model, we propose the following scheme: 1. given a node i located in layer α (where the layer represents the age-group associated with i), the probability that any of its stubs ends up at a node in any layer β (including the same layer) is p αβ . this probability can be extracted from the mixing matrix as 2. the stub from node i will match the stub of node j, situated in layer β, with probability k j /∑ l2β k l , where the denominator indicates the addition over the degree of all nodes present in layer β. hence, the expected number of edges between nodes i and j will be given by yet, note that incorporating the mixing patterns introduces a restriction in the degree distribution. indeed, one of the important properties of the mixing patterns matrix is that it has on the other hand, if the full contact distribution of the population is known, regardless of their age, it is possible to build the contact network of the population (c). lastly, when both the contact distribution and the interaction patterns between different age groups are known, the individual heterogeneity and the global mixing patterns can be combined to create a multilayer network in which each layer represents a different age group (c+m). panel b: demographic structure of italy in 2005 [57] . panel c: age-contact patterns in italy obtained in the polymod study [14] . panel d: contact distribution in italy obtained in the polymod study [14] . the x axis represents the number of daily contacts and the y axis the fraction of individuals that have reported such amount of contacts. the distribution is fitted to a right-censored negative binomial distribution since the maximum number of contacts that could be reported was 45. https://doi.org/10.1371/journal.pcbi.1008035.g001 to verify reciprocity, i.e., that is, the number of contacts going from group α to group β has to be the same as the ones from β to α (if the populations of each group were equal, this would lead to a symmetric matrix). it is easy to see that eq (1) only fulfills this property if x and, thus, where hki α represents the average degree in layer α. hence, even though the shape of the distribution can be chosen freely, the mixing matrix fixes the average degree of each layer. eqs (1) and (4) to determine the consequences of each of the previous assumptions, we first consider a general susceptible-infected-susceptible (sis) markovian model [58, 59] . in this model, the recovery rate of each infected individual is modeled by a poisson process with rate δ. in turn, each successful contact emanating from an infected individual (i.e., a contact that transmits the disease) is modeled as a poisson process with rate λ. we denote by y i the bernoulli random variables that are equal to one if individual i is infected or zero otherwise. complementary, the only ingredient left to be defined is how the contact process between individuals actually takes place. in general, in its exact formulation, we can do so by introducing the matrix a, which denotes whether two individuals can contact each other or not [58, 59] : with this formulation we can already study the spreading of an epidemic on any network, models c and cm. indeed, assuming that the states are independent, i.e., hy i y j i = hy i ihy j i�y i y j , we get considering that the nodes with the same degree are statistically equivalent, we can obtain the epidemic threshold using the heterogeneous mean field approximation [60] , this well-known result from network science clearly shows the importance of the heterogeneity of the contacts, since it depends on the second moment of the distribution. in the case of italy, using this expression we obtain a theoretical threshold of τ cm = 0.033 and τ c = 0.035 for the cm and c models, respectively. for the m model, since individuals are indistinguishable, eq (6) is rewritten as where m αβ is the matrix depicted in fig 1c, and y α the fraction of infected individuals in layer α. in this case, using the next generation approach [61, 62] , the epidemic threshold is regarding italy, the spectral radius of m is ρ(m) = 22.51, resulting in an epidemic threshold of τ m = 0.044. lastly, the equation governing the h model is where the epidemic threshold is according to fig 1d, the epidemic threshold in our system is thus τ h = 0.052. thus, in this case, the following relation holds: some observations are in order. first, even though the average number of contacts is the same in all models, the epidemic threshold is completely different. besides, increasingly adding heterogeneity to the model lowers the epidemic threshold. this is especially relevant when going from classical mixing models to network models. indeed, when we introduce the whole contact distribution, we are indirectly adding the possibility of having super-spreading events, which, as noted before, is missing in the classical approaches. on the other hand, as expected, the difference between both network models is relatively small ( t cm t c ¼ 1:06) since the main driver of the epidemic threshold is the contact distribution. nonetheless, as we shall see next, for other scenarios, the multilayer framework will yield quite different results from model c. to asses the quality of our theoretical analysis, our first step is to obtain the epidemic threshold for each configuration numerically. to do so, we create an artificial population of 10 6 individuals and assign them an age according to the demographic structure of the italian population [57] . then, we simulate a stochastic sis markov model, with δ = 1 and multiple values of λ for each of the four contact models under consideration (see materials and methods). in fig 2a, we show the attack rate (total number of cases over the whole population) as a function of λ. the overall behavior of the four scenarios is qualitatively similar, although large differences are observed in the value of the epidemic threshold (see inset), as predicted. to properly characterize the value of the epidemic threshold and compare it with the theoretical expectations, we use the quasistationary state (qs) method [59, 63] . this technique allows computing the susceptibility of the system, which presents a peak at the epidemic threshold (see materials and methods). the caveat is that it is highly dependent on the system size since the epidemic threshold is only properly defined for infinite systems. nevertheless, in fig 2b we compute the susceptibility, χ for the four configurations with system sizes ranging from 10 4 to 10 6 individuals and we can see that for the latter the peak of the susceptibility is already quite close to the predicted value of the epidemic threshold, validating our theoretical approach. next, we focus on studying the impact that the disease has on each age group under the different configurations, fig 2c. we set the value of λ in each case so that the attack rate is equal to 0.4, since the four scenarios converge to that value for similar values of λ (see fig 2a) . using the homogeneous mixing approximation, we obtain a distribution of infected individuals across ages proportional to the demographic structure of the population (fig 1b) , as one would expect given that all individuals are virtually indistinguishable for the dynamics. the same result is obtained for the c model, in which the age of the nodes is completely independent of the network structure. at variance with these results, if we incorporate the heterogeneous mixing patterns of the population either in the age-mixing (m) model or in the multilayer network (cm) setting, the incidence in each age group would be quite different, see fig 2c. note that we have again set λ so that the overall incidence is 0.40 in all cases −this assures that the total number of infected individuals is the same, only its distribution across age classes is different. results show that in both scenarios the prevalence is much higher for teenagers and smaller for the older cohorts than in the homogeneous mixing model. although the sis model facilitates the theoretical and numerical analysis of the system, especially near the epidemic threshold, it is too simplistic to model real diseases such as ili. thus, to highlight the impact of these observations on a more realistic scenario, we slightly modify the model by incorporating the removed compartment so that the dynamics are governed by a susceptible-infected-removed (sir) model, which is better suited for studying ili [64] . it has been recently shown that using a constant and group-independent basic reproduction number, r 0 , might not describe well key features of the disease dynamics in realistic scenarios [28] . for this reason, we first explore the dependency of this parameter with the age of the individual in the two networked scenarios. to do so, we simply count the total number of newly infected individuals that a single seeded infectious subject would produce in a fully susceptible population over 10 8 simulations, with the value of λ set so that the average value of r 0 is 1.3 inline with typical values for influenza [65] . fig 3a shows the value of r 0 as a function of the age of the seed node in the network in which all nodes have the same degree distribution. clearly, the same r 0 value is obtained regardless of the age of the nodes, as it should be given that both their degree and their connections are independent of their age. conversely, in the multilayer network where the mixing patterns of the population are incorporated, fig 3b, the situation changes completely. the value of r 0 is above the average for teenagers and adults but below the average for the elderly, highlighting the importance of the underlying structure in the value of r 0 . lastly, we study the effect of vaccinating a fraction of the nodes before the epidemic begins. this sort of contention measures are among those that can benefit the most from knowledge about the structure of the population, as they allow devising more efficient vaccination strategies. first, we set the baseline scenario to values compatible with the 2018-2019 ili epidemic in italy. according to the world health organization, the total attack rate was 13.3%. besides, an important fraction of the population was vaccinated preemptively. in italy, vaccination is recommended for several groups of people, such as those with chronic medical conditions, firefighters, health care workers, or the elderly [66]. of these groups, the only one that we can distinguish in our model is the elderly, but it is also the one with the largest vaccination rates. unfortunately, the uptake of the vaccine has been decreasing for the past few years, and now is close to 50% [67] . even more, the effectiveness of the vaccine is estimated to be around 60% yielding an effective vaccination rate of 30% in the elderly [68] . hence, to obtain the baseline values in our model, we set 30% of the elderly in the recovered state initially and set the value of λ so that the attack rate is 13.3%, fig 4a. our first observation is that in the c scheme, we trivially obtain a reduction in the attack rate among the elderly due to their vaccination, but otherwise, the incidence is the same in all age groups. on the other hand, both in the m and cm models, the attack rate depends highly on the age of the individual. to gauge the effect of increasing vaccination rates, we vaccinate 1% of the total population (assuming that the effectiveness is 60% for all age-groups). note that since the elderly group represents 19% of the population, the initial vaccination rate was roughly 10% of the total population. if these new vaccines are administered randomly, we can see that the effect is just a homogeneous reduction of 5-6% in all age groups, independently of the model, fig 4b. conversely, if that same amount of new vaccinations is targeted, the situation changes completely. in the m model, we vaccinate individuals belonging to the group with 15-19 years old since it is the one with the largest number of contacts and the highest attack rates. we can see that the overall reduction is much larger than in the previous case, and especially so in this particular group, see fig 4c. in the c and cm models, instead, we apply the vaccines to individuals with the largest degrees. we can see that the reduction is larger in the c setting than in the cm one. this result might seem counter-intuitive since the same measure is applied to both systems. however, note that while in the c model the largest degrees are homogeneously distributed across the population, in the cm model they are concentrated in specific age groups, or layers. furthermore, since nodes in the same layer tend to be connected together, the previous observation implies that the effect of removing hubs will be lower. to verify this, we have rewired the connections of the cm model while preserving the age, degree and vaccination status of each node. as we can see, in such case we recover the same value as in the c model. in other terms, the correlations induced by the age mixing patterns lower the effectivity of this vaccination strategy. note also that in both the random and the targeted vaccination schemes, the number of new vaccines introduced in the system is exactly the same, only who is vaccinated changes. models can range from simple homogeneous mixing models to high-resolution approaches. the latter, even though it might provide better insights, is also much more data demanding. as a compromise between the two, network models can capture the heterogeneity of the population while keeping the amount of data necessary low. nevertheless, most network approaches focus only on determining the role that the difference in the number of contacts of the population has on the impact of disease dynamics but ignore other types of heterogeneities such as the age mixing patterns. we have shown that to determine the epidemic threshold of the population properly, the heterogeneity in the number of contacts cannot be neglected, making the simple homogeneous approach and the homogeneous approach with age mixing patterns ill-suited for it. in fact, a description that ignores the age mixing patterns of the population can capture much better the value of the epidemic threshold. furthermore, we observe two different regimes in the attack rate as a function of the spreading rate. for low values of the spreading rate, individual heterogeneity plays a more important role, yielding larger attack rates than the homogeneous counterparts. however, after a certain value, the phenomenology reverses, i.e., larger attack rates are obtained for the homogeneous approaches rather than for the networked versions. the reason is that, in homogeneous models, an infected agent can contact everyone in the population, and thus it can keep infecting individuals even if the attack rate is high. when the network is taken into consideration, it is possible that nodes run out of susceptible individuals within their vicinity, virtually preventing them from spreading the disease any further. on the other hand, if we study the distribution of infected individuals across age cohorts, we can see that the c scheme is no longer valid, yielding the same results as the simple homogeneous mixing approach. if the age mixing patterns are added into the model, either in the m or cm schemes, a larger fraction of young individuals will be infected, while the incidence in elder cohorts is reduced. hence, even though the c approach can predict fairly well the value of the epidemic threshold, it cannot be used to study the spreading of diseases in which taking into account the age of the individuals is important beyond the epidemic threshold. conversely, the multilayer network of the cm model can describe both the epidemic threshold and the distribution of the disease across age groups correctly. in other words, it combines both the importance that individual heterogeneity has with the inherent assortativity present in human interactions. individual heterogeneity also introduces important variations in the measured value of r 0 . this observation is quite important since it shows that for the proper evaluation of r 0 during emerging diseases, the sampling of the population has to be done carefully. biases in the sampled individuals, such as having too many young individuals, could lead to estimations of r 0 much larger than its actual value. even more, this is not limited to the age of the individuals since we have also seen the importance of individual heterogeneity in the dynamics. of utmost relevance, if in the sample, there are individuals with an average number of contacts higher than the normal population, the estimations of r 0 would also be higher. lastly, we have also observed the crucial role that heterogeneity plays if we want to devise efficient vaccination strategies. the role of networks in this regard is known to be important not only because there are tools that allow identifying the most important individuals, but because it provides a clear way to study herd immunity. yet, if we do not take into account the contact distribution of the population the effectivity of vaccination campaigns will be lower. conversely, if we rely simply on the contact distribution of the population and disregard their mixing patterns, we would overestimate the effect of vaccination. as the current covid-19 pandemic has shown, accounting for both the age and the contact heterogeneity of individuals is crucial to control the epidemic. it is yet unknown the exact role that age plays in this disease, although preliminary results show that children are less susceptible and that the case fatality rate for older individuals is much higher. similarly, large super-spreading events are possible such as the ones detected in south korea, boston or spain [19, 69] . the latter country is also among the ones most affected by the current epidemic, but empirical information about the age mixing patterns of the population is not available [46, 69] . thus, to the inherent problems of forecasting the evolution of an emerging disease [70, 71] we have to add our ignorance about these factors which, as we have shown in this article, can substantially modify the predictions. this highlights once again the importance of obtaining precise information about the behavior of the population, enhancing our preparedness for this type of event. to sum up, we have shown the importance that individual heterogeneities have on the spreading of infectious diseases. yet, although in general the more details in the model the better, it is also important to take into account the inherent limitations about data that currently exist. therefore, it is crucial to correctly gauge what can and cannot be done, given the information available to us. in particular, we have shown that to predict the epidemic threshold, it is indispensable to know the degree distribution of the population. nonetheless, this is not strictly needed to evaluate the impact of a disease away from the threshold. yet, adding this information, even though it does not dramatically change the predicted outcomes of the epidemic under normal conditions, could be pivotal to devise efficient vaccination strategies. furthermore, we have seen that the underlying information of the system also has an impact on quantities that are commonly measured and used in real settings, such as r 0 , implying that care must be taken when extrapolating the results from one study to the other. in all cases, we consider populations of 10 6 individuals. in the h model, since individuals are indistinguishable, the impact of the disease over the age groups is computed by randomly extracting values from the demographic distribution of italy in 2005 [57] . in the m model, the size of each age-group is computed using the same procedure. besides, the age-mixing matrix was corrected so that reciprocity is fulfilled, and the average connectivity is exactly 19.40 [50] . in the c model, we randomly extract the degree of each node from a right-censored negative binomial distribution adjusted to the survey data from polymod [14] . then, links are sampled performing a bernoulli trial over each pair of nodes respecting that ha ij i ¼ k i k j = p l k l . a similar procedure is followed to create the multilayer with age mixing patterns, but in this case, each layer has its own values for the negative binomial distribution, according to the data (see fig 1d) , and the probability of establishing a respects ha ij i ¼ p aðiþ;bðjþ k i k j = p l2aðjþ k l where p α(i),β(j) is the probability that a link from a node with the same age as node i ends up at a node with the same age as node j, and α(j) is the layer to which j belongs. we remark that the network is simplified, removing multiple edges. close to the critical point, the fluctuations of the system are often high, driving the system to the absorbing state [59, 63] . to avoid this problem, the quasistationary state (qs) method stores m active configurations previously visited by the dynamics. at each step, with probability p r , the current configuration (as long as is active) replaces one of the m stored ones. then, if the system tries to visit an absorbing state, the whole configuration is substituted by one of the stored ones. the system evolves for a relaxation time, t r , and then the distribution of the number of infected individuals, p n , is obtained during a sampling time t a . lastly, the threshold is estimated by locating the peak of the modified susceptibility χ = n(hρ 2 i − hρi 2 )/hρi, where hρ k i is the k-th moment of the the distribution of the number of infected individuals, p n (note that hρ k i = ∑ n n k p n ). in our analysis, the number of stored configurations and the probability of replacing one of them is fixed to m = 100 and p r = 0.01, while the relaxation and sampling times vary in a range depending on the size of the system, t r = 10 4 − 10 6 and t a = 10 5 − 10 7 . heterogeneity in pathogen transmission: mechanisms and methodology the role of population heterogeneity and human mobility in the spread of pandemic influenza an infectious disease model on empirical networks of human contact: bridging the gap between dynamic network data and contact matrices a review of simulation modelling approaches used for the spread of zoonotic influenza viruses in animal and human populations. zoonoses and public health modeling infectious diseases in humans and animals sexual practices and risk of infection by the human immunodeficiency virus gonorrhea transmission dynamics and control heterogeneities in the transmission of infectious agents: implications for the design of control programs transmission dynamics of hiv infection models for vector-borne parasitic diseases age-related changes in the rate of disease transmission: implications for the design of vaccination programmes sexual lifestyles and hiv risk aids and sexual behaviour in france social contacts and mixing patterns relevant to the spread of infectious diseases complex networks: structure and dynamics superspreading and the effect of individual variation on disease emergence network theory and sars: predicting outbreak diversity stochasticity and heterogeneity in the transmissiondynamics of sars-cov-2 infectious disease transmission and contact networks in wildlife and livestock a high-resolution human contact network for infectious disease transmission statistical physics of vaccination networks and epidemic models strategies for containing an emerging influenza pandemic in southeast asia strategies for mitigating an influenza pandemic mitigation strategies for pandemic influenza in the united states spread of zika virus in the americas measurability of the epidemic reproduction number in data-driven contact networks reactive school closure weakens the network of social interactions and reduces the spread of influenza recalibrating disease parameters for increasing realism in modeling epidemics in closed settings robust modeling of human contact networks across different scales and proximity-sensing techniques contact patterns in a high school: a comparison between data collected using wearable sensors, contact diaries and friendship surveys data on face-to-face contacts in an office building suggest a low-cost vaccination strategy based on community linkers what's in a crowd? analysis of faceto-face behavioral networks empirical temporal networks of face-to-face human interactions mixing patterns between age groups in social networks disease control in age structure population infectious diseases of humans: dynamics and control using empirical social contact data to model person to person infectious disease transmission: an illustration for varicella the impact of demographic changes on the epidemiology of herpes zoster: spain as a case study age-structure and transient dynamics in epidemiological systems global dynamics of a discrete age-structured sir epidemic model with applications to measles vaccination strategies parental vaccination to reduce measles immunity gaps in italy. elife contact network structure explains the changing epidemiology of pertussis data-driven model for the assessment of mycobacterium tuberculosis transmission in evolving demographic structures. proceedings of the national academy of sciences a systematic review of social contact surveys to inform transmission models of close-contact infections inferring the structure of social contacts from demographic data in the analysis of infectious diseases spread projecting social contact matrices in 152 countries using contact surveys and demographic data inferring high-resolution human mixing patterns for disease modeling projecting social contact matrices to different demographic structures high-resolution epidemic simulation using withinhost infection and contact data epidemic spreading in scale-free networks transmission dynamics of an sis model with age structure on heterogeneous networks effects of vaccination and population structure on influenza epidemic spread in the presence of two circulating strains incorporating disease and population structure into models of sir disease in contact networks multiple lattice model for influenza spreading world population prospects 2019, custom data acquired via website virus spread in networks fundamentals of spreading processes in single and multilayer complex networks dynamical processes on complex networks the construction of next-generation matrices for compartmental epidemic models the impact of regular school closure on seasonal influenza epidemics: a data-driven spatial transmission model for belgium epidemic thresholds of the susceptible-infected-susceptible model on networks: a comparison of numerical and theoretical results age-specific contacts and travel patterns in the spatial spread of 2009 h1n1 influenza pandemic estimates of the reproduction number for seasonal, pandemic, and zoonotic influenza: a systematic review of the literature. bmc infectious diseases seasonal influenza vaccination and antiviral use in eu/eea member states. european centre for disease prevention and control association between vaccination coverage decline and influenza incidence rise among italian elderly adjuvanted influenza vaccine for the italian elderly in the 2018/19 season: an updated health technology assessment evaluation of the potential incidence of covid-19 and effectiveness of containment measures in spain: a data-driven approach forecasting covid-19. front phys. 2020 predictability: can the turning point and end of an expanding epidemic be precisely forecast? arxiv key: cord-262954-saqo900k authors: esme, mert; koca, meltem; dikmeer, ayse; balci, cafer; ata, naim; dogu, burcu balam; cankurtaran, mustafa; yilmaz, meltem; celik, osman; unal, gulnihal gokce; ulgu, mustafa mahir; birinci, suayip title: older adults with coronavirus disease 2019; a nationwide study in turkey date: 2020-09-01 journal: j gerontol a biol sci med sci doi: 10.1093/gerona/glaa219 sha: doc_id: 262954 cord_uid: saqo900k background: a novel coronavirus (severe acute respiratory syndrome coronavirus 2 [sars-cov-2]) occurred in china in december 2019 and has spread globally. in this study we aimed to describe the clinical characteristics and outcomes of hospitalized older adults with coronavirus disease 2019 (covid-19) in turkey. methods: we retrospectively analyzed the clinical data of hospitalized patients aged ≥ 60 years with confirmed covid-19 from march 11, 2020, to may 27, 2020 using nationwide health database. results: in this nationwide cohort, a total of 16942 hospitalized older adults with covid-19 were enrolled, of whom 8635 (51%) were women. mean age was 71.2 ± 8.5 years, ranging from 60 to 113 years. mortality rate before and after curfew was statistically different (32.2% vs 17.9%; p & 0.001, respectively). through multivariate analysis of the causes of death in older patients, we found that male gender, diabetes mellitus, heart failure, chronic kidney disease, dementia, cancer, admission to intensive care unit, computed tomography finding compatible with covid-19 were all significantly associated with mortality in entire cohort. in addition to abovementioned risk factors, in patients aged between 60-79 years, coronary artery disease, oxygen support need, total number of drugs, and cerebrovascular disease during hospitalization, and in patients 80 years of age and older acute coronary syndrome during hospitalization were also associated with increased risk of mortality. conclusions: in addition to the results of previous studies with smaller sample size, our results confirmed the age-related relationship between specific comorbidities and covid-19 related mortality. named severe acute respiratory syndrome coronavirus 2 (sars-cov-2) has recently emerged and spread rapidly causing a pandemic (1) . as of may 28, 2020, there were 5,593,631 confirmed cases of covid-19 with 353,334 deaths globally (2) . the centers for disease control and prevention (cdc) reported that individuals older than age 65 comprise 17% of the total population in the united states, though they are responsible for 31% of infections, 45% of hospitalizations, 53% of intensive care unit (icu) admissions and 80% of deaths caused by . in a study with 44,672 confirmed cases, the case fatality rate (cfr) is 2.3 %, however 70-80-year-old age group patients have a cfr of 8.0%, and patients above age 80 have a cfr of 14.8% (4) . this suggests that older adults are more susceptible to and are at significantly increased risk for morbidity and mortality compared with the general population (5) . physiologic changes of aging, multiple age-related comorbid conditions such as heart and lung disease, diabetes, dementia, and polypharmacy are associated with poor outcomes in older patients (6). the first case in turkey was detected on march 11, 2020. as of may 28, 2020, there were 159,797 confirmed covid-19 cases and 4431 deaths (2) . in addition to the several measures taken to prevent the spread, a curfew imposed for whom aged ≥65, on march 21, 2020, intending to lower the mortality among geriatric individuals (7) . this study aims to describe the clinical characteristics and to evaluate the outcomes of the geriatric patients with covid-19 in a nationwide basis, which might provide evidence for the risk stratification and help to improve the clinical practice. a c c e p t e d m a n u s c r i p t 7 every patient aged 60 years and over with confirmed covid-19 by positive real-time reverse transcriptase polymerase chain reaction (rt-pcr) test in turkey between march 11 and may 27, 2020 were screened retrospectively. epidemiological, clinical, and radiological characteristics along with treatment and outcome data were obtained from turkish ministry of health national covid-19 database. presentation symptoms such as fever, cough, and shortness of breath were also recorded however they were excluded from the analysis because of the great number of missing data. the presence of underlying comorbidities and the complications of covid-19 after admission were identified based on the international classification of diseases and injuries-10 diagnostic codes on the database. this study was carried out in accordance with the permission of the ministry of health issue numbered 95741342-020. spss for windows v.23.0 (spss inc., chicago, il) was used for the statistical analyses. variables were examined using visual and analytical methods to determine whether they were normally distributed. categorical variables were shown as numbers and frequencies, with differences being analyzed by the chi-square test or fisher's exact test, where appropriate. continuous data that followed a normal distribution was described with mean and standard deviation and between-group comparisons were performed by independent samples t-test. when distributions were not normal, the data were described with median (min-max) and group comparisons were done using the mann -whitney u test. the unadjusted logistic regression model was used to assess the significant predictors of mortality. multivariate models were also generated by adjusting gender, presence of hypertension (ht), diabetes a c c e p t e d m a n u s c r i p t 8 mellitus (dm), chronic obstructive pulmonary disease (copd), coronary artery disease (cad), atrial fibrillation (af), chronic kidney disease (ckd), dementia, depression, malnutrition, and hyperlipidemia (hl) in model. patients were categorized into two groups based on their age (60-79 and 80-133) while performing multivariable logistic regression. hosmer-lemeshow goodness-of-fit statistics were used to assess model fit. a 5% type i error level was used to infer statistical significance. the total number of the ≥60 years-of-age patients infected with sars-cov-2 until date of may 27 was 24510 of whom 16942 (69.1%) hospitalized and 7568 (30.9%) were treated as outpatients. while the mean age of all patients was 71.2 ± 8.5, it was 70.6 ± 8.2 and 71.8 ± 8.8 for the males and females, respectively. number of hospitalized and non-hospitalized patients, sex distribution and mortality rates by age groups are shown in table 1 . on admission, 1663 people (9.8%) were taken to icu directly and 15279 patients (90.2%) were hospitalized in normal wards of whom 21.1% (n=3224) were transferred to icu during follow-up. while the rate of hospitalization in the 60-64 age group on admission was 5.5%, 18 .9% of the patients in this age group required intensive care during hospitalizations. in the 80+ age group, 17.4% were directly hospitalized in icu, whereas 43.1% of the patients who were hospitalized in normal wards firstly were required intensive care eventually. median durations of icu stay were statistically similar among the age groups and approximately 6 days. however, there was a significant difference between the age groups in the total length of hospital stay which increased with age. similarly, rates of need for oxygen support and requirement for intubation were increasing with the age. the distribution of patients' service admissions, icu follow-ups and intubation rates by age groups are shown in table 1 . during hospitalization, 57.6% of people who had a history of icu stay and 2.7% of whom without a history of icu stay died. mortality rates for the patients who were intubated and without intubation were 71.4% and 5.2%, respectively. mortality rates increased with advancing age for both icu patients and intubated patients. the details of these rates according to age groups is shown in table 2 . to evaluate the effectivity of the partial curfew which was imposed for the individuals ≥65years-of-age starting on march 21 st ,2020 considering the 14-day incubation time of the virus, the patients were divided into two, which were diagnosed before and after april 5, 2020 after exclusion of the patients of age group 60-64 from the study sample. of the 3355 patients aged ≥65 who were diagnosed with covid-19 before april 5, 1081 (32.2%) died. whereas it was 1623 (17.9%) who died among the 9050 patients who were diagnosed after april 5, 2020 as of may 27, 2020. the difference between the fatality rates of these two groups was statistically significant (p <0.001). in table 3 , the effects of curfew on the rates of mortality, icu hospitalizations and intubations are shown. computed tomography (ct) of the chest was performed at least once in 79.5% of the patients of which 61.9% were found to be compatible with covid-19 radiological findings. in the ct examination, in which bacterial, viral, and mixed infection findings, which are frequently confused with the covid-19 clinically, were also differentiated, and 1.1% was found to be compatible with bacterial and 42% with viral pneumonia. in turkey, 34.5% of the patients infected with sars-cov-2 over the age of 60 and 40.8% of the age group ≥80 were given favipiravir for treatment. hydroxychloroquine, which was commonly used as well as favipiravir, was given to 79.3% of the patients. other agents tried in treatment regimens other than hydroxychloroquine and favipiravir were lopinavir / a c c e p t e d m a n u s c r i p t 10 ritonavir, high-dose vitamin c, azithromycin and other macrolide antibiotics, quinolone group antibiotics, tocilizumab and steroids. studies till now showed that some comorbidities may constitute risk factors for poor prognosis. among these, dm, ht, copd, cad, hl, heart failure (hf), af, ckd, dementia, depression, malnutrition, osteoporosis, urinary incontinence, and malignancy in older patients were examined in our study. the table related to the frequencies of these comorbidities according to age groups can be accessed from the supplementary appendix in table s1 . complications that develop during hospitalization such as acs, deep vein thrombosis (dvt), cve, seizures, falls and fractures were examined and the most striking among these was the frequency of dvt which was developed in 534 patients (3.2%). in univariate regression analysis, acs was observed to increase the mortality risk by 3.42 (table s2 ). the factors associated with covid-19-related mortality were examined, firstly with univariate regression model which included age and the comorbidities. considering that the prevalence of certain chronic diseases that might affect the vulnerability of the patient increases with advancing age, the analyses was carried out for the whole group, 60-79 years old and ≥80 age group, separately. age and male sex increased the risk of mortality. need for oxygen support seemed to be a poor prognostic factor in terms of mortality. polypharmacy which is a common problem and an indirect indicator of frailty for older patients, caused an increased risk of mortality per drug added. dm, ht, copd, cad, hl, hf, af and ckd, which are common comorbidities in the older patients, were shown to increase mortality for a c c e p t e d m a n u s c r i p t 11 whole sample and dm, cad, af, copd, hf, and ckd were common risk factors for mortality in separate age groups. dementia, depression, and malnutrition are geriatric syndromes that cause frailty in older patients and increase morbidity and mortality. in univariate regression, these geriatric syndromes increase mortality risk in covid-19 patients. odds ratios for dementia and malnutrition were 2.33 (ci: 2.08-2.60) and 2.73 (ci: 2.01-3.7), respectively (both p<0.001). other factors affecting mortality are accessible in supplementary appendix (table s3) . multivariate regression analysis was conducted after dividing the whole sample into two agegroups, as 60-79 and ≥80 with the aim of obtaining more homogeneous groups by reducing the known effect of advancing age on mortality. variables such as gender, ht, dm, copd, cad, af, ckd, dementia, depression, malnutrition, and hl were included in the model. in the 60-79 age group, male sex, ht, dm, hf, ckd, dementia, and cancer diagnosis; in the age group of ≥80, male sex, dm, hf, dementia, and malnutrition were shown to increase mortality risk significantly (table 4) . covid-19 has caused an ongoing pandemic that affected people of all ages. however, it was recognized as more like a geriatric health disaster (8), with a high mortality rate in older adults with multimorbidities. despite this, existing data yielded from studies included particularly older patients is scarce. the present study was conducted to investigate the clinical characteristics and outcomes of covid-19, specifically for older adults on a nationwide scale. data on patients aged 60 and over who were infected with sars-cov-2 in turkey, were obtained from the national registry system of the ministry of health. thus, it is estimated that this study will contribute significantly to the literature owing to its large sample size and scope. a c c e p t e d m a n u s c r i p t 12 the first covid-19 case in turkey was detected on march 11, 2020 which was the date who declared the outbreak a global pandemic (9). the first covid-related death occurred on march 15, 2020 and then the disease had spread across the country with a trend similar to rest of the world. to reduce the spread of this highly contagious infection, turkey responded by taking precautions quite rapidly. the scientific advisory board established within the ministry of health gave recommendations on the management and treatment of the disease and published a guideline that were being updated according to current scientific data. in addition to the general preventive measures like prohibitions of gatherings and closure of all schools, mosques and public places, weekend curfews and a partial lockdown for the citizens aged ≥65 and ≤20 were imposed. in turkey, universal health insurance system enables for all registered individuals to reach healthcare services free of charge. during the outbreak, the turkish ministry of health expanded its coverage to provide testing and treatment for all residents free of charge. as of may 27, 2020, the crude cfr was 2.7% for all cases in turkey. the main factor that kept the cfr lower compared to many countries is probably that individuals aged 60 and older make up 13.3% of the population. the percentage of individuals aged 80 and over is only 1.8% (10) . older patients (≥60 years of age) accounted for approximately 15% of all cases and 81% of nonsurvivors. cfr was 14.7% for the older patients including both hospitalized cases and outpatients and was 18.5% for hospitalized patients. proportion of deceased cases increased with age, it was 32.8% and highest for the age group 80 and over. besides all the preventive measures taken with the onset of the outbreak in turkey, the imposition of a partial curfew for older individuals has been shown to significantly reduce the mortality rate in this group in addition to reductions in proportions of requirement for intubation and intensive care. the fact that advanced age is among the important risk factors for covid-19 related mortality has been almost certainly demonstrated by the evolving evidence on this subject a c c e p t e d m a n u s c r i p t 13 (11, 12) . however, the varying rates in different countries might have occurred due to multiple factors such as the proportion of older adults in the populations, how widespread the testing strategy that countries adopted, timing of the measures taken for risk groups as well as for general population, health centers' preparedness for the pandemic, and sufficiency of the resources in relation to the magnitude of the case surge. latter two may also explain how mortality rates differ from region to region in a country. the sample size and sampling time during the course of the outbreak, and whether the study was a single-center experience, or multi-centered also might have resulted in changes in calculated cfrs (11, 13) . in the very first reports from wuhan, the epicenter of the outbreak, fatality rate of the disease was frighteningly high for older adults. for instance, chen et al (14) reported the mortality rate of the older patients from a university hospital located in wuhan as 34.5% whereas it was 4.7% for younger patients. in our study sample, cfr of the hospitalized patients was 18.5% and reached to 32.8% for the age group ≥80. it was higher than the rate for the same age group reported by wu et al. (4) , and in line with the results of a study from united states (us) (15), and based on data from the pacific coast of us, lower than the rates which was calculated as 37.3% for the hospitalized patients aged 80 years and older (16). in new york city, the epicenter for us, cfrs reported as even higher: 21% for the whole sample and, 32% for the patients 60 years and older and 53% for the age group ≥80 (17) . it is largely known that older individuals more commonly suffer from critical illness, namely requirement for hospitalization, intensive care and intubation are more frequent related to covid-19 (12, 18) . thus, the high mortality rates shown in these studies can be partially explained by the relative shortage of healthcare resources due to the higher proportion of older individuals compared to our study. this could probably be the case in italy where latest update reports declared that 53.2% of all cases were aged 60 years and over whose fatality rate approximately 25% (19) (20) . were introduced with relatively lower viral load even they were infected.. as a result of the decrease in the viral load, we think that the related disease course may have been observed milder as discussed in a few articles in the literature (25, 26) . our results indicated that advancing age was also associated with more serious illness. it was 9.8% of older adults who had required intensive care on admission, and it increased with age and reached 17.4% for the age group ≥80. similarly, icu requirements during the follow-up of the patients rise with increasing age which was 18.9% for the age group 60-64 and as high as 43.1% for the patients aged ≥80. length of icu stay did not differ between age groups. comparison with other studies in the literature may be misleading, as the criteria for icu a c c e p t e d m a n u s c r i p t 15 admission may vary across countries and health-centers, depending on the availability of intensive care settings of different levels. however, several studies underscored increasing age among the main predictors of critical or severe illness (12, 14, 18) . correspondingly, proportions of the patients who required oxygen support and invasive mechanical ventilation (imv) were higher with increasing age. admission to icu and requirement for imv were both associated with higher rates of mortality: 57.6% and 71.4%, respectively. one of the earliest studies from china (27) (12) . mortality rates of patients might have varied according to whether early or late intubation strategies was adopted across different centers. male sex is another significant risk factor for mortality (14, 28) and is associated with a higher risk for a more severe clinical course (12, (29) (30) (31) that result in increased frequency of hospitalizations (32), increased probability of icu admission (16) and death for all age groups (33) . the present study revealed that, in univariate analysis male sex associated with 1.7-fold increased risk for death for older population. in multivariate analysis, this association revealed to be stronger for the -younger‖ geriatric population with an or of 2.0 for the age group of 60-79 whereas it was calculated to be 1.5 for the patients aged 80 and older. this result is consistent with the findings reported in a review: results of pooled data from four countries of europe showed the ratio of male-to-female case fatality to be most prominent for the age group of 50-59 and followed a decreasing trend through increasing age (32) . hence, it could be concluded that the age and sex interaction in covid-19 fatality had been confirmed with the results of our study. underlying multiple chronic diseases constitute another important risk factor for severe illness and covid-related mortality (14, 34, 35) . determined frequencies of several comorbidities a c c e p t e d m a n u s c r i p t 16 and geriatric syndromes of the study sample revealed that ht, cad, and dm were the three most common coexisting diseases. proportions of the comorbidities were consistent with the results of the previous prevalence studies representing all population of geriatric age group in turkey (36, 37) , however, far more higher than other similar studies including older patients with covid-19 (14, 18, 38) . rates of all investigated common comorbidities and geriatric syndromes were significantly higher for the deceased patients with an only exception of osteoporosis. moreover, dm, hf, ckd, cancer diagnosis and dementia were the comorbidities which were independently associated with mortality in multivariable regression. taking all these into account, it could be suggested that the relatively high cfr of our sample was partially due to the fact that the population described in this study composed of more or less ‗frailer' individuals having multiple comorbidities (39) (40) (41) . in a recent editorial, authors coined a term as -covid spiraling frailty syndrome‖ to explain the special vulnerability of older adults with dm and ht to covid-19 related death (39) . further, in sars-ras study, iaccarino et al emphasized that in addition to advanced age, the most important factor determining mortality was ‗physical frailty' caused by disease burden measured with charlson comorbidity index (42). along with other comorbidities, hl was more prevalent among the deceased patients. notwithstanding this, multivariate regression revealed hl as an independent factor for lower mortality risk for the patients aged ≥80. considering the results that malnutrition was independently associated with higher mortality risk and observed with relatively higher frequency in this age group of patients, it may be suggested that the protective effect of hl against mortality could be originated from the inverse relationship with malnutrition (43) . among the mentioned chronic diseases, dementia deserves special emphasis for the scope of present study. ten percent of the study sample had diagnosed with dementia and its frequency increase with age from 1.3% for the age group of 60-65 to 28.2% for the age group of ≥80. the results that it was seen more frequently in patients who deceased and an independent risk factor for mortality in regression analyses, were in line with the results reported by bianchetti et al (47) . with growing evidence and experience on management of covid-19, ct gained more importance for the diagnosis. its sensitivity was reported between 60%-98% in different studies (48, 49). lian et al. reported that, older patients were more commonly and severely presented with multiple mottling and ground-glass opacity which are among the typical findings for covid-19 (18) . further, ai et al. found the positive predictive value and accuracy of ct imaging higher for the patients 60 years and older in comparison with that for younger (48). in the present study, 79.5% of the patients were evaluated with chest ct and most of them (61.9%) classified to be consistent with typical covid-19 findings. there are some limitations of the present study. first, since the data extracted from medical records retrospectively, data related to symptomatology of the patients, physical examination findings, comprehensive geriatric assessment, frailty, and malnutrition evaluations were missing or incomplete. second, patients were not classified according to severity of clinical status. third, it includes only rt-pcr confirmed cases. a c c e p t e d m a n u s c r i p t 18 to the best our knowledge, this study is the largest sample nationwide study to examine the clinical features and outcomes of older individuals diagnosed with covid-19 so far. in addition to supporting the results of the previous studies with smaller sample sizes which had put forward the association of the factors like older age, male gender, and excessive comorbidity with the severity and mortality of the disease, our work confirmed the age-related relationship between specific comorbidities (dm, hf, ckd and cancer) and mortality, which have contradictory results in the available literature. furthermore, as far as we know, for the first time, geriatric syndromes such as dementia, malnutrition, depression, and urinary incontinence were also included in the analysis investigating the factors associated with mortality. in conclusion, sars-cov-2 in turkey as well as all over the world has led to an ongoing epidemic that affected older individuals disproportionately. patients aged 60 and older constituted more than 80% of the deceased patients. timely preventive measures and lockdowns seemed to be contributed to the reduction of mortality at least for geriatric population. except for osteoporosis, all the mentioned comorbidities and geriatric syndromes were more common among the nonsurvivors. multivariate logistic regression revealed male sex, dm, hf, ckd, cancer, and dementia as the independent risk factors for mortality. besides, for the -older old‖ patients (age group ≥80) malnutrition was an additional independent risk factors and hl was related to lower mortality risk. we declare no competing interests. a c c e p t e d m a n u s c r i p t a pneumonia outbreak associated with a new coronavirus of probable bat origin world health organization, coronavirus disease 2019 -situation report-129 severe outcomes among patients with coronavirus disease united states characteristics of and important lessons from the coronavirus disease 2019 (covid-19) outbreak in china: summary of a report of 72 314 cases from the chinese center for disease control and prevention sars-cov-2 and covid-19 in older adults: what we may expect regarding pathogenesis, immune responses, and outcomes covid-19 outbreak control, example of ministry of health of turkey covid-19 and crosstalk with the hallmarks of aging who timeline -covid-19 case fatality risk of the first pandemic wave of novel coronavirus disease 2019 (covid-19) in china factors associated with hospital admission and critical illness among 5279 people with coronavirus disease 2019 in new york city: prospective cohort study updated understanding of the outbreak of 2019 novel coronavirus (2019-ncov) in wuhan clinical characteristics and outcomes of older patients with coronavirus disease 2019 (covid-19) in wuhan, china (2019): a single-centered, retrospective study covid-19) -united states incidence, clinical outcomes, and transmission dynamics of severe coronavirus disease in california and washington: prospective cohort study presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with covid-19 in the new york city area analysis of epidemiological and clinical features in older patients with corona virus disease 2019 (covid-19) out of wuhan cov-2 surveillance group. epidemia covid-19, aggiornamento nazionale case-fatality rate and characteristics of patients dying in relation to covid-19 in italy an efficient covid-19 prediction model validated with the cases of china, italy and spain: total or partial lockdowns fast and local: lockdown policies affect the spread and severity of covid-19 coronavirus disease-19: the first 7,755 cases in the republic of korea viral dynamics in mild and severe cases of covid-19 cov-2 viral load predicts covid-19 mortality clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study a geroscience perspective on covid-19 mortality coronavirus disease 2019 in china the time-varying serial interval of the coronavirus disease (covid-19) and its gender-specific difference: a data-driven analysis using public surveillance data in hong kong and shenzhen clinical characteristics of refractory covid-19 pneumonia in wuhan, china. clinical infectious diseases impact of sex and gender on covid-19 outcomes in europe gender differences in patients with covid-19: focus on severity and mortality. front public health prevalence of comorbidities and its effects in patients infected with sars-cov-2: a systematic review and meta-analysis epidemiology of covid-19 in a long-term care facility in king county twelve-year trends in the prevalence and risk factors of diabetes and prediabetes in turkish adults changes in hypertension prevalence, awareness, treatment, and control rates in turkey from baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region covid-19 spiraling of frailty in older italian patients frailty index predicts poor outcome in covid-19 patients. intensive care medicine untangling the concepts of disability, frailty, and comorbidity: implications for improved targeting and care multimorbidity predict death among covid-19 patients: results of the sars-ras study of the italian society of hypertension. hypertension. 2020:hypertensionaha12015324 serum lipids and neopterin in urine as new biomarkers of malnutrition and inflammation in the elderly letter to the editor: low-density lipoprotein is a potential predictor of poor prognosis in patients with coronavirus disease 2019 the role of lipid metabolism in covid-19 virus infection and as a drug target clinical presentation of covid19 in dementia patients. the journal of nutrition covid-19) in china: a report of 1014 cases chest ct findings in cases from the cruise ship -diamond princess‖ with coronavirus disease 2019 (covid-19) we thank to all health care workers in turkey who contributed. a c c e p t e d m a n u s c r i p t 20 a c c e p t e d m a n u s c r i p t 23 a c c e p t e d m a n u s c r i p t key: cord-296494-6kn4mr04 authors: saban-ruiz, j.; ly-pen, d. title: covid-19: a personalized cardiometabolic approach for reducing complications and costs. the role of aging beyond topics date: 2020-05-12 journal: j nutr health aging doi: 10.1007/s12603-020-1385-5 sha: doc_id: 296494 cord_uid: 6kn4mr04 covid 19 is much more than an infectious disease by sars-cov-2 followed by a disproportionate immune response. an older age, diabetes and history of cardiovascular disease, especially hypertension, but also chronic heart failure and coronary artery disease among others, are between the most important risk factors. in addition, during the hospitalization both hyperglycaemia and heart failure are frequent. less frequent are acute coronary syndrome, arrhythmias and stroke. accordingly, not all prolonged stays or even deaths are due directly to sars-cov-2. to our knowledge, this is the first review, focusing both on cardiovascular and metabolic aspects of this dreadful disease, in an integrated and personalized way, following the guidelines of the cardiometabolic health/medicine. therefore, current personalized aspects such as aceis and arbs, the place of statins and the most appropriate management of heart failure in diabetics are analysed. aging, better than old age, as a dynamic process, is also considered in this review for the first time in the literature, and not only as a risk factor attributed to cardiovascular and non-cardiovascular comorbidities. immunosenescence is also approached to build healthier elders, so they can resist present and future infectious diseases, and not only in epidemics or pandemics. in addition, to do this we must start knowing the molecular mechanisms that underlying aging process in general, and immunosenescence in particular. surprisingly, the endoplasmic reticulum stress and autophagy are implicated in both process. finally, with a training in all the aspects covered in this review, not only the hospital stay, complications and costs of this frightening disease in high-risk population should be reduced. likely, this paper will open a gate to the future for open-minded physicians. disease had been published, but none are about an integrated cardiometabolic approach (see table 1 ). our questions are, why?, and beyond, would it be useful?. the term "cardiometabolic medicine" (cmm), synonym of "cardiometabolic health" (cmh), was launched officially in october 2006 in boston, with the celebration of the first congress, a meeting point for physicians from different specialties, biologists, biochemists, pharmacists, cardiovascular bioengineers and researchers in all these fields. the term "cardiometabolic» had previously used by pescatello in 1999 for obesity (13) , by sowers in 2001 for "cm syndrome" (14) , and by vasudevan & ballantyne in 2005 (15) for "cm risk» in two phases. firstly, the term was used by khan, buse, ferrannini and stern in a symposium whose proceedings were never published. fortunately, their conclusions were collected and valued as of great interest by other authors (vasudevan & ballantyne) ; they published them that same year (15) laying the groundwork for a new enlightened medicine. this medicine, the cmm, is much more eagerly, dynamic, open that the classical cardiovascular medicine, and at the same time much more predictive, preventive and anticipatory. to topping it all off, the cmm is the prototype of the modern "precision medicine", on which the american government spent so many millions in research during the last decade (16) . this cmm approach is not new, we saw it was born starting this 21st century, but we frequently forget, at the expense of the most classical cardiovascular term, actually dating from the 20th century. despite the latter one, is still useful in certain specialties (cardiology, neurology and vascular surgery), it is seldom useful for defining prevention strategies. therefore, cmm had allowed detection of causes and had predicted the consequences of a rise of cardiometabolic diseases across the world (especially in low-and middle-income countries) (17) , and had proven to prevent and predict events (18) , and at the same time, facilitating the cost analysis. bearing this in mind, it is quite likely, that if we have fewer complications, particularly severe ones (cardiac arrest, ventricular tachyarrhythmia, acute heart failure, acute coronary syndrome, haemorrhagic or massive ischaemic stroke), this integrated approach could cut down the elevated mortality in the highest risk group (cancer, copd and oldest subjects with comorbidities), usually preceded by a multi-organ failure. seven types of hcov had been described. on one side, we have four genuinely human ones (229e, nl63, oc43 and ku1) which are responsible for almost 30% of common colds. on the other hand, three mutated variants of acov had been described (see below) causing zoonotic disease when infecting human beings. (19) this happened also with the nipah virus infection in 1998 (malaysia) and 2004 (bangladesh) from the so-called "fruit bat". after this outbreak, as they did after latest mers epidemic, the cepi (coalition for epidemic preparedness innovations), worked successfully on vaccines to prevent future epidemics with both viruses. in relation to mutated cov they are included strangely enough as hcov. (20) in either case, unlike the first group of regarding acov, the main target is usually the digestive tract, and rarely can induce a mild bronchitis (22, 23) . like all coronaviruses, sars-cov-2 is composed of rna involved by a glycoprotein and lipid membrane. this is not a specific membrane composition of this subfamily of viruses, but of all membranes of living beings, including plants (these are surrounded by a cell wall). this new virus´ membrane contains moreover specific proteins of cov named s, e, n and m proteins. regarding the external is named "s" protein, forms spikes (hence its name), and have two subunits (s1 and s2) that allows it, if recognized by the right receptor (see below), to penetrate into the cells. from what is known so far in covid-19, the mutation especially affects it, making it especially harmful. the "e" protein is key to infect other cells. the "n" protein, a haemagglutinin-esterase protein that allows them to camouflage the genetic material. finally, the "m" (membrane) protein plays a central role in virus assembly, interacting through both the transmembrane domain and endodomain, turning cellular membranes into workshops where virus and host factors come together to make new virus particles (24) . even more interesting, taking into account that at least 50% of covid-19 patients have hyperglycaemia on admission or in the first days of hospitalization (25) , the transmembrane domain has a potential n-glycation site (26) that in covid-19 would deserve further research. the reason is that other proteins (e.g. ldl, myelin-proteins, collagen, myosin) become more pathogenic when they bind non-enzymatically to glucose (27) . on the other hand, a host transmembrane serine protease, tmprss2, synthesized by the microvascular endothelium, promotes the entrance of sars-cov into the cells in two steps: firstly, tmprss2 acts on the s2 facilitating fusion of the virus to the cell membrane. secondly tmprss2 activates the spike and cleaves the receptor that is ace2 (angiotensin-i converting enzyme-2), located in the pneumocytes type ii, facilitating interaction and penetration (28) . a recent report suggests a role for tmprss2 variants and expression levels in modulating covid-19 severity (29) . regardless the initial cases of the pandemic outbreak, that are still under investigation, all the cases after the second week, were inter-human transmission, with a mean incubation period of about 5.2 days. a single systematic review found no statistically significant difference in common symptoms between patients with severe or mild / moderate covid-19 (30) . in an initial phase, the virus enters through the upper airway and may produce signs and symptoms like fever, malaise, myalgia and occasionally sore throat and sneezing. afterwards, it descends into the lower airway and there it is responsible for a dry or barely productive cough. not uncommonly, the virus colonizes the airway and patients remain asymptomatic for about two weeks; they can be contagious in this period, whilst this has not been documented in patients with common flu. fever is the most common symptom, but is accompanied by generalized myalgia only in 44% of total affected, markedly different from the flu, where it is close to 100%. other frequent symptoms are cough (present in about 75%), anosmia is a frequent symptom, up to 60% of confirmed cases in some series (30) , headache and drowsiness (<10%), and confusion (<5%, especially in older patients). occasionally in this phase the patient may have sore throat, ageusia and rhinorrhoea (<5-10%), and gastrointestinal reaction (<10%) (7, 25) . in a second phase, presumably preceded of a virus-receptor interaction (see below), it is possible a pulmonary involvement, but not always. if this happens, dyspnoea is more frequent in severe cases and, in some studies, is a marker of severe disease (30) . dyspnoea usually coincides with the appearance of lung infiltrates in the chest x-ray and ct-scan. in a third phase, by the seventh to the tenth day about 20% of patients can develop acute respiratory distress syndrome (ards) and 10% a multiple organ failure (7, 25) . regarding lung involvement, the main target in covid-19, the sars-cov-2 induces a direct damage at this level, via the same receptor that sars-cov used in 2003, the carboxypeptidase ace2 (angiotensin-i converting enzyme type 2) (31), the homologue of ace, a dipeptidylcarboxypeptidase. ace is the classical enzyme of ras that cleaves angiotensin i to generate angiotensin ii, which is a key effector peptide of the system and exerts multiple biological functions. ace is occasionally named incorrectly as ace1, is simply ace because history, including the scientific history, cannot be rewritten. ace is the main enzyme of the ras with low ace2 levels in blood (28) but these levels increase in patients treated with aceis/arbs, generally with hypertension (htn) and/or diabetes mellitus (dm) (32) . at a local level, ras, with all its components such as ace, renin, angiotensinogen and aii, was firstly reported in dog's brain and later in other organs (28, 33) . ace in vascular cells is expressed in the endothelial cells (ec) and smooth muscle cells (smc) independently; so, ace in smc, unlike the ec, is insulin-dependent (34) including the lymphatic system. on their behalf, its homologue ace2 is expressed mainly locally (by the local ras) with a low production by the systemic raas axis which include, unlike the local system, the aldosterone in the equation. ace2 is one of the type-i integral proteins, expressed fundamentally at the cell surface as an ectoenzyme and is found at heart, kidney, small intestine, lung (type ii pneumocytes), pancreas and liver among others. the expression of ace2 in the endothelium and vascular smc opens an unexplored pathway in subjects with covid-19 who develop acute coronary syndromes. it had been demonstrated that in patients treated with ras-blockers, the risk of atherothrombosis decreases. this could be explained because by dampening local a-ii and vice versa, an over activated ace2 could produce the opposite effect (35) ; this does not happen in older people, because they have ace2 expression reduced in all organs in which it has been described, but especially at the vascular level (36) . at both the systemic and vascular level, ace2 acts as a buffer, so that angiotensin-ii does not rise excessively when its receptor is exogenously blocked. therefore, ace2 is a key counter regulatory enzyme that degrades angiotensin ii to angiotensin-(1-7), thereby attenuating its effects on vasoconstriction, sodium retention, and fibrosis. although angiotensin ii is the primary substrate of ace2, that enzyme also cleaves angiotensin i to angiotensin-(1-9) and participates in the hydrolysis of other peptides (28) . both aces uses zn² + and clas cofactors for being metalloproteases (37) . it could have therapeutic implications especially in people who use zinc as a nutraceutical (38) . the ace2, but not the ace is expressed in the type ii pneumocytes (28) but it cannot be ruled out that endothelial ace2 could collaborate coming from neighbouring microvascular endothelial cells as demonstrated in sars (39) . the true physiological significance of ace in the pneumocyte is currently unknown. after learning the important role played by ace2 in sars and covid-19, it is strange that the cov nl63-s, which also binds to ace2, do not cause severe lung disease. (40) this would lead us to investigate a co-receptor in covid-19, a pathway that is not being considered. there is no doubt that in covid-19, the immunology plays a relevant role from the beginning. in the initial contagiousness, the older people are more vulnerable because of their immunosenescence (41) . afterwards, the immunology is responsible of the fever, inducing the virus directly a secretion of mip1a/ ccl3 by the macrophage in the phase 1; this is responsible of a monophasic fever at hypothalamic level (42) , that is resistant to non-steroidal anti-inflammatory drugs (nsads) (e.g. ibuprofen, a cyclooxygenase inhibitor). in contrast, the fever induced by tumoral necrosis factor alpha (tnfα) and interleukin 1 (il-1), the two usual endogenous pyrogens in flu and other viral infections, they do respond to nsaids (43) . mainly in risk groups, by the seventh to the tenth day, some patients can develop a more severe phase; it has been correlated with chemokine secretion from endothelial cell (mcp-1) and the macrophage (cxcl10/ip-10). the massive knock-on (or pull effect) of chemokines attracts new macrophages, that are hyperactivated and release large amounts of cytokines, that can act locally or pass into the circulation. the more severe cases are related to a cytokine storm (commanded by il6), related to a macrophage activation syndrome (mas), which is the cause not only of adrs but occasionally, of myocarditis (see below), and in the most severe cases. of a multi-organ failure. this syndrome, initially described as multiple organ dysfunction syndrome (44), is not always lethal despite the impaired function of the liver, kidneys and brain (among other organs), but even when not lethal can leave disabilities in up to 15-20% of the patients. the genome of this mutated coronavirus, has been published recently (45) and it is the basis for the investigation of an adequate vaccine (46) . alignment of the full-length genome sequence showed that is a positive-sense rna, 29903-bp (watson-crick base pairs) betacoronavirus. the closest relationship was with the bat sars-like coronavirus strain (batcov ratg13), with 96% identity. the other rational therapy, convalescent plasma transfusion (47), are not available at present. in the meantime, different therapies have been tried and their results may be considered as frustrating in high risk groups (6) . recently, two antiviral agents, remdesivir and ivermectin, are being tested at a great scale. remdesivir, a classical antiviral agent, up to now not traded worldwide (48) ; ivermectin, a classical antiparasitic drug recently approved by the fda for this epidemic because of its antiviral action (49) . regarding to hydroxychloroquine / azithromycin (hc/ az) and corticosteroids, two of the most tested therapies, we would like to point out a couple of comments related to their cardiometabolic aspects. firstly, hc and az induce inhibition of cardiac herg/ikr (rapid ik) potassium channel, inducing mild qt prolongation, with subsequent risk of ventricular arrhythmia and even cardiac arrest, thus needing qt monitoring. secondly, high doses of corticosteroids not only produce hyperglycaemia in patients, even in not diabetics (50) , but also raise blood pressure and in many cases lead to hypokalaemia, increasing the risk of arrhythmias. other causes of non-diabetic hyperglycaemia, in many cases associated to corticosteroid administration would be high doses of loop diuretic, sepsis and very especially the enteral and parenteral nutrition (50, 51) . it is clear that we are still far from a useful vaccine and convalescent plasma transfusion. furthermore, usual management of the disease is not enough, and two of the most commonly used treatments either have frequent side effects (corticosteroids) or have potentially severe adverse effects (hc/ az). the question now is, what can we do pro-actively, in the meantime? within the cardiometabolic (cm) aspects of covid-19, we first looked at dm and htn. both of them, in addition to be among the main risk factors for pandemic mortality, are strictly related to age, weight gain and low physical activity. dm and htn form part of three syndromes closely related but not synonymous, the metabolic syndrome (ms) (52), the cm syndrome (14) and the cm risk (53) . ms is the core of the other two (figure 1) , and cm risk is the core of cmm/cmh born just a year later. in the past, during the sars and mers outbreaks, the high prevalence of dm and htn was attributed to the age (54) but no further studies were conducted. in covid-19, in a population of 686 patients with mean age 48.9 years, 42.7% females, the composite endpoints that consisted of admission to the intensive care unit (icu), invasive ventilation or death, were analysed. the most prevalent comorbidity was htn followed by dm. after adjusting for age and smoking status, dm and htn had similar hazard ratio of reaching to the composite endpoints, but they never overtook copd nor cancer (55) . it is known that other rna viruses such as enterovirus b, coxsackie (b1, b3 and b5) and human mastadenovirus c are implicated in autoimmune destruction of pancreatic islet β cells, which results in a typical autoimmune t1dm (56) . the question that immediately can be raised is if sars-cov-2 (also a rna virus) is able to cause also a typical autoimmune t1dm. this possibility has not been discarded, but it would be more likely a not autoimmune, atypical t1dm (57) . it looks strange that no cases of this type of dm had been described, in more than a million and a half test-confirmed patients, while in sars, many cases were described in less than one thousand infected patients (58) . the most surprising fact about this study, was that the pancreas damage was correlated with the expression of ace2 in the endocrine tissues of the pancreas, leaving no doubt about a cause and effect relationship. in relation to the heart, both htn and dm can predispose to myocardiopathy (59) and in presence of viral respiratory infections, like flu annually (60) or now in covid-19 (61), can predispose to heart failure (hf). this is without doubt the most frequent cardiac complication of these patients, especially if we add anaemia and/or tachyarrhythmia (flutter and atrial fibrillation, episodes of supraventricular or ventricular tachycardia) both not uncommon in intensive care units (62, 63) . in addition, sars-cov-2 can induce severe myocarditis with tnt and nt-probnp as biomarkers (64) (65) (66) . this is not a surprise, because in animal models of cov, myocarditis was described almost 30 years ago, in 1992 (67); but in sars, although creatine-kinase mb isoenzyme was a predictor for death (58) no study has demonstrated any case of well-documented myocarditis. covid-19 patients who develop myocardial injury, usually dm and/or elderly patients, have a more acute presentation, with higher incidence of adsr and more frequent need for assisted ventilation than those without myocardial injury (64) . the likely damage of the myocardium in covid-19 may be, at least partially, from the release of cytokines and secondary activation of the nf-kb signalling pathway (68); actually, the virus cannot penetrate because this cell does not have a receptor for it (69) . although abundant ace2 (sars-cov and sars-cov-2 receptor) immunostaining was found in the heart, unfortunately the authors did not specify if was in the endocardium and/or myocardium of the affected tissue (70) . in aged covid-19 patients or with history of coronary artery disease (cad) an acute coronary syndrome (acs) can also be seen for plaque vulnerability in the presence of a pro-inflammatory state with cytokine release (71) but from the experience in animals, could it be plausible that any of them could be due to arteritis? as we already pointed out at the beginning of this paper, arteriviridae, of the order of nidovirales (like the cov), are responsible of equine viral arteritis (eva) (72) a disease that has too many similarities with covid-19. the main one is that both of them can present with interstitial pneumonia and the microscopic findings, included diffuse alveolar damage with exudates, lymphocytic inflammation and multinucleated giant cells, suggesting hyperactive macrophages, were seen alongside large atypical pneumocytes (51) . in eva´s necropsies, antigens can be demonstrated not only within the cytoplasm of the epithelial cells, but also within endothelial, macrophages and cardiac myocytes (51), something has not been proven in covid-19, at least not yet. it should also be considered in covid-19 the suitable diagnosis and management of other vascular complications such as stroke and finger ischaemia, both frequent in the icus (73, 74) . if we look at figure 1 and table 2 , we can observe that there are as many possible combinations as patients; that implies that treatments must be personalised. this had been advocated during last years by the most prestigious societies and institutes, such as the aha, ada, aace, esc, easd and the nice institute among others. among all these combinations, we have chosen the following three, because they are highly topical in the cmm. they can be applied to patients with covid-19 in their acute phase of hospitalization or from the respiratory point of view, in a more stable phase (prehospitalization phase or when they are already convalescing at home). the first aspect regarding personalised treatment is related to htn and covid-19, a debate about keeping or discontinuing aceis and arbs started. the european medicines agency (ema), european society cardiology (esc) and american college cardiology (amc) all agreed that they should be continued in well-controlled patients and also in patients with previous cardiovascular pathologies of various kinds (28, 32 -hdl-c and tg (metabolic syndrome) -ldl-c 2 (cardiometabolic risk) if fh is suspected request a genetic ldl/apob100 receptor study -apob and non-hdl-c (new targets alternative to ldl-c) (1) in hospital setting, glycaemia, hscrp and ferritin are not valuable in a basal cardiometabolic status. must be repeated at 2-month follow-up; (2) ldl-p (particle) (nmol/l) better than ldl-c if a nuclear magnetic resonance spectroscopy is available; (3) if ca is high or p is low: request pth (parathyroid hormone). also request pth, if gfr is<50; (4) as stress measure in aging and as diagnostic tool in patients with suspected secondary htn. have reduced ace2 expression and upregulation of angiotensin ii (aii) and consequently its proinflammatory signalling way could be hyper-activated. the increase in ace2 levels, and consequent reduction of aii, aceis/arbs treatment would be especially beneficial for this age subgroup, in line with the evidence of a protective role of aii antagonism against sepsisassociated acute lung injury (22) . on the other hand, sars-cov-2 particularly attacks dm patients (75) , more frequently and with greater severity, being dm the cardiometabolic disease par excellence because they are often accompanied by other risk factors and atherotrombotic disease (atd) (76) . from lessons learned from experimental dm, we know that affected animals have a decreased vascular expression of ace2, and it has been associated with an increased predisposition to atd, coincidentally, as in elderly patients (77) . this would lead us to extend the trials with rasblockers recommended by the nia (36), if it were not for the fact that most of them are already on that treatment. the second aspect should be regarding the use of statins, the star drug treatment of cmm/cmh in an outpatient context. this is a subject of debate in hospitalized patients except for those with previous history or recent stroke or acs, and possibly in those with familiar hypercholesterolemia, but only if a prolonged benefit is presumed. apart from this, the risk/ benefit balance in patients with covid-19 remains to be clarified. the third aspect would be the combination of t2dm and heart failure (hf) (the most frequent cardiac complication in any of the phases of the disease), which is present in a high percentage of patients, especially those at higher risk. excluding secondary dm (corticosteroids, diuretics, sepsis, enteral / parenteral nutrition), these patients would benefit from taking a sglt2 inhibitors (sodium-glucose co-transporter-2, or gliflozins) (78) when they are in a stable phase. in these patients, the risk of ketoacidosis is quite low, but it may happen in the hospitalized patient (myocardial or cerebral infarction, sepsis ...) and more likely, if they are being treated with these drugs. a recent theory explains that at least one of the mechanisms about the metabolic syndrome genesis could be a chronic activation of the sympathetic nervous system. according to this theory, sglt2 inhibitors could have strong beneficial effects, not only in heart failure but also in a general cv level. this likely cv protection by sglt2 inhibitors is detailed in figure 2 furthermore, in hf we should consider not only the association with dm, but also its type; i.e., if hf is acute or chronic, and if chronic, to consider if reduced or preserved ejection fraction (hfref or hfpef), because they have different therapeutic approaches (79) . synthesising all the above, it looks like we are facing a disease, which is much more than an infectious/immune respiratory disease: simultaneously, it is also a cardiometabolic disease. the respiratory side is well known and managed, with poor results in the risk group, exactly the one that has more cardiometabolic alterations. regarding this group of disorders, discussed in detail above, we do not know why they are always approached separately, when there are many advantages of their overall management, and it would have an unavoidable impact on morbidity, lethality and costs as demonstrated in patients followed up in outpatient clinic (27, 28) . in this sense, are we really optimizing the main targets during the hospitalisation? do we give the value it really has?. we are not speaking of ldl-cholesterol, as in the case of high cv risk patients followed as outpatients. in the presence of recent events where the ldl can be important, but even more important is the inflammation, to justify treatment with statins (80) . except in this last group, we speak of high and low blood pressure and/or high and low glycaemia, both type of decompensations are important in the two diseases. however, if we have to choose in the case of blood glucose, hypoglycaemia can have more serious consequences, especially in older patients, as the ada stated in their last report (81) . furthermore, we talk also of early detection and treatment of heart failure, arrhythmia or stroke that can go unnoticed in icu patients with induced coma, and so many more aspects that should not be overlooked by monitoring only the lung disease when this is not the one that will always kill our patients. one of the great advantages that cmm has over classic cv medicine, and that we did not say previously, is that cmm is seriously concerned with aging, both at clinical level (for healthy aging) and at research level. in the same sense, whilst most researchers and clinicians interested in covid-19 have attributed its greater aggressiveness to previous comorbidities (6), as convinced cmm supporters and of its interest in the aging process, we believe that despite our suspicions are correct, this is not enough. we will review the molecular aspects that underlie human aging and whether any of these mechanisms are involved in immunosenescence. if this is true, it will be easier in the future to deal with the whole process of aging, by slowing down the harmful processes and favouring the beneficial ones. a modern theory of aging named «a vascular theory of aging» (81), has rescued from oblivion two old aphorisms: «man has the age of his arteries» (thomas sydenham, 17th century) and «man has the age of his endothelium» (rudolf altschul) (82). both were visionaries, but especially the latter when he published his book (in 1954) without even knowing the nitric oxide, the main endothelial product, discovered in the 1980s, leading furchgott, ignarro and murad, to be recognized as the nobel prize in physiology or medicine in 1998. advances in the physiology in the last decade consider atherothrombosis and aging as an inflammatory disorder (81) but, which molecular aspects are common to both conditions?. there are many important molecular aspects involving them, but the principal one is the combined activation of what we consider as the «lethal triad». the three elements of this triad are: 1) the mtor (mammalian target of rapamycin), 2) the nf-kb (nuclear factor kappa-b) signalling pathways (83) on one side, and 3) the nox enzymes (84) of the submembranous cytoplasm on the other side, which release more free radicals than the mitochondria itself. this triad alters the lipidoma at three levels, (membranous, cytoplasmic and circulating), as well as the so-called endoplasmic reticulum stress. this is a key process to understand both the endothelial dysfunction (85) preceding atherotrombotic disease (atd), and the dysfunction of the beta cell (86) in t2dm and in the aging process (87) in part by the endothelial dysfunction at microvascular level within of vascular theory of aging (81) . fortunately, autophagy and especially mitophagy (mitochondrial autophagy) (88) protect us from apoptosis (programmed cell death), as long as our genetics and epigenetics (influenced by healthy nutrition and regular physical activity) allow it. finally, regarding the immunosenescence, its three hallmarks are: 1) the reduction in the number of peripheral blood naïve t cells population; 2) a relative increase in the frequency of cd28 memory t-cells subset, and 3) a low-grade chronic inflammation that characterizes aging: "inflamm-aging" or "inflammaging". (89) surprisingly, there are extensive data showing, moreover, that latent persistent human cytomegalovirus infection is also associated with age-related immune dysfunction in the t cells, which might enhance immunosenescence. in this way, in the case of covid-19, in older groups, a virus could be predisposing to another virus. (90) if we can still get even more surprised, both the endoplasmic reticulum stress and autophagy are involved in the process of immunosenescence (91) . in accordance with the above, could the immunosenescence be related to the special aggressiveness of covid-19 in the elderly?. the coronavirus disease 2019 (covid-19) outbreak is evolving rapidly worldwide. from a dangerous situation due to its respiratory facet, there is another less well-known one (at least up to now), the cardiometabolic facet that can precede, accompany or even kill us if we do not keep our eyes open. the high lethality of sars-cov-2 in subjects with previous hypertension, diabetes and atherotrombotic disease. in addition to several cardiovascular complications arising during the hospitalization, include severe arrhythmias, acute heart failure by myocarditis and stroke. often forgotten in reported series, are an ample justification that we are dealing with a disease of a great cardiometabolic potential that we should not overlook. other cardiometabolic aspects, like the possible n-glycation of viral protein m in patients with hyperglycaemia will need further investigation. in addition, the role of serinprotease tmprss2, synthesized by the endothelium and involved in the interaction of the virus with its recipient, could be a potential target for the treatment. its secretion is not the unique endothelial product, also ace2, considered only of pulmonary origin could derive from the microvascular endothelium as demonstrated in sars. the role of convalescent plasma transfusion and recent antiviral agents such as ivermectin and remdesivir, in improving covid-19 prognosis in high-risk patients remains to be demonstrated. in the meantime, here we have learned that cardiometabolic medicine could help us to reduce, using an anticipative and integrated approach, the morbidity and mortality related to this current sars-cov-2 pandemic while reducing costs. finally, the molecular aspects of aging in general and in the immunosenescence in particular, will serve us better in the near future. knowing what happens, the solution is a matter of time. with healthier old people, we will make it more difficult for viral infections in general, not only in the course of epidemics or pandemics. on the other hand, in these situations, the best way for prevention is to not let them happen and for this purpose, cepi (coalition for epidemic preparedness innovations) exists, let us help them with more resources. nidovirus infections: experimental model systems of human neurologic diseases equine viral arteritis in breeding and sport horses in central spain world health organization working group on international and community transmission of sars. public health interventions and sars spread genomics and zoonotic infections: middle east respiratory syndrome early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia the origin, transmission and clinical therapies on coronavirus disease 2019 (covid-19) outbreak -an update on the status novel coronavirus 2019-ncov: prevalence, biological and clinical characteristics comparison with sars-cov and mers-cov cardiovascular considerations for patients, health care workers, and health systems during the coronavirus disease 2019 (covid-19) pandemic cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (covid-19) covid-19 and the cardiovascular system potential effects of coronaviruses on the cardiovascular system. a review csc expert consensus on principles of clinical management of patients with severe emergent cardiovascular diseases during the covid-19 epidemic exercise prescription and management for cardiometabolic health update on the cardiometabolic syndrome cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus precision medicine understanding the rise of cardiometabolic diseases in low-and middle-income countries prevention or reversal of cardiometabolic diseases pathways to zoonotic spillover identification of new human coronaviruses three emerging coronaviruses in two decades the story of sars, mers, and now covid-19 the discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice interspecies transmission and emergence of novel viruses: lessons from bats and birds a structural analysis of m protein in coronavirus assembly and morphology clinical features of patients infected with 2019 novel coronavirus in wuhan, china sequence analysis of the membrane protein gene of human coronavirus oc43 and evidence for o-glycosylation role of glycated proteins in the diagnosis and management of diabetes: research gaps and future directions renin-angiotensin-aldosterone system inhibitors in patients with covid-19 ace2 and tmprss2 variants and expression as candidates to sex and country differences in covid-19 severity in italy on behalf of the oxford covid-19 evidence service team centre for evidence-based medicine, nuffield department of primary care health sciences, university of oxford (2020) in patients of covid-19, what are the symptoms and clinical features of mild and moderate cases? tissue distribution of ace2 protein, the functional receptor for sars coronavirus. a first step in understanding sars pathogenesis coronavirus disease 2019 (covid-19) infection and renin angiotensin system blockers jama cardiol physiology of local renin-angiotensin systems insulinmediated regulation of the endothelial renin-angiotensin system and vascular cell growth angiotensinconverting enzyme 2 attenuates atherosclerotic lesions by targeting vascular cells the dilemma of coronavirus disease 2019, aging, and cardiovascular disease. insights from cardiovascular aging science angiotensin-converting enzyme-2 (ace2): comparative modeling of the active site, specificity requirements, and chloride dependence zinc and its importance for human health: an integrative review expression of severe acute respiratory syndrome coronavirus receptors, ace2 and cd209l in different organ derived microvascular endothelial cells human coronavirus nl63 employs the severe acute respiratory syndrome coronavirus receptor for cellular entry cellular senescence and the senescent secretory phenotype: therapeutic opportunities fever induced by macrophage inflammatory protein-1 (mip-1) in rats: hypothalamic sites of action the history of fever, leukocytic pyrogen and interleukin-1 progressive, or sequential systems failure. a syndrome of the 1970s genomic characterisation and epidemiology of 2019 novel coronavirus: implications for virus origins and receptor binding developing covid-19 vaccines at pandemic speed convalescent plasma to treat covid-19: possibilities and challenges remdesivir and chloroquine effectively inhibit the recently emerged novel coronavirus (2019-ncov) in vitro the fda-approved drug ivermectin inhibits the replication of sars-cov-2 in vitro management of diabetes and hyperglycemia in hospitalized patients. www.endotext.org management of hyperglycemia during enteral and parenteral nutrition therapy cardiometabolic risk assessment: an approach to the prevention of cardiovascular disease and diabetes mellitus diabetes mellitus, hypertension, and death among 32 patients with mers-cov infection, saudi arabia et al on behalf of china medical treatment expert group for covid-19. comorbidity and its impact on 1590 patients with covid-19 in china: a nationwide analysis immunology in the clinic review series; focus on type 1 diabetes and viruses: the enterovirus link to type 1 diabetes: critical review of human studies autoantibody negative new onset type 1 diabetic patients lacking high risk hla alleles in a caucasian population: are these type 1b diabetes cases? binding of sars coronavirus to its receptor damages islets and causes acute diabetes from left ventricular hypertrophy to congestive heart failure: management of hypertensive heart disease interactions between influenza and heart failure hospitalizations-diagnostic and pathogenetic issues covid-19 illness and heart failure: a missing link? jacc: heart failure anemia in intensive care: a review of current concepts incidence and type of cardiac arrhythmias in critically ill patients: a single center experience in a medical-cardiological icu association of coronavirus disease 2019 (covid-19) with myocardial injury and mortality jama cardiol sars-cov-2: a potential novel of fulminant myocarditis first case of covid-19 infection with fulminant myocarditis complication: case report and insights an experimental model for myocarditis and congestive heart failure after rabbit coronavirus infection cardiomyocyte-specific iκb kinase (ikk)/nf-κb activation induces reversible inflammatory cardiomyopathy and heart failure angiotensin-converting enzyme gene expression in skeletal muscle in patients with chronic heart failure binding of sars coronavirus to its receptor damages islets and causes acute diabetes pro-inflammatory cytokines in acute coronary syndromes: from bench to bedside equine viral arteritis critical care monitoring for cerebrovascular disease causes and outcomes of finger ischemia in hospitalized patients in the intensive care unit diabetes and covid-19 the hoorn study. von willebrand factor, c-reactive protein, and 5-year mortality in diabetic and nondiabetic subjects interaction of diabetes and ace2 in the pathogenesis of cardiovascular disease in experimental diabetes a new class of drugs for heart failure: sglt2 inhibitors reduce sympathetic overactivity discriminating clinical features of heart failure with preserved vs. reduced ejection fraction in the community american diabetes association: older adults: standards of medical care in diabetes 2020 a vascular theory of aging endothelium: its development, morphology, function and pathology nf-κb signaling as a driver of ageing nadph oxidases: key modulators in aging and age-related cardiovascular diseases endoplasmic reticulum stress: a critical molecular driver of endothelial dysfunction and cardiovascular disturbances associated with endoplasmic reticulum stress in the β-cell pathogenesis of type 2 diabetes endoplasmic reticulum stress coping mechanisms and lifespan regulation in health and diseases mitophagy: mechanisms, pathophysiological roles, and analysis immunosenescence and its hallmarks: how to oppose aging strategically? a review of potential options for therapeutic intervention front mechanisms underlying t cell immunosenescence: aging and cytomegalovirus infection front. microbiol endoplasmic reticulum stress in immunity the authors are indebted to dr. joseph hogg, partner at abbey house medical centre, for his critical review, helpful comments and careful english revision. ethical standards: not applicable. key: cord-324635-27q3nxte authors: bouza, emilio; brenes, francisco josé; domingo, javier díez; bouza, josé maría eiros; gonzález, josé; gracia, diego; gonzález, ricardo juárez; muñoz, patricia; torregrossa, roberto petidier; casado, josé manuel ribera; cordero, primitivo ramos; rovira, eduardo rodríguez; torralba, maría eva sáez; rexach, josé antonio serra; garcía, javier tovar; bravo, carlos verdejo; palomo, esteban title: the situation of infection in the elderly in spain: a multidisciplinary opinion document date: 2020-09-08 journal: rev esp quimioter doi: 10.37201/req/057.2020 sha: doc_id: 324635 cord_uid: 27q3nxte infection in the elderly is a huge issue whose treatment usually has partial and specific approaches. it is, moreover, one of the areas where intervention can have the most success in improving the quality of life of older patients. in an attempt to give the widest possible focus to this issue, the health sciences foundation has convened experts from different areas to produce this position paper on infection in the elderly, so as to compare the opinions of expert doctors and nurses, pharmacists, journalists, representatives of elderly associations and concluding with the ethical aspects raised by the issue. the format is that of discussion of a series of pre-formulated questions that were discussed by all those present. we begin by discussing the concept of the elderly, the reasons for their predisposition to infection, the most frequent infections and their causes, and the workload and economic burden they place on society. we also considered whether we had the data to estimate the proportion of these infections that could be reduced by specific programmes, including vaccination programmes. in this context, the limited presence of this issue in the media, the position of scientific societies and patient associations on the issue and the ethical aspects raised by all this were discussed. authors for their corrections and amendments. the final document has been reviewed by all the authors. we will now review the questions posed, the arguments made and the conclusion reached for each one. what do we mean when we talk about the elderly? how many are there in spain? how many will there be in the near future? presentation: the who publishes reports on ageing and health, or old age and its consequences, on a regular basis, at least since the 60's. cited here are a few more. we reproduce a paragraph in full [1, 2] "today, for the first time in history, most people can aspire to live beyond the age of 60. in low and middle-income countries, this is largely due to the significant reduction in mortality in the early stages of life, especially during childbirth and infancy, and in mortality from infectious diseases. in high-income countries, the sustained increase in life expectancy today is mainly due to the decline in mortality among older people". the report focuses on a redefinition of healthy ageing based on the notion of functional capacity: the combination of the individual's intrinsic capacity, relevant environmental characteristics and the interactions between the individual and these characteristics. in spain, according to data from the national institute of statistics [3] , 18 .7% of the population is currently over 65. that's about 8.7 million people. if we focus on those over 85, they currently account for 6% of the total population (about 2.8 million). forecasts for 2031 put the number of people over 65 years old at 12 million (26.2% of the population) and those over 85 at 3.9 million (8.5% of the population). thus, between 1960 and 2031, the number of people over 65 will have increased by a factor of 5 (from 2.5 to 12 million), and the percentage will have increased by a factor of 3 (from 8.2 to 26.2 %), while the number of people over 80 will have increased by a factor of 10 (from 370,000 to 3.9 million) and the percentage will have increased by a factor of 6 (from 1.2 to 8.5 per %). once the figures have been established, it is necessary to clarify that, according to the dictionary of the royal spanish academy of language (drael), "old" is "that person of age, commonly one who has turned 70". however, age is a purely theoretical value to distinguish a person as "old" or "elderly". taking the age of 65 as the threshold for the onset of old age dates back to the late 19th century, when less than 10% of those born reached that age. today, more than 90% of people reach the age of 65, so this age limit is shifting towards older ages. nowadays the concept of "old" is more related to "function" than to age. thus, the drael defines health as "that state in which the organic being normally exercises all its functions". therefore, one of the most relevant aspects in considering a person "old" is that they need help to carry out the activities of daily life (bathing, dressing, feeding, moving, etc.). we can find totally independent people in their 80's and others with a high degree of dependency in their 60's. formato es el de la discusión de una serie de preguntas preformuladas que fueron discutidas entre todos los presentes. empezamos discutiendo el concepto de "anciano", las razones de la predisposición a la infección, las infecciones más frecuentes y sus causas, y la carga laboral y económica que suponen para la sociedad. también preguntamos si teníamos datos para estimar la proporción de estas infecciones que podrían ser reducidas por programas específicos, incluyendo programas de vacunación. en este contexto, se discutió la baja presencia de este problema en los medios de comunicación, la posición de las asociaciones científicas y de pacientes sobre el problema y los aspectos éticos que todo esto plantea. the ageing of the population in more developed societies is an incontrovertible fact. in the face of the indisputable success in achieving a longer life for a large proportion of the population, questions arise as to the viability of social protection systems. by 2030, over 25% of the population will be classed as elderly and their quality of life will depend, to a large extent, on avoiding preventable diseases such as infectious diseases. it is a well-known fact that the elderly constitutes a risk group for distinct types of infectious diseases, whose diagnosis and treatment are hindered by several factors. around this fundamental fact, however, we find a lack of answers to simple questions about the size of the problem, its epidemiology, the capacity of the social response to it and the need to plan useful preventive measures to minimise risk and reduce costs. for this reason, the health sciences foundation, which has prevention as one of its main objectives, has organised a discussion and opinion meeting on the infectious diseases situation in the elderly in spain, aiming to answer a series of questions accepted by all the participants. greater difficulty in eliminating secretions. in the digestive tract it is common to find diverticuli in the mucosa that act as microorganism reservoirs. also, losses in secretory function with a tendency to gastric achlorhydria, but, above all, motor function which at oesophageal level, can favour aspiration phenomena. in the urogenital system there are usually alterations arising from pregnancy, childbirth, previous surgeries and local manipulations that make the free flow of urine difficult. in this vein, it is worth adding the frequency of subjecting the elderly to diagnostic or therapeutic examinations that may favour infections. in addition to the deterioration of mechanical barriers, there are losses in non-specific defence mechanisms. these include limitation to increase blood flow and vascular permeability at the infection entry points. the ability to mobilise polymorphonuclear leukocytes rapidly and the agility of phagocyte function is also impaired. chemotactic capacity decreases from the age of 70, as does the capacity for the intracellular destruction of microorganisms. ageing is associated with a chronic, progressive, nonspecific, low-level pro-inflammatory state, for which the english literature has coined the term "inflammageing", which favours an environment conducive to infection and further limits the possibilities of an effective response to it. the deterioration of adaptive immunity ("immunosenescence") associated with the ageing process has been known for years and affects both innate and acquired immunity [4] [5] [6] . immunosenescence includes qualitative losses in t-lymphocyte subpopulations with decreased activity of cd-4 helpers, cytotoxic cd-8s and a limitation in generating t-cell growth factor. ageing determines a tendency to invert the cd4/cd8 t-cell ratio. the number of dendritic cells decreases with age and the response of nk cells to stimulating cytokines is limited. it also increases the activity of cd-8 suppressors. b-lymphocytes are limited in their ability to produce antibodies and to respond to external antigens. furthermore, there is an increase in the production of autoantibodies and circulating immune complexes. a third group of factors that add to the microorganisms and the individual are environmental and social factors, such as hygiene neglect, poverty, isolation and a sedentary lifestyle. the fact of living in nursing homes and the increase in hospitalisations favours an insufficiently quantified environmental exposure [7] . there are multiple factors that explain the higher incidence of infections in the elderly. the clearest are those that have to do with alterations of the defensive barrier mechanisms. immunosenescence is a complex concept involving various alterations in the immunity of the elderly. what are the main clinical syndromes of infection in the elderly? the frequency and even the aetiology of infections af-therefore, the "elderly" is an enormously heterogeneous group in aspects such as the prevalence of chronic diseases (ischaemic heart disease, hypertension, diabetes, copd, etc), the need for consumption of drugs and the existence or nonexistence of physical, mental (dementia, depression) and social (loneliness, isolation, poverty) problems. conclusion: -the definition of elderly is artificial and refers to any person over a certain age (which can be set at 65, 70 or older) who has serious limitations in the exercise of their physical, mental or social functions. -in our society, currently, almost 20% of the population would meet a definition of elderly based exclusively on the criterion of age, but it is estimated that, with this criterion, the percentage in spain will be greater than 25% by the year 2031. the changes that take place throughout the ageing process favour the existence of infections. the simplest explanation is that with age the numerator of the aggression/defence equation increases (greater arrival of microorganisms that are also more virulent) and the denominator decreases (less defence capacity on the part of the organism). we can therefore divide the causes of the elderly person's predisposition to infection into those that depend on the microorganisms and those that depend on the host's defence mechanisms. there is no evidence that the microbiota of the elderly is quantitatively different from that of younger populations, nor necessarily more aggressive. however, it is an incontestable fact that previous infections, antimicrobial treatments, the greater ease of microorganism acquisition and living in proximity to other elderly people, can predispose the elderly to colonization and subsequent infection by multi-resistant microorganisms, with the presence of "superinfections", with a worse response to antimicrobials and increased resistance to them. in terms of host defence mechanisms, there are many factors that make the elderly more labile. mechanical barriers, for example, are the first element of defence, but they deteriorate progressively throughout the ageing process, facilitating the entry of microorganisms. the skin and mucous membranes experience physiological losses and often also those resulting from local or systemic diseases. the most important changes are: thinning, with loss of epithelial and mucosal cells, worse hydration and vascularization, loss of elasticity, decrease in mucous gland secretions of antimicrobial peptides, worse healing, loss of cellular macrophages in the skin (langerhans cells) and immobility with increased local pressure in certain areas. in the respiratory system, there is a decrease in the number of cilia and a slowing down of their activity, a reduction of alveolar macrophages, a decrease of the cough reflex and pend on their situation. in independent elderly people, the most common infections are respiratory conditions caused by viruses or bacteria prevalent in the community, urinary tract infections and intra-abdominal infections. in contrast, in institutionalised elderly people, bladder catheter-related utis, aspiration pneumonias, skin and soft tissue infections, and infections of the gastrointestinal tract predominate. which microorganisms are most common? how does the problem of multi-resistance impact on the elderly? presentation: it is important to remember that infections in the elderly may be caused by a greater variety of microorganisms than in the younger population, so it is essential to obtain samples for culture before administering empirical antimicrobial treatment [8] . thus, for example, while the vast majority of utis in young patients are caused by e. coli, in the elderly their relative importance is less. in the case of pneumonia, there is a higher incidence of gram-negative bacilli (gnb) and as far as meningitis is concerned, they are rarely of viral aetiology, while we must consider gnb and listeria monocytogenes. in a spanish study, including 333 elderly patients (mean age 81.6 years), with utis, the most frequently isolated microorganisms were e. coli, (67%), enterococcus faecalis (15%), klebsiella pneumoniae (10%) and pseudomonas aeruginosa (9%). in up to 8% of cases, more than one microorganism was isolated in the urine. the frequency of bacteraemia was higher with e. coli and lower with e. faecalis and p. aeruginosa and bacteraemia was not associated with a worse prognosis [22] . the frequency of multi-resistance increases with age and comorbidity. in this spanish study, the proportion of extended-spectrum beta-lactamase (esbl) producing e. coli and k. pneumoniae isolates was 20.1% and 36.3%, respectively. in the previously mentioned study of patients attending the emergency department, the elderly accumulated more risk factors for multi-resistance (p < 0.001) and suffered from septic syndrome more frequently (p < 0.001) [16] . there are few studies that analyse the overall aetiology of respiratory infections in older patients, and most work focuses on describing specific populations or groups of pathogens. the aetiological affiliation rate of respiratory infections in the elderly is very low (<30%), and this is due, among other things, to the difficulty many patients have in producing sputum and to the high frequency of empirical treatment [21] . if we analyse the aetiology of cap, the most frequent pathogen is s. pneumoniae (20-80%), followed by h. influenzae (3-39%), respiratory viruses (3-30%), legionella spp.(1-17%) and gnb (3-14%) . it is also necessary to remember the importance of viral pathogens in this population, since the prescription rate of unnecessary antimicrobials is very high in them (46% of the elderly with viral symptoms) [23] . in a study conducted in china, in 6 sentinel hospitals, it was observed that 31.64% of elderly patients with respiratory infection had a viral aetiology (41.8% among extra-hospital infections and 25.7% among fecting the elderly vary depending on the clinical environment (home, nursing home, hospital) and the functional status of the patient. in older, independent and healthy people, respiratory conditions caused by viruses or bacteria prevalent in the community, urinary tract infections (utis), whether catheter-related or not, and intra-abdominal infections (cholecystitis, diverticulitis) are common. in contrast, in institutionalised elderly people, utis related to the bladder catheter, aspiration pneumonia, skin and soft tissue infections and those of the gastro-intestinal tract (git) predominate. in hospitalised elderly people we have to consider nosocomial pneumonia, intravascular catheter associated infections and c. difficile infections as the most prevalent [8] [9] [10] [11] [12] [13] [14] . there is limited data analysing the comparative overall frequency of the different syndromes. in elderly people living in nursing homes, utis (at least 30-40% of healthcare-associated infections), respiratory infections, skin and soft tissue infections and those of the git predominate [15] . in a recent spanish multicentre descriptive study, conducted in 49 emergency departments, 11,399 patients were included, of whom 4,255 (37.3%) were at least 65 years old. compared to younger adults, older patients (mean 78.8 years) had respiratory, urinary and intra-abdominal infections more often, while there was no difference in the frequency of other syndromes [16] . these data are confirmed in chinese studies that analyse elderly patients attending emergency departments and also show a significantly higher incidence of respiratory and urinary infections [17, 18] . in the case of utis, the relative prevalence is influenced by the gender of the patient. thus, for long-term care facility (ltcf) residents and in hospitalised elderly people, uti is the number one cause of infection and is the second most common in older women living in the community [19] . the incidence in men ranges from 0.05/person year (1/20) in men aged 65-74 and reaches 0.08 (1/12) in men over 85. in women, the incidence of uti increases with menopause (0.07 per person/ year: 1/14), increasing to 0.13 per person-year (1/7.5) after age 85 [20] . in indwelling catheter-wearing patients, the incidence of utis is 3.2 cases per 1,000 catheter days, compared to only 0.57 per 1,000 days for all residents (x18). urinary tract bacteraemia was 3-39 times more common in patients with permanent urinary catheterization [20] and uti is also the most frequent cause of community-acquired bacteraemia in the elderly (40-57%). with respect to respiratory infections, the annual incidence of community acquired pneumonia (cap) ranges from 8-18.2 episodes per 1,000 people over 65 years of age and represents 30-40% of hospitalisations in this age group [21] . in japan, 96% of deaths from pneumonia occur in patients over 65 years of age. the risk of cap is 4 times higher in those over 65 compared to those under 45 and 10.8 times higher in those over 85 compared to adults aged 50-64. viral infections are also common in this age range, as we will see later. the most prevalent infections in the elderly de-is estimated at between 4 and 5 episodes per 1,000 days of stay in the residence [33, 34] . the figures rise to 11 for those with some kind of prosthetic material [35] . we have several european halt studies (healthcare-associated infections and antimicrobial use in long term care facilities), with participation from 24 countries, including spain, with a prevalence of infection of 4.7% and 5% at two different times [36] [37] [38] . a french multi-centre study, conducted in 578 nursing homes with 445,000 beds, shows an infection prevalence of 11.23% [39] . the first data on infection in nursing homes in spain come from the epinger study, conducted in community health centres in catalonia, which reported a prevalence of 6.5%, although it should be pointed out that in catalonia the concept of the community health centre would include medium-long term patients, while in the rest of the spanish autonomous communities this concept would be limited to nursing homes [40] . in another study, conducted by san sebastian's fundación matía, an infection prevalence between 6.44% and 4.80% was reported [41] . data derived from the vincat study in catalonia show a prevalence of healthcare-associated infection in long-term care centres of 10.2%, with a great diversity, depending on the type of care unit (subacute 22.3%, palliative 18.7%, convalescent 11.7%, long stay 8.1%) [42] . home is the most recommendable place for the healthy elderly to live, and even for the elderly patient, with healthcare falling to primary care professionals, although sometimes with the collaboration of some hospital resources. the ministry of health, social services and equality has for the first time published the results of the primary care clinical database (bdcap), a tool that allows for a more precise and systematized knowledge of the main health problems in spain dealt with by the doctors on the healthcare frontline. thanks to this register, a detailed picture of the health problems of the spanish population is available from primary care [43] . in this database, infections appear among those over 64 years old with an elevated frequency of 634.1 cases a year per 1,000 people (569.9‰ men and 682.7‰ women). the most frequent correspond to the respiratory system (317 cases/1000 persons/year), followed by urinary tract infections with (84.4 cases/1000 persons/year) and clear female predominance. finally, nosocomial infections are those that occur in hospitalized patients and are present more than 48 hours after admission. they are acquired by transmission from the environment, from other patients or from healthcare personnel. they are considered to be the most preventable cause of serious adverse events in hospitalised patients [44] . in general, these infections are related to invasive diagnostic or therapeutic procedures (urethral catheterization, surgical procedure, vascular catheter, invasive mechanical ventilation), all of which have in common the disruption of the host's own defences by a device or an incision, allowing the invasion of nosocomial infections) [24] . the most common cause was influenza (14% of all patients studied). rsv is also a significant pathogen in this population [25, 26] . the most important cause of git infection in the elderly is clostridioides difficile. c. difficile (c-diff) infection is currently the most prevalent nosocomial infection, affecting in more than 70% of the episodes patients over 65 years of age [27] . moreover, it is in this population that c-diff causes the highest morbidity and mortality, with an increase in c-diff-related mortality from 5.7 to 23.7 deaths per million population per year from 1999 to 2004 [28] in patients with an average age of 84 years having been described in the usa. it is interesting to note the safety of using the same therapeutic options in elderly patients, including faecal microbiota transplantation [29, 30] . the microorganisms causing infection in the elderly are qualitatively the same as in the population of other age groups, although there are quantitative variations. where do they get these infections? what proportion are acquired in nursing homes? at home? in hospital? in addition to the hospital and home environment, the elderly can acquire infections elsewhere, and in particular in other care units. this is the reason why, almost 20 years ago (2002), the term "health care-associated infection" began to be used, which is not only limited to hospitalized patients, but also extends the concept to patients in contact with the health system (home care of patients with high comorbidity and complexity; day care centres; major outpatient surgery units; outpatient dialysis centres; community health centres for chronic or convalescent patients). to a great extent, it is in nursing homes where patients with more comorbidities, polypharmacy consumption, a high degree of dependency and a high prevalence of invasive devices (bladder catheter, nasogastric tube, percutaneous gastrostomy) will be treated. in addition, the environment can facilitate the transmission of microorganisms between residents and healthcare personnel, as well as between residents. for all these reasons and the excessive or inappropriate use of broad-spectrum antibiotics, either empirically or prophylactically, multi-drug-resistant (mdr) infections can be generated. implementation of effective preventive measures in this population is very difficult to organise. in the united states of america, it is estimated that approximately 1.5 million people live in nursing homes and suffer between 1.6 and 3 million episodes of infection annually [31] . the prevalence of infections in these residences is estimated at 10% of the residents [32] and the incidence of new infections infectious diseases are the second cause of such admissions (16.2%), only surpassed by cardiovascular diseases (28.6%). pneumonia and sepsis are the most common infections causing admission in this population [48] . the elderly population also has longer hospital stays (5.5 days for those over ≥65) than those between 45 and 64 (5.0 days) and those between 15 and 45 (3.7 days) [49] . the elderly are treated by virtually every unit in a hospital but it is worth mentioning that those over 65 years of age represent 40% of those admitted to intensive care units [50] . the other group of interest is that of specialised geriatric units, not available in all hospitals, which have been shown to improve the functional status of patients and reduce the number of discharges to long-term care homes [51] . in a study by saliba et al., conducted in israel [52] , out of a total of 81,077 hospital admissions in the elderly between 2001 and 2010, the proportion of admissions due to infectious diseases rose from 16.9% in 2001 to 19.3% in 2010. globally, the most frequent infections causing admission were: those of the lower respiratory tract (lrt) (41.0%), followed by the utis (21.4%), upper respiratory tract (10.2%) and hepatobiliary (9.8%). in spain we do not have precise answers to the questions asked. the proportion of serious infections in the elderly requiring hospitalisation depends on several factors: type of infection, severity of infection and other factors such as the degree of frailty of the elderly, their place of residence and their ability to receive care at home. the environment and the resources available also influence the hospitalisation decision. however, in our environment, most serious infections in the elderly will require hospitalisation for at least a few hours. in spain, serious infections in the elderly can be treated by different professionals depending on the type and severity of the infection, and the environment in which it occurs. a high percentage are treated by "generalists" hospital specialists, or geriatricians. where infectious disease specialists are available they are of course involved in their management, either in beds in their own departments or as consultants. they can also be treated by specialists of the affected organ such as orthopaedic surgeons in the case of infections of prosthetic material, or vascular surgeons in the case of infections of vascular ulcers. and if, in the end, hospital admission is not decided, the patient is cared for by the primary care team. as an example, we have collated the urinary tract infections treated at the hospital general universitario gregorio marañón between 2015 and 2018. when uti is the main diagnosis that motivates admission (about 700 cases a year) about 90% of cases are cared in the medical departments. when it comes to secondary diagnosis (about 2,000 cases per year), the internal medicine and geriatrics departments take care of about 75% of the cases. preventive programmes, such as flu vaccination programmes, reduce the need for hospitalisation for respiratory infections by nearly 30%, both inside and outside spain [53] [54] [55] . microorganisms that are part of the patient's usual microbiota (endogenous microbiota), or selected by the selective antibiotic pressure (secondary endogenous microbiota), or by one found in the hospital environment (exogenous microbiota). to understand the main epidemiological data on hospital infections, the epine study (estudio de prevalencia de las infecciones nosocomiales en españa (study on the prevalence of nosocomial infections in spain)) was developed. this is a multi-centre system for monitoring nosocomial infections, based on the production of an annual prevalence study, which has been conducted since 1990 in a large group of hospitals in spain and was promoted by the spanish society of preventive medicine, public health and hygiene. its methodology guarantees a homogeneous and systematic collection of information, which allows us to understand the prevalence of healthcare-associated infections (hais) at a national level, by autonomous regions and hospitals. since 2012, every 5 years the epine study has been produced jointly with the european study (in 2012 and 2017) under the coordination of the ecdc [45] . based on the latest data published, in november 2017 (313 hospitals and 61,673 patients), a prevalence of nosocomial infection in patients over 65 years of age of 6.07% (infections acquired during the current admission), 7.45% (infection acquired during the current or previous admission) and 8 .76% (the total, including the centre's own or imported) has been reported. it should also be noted that this register shows that in 22% of patients over 65 years of age admitted for an infection, the infection had been acquired in the community (patient's home). the home, nursing homes and community health centres, healthcare centres other than hospitals and the hospital itself are often the places where the elderly acquire infections. the studies reviewed allow us to estimate a prevalence of infection of between 4 and 10% in nursing homes in spain, depending on their complexity, and between 6 and 9% in hospitalised elderly people. in primary care and in the residential environment, there is no homogeneous epidemiological record of this problem. what proportion of severe infections in the elderly require hospitalisation? by whom are they treated? in the united states of america, patients over 65 years of age account for almost 40% of total adult admissions and the cost of these hospitalisations represents nearly 50% of the total cost for hospitalisation, although those over 65 years of age account for less than 20% of the total adult population [46, 47] . those over 65 years of age are admitted to hospital three times more often than those between 45 and 65 years of age, and those aged 85 or over account for 9.2% of all hospital discharges, although they represent only 1.8% of the population as a whole. moreover, in our opinion, in these departments, emergency assessment should not be focused only on the isolated episode for which the patient consults, but the particulars of the elderly person, their functional, mental and social situation should be taken into account. this is a huge workload for the ed. finally, we should bear in mind that the training of ed physicians on these issues is limited [63] as a direct consequence of the self-training of current professionals, which is not always complete, and the lack of a regulated medical specialty in the ed. in spain, between 15 and 25% of emergency department visits occur in the elderly. elderly people come in 14.5% of the time for infections and one third of the infections seen in the emergency departments occur in the elderly. the population over 65 years of age who attend the emergency department often have multiple pathologies and clinical manifestations of infection that may be atypical. in the spanish national health service, emergency activity accounts for a total of 47.2 million consultations per year, of which 26.5 million are attended to in primary care (pc) (outpatient or home), with an average attendance of 0.6 people/ year [64] one-third of emergency consultations in pc are related to infections [65] . in the older patient, infections are more frequent and serious, associated with greater morbidity and mortality [65] [66] [67] . among the elderly, the rate of infection reaches 634.1 cases per thousand people per year. the most frequent correspond to the respiratory system (317 cases per thousand), particularly those of the upper respiratory tract, followed by acute bronchitis and bronchiolitis and pneumonia [65, [67] [68] [69] . in second place are utis, mainly affecting women (114.8 cases per thousand compared to 44.2 per thousand for men) [67]. these are followed by skin and soft tissue infections [69] . most of these cases are dealt with in primary care and only those more serious situations and of uncertain diagnosis are referred. in 75%-80% of cases, cap is diagnosed in pc [65, 70] and streptococcus pneumoniae is the cause of two-thirds of these cases. invasive forms of pneumococcal disease (ipd) are less common, occur in patients with certain risk factors and have high mortality rates [70] . the vast majority of vaccination programmes in spain are carried out in primary care, but the vaccination schedule for older people is neither complete nor promoted as it should be. what is the workload represented by elderly patients in hospital emergency departments? the number of visits to hospital emergency departments (ed) has been increasing progressively for decades. this increase is greater in the elderly, whose population accounts for 15-25% of all visits to the hospital [56] . the incidence and impact of infection in the ed is estimated quite reliably. in spain it is 14.3%, 21% in the usa and around 30-40% in countries such as nicaragua and mexico [57] . the elderly are characterised by a higher probability of atypical presentation of diseases, of suffering from multiple diseases and of consuming many drugs. with regard to emergency care, this implies a more complex clinical evaluation, which translates into a greater request for additional tests and consultations with other specialists, longer stays in the ed (extended periods under observation and in ssus), as well as a greater probability of admission, discharge with undetected or untreated problems and return visits to the ed [58] . all this entails a high risk of adverse episodes [58] and a significant impact on healthcare pressure, resulting in a negative effect on ed saturation [59, 60] . likewise, the prevalence of the frail elderly in the community varies according to the diagnostic criteria. in a study conducted on elderly people admitted to the observation room of an ed in a spanish tertiary hospital, it was verified that only one of them did not have any fragility criteria and on admission almost half of them suffered significant dependence [61] . the detection of the high-risk or fragile patient is fundamental for these departments, for decision-making and in particular for discharge directly from the emergency department. we could highlight that in the recent work of the in-fur-semes group, in a study conducted in 49 spanish eds, 31.7% of infections occurred in patients over 70 years old. of these, 36% were urinary and 51.2% were lower respiratory. in conclusion, when compared with a similar study, conducted twelve years earlier, an increase in the prevalence of infections is observed, with an older patient profile, comorbidity, risk factors for mdr microorganisms and septic syndrome [62] . the latter almost always presents itself as an acute confusional syndrome, which implies a complex differential diagnosis. to what extent do you think that infection in the elderly is preventable? what proportion could be avoided with proper vaccination? in an article published by umscheid et al. [79] , not specifically addressing to the elderly field, it is estimated that 65%-70% of cases of catheter-related bacteraemia or catheter-associated urinary tract infection and 55% of pneumonias from mechanical ventilation or skin and soft tissue infections could be prevented in the hospital environment using the methodology currently available. an infection control programme for older patients includes methods for surveillance and recording of infections, recording and management of multi-resistant microorganisms, outbreak contingency plans, isolation policy and standard precautions, hand hygiene programmes, ongoing education of employees, resident health plans, audits and plans for reporting incidents to health authorities [80] . this set of resources is not available to most of the world's elderly. a group of experts, gathered in a delphi study on infection prevention measures in patients admitted to institutions for the elderly, agreed on 302 recommendations [81] but unfortunately the level of evidence on the effectiveness of each of them is very limited. data on the reduction of different infections by different measures are extremely scattered and limited. some examples are the reduction by 53% of periprosthetic infections with antibiotic prophylaxis [82] , a 60% reduction in episodes of influenza with the physical separation of the young and the elderly, [83] or a 48% reduction in episodes of pneumococcal pneumonia with the 23-valent vaccine [84] . makris et al. [85] conducted a study to test the effect of an infection control programme in 8 institutions for the elderly in the united states of america. they divided the centres into test centres (4) and control centres (4) and studied the incidence of infections in both groups before and after the programme was introduced. in the year prior to the intervention, test sites experienced 743 infections (incidence density rate, 6.33) and control sites 614 infections (incidence density rate, 3.39). in the intervention year, the test centres reported 621 infections, a decrease of 122 infections (incidence density rate, 4.15), while in the control centres, the number of infections increased slightly to 626 (incidence density rate, 3.15). the greatest reduction in infections at the testing centres was in upper respiratory tract infections (p = 0.06). the intervention programme consisted mainly of implementing environmental cleanliness, hand washing programmes and educational talks. therefore, and speculatively, we dare to estimate that a the infection rate in the elderly exceeds 500 episodes per 1,000 sick people per year. primary care handles the vast majority of these episodes and refers only the most serious cases. primary care is responsible for the vaccination programme for elderly people who attend to request it. the vaccination schedule for older people is neither comprehensive nor proactively promoted. what does infection in the elderly entail in terms of days of hospitalisation, financial expenditure and death? to approximate data/figures for variables such as "days of hospitalisation, economic expenditure and death" in a field as broad as "infection in the elderly" is enormously complicated. it must be taken into account that the infectious pathology is very varied and that it can affect people with different locations (community, community health centre or the hospital itself) and conditions. for example, with reference to nursing homes, lim et al. estimate 4 episodes of infection for every 1,000 cumulative days spent in the home in a small group in australia [71] , while much more extensive north american data report 12% of nursing home residents having an infection at the time of the study [32] . this leads to estimates of between 1.64 and 3.83 million episodes of infection per year [31] with annual costs of no less than us$ 1 billion, prior to 2000. in a study conducted in brazil, the cost of an infection in the elderly requiring admission is estimated at 28,714 brazilian reals (€ 6,305). patients are admitted for a median of 24 days compared to a median of 9 days for elderly people admitted for non-infectious causes [72] . of that cost, only 5% is attributable to the purchase of antibiotics. there is a greater volume of data for community-acquired pneumonia (cap) [73] [74] [75] [76] . the cost of cap varies greatly depending on where the treatment takes place. a spanish study [77] found a cost of only € 196 in the case of an outpatient, compared to €1,153 for pneumonia requiring hospitalisation. the costs were higher for subjects ≥65 years. mortality increases significantly in the older patient (25%) with respect to the general population (10%). it is worth noting a publication in spain with a sample of 2,049 subjects, where mortality due to pneumonia is more clearly related to the age group than to the aetiological agent [78] . we have not found precise data calculating overall clearly no one disputes the usefulness of ongoing education in many aspects of life and particularly in the reduction of nosocomial infections. that said, the literature review on the impact of educational programmes on nosocomial infection is irregular, fragmented and often difficult to assess. published studies generally include education as part of intervention programmes in which other measures are included, making it difficult to assess the role of education in isolation. it is also common to talk about the success or failure of an educational programme without detailing what the programme is, what content it has, how it has been implemented and how many people have accessed it. to complicate matters, in the case of the elderly, we have at least three different areas: home, nursing homes and institutions for the elderly and hospitals. in the first, the educational scope is very general and imprecise and is based on the public health and vaccination campaigns that are usually received not only by the elderly population but by the population in general. in the hospital field, we must assume that the literature produced on the impact of educational measures in the different syndromic entities generally includes the elderly population, but does not specifically differentiate it. most of the limited existing information, which we can consider specific to older people, is that generated in nursing homes and institutions that implement these programmes. a study conducted in the usa on 2,514 randomly selected nursing homes [91] asked the homes for information on 34 points related to infection control programmes. most of those responsible for control programmes, when they responded, claimed to have not only that responsibility but others as well (54%) and also to have no specific training in infection prevention (61%). there was great variability in practices carried out in each residence and 36% acknowledged having received an official citation for deficiencies in such control. those residences cited for deficiencies had a statistically lower proportion of staff trained in infection control. this is therefore an area with clear opportunities for improvement. in a systematic review on non-pharmacological infection prevention in long-term care facilities, only 24 papers were selected, the majority of which were randomised studies (67%) and the most common reason was prevention of pneumonia (66%). 54% showed favourable results for the interventions, but the studies had many potential biases [92] [93] [94] [95] [96] [97] [98] [99] . from these studies the 5 main quality markers in infection control in a nursing home were deduced, namely: percentage of long-term patients with pressure ulcers, urinary tract infection, bladder catheter, and vaccinated against influenza and pneumococcal infection. high quality infection control programme in nursing homes could reduce infection rates by up to 50%. but even if we estimate much lower figures, the impact on morbidity, mortality and the economy of such programmes would be enormous and would certainly outweigh their implementation costs. with reference to the second part of the question, the possibility of reducing the problem with vaccines, the data are again scattered and studied for different vaccines individually. in addition, information on the elderly must often be inferred from data on the general population. we refer readers to a recent review on the subject [86] . below is some data on the impact of vaccines of particular interest to the older population. gross et al. [87] in a meta-analysis of 20 cohort studies estimate the effectiveness of influenza vaccination at 56% in preventing respiratory infections, 53% in preventing pneumonia, 50% in preventing hospitalisations and 68% in preventing deaths. in the case of zoster, the vaccine's efficacy is estimated at more than 90% with minimal adverse effects [88] different pneumococcal vaccines have different impacts on the incidence of invasive pneumococcal disease (ipd) infection. a systematic review shows reductions in ipd incidence ranging from 61% as a combined effect of the use of pcv7, pcv10 and pcv13 in those over 65 in canada [89] to a 21% reduction as an effect of the use of pcv7 and pcv13 in israel [90] . with these data it is possible to imagine the added protection that adequate vaccine coverage would provide. an estimated 50,000 americans die each year from vaccine-preventable diseases, and 99% of those who die are adults [86] . increased provision of medical care in large care homes (e.g. those with more than 200-250 beds) could reduce the referral of many elderly residents to hospital emergency services. this provision of medical care would not necessarily be very complex and would cover both simple diagnostic material and the possibility of establishing and carrying out pharmacological therapeutic courses at the centre itself, the prescription of which in most cases still requires medical staff from outside the centre. it would be a way to reduce costs, lessen the burden on the elderly and reduce the overload on hospital emergency departments. it is impossible to give a precise answer to the questions asked, but it seems reasonable to assume that with appropriate prevention programmes, acquired infections in institutionalised elderly people could be reduced by up to 50%. strict adherence to a vaccination programme for the elderly would have an enormous impact on reducing suffering, death and economic waste. what data exist on the effectiveness of educational measures on the incidence of infection in the elderly? ties specifically dedicated to infection. by way of an example, in spain, this occurs among specialists in microbiology and infectious diseases and intensive care specialists. 9.-specifically promote research aimed at preventing infection in elderly patients. 10 .-introduce much more active involvement of patient associations in their management structures. what we say about societies primarily dedicated to the elderly, can be similarly assumed and applied to societies primarily dedicated to infectious diseases and microbiology. the role of the scientific societies dedicated to geriatrics and infectious diseases is to promote alliances in the common field of infection, in aspects of care, teaching and research. they need to look less to the interests of their members and be more proactive in promoting the interests of the patients they serve and incorporate patient associations more into their structures. capacity, understood as the possibility or potential for influence, is qualified by two variables. firstly, for offering free and truthful scientific information at the service of the community. and secondly, for facilitating the adoption of the best possible political decisions with consistency and realism. the rapprochement between professionals in the scientific and political fields must be adjusted to the interest of citizens, who can act as the third pillar in a transparent relationship model and as guarantor of equity befitting a democratic system of government [110] . while scientific experts advise and inform, it is the responsibility of politicians to make decisions and promote efficient measures to the benefit of the population. a complementary characteristic inherent to the scientific task is to exercise a dissemination action of the activity itself, in understandable terms and through accessible and reliable systems [111] . the configuration of platforms within scientific societies and the growing number of independent agencies advising political power represent a reality that aims to bring the contributions of science closer to the systems of governance [112] . in our country, the main function of the congress of deputies is legislative, which entails the approval of laws. the constitution recognises the legislative initiative of the government, the congress of deputies, the senate, the assemblies of the autonomous communities and the people's legislative initiative on the proposal of no less than 500,000 citizens, subject to the provisions of an organic law. these bills are known in spain as law projects when presented by the government and propositions in other cases. they are always submitted to the congress of deputies, except for the propositions of the senate which have to be considered scientific societies are professional associations that bring together generally specific groups (doctors, nurses, technicians, etc.) that essentially seek to defend the professional interests of their members. until now, it has not been common for groups of patients affected by different diseases under the thematic umbrella of each society to participate in them. in spain their impact and political credit is variable. among the most important objectives of most of these societies are such issues as training programmes for professionals, aspects related to the health education of the population in their particular field of competence, research grants, the preparation -sometimes in collaboration with societies of another related specialty -of specific diagnostic and therapeutic protocols, publications and congresses focussed on these topics, and a wide range of other activities, including health policy recommendations to the corresponding administrations that have a direct bearing on the issues discussed here. membership of societies is also not uniform, and often it is the more "senior" components of the profession that are most highly represented in them. their role, in our opinion, is to continue to improve the teaching, care and research produced in the societies' chosen fields in favour of patients, exercising ever greater mediation between the demands of patients and healthcare administration [100] . all societies must go far beyond issuing guidelines and therapeutic recommendations [81, [101] [102] [103] [104] [105] [106] [107] [108] [109] . in our view, scientific societies dealing with diseases of the elderly should promote, in the field of infectious diseases, among others, the following topics: 1.-encourage a proportionate share of its members to subspecialise in infectious diseases. 2.-coordinate and direct multidisciplinary teams specifically dedicated to the infection in the elderly and its prevention. 3.-participate more actively in specific programmes to reduce infections in the elderly, both at the nursing home level and at home and in hospital. 4.-implement vaccination campaigns in the elderly, taking particular advantage of admission to long-stay centres or hospital as opportunities to vaccinate. 5.-to design and disseminate educational projects on infection prevention practices for the elderly in their different environments. 6.-put pressure on health authorities to carry out a large national programme to reduce infection in older people. 7.-to include in the training programme of residents in geriatrics, a rotation in infectious diseases and microbiology as an essential part of the curriculum. 8.-create scientific and professional alliances with socie-to offer a unique system to access scientific information allowing the recovery of different types of documents such as: journals, books, images, theses, and conference proceedings. revista española de geriatría y gerontología (the spanish journal of geriatrics and gerontology) is the publication channel of the society of the same name, a publication founded in 1966 and the doyenne of the specialty in the spanish language [119] . medes is an initiative of the fundación lilly and its database, open and free, contains bibliographical references published since 2001 in a selection of 98 spanish journals covering 50 subjects in medicine, pharmacy and nursing, published in spanish, with 100,000 articles [120] . finally, pubmed is the widely implemented search engine, with free access to the medline database of citations and abstracts of biomedical research articles, offered by the united states national library of medicine and integrating 5,255 worldwide journals since 1966 [121] . the search was conducted with a double strategy: free text and controlled text using "mesh". in the first strategy, a free text search was conducted in the "science direct" and "clinical key" databases with the term 'infection in geriatrics' resulting in 508 and 1,191 findings respectively. the primo search engine (castilla y león online library) returned a total of 190 results for the same term. secondly, and also in free text, with the term 'infection in the elderly', we proceeded to consult revista española de geriatría (the spanish journal of geriatrics), which generated 195 results and medes (medicine in spanish) with 84 results. the second strategy of controlled text was conducted in the pubmed database, returning the following findings: <infection and geriatrics>: 997 results; <infection and aged> (people from 65 to 79 years old): 122.698 results and <infection and aged or aged, 80 and over>: 122.698 results (identical to the previous one). its development over the last decade has been progressive (from figures close to 4,000 in the 2009-2010 biennium, to over 5,000 from 2014 to 2017), excluding the year 2018 from the assessment. we have adopted their classification into thematic areas [122] and the twelve in which 95% of the results were concentrated are: sepsis and bacteraemia, pneumonia, urinary tract infections, central nervous system infections, endocarditis, prosthetic infections, skin infections, gastrointestinal infection, hiv infection, fever of unknown origin, multi-resistance and vaccinations. the scientific output on infections in the elderly, calculated by different databases, has been increasing in the last decade. how do the problems of the elderly impact on the mainstream media? how should the media contribute to the reduction of infection in the elderly? the impact of the problems of the elderly in the media is in the senate, which will later submit them to congress [113] . non-legislative bills, motions and proposals for resolutions are acts of a similar nature that seek the adoption of a non-legislative resolution by congress, by which congress expresses its position on a given subject or issue, or addresses the government urging it to act in a particular direction. the health and social services commission of the congress in the xii legislature offers access on its website to the 226 initiatives processed since its constitution in september 2016 until its dissolution in march 2019, representing an average of 75 per year [114] . of these, those referring to the field of infectious pathology as a whole do not exceed 3%. of particular relevance in the field of infectious pathology have been those relating to the national plan for the elimination of hepatitis c and antibiotic resistance. governance designates the effectiveness, quality and good orientation of state intervention, which provides the state with a good part of its legitimacy in what is sometimes defined as a "new way of governing". above all, it is used in economic, social and institutional operational terms [115] . an inherent aspect of the exercise of policy is the performance of "authority", which is equally composed of legitimacy (right to exercise), personal prestige (moral strength, leadership, honesty, knowledge, efficiency) and power (ability to administer and lead). it is precisely in the "personal prestige" where their synergy with the scientist (also covered by knowledge, honesty and leadership) should be the lever for the improvement of the society they both serve. initiatives on proposals or projects with reference to infection issues represent less than 3% of the total. of particular relevance in recent years have been those relating to the national plan for the elimination of hepatitis c and antibiotic resistance. in order to respond to the scientific output on infection in geriatrics, we will proceed to describe the data sources, the search methodology and the findings, in a way deliberately guided by the recommendations of professionals in our workplace libraries. sciencedirect [116] is a digital platform that has provided subscription access to a large research database, hosting more than 14 million publications from 3,800 academic journals and 35,000 e-books since 1997. clinical key [117], owned by "elsevier clinical solutions", has an intelligent search system, establishing the connection of medical terms with related content. it accesses a collection of resources of clinical guides, algorithms and patient files from fisterra, the database of monographs of medicines marketed in spain, the treaties of the medical surgical encyclopaedia, and books and journals in spanish from the cited publisher. primo is the discovery/search tool used by the castilla y león healthcare online library [118] as a small demonstration of this paradox -the contrast between the rising presence of the elderly in society and their lukewarm representation in the media-, we offer a chart with a comparison of publications on the websites of three generalist newspapers, "el país", "el mundo" and "abc", between the years 2016-2018, with the search for "elderly" and "infection" as key words. a total of 96 news items are recorded that mention the subject studied ( figure 1 ). this is little news, and in most cases linked to events and to the elderly as a risk group. this sample would require further media analysis to ratify this tendency in the treatment of the problems of the elderly and the infections they suffer, but it serves as the tip of the iceberg of relegation, insensitivity and atrophy in news treatment. since the onset of the economic crisis in 2008, the number of dedicated journalists specialising in social and health issues has been substantially reduced in order to divert manpower and resources mainly to political and economic content. if, in this situation, health, science and social issues have been scaled down and cut back in the operation of the media, the elderly, as journalistic content, have been pushed to the very margins of the newsrooms with complete normality; with no agenda, no specialists, no briefings, no planning, no contextualization; to see themselves as mere circumstantial, inconsequential, occasional content, with a light, sometimes frivolous treatment, lacking depth and sensitivity; building a narrative of topics, irrelevance and disconnection from their value and presence in society. this media portrayal of the elderly is in contrast to the ageing of the population, where reliable and accurate statistics limited, deficient, incomplete, unfocused, out of context, stereotyped and with a not particularly constructive, realistic or objective bias. the elderly are invisible in the media and when they appear, the content relating to them is characterised by simplification, victimhood, dramatization and superficiality. the image that the media convey of old age is linked to inactivity, unproductiveness, seniority, illness, dependence and deterioration. old age and its problems, circumstances, needs and contributions, as a social agent and subject, are not among the priorities and themes of general media planning. other groups, sectors, actors or social issues such as immigration, feminism, equality, children, domestic violence, ngos and their services, new technologies and their advantages, effects and risks, harassment in all its forms, health and sanitation, or scientific advances have much more visibility, relevance, monitoring, currency and presence in the media. the problems related to a stage of life that we can place at around 80 years provoke a disinterest and sidelining in the information and journalism that only is unblocked in the face of news related to events, diseases, negative or sensationalist facts or anecdotes, offering a fixed, unmoving and old-fashioned image of a sector of the population that, nevertheless, is increasing due to the increase in life expectancy. in a world where the 21st century grants youth and technology all the plaudits as to what is interesting and important, whether in the press, television, radio, websites or social networks, ageing and old age, as a concept, social and population sector, and newsworthy subject, are moved to a second or third tier on the podium of current affairs and information. citations regarding "infections" in the "elderly" in 3 major general journals of spain formation on the elderly and very elderly has been strengthened, is to promote health and healthcare information in relation to this sector of the population. in this context, the media would be in a position to treat and report, with much higher presence and representation criteria than at present, on the infections of the elderly within the framework of their health and well-being. it is very difficult to reach this third step without the two previous actions, since the handling of a health problem such as infection in the elderly by the media requires a commitment and responsibility in several phases that is part of a comprehensive strategy to provide a journalistic treatment of their problems on a par with their representation and contribution to society. it is necessary to present older people and the elderly removed from the clichés and stereotypes that link them directly and almost solely to the events, the deterioration of their health, family dependence or the hindrance or burden of their role and function in society. it is necessary to offer complete and balanced information in which tasks such as interest in culture, modernity, the future, technology or travel; their capacity to lea in civil society, family, business or education; their initiative in domestic and community tasks; their political or social contributions; or their skills in the practice of sport are inherent. in short, to show their vitality, enthusiasm, enterprise, activity, determination, solidarity or collaboration, beyond their problems or difficulties, which must also be reflected and analysed. it should not be forgotten that though the generation of elderly people now over 75/80 years old may have a more traditional, reserved and passive profile in certain cases -by no means in all-, the new generation of elderly people forecast for 2050, where their number will rise greatly, will experience a huge change with regard to the distorted image of the elderly today. the information that the general media dedicates to the problems of the elderly is minimal, distorted and biased. it is full of clichés and stereotypes that link them directly and almost exclusively to events, the deterioration of their health, family dependency or the hindrance or burden of their role and function in society. information on infections in this population group is even more scarce. presentation: the answer is yes, without a doubt [95, [127] [128] [129] [130] [131] [132] [133] [134] [135] [136] [137] [138] . the reasons are detailed below: studies conducted following scientific evidence criteria in recent years show that pharmaceutical care and the intervention of the pharmacist improve the overall quality of patient care, while the who itself states that point to a doubling of the number of older people by 2050. the data show that in 1960 in spain, there were 6.7 million children under 10 years and 0.4 million people over 80 years, in 2015 the number of children under 10 had fallen to 4.6 million, and over 80 risen to 2.7 million; by 2050 the trend becomes even more acute, with under 10 years predicted at 3.8 million, and over 80, 6.2 million [123, 124] . globally, in the century from 1950 to 2050, total population will triple; the population over 60 will grow by a factor of 10; and the population over 80 by a factor of 28, this last group going from 14 million in 1950 to 386 million in 2050. if information concerning and affecting the elderly continues to be ignored, marginalised and simplified in the media, they will neglect and fail in their mission of gathering information, analysis, data and opinions from a sector of the population with enormous influence on the life and events of a country. without rigorous, truthful, balanced, comprehensive and complete information on the phenomenon of old age, the view and expression of reality will be distorted, fragmented and fractured. to help reduce infection in the elderly, the media must take several steps beforehand and activate new information strategies and actions [125, 126] . review and reformulation of the contents for current events, relevance and interest agendas. the first step is to place general social and health issues on the same level of importance as national or international political, economic or sports information, with the consequent allocation of space, dedication and resources. enhancement of content for the elderly in social and health information. within the social and health content, the news of the old and elderly must be equated in relevance, dedication, selection, monitoring and treatment to other issues related to this journalistic field, with emphasis on the quantity and quality of the information, from the rigour, planning and contextualization to gather studies and data, human stories, opinions, difficulties and needs, social influence, contributions, and challenges in this sector of the population. the aim is to offer a complete, balanced, objective and true vision of their reality, their contributions, their heterogeneity, their variety, their complexity, their evolution and their demands and needs. the problems arising from the increase in age, health, coexistence and economic situation, as well as cultural, sociological, family and psychological aspects, must be approached with an informational style and treatment where ageing is considered from the standpoint of normality in life, with its ups and downs, and not as a hindrance, obstacle or inappropriate or unsustainable expense. the social and cultural role of the elderly, their knowledge and experience, their skills and abilities, should be valued as useful and enriching elements to society. promotion of health and sanitation information in the elderly. the next step for the media, once the general in-ed following scientific evidence criteria in recent years show that pharmaceutical care and the intervention of the pharmacist improve the overall quality of patient care, while the who itself states that pharmacists "contribute decisively to the rational use of medicines". what is the administration doing and what can it do to reduce these problems? from an educational point of view? from the legislative-regulatory point of view? in order to reduce these problems, the state administration must, among other things, launch: 1. prevention strategies and measures to control the transmission of the infection. 2.-vaccination programmes in the elderly. 3.-training and information programmes for health professionals, particularly in the area of rational use of antimicrobials and promotion of the use of appropriate definitions [140, 141] pharmacists "contribute decisively to the rational use of medicines". the decision on how to treat a given infection correctly with the most appropriate antimicrobial requires detailed knowledge of microbiological, clinical and pharmacological issues, but the causes of an optimal result go beyond this and extend to the so-called non-pharmacological basis, among which the behaviours of doctors, patients and pharmacists, as well as the relationships between them, play a fundamental role. the pharmacist is one of the apices of the so-called "human factor triangle" (made up of doctor-patient-pharmacist), a mirror image of the famous "davis triangle" (antimicrobial-microorganism-host). currently, pharmaceutical care aims to obtain the maximum clinical benefit from medicines and to achieve the lowest possible risk in the use of those medicines, which entails the identification, resolution and prevention of medication-related problems (mrp): adverse drug reactions (adr), drug-drug interactions (ddi), deficiencies in physician prescription, errors in the use of medication by the patient and breaking the vicious circle so frequent in the use of antimicrobials formed by self-medication -noncompliance -storage. pharmaceutical care is a process, which includes different stages: active dispensation (supply, delivery, dispatch >>> assistance, help, care), educational advice (health advice in response to a consultation/problem or instruction on the acquisition of a medicine) and pharmacotherapeutic follow-up (documentation and registration of the activity). as far as the hospital pharmacist is concerned, it must be said that they not only participate actively in the rational use of antimicrobials from their role as an active member of the pharmacy commission and the antimicrobial committee, but also get involved on a daily basis in the prudent and correct application of antimicrobial therapy, in order to obtain the most beneficial result from the clinical point of view and the most efficient from the pharmaco-economic point of view. this implies that: the appropriate antimicrobial has been prescribed in accordance with a correct diagnosis and the special characteristics of the elderly patient, it is dispensed under the proper conditions, administered at the indicated doses, at the intervals and for the period intended, it is used with the lowest possible cost, in such a way as to prevent or minimise the development of bacterial resistance and it achieves the desired therapeutic objective. in short, both the community and the hospital pharmacist as first-level health agents play a central role in the field of therapeutic adherence and rational use of antimicrobials, proposing their use in terms of quality of treatment and considering antimicrobials not only by virtue of the active ingredient contained in the corresponding pharmaceutical specialty, but also in terms of useful information ("software"). furthermore, both must take into account that antibiotics and vaccines are the paradigm of societal treatment and the treatment or non-treatment of an individual can affect the community [139] . conclusion: the answer is yes, without a doubt. studies conduct-another precaution is the sanitation of the space in which the elderly person stays so as to make it a healthy environment, including daily cleaning of surfaces, objects and utensils, ventilation, illumination preferably with natural light, and appropriate environmental temperature and humidity [156] . the tendency to unbalanced diets, malnutrition and low fluid intake increases susceptibility to infection. it is essential to promote healthy lifestyles and to provide structured plans for eating, drinking and exercise adapted to individual needs taking preferences and health problems into account [157] [158] [159] [160] [161] [162] . another strategy is the vaccination of the elderly and carers, adjusted for age, particular situation and the approved schedule in each autonomous community [163] . although infectious diseases in the elderly do not always have obvious signs and symptoms, the caregiver detects changes in their baseline situation that may lead to a suspicion of the presence of an infectious process, so education should be provided on how to proceed in the light of this suspicion and what to do when it is confirmed. finally, it is necessary to emphasise the effective management of treatment (dose, administration and side effects) and periodically monitor therapeutic adherence, avoiding self-medication, in order to achieve the optimal effects of non-pharmacological and pharmacological measures, so as to enable prevention, delay deterioration, recover or maintain health [164] . nurses develop interventions for prevention, monitoring and therapeutic adherence control, participating in the care plan for infection in the elderly. the implementation of many of the health promotion and care plans and regulations is the direct responsibility of the nursing profession. how do senior citizens' associations deal with this problem? the issue of health is a priority for the elderly and infection in particular is one of the most frequent causes of morbidity and mortality in the elderly, as has already been mentioned. elderly associations have traditionally focused on chronic rather than acute diseases and therefore have a huge role to play in this area. it is the mission of the elderly associations to encourage and promote the residence of the elderly in a family and social environment that is agreeable to them. it is well known that an older person who lives comfortably at home with family members has less risk of acquiring infections than one who lives alone. in the case of the elderly institutionalised in residences, the elderly associations have the mission to ensure the quality tions for the prevention and control of healthcare associated infections (hais). some examples of the above are programmes such as: "antibiotics: take them seriously" (2017); the "world antibiotic awareness week" (2018); the "european antibiotic awareness day" (2018). a national plan against antimicrobial resistance (pran) run by the spanish agency of medicines and health products (aemps) is essential [142, [143] [144] [145] [146] [147] . the administration has a constitutional mandate to promote health, which is of particular concern to groups as vulnerable as the elderly. among the measures to be implemented, those of an educational nature are especially necessary, both for patients and for their caregivers and healthcare personnel. from a legislative-regulatory point of view, we cannot forget that spain has one of the best health systems in the world. what is the role of nursing in managing and reducing infection in the elderly? how does the training of the caregiver affect this? nurses develop preventive interventions, participate in the monitoring, control, therapeutic adherence and care plan when the infection is established. these competencies are developed inside and outside of healthcare institutions. in the home setting, the focus is on education and providing support for safe practices [148] [149] [150] [151] . professionals, caregivers and elderly people have to distinguish modes of transmission, identify risk factors and susceptible people who may become reservoirs or constitute a vehicle of contagion and understand basic protective and barrier measures. the simplest, most effective and universal procedure is hand hygiene. the world health organization identifies five key times for washing: before and after contact with the person, before performing a clean/septic task, after the risk of exposure to body fluids, and after contact with the patient's environment [152] [153] [154] . when hygiene guidelines are given, it is worth noting other times: before, during and after handling or preparing food, before eating, before giving medication, before and after treating a wound or handling clinical devices, after using the bathroom and after handling used clothing, whether personal, bath or bedding, diapers or waste. after washing, it is important to dry the hands. personal hygiene and topical hydration are other prevention strategies. the skin constitutes a natural protective barrier and is particularly labile in the elderly. its daily care guarantees its integrity and protects it from external assault. this includes body hygiene and protective measures aimed at moisture control and injury prevention. some studies highlight the importance of oral hygiene in relation to respiratory diseases [155] . the great social esteem that existed in ancient cultures for the elder of the group or tribe is well known. he was not only the oldest person but also the biological father, the political leader and, in many cases, the religious authority. and, as anthropologists have pointed out more than once, the "hard disk" of the community, aware of past events of which the younger generations are not, thereby bringing the social group together and giving it its own identity. hence, the elders were not only respected but highly valued and even revered. it is enough to open the books of the bible, for example, to find testimonies of this. its pages over and over again reverential respect for the elder, applying such venerable terms as "patriarch". the bible attributes an extraordinary longevity to the first patriarchs (gen 5; 11,10-26), and even to the later patriarchs, like abraham (gen 17,1.17; 18,12) and moses (dt 31,1; 34,7), and to the prophets, it is difficult to represent them as young people. respect leads the bible authors to attribute centuries-long lives to them. longevity is a sign of their wisdom. the so-called wisdom literature bears good witness to this veneration for the elderly. in the book of ecclesiasticus we read: in your youth you did not gather. how will you find anything in your old age? how appropriate is sound judgment in the grey-haired, the contrast between the ancient civilization of israel and the archaic greek culture, as presented in the homeric poems, is surprising. it is difficult to imagine ulysses, hector or achilles as elders, even though in those poems there are also venerable subjects such as menelaus, agamemnon and priam. the contrast between agamemnon and achilles is particularly significant, for the poet paints the former as an ambitious and selfish man, with an excessive ego who confronts achilles, his best warrior, again and again. heroes, those beings that the greeks considered perfect and semi-divine, are by necessity young and in the fullness of their life force. in greek statuary of these institutions, that they are equipped with the appropriate medical, nursing and social services and that a systematic accreditation of these services is achieved. ideally, these centres should have very significant prevention measures in place and should work closely, on the one hand, with the primary care physicians responsible for the patients, and on the other hand, with the reference hospitals to which the patients have to be transferred at some point. elderly associations must continue to work to improve the care of the elderly in emergency departments, not only from a technical point of view, but also by ensuring the agility of the assessment and dignified conditions for the elderly in these departments. finally, the elderly who are hospitalised are patients who require very rapid mobilization, avoidance of exposure to multi-resistant microorganisms and the fastest possible transfer back to where they came from. elderly associations promote the provision of geriatric beds and services in all hospitals, where structures and organisations are set up specifically to serve the needs of elderly patients with a comprehensive idea of their care. as we have mentioned, prevention is better than cure, and in that sense, the elderly associations can play an important role in emphasizing to the authorities, to the groups of affected people and to healthcare personnel the importance of promoting vaccination campaigns [86] in short, associations for the elderly, whether they are focused on health or not, can play a very positive role that is often overlooked when it comes to improving health. they could work, if possible, promoting and propagating vaccination campaigns. they could also contribute more than they do to other forms of health education, from those oriented towards nutrition or physical activity, to those focused on fighting toxic habits or reporting abuse. all this is of general interest, as well as directly and indirectly affecting the field of infectious pathology. following the recommendations of the expert consensus on frailty in the elderly, active ageing and drug screening in polymedicated patients are important in preventing infections in these patients. elderly associations must play a major role in demanding quality care policies for elderly patients, both in the fields of prevention and treatment. target areas for intervention are the home environment, the outpatient system, nursing homes, hospital emergency departments and hospital care. patient associations can contribute more than they do to other forms of health education, from those oriented towards nutrition or physical activity, to those focusing on combating toxic habits or reporting abuse. what ethical aspects would you highlight in all these problems? modern systems of work organisation have made "efficiency" a major objective of the culture of the second stage of life. there is no doubt that in spain, for example, efficiency has increased three or fourfold in the last half century. and here is the origin of the problem. what do you do when you are no longer "efficient", at least in the way the economy defines efficiency? efficiency is a value that belongs to the category of socalled "instrumental values", "reference values" or "technical values". they are so called as they have no value in themselves, but only in reference to something else or another value. let's think, for example, of a drug. there is no doubt that it has value, at least financially. its most valuable asset is to relieve a symptom or cure a disease. if it wasn't good enough, we'd say "it's not good enough", and we wouldn't pay for it. this means that the value of the drug is in reference to something other than itself, such as well-being, health, life, etc. this happens to all technical instruments. if we were to find a more effective or less expensive drug, there is no doubt that we would choose it, because this is what efficiency is about: the cost/benefit ratio. efficiency is the unit of measurement for instrumental values. the problem is that not everything is instrumental. if they are always in the service of others, it means that these others must stand on their own, otherwise we fall into an infinite regression. these are called "intrinsic values" or "fundamental values". they are the most important in life. they are essential values, values that have worth in their own right, without reference to others. think, for example, of dignity. or many others, such as health, life, beauty, well-being, justice, solidarity, etc. these are all intrinsic values. without them, life is meaningless [165] . furthermore, they have the characteristic of not being measured in monetary units, nor is efficiency a criterion. "health is priceless" it has always been said; "true love is neither bought nor sold"; "only the foolish confuses value and price" said antonio machado. and the list could go on [166] . we can now understand the importance of promoting a culture of old age. during our working life there is no doubt that the fundamental criterion must be efficiency, and therefore economy. but that is, at the same time, the least human part of life. the day is not far off when that part of our existence can be transferred to the robots. and the problem arises: what will we humans do then? will we have anything to do? older people have a fundamental mission in our society, and that is to take charge of promoting intrinsic values and passing them on to younger generations. it's not all about economics. it's not all about efficiency. there are other values, which moreover are the most important, the most human. conclusion: promoting a new culture of the elderly should lead us to avoid not only the discrimination that has occurred throughout western culture, and particularly in recent centuries, but also to give impetus to the promotion of intrinsic values, the most humane, the most important in the lives of individuals and societies. this is the very im-it is impossible to see the decrepitude of the elderly person represented. the poet menander coined a sentence that soon became famous and that plautus translated into latin: quem di diligunt, adulescens moritur, "those loved by the gods die young" (bacchides, 816-817). perfection is in youth, and old age is almost embarrassing. aristotle says that "disease is an acquired old age, old age a natural disease" (gen. an. 784 b . it was important to remember this about the attitude of our culture, the western one, towards the elderly. they've never been held in high esteem. moreover, we can be seen that this esteem has been decreasing over time. this is demonstrated by the words we use to refer to this age group. "viejo" (old) comes from the latin vetus, the opposite of novus, both of which are terms that were designating things, not people. for people, the correct terms were senex and its opposite iuvenis. from senex comes our word "senescence", only used in a very limited sense today. cicero wrote a dialogue de senectute, using the correct term in his language. though, in the various spanish editions that exist, the translation is invariably sobre la vejez. (on old age). old age is not only an improper term, but also a derogatory one. no one sees it that way anymore, because they don't know about this process. but the transition from one term to another is an evident sign of the devaluation that the figure of the elder has undergone in western culture, even though it was originally already much lower than that of other cultures. if we add to this the spectacular increase in life expectancy at birth in the last century, it turns out that this devalued period, which until the beginning of the 20th century was almost anecdotal in the life of western society (it should be remembered that life expectancy at birth in spain had been stable at 25-30 years from the neolithic revolution to the end of the 19th century), has become a period of no lesser and sometimes greater duration than the active life of a person. so much so that human life today can very well be divided into three 30-year periods, the first of which is devoted to vocational training, the second to production, and the third.. it is not very clear to what, among other things, because the training we were given in the first 30 years was aimed at being productive in the second phase, but we were never educated for the "third age". the third and final phase of life, which today has an average duration of 30 years, is a continuous source of problems. it is, at least, in the economic order, as the present pension system seems difficult to maintain, and will be impossible in the near future. but, as important as this is, that's not the biggest problem. the most serious issue is that we have condemned the elderly to being a "passive class", whom inserso (the institute for the elderly and social services) has to ferry from one place to another in order to at least distract them. there is talk of discrimination and abuse of the elderly. in my opinion, the greatest discrimination is this, the fact that the elderly have been deprived of their own role in society; or, to put it another way, the total absence of what i have been calling the "third age culture" for some time [165] . yes, third age culture. the third age has its own culture, distinct from the second age. portant active role that members of the third age have been entrusted with, given that in our culture the second age is obsessively consumed by the promotion of economic efficiency. does this matter for the control of infection in the elderly? as has already been said in previous interventions, the dynamic, active elderly, who feel that they have a mission to fulfil in society, are undoubtedly in a better position to avoid infections and to combat them when they do occur. it is not true that, as aristotle said, old age is a "natural disease". there are many reasons to claim that it is not merely a part of life, but in many ways the most important. and it will be even more so in the future. special considerations for antimicrobial therapy in the elderly fever and aging intraabdominal infection: diagnosis and treatment in the elderly patient intraabdominal infections in the elderly infections in nursing homes: epidemiology and prevention programs systemic inflammatory response syndrome is more associated with bacteremia in elderly patients with suspected sepsis in emergency departments emergency department (ed) utilization of oldest old men in a veterans care home in taiwan urinary tract infections in the elderly population bacteruria and urinary tract infections in the elderly bacterial pneumonia in older adults effect of bacteremia in elderly patients with urinary tract infection antibiotic prescribing for nonbacterial acute upper respiratory infections in elderly persons viral pathogens among elderly people with acute respiratory infections in shanghai, china: preliminary results from a laboratory-based surveillance respiratory syncytial virus burden among adults during flu season: an underestimated pathology respiratory syncytial virus and other respiratory viral infections references the world report on ageing and health: a policy framework for healthy ageing world report on ageing and health. world health organization las personas mayores en españa. datos estadísticos estatales y por comunidades autónomas ministerio de sanidad hallmarks of human "immunosenescence": adaptation or dysregulation? age and immunity: what is "immunosenescence altered host response and special infections in the elderly principios básicos sobre las infecciones en patología geriátrica clinical features of infection in older adults infections in elderly persons. an altered clinical presentation pneumonia in the elderly: empiric antimicrobial therapy infecciones en hospitales de larga estancia, centros residenciales y otras unidades geriátricas prevalence of healthcare-associated infections in long-term care facilities in catalonia. vincat program prevalencia de problemas de salud en la población asignada a atención primaria. principales resultados. actualizado el 14 de marzo de epidemiologia general de las infecciones nosocomiales. sistemas y programas de vigilancia epine-pint prevalence survey of healthcare-associated infections and antimicrobial use in acute hospitals, ecdc healthcare cost and utilization project facts and figures number, percent distribution, rate, days of care with average length of stay, and standard error of discharges from short-stay hospitals, by sex and age: united states healthcare cost and utilization project, statistical brief #141, agency for healthcare research and quality intensive care for critically ill elderly: mortality, costs, and quality of life. review of the literature a randomized trial of care in a hospital medical unit especially designed to improve the functional outcomes of acutely ill older patients trends in the burden of infectious disease hospitalizations among the elderly in the last decade time-series analysis of the relation between influenza virus and hospital admissions of the elderly in onin older adults with moderate to severe influenza-like illness clostridium difficile infection in the elderly: an update on management increase in clostridium difficile-related mortality rates fecal transplantation for treatment of clostridium difficile infection in elderly and debilitated patients fecal microbiota transplantation for recurrent clostridium difficile infection in the elderly: long-term outcomes and microbiota changes the burden of infection in long-term care infections in long-term care populations in the united states standardized infection surveillance in long-term care: interfacility comparisons from a regional cohort of facilities severe consequences of healthcare-associated infections among residents of nursing homes: a cohort study infection rate and colonization with antibiotic-resistant organisms in skilled nursing facility residents with indwelling devices european centre for disease prevention and control. protocol for validation of point prevalence surveys of healthcare-associated infections and antimicrobial use in european long-term care facilities -2016-2017 version 1.1. stockholm: ecdc antimicrobial prescribing and infections in long-term care facilities (ltcf): a multilevel analysis of the halt 2016 study healthcare-associated infections and antimicrobial use in long-term care facilities: the irish experience with the halt surveys burden of infections among 44,869 elderly in nursing 67. giménez o. los problemas de salud más frecuentes en atención primaria 7dm protocolo diagnóstico y tratamiento empírico en urgencias de las infecciones broncopulmonares en los ancianos y en pacientes inmunosuprimidos actualización en infecciones y atención primaria. fármaco salud com vacunación frente a la neumonía adquirida en la comunidad del adulto surveillance of infection burden in residential aged care facilities custo e caracterizacao de infeccao hospitalar em idosos characteristics and management of community-acquired pneumonia in the era of global aging influence of socioeconomic status on community-acquired pneumonia outcomes in elderly patients requiring hospitalization: a multicenter observational study clinical and economic burden of community-acquired pneumonia among adults in europe socioeconomic status, life expectancy and mortality in a universal healthcare setting: an individual-level analysis of >6 million catalan residents a population-based study of the costs of care for community-acquired pneumonia a composite of functional status and pneumonia severity index improves the prediction of pneumonia mortality in older patients estimating the proportion of healthcare-associated infections that are reasonably preventable and the related mortality and costs infection control issues in older adults guidelines for infection control in nursing homes: a delphi consensus web-based survey reduction in hospital admissions for pneumonia in non-institutionalised elderly people as a result of influenza vaccination: a case-control study in spain effectiveness of the mf59-adjuvanted influenza vaccine in preventing emergency admissions for pneumonia in the elderly over 64 years of age puntos clave en la asistencia al anciano fragil en urgencias sepsis in the emergency department: key points, controversies, and proposals for improvements in latin america grupo de trabajo evadur: eventos adversos ligados a la asistencia en los servicios de urgencias de hospitales españoles saturación de los servicios de urgencias. una propuesta desde el sistema para un problema del sistema la saturación de los servicios de urgencias: una llamada a la unidad la detección del paciente anciano frágil en el área de observación de urgencias estudio infurg-semes: epidemiología de las infecciones atendidas en los servicios de urgencias hospitalarios y evolución durante la última década the core curriculum and educaton committee for the international federation for emergency medicine informe anual del sistema nacional de salud (sns) impact of an educational program for the prevention of colonization of intravascular catheters impact of a pharmacist-driven education initiative on treatment of asymptomatic bacteriuria a formative research-guided educational intervention to improve the knowledge and attitudes of seniors towards influenza and pneumococcal vaccinations prevention of catheter-associated urinary tract infections in patients with hip fractures through education of nurses to specific catheter protocols educational vaccine tools: the french initiative e-learning education solutions for caregivers in long-term care (ltc) facilities: new possibilities. educ health (abingdon) report of working group 3: specialist training and continuing medical education/professional development in the infection disciplines guidelines for the evaluation and treatment of pneumonia executive summary of the diagnosis and treatment of urinary tract infection: guidelines of the spanish society of clinical microbiology and infectious diseases (seimc) european geriatric medicine society (eugms) and the world association for infectious diseases and immunological disorders (waidid) influenza vaccination in high-risk groups: a revision of existing guidelines and rationale for an evidence-based preventive strategy guidelines for the management of community-acquired pneumonia in the elderly patient updated vaccine guidelines for aging and aged citizens of europe clostridium difficile-associated disease: impact of the updated shea/idsa guidelines periprosthetic infection in elderly patients treated with hemiarthroplasty of the hip following intracapsular fracture. should we use antibiotic-loaded bone cement? social contact patterns and control strategies for influenza in the elderly protective effects of the 23-valent pneumococcal polysaccharide vaccine in the elderly population: the evan-65 study effect of a comprehensive infection control program on the incidence of infections in long-term care facilities the situation of vaccines for the prevention of infections in adults: an opinion paper on the situation in spain the efficacy of influenza vaccine in elderly persons. a meta-analysis and review of the literature efficacy of the herpes zoster subunit vaccine in adults 70 years of age or older pneumococcal vaccination programs and the burden of invasive pneumococcal disease in ontario, canada pneumococcal meningitis in adults after introduction of pcv7 and pcv13, israel infection prevention and control programs in us nursing homes: results of a national survey infection prevention in long-term care: a systematic review of randomized and nonrandomized trials cluster randomised controlled trial of an infection control education and training intervention programme focusing on meticillin-resistant staphylococcus aureus in nursing homes for older people a descriptive study of a novel pharmacist led health outreach service for those experiencing homelessness pharmacist adscription to intensive care: generating synergies a pharmacist-led program to evaluate and reduce polypharmacy and potentially inappropriate prescribing in older hiv-positive patients an automated, pharmacist-driven initiative improves quality of care for staphylococcus aureus bacteremia urine culture guided antibiotic interventions: a pharmacist driven antimicrobial stewardship effort in the ed impact of a pharmacist-driven protocol to decrease proton pump inhibitor use in non-intensive care hospitalized adults ed pharmacist monitoring of provider antibiotic selection aids appropriate treatment for outpatient uti pharmacist-driven antimicrobial optimization in the emergency department design and analysis of a pharmacist-enhanced antimicrobial stewardship program in thailand patient satisfaction from two studies of collaborative doctor-pharmacist prescribing in australia pharmacist interventions on antibiotic use in inpatients with respiratory tract infections in a chinese hospital a pharmacist-initiated program of intravenous to oral antibiotic conversion análisis sobre de adherencia al tratamiento en pacientes crónicos desde el punto de vista de la farmacia bone and joint infections in the elderly: practical treatment guidelines fungal urinary tract infections in the elderly: treatment guidelines analysing power and politics in health policies and systems latent influence networks in global environmental politics biblioteca sanitaria online de castilla y león. una apuesta por la integración national library of medicine. institute of health un perfil de las personas mayores en españa, 2019. indicadores estadísticos básicos". madrid, informes envejecimiento en red nº 22 características de la comunicación en el anciano decálogo para el buen trato a las personas mayores adultos mayores y medios de comunicación. ¿amigos o enemigos?. no solo arrugas microbiological comparison of hand-drying methods: the potential for contamination of the environment user, and bystander the effect of chlorhexidine in reducing oral colonisation in geriatric patients: a randomised controlled trial normas básicas de higiene del entorno en la atención sanitaria. camberra (autralia): desing one interacción entre la nutrición y las infecciones a nivel global: una revisión guía de buena práctica en geriatría. hidratación y salud. madrid beneficios de la actividad física en personas mayores. rev int med cienc activ fis deporte educación para la salud: infecciones y su prevención en personas mayores infection prevention and control in nursing homes: a qualitative study of decisión-making regarding isolation-based practiques grupo de vacunas de la sociedad española de geriatría y gerontología (segg) epidemiología general de las infecciones nosocomiales. sistemas y programas de vigilancia anales de la real academia de ciencias morales adherencia terapéutica (grupo oat) es, editor. madrid2018 definitions of infection for surveillance in longterm care facilities surveillance definitions of infections in long-term care facilities: revisiting the mcgeer criteria comunidad de madrid. prevención y control de las enfermedades transmisibles en atención primaria. gráficas monterreina s a plan nacional frente a resistencia a antibióticos plan nacional frente a la resistencia a los antibióticos (pran) comunidad de madrid. guía de uso de antimicrobianos en adultos con tratamiento ambulatorio programa marco para el control de las resistencias a los antimicrobianos en la comunidad de madrid (resiste) resolución nº 20/2017, de 14 de diciembre de 2017, por la que se ordenan determinados aspectos del ejercicio profesional enfermero en el ámbito de la prevención y control de infecciones infection prevention and control in households nursing challenges and implications guía de aplicación de la estrategia mundial de la oms para la mejora de la higiene de las manos y del modelo "los cinco momentos de la higiene de manos medidas de prevención de la trasmisión de organismos entre pacientes hospitalizados. higiene de manos the hygienic efficacy of different hand-drying methods: a review of the evidence the authors declare that they have no conflict of interest. this publication has been funded by glaxosmithkline. key: cord-257765-ljt9rn8z authors: ghisolfi, selene; almås, ingvild; sandefur, justin c; von carnap, tillman; heitner, jesse; bold, tessa title: predicted covid-19 fatality rates based on age, sex, comorbidities and health system capacity date: 2020-09-09 journal: bmj glob health doi: 10.1136/bmjgh-2020-003094 sha: doc_id: 257765 cord_uid: ljt9rn8z early reports suggest the fatality rate from covid-19 varies greatly across countries, but non-random testing and incomplete vital registration systems render it impossible to directly estimate the infection fatality rate (ifr) in many lowand middle-income countries. to fill this gap, we estimate the adjustments required to extrapolate estimates of the ifr from high-income to lower-income regions. accounting for differences in the distribution of age, sex and relevant comorbidities yields substantial differences in the predicted ifr across 21 world regions, ranging from 0.11% in western sub-saharan africa to 1.07% for high-income asia pacific. however, these predictions must be treated as lower bounds in lowand middle-income countries as they are grounded in fatality rates from countries with advanced health systems. to adjust for health system capacity, we incorporate regional differences in the relative odds of infection fatality from childhood respiratory syncytial virus. this adjustment greatly diminishes but does not entirely erase the demography-based advantage predicted in the lowest income settings, with regional estimates of the predicted covid-19 ifr ranging from 0.37% in western sub-saharan africa to 1.45% for eastern europe. key policy decisions for covid-19 containment hinge on its infection fatality rate (ifr). data from the hardest-hit countries show that the ifr varies by sex, age and certain comorbidities, suggesting a method to extrapolate estimates to new contexts with limited data infrastructure. [1] [2] [3] [4] [5] [6] [7] in this article, we combine recent estimates of the sex-specific and agespecific ifr from france with data on comorbidities conditional on death with covid-19 in italy to calculate the inverse: an ifr conditional on sex, age and comorbidity (cifr). we apply these estimates to the distribution of sex, age and relevant morbidities for 187 countries from the global burden of disease (gbd) data set. 7 results reveal substantial differences across 21 world regions, with demographics-based ifr predictions ranging from 0.11% in western sub-saharan africa to 1.07% for high-income asia pacific. despite the comparatively low ifr estimates our model predicts for the lowest income regions, these ifr estimates are appreciably higher than other recent estimates for the same areas. 8 we understand these predicted ifrs as lower bounds on mortality in low-and middleincome countries, since they are derived implicitly assuming access to advanced healthcare. to account for the likelihood of higher fatality rates in under-resourced health systems, we adjust the predicted ifrs for differences in the relative odds of infection fatality from childhood respiratory syncytial virus (rsv) between world regions as a proxy for local capacity to treat viral respiratory illnesses. this adjustment greatly summary box ► given limited testing and vital statistics data, few measures of the covid-19 infection fatality rate (ifr) exist for developing countries. ► in europe and north america, measures of covid19 ifrs are known to vary by age, gender and comorbidities. ► existing model-based estimates for the developing world have not fully accounted for these factors in predicting ifrs. ► using variation in demographics, comorbidities and health system capacity, we predict covid-19 ifrs for 187 countries, ranging from 0.43% in western sub-saharan africa to 1.45% in eastern europe. ► despite lower measured health system capacities, predicted ifrs for most of sub-saharan africa nonetheless remain well below ifrs for high-income countries, while eastern europe is predicted to fare particularly poorly. ► policy-makers in low-income countries should be cognizant that any demographic advantages with respect to covid-19 fatality rates are likely to be partially offset by disadvantages in health system capacity. diminishes, but does not entirely erase, the demographybased advantage predicted in the lowest income settings, with regional estimates of the predicted covid-19 ifr ranging from 0.43% in western sub-saharan africa to 1.45% for eastern europe. here we outline the calculation of our benchmark: the predicted cifr status, starting from the ifr estimates by age and sex reported in salje et al 4 for france. the latter are, to our knowledge, the most recent peer-reviewed ifr estimates for covid-19 which report variations for all age brackets and differentiate by sex. they are lower than earlier figures from walker et al 9 , particularly among younger age groups, but are quite similar in the highest age brackets. the core assumption behind our approach is that variation in the ifr within france by age, sex and comorbidity can be used to predict the variation in ifrs across countries based on their age, sex and comorbidity distributions. to date these are the key factors that have well studied, statistically and clinically significant associations with covid-19 severity and death. importantly, we do not require that the underlying distributions of age, sex or comorbidities are similar between france and other countries in our sample; on the contrary, differences across countries in these distributions will drive the variation in predicted ifrs. we now demonstrate our method to extricate from the french age and sex-specific ifrs that part which we claim is portable across contexts: the probability of dying (d) given infection from covid-19 (i) and the age (a), sex (s), and comorbidity status (c) of patients, that is, p ( d|c; i, a, s ) . we term this the cifr and use subscripts for notational convenience, so that cifr = p ias ( d|c ) applying bayes' rule, we can recover this cifr by relating it to the ratio of comorbidity prevalence among covid-19 fatalities relative to covid-19 infections (conditional on age and sex) and age and sex-specific ifrs: we now discuss how we measure each of these probabilities. (1) p ias ( c|d ) denotes the probability of comorbidity status given death of covid-19, age and sex. we rely on the assumption that this probability is independent of age and sex, p ias ( c|d ) ≈ p ( c|d, i ) , which is supported by data from new york city. (as shown in online supplemental figure 1, data from new york city indicate that among those who die from covid-19, the share that has any comorbidity is stable across age groups and very similar for both.) we calculate p ( c|d, i ) , using the italian istituto superiore della sanità reports on the number of comorbidities conditional on covid-19 death. 10 the choice to combine data from france and italy was motivated by the fact that the latest published estimates of mortality by age and gender come from france, while reliable data on comorbidities among covid-19 deaths are available for italy but not france. given our assumption that the cifr is portable across contexts (with the same health system capacity), countries with the same comorbidity and sex distribution at each age should have the same age-specific ifr. we show in theonline supplemental figure 1 that france and italy are similar in terms of comorbidity and sex distributions for a given age, and that the age-specific ifr estimates for the two countries (reported in salje et al 4 and ferraro et al 11 ) are very close. thus by equation (1), the two countries should also have the same prevalence of comorbidities among their covid-19 fatalities at each age. (2) p ias ( c ) denotes the presence of underlying conditions given infection, age and sex. we assume p ias ( c ) ≈ p ( c|a, s ) and take the probability of having any covid-19-relevant comorbidity by age and sex in france from the gbd data set. this assumption would be violated if the pool of infected systematically differs from the general population. recent evidence from the usa suggests that comorbidities are as present among the infected as in the general population. 12 furthermore, data from italy show attack rates above 50% in some provinces. this, together with the absence of widespread immunity 11 further supports this claim. note that for simplicity we rely on an indicator for any covid-19relevant comorbidity, although the type, number and combination of different diagnoses are likely to affect the cifr. the comorbidities considered relevant for covid-19 by clark et al 7 are the following: cardiovascular diseases, chronic kidney diseases, chronic respiratory diseases, chronic liver disease, diabetes mellitus, cancers with direct immunosuppression, cancers with possible immunosuppression, hiv/aids, tuberculosis, chronic neurological disorders, sickle cell disorders. (3) p ias ( d ) denotes the sex and age-specific ifrs from salje et al 4 which come from france. with these ingredients, we can calculate the cifr assuming healthcare levels similar to high-income countries (hics) in (1), which we find to be an increasing and non-linear function of both age and comorbidity (figure 1 and table 1, labelled 'hic'). for those without a comorbidity, the cifr is effectively zero and flat up to the age of 50, and then increases roughly 20-fold between 50-59 and 70-79 years (from 0.01% to 0.17% for women and from 0.02% to 0.48% for men). with a comorbidity, the pattern is similar, but because the cifr is already higher at younger ages, the age gradient is flatter, roughly doubling the cifr for each decade above age 50. the difference in the cifr between patients with and without comorbidities is large but declines rapidly with age. finally, the female cifr is lower than the male cifr for each age and comorbidity status. we integrate the cifr over each country's sex, age and comorbidity distribution to obtain a country-specific average ifr. figure 2 shows our main results, aggregated bmj global health figure 1 cifrs, adjusted for health system capacity, by country income group (log scale). cifrs, infection fatality rates conditional on age, sex and comorbidity; hics, high-income countries; lics, low-income countries; lmics, lower middleincome countries; umics, upper middle-incomecountries. bmj global health by 21 world regions (we display the unaggregated results in online supplemental figure 2). we find substantial variation in predicted ifrs across regions-by a factor of 10 between the highest (high-income asia pacific with an ifr of 1.07%) and the lowest (western sub-saharan africa with an ifr of 0.11%). the variation is systematic, as low-income regions have lower predicted ifrs than high-income regions. demography is a key driver of these results: age distributions vary substantially across regions, with sub-saharan africa and oceania having the youngest and richer regions having the oldest populations. regional variation in comorbidities also helps explain variation in predicted ifrs across regions: highincome regions display more comorbidities among the elderly than low-income settings, while the reverse is true among the young and middle-aged segments of the population. finally, because the ifr is always lower for women than for men, variation in sex imbalances in the highest age brackets (tilted toward women everywhere) also contributes to variation in the average ifr. we interpret our predicted ifr estimates as lower bounds on the true probability of dying from covid-19 in low and middle-income settings, as data on fatalities come from countries with advanced health systems. health system weaknesses in lower income settings likely imply that a larger proportion of severe covid-19 cases result in death due to suboptimal medical care, and this will likely diminish the demographic advantages of lowincome countries (lics). to account for this, we adjust our ifr estimates for health-system strength based on a region's demonstrated capacity to prevent fatalities from viral lung infections. we derive this adjustment from comparative regional hospital case fatality rates for rsv among children aged 0-59 months. we chose this demographic to derive our health system capacity measure because restricting attention to this age bracket approximately purges the rsv ifrs of crosscountry variation in the distribution of ages, comorbidities (as children under five have very low burdens of chronic diseases such as hypertension, kidney disease or other conditions of organ degradation) and sex (as sex ratios under 5 years are more balanced than for older groups). with nearly equivalent age, sex and comorbidity rates in this demographic, we take remaining cross-country variation in the ifr for rsv to be attributable principally to health system capacity. we choose rsv acute lower respiratory infection (alri) as a proxy for covid-19 as they are viral lower respiratory infections with overlapping symptoms. like covid-19, rsv usually causes mild symptoms, but occasionally develops into a life-threatening illness. as with all viruses, neither is treatable with antibiotics, and, until covid-19, rsv was unique among the major organisms that cause death from respiratory tract infections to have neither any vaccine nor recognised treatment. 13 14 normalising the ifr for childhood rsv in hics to 1, we apply the ratio of these ifrs between regions to scale up our demography-adjusted and comorbidity-adjusted ifr predictions. unfortunately, we lack country-level ifr estimates. however, shi et al 15 provide data from which rsv ifrs for severe cases can be inferred by world bank income level: hics, lics, lower middle-income countries (lmics) and upper middle-income countries (umics). the ratios of the ifrs for children hospitalised with rsv between hics and lics, lmics and umics from this data are 8.54, 5.45 and 3.23, respectively. while we assume that all severe cases warranting hospitalisation obtain it in hics, this is not necessarily the case in other income groups, and thus these relative hospital fatality ratios require an adjustment to become infection fatality ratios. we take this adjustment from wang et al, 16 from which the relationship between hospital case fatality rates and ifrs can be mapped for lmics and hics for childhood influenza, another comparable respiratory virus. using this mapping, we translate our rsv ifrs specifically among hospitalised children into ifrs among all severe cases, which are estimated to have ratios to hic ifrs of 7.40, 4.72, 2.80 for lics, lmics and umics, respectively. taking these ratios as ors rather than risk ratios (to maintain coherent probability bounds), we rescale bmj global health the predicted cifrs by these region-specific adjustments to calculate a cifr conditional on regional health system capacity (see online supplementary appendix a1 for details). adjusting for health system capacity increases the cifr in poorer regions by almost an order of magnitude ( figure 1 and table 1 ). at ages 60 and below, the cifr is increased by a factor of 6-7 in lics, by a factor of 4 in lmics and by a factor of 2-3 in umics. for older ages, the increase in the cifr is less stark, but the adjusted cifr is still two to four times as large as the unadjusted one. lower health system capacity thus both increases the cifr at each age and comorbidity status and flattens its age gradient. with this health system-adjusted cifr in hand, we recalculate the country-specific ifrs (and add them to figure 2 and online supplemental figure 2 ). the health system strength adjustment starkly increases the predicted covid-19 ifrs for the lowest income regions, nearly though not entirely erasing their demographic advantages: the predicted ifrs double on average in umics, almost triple in lmics and increase by a factor of 3.7 in lics. as examples, ifrs increase from 0.13% to 0.44% in sub-saharan africa, from 0.39% to 0.73% in latin america and from 0.31% to 0.73% in south and central asia. eastern europe is predicted to have particularly high ifrs (1.43%), as it is characterised by an ageing population, high prevalence of comorbidities at a given age and low predicted health system capacity based on its income levels. our method of accounting for differences in health system capacity is crude in that we currently only have indicative numbers for rsv alri by income group, rather than national-level adjustments. however, the wide gap in childhood respiratory tract ifrs of between 2.8-fold and 7.4-fold between income groups has implications for covid-19 ifrs that are too large to ignore. we can test the validity of our core assumption, namely, that variation in age, sex and comorbidity distributions as well as health system capacity explain differences in ifrs across countries by comparing our predicted ifrs to independently measured ifrs. for this exercise, we consider all studies reporting either ifrs or infection rates for populations with available covid-19 fatalities, which were listed in the systematic review by meyerowitz-katz and merone 17 or retrieved through an online search on july 2. out of the 32 studies selected in this way, 6 studies measure infection rates by testing for seroprevalence of covid-19 antibodies in population-based random samples. we judge this to be the best method of estimating infection rates and thus ifrs, because random sampling is required to be truly representative, and antibody seroprevalence indicates all cumulative cases, whereas 'swab' tests only detect current cases. we thus compare our predicted ifrs first and foremost to the estimates in these six studies. while five of the six random sample studies are located in hics, one is from an umic, allowing for validation of the health systemadjusted ifrs constructed in the previous section. in a second step, we use all published ifr estimates in the comparison, including those which use convenience samples, adjusted case fatality rates (cfrs) or 'swab' tests. the results are presented in figure 3a , where we plot the independent ifr estimates for the six random sampling studies in different countries on the horizontal axis against our predicted ifrs-using the health systemadjusted ifrs from the previous section-on the vertical axis. the independent estimates and our predictions are reported in table 2. comparing our estimates to these studies, we find a correlation of 61%, demonstrating that our method can successfully predict a considerable portion of the cross-country variation in ifrs. we note that switzerland 18 and sweden 19 are close to the 45° line, as are the estimates from spain 20 and iceland, 21 which have been acknowledged to be well designed, randomised data collection efforts. for brazil, 22 which tests the validity of our approach outside of high-income health systems, the health system-adjusted ifr also closely matches the independently estimated ifr, while the crude ifr is substantially lower at 0.40% (consistent with our expectation that failing to adjust for health system capacity provides a lower bound on the true ifr outside of hics). belgium, 23 on the other hand, has a very high ifr relative to our predicted number, but this source counts all suspect deaths in nursing homes as covid-19 deaths (as reported in https://www. bbc. com/ news/ world-europe-52491210), yielding the highest ifr among the included studies. figure 3b reports the results from a comparison with all the same studies listed in meyerowitz-katz and merone 17 plus four additional random seroprevalence studies representative at subnational level. twenty-six studies come from hics and six from umics. the estimates displayed in this panel are much more noisy, including wide variations within single countries. nonetheless, our method does retain a positive correlation, although a lower one, even with these measured ifrs. note that we lack coverage for lics in this validation exercise. the lack of representative seroprevalence studies and covid-19 mortality data to estimate ifrs in such contexts is a key motivation for this study and highlights the need for modelled predictions. for example, we are aware of two serological studies measuring prevalence rates from countries in sub-saharan africa: one based on a representative sample of nampula, mozambique, 24 and another of kenyan blood donors. 25 however, fatality data appear unreliable: even attributing all recorded deaths from covid-19 in mozambique and kenya (6 and 154 total deaths, respectively) to the surveyed regions of nampula and nairobi, the estimated ifrs would be disproportionately low at 0.018% and 0.028%. our results illustrate the possibility of predicting covid-19 ifrs with a methodology that (1) uses information readily available for most of the world-namely age and comorbidity distributions as well as proxies for health system capacity, (2) relies on parsimonious and transparent assumptions and (3) appears broadly consistent with the limited set of ifrs generated from random covid-19 testing. although we produce estimates at national level, subnational variability in distributions of comorbidities, age and sex may be important enough to require ifr estimations at subnational level. a merit of our approach is its portability to any community level where comorbidity, sex and age distributions and health system capacity (compared with france) are known. while our calculations including adjustments for health system strength still suggest somewhat lower ifrs in the least developed economies than in the most advanced economies, our estimates are significantly higher than ifrs used in other recent covid-19 forecasts for africa, 8 and middle-income countries. 9 in the absence of widespread testing or reliable vital registration systems, transparent calculations of likely ifrs provide an important input into optimal policy design under extreme uncertainty, particularly as the pandemic expands into new geographies and/or a second wave of infections arrives. twitter justin c sandefur @justinsandefur contributors all authors contributed to the design of the research. sg and tb compiled and analysed the data. tb, sg, jh and jcs contributed to writing. ia and tvc reviewed and edited the manuscript. funding this study was supported by bill & melinda gates foundation. competing interests none declared. patient consent for publication not required. provenance and peer review not commissioned; externally peer reviewed. data availability statement data are available upon request. open access this is an open access article distributed in accordance with the creative commons attribution 4.0 unported (cc by 4.0) license, which permits others to copy, redistribute, remix, transform and build upon this work for any purpose, provided the original work is properly cited, a link to the licence is given, and indication of whether changes were made. see: https:// creativecommons. org/ licenses/ by/ 4. 0/. justin c sandefur http:// orcid. org/ 0000-0002-2233-834x demographic science aids in understanding the spread and fatality rates of covid-19 likelihood of survival of coronavirus disease 2019 estimating the infection and case fatality ratio for coronavirus disease (covid-19) using ageadjusted data from the outbreak on the diamond princess cruise ship estimating the burden of sars-cov-2 in france estimating excess 1-year mortality associated with the covid-19 pandemic according to underlying conditions and age: a population-based cohort study coronavirus disease 2019 (covid-19) daily data summary how many are at increased risk of severe covid-19 disease? rapid global, regional and national estimates for 2020 the potential effects of widespread community transmission of sars-cov-2 infection in the world health organization african region: a predictive model the global impact of covid-19 and strategies for mitigation and suppression. imperial college covid-19 response team characteristics of covid-19 patients dying in italy how deadly is covid-19 ? a rigorous analysis of excess mortality and age-dependent fatality rates in italy covid-19 testing, hospital admission, and intensive care among 2,026,227 united states veterans aged 54-75 years respiratory syncytial virus in young children symptoms and care, respiratory syncytial virus global, regional, and national disease burden estimates of acute lower respiratory infections due to respiratory syncytial virus in young children in 2015: a systematic review and modelling study global burden of respiratory infections associated with seasonal influenza in children under 5 years in 2018: a systematic review and modelling study a systematic review and metaanalysis of published research data on covid-19 infection-fatality rates repeated seroprevalence of anti-sars-cov-2 igg antibodies in a population-based sample from första resultaten från pågående undersökning av antikroppar för covid-19-virus antibody study shows just 5% of spaniards have contracted the coronavirus spread of sars-cov-2 in the icelandic population remarkable variability in sarscov-2 antibodies across brazilian regions: nationwide serological household survey in 27 states 3% of belgians have antibodies against coronavirus inquérito sero-epidemiológico de sars-cov-2 na cidade de nampula -resultados preliminares preliminary report of sars-cov-2 antibody prevalence among blood donors in kenya key: cord-315126-713k0b9u authors: rudolph, cort w.; rauvola, rachel s.; costanza, david p.; zacher, hannes title: generations and generational differences: debunking myths in organizational science and practice and paving new paths forward date: 2020-09-04 journal: j bus psychol doi: 10.1007/s10869-020-09715-2 sha: doc_id: 315126 cord_uid: 713k0b9u talk about generations is everywhere and particularly so in organizational science and practice. recognizing and exploring the ubiquity of generations is important, especially because evidence for their existence is, at best, scant. in this article, we aim to achieve two goals that are targeted at answering the broad question: “what accounts for the ubiquity of generations despite a lack of evidence for their existence and impact?” first, we explore and “bust” ten common myths about the science and practice of generations and generational differences. second, with these debunked myths as a backdrop, we focus on two alternative and complementary frameworks—the social constructionist perspective and the lifespan development perspective—with promise for changing the way we think about age, aging, and generations at work. we argue that the social constructionist perspective offers important opportunities for understanding the persistence and pervasiveness of generations and that, as an alternative to studying generations, the lifespan perspective represents a better model for understanding how age operates and development unfolds at work. overall, we urge stakeholders in organizational science and practice (e.g., students, researchers, consultants, managers) to adopt more nuanced perspectives grounded in these models, rather than a generational perspective, to understand the influence of age and aging at work. people commonly talk about generations and like to make distinctions between them. purported differences between generations have been blamed for everything from declining interest in baseball (keeley, 2016) to changing patterns of processed cheese consumption (mulvany & patton, 2018) . in the workplace, generations and generational differences have been credited for everything from declining levels of work ethic (e.g., cenkus, 2017; cf. zabel, biermeier-hanson, baltes, early, & shepard, 2017) , to higher rates of "job-hopping" (e.g., adkins, 2016; cf. costanza, badger, fraser, severt, & gade, 2012) . despite their ubiquity, a consensus is coalescing across multiple literatures that suggests that all the attention garnered by generations and generational differences (e.g., lyons & kuron, 2014; twenge, 2010) has been "much ado about nothing" (see rudolph, rauvola, & zacher, 2018; rudolph & zacher, 2017) . that is to say, the theoretical assumptions upon which generational research is based have been questioned and there is little empirical evidence that generations exist, that people can be reliably classified into generational groups, and, importantly, that there are demonstrable differences between such groups that manifest and affect various work-related processes (heyns, eldermire, & howard, 2019; jauregui, watsjold, welsh, ilgen, & robins, 2020; okros, 2020; stassen, anseel, & levecque, 2016) . indeed, a recent consensus study published by the national academies of sciences, engineering, and medicine (nasem) concluded that "categorizing workers with generational labels like 'baby boomer' or 'millennial' to define their needs and behaviors is not supported by research, and cannot adequately inform workforce management decisions…" (nasem, 2020a; see also nasem, 2020b) . of equal importance to the theoretical limitations, common research methodologies used to study generations cannot unambiguously identify the unique effects of generations from other time-bound sources of variation (i.e., chronological age and contemporaneous period effects). given all of this, some have argued that there has never actually been a study of generations , and thus, the entire body of empirical evidence regarding generations is, to a large extent, wrong. still, it is easy to find examples of empirical research that claim to find evidence in favor of generational differences (e.g., dries, pepermans, & de kerpel, 2008; twenge, 2000 ; see costanza et al., 2012 , for a review) and theoretical advancements that aim to direct such empirical inquiries (e.g., dencker, joshi, & martocchio, 2008) . moreover, some see generations as a useful heuristic in the process of social sensemaking: generations are recognized as social constructions, which help give meaning to the complexities and intricacies of aging and human development in the context of changing societies (e.g., campbell, twenge, & campbell, 2017; lyons, urick, kuron, & schweitzer, 2015) . considering all of this, we are faced with a variety of competing and contradictory issues when trying to sort out what bearing, if any, generations have on organizational science and practice. on the one hand, evidence for the existence of generations and generational differences is limited. on the other hand, the idea of generations is pervasive and is used to explain myriad patterns of thinking, feeling, and behaving that we observe day-to-day, especially in the workplace. thus, there exists a tension between what science "says" about generations and what people "do" with the idea of generations. given this, the continued popularity of generations as a means of understanding work-related processes is worthy of closer investigation. this popularity begs the question, "what accounts for the ubiquity of generations, despite a lack of evidence for their existence and impact?" this manuscript explores two answers to this question. one answer to this question is a lack of knowledge about what the science of generations tells us, leading to misunderstandings of the evidence about generations, their existence, and their purported impact. thus, the first goal of this article will be to review and debunk ten common myths about generations and generational differences at work and beyond. a second answer to this question is a lack of knowledge regarding, and exposure to, alternative theoretical explanations for understanding (a) the role of age and aging at work and (b) the persistence of generations as a tool for social sensemaking. more specifically, we argue that, owing to a lack of knowledge about alternative explanations and supported by their ubiquity and popular acceptance (e.g., in the popular business and management press; see howe & strauss, 2007; knight, 2014; shaw, 2013) , generations are more often than not the "default" mode of explanation for complex age-related phenomena observed in the workplace and beyond (e.g., because they are familiar and comfortable explanations, which are easy to adopt, and seem legitimate on their face). accordingly, the second goal of this paper is to further advance two alternative models for understanding age and aging at work that do not rely on generational explanations and that can explain their existence and popularity-the social constructionist perspective and the lifespan development perspective. this is an important contribution, because simply pointing out the obvious pitfalls of generations and generational explanations can only go so far toward changing the way that people think about, talk about, study, and enact practices that involve generations. just advising people to drop the idea of generations without providing alternative models would be counterproductive to the goal of enhancing the credibility of organizational science and practice. thus, our hope is that by providing workable alternatives to generations, researchers and practitioners will be encouraged to think more carefully about the role of age and the process of aging when enacting the work that they do. the social constructionist perspective offers that generations and differences between them are constructed through both the ubiquity of generational stereotypes and the socially accepted nature of applying such labels to describe people of different ages (e.g., consider the recent "ok boomer" meme; hirsch, 2020) . the social constructionist perspective helps address and explain the question of why generations are so ubiquitous. complementing this, the lifespan perspective is a well-established alternative to thinking about the process of aging and development that does not require one to think in terms of generations. the lifespan perspective frames human development as a lifelong process which is affected by various influences-not including generations-that predict developmental outcomes. despite its longstanding role in research on aging at work (e.g., baltes, rudolph, & zacher, 2019) , the lifespan perspective has been infrequently considered as an alternative model to generations, perhaps because it has not often been treated in accessible terms. these complementary approaches-the social constructionist and the lifespan development perspective-offer alternative paths forward for studying age and age-related processes at work that do not require a reliance on generational explanations. thus, as described further below, these perspectives by-and-large circumvent the logical and methodological deficiencies of the generations perspective. they also offer actionable theoretical and practical guidance for identifying the complexities involved in understanding age and aging at work. first, we outline and "bust" ten myths about generations and generational differences (see table 1 for a summary). these myths were chosen in particular, because we deemed them to be the most pressing for research and practice in the organizational sciences, broadly defined, in that they reflect commonly highlighted topics, and bear potential risks if not properly addressed. then, we introduce and outline the core tenets of the social constructionist and lifespan development perspectives, giving examples of how their applications can complement each other in supplanting generational explanations in both science and practice. finally, we conclude by drawing lines of integration between these two perspectives, in the hopes that these alternative ways of thinking will inspire myth #1: generational "theory" was meant to be tested -the sociological concept of "generations" has been re-characterized and misappropriated over time. -generational "theory" is not falsifiable, nor was it intended to be. -culture, and the generational groups it forms and is formed by, cannot be disentangled. myth #2: generational explanations are obvious -the mechanisms by which generations emerge are oversimplified in the literature. -explanations for social phenomena are more likely associated with other time-based sources of variation than generations. -sources of time-based variability are often conflated and confused with one another in popular discourse and in research. myth #3: generational labels and associated age ranges are agreed upon -the specific birth year ranges that define each generational grouping vary substantially. -there are notable differences in the ways researchers address cross-cultural variability in generational research. -inconsistencies in labeling have significant conceptual and computational implications for the study and understanding of generations. myth #4: generations are easy to study -the conceptualization of generations as the intersection of age and period make them impossible to study. -there exists no research design that can disentangle age, period, and cohort effects. -artificially grouping ages into "generations" does nothing to solve the confounding of age, period, and cohort effects. myth #5: statistical models can help disentangle generational differences -no statistical model exists that can unambiguously identify generational effects. -as long as age, period, and cohort are defined in time-related terms, they will be inextricably confounded with one another. -this issue has befuddled social scientists for so long that it has been called "a futile quest." myth #6: generations need to be managed at work -research generally does not and cannot support the existence of generational differences, so there is nothing to "manage" in this regard. -generations give a convenient "wrapper" to the complexities of age and aging in dynamic environments. -generations are highly deterministic. -it is more rational and defensible to suggest that individuals' age, life stage, social context, and historical period intersect across the lifespan. myth # 9: studying age at work is the antidote to the problems with studying generations -age and aging research are neither remedies for nor equivalent approaches to the study of generations. -despite its limitations, aging research draws on sound theories, research designs, and statistical modeling approaches. -studying age alone is not a substitute for generational research; rather, it transcends generational approaches and engenders more useful and tenable conclusions for researchers and practitioners alike. myth #10: talking about generations is largely benign -talking about generations is far from benign: it promotes the spread of generationalism, which can be considered "modern ageism." -generationalism is defined by sanctioned ambivalence and socially acceptable prejudice toward people of particular ages. -use of generations to inform differential practices and policies in organizations poses great risk to the age inclusivity, and the legal standing, of workplaces. researchers and practitioners to adopt alternatives to thinking about aging at work in generational terms. myth #1: generational "theory" was meant to be tested the sheer number of empirical studies purporting to test generational "theory" would suggest that such theory was intended for testing. however, this is far from the case. the concept of generations as we know it stems from early functionalist sociological thought experiments, derived from foundational work by mannheim (1927 mannheim ( /1952 and others (e.g., ortega y gasset, 1933; see also kertzer, 1983) . adopting the term in a largely historical, rather than familial or genealogical, sense, these authors offered "generations" as social units that account for broad societal and cultural change. generations were suggested to emerge through "shared consciousness," which developed across individuals (e.g., those at similar life stages) after common exposure to formative events (e.g., political shifts, war, disaster; see ryder, 1965 ). this consciousness, in turn, was theorized to shape unique values, attitudes, and behaviors that characterize a given generation's members, especially to distinguish one generation from its predecessor. these attributes subsequently impact how these individuals interact with and influence society. here, a tautology emerges: culture begets generations and generations beget culture. this is a potentially useful perspective for describing macro-scale interactions between social groups and the social environments in which they live-that is, it is useful as a functionalist sociological mechanism, as the concept of generations was intended. however, this perspective also implies that culture, and the generational groups it forms and is formed by, cannot be disentangled. generational "theory" is not falsifiable, nor was it intended to be. attempts to empirically study generations have extended these ideas into positivist and deterministic practices for which they were not intended. even life course research (e.g., elder, 1994) , which centers on the impact of social change and forces on individuals' lives as opposed to societal change, does not directly "test" for generational differences, per se. instead, it uses generations conceptually in explicating the roles that historical, biological, and social time play in life trajectories. in fact, mannheim's (1927 mannheim's ( /1952 work was partly a critique of the overemphasis on absolutist/biological perspectives in the study of social and historical development, including the objective treatment of time (pilcher, 1994) . this makes it all the more puzzling and problematic that generational "theory" has been applied to discrete quantitative increments (i.e., age and year ranges to define cohorts), and in a fashion that ignores the "non-contemporaneity of the contemporaneous" (i.e., the fact that being alive at the same time, or even being alive and of a similar age at the same time, does not mean history is experienced uniformly; troll, 1970, p. 201) . when considering the roots of "generations," it is apparent that the concept has been re-characterized and misappropriated. one appealing, if overstated, quality of generations is that there are unique characteristics that are (assumed to be) associated with various cohorts. moreover, it is assumed that lines can be drawn between generations to distinguish them from one another on the basis of such characteristics. these characteristics, which are said to be influenced by the various events that supposedly give rise to generations in the first place, "make sense" in a way that give generations an air of face validity. for example, it seems very rational and indeed quite self-evident to many that living through the great depression made the silent generation more conservative and risk-avoidant and that helicopter parents and the rise of social media made millennials narcissistic and cynical. these and other observed social phenomena such as job-hopping and materialism are frequently ascribed to generations. however, looking more deeply into the identification of these critical events, as well as the mechanisms by which generations supposedly emerge, reveals a far more complex, nuanced picture than a generational explanation would have us believe. in order to understand why the events that created generations may, or may not, have been impactful, it is important to understand how the critical events purported to give rise to them are identified. as one example, in their popular book, strauss and howe (1991) offer a taxonomy of generations, developed by tracing historical records in search of what they called "age-determined participation in epochal events…" (p. 32). to strauss and howe, such events were deemed to be so critical that they contributed to the creation of a unique generation. this post hoc historical demographic approach benefits from the passage of time: it is far easier to identify critical events retrospectively, rather than when they are actually occurring. although major events like economic depressions and wars likely qualify as epochal, dozens of other events have been proposed to be critical in the formation of generations, only to fade into historical oblivion within a matter of a few years. for example, in defining supposedly seminal events in the development of the millennial generation, howe and strauss (2000) cite the case of "baby jessica" (n.b. on october 14, 1987, 18-month-old jessica mcclure morales fell into a well in her aunt's backyard in midland, texas. after 56 h, rescue workers eventually freed her from the 8-in. well casing 22 ft below the ground; helling, 2017) . why this event should help form a generation is uncertain, as is whether or not millennials were or have been systematically impacted by her saga and subsequent rescue. rather than being obviously generational, explanations for many social phenomena are more likely to be associated with age or period effects, both of which are other time-based sources of variation that are often conflated with generational cohorts. specifically, there are three sources of time-based variation that need to be accounted for to make claims about generations: age, period, and cohort effects (see glenn, 1976 glenn, , 2005 . age effects refer to variability due to time since birth, in that chronological age is simply an index of "life lived" (e.g., wohlwill, 1970) . period effects refer to variability due to contemporaneous time and refer to the effects of a specific time and place (i.e., the year 2020). finally, cohort effects are those that are typically taken as evidence for generations, referring to the year of one's birth. to make claims about generations, therefore, it is necessary to rule out the effect of age (i.e., developmental influences) and period (i.e., contemporaneous contextual influences). there are numerous examples of how these sources of variability are conflated and confused with one another. consider that popular press accounts of millennials have until recently painted them to be dedicated urban dwellers who favored ridesharing services and eschewed traditional families (e.g., barroso, parker, & bennet, 2020; godfrey, 2016) . however, adults in this age range have more recently been observed moving to the suburbs, buying houses and cars, and having children (e.g., adamczyk, 2019) . this is not a generational effect but rather a phenomenon attributable to the fact that millennials are reaching the normative age where people get married, start families, and purchase houses. this is a product of age and context, not generation or period. the picture becomes even more complex given other contextual factors not necessarily bound to time, for example, when considering that the average age of first conception is higher in urban, compared to rural, areas (bui & miller, 2018) . another example comes from data showing that high school and college students are less likely to hold summer jobs today than 20 years ago (desilver, 2019) . this is not a generational effect, but rather is attributable to contemporaneous economic conditions. as a final example, after 9/11, there was a modest increase in the number of people enlisting in the united states army, which is an example of a period effect (dao, 2011) . however, this change has also been misattributed in various ways to a generational effect (e.g., graff, 2019) . notably, iñ 2019 (i.e., when those born in~2001 turned~18 and were eligible to join the army), there were historically low rates of enlistment (goodkind, 2020) . if this rate had been particularly high, one might conclude evidence for a generational effect, such that people born in 2001 grew up in a time and place that demanded enlistment. however, this is not the case-growing up in a post 9/11 world did not make this cohort more likely than others to join the army. in summary, whereas certain historical events might be easily identifiable as epochal, the extent to which recent events are defined as such might not be known for some time. moreover, this idea assumes that epochal events actually matter for the formation of distinct generations, a key argument in generations theory that is by-and-large untested, and indeed untestable. moreover, consider that "global" events (i.e., those that affect all members of a population regardless of age, not just those born in a particular time and place, like a global pandemic) almost certainly manifest as period, not generational cohort effects (rudolph & zacher, 2020a . generations and the events that are purported to give rise to them are far from obvious and to attribute current individual characteristics to the occurrence of specific events is misguided. furthermore, many of the "obvious" generational effects often attributed to such events are much more likely due to other factors associated with age and/or period. whereas generational labels are well-known and widely recognized, the specific birth year ranges that define each generational grouping and the consistency with which such groupings are applied across time, studies, and location, vary substantially. for example, smola and sutton (2002, p. 364 ) identified a great deal of variation in the start and end years that define different generational groups and the names used to describe various generations, noting "gener-ations…labels and the years those labels represent are often inconsistent" (p. 364). in their meta-analysis, costanza et al. (2012) found similar discrepancies with variations in start and end dates ranging from 3 to 9 years depending on the study, the variables of interest, and the source of the generational year ranges being used. similar conclusions were reached by in their review of generations in the leadership literature. beyond these definitional inconsistencies, there are notable differences in the way researchers address cross-cultural variability in generational research. the ubiquity of the labels and their pervasiveness in the literature has led researchers from countries other than the usa to use labels (e.g., "baby boomers") when doing so does not make sense, as the events that supposedly influenced individuals and gave rise to these generations in the first place clearly differ from country to country. moreover, consider that the term "millennials" is not meaningful in countries that use chinese, islamic, jewish, buddhist, sakka, or kolla varsham calendars (deal, altman, & rogelberg, 2010) and that generations are often labeled based on political or cultural events and epochs. for instance, members of the greek workforce have been categorized into the divided generation, the metapolitefsi generation, and the europeanized generation (papavasileiou, 2017) . in israel, generations are identified by wars and thus have shorter ranges (deal et al., 2010) . the german media has variously labeled younger people as generation c64, generation golf, or generation merkel. in china, generations are pragmatically called the post-50s generation, post-60s generation, and so on, whereas in india, the three main generational groups are labeled conservatives, integrators, and y2k (srinivasan, 2012) . one approach researchers have adopted for dealing with the complexities of cross-cultural variation in generational labeling is to ignore the issue and simply use us-based generational labels and years when studying individuals in other countries. for example, yigit and aksay (2015) looked at turkish gen x and gen y health professionals, roughly using us date ranges for these groups. a second approach has been to use the date ranges associated with us generations but assign country-specific labels to those same periods. utilizing this approach, weiss and zhang (2020) picked birth year ranges and adopted or developed generational labels in three different countries. for example, for the years 1946-1965, they labeled the generations as the "68er generation" in germany, "baby boomer" in the usa, and the "new china generation" in china. a third approach has been to develop country-specific generational groups based on local events that impacted people in that county, a strategy used by to and tam (2014) who identified four distinct post-wwii generations in china. inconsistencies in labeling have significant conceptual and computational implications for the study and understanding of generations and especially so if one wishes to conduct comparative cross-national and/or cross-cultural research. importantly, we would argue that the validity of the generations concept and its utility for understanding individual, group, and organizational phenomena is very limited due to a number of factors, including (a) researchers' inability to agree on the start and end dates for different generations; (b) inconsistencies in the classification and labeling systems that characterize them; (c) disagreement on the specific significant influencing events that supposedly gives rise to them, such as the extent to which the timing of events plays a role, including the length of time that is associated with their influence, and the lag required to observe such influences; and (d) the issue of cross-cultural equivalencies. as such, defining generations represents a moving target, which is a significant liability for science and evidence-based practice. although there have been numerous attempts to study generations and generational differences, it is clear that these phenomena have not been studied very well. indeed, it is not only difficult to study generations as they have been framed in the literature but also impossible. as noted above, research on generations is typically based upon birth year ranges, which is to say that they are derived from information about birth cohorts. a common problem emerges when one tries to study cohort effects in cross-sectional (i.e., single time point) research designs, which are the most commonly applied designs used to make inferences about generations (see costanza et al., 2012) . namely, age, period, and cohort effects are confounded with each other in such designs. this confounding is best understood through an example. let us assume that a hypothetical cross-sectional study is conducted in the year 2020 (i.e., the year constitutes the "period effect" in this case). if we reduce the logic of generations a bit and define a cohort effect in terms of a single birth year (e.g., those born in 1980), then the effect of age (i.e., time since birth; 40 years) is completely confounded with cohort. this is because: in this example, any differences that researchers observe as a function of assumed cohort variability may instead be due to the age of the individuals when they were studied. this pattern would likewise be extrapolated to any age-cohort combinations studied in a single period. the linear dependency among the three effects means that unique effects of age cannot be separated from whatever cohort effect might exist and vice versa. one common attempt to circumvent this confounding is to artificially group members of different cohorts together to form generational groups. however, this practice is likewise fraught with the same issues raised just above. another hypothetical cross-sectional study helps to illustrate why: in this study, let us assume that we want to define two arbitrary groupings of birth cohorts, representing people born between 1981 and 1990 ("generation a") and those 1991-2000 ("generation b"), to disentangle age and cohort effects from one another. the variability due to birth cohort in each generation is 10 years; however, as in our previous example, the age range within cohorts is likewise 10 years. thus, this approach does little to solve the dependency other than shifting the scaling of age. as the rank order of cohort versus age has not changed (relatively older people are in "generation a" and relatively younger people are in "generation b"), there is still a correlation between age and generational groups in this study. moreover, this approach has other limitations, including the loss of statistical power to detect age effects (see rudolph, 2015) and a confusing logic of cohort versus age effect interpretations (e.g., the oldest members of "generation a" are closer in age to the youngest members of "generation b" than to the average age of their own generational group). from a research design standpoint, this issue of confounding represents an unresolvable problem, which has long been known and lamented in the literature (e.g., glenn, 1976 glenn, , 2005 . other research designs are unfortunately no better geared than cross-sectional designs to address this issue, or they do not address variability in cohort effects at all. for example, in typical longitudinal designs, cohort effects are held constant (i.e., from the first time point, people's birth year does not vary) and period is allowed to vary (i.e., as data are collected from the same people across multiple time points). however, in such designs, period effects are conflated with age (i.e., as people "get older" across time). expanded longitudinal approaches, such as cohort sequential designs (e.g., sampling 20-year-olds at each time point, t 1 − t k , adding successive cohorts of 20-year-olds at each time point) may be able to separate age/aging from period and cohort effects, depending on how "cohort" is defined. however, such studies require immense resources and time (e.g., 20+ years or more of data collection, including long-term data management and subject retention efforts; see baltes & mayer, 2001) . as such, and perhaps not surprisingly, we are unaware of any applications of such designs to the study of generations at work. an alternative that has been employed by some researchers (e.g., twenge, konrath, foster, campbell, & bushman, 2008) is a cross-temporal approach, often employing time-lagged panels or cross-temporal meta-analyses (discussed further below). cross-temporal approaches use data collections from members of different cohort groups, collected during different periods, holding age constant (e.g., data from panels of 25year-olds and 50-year-olds collected in 2000, 2010, and 2020 or research done on college students every year from 1990 to the present). the logic of cross-temporal methods is to compare groups of similarly aged individuals (i.e., to "control" for age by holding its value constant) across time and then argue that cohort effects are more likely the cause of any observed differences than period effects. among other issues, crosstemporal approaches have been criticized for their reliance on ecological correlations (i.e., correlations among variables that represent group means) and design assumptions (see trzesniewski & donnellan, 2010; trzesniewski, donnellan, & robins, 2008) raising significant concerns about them as a way to study generations. specifically, ecological correlations can misrepresent relationships when contrasted with correlations among individual observations (see robinson, 1950) . overall, the methodological and design challenges associated with studying generations are substantial and the conceptualization of generations as the intersection of age and period makes them impossible to study. thus, studying generations is only "easy" to the extent that one is willing to ignore the issues raised here. given these concerns, we echo the recommendations of rudolph and zacher (2017) , who suggest that "…both research and practice would benefit from a moratorium on time-based operationalizations of generations as units for understanding complex dynamics in organizational behavior" (p. 125). given the design challenges noted above, it is perhaps not surprising that researchers have tried a variety of statistical techniques to resolve the age, period, and cohort confounding problem. unfortunately, the great majority of generational studies to date have employed the least useful approach to doing so, pairing cross-sectional designs with comparisons of generational cohort means (e.g., typically via linear models, such as t tests or other variants of anova-type models). as noted, cross-sectional approaches control for period effects but confound cohort and age effects with one another and this confounding cannot be resolved statistically through any means. to be clear, this is not a function of a lack of innovation regarding statistical modeling techniques. on the contrary, as long as age, period, and cohort are defined in timerelated terms, they will be inextricably confounded with one another in cross-sectional research designs. with respect to cross-temporal approaches, some researchers have implemented a specific technique referred to as "cross-temporal meta-analysis" (ctma). ctma shares certain features with traditional meta-analysis (e.g., studies assumed to be representative of a population of all possible studies on a given phenomenon are taken from the literature and synthesized). in a typical ctma, age is more or less held constant by narrowing the sampling frame of studies included (e.g., by only considering studies of college age students). by holding age constant and looking at the effects of time on outcomes (i.e., by considering the relationship between year of publication and mean levels of a given phenomenon derived from contributing studies), ctma models change over time in a phenomenon. however, although age is to some extent held constant, recall that cross-temporal methods inherently confound period and cohort effects with one another. thus, any identified cohort effect cannot be unambiguously separated from period effects in ctma. although research employing ctma has argued that generations are more likely than period effects to explain observed differences, such work also recognizes that period effects are equally likely explanations for any results derived therefrom (e.g., twenge & campbell, 2010) . furthermore, a recent paper by rudolph, costanza, wright, and zacher (2019) used monte carlo simulations to test the underlying assumptions of ctma, finding that it may misestimate cohort effects by a factor of three to eight times, raising questions about both the source and magnitude of any differences identified. a final analytic technique that has been occasionally employed to disentangle age, period, and cohort effects is cross-classified hierarchical linear modeling (cchlm; yang & land, 2006 . applying cchlm to generational research, age is treated as a fixed effect and period and cohort are allowed to vary as random effects. importantly, however, decisions about how such effects should be specified are somewhat arbitrary, because it is also possible that cohort and period could be fixed and age random in the population, resulting in different outcomes and conclusions from such models that are largely dependent on analytic decisions rather than reflecting "true" population effects. thus, without generally unknowable insights into "what" to hold constant in estimating such models, cchlm results in ambiguous parameter estimates for age, period, and cohort effects. to this end, a series of simulation studies by bell and colleagues (bell & jones, 2014 ; see also bell & jones, 2013 , for further commentaries) has shown that the yang and land methodology for separating age, period, and cohort effects simply does not "work." even ignoring this issue, cchlm does little to solve the problem of age, period, and cohort confounding, because the three variables are still linearly dependent upon each other and hence computationally inseparable. something (typically age) has to be held constant in such models to separate these variables from one another, and even then, ambiguities in how to interpret confounded effects of period and cohort still abound. in short, none of the statistical techniques that have been used to study generations can fully separate age, period, and cohort effects (see costanza, darrow, yost, & severt, 2017 , for a full discussion) and cannot solve the conceptual or design problems noted earlier. this known issue has befuddled social scientists for quite some time. for example, more than 40 years ago glenn (1976) referred to this problem as "a futile quest." given the proliferation of research and popular press articles identifying generational differences, it is not surprising that practitioners and academics have suggested that people in different generations need to be managed differently at work (e.g., baldonado, 2013; lindquist, 2008) . there are two main problems with these recommendations. first, as has been noted, research generally does not and cannot support the existence of generational differences. conceptual, theoretical, methodological, and statistical issues abound in this literature, and absent clear, convincing, and valid evidence for the existence of generational differences, there is no justification for managing individuals based on their supposed generational membership (nasem, 2020a (nasem, , 2020b rudolph & zacher, 2020c) . eschewing the notion of generations does not mean that one must ignore that individuals change over the course of their lifespan or that their needs at different stages in their careers will vary. however, it is important to note that there is not a credible body of evidence to suggest that such changes are generational or that they should be managed as "generational differences" at work. indeed, as already noted, much of what lay people observe as "generational" at work is likely more accurately attributed to either age or career stage effects masquerading as generational differences. there is a broad and well-supported literature on best practices for hr, leadership, and management (e.g., kulik, 2004) and customizing policies and practices based on those recommendations rather than generational stereotypes makes much more sense. furthermore, there is a burgeoning literature on the positive influence that agetailored policies (e.g., age-inclusive human resource practices that foster employees' knowledge, skills, and abilities, motivation, effort, and opportunities to contribute, irrespective of age) for building positive climates for aging at work and supporting worker productivity and well-being (see böhm, kunze, & bruch, 2014; rudolph & zacher, 2020d) . for example, research suggests that workers of all ages benefit from flexible work policies that allow for autonomy in choosing the time and place where work is conducted (see rudolph & baltes, 2017) . second, as alluded to earlier, management strategies that are based on generations have the potential to raise legal risks for organizations. for example, in the usa, provisions of the civil rights act of 1964, the age discrimination in employment act of 1967, and the americans with disabilities act of 1991 disallow the mistreatment of individuals from certain groups based on a variety of characteristics. although generational membership is not directly covered by such legislation, under the adea, age is a protected class for workers aged 40+. given the conflation of generational effects with age, life, and career stage, employment-related decisions tied to generations could be interpreted as prima facie evidence of age-related discrimination (e.g., swinick, 2019) . indeed, organizations that market themselves to and build personnel practices around generations and generational differences have been implicated in age discrimination lawsuits (e.g., rabin vs. pricewaterhousecoopers, 2017). combined with the absence of valid studies supporting generationally based differences, organizations open themselves up to an unnecessary liability if they manage individuals based on generational membership (costanza & finkelstein, 2015 ; for a related discussion of various policy implications of managing generations, see rudolph, rauvola, costanza, & zacher, 2020) . recently, costanza, finkelstein, imose, and ravid (2020) reviewed the applied psychology, hr, and management literatures looking for studies about how organizations should manage generations in the workplace. they identified a range of inappropriate inferences and unsupported practical recommendations and systematically refuted them based on legal, conceptual, practical, and theoretical grounds. we echo their conclusion here, regarding advice from managing based on generational membership (p. 27): "instead of customizing hr policies and practices based on such [generational] differences, organizations could use information about their overall workforce and its characteristics to train recruiters, develop and refine policies, and offer customizable benefits packages that appeal to a broad range of employees, regardless of generation." that said, we do not think that the idea of generations should be ignored altogether in the development of management strategies. instead, the focus should be shifted away from managing assumed differences between members of different generations and toward managing perceptions of generations and generational differences. considering evidence that people's beliefs and expectations about age and generations feed into the establishment of stereotypes that interfere with work-relevant processes (e.g., king et al., 2019; perry, hanvongse, & casoinic, 2013; raymer, reed, spiegel, & purvanova, 2017; van rossem, 2019) , this is a particularly important consideration and is, in and of itself, a topic worthy of further study. while it may feel "new" to blame members of younger generations for changes in the work environment, this is a form of uniqueness bias: we think our beliefs and experiences are new, when in reality similar complaints have been levied against relatively younger and older people for millennia. indeed, generationalized beliefs about the inflexibility and "out of touch" nature of older generations, or the laziness, self-centeredness, and entitlement of younger generations, have repeated with remarkable consistency across recorded history (rauvola, rudolph, & zacher, 2019) . one of the more obvious examples is in referring to generations with self-referent terminology: new york magazine wrote about youth in the so-called "me" decade (wolfe, 1976) over 30 years prior to twenge's (2006) work on "generation me," time magazine's (stein, 2013 ) publication on the "me me me" generation, and even the british army's recent use of the phrase "me me me millennials…your army needs you and your self belief" in recruitment ads (nicholls, 2019) . lamentations about young people "killing things" are far from radical as well. modern claims are made about youth ending an absurd number of facets of life, ranging from institutions such as marriage and patriotism to household products like napkins, bar soap, and "light" yogurt (bryan, 2017) . moreover, similar concerns have been voiced throughout the years regarding the rise and fall of consumer preferences, including concerns about young people upending and revolutionizing romantic relationships and transportation (e.g., thompson, 2016) , or being corrupted by new forms of popular media like the radio in the 1930s (schwartz, 2015) . a more realistic explanation exists for both shifts in consumer preferences as well as changes and disruptions in the nature of work: the contemporaneous environment, and innovations and unexpected changes therein. to take a recent example, the global covid-19 pandemic has tremendously impacted and transformed how and where work is conducted (kniffin et al., 2020; . while "non-essential" workers are conducting more work virtually and with more flexible hours, other workers deemed "essential" are working in environments with new health and safety protocols and often with different demands and resources in place (e.g., with respect to physical equipment, coworker and customer contact). even more workers have been furloughed or laid off altogether, with the need to turn to alternative forms of work to maintain income or, when feasible, resorting to early retirement (see bui, button, & picciotti, 2020; kanfer, lyndgaard, & tatel, 2020; van dalen & henkens, 2020) . these changes have led to a dramatic pivot for many organization, managers, and individual workers, far surpassing the speed and degree to which more gradual, "generational" workplace changes have supposedly occurred. not only this, but such changes have had outcomes for workers and society that contradict what generational hypotheses would predict. for example, generational stereotypes suggest that relatively older workers would struggle with technological changes at work while relatively younger workers would thrive. however, the move to work-from-home arrangements has resulted in positive benefits for some, including helpful and flexible accommodations, or health and safety protections, as well as new challenges for others, such as the need to balance childcare or eldercare with work while at home, while still others face newfound isolation and lack of in-person social support coupled with great uncertainty (alon, doepke, olmstead-rumsey, & tertilt, 2020; douglas, katikireddi, taulbut, mckee, & mccartney, 2020) . these changes create a diverse set of advantages and disadvantages for individuals of all ages. rather than blaming those of younger generations for disrupting work and life more generally, societal trends and events are a more appropriate, fitting, and ultimately addressable explanation (i.e., through non-ageist interventions and policies). myth #8: generations explain the changing nature of work (and society) generations are an obvious and convenient explanation for the changing nature of work and societies. however, as discussed previously, convenience and breadth in applying generational explanations does not translate into validity. because they can easily and generally be applied to explain age-related differences, generations give a convenient "wrapper" to the complexities of age and aging in dynamic environments (i.e., both within and outside of organizations). however, this wrapper restricts and obscures the complexities inherent to both individuals and the environments in which they operate. generations are highly deterministic, suggesting that individuals "coming of age" at a particular time (i.e., members of the same cohort) all experience aging and development uniformly (i.e., cohort determinism; walker, 1993) . with so many other demonstrable age-related and person-specific factors (e.g., social identities, personality, socioeconomic status) that have bearing on individuals' attitudes, values, and behaviors, as well as how these interact with contextual and environmental influences, the prospect of generations overriding all such explanations is implausible. assuming otherwise wipes away a tremendous amount of potentially useful detail and heterogeneity. moreover, this perspective stipulates that events in a given time period impact younger people and not older people, such that historical context only influences individuals up to a certain (early) point in their development. this aligns with the idea that identity is "crystallized" or "ratified" at a certain age and development or change is more or less halted thereafter (ryder, 1965) . however, ample evidence suggests that this is far from the case, with age-graded dynamics in such areas as personality emerging across the breadth of the lifespan (e.g., bianchi, 2014; donnellan, hill, & roberts, 2015; staudinger & kunzmann, 2005) and alongside external forces (e.g., economic recessions). our ability to dismiss crystallization claims is not merely empirical: although current methods and analyses used cannot fully disentangle age from cohort, lifespan development theory promotes the ideas of lifelong development, multiple intervening life influences, and individuals' agency in shaping their identity and context (e.g., baltes, 1987) . accordingly, it is more rational and defensible to suggest that individuals' age, life stage, social context, and historical period intersect across the lifespan. these intersections, in turn, produce predictable as well as unique effects that translate into different attitudes, values, and behaviors, but not as a passive and predetermined function of an individual's generation. myth # 9: studying age at work is the antidote to the problems with studying generations age and aging research are neither remedies for nor equivalent approaches to the study of generations. first, there are a broad range of phenomena encompassed in both research on "age at work" and "aging at work" (e.g., see discussion of "successful aging" research components in zacher, 2015a). these two areas are related but distinct, spanning the study of age as a discrete or sample-relative sociodemographic (i.e., age as a descriptive device, especially between person), age as a compositional unit property (e.g., age diversity in a team, organization), and age as a proxy for continuous processes and development over time (i.e., age representing the passage of time, especially within-person in longitudinal research). each of these forms has a multitude of potential contributions to our understanding of the workplace, and these contributions should not (and cannot) be reduced to generational cohortbased generalizations. second, and as noted earlier, although aging research is confounded by cohort effects, it draws on sound theories, research designs, and statistical modeling approaches (bohlmann, rudolph & zacher, 2018) . the study of generations at work, however, relies upon theories unintended for formal testing and flawed data collection methods and analyses (costanza et al., 2017) . moreover, whereas both age and aging research treat time continuously, generational research groups people into cohort categories. this results in a loss of important nuance and information about individuals, with results prone to either over-or underestimated age effects. the practice of cohort grouping also creates a "levels" issue in generational research to which age and aging research are not subject: studying aging focuses on the individual level of analysis, whereas (sociological) generational research "groups" individuals into aggregates and then incorrectly draws inferences about individual outcomes. this mismatch of levels can produce ecological or atomistic fallacies (i.e., assumptions that group-level phenomena apply to the individual level and vice versa), depending on whether group-or individual-level data are used to draw conclusions (rudolph & zacher, 2017) . thus, although age and aging research present robust opportunities for understanding how to support the agediverse workforce, generational research provides incomplete conclusions about, and unclear implications for, understanding trends in the workplace. studying age alone is not a substitute for generational research; rather, it transcends generational approaches and engenders more useful and tenable conclusions for researchers and practitioners alike. talking about generations is far from benign: it promotes the spread of generationalism, which can be considered "modern ageism." just as "modern racism" is characterized by more subtle and implicit, yet no less discriminatory or troubling, racist beliefs about black, indigenous, and people of color (bipoc; e.g., mcconahay, hardee, & batts, 1981) , generationalism is defined by sanctioned ambivalence and socially acceptable prejudice toward people of particular ages. these beliefs are normalized and pervasive, reiterated across various forms of popular media and culture to the point that they seem innocuous. however, generationalism leads to decisions at a variety of levels (e.g., individual, organizational, institutional) that are harmful, divisive, and potentially illegal. media outlets play a large role in societal tolerance and acceptance of generationalism (rauvola et al., 2019) . new "generations" are frequently proposed in light of current events, and age stereotyping becomes further trivialized with each iteration. adding to this, an abundance of generational labels "stick" while others do not-"igen," "generation wii," "generation z," and "zoomers" all vie to define the "post-millennial" generation (raphelson, 2014) , and "generation alpha" (a name inspired in part by naming conventions during the 2005 hurricane season; mccrindle & wolfinger, 2009) now faces competition from "gen c" to define the next generation. "gen c" (or "generation corona;" see rudolph & zacher, 2020a has gained traction in the media alongside the recent covid-19 pandemic, with some suggesting that "coronavirus has the potential to create a generation of socially awkward, insecure, unemployed young people" (patel, 2020) . these labels differ markedly by country as well, as noted earlier, adding to the trivialization and confusion. more and more, these labels are also used to add levity, and/ or to avoid blatant ageism, to deep-seated sociopolitical divides and conflicts portrayed in the media. take, for example, the rise of "ok boomer" alongside resentment toward conservatism (romano, 2019) , or the labeling of the "karen generation" to encapsulate white privilege and entitlement, especially among middle-to upper-class suburban women (strapagiel, 2019) . although often treated as harmless banter, this lexicon filters into influential research and policy-based organizations (e.g., "gen c" in the lancet, 2020), legitimizing the use of generational labels and associated age stereotypes in discourse and decision-making. as suggested above, in many countries, age is a protected class and the use of generations to inform differential practices and policies in organizations (e.g., hiring, development and training, benefits) poses great risk to the age inclusivity, and the legal standing, of workplaces (see also costanza et al., 2020) . whether a generational label is new and catchy or accepted and seemingly mundane, it is built on the back of modern ageism, and generationalism-just like other "isms"-is far from benign. with the preceding ten myths serving as a backdrop, we next introduce two models-the social constructionist perspective and the lifespan development perspective-that serve as alternative and complementary ways of thinking about, and understanding thinking about, generations and generational differences. indeed, we propose that these are complementary models. specifically, whereas the social constructionist perspective serves as a way of understanding why people tend to think about age and aging in generational terms, the lifespan development perspective serves as an alternative to thinking about age and aging in generational terms. considering the ten myths reviewed above, it is clear that the evidence for the existence of generations and generational differences is lacking. moreover, when applying a critical lens, what little evidence does exist does not hold up to theoretical and empirical scrutiny. what, then, are we left to do with the idea of generations? that is to say, how can we rationalize the continued emphasis that is placed on generations in research and practice despite the lack of a solid evidence base upon which these ideas rest? on the surface, this may seem to be a conceptually, rather than a practically, relevant question. however, there is a booming industry of advisors, gurus, and entire management consulting firms based around the idea of generations (e.g., hughes, 2020) . in whatever form it takes, generationally based practice is built upon the rather shaky foundations of this science, putting organizations and their constituents at risk-not only of wasted money, resources, and time, but of propagating misplaced ideas based on a weak, arguably non-existent evidence base . as the organizational sciences move toward the ideals of evidence-based practice, generations and assumed differences between them are quickly becoming yet another example of a discredited management fad (see abrahamson, 1991 abrahamson, , 1996 røvik, 2011) . borrowed from sociological theoretical traditions, the social constructionist perspective focuses on understanding the nature of various shared assumptions that people hold about reality, through understanding the ways in which meanings develop in coordination with others, and how such meanings are attached to various lived experiences, social structures, and entities (see leeds-hurwitz, 2009 )-including generations. comprehensive treatments of the core ideas and tenets of the sociological notion of social constructionism can be found in burr (2003) and lock and strong (2010) . the social constructionist perspective on generations, which is based upon the idea that generations exist as social constructions, has been advanced as a means of understanding why people often think about age and aging in discrete generational, rather than continuous, terms (e.g., rudolph & zacher, 2015 ; see also lyons & kuron, 2014; lyons & schweitzer, 2017; weiss & perry, 2020) . the social constructionist perspective has utility as a model for understanding various processes that give rise to generations and for understanding the ubiquity and persistence of generations and generationally based explanations for human behavior. in an early conceptualization of this perspective, zacher and rudolph (2015) proposed that two processes reinforce each other to support the social construction of generations. specifically, (1) the ubiquity and knowledge of generational stereotypes drive (2) the process of generational stereotyping, which is by-and-large socially sanctioned. these two processes fuel the social construction of generational differences, which have bearing on a variety of work-related processes, not least of which is the development of "generationalized" expectations for work specific attitudes, values, and behaviors. such generationalized expectations set the stage for various forms of intergenerational conflicts and discrimination (i.e., generationalism; rauvola et al., 2019) at work. the social constructionist perspective on generations is grounded in three core principles: (1) generations are social constructs that are "willed into being"; (2) as social constructs, generations exist because they serve a sensemaking function; and (3) the existence and persistence of generations can be explained by various processes of social construction. the social constructionist perspective is gaining traction as a viable alternative to rather rigid, deterministic approaches of conceptualizing and studying generations, even among otherwise staunch proponents of these ideas. for example, campbell et al. (2017) offer that "…generations might be best conceptualized as fuzzy social constructs" (p. 130) and lyons et al. (2015) echo similar sentiments about the role and function of generations. to further clarify this perspective, we next expand upon these three core ideas that are advanced by the social constructionist perspective, providing more details and examples of each, and offering supporting evidence from research and theory. first, the social constructionist perspective advances the idea that generations and generational differences do not exist objectively (see berger & luckman, 1966 , for a classic treatment of this idea of the "socially constructed" nature of reality). rather, generations are "willed into being" as a way of giving meaning to the complex, multicausal, multidirectional, and multidimensional process of human development that we observe on a day-to-day basis, especially against the backdrop of rapidly changing societies. adopting a social constructionist framework motivates an understanding of the various ways in which groups of individuals actively participate in the construction of social reality, including how socially constructed phenomena develop and become known to others, and how they are institutionalized with various norms and traditions. to say that generations are "social constructs," or that generations reflect a process of "social construction," implies that our understanding of their meanings (e.g., the "notion" of generations; the specific connotations of implying one generation versus another) exists as an artifact of a shared understanding of "what" generations "are," and that this is accepted and agreed upon by members of a society. moreover, and to the second core principle, the social constructionist perspective suggests that generations serve as a powerful, albeit flawed, tool for social sensemaking. generations provide a heuristic framework that greatly simplify people's ability to quickly and efficiently make judgments in social situations, at the risk of doing so inaccurately. in other words, generations offer an easy, yet overgeneralized, way to give meaning to observations and perceptions of complex age-related differences that we witness via social interactions. this idea is borrowed from social psychological perspectives on the development, formation, and utility of stereotypes. when faced with uncertainty, humans have a natural tendency to seek out explanations of behavior (i.e., their own, but also others'; see kramer, 1999) . this process reflects an inherent need to makes sense of one's world through a process of sensemaking. an efficient, albeit often flawed, strategy to facilitate sensemaking is the construction and adoption of stereotypes (hogg, 2000) . stereotypes are understood in terms of cognitive-attitudinal structures that represent overgeneralizations of others-in the form of broadly applied beliefs about attitudes, ways of thinking, behavioral tendencies, values, beliefs, et cetera (hilton & von hippel, 1996) . applying these ideas, the adoption of generations, and the accompanying prescriptions that clearly lay out how members of such generations ought to think and behave, helps people to make sense of why relatively older versus younger people "are the way that they are." additionally, generational stereotypes can be enacted as an external sensemaking tool, as described, but also for internal sensemaking (i.e., making sense of one's own behavior). indeed, there is emerging evidence that people internalize various generational stereotypes and that they enact them in accordance with behavioral expectations (i.e., a so-called pygmalion effect, see eschleman, king, mast, ornellas, & hunter, 2016) . third, the social constructionist perspective offers that generations are constructed and supported through different mechanisms. the construction of generations can take various forms, for example, in media accounts of "new" generations that form as a result of major events (e.g., pandemics; rudolph & zacher, 2020a , political epochs (e.g., "generation merkel" mailliet & saltz, 2017 ; "generation obama," thompson, 2012) , economic instability (e.g., "generation recession," sharf, 2014) , and even rather benign phenomena, such as growing up in a particular time and place (e.g., "generation golf," illies, 2003) . a major source of generational construction can be traced to various "think tank"-type groups that purport to study generations. from time to time, such groups proclaim the end of one generation and the emergence of new generational groups (e.g., dimock, 2019) . these organizations legitimize the idea of generations in that they are often otherwise trusted and respected sources of information and their messaging conveys an associated air of scientific rigor. relatedly, authors of popular press books likewise tout the emergence of new generations. for example, twenge has identified "igen" (twenge, 2017) as the group that follows "generation me" (twenge, 2006) , although neither label has found widespread acceptance outside of these two texts. importantly, all generational labels, including these, exist only in a descriptive sense, and it is not always clear if the emergence of the generation precedes their label, or vice versa. for example, consider that twenge has suggested that the term "igen" was inspired by taking a drive through silicon valley, during which she concluded that "…igen would be a great name for a generation…" (twenge, as quoted in horovitz, 2012) , a coining mechanism far from mannheim's original conceptualization of what constitutes a generation. the contemporary practice of naming new generations has its own fascinating history (see raphelson, 2014) . indeed, the social constructionist perspective recognizes that the idea of generations is not a contemporary phenomenon; there is a remarkable historical periodicity or "cycle" to their formation and to the narratives that emerge to describe members of older versus younger generations. as discussed earlier, members of older generations have tended to pan members of younger generations for being brash, egocentric, and lazy throughout history, whereas members of younger generations disparage members of older generations for being out of touch, rigid, and resource-draining (e.g., protzko & schooler, 2019; rauvola et al., 2019) . likewise, the social constructionist perspective underlines that generations are supported through both the ubiquity of generational stereotypes and the socially accepted nature of applying such labels to describe people of different ages. in summary, the social constructionist perspective offers a number of explanations for the continued existence of generations, especially in light of evidence which speaks to the contrary. specifically, by recognizing that generations exist as social constructions, this perspective helps to clarify the continued emphasis that is placed on generations in research and practice, despite the lack of evidence that support their objective existence. moreover, the social constructionist perspective offers a framework for guiding research into various processes that give rise to the construction of generations and for understanding the ubiquity and persistence of generations and generationally based explanations for human behavior. next, we shift our attention to a complementary framework-the lifespan perspective-which likewise supports alternative theorizing about the role of age and the process of aging at work that does not require the adoption of generations and generational thinking. then, we will focus on drawing lines of integration between these two perspectives. the lifespan development perspective is a meta-theoretical framework with a rich history of being applied for understanding age-related differences and changes in the work context (baltes et al., 2019; baltes & dickson, 2001; rudolph, 2016) . more recently, the lifespan perspective has also been advanced as an alternative to generational explanations for work-related experiences and behaviors (see rudolph & zacher, 2017; zacher, 2015b) . contrary to generational thinking and traditional life stage models of human development (e.g., erikson, 1950; levinson, darrow, klein, levinson, & mckee, 1978) , the lifespan perspective focuses on continuous developmental trajectories in multiple domains (baltes, lindenberger, & staudinger, 1998) . for instance, over time, an individual's abilities may increase (i.e., "gains," such as accumulated job knowledge), remain stable, or decrease (i.e., "losses," such as reduced psychomotor abilities). baltes (1987) outlined seven organizing tenets to guide thinking about individual development (ontogenesis) from a lifespan perspective. specifically, human development is (1) a lifelong process that involves (2) stability or multidirectional changes, as well as (3) both gains and losses in experience and functioning. moreover, development is (4) modifiable at any point in life (i.e., plasticity); (5) socially, culturally, and historically embedded (i.e., contextualism); and (6) determined by normative age-and history-graded influences and nonnormative influences. regarding the final tenet, normative age-graded influences include person and contextual determinants that most people encounter as they age (e.g., decline in physical strength, retirement), normative history-graded influences include person and contextual determinants that most people living during a certain historical period and place experience (e.g., malnutrition, recessions), and non-normative influences include determinants that are idiosyncratic and less "standard" to the aging process (e.g., accidents, natural disasters). finally, baltes (1987) argued that (7) understanding lifespan development requires a multidisciplinary (i.e., one that goes beyond psychological science) approach. in summary, the lifespan perspective recognizes that individuals' development is continuous, malleable, and jointly influenced by both normative and non-normative internal (i.e., those that are genetically determined; specific decisions and behaviors that one engages in) and external factors (i.e., the sociocultural and historical context). a generational researcher may ask research questions like (a) "how does generational membership influence employee attitudes, values, and behaviors?" or (b) "what differences exist between members of different generations in terms of their work attitudes, values, or behaviors?" then, likely based on the results of a cross-sectional research design that collects information on age or birth year and work-related outcomes, a generational researcher would likely categorize employees into two or more generational groups and take mean-level differences in outcomes between these groups as evidence for the existence of generations and differences between them. contrary to this, a lifespan researcher would be more apt to ask research questions like (a) "are there age-related differences or changes in work attitudes, values, and behaviors?" or (b) "what factors serve to differentially modify employees' continuous developmental trajectories?" they would seek out cross-sectional or longitudinal evidence for age-related differences or changes in attitudes, values, and behaviors, as well as evidence for multiple, co-occurring factors, including person characteristics (e.g., abilities, personality), idiosyncratic factors (e.g., job loss, health problems), and contextual factors (e.g., economic factors, organizational climate) that may predict these differences or changes. the lifespan perspective generally does not operate with the generations concept, but does distinguish between chronological age, birth cohort, and contemporaneous period effects. as described earlier, generational groups are inevitably linked to group members' chronological ages, as they are based on a range of adjacent birth years and typically examined at one point in time. accordingly, tests of generational differences involve comparisons between two or more age groups (e.g., younger vs. older employees). in contrast to tenets #1, #2, and #3 of the lifespan perspective, generational thinking is static in that differences between generations are assumed to be stable over time. the possibility that members of younger generations may change with increasing age, or whether members of older generations have always shown certain attitudes, values, and behavior, are rarely investigated. moreover, generational thinking typically adopts a simplistic view of differences between generational groups (e.g., "generation a" has a lower work ethic than "generation b") as compared to the more nuanced lifespan perspective with its focus on stability or multidirectional changes, as well as the joint occurrence of both gains and losses across time. with regard to the lifespan perspective's tenet #4 (i.e., plasticity), generational researchers tend to treat generational groups as immutable (i.e., as they are a function of one's birth year) and their influences as deterministic (i.e., all members of a certain generation are expected to think and act in a certain way; so-called cohort determinism). in contrast, the lifespan perspective recognizes that there is plasticity, or within-person modifiability, in individual development at any age. changes to the developmental trajectory for a given outcome can be caused by person factors (e.g., knowledge gained by longterm practice), contextual factors (e.g., organizational change), or both. for instance, lifespan researchers assume that humans enact agency over their environment and the course of their development. development is not only a product of the context in which it takes place (e.g., culture, historical period) but also a product of individuals' decisions and actions. this notion underlies the principle of developmental contextualism (lerner & busch-rossnagel, 1981) , embodied within the idea that humans are both the products and the producers of their own developmental course. research on generations and intergenerational exchanges originated and still is considered an important topic in the field of sociology (mayer, 2009) , which emphasizes the role of the social, institutional, cultural, and historical contexts for human development (settersten, 2017; tomlinson, baird, berg, & cooper, 2018) . in contrast, the lifespan perspective, which originated in the field of psychology, places a stronger focus on individual differences and within-person variability. nevertheless, the lifespan perspective's tenet #5 (i.e., contextualism) suggests that individual development is not only influenced by biological factors but also embedded within the broader sociocultural and historical context. this context includes the historical period, economic conditions, as well as education and medical systems in which development unfolds. even critics have acknowledged that these external factors are rather well-integrated within the lifespan perspective (dannefer, 1984) . that said, most empirical lifespan research has not distinguished between birth cohort and contemporaneous period effects. for example, studies in the lifespan tradition have suggested that there are birth cohort effects on cognitive abilities and personality characteristics (elder & liker, 1982; gerstorf, ram, hoppmann, willis, & schaie, 2011; nesselroade & baltes, 1974; schaie, 2013) . possible explanations for these effects may be improvements in education, health and medical care, and the increasing complexity of work and home environments (baltes, 1987 ). an important difference to generational research is that these analyses focus on individual development and outcomes and not on group-based differences. in contrast to research in the field of sociology, the lifespan perspective generally does not make use of the generations concept and associated generational labels. instead, in addition to people's age, lifespan research sometimes focuses on birth year cohorts (baltes, 1968) . however, the lifespan perspective does not assume that all individuals born in the same birth year automatically share certain life experiences or have similar perceptions of historical events (kosloski, 1986) . according to baltes, cornelius, and nesselroade (1979) , researchers interested in basic developmental processes (e.g., child developmental psychologists) that were established during humans' genetic and cultural evolution may treat potential cohort effects as error or as transitory, historical irregularities. in contrast, other researchers (e.g., social psychologists, sociologists) may focus less on developmental regularities and treat cohort effects as systematic differences in the levels of an outcome, with or without explicitly proposing a substantive theoretical mechanism or process variable that explains these cohort differences (e.g., poverty, access to high-quality education). empirical research on generations is typically vague with regard to concrete theoretical mechanisms of assumed generational differences (i.e., beyond the notion of "shared life events and experiences," such as the vietnam war, 9/11, or the covid-19 pandemic) and typically does not operationalize and test these mechanisms. in proposing the general developmental model, schaie (1986) suggested decoupling the "empty variables" of birth cohort and time period from chronological age and reconceptualizing them as more meaningful variables. specifically, he re-defined cohort as "the total population of individuals entering the specified environment at the same point in time" and period as "historical event time," thereby uncoupling period effects from calendar time by identifying the timing and duration of the greatest influence of important historical events (schaie & hertzog, 1985, p. 92) . thus, the time of entry for a cohort does not have to be birth year and can include biocultural time markers (e.g., puberty, parenthood) or societal markers (e.g., workforce entry, retirement; schaie, 1986) . similarly, the more recent motivational theory of lifespan development has discussed cohort-defining events as age-graded opportunity structures (heckhausen, wrosch, & schulz, 2010) . thus, from a lifespan perspective, cohorts are re-defined as an interindividual difference variable, whereas period is re-defined as an intraindividual change variable (schaie, 1986) . tenet #6 of the lifespan perspective suggests that individuals have to process, react to, and act upon normative age-graded, normative history-graded, and non-normative influences that co-determine developmental outcomes (baltes, 1987) . the interplay of these three influences leads to stability and change, as well as multidimensionality and multidirectionality in individual development (baltes, 1987) . importantly, the use of the term "normative" is understood in a statistical-descriptive sense here, not in a value-based prescriptive sense; it is assumed that there are individual differences (e.g., due to gender, socioeconomic status) in the experience and effects of these influences (baltes & nesselroade, 1984) . moreover, the relative importance of these three influences can be assumed to change across the lifespan (baltes, reese, & lipsitt, 1980) . specifically, normative age-graded influences are assumed to be more important in childhood and later adulthood than in adolescence and early adulthood (i.e., due to biological and evolutionary reasons). in contrast, normative history-graded determinants are assumed to be more important in adolescence and early adulthood than in childhood and old age (i.e., when biological and evolutionary factors are less important). finally, non-normative influences are assumed to increase linearly in importance across the lifespan (baltes et al., 1980 ; see also rudolph & zacher, 2017) . indeed, the assumed differential importance of these influences across the lifespan differs markedly from the cohort deterministic approach implied in generational theory and research. according to baltes et al. (1980) , idiosyncratic life events become more important predictors of developmental outcomes with increasing age due to declines in biological and evolutionary-based genetic control over development and the increased heterogeneity and plasticity in developmental outcomes at higher ages. despite the assumed relative strengths of these normative and non-normative influences across the lifespan, they are at no point completely irrelevant to individual development. for example, in the work context, the theoretical relevance of history-graded influences on work-related outcomes may be a factor that determines the strength of potential effects (zacher, 2015b) . for instance, experiencing a global pandemic is more likely to influence the development of individuals' attitudes-not an entire generations' collective attitudes-toward universal health care than it is to influence their job satisfaction. moreover, individuals' level of job security may not only be influenced by the pandemic but also by their profession and levels of risk tolerance. in summary, the lifespan development perspective offers a number of alternative explanations for the role of age and the process of aging at work that do not rely in generational explanations. specifically, by recognizing that development is a lifelong process that is affected by multiple influences, this perspective helps to clarify the complexities of development, particularly the processes that lead to inter-and intraindividual changes over time. with a clearer sense of these two alternative perspectives, we next shift our attention to outlining various points of integration between them. with a clearer sense of the core tenets of the social constructionist and lifespan development perspectives, we now turn our attention to clarifying lines of integration between these two approaches. while seemingly addressing different "corners" of the ideas presented here, there are a number of complementary features of the social constructionist and lifespan development perspectives to be noted. first, both perspectives generally eschew the idea that generations exist objectively and are meaningful units of study for explaining individual and group differences. second, both perspectives offer that the complexities that underlie the understanding of age and the process of aging at work cannot be reduced to rather simple mean-level comparisons. third, both perspectives are generative, in that they encourage research questions that go beyond common ways of thinking. fourth, and relatedly, both perspectives provide frameworks for more "directly" studying aging and development-whether in the form of how we collectively understand and conceptualize these processes (the social constructionist perspective), or how individuals continuously and interactively shape their own life trajectory (the lifespan development perspective). together, rather than relying on determinism, these perspectives capitalize on the subjective, dynamic, and agentic aspects of life in organizations and society, allowing for more rigorous and representative research into meaning, creation, stability, and change in context. beyond these complementary features, we propose six additional commonalities that serve as the basis for a more formal integration of these two perspectives with one another (see table 2 for a summary). first, both perspectives recognize the role of context, in that both development (the lifespan development perspective) and sensemaking (the social constructionist perspective) occur within social contexts. second, both perspectives describe processes of action, creation, negotiation, and/or codification. whereas the lifespan perspective focuses on how these processes create identity, beliefs, and habits or behaviors that emerge over time through active self-regulatory, motivational processes, discovery, and (self)acceptance/selectivity, the social constructionist perspective focuses more so on the development of truths and meaning that emerge from collective dialogues, understandings, and traditions through acceptance and institutionalization. third, both perspectives acknowledge the fundamental roles of internal and external comparisons. for example, the lifespan perspective offers that successful development is judged both externally (e.g., in comparison with important others, normative age expectations, or timetables) and internally (e.g., in comparison with younger or desired state selves). similarly, social constructions can be focused externally (e.g., in the form of stereotypes) as well as internally (i.e., to make sense of one's own behavior or identity). fourth, both perspectives highlight learning and reinforcement processes that are derived from environmental sources. the lifespan perspective offers that adaptiveness (e.g., how successfully someone is developing/aging) and the self (as well as identities, values, behaviors, etc.) are learned from and reinforced by feedback from various aspects of the environment. similarly, social constructions are derived from and reinforced by multiple environmental sources, including those with perceived status, "weight," and legitimacy. fifth, by offering that development is a modifiable, discontinuous process (the lifespan development perspective) and that social constructions are constantly re-defined and re-emerge into public consciousness (the social constructionist perspective), both perspectives focus on continuous evolution, revision, and change. the final commonality to be drawn across these two perspectives is that they both focus on predictable influences that characterize certain spans of time, especially around significant events or "turning points." the lifespan perspective offers that, although complex and plastic, development does have some predictable aspects and influences due to their significance in the life course (e.g., age-graded events). complimenting this, many social constructions, although in constant flux and redefinition, fall back on the same key concepts due to their pervasiveness in public consciousness (e.g., the laziness of youth) at certain "key moments" in history (e.g., to explain or cope with societal change). beyond the benefits of considering alternative models to generations, and integrations thereof, it is important to mention the limitations of these alternative perspectives. for example, it could be argued that, because it does not provide formalized predictions, the social constructionist perspective is "hard to study." additionally, the lifespan perspective can be -identity, beliefs, and habits or behaviors emerge over time through active self-regulatory and motivational processes, discovery, and (self-)acceptance and selectivity. commonality #3: fundamental roles of internal and external comparison -social constructions are applied externally (e.g., stereotypes) as well as internally (i.e., to make sense of one's own behavior and identity). -"successful development" is compared externally (e.g., in comparison with important others, normative age expectations and timetables) and internally (e.g., in comparison with younger or desired state selves). commonality #4: learning and reinforcement from environmental sources -constructions are derived from and reinforced by multiple sources, including those with perceived status, "weight," and legitimacy. -both adaptiveness (e.g., how "well" someone is developing/aging) and the self (as well as identities, behaviors, etc.) are learned from and reinforced by feedback from various aspects of environment. commonality #5: continuous evolution, revision, and change -social constructions are constantly re-defined and re-emerge into public consciousness. -there is no single linear or normatively staged process that can define development; development is modifiable across the full lifespan. commonality #6: predictable influences characterize certain spans of time, especially around a significant event or "turning point" -many social constructions, although in constant flux and redefinition, fall back on the same key concepts due to their pervasiveness in public consciousness (e.g., laziness of youth) at certain "key moments" in history (e.g., to explain or cope with societal change). -although complex and plastic, development has certain predictable aspects and influences due to their significance in the life course (e.g., age-graded socialization events). criticized, just as it is lauded, for its focus on individual agency: as noted earlier, psychological perspectives often place a premium on studying individual-level mechanisms rather than other levels of influence . thus, without directed efforts on the part of researchers to attend to these aspects of lifespan development theory in their work, it can be easy to fall into the "trap" of ignoring structural factors (e.g., socioeconomic status, governmental policy, institutionalized discrimination) that have bearing on and may constrain individuals' agentic influence on their life trajectory (for an integration of the psychological lifespan perspective and the sociological life course perspective in the context of vocational behavior and career development, see zacher & froidevaux, 2020) . still, and for the many reasons noted throughout this manuscript, we do not contend that generational cohort membership is one of these structural factors, and a generational approach ignores these other forces even more flagrantly. overall, we argue that organizational researchers and practitioners should move beyond the notion of generations for understanding the complexities of age at work. to do so, we urge the adoption of the alternative theoretical models we have outlined here, as well as considerations of their integration. to this end, those interested in studying the role of age at work should adopt a lifespan, rather than a generational, perspective, whereas those interested in studying the persistence of generational thinking would be well served to consider the adoption of a social constructionist perspective. moreover, to understand more holistically the role of age and the construction of aging at work, it may be useful to adopt an integrative view on these two perspectives, embodied within the six commonalities between them that we have outlined above (see also table 2 ). generational thinking is problematic because it assumes that aggregate social phenomena can explain individual-level attitudes, values, and behavior. in contrast, adopting a lifespan perspective means taking a multidisciplinary lens to understanding age-related differences and changes at work by specifically focusing on how the interplay between person characteristics and contextual variables serve to modify individual development. moreover, the social constructionist perspective offers guidance for unpacking the meanings people attach to assumptions that are made about these aggregate social phenomena, further aiding in understanding the complexities at play here. we consider recommendations for research and practice adopting these perspectives, next. the social constructionist perspective on generations highlights a number of potential areas for research and practice. given their longstanding and culturally/historically embedded nature, the social constructionist perspective recognizes that the idea of generations is not likely to go away, even with a lack of empirical methods or evidence to support their existence. instead, this perspective calls for a paradigm shift in generational research and practice, away from the rather positivist notion of "seeking out" generational differences and instead toward a focus on studying and understanding those processes that support the social construction of generations to begin with. considering research, the focus could be on those antecedents (e.g., intergroup competition and discrimination; north & fiske, 2012; i.e., to address the question, "why do these social constructions emerge?") and outcomes (e.g., selffulfilling prophecies-i.e., to address the question, "what are the consequences of willing generations into being?") of socially constructed generations. conducting research from a social constructionist perspective requires adopting methodologies that may not be common in organizational researchers' "tool kits." for example, rudolph and zacher (2015) used sentiment analysis, a natural language processing methodology, to analyze the content of twitter dialogues concerning various generational groups to understand the relative sentiment associated with each. indeed, it would arguably be difficult to study generations from this perspective by adopting a typical frequentist approach to hypothesis testing. this perspective is less about gathering evidence "against the null hypothesis" that generations or differences between them exist in a more or less "objective" (i.e., measurable) way. instead, it is more about understanding, phenomenologically, the various processes that give rise to people's subjective construction of generations, the systems that facilitate attaching meaning to generational labels, and the structures that support our continued reliance on generations as a sensemaking tool in spite of logical and empirical arguments against doing so. more practically, understanding why people think in terms of generations can help us to develop interventions that are targeted at helping people think less in terms of generations and more in terms of individuating people on the basis of the various processes outlined in our description of the lifespan perspective (i.e., personal characteristics; idiosyncratic and contextual factors). the social constructionist perspective also encourages changing the discourse among practitioners, shifting the focus away from managing generations as discrete groups and toward developing more age-conscious personnel practices, policies, and procedures that support workers across the entirety of their working lifespans (e.g., rudolph & zacher, 2020c) . we thus urge practitioners to adopt a social constructionist perspective and shift focus away from promoting processes to manage members of different generations to a focus on managing the perceptions of generations and their differences. by recognizing the constructed nature of generations, the social constructionist perspective decouples beliefs about generations from these broad and overgeneralized assumptions about their influence on individuals. just as the social constructionist perspective highlights a number of potential areas for research and practice, so too does the lifespan perspective. to this end, and to move research on the lifespan perspective on generations forward, rudolph and zacher (2017) argued that, at the individual level of analysis, the influence of age-graded and historical/contextual influences are inherently codetermined and inseparable. accordingly, in their lifespan perspective on generations, they proposed that the influence of historically graded and sociocultural context variables occurs at the individual level of analysis only, and not as a manifestation of shared generational effects (proposition 1). they suggested that future research should focus on individual-level indicators of historical and sociocultural influences. furthermore, they argued that age, period, and cohort effects are both theoretically and empirically confounded and, thus, inseparable (proposition 2). finally, consistent with schaie's (1986) general developmental model, they suggested that cohorts should be operationalized as interindividual differences, whereas period effects should be defined in terms of intraindividual changes (proposition 3). in terms of more practical implications of the lifespan perspective, we urge practitioners to adopt principles of lifespan development in the design of age-conscious work processes, interventions, and policies that do not rely on generations as a means of representing age. indeed, researchers and practitioners alike should take steps to avoid the pitfalls of "generational thinking," which yields several dangers that can be overcome by lifespan thinking (rauvola et al., 2019; rudolph & zacher, 2020c) . first, generational thinking categorizes individuals into arbitrary generational groups based on a single criterion (i.e., birth year) and is therefore socially exclusive rather than inclusive; in contrast, the lifespan perspective conceptualizes and operationalizes age directly as a continuous variable (baltes, 1987) . second, generational thinking reduces complex age-related processes into a simplistic dichotomy at a single point in time; the lifespan perspective adopts a multidimensional, multidirectional, and multilevel approach to represent the complexities of aging more appropriately. third, generational thinking overemphasizes the role of (ranges of) birth cohorts in influencing work outcomes; in contrast, the lifespan perspective emphasizes interindividual differences and intraindividual development (as well as interindividual differences in intraindividual development). finally, generational thinking is dangerous because it assumes that generational group membership determines individual attitudes, values, and behavior. in contrast to this, the lifespan perspective, which entails the notion of plasticity, suggests that intraindividual changes in developmental paths are possible at any age and that individuals can enact control and influence their own development. this manuscript sought to achieve two goals, related to helping various constituents better understand the complexities of age and aging at work, and dissuade the use of generations and generational differences as a means of understanding and simplifying such complexities. first, we aimed to "bust" ten common myths about generations and generational differences that permeate various discussions in organizational sciences research and practice and beyond. then, with these debunked myths as a backdrop, we offered two complementary alternative models-the social constructionist perspective and the lifespan perspective-with promise for helping organizational scientists and practitioners better understand and manage age and the process of aging in the workplace and comprehend the pervasive nature of generations as a means of social sensemaking. the social constructionist perspective calls for a shift in thinking about generations as tangible and demonstrable units of study, to socially constructed entities, the existence of which is in-and-of-itself worthy of study. supplementing these ideas, the lifespan perspective offers that rather than focusing on simplified, rather deterministic groupings of people into generations, development occurs in a continuous, multicausal, multidirectional, and multidimensional process. our hope is that this manuscript helps to "redirect" talk about generations away from their colloquial use to a more critical and informed perspective on age and aging at work. managerial fads and fashions: the diffusion and rejection of innovations management fashion, academic fashion, and enduring truths millennials are fleeing big cities for the suburbs millennials: the job-hopping generation the impact of covid-19 on gender equality (no. w26947) motivating generation y and virtual teams using life-span models in industrial-organizational psychology: the theory of selective optimization with compensation work across the lifespan longitudinal and cross-sectional sequences in the study of age and generation effects theoretical propositions of life-span developmental psychology: on the dynamics between growth and decline cohort effects in developmental psychology life-span theory in developmental psychology the berlin aging study: aging from 70 to 100 paradigm lost and paradigm regained: critique of dannefer's portrayal of life-span developmental psychology life-span developmental psychology how millennials approach family life the impossibility of separating age, period and cohort effects another 'futile quest'? a simulation study of yang and land's hierarchical age-period-cohort model the social construction of reality. a treatise in the sociology of knowledge entering adulthood in a recession tempers later narcissism methodological recommendations to move research on work and aging forward spotlight on age-diversity climate: the impact of age-inclusive hr practices on firm-level outcomes rip: here are 70 things millennials have killed the age that women have babies: how a gap divides america. the new york times early evidence on the impact of covid-19 and the recession on older workers (no. w27448) social constructionism fuzzy but useful constructs: making sense of the differences between generations millennials will work hard, just not for your crappy job generational differences in work-related attitudes: a metaanalysis a review of analytical methods used to study generational differences: strengths and limitations generationally-based differences in the workplace: is there a there there? industrial and organizational psychology: perspectives on sciences and practice the cambridge handbook of the changing nature of work adult development and social theory: a paradigmatic reappraisal they signed up to fight. the new york times millennials at work: what we know and what we need to do (if anything) towards a theoretical framework linking generational memories to workplace attitudes and behaviors in the u.s., teen summer jobs aren't what they used to be defining generations: where millennials end and generation z begins personality development across the lifespan: current findings and future directions mitigating the wider health effects of covid-19 pandemic response exploring four generations' beliefs about career: is "satisfied" the new "successful time, human agency, and social change: perspectives on the life course hard times in women's lives: historical influences across forty years childhood and society the effects of stereotype activation on generational differences cohort differences in cognitive aging and terminal decline in the seattle longitudinal study cohort analysts' futile quest: statistical attempts to separate age, period and cohort effects cohort analysis will millennials just uber their life? forbes facing falling enlistment numbers, the u.s. army takes a new approach to recruitment: mom and dad the 9/11 generation comes of age a motivational theory of life-span development baby jessica on the 30 year anniversary of her rescue from a well: her life as a wife and mom. people magazine unsubstantiated conclusions: a scoping review on generational differences of leadership in academic libraries follow the dancing meme: intergenerational relations in the workplace subjective uncertainty reduction through self-categorization: a motivational theory of social identity processes after gen x, millennials, what should next generation be? usa today millennials rising: the next great generation the next 20 years: how customer and workforce attitudes will evolve need to keep gen z workers happy? hire a 'generational consultant'. new york times magazine generation golf zwei generational 'othering': the myth of the millennial learner for whom the pandemic tolls: a person-centric analysis of older workers. work, aging and retirement derek jeter has had it with millennials and their lack of interest in baseball. the comeback generation as a sociological problem generational differences at work are small. thinking they're big affects our behavior covid-19 and the workplace: implications, issues, and insights for future research and action managing people from 5 generations isolating age, period, and cohort effects in developmental research: a critical review motivation to reduce uncertainty: a reconceptualization of uncertainty reduction theory human resources for the non-hr manager social construction of reality individuals as producers of their development: a life-span perspective the seasons of a man's life recruiting the millennium generation: the new cpa social constructionism: sources and stirrings in theory and practice generational differences in the workplace: a review of the evidence and directions for future research generational differences in the workplace: there is complexity beyond the stereotypes. industrial and organizational psychology a qualitative exploration of generational identity: making sense of young and old in the context of today's workplace generation merkel' yearns for continuity and stability. france 24 the problem of generations new directions in life course research has racism declined in america? it depends on who is asking and what is asked the abc of xyz: understanding the global generations categorizing workers' needs by generation such as baby boomers or millennials is not supported by research or useful for workforce management adolescent personality development and historical change: 1970-1972. monographs of the society for research in child development british army targets 'snowflakes, binge gamers and me, me, me millennials' in new recruitment drive. the telegraph an inconvenienced youth? ageism and its potential intergenerational roots generational theory and cohort analysis the modern theme age-based generations at work: a culturespecific approach generation corona" will miss out on life's opportunities. new creative spaces can help making a case for the existence of generational stereotypes: a literature review and exploratory study mannheim's sociology of generations: an undervalued legacy kids these days: why the youth of today seem lacking from gis to gen z (or is it igen?): how generations get nicknames. national pubic radio on the limits of agency for successful aging at work. industrial and organizational psychology: perspectives on science and practice generationalism: problems and implications an examination of generational stereotypes as a path towards reverse ageism ecological correlations and the behavior of individuals ok boomer" isn't just about the past, it's about our apocalyptic future from fashion to virus: an alternative theory of organizations' handling of management ideas a note on the folly of cross-sectional operationalizations of generations. industrial and organizational psychology lifespan developmental perspectives on working: a literature review of motivational theories pandemics: implications for research and practice in industrial and organizational psychology. industrial and organizational psychology: perspectives on science and practice age and health jointly moderate the influence of flexible work arrangements on work engagement: evidence from two empirical studies crosstemporal meta-analysis: a conceptual and empirical critique leadership and generations at work: a critical review answers to 10 questions about generations and generational differences in the workplace intergenerational perceptions and conflicts in multi-age and multigenerational work environments considering generations from a lifespan developmental perspective the kids are alright: taking stock of generational differences at work. the industrial-organizational psychologist the covid-19 generation": a cautionary note covid-19 and careers: on the futility of generational explanations the cambridge handbook of the changing nature of work age inclusive human resource practices, age diversity climate, and work ability: exploring between-and within-person indirect effects. work, aging and retirement the cohort as a concept in the study of social change beyond calendar definitions of age, time, and cohort: the general developmental model revisited developmental influences on adult intelligence: the seattle longitudinal study measurement in the psychology of adulthood and aging american children faced great dangers in the 1930s, none greater than some things i have learned about aging by studying the life course the recession generation: how millennials are changing money management forever sticking points: how to get 4 generations working together in the 12 places they come apart generational differences: revisiting generational work values for the new millennium multi generations in the workforce: building collaboration generatieverschillen op de werkvloer: 'what people believe is true is frequently wrong positive adult personality development: adjustment and/or growth? millennials: the me me me generation generations: the history of america's future, 1584 to 2069 ok boomer"… from internet meme to workplace age discrimination america in 1915: long hours, crowded houses, death by trolley. the atlantic generational differences in work values, perceived job rewards, and job satisfaction of chinese female migrant workers: implications for social policy and social services flexible careers across the life course: advancing theory, research and practice issues in the study of generations rethinking "generation me": a study of cohort effects from 1976-2006 is "generation me" really more narcissistic than previous generations the age of anxiety? birth cohort change in anxiety and neuroticism generation me: why today's young americans are more confident, assertive, entitled-and more miserable than ever before a review of the empirical evidence on generational differences in work attitudes igen: why today's super-connected kids are growing up less rebellious, more tolerant, less happy-and completely unprepared for adulthood-and what that means for the rest of us generational differences in psychological traits and their impact on the workplace birth cohort differences in the monitoring the future dataset and elsewhere: further evidence for generation me-commentary on trzesniewski & donnellan (2010) egos inflating over time: a cross-temporal meta-analysis of the narcissistic personality inventory the covid-19 pandemic: lessons for financially fragile and aging societies. work, aging and retirement generations as social categories: an exploratory cognitive study of generational identity and generational stereotypes in a multigenerational workforce intergenerational relations and welfare restructuring: the social construction of an intergenerational problem implications of generational and age metastereotypes for older adults at work: the role of agency, stereotype threat, and job search self-efficacy multiple sources of aging attitudes: perceptions of age groups and generations from adolescence to old age across china, germany, and the united states the age variable in psychological research the "me" decade and the third great awakening a mixed models approach to the ageperiod-cohort analysis of repeated cross-section surveys, with an application to data on trends in verbal test scores age-period-cohort analysis: new models, methods, and empirical applications a comparison between generation x and generation y in terms of individual innovativeness behavior: the case of turkish health professionals generational differences in work ethic: fact or fiction? successful aging at work using lifespan developmental theory and methods as a viable alternative to the study of generational differences at work. industrial and organizational psychology life stage, lifespan, and life course perspectives on vocational behavior and development: a theoretical framework, review, and research agenda publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord-305743-rnfn6opa authors: anton, stephen d.; cruz-almeida, yenisel; singh, arashdeep; alpert, jordan; bensadon, benjamin; cabrera, melanie; clark, david j.; ebner, natalie; esser, karyn a.; fillingim, roger b.; goicolea, soamy montesino; han, sung min; kallas, henrique; johnson, alisa; leeuwenburgh, christiaan; liu, andrew c.; manini, todd m.; marsiske, michael; moore, frederick; qiu, peihua; mankowski, robert t.; mardini, mamoun; mclaren, christian; ranka, sanjay; rashidi, parisa; saini, sunil; sibille, kimberly t.; someya, shinichi; wohlgemuth, stephanie; tucker, carolyn; xiao, rui; pahor, marco title: innovations in geroscience to enhance mobility in older adults date: 2020-10-22 journal: exp gerontol doi: 10.1016/j.exger.2020.111123 sha: doc_id: 305743 cord_uid: rnfn6opa aging is the primary risk factor for functional decline; thus, understanding and preventing disability among older adults has emerged as an important public health challenge of the 21st century. the science of gerontology – or geroscience has the practical purpose of “adding life to the years.” the overall goal of geroscience is to increase healthspan, which refers to extending the portion of the lifespan in which the individual experiences enjoyment, satisfaction, and wellness. an important facet of this goal is preserving mobility, defined as the ability to move independently. despite this clear purpose, this has proven to be a challenging endeavor as mobility and function in later life are influenced by a complex interaction of factors across multiple domains. moreover, findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function. for these reasons, behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function. other pharmaceutical interventions, such as oxytocin, and complementary and alternative interventions, such as massage therapy, may enhance physical function both through direct effects on biological mechanisms related to mobility, as well as indirectly through modulation of cognitive and socioemotional processes. thus, the purpose of the present review is to describe evolving interventional approaches to enhance mobility and maintain healthspan in the growing population of older adults in the united states and countries throughout the world. such interventions are likely to be greatly assisted by technological advances and the widespread adoption of virtual communications during and after the covid-19 era. stephen d. anton a (santon@ufl.edu), yenisel cruz-almeida b (cryeni@ufl.edu), arashdeep singh c (a.singh@ufl.edu), jordan alpert d (jordan.alpert@ufl.edu), benjamin bensadon a (bensadon@ufl.edu), melanie cabrera a (melanie.cabrera@ufl.edu), david while prolongation of life remains an important public health goal, of even greater significance is that extended life should involve preservation of the capacity to live independently and to function well [1] . the field of geroscience seeks to understand the genetic, molecular, and cellular mechanisms that make aging a major risk factor and driver of common chronic conditions and diseases of older people. interventions targeting the fundamental biology of human aging have the potential to delay, if not prevent, the onset of aging-associated conditions [2] [3] [4] [5] [6] . the unprecedented growth of the aging population and increasing prevalence of chronic disease have underscored an urgent need for such interventions. if this the current trend in aging continues, the number of older persons (aged >60 years) will nearly triple in size globally, increasing from 673 million in 2005 to almost 2 billion by 2050 [7] . accordingly, the science of gerontologyor geroscience -has the practical purpose of understanding how aging processes enable diseases and to then apply this knowledge to reduce the emergence and progression of age-related diseases and disabilities. the ultimate goal is to develop feasible, practical, and safe interventions to delay the development of chronic diseases and conditions, while also increasing enjoyment, satisfaction, and quality of life, during the latter stages of an individual's lifespan. [8] interventions that can achieve these objectives may also dramatically lower health care costs. as we have previously described, [9, 10] a hallmark of successful aging is mobility, i.e. the ability to move without assistance, which is necessary for the maintenance of basic independent functioning [11, 12] . additionally, mobility performance (i.e., walking speed) has emerged as a surrogate marker of overall health and functional ability among older adults. [13] improvements in usual gait speed predict better survival and quality of life in older adults [14] . in contrast, mobility limitation is associated with more rapid functional decline, reduced quality of life [15] , as well as hospitalization, nursing home placement, and increased mortality [16] [17] [18] [19] [20] (see figure 1 ). for these reasons, understanding and preventing mobility disability among older adults has emerged as one of the most important public health opportunities of the 21 st century. therefore, identification of promising interventions to preserve mobility that can be widely implemented in older adults is a major clinical and public health priority [21] . since our previous review, [9] several advances in the field of geroscience have been achieved and are highlighted in this paper. for example, discoveries made in the past few years have illuminated the complex interactions between the brain and the body in affecting changes in mobility with aging. more specifically, the important role that the central and neuromuscular systems have in affecting mobility has spawned a host of new treatment options, such as use of neuro-modulatory adjuvants (e.g., transcranial direct stimulation) to enhance the beneficial effects of physical activity. in line with this, a growing body of research indicates that interventions designed to improve cognitive/emotional function (e.g., oxytocin) also have benefits effects on mobility and physical function. thus, it appears virtually impossible to influence an individual's cognitive/emotional function without affecting their physical function, and vice-versa. an increased understanding of biopsychosocial factors that may contribute to functional decline can aid in the development of future interventions designed to improve mobility and function in at-risk older adults. aided by technological developments, the range of interventions now available has greatly increased in the past five years. thus, we have expanded our conceptual model to incorporate technology, neural factors, and environmental factors. although there is a strong consensus on this goal, there are challenges to developing such interventions as an older adult's mobility and functional level are affected by factors across j o u r n a l p r e -p r o o f journal pre-proof multiple domains. moreover, the complex interactions between factors within biological, psychological, and social domains may increase the risk for functional decline and other agerelated chronic disease conditions. as such, promising interventions will need to take into account these multifaceted interactions and also recognize that affecting change in one domain can lead to changes in other domains. with this goal in mind, we first review the role of specific biological contributors to functional decline. next, we describe key behavioral and psychosocial factors that can affect physical function and risk for functional decline in older adults. we then discuss promising interventions from clinical trials that can enhance physical function and mobility, as well as the role of smart and connected technologies in the delivery of these interventions (see figure 2 ). in the final sections, we discuss the importance of preclinical models in guiding intervention selections, statistical considerations in aging research, as well as key strategies to effectively disseminate and implement efficacious interventions in clinical and community settings. the rising prevalence of metabolic syndrome in older adults, a condition diagnosed based on the presence of three or more metabolic risk factors, including abdominal obesity, high triglycerides (tg), low hdl-cholesterol (hdl-c), high blood pressure (bp), and impaired glucose tolerance, correlates with sedentary lifestyles, and poor nutrition habits [22] [23] [24] [25] . approximately one-third of older adults in the usa are obese; however, nearly 55% of those aged 60 years or older are estimated to have metabolic syndrome [26] . given the aging us population, the disproportionately high prevalence of the metabolic syndrome in older adults is a significant public health concern, as it substantially increases the risk for cardiovascular disease j o u r n a l p r e -p r o o f journal pre-proof (cvd) [27] [28] [29] [30] and is associated with increased all-cause mortality, disability, cvd mortality, myocardial infarction, and stroke [31] . additionally, the metabolic syndrome is associated with impairments in basic activities of daily living, social activities, and lower extremity mobility [7, 32] . aging typically promotes a loss of fat-free mass which parallels to the reduction in metabolic rate and energy expenditure, particularly after the age of 50 [32] . this age-related muscle loss (i.e., sarcopenia) can diminish both the metabolic and mechanical functions of the skeletal muscle, [33, 34] a point of concern since skeletal muscle has the greatest contribution to an individual's metabolic rate [35] . in addition to the loss of total muscle mass, the muscle quality also declines with age due to increased fat infiltration within the muscle thus resulting in decreased muscle strength [36] and power [37] . after the age of 50, it is noteworthy that adults lose muscle strength (i.e., dynapenia) at a much faster rate, approximately 3-4% year, than they lose muscle mass, approximately 1-2% per year. therefore, while muscle atrophy and weakness are certainly correlated, the former cannot fully explain lost muscle strength in late-life. moreover, muscle weakness is a major independent contributor to maintaining physical independence in later life. [38] [39] [40] [41] [42] [43] it was originally thought that the loss of skeletal muscle mass largely explained the muscle weakness observed in older adults; however, more recent findings suggest that other anatomical and physiological factors also play an important role in muscle weakness. the mechanisms determining loss of muscle strength or power output are related to both neurological and skeletal muscle properties, as it is well known that the output from these sources control j o u r n a l p r e -p r o o f journal pre-proof muscle force and power production. within the neuromuscular system, there are several potential mechanisms that may contribute to reductions in strength during aging, including reduced excitatory drive to the spinal motor neurons, reductions in motor neuron discharge rates, impairments in neuromuscular transmission, muscle cell death, muscle protein imbalance, reduced repair/regeneration of muscle cells and impairments in the excitation-contraction (e-c) coupling processes. aging in humans has been shown to be accompanied by robust reductions in the population of motor neurons and axon density [44] [45] [46] [47] . between the ages of 60 and 70 there is a ~30% reduction in the number of functional motor units (motor units = motoneuron and innervated muscle fibers) [48] [49] [50] [51] and once the loss of motor units reaches a critical threshold, muscle strength begins to decline [52] . the exact underlying mechanisms of exhausted nmj plasticity and motor neuron cell death remain obscure, but many factors such as deregulated inflammation, autophagy, reduced igf-1 signaling, oxidative stress, and mitochondria dysfunction have been suggested to drive accelerated loss of muscle mass and function in late life [53, 54] . many factors contribute to a loss of automaticity of walking in older adults. one likely factor is impairment of the communication between the nervous system and muscle. motor neurons innervate their axon terminals to the skeletal muscle fibers to form a neuromuscular junction (nmj), which allows the presynaptic motor neurons to transmit chemical signals to the post-synaptic muscle fibers, leading to muscle contraction. during most of the adult life, there is considerable plasticity of the nmj, where surviving motor units expand through collateral axonal sprouting to reinnervate any denervated nmjs [54] [55] [56] . exhaustion of this plasticity (persistent denervation and failed reinnervation) accelerates muscle atrophy during aging and is associated with movement impairment and functional decline [44, 57] . accumulating evidence supports that models of cognitive brain aging may help us understand the decline in walking function in older adults [58] [59] [60] . changes in brain structure and function may also contribute directly to loss of automaticity, as well as reduce the capacity for recruiting additional resources to compensate for the loss of automaticity [60, 61] . additional research is needed to better understand the major modifiable neural factors that influence control of walking with older age, so that targeted interventions can be designed [58] . chronic pain conditions represent three of the five leading causes of disability in the us, including low back pain, which is the leading cause of disability both in the us and worldwide [62, 63] . while pain affects individuals throughout the lifespan, older adults are disproportionately impacted [64] . another important contributor to mobility decline among older adults is movement-evoked pain (mep). mep refers to pain that is generated or exacerbated through physical movement or activity, and some evidence suggests that mep may be driven by different mechanisms than pain at rest [65] . recent findings in middle-aged and older adults with knee pain demonstrated a relationship between mep and physical performance, highlighting the need to directly measure mep when assessing functional performance in older adults [66] . thus, one key mechanism through which pain may contribute to functional decline is through activity limitations among older adults [67] [68] [69] [70] [71] [72] [73] . emerging evidence also suggests that pain may affect aging processes. indeed, several recent studies suggest that pain is associated with cellular aging. specifically, a combination of high psychosocial stress and high levels of knee pain were associated with shorter telomeres among j o u r n a l p r e -p r o o f journal pre-proof middle-aged and older adults [74] , and subsequently these authors showed that more severe knee pain was associated with shorter telomeres [75] . more recently, chronic pain in older adults has been associated with brain aging [76] and a validated epigenetic measure of aging [77] . thus, the relationship between pain and aging appears to be bidirectional and complex, impacting multiple body systems. one area that is gaining recognition for the potential to impact aging processes is circadian rhythms, which are endogenously generated 24h cycles that can be observed in behavior, physiology and metabolic processes. driven by the circadian clock, circadian rhythms are found in virtually every cell in the body [78] . over the last ten years, research has uncovered that the circadian clock functions within cells to support daily tissue homeostasis, and disruption of the clocks leads to lowered resilience [79] . studies in animal models support the decline in function of the circadian system with age, and this age-related decline appears to impact virtually all systems in the body including skeletal muscle and areas of the brain important for learning and memory [80] [81] [82] . in humans, studies have shown that circadian output changes with aging of muscle mass and strength [85] [86] [87] [88] [89] . thus, the available evidence to date strongly implicates mitochondria as having a pivotal role in the pathogenesis of age-related functional decline, and it has been suggested that a substantial decrease in mitochondrial oxidative capacity in aging muscle might contribute to reduced exercise capacity in older adults [90] . why there is a decrease in mitochondrial function with aging remains under debate, but emerging science indicates that there is a clear connection between mitochondrial biogenesis and function with fuel metabolism and circadian rhythms [91] . cardiovascular disease (cvd) is a leading cause of death among older adults in the united states and the prevalence increases proportionally with age. in particular, 70% of older adults between 60-79 years old and 85% of older adults 80 years and older suffer from cvd [92] . during aging, endothelial dysfunction induced by oxidative stress, inflammation and decline in bioavailability of nitric oxide (no) leads to arterial stiffness, which overloads the heart leading to ventricular hypertrophy and myocardial fibrosis [93] . endothelial dysfunction and the overloaded heart reduce arterial-ventricular coupling, reflecting impaired global cardiovascular performance [94] . recent evidence has demonstrated that subclinical declines in cardiovascular function contribute to functional decline by impaired peripheral tissue perfusion [95] . although sepsis can affect all ages, it is recognized to be the "quintessential disease of the elderly" [96] . studies have shown that both the incidence of sepsis and hospital mortality increases exponentially beyond the age of 65 years, with more than 1 million us medicare recipients hospitalized each year with sepsis. numerous age-related factors increase the risk for j o u r n a l p r e -p r o o f developing sepsis including comorbidities (e.g., chronic lung disease and renal insufficiency), malnutrition, increased aspiration risk from altered mental status and decreased gag/cough reflex and immobility. the diagnosis of sepsis is commonly delayed in older patients because of a blunted systemic inflammatory response syndrome (sirs) and the presence of comorbidities that can cause confounding symptoms. as a result, older patients present as septic later in the process. they are more likely to progress into septic shock due to limited cardiac reserve and have worsening of existing organ dysfunctions. the principal cause of sepsis is a dysregulated systemic immune response, which is negatively affected by aging. in contrast to younger adults, older patients have difficulty returning to immunity homeostasis, increasing their risk for sepsis recidivism. pre-existing sarcopenia, frailty and cognitive disabilities all adversely affect recovery. additionally, ongoing sirs induces profound catabolism with tremendous loss of vital lean body mass despite early nutritional support intervention. moreover, care for sepsis in the icu often involves bedrest and mechanical ventilation, exacerbating the ongoing loss of muscle mass and function. once sirs has resolved, older sarcopenic sepsis survivors have anabolic resistance that makes them nonresponsive to nutritional and physical therapy interventions. our senses, hearing, vision, touch, smell, and taste play critical roles in survival throughout the course of life. aging can affect all of these sensory systems, but the auditory system is thought to be especially vulnerable to age-related damages. hearing loss is the third most prevalent chronic health condition affecting older adults and age-related hearing loss (ahl) is the most common form of hearing impairment [97] . the world health organization(who) estimates that one-third of persons over 65 years are affected by hearing j o u r n a l p r e -p r o o f loss [98] . worldwide, approximately 466 million people suffer from hearing impairment and this number is expected to rise to 630 million by 2030 and over 900 million by 2050. ahl is characterized by poor speech understanding (especially in noisy situations), central auditory processing deficits, and social isolation [99] . as humans age, both males and females undergo various changes in hormone levels, leading to numerous long term and significant internal changes. although some of these changes may be more detrimental than others, common and problematic alterations include loss of muscle mass [100] , decreased bone mass [101] , and various cognitive impairments [102] , which all increase risk for mobility loss and loss of independence. in men, aging is often associated with decreased testosterone [100] , which has been linked to bone loss [103] and decreased muscle mass [104] . with the loss of muscle and bone comes an increased risk of sarcopenia, oftentimes resulting in frailty, decreased functional mobility, and growing difficulties with independent living. in females, decreased estrogen levels post-menopause are often postulated to increase one's risk of sarcopenia and frailty [100] . loss of estrogen is accompanied by an increase of pro-inflammatory cytokine il-6, which downregulates insulin-like growth factor-1(igf-1) [100] . high il-6/low igf-1 levels have been shown to significantly limit walking and mobility tasks of daily living [105] , increasing the risk for progressive disability in older females. in addition to sex hormones, a decline in growth hormone (gh) has been observed with aging and is often associated with various changes in body composition, as well as physical and psychological functions [101] . as one approaches the fourth decade of life, there is a progressive decrease of gh secretion by ~15% each decade thereafter [101] . age-related increases in body j o u r n a l p r e -p r o o f mass index (bmi) and diminished functional capacity tend to parallel the decline in gh secretion, although many other factors also likely contribute [101] . in many cases, physical disability is directly caused or aggravated by acute events (stroke and hip fracture) and disease states (heart failure, coronary heart disease, diabetes, arthritis and peripheral artery disease) [106, 107] . however, a large and growing number of older adults experience progressive declines in physical function over several years culminating in agerelated physical disability with no clear connection to a single disease [108, 109] . research over the past decade has highlighted the role of multiple body/biological/health systems in contributing to this decline. moreover, many age-related conditions appear to affect other systems and may induce similar adverse changes at the cellular level. among the behavioral factors, low levels of physical activity combined with excessive and unhealthy calorie intake appear to strongly contribute to functional decline among older adults [110] . in line with this, a recent review of trends in us health by the u.s. burden of disease collaborators found that high body mass index (bmi), smoking, and high fasting plasma glucose are the three most important risk factors for disease and disability in the united states [111] . among these, only the prevalence of smoking is decreasing, while bmi and fasting plasma glucose levels are steadily increasing. skeletal muscle loses the ability to switch between metabolizing lipids and carbohydrates. in addition to the role caloric excess can have in promoting metabolic inflexibility, there is also increasing evidence that the "western-type" diet that is high in sugar, fat, and processed foods seems to be associated with less ideal aging phenotypes [112] . high levels of sedentary behavior (sitting) contributes to lipid accumulation [113] [114] [115] , metabolic impairments [116] , and loss of muscle mass during aging [117] , all of which strongly contribute to functional decline [118] [119] [120] [121] . these findings are of concern as the majority of middle-age americans spend over half their waking day (~8-9 hours) engaged in sedentary pursuits [122, 123] , with older adults spending an even greater proportion (75%) of their waking hours engaged in sedentary behavior (~11 hours per day) [124] . moreover, each additional hour of sedentary behavior was associated with increased risk of the metabolic syndrome, whereas every additional hour of light intensity activity was associated with reduced risk. perhaps the most common complaint older adults have is the lack of quality sleep. sleep affects nearly every tissue and system in the body, from the brain, heart and muscle to metabolic, endocrine, cardiovascular and immune functions, as well as numerous cognitive processes such as learning and memory, emotion and motor control [125] . similar to food and water, sleep is a basic human need, and sleep timing, duration, and quality are all essential to health. despite this, sleep deficiency is prevalent in modern society, including an insufficient amount of sleep, low quality sleep, and sleep at the wrong time of day. according to a recent report from the centers for disease control and prevention (cdc), 30% of u.s. adults report some form of sleep deficiency [126, 127] . sleep deficiency is more prevalent in older adults, exhibiting common nighttime sleep abnormalities, such as early bedtime and rise time, sleep fragmentation (i.e. less consolidated sleep with frequent awakenings), short sleep duration, less total sleep, and deep sleep [128] ; which is correlated with more frequent daytime naps. in fact, 1 in 4 older adults report severe daytime sleepiness that affects daytime mental and physical performance [129] . these agerelated sleep deficiencies have significant consequences for brain and body health, increasing the risk of chronic inflammatory and neuropsychiatric diseases, metabolic and cardiovascular disease, as well as mental health problems and even pain. for example, poor sleep quality and chronic pain are both tied to significant reductions in quality of life in aging [130] . emerging evidence from our group suggests that sleep may negatively impact brain structure and function in older individuals, which may lead to worse self-reported pain [131, 132] . an increased understanding of the behavioral factors that contribute to functional decline in otherwise healthy older adults can assist in both identifying at-risk older adults and designing targeted interventions for individuals in the later stages of life that maintain mobility and slow the rate of functional decline. it is recognized that there are many causes of functional decline and ultimately disability. while we believe behavioral factors, including over and undernutrition, physical inactivity, and sleep, have a central role in maintaining mobility in later life, the pathways leading to physical disability in older adults are likely complex and involve consideration of a larger number of etiologic factors. environment and social relationships can serve as either risk or protective factors for aging adults. environmental factors across the lifespan interact with biology and contribute toward health outcomes [133] . research shows that early life stressors can influence biological functioning, priming the stress system toward a level of heightened sensitivity increasing greater risk for later life health conditions and earlier mortality [134] . as individual age, environmental factors, life experiences, and personal and financial resources can buffer or exacerbate healthrelated conditions. social relationships also influence health and well-being. limitations in social relationships can be experienced as social isolation and loneliness [135] . of concern, approximately one fourth of adults, individuals aged 65 years and older meet social isolation criteria and among individuals aged 60 years and older, greater than 40% endorse loneliness [135] . age-related life changes that increase susceptibility to social isolation and loneliness includes changes in health status limiting functioning and mobility; changes in family structure (divorce, childless); death of friends, family members, and spouse; auditory and visual changes reducing the ability to communicate and interact; and resource reductions including healthcare access and quality of care [135] . there is also research evidence that socially isolated older adults are less physically active independent of any mobility limitations [136] . however, whether or not declines in mobility mediate the well-established relationship between social isolation and all-cause mortality [137, 138] remains unclear. minority older adults are at an even greater risk to the health consequences of environmental and social factors. higher frequency of negative environmental exposures, limited j o u r n a l p r e -p r o o f environmental resources, possible language limitations, and experiences of stigma and discrimination might be further contributing to increased risk of morbidity and mortality [133] . despite this increased risk for poor health outcomes, access to medical care is often limited and the extended wait times to receive care may discourage healthcare utilization, particularly preventive health services among minority populations [139] [140] [141] . thus, environmental and social factors represent an area where research and evidence-based strategies can contribute to improved health outcomes [133, 142, 143] . older adults perceive mobility as essential to feeling whole and identify mobility assistance and adaptation as key to managing age-related changes [144] . in fact, older adults who met just one of five established frailty phenotype criteria were more likely to also be depressed, suggesting frailty has both physical and psychological components [145] . also noteworthy, psychological factors such as balance efficacy and falls efficacy have previously been found to be more important than physical factors (e.g., fall history, medical morbidity, and balance tests) in predicting future falls [146] . theoretically, self-efficacy for specific tasks, mood, and behavior have a reciprocal influence on an older person's decision making and performance. for example, lower baseline self-efficacy for functional tasks predicted decreased walking performance and stair ascent among older women with osteoarthritis [147] . falls efficacy, a measure of falls-specific selfefficacy, can be independently predicted by normal walking pace, anxiety, and depression [148] . dizziness, another common mobility-related complaint of older adults, has been associated with lower falls efficacy and slower walking speed [149] . these trends are consistent with other data j o u r n a l p r e -p r o o f showing fall history and female gender independently predict fear of falling [150] and mobility device use [151] . consistent with the data on the importance of psychosocial factors in mobility, a number of mobility-related clinical interventions are integrating falls-specific self-efficacy [152 2017 ], balance-specific [153] and other psychological concepts into trials targeting frailty in older adults [154] . further, these trials are also targeting motivation for physical activity [155] , adherence to exercise programs [156] , fall prevention [157] , and interventions to reduce the fear of falling and improve balance such as yoga [158] . protocols are emphasizing the need to tailor to older adult's preferences, personal choice, and providing social support [159] . these factors should align with older adults' own attitudes and perceived needs [160] , as well as older adults' perceived enablers and barriers to participation in strength and balance activities (barriers = risk of cardiac events, death, and hyper muscularity; enablers = potential improvement in the ability to complete daily activities, prevent deterioration /disability, and decreased risk and fear of falling) [161] . in a 6month integrated care program that included problem-solving psychotherapy reported improvements in frailty were sustained at one year follow up [162] . although these studies suggest promising results, the integrated biopsychosocial approach to mobility is still underutilized. poor nutrition may be a key factor that promotes metabolic syndrome and can exacerbate a decline in physical function and mobility. given the link between metabolic syndrome or obesity with the musculoskeletal decline among the older population, it is no surprise that dietary interventions that reduce bodyweight also improve health outcomes in older adults. dietary j o u r n a l p r e -p r o o f restriction (or caloric restriction), defined as a mild reduction of energy intake without malnutrition, delays aging in nearly all animal species tested so far [163] . in addition to promoting longevity in various model organisms (e.g., yeast, worm, fly, mouse) [163, 164] , dietary restriction had also been shown to be beneficial for enhancing physical function and mobility in older adults [254] [255] [256] [257] . furthermore, in overweight humans, caloric restriction has been shown to reduce several cardiac risk factors [165] [166] [167] , improving insulin-sensitivity [168] , and enhancing mitochondrial function [169] . current challenges: despite health-promoting biological changes, there are two important concerns related to calorie restriction interventions in older adults. first, weight loss could accelerate aging-associated muscle loss and thereby have adverse effects on physical function [170, 171] . second, most individuals have difficulty engaging in caloric restriction over the long-term and frequently regain weight that was lost [172] . for these reasons, alternative innovative dietary approaches for reducing body weight, specifically body fat, in overweight, older adults at risk for the functional decline are currently being explored. innovations from geroscience: one alternative dietary approach that has been suggested to produce similar biological changes as calorie restriction that has received increasing interest from the scientific community is intermittent fasting or time-restricted eating (tre) [173] . in contrast to traditional calorie restriction paradigms, there is typically no restriction to calorie consumption in tre during designated eating periods (typically 8 -12 hours). in a recent review of the effects of intermittent fasting regimens, specifically tre and alternate-day fasting, we found that tre produced significant reductions in body fat without significant loss of lean tissue, suggesting it may be an effective intervention approach for overweight, older adults [173] . another area of increasing scientific interest is understanding the role of dietary composition in impacting human physiology and physical performance. for example, the mediterranean diet, which consists of healthy fats, fiber, fish, and minimally processed, plantbased foods, has been shown to provide health benefits including improving cardiovascular function, glucose control and decreasing body weight among older adults [174] [175] [176] . also, noteworthy, in some preclinical studies conducted in rodent models, the ketogenic diet has been shown to extend longevity and healthspan, [270[177] improve memory and cognition, [177] [178] [179] and improve endurance athletic performance [274, 275] . based on such findings, the lowcarbohydrate, high-fat ketogenic diet has attracted increasing attention as a potential dietary intervention to promote healthy aging. future directions: to date, the impact of diet interventions on physical function and mobility among seniors with aging-associated morbidities is unknown. although some risk may be associated with lifestyle-based weight loss interventions in older adults, obesity, and sedentary lifestyle are known to predict the development of disability in otherwise healthy older adults [119, 180] . however, randomized controlled studies are needed to demonstrate whether the benefits of these interventions outweigh the risks before implementing these interventions on a broad scale. an important primary focus of these interventions should be enhancing and/or maintaining fat-free mass, as high-quality muscle is the primary driver of metabolism and also directly impacts mobility and physical function [14, 181] . notably, as multimorbidity is often a characteristic feature observed in older individuals with impairments in mobility, a geroscience approach will be instrumental in determining the long-term efficacy of nutrition-based interventions and addressing the potential challenges with aging-associated comorbidities. exercise provides benefits to all major body systems, including the nervous system. aerobic exercise, in particular, can enhance brain health by upregulating neurotrophic factors that improve nerve structure and function [182] . to prevent functional decline, the american college of sports medicine (acsm) guidelines for older adults recommend a regular exercise program that includes a combination of endurance and resistance training [183] . in support of these recommendations, low-intensity aerobic activity such as walking 4-7 days per week [184] or going up and down a 10-stair staircase [185] , have been shown to be protective against loss of mobility and functional decline [184] [185] [186] . current challenges: while structured physical activity is a powerful tool to improve overall health in older adults, involvement in structured physical activity may be overwhelming for frail older adults who are home-bound and have poor physical performance. older adults may not be capable of participating in structured, institution-based physical activity programs with multiple visits to research sites due to poor health status and distant living locations. innovations from geroscience. our group has shown that a structured, moderate-intensity physical activity program compared with a health education program reduced the incidence of major mobility disability over 2.6 years among older adults at risk for disability [187] . other studies have found that resistance training can reduce and delay age-related changes in functional mobility [188] , improves leg strength [189] , and prevents falls by improving transfer of weight and swooping motions in the elderly [190] . reduction of sedentary behavior may be an alternative way to deliver a home-based and remotely supervised intervention to improve the functional status in older adults who cannot engage in center-based physical activity programs. for example, an intervention to reduce sedentary time over 12-weeks improved scores on the short physical performance battery (sppb) and self-reported moderate-to-vigorous physical activity (mvpa) levels in older men and women [192] . such it could be a promising intervention to improve physical function in frail older adults in a home-based setting. strong positive associations between breaks in sedentary time with physical function in older adults have also recently been reported [193] . challenges: remotely delivered interventions are more difficult to achieve long-term adherence to the intervention tasks. additionally, considering heterogenous levels of daily activity and sedentary time among individuals, it is challenging to set daily frequency of sedentary time reduction breaks and design the methods for prompting these breaks as well as an amount of steps to be reached daily. [194] innovations from geroscience: thanks to new developments of well-accepted wearable technology in older adults [195] , such as the fitbit alta device, activity and sedentary-behavior levels can be monitored and registered remotely, and importantly, users can be reminded automatically to transition from sitting to standing position and perform brief light-intensity activity such as leisurely walking [196] . for example, participants using wearable technology aimed to achieve a minimum goal of 25% increase in daily posture breaks, and an additional 1,000 steps a day to baseline, which is considered clinically meaningful in a geriatric rehabilitation population [197] . this novel and practical approach, is less physically strenuous, j o u r n a l p r e -p r o o f does not require frequent visits to research sites, and can be operated and monitored remotely by a research team. future directions: future randomized clinical trials are needed to test wearable technologies in a population of frail older adults with poor physical function, multi-morbidities, and live a far distance from research facilities. given the importance of physical activity and exercise for healthy aging, it is important to consider how these can be optimized to promote neural control of walking. the mode of activity/exercise may be important, and there may be adjuvant interventions that promote neural plasticity. innovations from geroscience. task-specific aerobic exercise that incorporates complex walking tasks and other activities of daily living may be especially helpful for mobility function [198] . an example of these interventions is the use of non-invasive neuromodulation such as transcranial direct current stimulation (tdcs), a mild form of electrical stimulation that is safely delivered via electrode sponges placed on the scalp. tdcs does not directly activate brain neurons, but rather alters the neuronal membrane potential, which is believed to alter the likelihood of eliciting neuron activity (either increased or decreased likelihood, depending on the stimulation parameters) [199] . when paired with task practice, excitatory tdcs might reinforce task-specific neural circuits, enhance learning, retention of new skills, and has been shown to benefit walking tasks in preliminary studies [200] [201] [202] [203] . cognitive interventions refer to a broad set of methods designed to improve or maintain cognitive functioning [204] . because many forms of cognition (e.g., memory, reasoning, speed, executive functioning, attention, working memory) are change with age, and are associated with functional losses in later adulthood [204] [205] [206] , the field of cognitive intervention research has been rather broad. methods of intervention have varied from cognitive training (e.g., providing elders with strategic instruction and practice/feedback in age-vulnerable cognitive domains i ), engagement [207] (having elders engage in complex real-world or leisure activities, including video games) [208] , quilting and digital photography [209] , performing arts [210, 211] interacting with technology [211, 212] , to a wide variety of physical and nutritional strategies (e.g., cardiovascular and strength training, anti-inflammatory diets [213] ). most of this research has sought to investigate whether interventions can improve cognition and/or cognitively demanding activities of daily living. innovations from geroscience. useful field of view training progressively and adaptively trains older individuals to improve the speed with which they make accurate perceptual judgments about targets presented in the center of the field of view, while also correctly noting the location of peripheral objects presented on a display [214] . restrictions in useful field of view have been associated with problems of mobility [215] , balance [216] and increased risk of falling [217] , although direct training benefits have not yet been widely reported. of relevance to the mobility domain, older drivers who received useful field of view training showed a roughly 50% reduction in five-year motor vehicle crash rates [218] , presumably because of the improved ability to rapidly monitor a broad visual display and to divide attention between central and j o u r n a l p r e -p r o o f peripheral targets. the unifying feature of each of these domains of successful cognitive training is the focus on divided attention. in all cases, training included the feature of exposing elders to two tasks at once with one task usually representing a balance/gait or visual-perceptual challenge. generalization of training to mobility tasks seems to be associated with the improved ability to attend to multiple tasks at once, or perhaps to be resistant to distracting tasks by having greater control over attentional prioritization (i.e., reducing the effects of distraction, or improving the ability to exert controlled attentional processing over mobility-relevant tasks). the question of whether cognitive interventions might also improve mobility and physical functioning has received less attention, but a few areas of inquiry have yielded supportive findings. first, dual-task training has been shown to improve standing balance, gait, and to reduce fall risk [213, [219] [220] [221] . the rationale for such studies is that balance and gait are thought to be under central (executive) control, and improving attentional capacity to concurrently conduct cognitive and motor challenges will improve the ability to maintain adequate mobility under distracting conditions, as distractions are thought to put elders at a high risk for falls. there are a number of hormonal interventions that have the potential to impact mobility and improve physical function. we focus on one promising compound, the neuropeptide oxytocin, which serves various adaptive and interrelated physiological, behavioral, and cognitive functions [222] . as a hormone, oxytocin is released into the peripheral circulation and acts directly on multiple organ systems. for example, in humans, low plasma oxytocin levels were associated with increased prevalence of chronic pain, and acute (i.e., one-time) intranasal oxytocin administration decreased experimental pain sensitivity, increased pain inhibition, and j o u r n a l p r e -p r o o f journal pre-proof improved mood and positive affect. in addition, there is increasing evidence of improved wound healing and anti-inflammatory effects associated with oxytocin [223] , promoting physical health. innovations from geroscience: the ability to administer oxytocin centrally via nasal spray [224, 225] , with minimal and inconsistent side effects [226] , has spurred research to explore the neuropeptide's therapeutic potential across functional domains, including physical health and in aging [227] [228] [229] [230] . going beyond its classic role in labor and lactation [231] , oxytocin has been demonstrated to modulate higher-order cognitive processing [232] , improve vasculature in the cardiovascular system, benefits weight control, and insulin sensitivity [222, 233] . oxytocin has also been shown to play a crucial role in endogenous analgesia and has recently been discussed as a promising treatment for pain in older individuals [234] . these analgesic mechanisms may be explained by oxytocin's role as both a neurotransmitter and a paracrine hormone and may be associated with brain-morphological processes. as a neurotransmitter, oxytocin may provide analgesia via widespread effects on the brain and spinal cord. in humans, emerging evidence supports an association between plasma oxytocin levels and brain volumes [235, 236] . preliminary data from a 4-week intranasal oxytocin intervention in older men found increased regional gray matter volume following oxytocin but not placebo treatment, with this oxytocin-induced enlargement in brain volume was associated with improved processing speed [237] . furthermore, animal models that administer repeated oxytocin treatment have documented brain changes driven by cell proliferation, differentiation, and dendritic complexity of new-born neurons in the hippocampus [238] . findings in both models offer promise for future investigations into the potential of intranasal delivery of oxytocin to counteract cognitive decline and positively affect physical health in aging. additionally, data j o u r n a l p r e -p r o o f from an animal model that systematically administered oxytocin found that the administration enhanced muscle regeneration after injury through activation of stem cells and mapk/erk signaling [239] . future directions: only one study to date has specifically examined the effects of intranasal oxytocin administration on physical health among older adults and found that 10-days of oxytocin spray was associated with less self-reported physical decline and reduced selfreported fatigue [240] . the promising findings from these diverse emerging fields call for more systematic research on both acute and chronic oxytocin intervention towards physical function among older adults. examination of exogenous oxytocin's direct and mediated effects, and interaction with the endogenous oxytocin system (e.g., naturally circulating neuropeptide levels, oxytocin receptor gene polymorphisms and methylation levels [228, 241] ), forms an interesting angle for future research on interventions promoting physical function and mobility in aging. in addition, there is growing support in the literature of sex dimorphism in the oxytocin system [226] , including in aging [241] , and evidence of sex-dimorphic effects of intranasally administered oxytocin on both brain [222, 228] and behavior [50, 222, 228] , including among older adults. in an age-heterogenous sample of generally healthy women and men, plasma oxytocin levels were higher in women than men, with young women showing the numerically highest levels and older men showing the numerically lowest plasma oxytocin levels [241] . based on this emerging evidence, future research on the application of oxytocin's effects across different functional domains during aging will benefit from consideratin of sex-by-age variations. pharmacological interventions targeted at underlying mechanisms of mobility decline may also lead to improvements in mobility and physical function in older adults. for example, cell senescence characterized by a loss of cell proliferative capacity, increased metabolic activity, and resistance to apoptosis is a major contributing factor to the development of various agerelated conditions. thus, targeting the removal of senescent cells or suppressing the senescenceassociated secretory phenotype may be helpful in improving physical function [242] . specifically, inhibition of cytoplasmic hsp90 (a chaperone protein needed for proper protein folding) induced by hsp90 inhibitors causes senescent cells to be more susceptible to apoptosis. other pharmacological agents aimed to help proper protein folding or remove misfolded protein aggregates may also delay the onset of age-related diseases and subsequently prevent or ameliorate physical functional decline from these sources. the idea that aging itself may be modified through a pharmaceutical intervention will be tested in the targeting aging with metformin (tame) proposal, the first clinical trial to examine an intervention to slow aging rather than to treat a specific age-related chronic disease in humans pharmacologically [243] . the impetus for this trial is that metformin has been demonstrated to have protective effects against several agerelated diseases in humans. however, there does not appear to be a single biological mechanism targeted. rather metformin appears to have broad systemic effects, which can enhance insulin sensitivity and upregulate stress responses at the cellular level. further, targeting cognition pharmacologically to improve mobility or prevent further decline may be possible, given the brain's neurotransmitter systems shared between cognitive function and the circuits controlling gait. specifically, drugs targeting the cholinergic, j o u r n a l p r e -p r o o f dopaminergic and glutamatergic systems have been reported with various degrees of success in individuals with alzheimer's and parkinson's disease [244] , but may be an additional option to explore in cognitively intact older adults with poor mobility. future directions: to date, there is very limited research focused on pharmacologically targeting aging for improving physical function. given the mosaic of aging processes and potential multi-factorial underlying mechanisms, a geroscience approach will be needed to test interventions with multi-functional properties that target the biopsychosocial contributors to aging processes. natural compounds may also represent an important source of potential new interventions for older individuals. similar to pharmaceutical agents, these compounds would likely be most effectively used as an adjunct treatment with lifestyle interventions, behavioral self-management programs, physical exercise, or cognitive interventions. current challenges: for the vast majority of these compounds, the findings have primarily been shown in preclinical models and have not yet been translated to humans, and/or few clinical trials have shown positive effects on mobility in older adults when biologically based approaches are used alone and not in combination with a behavioral intervention [245] . innovations from geroscience: studies to date suggest some natural compounds may be effective adjuvants to lifestyle interventions. in this section, we will focus on one promising nutraceutical compound, nicotinamide riboside (nr), a form of vitamin b3 that stabilizes the nad metabolome (nad+, nadh, nadp+ and nadph), which in a homeostatic state, mediates transformations from food into energy and repair processes [246, 247] . given the nad metabolome destabilizes with age [248] , supplementation with nr has been shown to stabilize j o u r n a l p r e -p r o o f the nad metabolome in a variety of tissues [249] . clinical studies have demonstrated excellent tolerabilty and safety of nr supplementation in middle-aged and older adults, and improved vascular function [250] and reduced fat tissue [251] following 6 weeks of supplementation. future directions: the effects of nr supplementation alone on physical performance in older humans are unclear, and therefore future studies warrant investigations of longer-duration nr supplementation on physical performance, weight loss and cardiovascular function in humans [252, 253] . much will be learned about the promise of preclinical findings to translate to humans, as well as their compatibility with other interventions, in the coming years. there are many promising complementary and alternative treatment modalities, including biofeedback, hypnosis, meditation, mindful exercise, massage and other types of body-work, acupuncture, and music therapy, that have the potential to improve mobility and physical function in older adults. here we will focus on the potential role of massage therapy (mt), which is a mind-body intervention that has been shown to improve muscle function and quality, preserve of neuromuscular function, improve sleep quality and psychological functioning [229, [254] [255] [256] [257] [258] ; [259] ; [260] . additionally, a growing body of literature supports the use of mt to treat chronic musculoskeletal pain associated with aging [261] [262] [263] [264] . current challenges: while mt shows significant promise for improving factors associated with physical function and quality of life, there are important considerations for older adults, including access, attitudes, and approach. attitudes towards complementary health approaches, specifically mt, are often biased towards a luxury service instead of an actual medical intervention. also declines in mobility and independence may inhibit treatment seeking. innovations from geroscience: specific to biological processes in aging, mt has been shown to modify gene expression, protein synthesis, and inflammatory responses [254] [255] [256] [257] , as well as improve peak isometric torque recovery following intense exercise [265] , and protect against loss of strength and fibrotic nerve and connective tissue changes associated with repetitive motion injuries [266] . massage therapy has also been demonstrated to modulate inflammatory processes that may be protective in aging [267, 268] . of particular relevance, recent preclinical studies using rodent models, demonstrated mt induced immunomodulatory changes (e.g., increased satellite cell number) comparable to those seen in younger animals without damaging muscle tissues. [269] the beneficial effects of massage therapy appear to take place quickly, as a single 10-minute massage therapy session following exercise-induced muscle damage was found to be beneficial for reducing inflammation and promoting mitochondrial biogenesis [270] . additionally, massage therapy is capable of altering proprioceptive feedback to the central nervous system [271, 272] , a critical component for maintaining mobility in aging. adults have yet to be fully elucidated, it is likely that massage therapy can serve a vital role in helping older adults maintain mobility by reducing pain, improving muscle functioning, maintaining proprioceptive abilities, and altering negative inflammatory processes, while improving psychological functioning [259, 260, [273] [274] [275] . although mt may need to be modified to accommodate older adults' needs, it appears to be a safe and effective intervention. given that mt acts upon multiple important pathways for mobility and independence, applying an integrated geroscience approach will improve our understanding of mt in addressing agerelated mobility and functional declines. there is now evidence to support a wide variety of intervention approaches to improve mobility and attenuate functional decline in older adults. both behavioral and biological interventions hold great promise for improving function and mobility and thereby extending healthspan and promoting wellness in functionally limited but healthy older adults. as noted previously, such interventions may enhance physical function directly, as well as indirectly through modulation of cognitive and socioemotional processes. these processes include depression, social stress, and anxiety, which all have high relevance in aging and may contribute to social isolation and reduced well-being among older adults. the utility of such interventions to produce desired outcomes is directly impacted by participant adherence to prescribed treatments, and even the most efficacious intervention can be ineffective if the patient fails to follow treatment recommendations. thus, it is very important to carefully evaluate the sustainability of such interventions, especially in light of research demonstrating that individuals who are not fully adherent to health interventions experience significantly fewer health benefits [276] . a variety of factors can affect long-term adherence to health promotion behaviors, including the complexity of the required changes, the number of decision points needed to carry out such changes on a daily basis, and a number of environmental, socio-cultural, and psychological influences [276] . this suggests the need for two approaches to enhance the effectiveness of behavioral and biologically-based interventions: 1) continued refinement of strategies that can enhance the delivery of and adherence to such interventions, and 2) development of novel intervention approaches (e.g., intermittent fasting and intermittent activity bouts) that have the potential to produce similar health benefits as traditional lifestyle approaches and also may be easier to sustain over the long-term. the role that technological advances may have in increasing the effectiveness of both traditional interventions, as well as more novel intervention approaches, is a topic of great interest. in the section below, we describe some of the key considerations in delivering digital and mobile health (mhealth) based interventions in older adults. personally-held devices, such as smartphones, smartwatches and fitness trackers, provide a ubiquitous infrastructure for researchers and clinicians to passively collect a moment-bymoment quantification of individuals' behavior in their own environment, or recently referred to as digital phenotyping. smartphones are considered the most common electronically held devices. pew research center (prc) conducted a survey about the ownership of smartphones in 2019 showing that 81% of americans and 53% of older adults own smartphones, usage doubling among americans and nearly quadrupling among older adults since 2010 [277, 278] . smartwatches are also growing rapidly. the international data corporation (idc) worldwide quarterly wearable device tracker published that smartwatches accounted for 44.2% of the wearable market in 2018 and is expected to rise to 47.1% by 2023 [279] . prc has published recently a survey showing that onein-five americans (21%) wear a smartwatch or a fitness tracker [280] . a recent study by manini and colleagues [281] about the perception of older adults (65+ years) towards the use of smartwatch technology for assessing pain showed an overall positive view. data collected using smart devices fall under two main categories: active and passive data. the essential difference between these two types is the involvement of participants in reporting data. the active data is described as questions or surveys that a participant has to self-j o u r n a l p r e -p r o o f report at specific times. this data is commonly used for ecological momentary assessment (e.g., pain, mood, or fatigue). in contrast, passive data collection does not require participants to report any data. participants are only required to carry the smart device to be able to continuously collect data through built-in sensors. the type of passively collected data and the quality depend on the availability and modalities of sensors. the most common sensors available are: 1) global positioning sensor (gps) that could be used to measure life-space mobility; which is a measure of the spatial size and frequency of interaction with the surrounding environment; 2) accelerometer that could be used to track physical activity pattern and energy expenditure; 3) microphone that could be used to collect voice samples to be used to extract vocal markers that can serve as a prognostic value for neurological disorders; and 4) call and text logs that can convey information about the size and reciprocity of a person's social network and can also serve as a prognostic value for neurological and psychological disorders. the huge amount of data collected from personally held devices contain hidden, but useful knowledge about the behavior of an individual. fortunately, the advancement of machine learning techniques allowed us to tap into this data and extract patterns. in recent years, sensors embedded into wearable and personal devices such as smartphones have made it possible to develop many mhealth apps, e.g. for tracking physical activity, monitoring blood pressure and heart rate, medication reminders, and many more [282, 283] . some mhealth apps additionally provide just in time (jit) interventions (figure 4) , such as prompting physical activity based on inferred levels of activity or daily steps. a number of recent studies have utilized such mhealth tools in controlled trials to examine mhealth interventions, especially for chronic disease management [284] . several studies have used mhealth intervention tools in cardiovascular and diabetes patients, including the pilot mobile atrial fibrillation (maf) [285] trial (n = 113, cluster randomized design pilot study). as the first mhealth trial of atrial fibrillation patients, maf showed improved drug adherence and anticoagulant satisfaction versus the usual care. in a larger study, the heart failure ii (tim-hf2) trial [286] (n = 1571, randomized parallel-groups), utilized remote monitoring and demonstrated that it could reduce the percentage of days lost due to unplanned cardiovascular hospital admissions and all-cause mortality. in a remote monitoring study, giacomelli et al. [287] showed that remote monitoring after hospitalization for heart failure in older adults had no impact on the primary end-point but it significantly improved patients' quality of life. physical activity promotion also has been examined in several mhealth trials, including the mactive [288] trial which showed that tracking and texting intervention increased physical activity. amorim and colleagues [289] carried out a randomized controlled trial by integrating mhealth, health coaching, and physical activity for patients sufferings from chronic low back pain, demonstrating feasibility and acceptance and a reduction in care-seeking after treatment discharge. other studies have examined mhealth interventions for promoting mental health in clinical trials, including using smartphone cognitive behavioral therapy for refractory depression [290] and smartphone-delivered intervention in patients with a serious and persistent mental health condition, with the improvement shown among patients from racial minority groups [291] . these recent intervention studies and especially controlled trials show promise for the potential scalability and acceptance of mhealth tools. an important but sometimes overlooked j o u r n a l p r e -p r o o f aspect of developing mhealth intervention tools is conducting formative usability evaluation research, besides evaluating efficacy in formal trials. tools must be designed to effectively communicate the proper information by being interactive, interoperable, engaging, and accessible for diverse audiences [292, 293] . therefore, the following attributes should be considered during the development, adoption, and implementation of mhealth tools: 1) ease of use; 2) how the tool fits within the policies, practices, and technical infrastructure of existing health and social systems; and 3) whether intended users can understand and apply the health information provided. performing needs analysis and audience analysis can help guide the design to achieve such objectives [293] . in summary, while mhealth tools may enhance the delivery of some interventions, especially in chronic disease management, evidence regarding their effectiveness for geriatric conditions is still mixed [284, 294] . additionally, most controlled trials have been carried out in high-income countries, and evidence on the effectiveness of such tools in lower-income countries is missing [284] . finally, there is a lack of end-to-end systems for sharing jit intervention results with providers through existing electronic health record (ehr) systems. both humans and animals exhibit an age-dependent progressive decline in mobility [295] [296] [297] [298] . thus, mechanistic studies of age-related mobility impairment in pre-clinical models could advance our understanding of the fundamental mechanisms underlying disability. for example, there is much that can be learned from the study of the simple organism c. elegans. despite its simple anatomy, c. elegans is capable of multifaceted behaviors in response to diverse environmental and intrinsic cues, and exhibits an age-associated decline in locomotion [296, 299] . the multitude of genetic tools available also makes c. elegans an invaluable model system for the study of cellular and molecular mechanisms underlying aging-related locomotor and j o u r n a l p r e -p r o o f movement decline [300] . in c. elegans, the progressive deterioration of muscle occurs with age, which resembles human sarcopenia [301] . importantly, the functional decline of motor neurons at the neural muscular junctions precedes the deterioration of muscle tissues during c. elegans aging [302] , indicating an important role of motor neurons in the age-related mobility impairment. findings from pre-clinical models have led to the identification of important biological mechanisms related to the aging process including mitochondrial function and dynamics [303, 304] , autophagy [305, 306] , oxidative stress [307] , chronic inflammation [308] , muscle composition [309] , hormonal factors [310] , and neurodegeneration [311] . moreover, preclinical studies have led to the transformative discovery that interventions targeting the fundamental biology of human aging have the potential to delay, if not prevent, the onset of aging-associated conditions [2] [3] [4] [5] [6] . ultimately a strong translational geroscience approach is needed to understand the disease-mediated pathways associated with functional decline and identify promising interventions to maintain mobility and physical function (see figure 4 ). as aging research becomes more information-based, statistics plays a critical role in almost all research topics discussed in the previous sections. for any given aging research project, statistical support is needed at almost all stages starting with the formulation of a scientific hypothesis, study design, data collection, data management and analysis, and conclusion making and ending with manuscript writing. often, the earlier a statistician is involved in an aging research project, the more productive the project will become. let us use a specific example to demonstrate how statistics can significantly help aging research. assume that a research project aims to investigate whether an intervention (e.g., a j o u r n a l p r e -p r o o f nutritional supplement) can improve older adults' mobility. to make the hypothesis more specific, we first need to determine major mobility measurements. according to webber [312] , mobility can be measured in five dimensions (i.e., cognitive, psychosocial, physical, environmental, and financial), and there are many different ways to measure mobility in each dimension. if we are interested in all five dimensions and would like to develop a single mobility index or choose some important ones from all possible mobility measures, then some preliminary studies to collect data on these measures are needed. the data from these preliminary studies can be analyzed by statistical modeling and variable selection approaches, allowing us to come up with either a single mobility index or a relatively small number of mobility measures. these variables can then be used as the response variables of the original study. second, the sample size for the study needs to be properly calculated. to do this, researchers need to specify the smallest meaningful difference between the intervention and control groups for each response variable. the next step is to check whether all model assumptions of the related sample size formula are valid. if not, then a new formula needs to be derived, which could be challenging. for data collection, statisticians are vital in determining which study design is best, such as deciding between a double-blinded randomized study or other types of studies. these steps of study design are extremely important to make the collected data useful in testing the major scientific hypothesis. after data collection, much statistical expertise is required to analyze the data and make solid conclusions. during data analysis, proper statistical methods that clearly describe the observed data need to be chosen, all model assumptions should be verified, and develop new statistical methods when necessary. primary care physicians and geriatricians play an instrumental role in the identification of older adults who have or are at risk for impaired mobility. unfortunately, healthcare providers encounter several barriers to the proper evaluation and treatment of mobility issues in older adults. some of these barriers include insufficient knowledge in latest research findings in the field of geroscience, time constraints in busy clinics, lack of needed resources for treatment interventions, weak patient support systems, and even language barriers in some minority communities. despite these barriers, most patients can be quickly and efficiently screened for cognitive concerns and/or mobility issues with validated assessments, such as the "get up and go" test. when appropriate, providers should deliver succinct but impactful counseling on the importance of adopting a healthy diet, practicing regular physical exercises, and obtaining adequate sleep. the use of educational hand-outs can be very helpful for some patients. clinicians should also use available resources for the enhancement of mobility, such as referrals to physical /occupational therapy, ophthalmology, audiology, and massage therapy. there is a need for more educational programs for healthcare providers covering the latest research findings in the treatment of geriatric conditions including impaired mobility. optimal communication between clinical researchers and clinicians might facilitate the prompt implementation of efficacious new treatments. collaboration among academic investigators and community partners also has the potential to increase the relevance of the research and its potential for addressing public problems such as general health disparities [313] and health problems more specific to seniors, such as limited mobility. such collaborations require (a) culturally sensitive, multidisciplinary academic research teams, (b) empowerment of community members through training them to assume leadership in implementing and disseminating research center-tested j o u r n a l p r e -p r o o f interventions and assisting in getting the institutional review board credentials for being equal research partners, (c) paying trained community member researchers as research professionals, (d) mobilizing community resources and partners (e.g., businesses and local officials) to make policy changes to reduce the social determinants of health (e.g., no/limited public transportation in target low-income black communities) that impede implementation and dissemination efforts. interventions shown to be efficacious in research centers are typically implemented and tested under controlled conditions with non-representative samples of motivated participants [314] . there is a need to implement and disseminate efficacious interventions in communities where uncontrollable social determinants of health (e.g., poverty, race and racism) and associated health disparities negatively influence the length and quality of community members' lives. these communities are where seniors, racial/ethnic minorities, the poor, and/or the medically underserved (i.e., health disparity groups) often live. because of this, ideal implementation and dissemination sites in such communities are churches [315, 316] and primary care centers [317] . it is these sites that commonly serve the aforementioned groups, are stable community structures with physical resources (e.g., meeting spaces), and have human resources (e.g., pastors and physicians) who can influence members of health disparity groups to participate in efforts to implement and disseminate health promotion interventions. the empirically supported community-based participatory research (cbpr) approach [318] is useful in implementing and disseminating efficacious interventions in communities in general and in racial/ethnic minority, poor, and/or medically underserved communities in particular. cbpr creates a paradigm shift from traditional research practices that have characterized academics as experts towards a collaborative research process in which academics are also learners [319] . accordingly, the cbpr approach requires that community members be j o u r n a l p r e -p r o o f actively involved in all aspects of the research process, including the selection of the research topic and methodology, participant recruitment, research implementation, data collection, interpretation of study results, and dissemination of research findings [319, 320] . the patient-centered culturally sensitive healthcare (pc-cshc) model [317] , explains the linkages between provider cultural sensitivity and patients' health outcomes and is useful in guiding implementation and dissemination in community-based healthcare settings. notably, cultural sensitivity extends beyond cultural competence and enables patients to feel comfortable with, trusting of, and respected by providers and researchers, and involves recognizing and overcoming biases and stereotypes that these groups have towards to each other [317] . the provider being culturally sensitive is one key aspect of the pc-cshc model and is a major factor in health promotion. further, patients must be allowed to determine what behaviors, methodologies, etc. enable them to feel comfort, trust and respect. the other key aspect of this model is patient and community empowerment. in accordance with the pc-cshc model, implementation and dissemination of research centertested interventions in community primary care sites that serve health disparity groups requiring that patients and community health workers are active partners with academic researchers. for example, patients should ideally be involved in focus groups and/or interviews to identify culturally sensitive strategies for making these efforts successful. community health workers, physicians, and other providers can then (a) implement these strategies and disseminate the target interventions, and (b) participate with researchers in town hall meetings to disseminate information to the community about the impact of these interventions. culturally diverse, multidisciplinary academic research teams can provide the training needed for physicians/providers and patients to be empowered, equitable partners in implementing and j o u r n a l p r e -p r o o f disseminating target interventions. such empowerment by academic researchers is particularly important for patients such as minority, senior, poor, and medically underserved patients with limited actual and/or perceived power to take charge of their health. patient empowerment is the appropriate response to the increasing national calls for social, health, and healthcare justice. can we really slow the decline in mobility that occurs during aging? and can function improve as we age? the good news is that the answer to both questions appears to be an emphatic yes. effective future interventions, however, will need to take into consideration factors across multiple domains, as well as the complex interaction among these factors. findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, can have a dramatic effect on an older person's mobility and function. additionally, several biological and behavioral factors have been identified as directly related to functional capacity. these are exciting times within the field of gerontology with novel discoveries happening across different fields of study that have direct implications for function and/or functional capacity. for example, the discoveries made within the biology of the aging realm have informed of the types of intervention targets that could truly make a difference in an older adult's functional capacity. furthermore, covid-19 has highlighted the importance of self-care and preventative medicine to promoting wellness and extend healthspan. covid-19 has also highlighted the clear need to protect our older population, particularly minority older adults, as there are clear biological and metabolic factors that increase older adults' susceptibility to this condition. additionally, covid-19 has greatly increased the adoption of virtual communication; j o u r n a l p r e -p r o o f thus, the acceptability of technologically based future interventions is likely to be much greater than prior to covid-19. before translating interventions on a broad scale, however, their suitability and effectiveness across a number of domains are needed to help inform decision making. clearly, there is an important need to evaluate safety outcomes, first and foremost, with the next benchmark related to whether such interventions are sustainable. there is also the need to carefully determine the types of randomized clinical trials that are best suited to address particular questions, as well as the appropriate comparison groups. j o u r n a l p r e -p r o o f j o u r n a l p r e -p r o o f highlights • findings over the past decade have highlighted the complexity of walking and how targeting multiple systems, including the brain and sensory organs, as well as the environment in which a person lives, can have a dramatic effect on an older person's mobility and function. • behavioral interventions that incorporate complex walking tasks and other activities of daily living appear to be especially helpful for improving mobility function. • effective future interventions, however, will need to take into consideration factors across multiple domains, as well as the complex interaction among these factors. • before translating interventions on a broad scale, however, their suitability and effectiveness across a number of domains are needed to help inform decision making. active life expectancy geroscience: linking aging to chronic disease age-related change in mobility: perspectives from life course epidemiology and geroscience physiological geroscience: targeting function to increase healthspan and achieve optimal longevity translational geroscience: emphasizing function to achieve optimal longevity a framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the tame united nations world populations prospects: the advances in geroscience: impact on healthspan and chronic disease successful aging: advancing the science of physical independence in older adults the impact of behavioral intervention on obesity mediated declines in mobility function: implications for longevity studies of illness in the aged. the index of adl: a standardized measure of biological and psychosocial function a guttman health scale for the aged role of gait speed in the assessment of older patients improvement in usual gait speed predicts better survival in older adults obesity, functional mobility and quality of life ability to walk 1/4 mile predicts subsequent disability, mortality, and health care costs association of mobility limitations with health care satisfaction and use of preventive care: a survey of medicare beneficiaries estimating transition probabilities in mobility and total costs for medicare beneficiaries association of long-distance corridor walk performance with mortality, cardiovascular disease, mobility limitation, and disability disability status, mortality, and leading causes of death in the united states community population active life expectancy for 10,000 caucasian men and women in three communities sedentary activity associated with metabolic syndrome independent of physical activity. diabetes care increasing prevalence of the metabolic syndrome among u.s. adults. diabetes care prevalence of the metabolic syndrome in us populations lumbar motoneurons of man: i) number and diameter histogram of alpha and gamma axons of ventral root macro emg in healthy subjects of different ages methods for estimating numbers of motor units in biceps-brachialis muscles and losses of motor units with aging physiological changes in ageing muscles the estimated numbers and relative sizes of thenar motor units as selected by multiple point stimulation in young and older adults motor unit number estimates in the tibialis anterior muscle of young, old, and very old men role of the nervous system in sarcopenia and muscle atrophy with aging: strength training as a countermeasure innervation and neuromuscular control in ageing skeletal muscle denervation drives mitochondrial dysfunction in skeletal muscle of octogenarians accumulation of severely atrophic myofibers marks the acceleration of sarcopenia in slow and fast twitch muscles failed reinnervation in aging skeletal muscle multimodal imaging of brain activity to investigate walking and mobility decline in older adults neural correlates of obstacle negotiation in older adults: an fnirs study. gait and posture neurocognitive aging and the compensation hypothesis automaticity of walking: functional significance, mechanisms, measurement and rehabilitation strategies the global burden of musculoskeletal pain-where to from here? global, regional, and national incidence, prevalence, and years lived with disability for 328 diseases and injuries for 195 countries, 1990-2016: a systematic analysis for the global burden of disease study prevalence of chronic benign pain disorder among adults: a review of the literature movement-evoked pain: transforming the way we understand and measure pain physical performance and movement-evoked pain profiles in communitydwelling individuals at risk for knee osteoarthritis interrelated neuromuscular and clinical risk factors that contribute to falls multisite pain is associated with long-term patient-reported outcomes in older adults with persistent back pain persistent pain quality as a novel approach to assessing risk for disability in community-dwelling elders with chronic pain risk factors for restriction in activity associated with fear of falling among seniors within the community the course of limitations in activities over 5 years in patients with knee and hip osteoarthritis with moderate functional limitations: risk factors for future functional decline. osteoarthritis cartilage profile of the elderly in physical therapy and its relation to functional disability reasons for functional decline despite reductions in knee pain: the multicenter osteoarthritis study chronic pain, perceived stress, and cellular aging: an exploratory study accelerated aging in adults with knee osteoarthritis pain: consideration for frequency, intensity, time, and total pain sites chronic pain is associated with a brain aging biomarker in communitydwelling older adults epigenetic aging is associated with clinical and experimental pain in community-dwelling older adults clinical neurophysiology of circadian rhythm sleep-wake disorders age-related changes in the circadian system unmasked by constant conditions. eneuro impact of sleep and circadian rhythms on addiction vulnerability in adolescents the role of the molecular clock in promoting skeletal muscle growth and protecting against sarcopenia a new face of sleep: the impact of post-learning sleep on recognition memory for face-name associations the aging clock: circadian rhythms and later life mitochondrial mechanisms of neuromuscular junction degeneration with aging. cells a cross-sectional study of muscle strength and mass in 45-to 78-yr-old men and women longitudinal muscle strength changes in older adults: influence of muscle mass, physical activity, and health muscle function decline and mitochondria changes in middle age precede sarcopenia in mice mfn2 deficiency links age-related sarcopenia and impaired autophagy to activation of an adaptive mitophagy pathway skeletal muscle mitochondria and aging: a review circadian rhythms and mitochondria: connecting the dots executive summary: heart disease and stroke statistics--2016 update: a report from the american heart association aortic stiffness and interstitial myocardial fibrosis by native t1 are independently associated with left ventricular remodeling in patients with dilated cardiomyopathy arterial-ventricular coupling with aging and disease concept of extremes in vascular aging enhancing recovery from sepsis: a review large cross-sectional study of presbycusis reveals rapid progressive decline in auditory temporal acuity who, prevention of blindness and deafness: estimates current concepts in age-related hearing loss: epidemiology and mechanistic pathways the role of hormones, cytokines and heat shock proteins during age-related muscle loss growth hormone in aging. the endocronology of aging growth hormone and insulin-like growth factor-1 (igf-1) and their influence on cognitive aging bone mineral status and bone loss over time in men with chronic systolic heart failure and their clinical and hormonal determinants serum levels of insulin-like growth factor-i (igf-i) and dehydroepiandrosterone sulfate (dhea-s), and their relationships with serum interleukin-6, in the geriatric syndrome of frailty hospital diagnoses, medicare charges, and nursing home admissions in the year when older persons become severely disabled disability in older adults: evidence regarding significance, etiology, and risk morbidity and disability in older persons in the years prior to death functional transitions among the elderly: patterns, predictors, and related hospital use sarcopenic obesity and complex interventions with nutrition and exercise in community-dwelling older persons--a narrative review the state of us health, 1990-2016: burden of diseases, injuries, and risk factors among us states does overall diet in midlife predict future aging phenotypes? a cohort study. the american journal of medicine the association between objectively measured sitting and standing with body composition: a pilot study using mri associations of physical activity and sedentary behavior with regional fat deposition reduced physical activity increases intermuscular adipose tissue in healthy young adults sedentary behavior, physical activity, and the metabolic syndrome among u.s. adults low muscle mass in older men: the role of lifestyle, diet and cardiovascular risk factors physical activity prevented functional decline among frail community-living elderly subjects in an international observational study obesity and mobility disability in the older adult decreased functional capacity and muscle strength in elderly women with metabolic syndrome prevalence of metabolic syndrome and its association with physical capacity, disability, and self-rated health among lifestyle interventions for elders (life) study participants sedentary and physically active behavior patterns among low-income african-american and white adults living in the southeastern united states the independent and combined associations of physical activity and sedentary behavior with obesity in adults: nhanes 2003-06 sedentary time is associated with the metabolic syndrome in older adults with mobility limitations--the life study why sleep is important for health: a psychoneuroimmunology perspective prevalence of healthy sleep duration among adults--united states sleep and human aging frequent napping is associated with excessive daytime sleepiness, depression, pain, and nocturia in older adults: findings from the national sleep foundation '2003 sleep in america' poll longitudinal relationship between sleep deficiency and pain symptoms among community-dwelling older adults in japan and singapore cortical thickness mediates the association between self-reported pain and sleep quality in community-dwelling older adults chronic musculoskeletal pain moderates the association between sleep quality and dorsostriatal-sensorimotor resting state functional connectivity in community-dwelling older adults the national institute on aging health disparities research framework effects of stress throughout the lifespan on the brain, behaviour and cognition social isolation and loneliness in older adults: opportunities for the health care system associations between social isolation, loneliness, and objective physical activity in older men and women social isolation, loneliness, and all-cause mortality in older men and women social isolation, loneliness and health in old age: a scoping review where we live: health care in rural vs urban america differential access to care: the role of age, insurance, and income on race/ethnicity-related disparities in adult perforated appendix admission rates national dissemination of multiple evidence-based disease prevention programs: reach to vulnerable older adults ethnicity-and socio-economic status-related stresses in context: an integrative review and conceptual model determinants of adherence in time-restricted feeding in older adults: lessons from a pilot study older adults' perceptions of mobility: a metasynthesis of qualitative studies frailty phenotype: evidence of both physical and mental health components in community-dwelling early-old adults balance confidence and fear of falling avoidance behavior are most predictive of falling in older adults: prospective analysis self-efficacy, pain, and quadriceps capacity at baseline predict changes in mobility performance over 2 years in women with knee osteoarthritis falls efficacy as a measure of fear of falling dizziness and its association with walking speed and falls efficacy among older men and women in an urban population falls and fear of falling: which comes first? a longitudinal prediction model suggests strategies for primary and secondary prevention mobility device use in older adults and incidence of falls and worry about falling: findings from the 2011-2012 national health and aging trends study effects of supervised slackline training on postural instability, freezing of gait, and falls efficacy in people with parkinson's disease a backward walking training program to improve balance and mobility in acute stroke: a pilot randomized controlled trial integrated primary and geriatric care for frail older adults in the community: implementation of a complex intervention into real life dietary carbohydrate restriction improves metabolic syndrome independent of weight loss one-year adherence to the otago exercise program with or without motivational interviewing in community-dwelling older adults walking can be more effective than balance training in fall prevention among community-dwelling older adults the effect of yoga on balance and fear of falling in older adults motivating older adults with cancer to keep moving: the implications of lifestyle interventions on physical activity attitudes and needs of residents in long-term care facilities regarding physical activity-a systematic review and synthesis of qualitative studies enablers and barriers to older people's participation in strength and balance activities: a review of reviews integrated care for geriatric frailty and sarcopenia: a randomized control trial the retardation of aging by caloric restriction: studies in rodents and primates dietary restriction and lifespan: lessons from invertebrate models long-term calorie restriction is highly effective in reducing the risk for atherosclerosis in humans calorie restriction or exercise: effects on coronary heart disease risk factors. a randomized, controlled trial caloric restriction alone and with exercise improves cvd risk in healthy nonobese individuals effect of calorie restriction with or without exercise on insulin sensitivity, beta-cell function, fat cell size, and ectopic lipid in overweight subjects calorie restriction increases muscle mitochondrial biogenesis in healthy humans weighty concerns: the growing prevalence of obesity among older adults the danger of weight loss in the elderly the future of obesity: new drugs versus lifestyle interventions flipping the metabolic switch: understanding and applying the health benefits of fasting health benefits of the mediterranean diet: metabolic and molecular mechanisms mediterranean dietary patterns and impaired physical function in older adults association between adherence to the mediterranean diet at midlife and healthy aging in a cohort of french adults the effects of the ketogenic diet on behavior and cognition ketogenic diet reduces midlife mortality and improves memory in aging mice a ketogenic diet improves cognition and has biochemical effects in prefrontal cortex that are dissociable from hippocampus physical activity and risk of cognitive impairment among older persons living in the community walking speed predicts health status and hospital costs for frail elderly male veterans aerobic exercise effects on cognitive and neural plasticity in older adults genomic comparison of the ants camponotus floridanus and harpegnathos saltator the effect of walking on lower body disability among older blacks and whites risk of functional decline among well elders maintaining mobility in late life. ii. smoking, alcohol consumption, physical activity, and body mass index effect of structured physical activity on prevention of major mobility disability in older adults: the life study randomized clinical trial resistance training for activity limitations in older adults with skeletal muscle function deficits: a systematic review effects of a fall prevention exercise program on muscle strength and balance of the old-old elderly is lower extremity strength gain associated with improvement in physical performance and disability in frail, community-dwelling elders? molecular transducers of physical activity consortium (motrpac): mapping the dynamic responses to exercise reducing sedentary behavior versus increasing moderate-to-vigorous intensity physical activity in older adults breaking-up sedentary time is associated with physical function in older adults intervening to reduce sedentary behavior in older adults -pilot results not just another walking program interventions to reduce sedentary behavior mobility after hospital discharge as a marker for 30-day readmission systematic review of functional training on muscle strength, physical functioning, and activities of daily living in older adults a technical guide to tdcs, and related non-invasive brain stimulation tools effects of noninvasive brain stimulation on cognitive function in healthy aging and alzheimer's disease: a systematic review and meta-analysis time-but not sleep-dependent consolidation of tdcs-enhanced visuomotor skills noninvasive cortical stimulation enhances motor skill acquisition over multiple days through an effect on consolidation enhancing working memory training with transcranial direct current stimulation cognitive interventions. handbook of the psychology of aging neuropsychology of aging characterizing and assessing cognitive aging. cognitive aging: progress in understanding and opportunities for action training versus engagement as paths to cognitive enrichment with aging computer and videogame interventions for older adults' cognitive and everyday functioning the impact of sustained engagement on cognitive function in older adults: the synapse project individualized piano instruction enhances executive functioning and working memory in older adults training older adults to use tablet computers: does it enhance cognitive function? gerontologist can acquired skill and technology mitigate age-related declines in learning rate? current and emerging trends in aging and work interventions to prevent age-related cognitive decline, mild cognitive impairment, and clinical alzheimer's-type dementia effects of cognitive training interventions with older adults: a randomized controlled trial useful field of view test wiifit plus balance test scores for the assessment of balance and mobility in older adults predictors of falling in older maryland drivers: a structural-equation model cognitive training decreases motor vehicle collision involvement of older drivers benefits of cognitive dual-task training on balance performance in healthy older adults effects of single-task versus dual-task training on balance performance in older adults: a double-blind, randomized controlled trial standardization in the mspe: key tensions for learners, schools, and residency programs chronic oxytocin administration as a tool for investigation and treatment: a cross-disciplinary systematic review oxytocin alleviates the neuroendocrine and cytokine response to bacterial endotoxin in healthy men sniffing neuropeptides: a transnasal approach to the human brain evidence for intranasal oxytocin delivery to the brain: recent advances and future perspectives a review of safety, side-effects and subjective reactions to intranasal oxytocin in human research oxytocin and socioemotional aging: current knowledge and future trends oxytocin modulates meta-mood as a function of age and sex. front aging neurosci ageing and oxytocin: a call for extending human oxytocin research to ageing populations--a mini-review lifespan oxytocin signaling: maturation, flexibility, and stability in newborn, adolescent, and aged brain oxytocin control of maternal behavior. regulation by sex steroids and offspring stimuli oxytocin and vasopressin in the human brain: social neuropeptides for translational medicine treatment of obesity and diabetes using oxytocin or analogs in patients and mouse models musculoskeletal pain and brain morphology: oxytocin's potential as a treatment for chronic pain in aging. front aging neurosci oxytocin's fingerprint in personality traits and regional brain volume alterations of brain volumes in women with early life maltreatment and their associations with oxytocin associations between oxytocin receptor gene (oxtr) methylation, plasma oxytocin, and attachment across adulthood repeated treatment with oxytocin promotes hippocampal cell proliferation, dendritic maturation and affects socio-emotional behavior oxytocin is an age-specific circulating hormone that is necessary for muscle maintenance and regeneration effects of a 10-day oxytocin trial in older adults on health and well-being plasma oxytocin and vasopressin levels in young and older men and women: functional relationships with attachment and cognition current nutritional and pharmacological anti-aging interventions metformin as a tool to target aging pharmaceutical intervention mobility aging decline locomotion and posture in older adults metformin and aging: a review discoveries of nicotinamide riboside as a nutrient and conserved nrk genes establish a preiss-handler independent route to nad+ in fungi and humans nad+ metabolism in health and disease impairment of an endothelial nad(+)-h2s signaling network is a reversible cause of nad(+) intermediates: the biology and therapeutic potential of nmn and nr chronic nicotinamide riboside supplementation is well-tolerated and elevates nad(+) in healthy middle-aged and older adults nicotinamide riboside supplementation alters body composition and skeletal muscle acetylcarnitine concentrations in healthy obese humans fat mobilization without weight loss is a potentially rapid response to nicotinamide riboside in obese people: it's time to test with exercise nicotinamide riboside-a missing piece in the puzzle of exercise therapy for older adults? the mechanisms of massage and effects on performance, muscle recovery and injury prevention fascial well-being: mechanotransduction in manual and movement therapies mechanotransduction and the regulation of protein synthesis in skeletal muscle mechanical strain stabilizes reconstituted collagen fibrils against enzymatic degradation by mammalian collagenase matrix metalloproteinase 8 (mmp-8) manual therapy as an effective treatment for fibrosis in a rat model of upper extremity overuse injury effect of therapeutic massage on insomnia and climacteric symptoms in postmenopausal women a randomised study of the effects of massage therapy compared to guided relaxation on well-being and stress perception among older adults massage therapy for pain-call to action nonpharmacologic therapies for low back pain: a systematic review for an american college of physicians clinical practice guideline massage therapy in chronic musculoskeletal pain managment: a scooping review of the literature noninvasive nonpharmacological treatment for chronic pain: a systematic review agency for healthcare research and quality massage timing affects postexercise muscle recovery and inflammation in a rabbit model could intermittent energy restriction and intermittent fasting reduce rates of cancer in obese, overweight, and normal-weight subjects? a summary of evidence a preliminary study of the effects of a single session of swedish massage on hypothalamic-pituitary-adrenal and immune function in normal individuals a preliminary study of the effects of repeated massage on hypothalamic-pituitary-adrenal and immune function in healthy individuals: a study of mechanisms of action and dosage the role of dna methylation in epigenetics of aging massage therapy attenuates inflammatory signaling after exercise-induced muscle damage the effect of foam rolling of the hamstrings on proprioception at the knee and hip joints effects of massage on muscular strength and proprioception after exercise-induced muscle damage the 2011 report on dietary reference intakes for calcium and vitamin d from the institute of medicine: what clinicians need to know massage therapy produces short-term improvements in balance, neurological, and cardiovascular measures in older persons the physiological and psychological effects of slow-stroke back massage and hand massage on relaxation in older people long-term adherence to health behavior change tech adoption climbs among older americans demographics of mobile device ownership and adoption in the united states idc forecasts steady double-digit growth for wearables as new capabilities and use cases expand the market opportunities. idc about one-in-five americans use a smart watch or fitness tracker perception of older adults toward smartwatch technology for assessing pain and related patient-reported outcomes: pilot study criteria for assessing the quality of mhealth apps: a systematic review a path to better-quality mhealth apps the impact of mhealth interventions: systematic review of systematic reviews mobile health technology for atrial fibrillation management integrating decision support, education, and patient involvement: maf app trial efficacy of telemedical interventional management in patients with heart failure (tim-hf2): a randomised, controlled, parallel-group, unmasked trial the effectiveness of remote monitoring of elderly patients after hospitalisation for heart failure: the renewing health european project healthy aging: the ultimate preventative medicine integrating mobile-health, health coaching, and physical activity to reduce the burden of chronic low back pain trial (impact): a pilot randomised controlled trial smartphone cognitive behavioral therapy as an adjunct to pharmacotherapy for refractory depression: randomized controlled trial hyperglycemia drives intestinal barrier dysfunction and risk for enteric infection online cancer communication: meeting the literacy, cultural and linguistic needs of diverse audiences evaluating health communication programs to enhance health care and health promotion unpacking mhealth interventions: a systematic review of behavior change techniques used in randomized controlled trials assessing mhealth effectiveness. digit health age-dependent changes in mobility and separation of the nematode caenorhabditis elegans identification by machine vision of the rate of motor activity decline as a lifespan predictor in c. elegans. neurobiology of aging drosophila as a model for age-related impairment in locomotor and other behaviors age-related change in mobility: perspectives from life course epidemiology and geroscience. the journals of gerontology series a, biological sciences and medical sciences age-dependent changes in mobility and separation of the nematode caenorhabditis elegans age-dependent changes and biomarkers of aging in caenorhabditis elegans stochastic and genetic factors influence tissue-specific decline in ageing c. elegans. nature functional aging in the nervous system contributes to age-dependent motor activity decline in c. elegans aberrant mitochondrial homeostasis in the skeletal muscle of sedentary older adults coordinated changes in mitochondrial function and biogenesis in healthy and diseased human skeletal muscle autophagy in the cellular energetic balance skeletal muscle autophagy and apoptosis during aging: effects of calorie restriction and life-long exercise autophagy, mitochondria and oxidative stress: cross-talk and redox signalling molecular inflammation: underpinnings of aging and age-related diseases effect of dietary restriction and exercise on lower extremity tissue compartments in obese, older women: a pilot study hypothalamic-pituitary-adrenal axis function and corticosterone receptor expression in behaviourally characterized young and aged long-evans rats aging, the central nervous system, and mobility mobility in older adults: a comprehensive framework health care use and barriers to care among latino immigrants in a new migration area. j health care poor underserved quality-of-care research: internal elegance and external relevance obesity interventions in african american faith-based organizations: a systematic review engaging black churches to address cancer health disparities: project church. front public health counseling psychologists and behavioral health: promoting mental and physical health outcomes. sage journals community-based participatory research conceptual model: community partner consultation and face validity the three r's: how community based participatory research strengthens the rigor community-based participatory research from the margin to the mainstream: are researchers prepared? circulation key: cord-288392-khjo6j8u authors: davern, melanie; winterton, rachel; brasher, kathleen; woolcock, geoff title: how can the lived environment support healthy ageing? a spatial indicators framework for the assessment of age-friendly communities date: 2020-10-21 journal: int j environ res public health doi: 10.3390/ijerph17207685 sha: doc_id: 288392 cord_uid: khjo6j8u the age-friendly cities and communities guide was released by the world health organization over a decade ago with the aim of creating environments that support healthy ageing. the comprehensive framework includes the domains of outdoor spaces and buildings, transportation, housing, social participation, respect and inclusion, civic participation and employment, communication and information, and community and health services. a major critique of the age-friendly community movement has argued for a more clearly defined scope of actions, the need to measure or quantify results and increase the connections to policy and funding levers. this paper provides a quantifiable spatial indicators framework to assess local lived environments according to each age-friendly cities and communities (afc) domain. the selection of these afc spatial indicators can be applied within local neighbourhoods, census tracts, suburbs, municipalities, or cities with minimal resource requirements other than applied spatial analysis, which addresses past critiques of the age-friendly community movement. the framework has great potential for applications within local, national, and international policy and planning contexts in the future. research has long recognized that environmental factors play a significant role in determining health and wellbeing in older age [1] , and there are rising proportions of older people in the populations across the world. consequently, the recently released united nations decade of healthy ageing 2020-2030 calls for sustained global action to generate transformative change in four priority areas: addressing ageism; creating age-friendly communities; delivering integrated and person centered care; and providing long-term care [2, 3] . increased urbanization and policy discourses supporting ageing in place add to the urgency to create and plan for age-friendly environments. on a global scale, life expectancy has increased from 47 years in the mid-20th century to an expected 78 years by the mid-21st century [4] and 21% of the world's population is predicted to be aged over 60 years by 2050 [5] . the world health organization (who) world report on ageing and health [6] documented how age-friendly environments play a which often includes transportation systems, land development patterns, and microscale urban design (e.g., footpaths) [27, 28] . a lived environment reflects the importance of locality and access to good urban design, as well as human-made and natural environments to support health and wellbeing in the local neighbourhoods where people live. this is consistent with the argument regarding the narrow application of the term "built environment" where both human made and natural worlds are conceived as though there is no separation between them [29] . spatial indicators provide a quantitative measurement of local lived environments using geocoded data (defined by x and y co-ordinates) developed using geographic information systems (gis). data linked to a street address can be mapped using gis and calculated as spatial indicators, providing aggregated measures across a range of geographic areas, including neighbourhoods or census tracts, suburbs, municipalities, regions, or states. aggregated geocoded data can be drawn from a range of existing administrative data sources that assess the lived environment and a range of social, economic, and environmental issues. spatial afc indicators consequently provide objective and cost-effective assessments of age-friendliness that are easily replicated across large geographic areas using desktop spatial analysis. these indicators can also be made readily accessible to local governments using online digital planning portals and liveability indicator systems for cities, like the australian urban observatory (auo.org.au) [30] . the development of quantifiable spatial indicators of afc addresses the major critiques of the afc initiative-that it is too descriptive in approach [31] , not measured or monitored by indicators [31] , and without a clear understanding of an indicator framework [32] . this paper proposes spatial indicator tools that can be applied for the assessment of afc in local lived environments using a gis methodology. these afc spatial indicators can also be applied in a variety of international contexts with direct relevance to the healthy cities movement [33] , the new urban agenda, and the 2030 agenda for sustainable development [34] . the 2030 agenda provides a global framework for sustainable urban development up until 2030 signed by all 193 members states with 169 specific targets. these include sustainable development goals (sdgs) with specific mention of older people in targets for goal 10 reduced inequalities, goal 11 sustainable cities and communities, and goal 17 partnerships for the goals. in addition, the decade of healthy ageing [3] calls for disaggregated data in twenty-eight indicators across eleven goals. spatial indicators measuring afc in lived environments are noted by the united nations as being necessary for the measurement and monitoring of any actions contributing to sustainable development (goal 17) and multi-stakeholder partnership development and policy and institutional coherence. they have been developed to address segregation or siloed approaches in the current planning approaches and to encourage discussion and action that can promote integrated policy, planning, and practice across urban planning and public health. often the outcome of afc remains the sole responsibility of health or social planning with little integration across important portfolios, such as transport or statutory or strategic planning. the implementation of afc principles must extend beyond practitioners with interest in ageing and should ideally be integrated across policy portfolios with budget and legislative support. this paper aims to introduce a new set of afc spatial indicators that can be used to quantify and assess the age-friendliness of local lived environments and monitor changes in age-friendliness over time consistent with the sdgs and 2030 agenda. these indicators seek to support the decade of healthy ageing, which includes a commitment to action in the development of age-friendly environments and improved measurement, monitoring, and research [8] as well as tools to support planners and practitioners working within government settings. these spatial indicators of afc also identify the importance of older people and their lived environments in sustainable urban development and the 2030 agenda. eight interconnected domains are included in afc ( figure 1 ). the selection of specific spatial indicators to assess the lived environment of each afc domain was made following a workshop held with all five authors to identify the most relevant measures for each of these domains. the multidisciplinary experience of the research team spans gerontology, public health, urban planning, psychology, epidemiology, sociology, health geography, health policy, governance, and community development. with all five authors to identify the most relevant measures for each of these domains. the multidisciplinary experience of the research team spans gerontology, public health, urban planning, psychology, epidemiology, sociology, health geography, health policy, governance, and community development. potential indicators were then judged against the key criteria recommended by the who (box 1) as well as other best practice principles for indicator application [36] including: direct links to policy; connection to theory and existing research; available time series data; connection to budgeting and planning; relevance to most people; and connection to lived reality. these latter criteria being understood and relevant to most people, particularly older people, are particularly important and informed by previous research in the development of a specific indicator of access to services for older people [37] , which included focus groups of older people to determine the local needs and services of highest importance. the selected measures also needed to be relevant to the majority of older people living in a wide range of lived environments, and to measure the most critical requirements for places that support afc principles. box 1. the criteria suggested for defining local afc indicators [15] . will variations in the indicator be observable over time due to specific actions? disaggregation possible: can the indicator be disaggregated by gender, age group, or across neighbourhoods? there are also other strategies that could be important in the local context, including ethnicity, socioeconomic status, etc. aligns with local goals and targets: does the indicator link to a broader local agenda? can be linked to action: does the indicator provide an understanding of the various actions that might need to be undertaken? within local influence: does the local government or community have the mandate or authority to act on this indicator? for example, a federal insurance scheme is mostly beyond the influence of the municipal government. easy to collect: are the data required to produce the indicator easy to collect in a timely manner? socially acceptable: is the collection of this information acceptable to the communities and individuals concerned? the following section describes each of the selected afc spatial indicators with research evidence provided to support each indicator (table 1 ). potential indicators were then judged against the key criteria recommended by the who (box 1) as well as other best practice principles for indicator application [36] including: direct links to policy; connection to theory and existing research; available time series data; connection to budgeting and planning; relevance to most people; and connection to lived reality. these latter criteria being understood and relevant to most people, particularly older people, are particularly important and informed by previous research in the development of a specific indicator of access to services for older people [37] , which included focus groups of older people to determine the local needs and services of highest importance. the selected measures also needed to be relevant to the majority of older people living in a wide range of lived environments, and to measure the most critical requirements for places that support afc principles. box 1. the criteria suggested for defining local afc indicators [15] . will variations in the indicator be observable over time due to specific actions? disaggregation possible: can the indicator be disaggregated by gender, age group, or across neighbourhoods? there are also other strategies that could be important in the local context, including ethnicity, socioeconomic status, etc. aligns with local goals and targets: does the indicator link to a broader local agenda? can be linked to action: does the indicator provide an understanding of the various actions that might need to be undertaken? within local influence: does the local government or community have the mandate or authority to act on this indicator? for example, a federal insurance scheme is mostly beyond the influence of the municipal government. easy to collect: are the data required to produce the indicator easy to collect in a timely manner? socially acceptable: is the collection of this information acceptable to the communities and individuals concerned? the following section describes each of the selected afc spatial indicators with research evidence provided to support each indicator (table 1) . additional contextual factors for consideration include: the estimated resident population; proportion of population aged more than 60 years; population age distribution including proportions of older and younger populations in area; ethnicity; education; homeownership; residential density; remoteness e.g., accessibility/remoteness indices or the distance between towns in rural settings; the risk of natural disasters; climatic conditions; and the impact of climate change. * recommended as priority indicators for inclusion. the suggested spatial indicators for each afc domain are presented in table 1 with the priority indicators notated with asterisks. this provides flexibility for practitioners in identifying the key spatial indicators of importance to afc or additional optional indicators where resources are available. additional information is provided below explaining why these indicators are recommended for each afc domain with detailed explanations of the supporting research evidence. the indicators recommended in the following section were identified in accordance with indicators acting as icebergs and highlighting issues of major importance [37] . only after the major factors have been quantitively assessed should further qualitative assessment be completed, similar to a hierarchy of need. for example, if there are no public open spaces available there is little point in assessing the maintenance, shelter, or facilities available in public open spaces within an area. additional qualitative assessment could also include local consultation with older residents and relevant stakeholders. the priority indicators identified for this domain are walkability for transport [38, 39] and access to public open space within 400 m [22] . these indicators are directly related to walking [40] [41] [42] , specifically in older people [43] , and associated with physical health benefits [44] and mental health benefits [45] . walkable neighbourhoods are important for older people because, along with the fact that they enable people to reach destinations with commercial and social opportunities [43, 46] , walking is also associated with maintaining functional independence [47] and better cognitive function [48] . similarly, public open spaces that are easy to visit with walkable access are important for older people and important in reducing social isolation and increasing physical activity [49] . data required to create indicators of walkability are commonly available within municipal and planning contexts. road network analysis (a way to walk), land use mix (destinations to walk to), and housing density (people to service the destinations) are common key components of walkability assessments. similarly, public open space location data are also regularly held by most municipal governments. footpaths are an important infrastructure supporting walking in older people [50, 51] , and walkability can also be refined by superimposing footpath access where spatial data are available. an example of a walkability for transport assessment for the regional city of launceston in tasmania, australia was calculated and is provided in figure 2 to demonstrate the value of neighbourhood level walkability assessments. the results clearly suggest that the inner neighbourhoods of the city of launceston have good walkability while the outer neighbourhoods are less supportive of walking for transport, particularly those on the eastern side of town. additional spatial indicators for consideration include intersections with visual and auditory signalled pedestrian crossings that allow time for older people to cross over roads, and particularly busy intersections [53, 54] . in australia, many regional towns avoid the use of signalized pedestrian crossings and opt for roundabout intersections, which encourage continual traffic flow and can be frightening for people with reduced mobility. access to public seating is also recommended to be available within local public open spaces to encourage rest stops while walking (overlapping with the suggested measure of accessibility to public open space). clean and safe public toilets are also recommended, including those with accessibility features [51] and should also be included within high quality public open spaces. accessible buildings are italicised in table 1 due to the difficulty in sourcing data that measure buildings developed according to universal design principles. if possible, these are recommended, as older people experience difficulties associated with access to public buildings and the lack of handrails, narrow corridors, and steps [51] . post occupancy evaluations are generally more common in sustainability assessments [55] and are time and staff resource intensive but could be considered as an alternative measure if no other data are available to assess buildings. additional spatial indicators for consideration include intersections with visual and auditory signalled pedestrian crossings that allow time for older people to cross over roads, and particularly busy intersections [53, 54] . in australia, many regional towns avoid the use of signalized pedestrian crossings and opt for roundabout intersections, which encourage continual traffic flow and can be frightening for people with reduced mobility. access to public seating is also recommended to be available within local public open spaces to encourage rest stops while walking (overlapping with the suggested measure of accessibility to public open space). clean and safe public toilets are also recommended, including those with accessibility features [51] and should also be included within high quality public open spaces. accessible buildings are italicised in table 1 due to the difficulty in sourcing data that measure buildings developed according to universal design principles. if possible, these are recommended, as older people experience difficulties associated with access to public buildings and the lack of handrails, narrow corridors, and steps [51] . post occupancy evaluations are generally more common in sustainability assessments [55] and are time and staff resource intensive but could be considered as an alternative measure if no other data are available to assess buildings. there is a growing body of evidence showing a positive association between healthy ageing and blue space [56] . this is worthy of future consideration but is not accessible within all lived environments and, hence, has not been included as a recommended measure within the outdoor space and building domain but could be considered as second tier measures. blue space is defined as outdoor environments (natural or manmade) that prominently feature water and are accessible proximally (being located in, on, or near water) or distally/virtually (being able to see, hear, or sense water) [57] . therapeutic design of a built environment using urban green and blue infrastructure was shown to be protective for healthy ageing while supporting those with cognitive decline, or illness [58] . similarly, a study of largely older people in hong kong found that general health was significantly higher in people with a sea view from their home [59] , while, in ireland, older people had a lower risk of depression in those with more sea views [60] . in addition, nature-based solutions, there is a growing body of evidence showing a positive association between healthy ageing and blue space [56] . this is worthy of future consideration but is not accessible within all lived environments and, hence, has not been included as a recommended measure within the outdoor space and building domain but could be considered as second tier measures. blue space is defined as outdoor environments (natural or manmade) that prominently feature water and are accessible proximally (being located in, on, or near water) or distally/virtually (being able to see, hear, or sense water) [57] . therapeutic design of a built environment using urban green and blue infrastructure was shown to be protective for healthy ageing while supporting those with cognitive decline, or illness [58] . similarly, a study of largely older people in hong kong found that general health was significantly higher in people with a sea view from their home [59] , while, in ireland, older people had a lower risk of depression in those with more sea views [60] . in addition, nature-based solutions, through green and blue space urban management planning, can mitigate the health impacts of climate change while addressing the need for climate resilience in local communities [61] . future revisions of the afc principles could consider the inclusion of more detailed measures of green and blue spaces in the domain of outdoor spaces and buildings to address changing climates around the globe. these could include access to local blue spaces, public and private tree canopy coverage, public street tree canopy coverage and the associated shade capability, in combination with the currently recommended measures of walkability and accessibility to public open space. these measures are very worthy of consideration but bring their own challenges in terms of data access and spatial capability making them harder to produce. consequently, they are suggested as potential expanded, not essential, measures of the afc lived environment assessment. transport is an important determinant of health [62, 63] influencing access to local services, engagement in paid and non-paid productive activities (such as employment or volunteering), maintaining and developing social networks and supports, and engaging in social and recreational activities. public transport has also been identified as a critical influence of liveability in a community [19] and active transport important to older people [64] . policy-relevant spatial public transport indicators are typically based on 400 m access or a 5-min walk [20, 65] . another important factor that influences the use of public transport is service frequency. consequently, access to any public transport stop provides a high-level assessment while access to frequent public transport provides a more refined assessment. similar measures are also included in the australian government's national cities performance framework (https://www.bitre.gov.au/national-cities-performance-framework). for older people, mobility is essential for social participation and wellbeing [66] . public transport is particularly important for older people who might have a reduced ability to drive. older people tend to use public transport more frequently if there is easy access to public transport in neighbourhoods at a distance less than 5 min away [67] . this is also consistent with existing research that found that the frequency of public transport and wait time affected older people's willingness to travel [68] and that a high proportion of older people are no longer driving [69] . data for these indicators can most often be sourced from public access data portals, open street map or general transit feed specification (gtfs) where public transport data are provided by transport agencies into a computer readable format for web developers [70] . gaining access to more detailed data describing public transport that meets disability standards is another very valid indicator and has been associated with increased satisfaction and perceived useability in older people [71] . similarly, access to a bus stop with an accompanying shelter and seat is also important for older people's mobility, as well as dropped curves, footpaths, and pedestrian signals [54] . housing is central to living a productive, meaningful, and healthy life, and housing quality is an important influence on self-reported health [72] . unaffordable housing is detrimental to mental health in low to moderate income households [73] . unaffordable housing has also been associated with an increased risk of poor self-rated health, hypertension, and arthritis, and renting, rather than owing a home, increases associations between unaffordable housing and self-rated health [74] . consequently, housing costs and gentrification [75] are particularly important to consider, with housing stress in lower income households being a particularly important indicator for the assessment of age-friendly cities. housing needs, sizes, and types can change as people age. older people might consider downsizing to smaller homes with reduced maintenance needs or to be closer to extended family for support to age in place [76] . in rural and regional areas, older people might need to move from larger farms and back into towns where services are more readily available. alternatively, frail older residents might require the support of aged care providers to support high care needs. addressing these issues means that communities need to understand the available housing diversity options (e.g., larger houses, smaller houses, units, and apartments to serve broad community needs) as well as access to services for residents. afc supports multiple housing options that are beneficial to all residents with many municipalities thinking primarily about formal aged-care accommodation when addressing housing needs for older people. even more concerning in australia, it is common for aged care facilities to be built on the outskirts of cities and towns where there is an abundance of inexpensive and undeveloped land. this isolates older people from the rest of the community, makes it harder for people to access and visit, decreases access to other community services, and decreases intergenerational contact within communities. the 30/40 housing affordability indicator is recommended and describes the proportion of households in the bottom 40% of household incomes spending more than 30% of their income on housing costs [77] . this measure is also referred to as the ontario measure where the interest in housing affordability first identified the disproportionate impact of housing costs on lower income households [78, 79] . understanding community demographic profiles, particularly age, in combination with the high incidence of 30/40 housing affordability issues should raise concerns for any community wanting to support age-friendliness. specifically, older adults on an aged pension within the private rental market will face significant challenges in housing affordability [80] . the indicator of access to services for older people was developed with older people themselves [37] and includes hospitals, general practitioners, aged care facilities, public transport stops, supermarkets, community centres, libraries, and universities of the 3rd age, and could also include places of worship and parks. this indicator also provides a useful assessment for the afc domain of community support and health services but is included in the housing domain to reinforce the importance of urban planning that supports the co-locations of services and housing options. the proportion of government owned dwellings could also be investigated as an additional support measure of afc, particularly in lower income areas. meaningful social relationships and participation are essential for good health, with health defined as a social phenomenon in the social determinants of health [81] . social participation has been associated with physical activity [82] , mental health [83] , reduced psychological distress [84] , reduced risk of myocardial infarction [85] , and up to a 50% increased likelihood of survival in people with strong social relationships compared to lifestyle risk factors [86] . for older people, social participation provides greater life satisfaction [87] , is protective against cognitive decline [88] , and contributes to resilience in older people [89] , especially in rural communities [90] . social participation is also being taken seriously internationally, and the united kingdom appointed a new minister for loneliness and a national government action plan on loneliness [91] . the recommended spatial indicators supporting social participation connect to the access to services for older people [92] that are included in the housing domain. two indicators are recommended: access to community centres and neighbourhood houses; and access to recreational services that cater to the needs of older people. shared or 'third spaces' such as these are critical social infrastructure [25] and essential in supporting social participation for older adults [93] . recreational services also support physical and mental health through opportunities for physical activity designed for older people and supporting community connections. another indicator recommended for inclusion is access to a local library, which also supports the afc domains of respect and social isolation, communications and information, and community support and health services. libraries provide multiple community benefits beyond simply lending books [94, 95] , including multimedia borrowing, technology training, community classes, lectures, and opportunities for intergenerational and community connections. libraries also support the need for learning opportunities across the course of life with universities of the third age (u3as) providing social and learning benefits to older people [96, 97] . this is associated with better physical health and activity levels [98] . places of worship are also considered an important facilitator of social connections and social capital [99] , particularly in humanitarian arrivals [100] and different cultures [101, 102] . respect and social inclusion are essential to ensure social participation for older people. there is much debate on the definition of social inclusion, though most studies refer to an objective participation in society and a more subjective assessment of whether the actual participation meets an individual's preferences [103] . most definitions of social exclusion emphasise the importance of social activities as a core component [104] . however, the effects of cumulative disadvantage, decreasing social networks, and age discrimination magnify the negative health and wellbeing impacts of social exclusion in later life [105] . a local or lived environment must provide accessible buildings, housing and transport, along with opportunities for social activities to occur if social inclusion and social participation are supported and encouraged. previous research on the services deemed important for older people has emphasised the importance of local services, such as shops [37, 69] , and this is supported by the use of new spatial indicators that can access formal and informal places to meet. these include recommended indicators of access to social clubs/senior citizens clubs or participation in international clubs, like rotary or probus, that are more formally organised by older people themselves. alternatively, informal opportunities for social inclusion include an indicator of distance-based access to local cafes that support broader intergenerational social opportunities. older people need a range of venues to create opportunities for social activities as a foundation for community respect and social inclusion. empowerment, autonomy and control [63, 106] , and employment conditions [107] were all found to be important influences of actual and self-reported health. control over one's own destiny has also been proposed [106] , consistent with an understanding of health being simultaneously influenced at the individual (micro/personal), place and community context (meso/community) as well as the larger societal context (macro/societal level) [108] . civic participation and employment are important influences of agency and autonomy in a society. consequently, it is important to understand how many older people are engaged in paid and unpaid productive activity in the community. this is best measured through the proportion of people who remain employed past the official retirement age (66 years in australia noting there is no official retirement age and eligibility for the aged pension is currently 66 years increasing to 67 years by 2023) or people aged 60 years or more who are engaged in regular volunteering. these indicators of paid and unpaid productive activity are also important measures of social engagement and civic participation and could be separated into additional age brackets or deciles (e.g., 60-75 years) for more detailed information. it is important to note that employment is also not defined according to hours worked, acknowledging both the civic connections and benefits that come from any level of paid employment and that retirement is not a single event and includes a diverse range of retirement patterns [109] . there has been criticism regarding the dominance of volunteering in measures of collective civic social participation in older people [110] with voting participation argued as a better measure of civic participation [111] . however, voting participation is less relevant in countries like australia where electoral voting is compulsory and volunteering activities are measured every 4 years. volunteering is also particularly important in regional areas of australia where third sector or non-profit organisations rely on older people volunteering [112] with increasing proportions of older people residing in rural locations [113] . in countries where voting is not compulsory (e.g., the usa), then voting participation could be considered as an additional measure of civic engagement. in 2016, approximately 86% of australian households had access to the internet [114] . this proportion decreased to 77% in remote areas where it is common to have a high proportion of older people within populations, with entertainment, social networking, and banking the most commonly supported activities supported by internet connection. internet access is also becoming more necessary to access information about the government, health, banking, and community services as well as to maintain contact with friends and family. finding information on services like these is also critical for older people to age in place and is necessary to support independent living and the connection to communities [115] . th information provision also extends beyond essential services and includes services provided by local libraries, which includes online books, audio, audio-visual, and educational resources that can be made available online for people with physical or geographical mobility restrictions. online streaming (e.g., netflix) is another more recent example of recreational activities supporting social connection and information provision. however, all these online resources require household internet access. access to a national radio service is another important source of information and becomes particularly important in emergency management, including preparation and recovery from natural disasters, such as floods, droughts, and bushfires, which are becoming increasingly more commonplace in australia. emergency sms messaging systems are also deployed during emergency situations to inform residents of impending safety risks but are worthless without adequate mobile phone reception. climate change is predicted to increase the likelihood of these emergency situations making telecommunications assessment essential in the support of afc. it is also necessary for developing technologies, including passive surveillance of movement monitoring within the home, personal alarm devices, and telehealth [116] , which have become increasingly accessible and necessary during the 2020 coronaviruses 2019 (covid-19) pandemic. communication is an important influence on the wellbeing of older people [117] , and both household internet and mobile phone reception provide essential telecommunication systems that support both intergenerational communication with family and friends, the communication of essential information [118] , and the ongoing adoption of new technologies [119] , as well as influence the quality of life [120] . currently, there is a paucity of references or inclusion of technological solutions offered to support afc and healthy ageing and technology, and icts have recently been suggested as a new smart age-friendly ecosystem framework [118] . suggestions included in this new framework to assist afc include: the development of smart housing; the inclusion of ageing in smart cities and engagement with the internet of things (iot); the better use of digital assistants (e.g., alexa) in the home; the use of digital robots for deliveries; electronic camera enabled doorbells; and motion sensors to detect mobility. technological features like these require inclusion during new housing development and have benefits across multiple afc domains beyond communication. they also require a rethink and interdisciplinary collaboration between planners, architects, developers, computer science, industry, and the government. while the opportunities are waiting for action, they also require engagement with older people themselves and their families using qualitative and ethnographic research methods [121] . this is an important area of growth and future development in afc and requires further research. access to primary health support services is essential and necessary for people to age in place. it is also the preferred option for most older people to maximise their health and wellbeing [122] . within the local community, access to general practitioners has been identified by older people themselves as essential community support services [36, 69, 123] and the key access point for primary health care. consequently, access to general practitioners was identified as an indicator of primary importance within community support and health services. these practitioners also provide gateway services and referrals to any other medical specialists, including geriatricians, who specialise in treating conditions that affect older people, including dementia. additional indicators that should be included relate to housing support either as in-home support packages or residential aged-care accommodation. all of these services are also included within a complete definition of social infrastructure, which has an important influence on subjective wellbeing [25] and are important components of liveability [19] . the approaches and spatial measures described above were applied in a case study in a regional context and rural centre in north-eastern victoria, australia. the regional town is located over 200 km north-east of the capital city of melbourne in the centre of the state of victoria, south-eastern australia. the major industries are agriculture and manufacturing, with a population of over 9000 people. both the state government department of health and the local municipality/council were interested in analysing and understanding afc and broader liveability given an increasingly ageing rural population. the spatial measures used to assess this included: walkability (with and without footpaths); access to public open space; access to public transport; housing affordability; housing diversity; government owned dwellings (social housing); access to services for older people; libraries; universities of the 3rd age; places of worship; volunteering; households with internet access; aged care facilities; and access to general practitioners. the results were presented to the local health department officials, the local municipality, and as a community presentation to residents at the local library. many of the challenges and barriers to afc planning were identified in the spatial measures and were confirmed by the lived experiences of residents from the local community. these included: poor walkability on the outer areas of town; difficulty getting to doctors and medical services located at the regional hospital located on the outer town boundary with limited public transport and poor walkability; disconnection between the older people, families, and younger people in the town due to the location of residential aged care on the town boundary next to the hospital; the importance of cafes and social spaces in the centre of town to support community and social connections; the value of the town's library, art facilities, and public open spaces; and inequity in the disadvantaged areas of the town that had reduced access to public transport and lower levels of household internet connections. the use of mapped spatial measures of afc was hugely beneficial for inter-agency conversations and planning initiatives as well as community conversations, engagement, and validation of the spatial analyses. the results also highlight the future negative impact of the age-friendliness of the town if future residential aged care development is supported in the outer areas of the town. the original who global age-friendly cities guide was developed in response to the rapid population ageing and urbanisation across the world and was informed by interviews conducted with older people themselves in over 33 different countries [7, 15] . the ultimate aim of afc is to create environments that support healthy ageing. this paper provided detailed, objective, and functional spatial measures of age-friendliness across lived environments that can be used to assess, monitor, evaluate, and communicate age-friendliness refined to the neighbourhood level. objective spatial measures of the lived environment are critical for the following reasons: to simplify assessments of afc; to provide a foundation level of knowledge about the age-friendliness of an environment; to assist local and state government planning by informing and monitoring future actions and interventions needed to promote healthy ageing in communities; and to include older people into targets of the 2030 sustainable development goals and the new urban agenda. the movement has previously been criticised for a lack of objective measurements and the need to connect these ideals into functional measures connected to policy, planning, and financial levers [10] . previous attempts at developing indicators of age-friendliness have been non-specific, non-coordinated, and reliant on survey-based responses (e.g., world health organization [15] ). such assessments are also beyond the budget, resources, capabilities, and motivation of local planning agencies and municipalities. the proposed spatial measures of age-friendliness across lived environments is relevant to planners, policymakers, advocacy organisations, governments, architects, industry, citizens and research audiences. the suggested indicators are provided to guide and inform discussions and interventions to promote healthy ageing. the measures can also be adopted and customised to local environments ranging in geographic and population sizes, rurality, climate conditions, and resource limitations. the proposed spatial indicators of afc address these issues through the application of gis technology to produce an objective assessment of the age-friendliness of local lived environments, drawing on indicators from the liveability literature that are specifically relevant to the values, preferences, and needs of older adults. these indicators provide measurement and quantification of afc domains consistent with the idea that value comes with measurement and leads to knowledge production as argued by lord kelvin over 200 hundred years ago [124] . the more simplistic interpretation of this, is that what is measured, is valued, and consequently is done. one of the critical issues raised in the recommended afc spatial indicators is the connection of all indicators within existing policy and planning contexts [13] . all the recommended indicators can be linked to existing policy and planning environments regardless of whether these have a local/municipal, state, or national focus. the connection of indicators to policy has been long identified within social indicator research [125, 126] . these indicators can assist governments in meeting their commitments to the sustainable development goals in a way that is meaningful for a growing segment of their populations. there is also an increasing interest and development in public health digital observatories. for example, relevant liveability indicators for the 21 largest cities of australia are available in the australian urban observatory (auo.org.au) launched in 2020. there is an opportunity to make spatial indicators available through novel data visualisation and ease of communication providing an influence on the policies required for healthy ageing across communities. the spatial indicators recommended for assessing afc domains can all be influenced and improved through policy levers. this includes the indicators suggested for outdoor spaces, transport, housing, social participation, respect and social inclusion, civic participation and employment, communications and information, community support, and health services. the indicator results can be influenced though local and immediate strategies or applied in advocacy with the responsible higher government agencies. this can include reviewing afc assessments within the context of current policy contexts, existing public health planning, liveability planning, transport planning, strategic planning, land use, and statutory planning it is also important to acknowledge the limitations of afc spatial indicators and understanding that these aggregated area-based results effectively act as icebergs of knowledge [35] providing a tip of the iceberg assessment of what is occurring, with additional information required to understand why the result is happening and how it can be addressed. consequently, the objective afc spatial indicators should also be combined with additional sources of knowledge. these include consultation and engagement with local older people themselves to expand understanding, prioritise actions, and support the greatest social and economic benefits and returns on investments that support improved health and quality of life for older people. given the diversity of cities, communities, and places, it is recognised that the achievement of all suggested indicators might not be feasible across all geographic settings. this is particularly relevant to rural and regional locales, which often have a lower population density and reduced levels of physical or social infrastructure. consultations with older people and combining subjective understandings with more objective afc spatial indicators will also help to inform the understanding of unique community contexts, including regional and remote areas. for example, high levels of walkability might not be possible across an entire town in a rural area with a small population. alternatively, signaled pedestrian crossings might not be necessary. however, a walkability assessment using the recommended walkability indicator could identify walking and transport barriers (e.g., a major road or bridge across a rail line) or identify the best location for new community services. alternatively, the distances and measures of accessibility listed within indicators may vary across diverse rural and regional settings, but as noted above, these definitions of access within indicators must be determined through consultation with the older adults and communities to a reach consensus on what can be reasonably expected within this locale. consequently, in certain settings, these proposed indicators should act as a tool to prompt place-specific discussions around what is important in terms of measurement indicators, and what is achievable (particularly in relation to what should constitute reasonable access). a notable challenge of afc planning is the absence of the relevant climate change implications in the current afc principles and domains and inclusion of ict and new technology. we recommend that future revision of afc should expand and account for the challenges associated with climate change given the implications on the health and wellbeing of older people [127] and the ultimate afc goal of healthy ageing. the relationship between older people's physical health and mental health with the environment, urban design, architecture, and afc could also be considered in the development of future indicators [128] . understanding and expanding afc spatial indicators for unique contexts and environments is needed in the future and this current foundation of recommended indicators can be applied and tested across a range of different locations. this could include localities with climatic extremes (e.g., heat, cold, and snow), regional and rural locations, international comparisons, and cultural differences to explore how communities differ and what additional indicators should be included. the major aim of this research was to propose a foundational set of objective afc spatial indicators that can be applied in any location with minimal resources and are directly aligned for policy intervention. this is particularly relevant to planning and policymakers working in government and was neither previously available nor consistently applied within afc locations. further research should investigate how this proposed suite of afc spatial indicators can be added to, refined, or customized to address the needs of many different locations, including the relevant subjective indicators to enhance knowledge. the inclusion of new technology and ict and addressing climate change are also increasing areas of interest in the future. environmental gerontology: making meaningful places in old age how healthy ageing can foster age-friendly environment? world health organisation. decade of healthy ageing 2020-2030; world health organisation the growth, ageing and urbanisation of our world world population prospects: the 2017 revision, key findings and advance tables; united nations, department of economics and social affairs world health organization. the global network for age-friendly cities and communities: looking back over the last decade, looking forward to the next; world health organization age-friendly cities and communities in international comparison: political lessons, scientific avenues, and democratic issues age-friendly communities: go big or go home age-friendly environments and life satisfaction among south korean elders: person-environment fit perspective review of assessment tools for baseline and follow-up measurement of age-friendliness overcoming barriers to livability for all ages: inclusivity is the key. urban plan a global pilot study of age-friendly city indicators world health organisation. measuring the age-friendliness of cities: a guide to using core indicators age-friendly communities evaluation guide: using indicators to measure progress; public health agency of canada ottawa developing indicators for evaluation of age-friendly communities in canada: process and results age-friendly cities: for whom? by whom? for what purpose? in age-friendly cities and communities in international comparison urban liveability: emerging lessons from australia for exploring the potential for indicators to measure the social determinants of health the development of policy-relevant transport indicators to monitor health behaviours and outcomes creating and applying public transport indicators to test pathways of behaviours and health through an urban transport framework developing indicators of public open space to promote health and wellbeing in communities examining associations between area-level spatial measures of housing with selected health and wellbeing behaviours and outcomes in an urban context conceptualising and measuring spatial indicators of employment through a liveability lens using spatial measures to test a conceptual model of social infrastructure that supports health and wellbeing indicators of a health-promoting local food environment: a conceptual framework to inform urban planning policy and practice concepts guiding the study of the impact of the built environment on physical activity for older adults: a review of the literature the built environment and human activity patterns: exploring the impacts of urban form on public health is it time to move beyond the limits of 'built environment' thinking? the conversation the average regional city resident lacks good access to two-thirds of community services, and liveability suffers. the conversation age and the environment: the global movement towards age-friendly cities and communities key characteristics of age-friendly cities and communities: a review is a healthy city also an age-friendly city? transforming out world: the 2030 agenda for sustainable development world health organization. the who age-friendly cities framework best practice principles for community indicator systems and a case study analysis: how community indicators victoria is creating impact and bridging policy, practice and research age-friendly cities and communities: access to services for older people developing a research and practice tool to measure walkability: a demonstration project transport walkability index: melbourne. mccaughey vichealth centre for community wellbeing examining associations between urban design attributes and transport mode choice for walking, cycling, public transport and private motor vehicle trips built environment correlates of walking: a review neighborhood-based differences in physical activity: an environment scale evaluation on behalf of the council on environment and physical activity (cepa)-older adults working group. the neighbourhood physical environment and active travel in older adults: a systematic review and meta-analysis physical activity-related health and economic benefits of building walkable neighbourhoods: a modelled comparison between brownfield and greenfield developments quality green space supporting health, wellbeing and biodiversity: a literature review where do they go and how do they get there? older adults' travel behaviour in a highly walkable environment the lifestyle interventions and independence for elders study: design and methods physical activity, including walking, and cognitive function in older women preference and relative importance for environmental attributes of neighbourhood open space in older people associations between neighborhood open space attributes and quality of life for older people in britain experiences of neighbourhood walkability among older australians living in high density inner-city areas walkability factsheet summary: assessing walkability in brighton, clarence and launceston for the local government association of tasmania inequitable walking conditions among older people: examining the interrelationship of neighbourhood socio-economic status and urban form using a comparative case study increasing independence for older people through good street design post-occupancy evaluation: an inevitable step toward sustainability blue space, health and well-being: a narrative overview and synthesis of potential benefits bluehealth: a study programme protocol for mapping and quantifying the potential benefits to public health and well-being from europe's blue spaces designing urban green blue infrastructure for mental health and elderly wellbeing urban blue space and health and wellbeing in hong kong: results from a survey of older adults coastal blue space and depression in older adults report prepared by the eklipse expert working group on nature-based solutions to promote climate resilience in urban areas the role of well-being in transport policy perspectives on active transportation in a mid-sized age-friendly city quantifying spatial gaps in public transport supply based on social needs importance of proximity to resources, social support, transportation and neighborhood security for mobility and social participation in older adults: results from a scoping study exploring frequency of public transport use among older adults: a study in adelaide public transport policy measures for improving elderly mobility ageing in place: the out-of-home travel patterns of seniors in victoria and its policy implications pioneering open data standards: the gtfs story evaluation of age-friendly guidelines for public buses poor housing quality: prevalence and health effects association between housing affordability and mental health: a longitudinal analysis of a nationally representative household survey in australia housing affordability and health among homeowners and renters beyond housing: perceptions of indirect displacement, displacement risk, and aging precarity as challenges to aging in place in gentrifying cities the quality of life of older people aging in place: a literature review housing affordability literature review and affordable housing program audit measuring ontario's increasing housing affordability problem senate select committee on housing affordability in australia. a good place is hard to find: housing affordability in australia housing tenure and the health of older australians dependent on the age pension for their income world health organisation. a conceptual framework for action on the social determinants of health: social determinants of health discussion paper 2; world health organisation the neighborhood social environment and physical activity: a systematic scoping review social ties and mental health types of social participation and psychological distress in japanese older adults: a five-year cohort study association of psychosocial risk factors with risk of acute myocardial infarction in 11 119 cases and 13 648 controls from 52 countries (the interheart study): case-control study social relationships and mortality risk: a meta-analytic review sense of community mediating between age-friendly characteristics and life satisfaction of community-dwelling older adults social networks, social integration, and social engagement determine cognitive decline in community-dwelling spanish older adults social networks and health in later life: a state of the literature. sociol. health illn engaging in my rural community": perceptions of people aged 85 years and over jo cox loneliness commission. combatting loneliness one conversation at a time: a call to action places and health: a qualitative study to explore how older women living alone perceive the social and physical dimensions of their neighbourhoods constructing and negotiating social participation in old age: experiences of older adults living in urban environments in the united kingdom the role and value of public libraries in the age of digital technologies building a global learning community of older people an international perspective on the university-of-the-3rd-age physical activity, body composition and general health status of physically active students of the university of the third age (u3a) bowling alone: the collapse and revival of american community building a new life in australia: an analysis of the first wave of the longitudinal study of humanitarian migrants in australia to assess the association between social integration and self-rated health race/ethnic and social-demographic correlates of religious non-involvement in america: findings from three national surveys social integration and religious identity expression among dutch muslims: the role of minority and majority group contact a review of social inclusion measures social exclusion and mental health: conceptual and methodological review social exclusion of older persons: a scoping review and conceptual framework how could differences in 'control over destiny' lead to socio-economic inequalities in health? a synthesis of theories and pathways in the living environment health inequalities among british civil servants: the whitehall ii study european strategies for tackling social inequities in health: levelling up part 2. studies on social and economic determinants of population health evolving patterns of work and retirement fifty-five years of research into older people's civic participation: recent trends, future directions productive aging and civic participation healthy ageing in australia's rural places: the contribution of older volunteers does place matter? reviewing the experience of disadvantage for older people in rural australia household use of information technology, australia information provision for an age-friendly community ageing in place in the united kingdom interpersonal communication in older adulthood intergenerational effects on the impacts of technology use in later life: insights from an international, multi-site study connecting at local level: exploring opportunities for future design of technology to support social connections in age-friendly communities effects of technology use on ageing in place: the izi pilots who doesn't think about technology when designing urban environments for older people? primary health care and older people the ideal neighbourhood for ageing in place as perceived by frail and non-frail community-dwelling older people oxford essential quotations lessons learned from the history of social indicators; redefining progress disappointments and legacies of social indicators climate change in an ageing world. helpage international knowledge synthesis for environmental decisions: an evaluation of existing methods, and guidance for their selection, use and development: a report from the eklipse project the authors declare no conflict of interest. key: cord-031494-uvxb0ak9 authors: lamming, dudley w.; carter, christy s. title: introduction: special issue on aging science talks: science for our community during isolation date: 2020-09-06 journal: transl med aging doi: 10.1016/j.tma.2020.09.001 sha: doc_id: 31494 cord_uid: uvxb0ak9 nan on the creation of aging science talks, the lessons learned, and their thoughts on how conferences may change going forward as a result. with the assistance of tma editors drs. matt kaeberlein and scott leiser, this special issue extends our coi further by giving a voice to some of those researchers, primarily but not exclusively ecrs, who took up our call and helped successfully launch the aging science talks coi through the presentation of their research during the early days of the pandemic shutdown. in order of presentation at "aging science talks": continue to join us, or join us for the first time: a schedule and links for all aging science talks are available at http://www.lamminglab.org/agingscitalks.html. this seminar series and this accompanying special issue describing the outcomes of this series have accomplished many things. first, we have created a forum for presenters, especially ecrs to highlight their work. we have created a forum for those presenters to publish their work, albeit in an extending abstract format to highlight their ongoing research. we have also highlighted the challenges of a pi and ecr in this time of covid and how the seminar influenced their perspectives. finally, we provide a way forward to maintain this community by still involving ecrs, considering the barrier of time zones, and appreciating time limitations of scientists returning to work during this pandemic. javier apfield presents "the heat shock transcription factor hsf-1 protects caenorhabditis elegans from peroxide stress mitochondrial hyperactivity as a potential therapeutic target in parkinson's disease goldberg discusses "integration of immune-metabolic signals to preserve healthy aging role of hematopoietic aging in cognitive decline dorota skowronska-krawczyk discusses "elovl2: not just a biomarker of aging high-throughput chromatin screens to identify targets of senescence and aging" [9] and reviews "the eroding chromatin landscape of aging stem cells extracellular vesicles and extracellular rna in references maintaining a scientific community while social distancing remote but not isolated improving trainee engagement in science: lessons from a virtual seminar series the heat shock transcription factor hsf-1 protects caenorhabditis elegans from peroxide stress mitochondrial hyperactivity as a potential therapeutic target in parkinson's disease integration of immune-metabolic signals to preserve healthy aging role of hematopoietic aging in cognitive decline not just a biomarker of aging high-throughput chromatin screens to identify targets of senescence and aging the eroding chromatin landscape of aging stem cells extracellular vesicles and extracellular rna in aging and age-related disease key: cord-280605-2i4gk7et authors: bachmann, maría consuelo; bellalta, sofía; basoalto, roque; gómez-valenzuela, fernán; jalil, yorschua; lépez, macarena; matamoros, anibal; von bernhardi, rommy title: the challenge by multiple environmental and biological factors induce inflammation in aging: their role in the promotion of chronic disease date: 2020-10-14 journal: front immunol doi: 10.3389/fimmu.2020.570083 sha: doc_id: 280605 cord_uid: 2i4gk7et the aging process is driven by multiple mechanisms that lead to changes in energy production, oxidative stress, homeostatic dysregulation and eventually to loss of functionality and increased disease susceptibility. most aged individuals develop chronic low-grade inflammation, which is an important risk factor for morbidity, physical and cognitive impairment, frailty, and death. at any age, chronic inflammatory diseases are major causes of morbimortality, affecting up to 5–8% of the population of industrialized countries. several environmental factors can play an important role for modifying the inflammatory state. genetics accounts for only a small fraction of chronic-inflammatory diseases, whereas environmental factors appear to participate, either with a causative or a promotional role in 50% to 75% of patients. several of those changes depend on epigenetic changes that will further modify the individual response to additional stimuli. the interaction between inflammation and the environment offers important insights on aging and health. these conditions, often depending on the individual’s sex, appear to lead to decreased longevity and physical and cognitive decline. in addition to biological factors, the environment is also involved in the generation of psychological and social context leading to stress. poor psychological environments and other sources of stress also result in increased inflammation. however, the mechanisms underlying the role of environmental and psychosocial factors and nutrition on the regulation of inflammation, and how the response elicited for those factors interact among them, are poorly understood. whereas certain deleterious environmental factors result in the generation of oxidative stress driven by an increased production of reactive oxygen and nitrogen species, endoplasmic reticulum stress, and inflammation, other factors, including nutrition (polyunsaturated fatty acids) and behavioral factors (exercise) confer protection against inflammation, oxidative and endoplasmic reticulum stress, and thus ameliorate their deleterious effect. here, we discuss processes and mechanisms of inflammation associated with environmental factors and behavior, their links to sex and gender, and their overall impact on aging. the inflammatory response is different in men and women. adult females develop stronger innate and adaptive immune responses than males. these sex-related differences can determine the ability of immune cells to generate an effective inflammatory response, which translates into epidemiological differences on the prevalence of various pathologies, including allergies (22), asthma (23, 24), autoimmune diseases (25), anaphylaxis (26), neonatal sepsis (27), and cancer (28), among several pathologies. the immune response of women is polarized towards an increased production of th2 cells, t regulatory cells (treg), m2 macrophages, il4, il10, and gata-3 cytokines, and decreased th1, th17, tbet, and rorgt lymphocytes (29-31). on the contrary, men show an immune response that depends on th1 lymphocytes (32, 33), high il33 production (34) and low levels of reactive mast cells (35) . men have also an increased response of microglia in the central nervous system (cns) and an increased presence of tnfa and prostaglandins in response to inflammatory stimuli (36). differences in inflammatory response between men and women vary among specific tissues. in the cns inflammation, women show greater levels of b-cell (cd19+, cd5+, cd1d hi b10) migration from the spleen to the site of injury than men, followed by an increase of macrophages/microglia (cd11b+, cd206), which appears to generate a lower neuroinflammatory response in female compared with male mice (37). in addition, women develop an increased immunoreactivity due to high numbers of ifn-producing dendritic cells (38, 39). female mice tend to have m2 phenotype and activated eosinophils and mast cells show a higher reactivity than in male mice (35, 40) . however, in response to an acute inflammatory stimulus, males produce higher amounts of inflammatory cytokines, cd8a+ neutrophil and t cells infiltration of the injury site (41). conversely, the inflammatory microenvironment in female mice is characterized by an increased production of antibodies (42, 43) and a differential pattern migration of antibody-secreting cells (42). the immune system responds differently in men and women not only because of the influence of sex hormones, but also differences in the patterns of autosomal methylation and x chromosome methylation, which determine distinctive profiles of gene expression (43, 44). sex hormones exert antagonist effects on the immune system: both estradiol and testosterone have a suppressive effect on the immune response (45). estrogen is the sex hormone with the greatest impact on the immune response, being described as one of the non-modifiable regulators of the immune system, due to its immunoregulatory and protective effects in many inflammatory models (46). however, this is contradictory with the fact that women have a higher prevalence of autoimmune diseases than men, although estrogens should be a protective condition (47). the sex-dependent difference in the immune response is time-, and estrogen dose-dependent (29). variations on the estrogen concentration during the ovulatory cycle, puberty or menopause, can promote the development of immune-related diseases (48). mice exposed to chronic estrogen-treatment generate hormone resistance, decreasing the clonal expansion of treg lymphocytes in autoimmune diseases (49, 50) . estrogen regulates immune response primarily through aand b-estrogen receptors (era/b), mitogen-activated protein kinase (mapk) pathways, estrogen-dependent 3′-5′-cyclic adenosine monophosphate (camp) response element-binding (creb), and modifications in the production of camp in immune cells (51). in addition to estrogen receptors, the presence of il receptors influences the type of immune response; female macrophages express greater amounts of il4 receptors than males. il4 receptors favor the m2 phenotype when stimulated by estrogen. in agreement with that, estrogen induces an increased expression of il4 on naive cd4+ t cells (40, 52) . for a better general view of estrogen´s mechanisms and effect on the innate immune system cells we recommend reviews that have extensively covered those topics (53-56). sex regulates gene expression in multiple human tissues, in fact, one third of the autosomal genes that are expressed in a sexbiased manner exhibit androgen or estrogen hormonal response elements (57, 58). sex hormones play a strong role in sexually dimorphic gene networks (59), inducing aberrant expression in immune response genes via differential methylation ccl18 cxcl5 il5 (60) . there are changes in the methylation pattern of sex-dependent immune response genes during embryonic development, which are reinforced in puberty by the estrogenmediated induction of active forms of chromatins that are maintained during adulthood (61) . immune response-related genes located in chromosomes 3 and x are differently expressed in b lymphocytes depending on the sex of the individual (62). among the differentially expressed genes that are relevant for the immune/inflammatory response, can be mentioned the toll-like signaling, cytokine receptors, jak-stat pathway and genes related to the activation of t-cell receptors (63) . phenotypically, the different pattern of gene expression may explain the greater female t-cell expandable capacity when exposed to an antigen (64) . female t cells present higher activation and division capacities than their male counterparts. however, male t cells can develop greater infiltration potential and a lower self-reactive phenotype than female ones (65, 66) . these differences could be due to the high expression of peroxisome proliferator-activated receptors (ppars) (64) , prostaglandins, and cyclooxygenase-2 (cox-2) in males (67) . the influence of sex on the immune response is observed throughout life and is accentuated with aging. in the neonatal stage, women have a lower concentration of regulatory t lymphocytes than men (68) . during childhood, men develop a more intense immune response and are more likely to develop infections by various pathogens compared with women (69, 70) . with increasing age, the dynamics and proportion of lymphocytes and myeloid cells differ depending on the sex due to the differential expression of 144 genes of the immune response in men and women (71) . also, in aged individuals, epigenomic changes generate a more robust innate and pro-inflammatory response in men and an increased activity in the adaptive immune response in women (72, 73) . in recent times, during the covid-19 pandemic, it has been observed that the infection by sars-cov-2 in older adults shows conspicuous differences; men have elevated plasma levels of il8 and il18 and a high amount of monocytes whereas women develop a robust activation of t lymphocytes (74) . this differences in the immune response could explain the higher mortality of covid19 in men than in women (75, 76) . to recapitulate, sex hormones and genetic expression patterns in men and women can generate distinct immune and inflammatory responses that determine singularities in the epidemiological distribution of immune diseases. research protocols in immune response and inflammation must be redefined to avoid results biased by sex. furthermore, research in women is urgently needed to define the efficacy for women of several therapies that were originally tested in men. the increase in noncommunicable diseases (ncds), such as obesity, hypertension and cancer as well as the low-grade chronic inflammation that characterizes most ncds (77) can be affected by environmental factors that change the immune response. lifestyle factors like nutrition can modulate the immune system. it has been reported in mice that western diet-induced systemic inflammation and reprogramming of myeloid cell precursors is mediated by the activation of the nlrp3 inflammasome, which is a key sensor of the innate immune system for metabolic danger signals, such as uric acid and cholesterol (78) . metabolic regulation appears to be very robust and long lasting, being reported that proper nutrition during pregnancy can reduce the risk for ncds in the offspring even at adult age (79, 80) . the impact of the diet on the immune response and inflammation some diet types can result in metabolic and epigenetic changes that affect immune function (81) , as reported in populations that consume a high-fat and low-fiber western diet, who show a prevalence of ncds higher than populations that consume a mediterranean diet or a diet based on bioactive compounds, like the hydroxytyrosol in olive oil (82) (83) (84) . there is evidence supporting the anti-inflammatory activity of phenolic extracts from olive oil, such as their ability to reduce lipopolysaccharide (lps)-stimulated nitric oxide (no) production by the raw-264.7 macrophage cell line. the hydroxytyrosol stearate and the hydroxytyrosol oleate decrease no production in a concentration-dependent manner (85) . in addition, olive oil extracts increase total plasma glutathione concentration (86) , increasing the antioxidative response of the individual. nordic diet has many similarities with the mediterranean diet, but its effects on low-grade chronic inflammation are less known. both diets include abundant fruits, vegetables, whole grain products, fish and vegetable oil, but restrict saturated fat and red and processed meats (87, 88) . observational (89, 90) and interventional (91, 92) studies report an inverse association between the adherence to nordic diet and the concentration of high sensitivity c-reactive protein (hscrp). single intervention studies reported beneficial effects, reducing il1 receptor a (il1ra) (87) and cathepsin s (93) , and downregulation of inflammatory mediators in the adipose tissue (94) and peripheral blood mononuclear cells (pbmcs) (95) . a key nutrient in fish are the n3 polyunsaturated fatty acids (pufas) (88) . the greenland inuit population, which has a high dietary intake of n3-pufas, have a lower incidence of myocardial infarction than the danish population (96) . numerous studies associate the cardioprotective effects of n-3 pufas to their effect on immunomodulation (97) (98) (99) , and control of inflammation, including neuroinflammation during aging (100) . the mechanism of the anti-inflammatory effects of n3-pufas n3-pufas can regulate the transcription and expression of inflammatory mediators such as cytokines, chemokines and adhesion molecules in cardiomyocytes, fibroblasts, endothelial cells, and monocyte-macrophages (101) (102) (103) (104) . anti-inflammatory effect of eicosapentaenoic acid (epa), docosahexaenoic acid (dha) and their biologically active metabolites (d and e resolvinsmediators derived from omega-3 fatty acids, primarily epa and dha that block the production of proinflammatory mediators and regulate leukocyte trafficking to inflammatory sites) can be mediated through one of the mechanisms capable of reducing inflammation of raw-264.7 cells and of primary intraperitoneal macrophages (105) . one of the mechanisms is the activation of g-protein coupled receptors (gpr), ea. gpr120 inhibition of toll-like receptor 4 (tlr4)-mediated inflammatory response, which blocks nfkb activation. the other is mediated by nuclear receptors, particularly ppars-a/g. dha binds to ppars with high affinity resulting in the activation of anti-inflammatory cascades (106) , which appears to be responsible for the beneficial health effects (97) . the inhibition of nfkb-mediated pro-inflammatory activity (107) is the common mechanism of immunomodulation by n3-pufas, being dha more effective than epa in reducing lps-n3-pufas induced inflammatory cytokine production by macrophages (108) . n3-pufas are incorporated into phospholipid bilayers and in human atherosclerotic plaques. their incorporation is associated with a reduction in the number of foam-and t cells, and a decrease in inflammation (109) . the increased incorporation of n3-pufas in membranes affects both the innate and adaptive immune responses, impairing the maturation of dendritic cells and the function of macrophages, as well as the polarization and activation of t and b cells (110) (111) (112) . it is well known that n3pufas compete with n6-pufas for being incorporated into cell membranes and for the active sites of cox-2 and lipoxygenase, resulting in the production of less potent pro-inflammatory or even anti-inflammatory mediators, such as the 3-series of prostaglandin and thromboxane (113) . resolvins reduce also neutrophil-derived ros production, favoring neutrophil apoptosis and clearance by macrophages, and inhibit chemokine signaling (114) . the partial agonist/antagonist activity of resolvin e1 (rve1) on the leukotriene b4 receptor on polymorphonuclear cells (pmns), inhibits nfkb activation, reduces release of pro-inflammatory cytokines and reduces infiltration by pmn (115) . moreover, rve1 reduces tnfa and ifng presence in the aortic wall, decreases the levels of the inflammatory marker crp and reduces macrophage infiltration of the intima. thus, rve1 attenuates atherosclerosis and atherosclerotic plaque formation (116) . aging is associated with the activation of inflammatory signaling pathways (117, 118) , which can be targeted by specific nutrients with anti-inflammatory effects, such as n3-pufas (119, 120) . in the brain, the main n3-pufa is dha, representing 12-14% of total fatty acids (121) . aging and neurological disorders are associated with decreased levels and turn-over rate of brain n3-pufas (122) (123) (124) (125) . in aged mice, n3-pufa supplementation and diets enriched in dha have been reported to revert age-induced spatial memory deficits and impairment on learning and memory (126) (127) (128) . in older adults, a low consumption of n3-pufas and decreased erythrocyte dha levels are associated with cognitive impairment (129, 130) . dietary supplementation with dha is positively correlated with an improvement in declarative memory test performance, improved cognitive function (131, 132) and a lower risk of developing neurological disorders (133) . the probable mechanisms by which n3-pufas mediate their effects in the resolution of age-related neuroinflammation are the increased synthesis of n3-pufa-derived rvd1 and decreased n6-pufaderived oxylipins, displaying an anti-inflammatory profile (134, 135) . to recapitulate, the evidence indicates that n3-pufas and their bioactive metabolites have immunomodulatory and antiinflammatory properties. potential cardioprotective lipid mediators, through multiple mechanisms, including changes in cell membranes composition, and modification of both cell signaling and gene expression, shift the pattern of lipid metabolites toward a more anti-inflammatory metabolite profile. dietary habits may be essential regulators of the inflammatory profile and promote healthy aging, reinforcing the recommendation of a n3-pufa rich diet. the long term chronic psychological stress is increasing among the world's population (136) . its circuit arises at high cortical centers through the limbic system to the hypothalamus, where corticotropin-releasing factor (crf) is produced, which is responsible for inducing the pituitary gland to liberate adrenocorticotropic hormone (acth) that signals the adrenal cortex to synthesize and secrete glucocorticoids (gcs) (137) . stress also activates the sympathetic nervous system (sns), particularly the adrenal medulla, activating chromaffin cells to produce epinephrine (epi), a main stress hormone along with gcs. the latter plays a key regulation feature inhibiting the hypothalamic-pituitary-adrenal (hpa) axis through negative feedback at the pituitary gland, hypothalamus, and medial prefrontal cortex, reducing crf secretion [rewieved in (138) ]. the interplay of social and environmental stressors induces inflammation through multiple biological mechanisms, including epigenetic factors (139) . studies in rats show that the methylation patterns of genes involved in the stress response, such as the glucocorticoid receptor (nr3c1) and crf, can be modified by psychosocial factors from early childhood (140) . similarly, early life adversity induces acute and long-lasting epigenetic modifications in nr3c1 genes, regulating hpa axis and cytokine production, reinforcing the importance of the activation inputs during critical periods of development (137, 141) . acute short-term emotional stress, such as speaking in public, leads to a transient increase in circulating inflammatory biomarkers and natural killer (nk) cells by the sns catecholaminergic activity (142) . on the contrary, chronic stress results in a reduction of cytotoxic nk activity, determining a poorer response to cytokines (143) . therefore, stress appears to have short term beneficial immune effects, whereas chronic stress in the absence of immune challenge has the opposite effect (138, 144) , activating constantly the hpa axis with the consequent persistent elevation of systemic gcs and reduction of nk cell responsiveness to cytokines (143) , affecting the balance of the t helper cell type 1/type 2 (th1/th2) cytokine networks, predisposing to a wide range of diseases (145) . the stress magnitude has been associated with il1b mrna overexpression in peripheral pbmcs, providing a molecular mechanism by which psychological stress is translated into an immune system response (146, 147) . when stress becomes chronic, such as in depression, there is a maintained overproduction of inflammatory cytokines, which have been associated with gcs resistance. immune cells become less sensitive to their anti-inflammatory effects because of their persistent secretion, leading to chronic low-grade inflammation (147, 148) . activation of the innate and adaptive immune system by chronic mild stressors increases inflammatory cytokines gene expression, maturation and trafficking of dendritic cells (dc), increased macrophage number and t cells recruitment and activation. social stressors can induce an increase in inflammatory responses and a state of gcs resistance at different levels (144, 149) . the acute repeated social defeat stress (rsds) and chronic restraint stress (crs) models induce an inflammatory response that results in neuroinflammation and depressive behavior (150) . stress activates the hpa axis and the sympatho-adrenomedullar (sam) axis causing neuroinflammation by circulating cytokines that crossed the blood-brain barrier (bbb) at the circumventricular organs and by cytokine bbb transporters. an inflammatory response that promotes bbb permeability, allowing more inflammatory factors entering the brain, including crf, metalloproteinase-9, il6, and tnfa (150) . additionally, microglia produce chemokines that attract monocytes into the brain (150) . activation of sns and hpa axis through continuous psychological stress dysregulate cytokine production, and together with the stress hormones corticosteroids and catecholamines, can affect endothelial adhesion molecules, causing endothelial damage (138) . corticosteroids could facilitate the infiltration of monocytes by increasing the expression of il1 and il6 receptors on endothelial cells. these monocytes and lymphocytes, after attaching to such sites, would commence the process of infiltration into the wall vessels, leading to foam cell formation and thrombotic events (138, 151) . chronic unpredictable mild stress (cums) decreases body mass and impairs the metabolism of carbohydrates and lipids. a model for cums showed an increased liver and pancreas protein-lipid peroxidation and protein oxidation (152) . high ros production in both organs could be a result of a response mechanism to stress at the cellular level. in the liver, protein oxidation can be due to the regulation of metabolic impairments by gcs and epi (152). the antioxidant system of the liver is in general more efficient than the pancreas. however, it is insufficient to clear the reactive species increased as consequence of chronic stress, which could be due to alterations in the antioxidant enzymatic activity (138) . altogether, stress appears to have short term beneficial effects on the immune function, whereas chronic stress (138, 144) activates persistently the hpa, elevating systemic gcs, and impairing the cytokine balance. the overproduction of inflammatory cytokines lead to gcs resistance driven by immune cells that lose their sensitivity to gcs, leading to a state of chronic low-grade inflammation (138, 145) . this gcs imbalance, shares common features with aging, mediating an enhanced neuroinflammatory priming (153) . the presence of psychological stress potentiates the defective immune response observed in aging, which at the same time conditionate an exaggerated sickness response to immune challenges (such as chronic stress). thus, chronic stress contributes to the phenomenon of inflammaging, which promotes the development of several age-related pathologies, including atherosclerosis and diabetes among others [reviewed in (154) ]. additionally, there is an impairment of the antioxidant defense system to manage ros production after chronic stress, resulting in the damage of various tissues (138) . in addition, people exposed to chronic stress age rapidly, showing a faster telomere shortening in their cells (155) (156) (157) . on the other hand, epigenetic changes acquired during critical developmental stages could shape chronic stress-response along the lifespan, either promoting or reducing pathological aging (139, 140) . substance abuse, such as alcohol and drugs, are important triggers of chronic inflammatory processes (158, 159) . the effects of alcohol on human health are complex and depend on multiple factors. however, many of those factors are associated with the generation of immunosuppression and increased morbimortality in heavy users. those effects, which have been previously reviewed by goral et al. (160) will not be discussed in this review. here, we will describe the effect of cocaine and methamphetamine abuse. both drugs are potent psychostimulants that, when repeatedly consumed, significantly disrupt the functioning of the cns, and modify the regulation of the immune response, leading to a chronic neuroinflammatory state (161) . in general, it is known that drug abuse, among other factors, increases nfkb transcription of multiple proinflammatory genes that spread across brain cell types further amplifying of nfkb transcription, as has been reviewed by crews et al. (162) . cocaine (benzoylmethylecgonine according to the international common denomination) is a strong stimulant tropane alkaloid that acts by modulating the catecholaminergic neurotransmitter dopamine. studies of the striatum of mice after the administration of various drugs showed that 1 h after administration of 25 mg/kg cocaine, there is a significant increase in gene arrays for hypoxia-inducible factor 1 (hif-1), transcription factors, and cytokine receptors (il6r, tnfa). two hours after cocaine administration, there is an increased gene expression for various tnf receptors, inducible no synthase (inos) and adhesion molecules (163) . in the nucleus accumbens of mice stimulated with cocaine, there is a significant increase in matrix metalloproteinase 28 (mmp28), macrophage colony stimulating factor (mcsf) and major histocompatibility complex ii (mhc-ii) (164) . the brain of human subjects consuming cocaine shows an increased density of macrophages and activated microglia (165) . cocaine induces the activation of microglia through the endoplasmic reticulum stress and autophagy pathways (166) . studies of human and rodent immune cell populations after cocaine administration show decreased numbers of t lymphocytes, modulation of nk activity and cytokine production (167) . among brain glial cells, astrocytes are the most abundant, and perform critical functions, being involved in neurogenesis, promotion of neuronal survival, elimination of free radicals, and the production of no to maintain neuronal homeostasis (166) . nevertheless, astrocytes can also be activated by toxic stimuli, leading to a new phenotype called "reactive astrocytes", similar with the changes observed after inflammatory activation. this phenomenon has been described in various neuropsychiatric disorders, such as alzheimer's and parkinson's disease, amyotrophic lateral sclerosis and multiple sclerosis (166) . the reactivity of astrocytes to toxic stimuli, such as cocaine, infection or disease, potentiates the neuroinflammatory process (168) . methamphetamine (desoxyephedrine; meth) is a synthetic adrenergic agonist with psychostimulatory effects, structurally related to the ephedrine alkaloid and adrenaline. studies on the effect of meth are limited. however, it has been determined that its abuse affects the immune response. animals exposed to both acute and chronic meth use show alkalization of normally acidic organelles in immune cells, inhibition of antigen presentation, and impairment of phagocytosis (169) . meth also generates mitochondrial oxidative damage, dysfunction of t lymphocytes and decreased production of antibodies and cytokines (159) . meth has effects in various tissues (170) . in the lungs, the number of t lymphocytes decreases compared with that of untreated animals, indicating a reduction in circulating cd3+ cells, and levels of il6 and il10 increases. in the spleen, recruitment of pmn and the number of ly-6g+ and f4/80+ are increased, whereas cd3+ cells are significantly reduced. in addition, levels of tnfa, ifng, il6, and il12 are higher than those of control mice. in the liver, there is an increase of t lymphocytes and macrophages, hepatocellular atrophy, and increased levels of ifng, tnfa, il1b, -4, -6, -10, and -12 in the group exposed to meth compared with control animals (170) . in the cns, meth can induce the activation of calpains and caspases; the production of ros with the subsequent induction of oxidative stress, and the release of high amounts of glutamate, causing excitotoxicity (171) . recently, raineri et al. reported that meth induces activation of astrocytes and microglia, increasing the levels of il6 and tnfa mrna and its receptor (tnfr1) in the mouse striatum and hippocampus (172, 173) . medical advances have resulted in the increment of the average life expectancy in developed countries. the aging of the population is associated with an increase in the number of older people using drugs of abuse. from 2000 to 2012, the number of cocaine users aged 55 or older that required treatment for drug addiction in the us increased by 63% (174, 175) . aging is associated with low-grade basal inflammation that can be compounded by substance use. as cocaine exposure is associated with elevated inflammation and altered immune functioning, the presence of cocaine use disorder might exacerbate inflammatory processes in aging adults (176) . a recent report by soder et al, compared the levels of inflammation (through the neutrophil to lymphocyte ratio) in older adults with cocaine use disorder (cud) and in healthy older adults, finding that the group with cud had a significantly higher baseline level of inflammation (176) . the use of illegal drugs such as cocaine or methamphetamine has not been shown to affect cognitive function in older adults at the clinical level. however, the evaluation of the cognitive function of young drug users reveals a decreased performance compared with healthy young people. in fact, the cognitive function of young drug users is similar to that of adults older than 60 years of age (174, 177, 178) . in summary, both cocaine and meth can directly impair the immune response, induce the activation of glial cells and stimulate the release of pro-inflammatory mediators in the cns. all those effects cause relevant changes in glial cell regulation and inflammatory activation, triggering chronic neuroinflammation and potentiating pathological aging. air pollution has become an important threat to public health. air pollutants consider a mixture of gases such as nitrogen oxides (nox), sulphur oxides (sox), tropospheric ozone (o3), volatile organic compounds (vocs), and particulate matter (pm) (179) . pm can enter the respiratory tract leading to severe in situ damage as well as inducing additional systemic effects (180) . the world health organization (who) suggests a maximum annual exposure of 10 μg/m³ of pm2.5, however, the exposure of 90% of the world's population exceeds the proposed limit (181) . exposure to air pollutants is associated with increased morbimortality associated with respiratory, cardiovascular, metabolic, neurological, carcinogenic and autoimmune diseases (17, (182) (183) (184) . inflammation is the main pathophysiological mechanism induced by air pollutants. in terms of the molecular and cellular mechanism induced by pollutants, pm and sox can generate ros, inducing oxidative stress, together with mitochondrial dysfunction and the consequent energy deprivation (185) (186) (187) . as a direct consequence, nfkb and mapk inflammatory pathways are activated, triggering an innate immune activation (188, 189) . despite the attempts to resolve the inflammatory event, the outcome appears to be an imbalance in lymphocyte homeostasis and immune system dysregulation, with inhibition of th1 and treg lymphocytes (190) . there is also an increase of th2 lymphocytes and recruitment of eosinophils, resulting in respiratory disorders such as asthma (186, 191, 192) . in parallel, pm deactivates the nuclear factor erythroid 2 pathway (nrf2), involved in antioxidant regulation and prevention of oxidative stress, a necessary process for the resolution of inflammation. therefore, to maintain oxidation-reduction reactions becomes impossible, becoming a breaking point towards increased ros production and the non-resolution of the inflammatory event (193) . another mechanism of action of pollutants is the activation of the aryl hydrocarbon receptor (ahr) by toxic agents. the binding of pm to ahr increases circulating th17 and decreases treg lymphocytes. increase in th17 associates to the release of il17, promoting an abrupt increase of th2 lymphocyte response. these changes promote the dysregulation of the immune response associated with the development of autoimmune processes (193) . aberrant increases in th17 may result in increased inflammation, with consequences such as asthma and acute respiratory failure syndrome (ards), due to neutrophil infiltration and tissue damage (194) . studies suggest the existence of a decline in treg levels and, therefore, an inability to suppress th1, th2 and phagocyte responses (195, 196) . in addition, exposure to pm has been associated with fibrotic events, where il17 increases synthesis and secretion of collagen in the lung parenchyma (197, 198) . in addition, it has been described that pm also induces the expression of tgfb, directly promoting fibroblast differentiation, which could also induce collagen deposition followed by a lower antifibrotic process in the liver (199) . pollutants may promote direct dna damage through oxidation of nitrogenous bases. hu and yu described in a 2019 paper different mechanisms and changes in mirna expression that comprise specific targets of dna methyltransferases, which can impair the methylation of tumor suppressor genes (200) . furthermore, urban populations show increased levels of mitochondrial methylation genes due to pm exposure (201) . there is evidence of the existence of methylation, acetylation and phosphorylation of histones h3 and h4, markers found in genes involved in the activation of immune cells and cardiovascular diseases (200, (202) (203) (204) (205) . altogether, air pollutants can generate dna adducts promoting carcinogenesis and deteriorate telomerase activity, as reviewed by martens and nawrot (2016) , and contributing to continuous dna damage and premature aging (206, 207) . in vivo studies suggest that the inflammatory activation is doseand time-dependent. mice exposed to pm show that both variables are determinant for the outcome. however, inflammatory effects and major genetic changes appear to be especially dependent on the exposure to high concentrations of pm. one possible explanation is that a prolonged exposure could induce an adaptive response of the inflammatory activation (208) , which may be mediated by the inactivation of the nrf2 pathway, generating a loss of antioxidant capacity and deregulation of the immune system (193) . the resolution appears to depend on the exposure context. acute exposure would result in high levels of ros and damage, whereas prolonged stimulation, even a low-grade one, generates a constant production of ros and chronic low-grade inflammation (187) , consequent with the potentiation of disease risk and an epigenetic age acceleration (206) , promoting pathological aging. direct causes of the deregulation of the inflammatory resolution process resulting from inhaled contaminants are still unknown, however, the burden of associated chronic diseases is expected to increase. it is mandatory to intensify environmental policies specifically in lower-middle-income countries in prevention of the development of inflammatory conditions and the subsequent chronic diseases. aging, characterized by a progressive loss of cellular functions, is an inevitable physiologic process inherent to all living beings (209) . the number of older adults is increasing. during the next 30 years, up to 22% of the world population will be older than 60 years (210) . this demographic change is accompanied by a higher incidence of ncds accumulated in the aging population (211) . therefore, various strategies have been proposed to improve the health and quality of life of older adults (212), along with recommendations for the development of public policies that support the fiscal expenditure resulting from ncds (213) . one of the most studied events of aging is the impairment of the immune system, characterized by an aberrant-increased activation of the innate immunity (214, 215) , and high levels of circulatory inflammatory mediators that establish an inflammatory environment, and a decrease of the adaptive immune response (216, 217) and a decrease of the adaptive immune response (214) due to this low-grade chronic inflammation (214, 218) , which together would promote the inflammaging phenomenon (219) . interestingly, it is proposed that age would not be the cause per se of these diseases associated with aging (214) . thus, there is a deterioration of the immune system's response to external stimuli, which depends on the individual's history (218) . also, several epigenetic mechanisms can modulate the immune response in aging, enhancing changes in intercellular communication that could perpetuate inflammatory events (220) . on the other hand, it is described that epigenetic clocks would be useful to analyze mechanisms associated with this environmental influence (221) . finally, they would be capable of modulating the immune response in aging, enhancing changes in intercellular communication that could perpetuate inflammatory events (220). multiple age-dependent changes play important roles in the promotion of ncds, with increased oxidative stress standing out as one of the main mechanisms. over the last two decades, evidence has revealed that increased oxidative stress and inflammation are involved in various ncds such as alzheimer's disease (219) , rheumatoid arthritis (222) , cardiovascular diseases (223, 224) , and cancer (225), among others. also, recent studies propose that the activation of nfkb signaling pathways could be the main driver of these associations (226) (227) (228) (229) . interestingly, de almeida et al. showed different sources of low-grade chronic inflammation that promote cardiovascular disease (226) . in the cns, high levels of ros lead to the activation of astrocytes and microglia, further increasing the overproduction of ros and proinflammatory cytokines that promote the development of neurodegenerative changes (217, 230, 231) . in fact, several systemic biomarkers appear to be associated with neuroinflammation and the development of cns diseases associated with aging (230) . these modifications trigger the phenotype of senescent or aged cells characterized as sasp (216, 232) extensively studied in the context of the deleterious effects of aging. however, sasp is also essential for remodeling and promoting wound healing, which requires a strict control of the inflammatory response, thus avoiding the induction of cell aging phenotypes that contribute to the development of chronic inflammatory diseases (233) . the immune imbalance in aging occurs due to various alterations in cellular behavior and phenotype, which cause functional deficiencies in immune cells (3) . for example, this context induces polarization of macrophages towards an inflammatory phenotype characterized by strong activation of the inflammasome (234) . thus, these events could induce il1b and tnfa release, changes in the chemoattraction of neutrophils mediated by the reduction of the intercellular adhesion molecule 1 (icam-1) expression, and the aberrant activation of the phosphoinositide lipid kinase-3 (pi3k) (235) . also, there is a decrease in the expression of pattern recognition receptors (prr), which leads to the activation of proinflammatory signaling promoting tissue damage (215, 216) . finally, the reduced level of certain hormones due to the impaired hypothalamic function causes the loss of muscle mass and an increase in adipose tissue, further contributing to the release of inflammatory cytokines and changes in metabolism (236) . despite the remarkable effort being made to understand the basis of the processes underlying the inflammatory imbalance during aging, it is not fully understood. in aging, there are cumulative epigenetic changes that promote low-grade inflammation (220, 237) , including a decrease in the global genome methylation, with increased methylation in specific regions, as those with repressive histone marks of cd8+ and cd4+ t cells (238) and bivalent chromatin domains (239) and histone acetylation and methylation. however, the influence of genomic methylation during aging remains undetermined (237) . several studies correlate the methylation of multiple sites on cpg islands with the increase of the low-grade inflammation marker, crp (220, 232, 240) . nonetheless, stevenson et al. propose that the dna methylation could be better associated with the low-grade chronic inflammation than crp (237) . in addition, the age-related mitochondrial dysfunction, with the resulting oxidative stress and decreased atp production (241) , affect the expression and activity of dna methyltransferases, which are responsible for maintaining the methylation pattern of dna (242) . the reduced methylation results in the demethylation of the tnfa promoter in leukocytes and macrophages (243) and the adhesion of immune cells to the endothelium (244) . also, many epigenetic events contribute to the differentiation of proinflammatory t cells, th17 (220) , which can compromise immunocompetence, associated with repression of differentiation of immune cells, loss of treg function (240) and the alteration of the hematopoietic stem cells differentiation (245) . thus, epigenetic mechanisms appear to have a major role in the inflammatory imbalance, which are associated with the accumulation of damage in time that ultimately leads to the perpetuation of a constant inflammatory response. according to the who, 60% of the world population is sedentary, lacking the benefits of physical exercise (246) . conditions such as sedentarism, unhealthy diet, overweight, obesity and aging induce chronic low-grade inflammation. physical exercise increases the anti-inflammatory potential and reduces the pro-inflammatory effect (247) . this equilibrium is partly modulated through tlrs (248) , which are fundamental for the recognition of prrs, including the damage-associated molecular patterns (damps) and the induction of an inflammatory response in the absence of pathogens. there is evidence that in young people, physical exercise decreases tlrs expression, co-stimulatory molecules cd80/ cd86, and mhcii (248, 249) in cd14+ monocytes. physical exercise also affects the adipose tissue. exercising reduces tlr4 mrna expression and tnfa production in adipocytes (250, 251) in obese mice. chronic physical exercise decreases tnfa and tlr4 gene expression in the skeletal muscle (252) . the evidence suggests that obesity-or cerebral ischemiainduced neuroinflammation, which are associated with the overexpression of tlr2 and tlr4, may be reduced by physical exercise through the reduction of tlrs expression as well as their downstream signaling molecules (tnfa, il1b, myd88, traf6, 552 tak1, and nfkb), together with the reduced microglial activation (253, 254) . there is evidence that cigarette smoking induces inflammatory status [reviewed in (255) ]. however, exercise training reduces smoke-induced inflammation. in that sense, training for 30 min with endurance exercise for 5 days in smoke-exposed mice demonstrated that therapeutic exercise training significantly reduces the expression of il1b and tnfa mrna in rectus femoris (256) . physical exercise has been used as a therapeutic tool in chronic pathological conditions. in that sense, obese older adults (body mass index 38 ± 2 kg/m2; 69 ± 1 years) undergoing an exercise program consisting in physical therapy, endurance, and resistance for 90 min, 3 days per week, show a reduced expression of tlr4, il6, and tnfa mrna in skeletal muscle (257) . in older adults, 8-week physical exercise reduces the expression of tlr4 and tlr2, as well as tlrs downstream mediators, such as myd88, p65, pp38, trif, ikki/ikkϵ, irf3, and pirf7 in pbmcs (258) . similarly, dendritic cells from multiple sclerosis patients undergoing an exercise (endurance and resistance) program for 12 weeks reduce tnfa and mmp9 secretion when stimulated with a tlr4 ligand (lps in combination with ifng, or a tlr7 ligand) (259) , suggesting that long-term physical exercise decrease tlr responsiveness. on the other hand, high-intensity physical exercise in untrained individuals induces inflammation, resulting in the increased expression of tlr4, ap1, nfkb, and p65 in mice myocardium and in adipose tissue (260) (261) (262) . physical exercise associated with eccentric contractions causes expression of tlr and nfkb in skeletal muscle and liver in rats (263, 264) . furthermore, this phenomenon induces muscle damage, which can increase chemotaxis, attracting nk, cd8+ 559 t cells, macrophages and neutrophils to the site of injury, promoting the production of cox560 2, inos, monocyte chemotactic protein-1 (mcp-1), tnfa, il6, and il1b, in addition to the production of ros and the activation of nfkb (265, 266) . in healthy young males, one session of intense endurance exercise (1 h intense cycling immediately followed by 1 h intense running), increases plasmatic concentrations of il6 and il10, in addition to increased gene expression of proinflammatory il1 receptor (il1r) and tlr signaling pathways. moreover, plasma myoglobin changes in correlation with neutrophil tlr4 gene expression (r= 0.74), suggesting that their transcriptional activity was particularly induced by damps (267) . therefore, inflammation and muscle damage are mainly associated with the type and intensity of the exercise, with loads that exceed individual physical abilities. chronic physical exercise generates epigenetic modifications. the physical exercise associated with an energy expenditure >500 kilocalories per week, results in hypomethylation of the il10 gene and hypermethylation of the tnfa gene (268) , with an inverse correlation between tnfa methylation and tnfa mrna expression (269) . the methylation of the caspase recruitment domain (asc) of the apoptosis-associated specklike protein gene, the main regulator of inflammasome and promoter of the activation of il1b and il18, decreases with aging. however, older adults who maintain physical exercises regularly express higher levels of asc methylation than subjects not exercising, which would imply a decreased release of inflammatory cytokines (270) (271) (272) (273) . similarly, in review a 6-month walk training can induce hypermethylation of the nfkb-2 gene, suppressing inflammation through the inhibition of the nfkb pathway (274) . as life expectancy increases, age-related diseases thrive. aging is a complex multifactorial process of molecular and cellular decline that renders individuals susceptible to disease and death. maintenance of cell integrity, cell metabolism and host-defense mechanisms are tightly regulated by the surrounding microenvironment. a growing body of evidence in different biological models has contributed towards identifying biological mechanisms that ward off structural and functional deterioration. these data offer us insights into healthy aging. molecular integrity of the genome, telomere length, epigenetic stability, and protein homeostasis are all features linked to more youthful stages (regardless of the age), associated with mitochondrial fitness, metabolic regulation, efficient intercellular communication, stem cell renewal, and regenerative capacity in tissues. a good understanding of the environmental and endogenous mechanisms that underlie agerelated normal and deleterious changes, and how these pathways interconnect, remains a major challenge for slowing pathological aging while extending older adults' healthy lifespan. the study of the environmental influence on the development of complex-chronic diseases shows that in addition to genetic predisposition, the pathogenesis is promoted by changes in metabolism and behavior, cellular environment, and epigenetic regulation patterns. the type of nutrient, or environmental cytokine milieu dramatically affects not only the homoeostasis of tissues but also of complete organs and even of the whole individual. thus, tissue stress, malfunction, and damage may induce inflammation alarm responses, which result either in resolution of tissue damage, restoration of normal cell function or development of chronic disease ( figure 1 ). older adults often present inflammaging, characterized by increased levels of proinflammatory cytokines il1, il6, il8, tnfa/crp (275) . however, the cellular sources of these cytokines are partially unknown. the increased inflammatory cytokines have been proposed to be a driver of unsuccessful aging (increased morbidity, degenerative processes, or frailty) and shortened health-span. the inflammatory scenario is complex and occurs in response to various internal and environmental stimuli ( figure 1 ) mediated mainly by a high level of proinflammatory cytokines. indeed, in healthy aging, increased production of the anti-inflammatory cytokines tgfb and il10, can regulate the pro-inflammatory state (276, 277) . research into the impact of environmental factors on inflammaging is at an early stage and the involved mechanisms are not completely understood. several hypotheses have been developed to explain the chronic inflammation: aging-related increase of stress (278) and oxidative stress (279) , dna damage in senescent cells [reviewed in (280) ], and stem cell aging (281) . the proposed mechanisms are likely interdependent, resulting in the generation of ros causing oxidative damage and amplification of the cytokines secretion, thus perpetuating a vicious circle of systemic inflammation where tissue injury and healing mechanisms proceed in parallel while damage slowly accumulates over the lifespan of the individuals. endocrine and metabolic alterations are linked to the shift towards a pro-inflammatory profile, which could explain some age-related pathologies, such as alzheimer's and parkinson's disease, osteoporosis, diabetes, cancer, and frailty (282, 283) . regarding stress-induced immune modifications, new evidence suggests that cross talk signals between the cns, endocrine and immune system are required for optimal response to stress [discussed in (284) ]. various stressors can affect the activity and regulation of immune cells via direct regulation by the autonomic and peptidergic system or through the release of neuroendocrine mediators. moreover, neuronal catecholamines modulate immune cell functions. these interactions are bidirectional, cytokines produced by immune cells, such as il1, can modulate the production of corticotropin-releasing hormone (crh) by the hypothalamus. chronic diseases are favored by some modern living conditions, such as the intake of high-caloric foods and the low level of physical activity, or endogenous signals produced by the chronic stress of modern life. there are many challenges in conducting research on biosocial processes, which will define novel disease-trigger factors. tailor-made approaches will depend on genetics, epigenetics and a constellation of factors depending on the historical as well as the present exposure to the environment. although environmental factors also express themselves as epigenetic changes, the combinatorial effect of the multiple factors generates complex patterns of epigenetic regulation, and the concomitant exposure to environmental factors can further modify the individual response. all authors contributed equally on the conception of the work, the analysis of literature and preparing the content of the review. rbe drafted and organized the manuscript. all authors contributed to the article and approved the submitted version. endogenous and environmental factors can be mostly beneficial (in green) and deleterious (in red) or can have both beneficial and deleterious effects depending on the specific context. the interplay of lifespan endogenous and environmental factors regulates the aging phenotype depending on dna damage, epigenetic changes, and inflammation. these drivers can induce functional aging hallmarks: changes in endocrine and metabolic regulation, and defective immune regulation that will further determine the response of the individual. in yellow we show processes that can participate in both protection and damage. exposure to various alarm signals induce an acute inflammation that, when associated with deleterious environmental and biological factors, potentiates chronic inflammation, which can be further promoted by excess ros production and oxidative stress that results from mitochondrial dysfunction or nox2 activity, leading to inflammaging and eventually to age-related disease. on the contrary, in the presence of protective environmental and biological factors, the initial inflammatory activation will be resolved and lead to a healthy aging process. ros, reactive oxygen species. sarcopenic obesity and inflammation in the inchianti study physiological aging: links among adipose tissue dysfunction, diabetes, and frailty immunosenescence: the potential role of myeloid − derived suppressor cells ( mdsc ) in age − related immune deficiency the hallmarks of aging circulating c1q complement/tnf-related protein (ctrp) 1, ctrp9, ctrp12 and ctrp13 concentrations in type 2 diabetes mellitus: in vivo regulation by glucose aging, inflammation and the environment both genetic and dietary factors underlie individual differences in dna damage levels and dna repair capacity pro12ala polymorphism of the pparg2 gene interacts with a mediterranean diet to prevent telomere shortening in the predimed-navarra randomized trial micrornas linking inflamm-aging, cellular senescence and cancer metabolic control of longevity immunobiography and the heterogeneity of immune responses in the elderly: a focus on inflammaging and trained immunity epidemiology of parkinson disease mitochondrial dysfunction and longevity in animals: untangling the knot. sci cardiac oxidative stress in diabetes: mechanisms and therapeutic potential nadph oxidase and mitochondria are relevant sources of superoxide anion in the oxinflammatory response of macrophages exposed to airborne particulate matter evaluation of oxidative damage and nrf2 activation by combined pollution exposure in lung epithelial cells emerging role of air pollution in autoimmune diseases inhibitory cross-talk upon introduction of a new metabolic pathway into an existing metabolic network child development and the physical environment psychological stress in childhood and susceptibility to the chronic diseases of aging: moving towards a model ofbehavioral and biological mechanisms sex steroidinduced dna methylation changes and inflammation response in prostate cancer integrative analysis of methylome and transcriptome in human blood identifies extensive sex-and immune cell-specific differentially methylated regions gender differences of b cell signature related to estrogen-induced ifi44l/baff in systemic lupus erythematosus gender differences of b cell signature in healthy subjects underlie disparities in incidence and course of sle related to estrogen peroxisome proliferator-activated receptor (ppar)alpha expression in t cells mediates gender differences in development of t cell-mediated autoimmunity sex-specific t-cell regulation of angiotensin ii-dependent hypertension. hypertens (dallas tex 1979 peroxisome proliferator-activated receptor (ppar)alpha and -gamma regulate ifngamma and il-17a production by human t cells in a sexspecific way sex differences in prostaglandin biosynthesis in neutrophils during acute inflammation sex disparity in cord blood foxp3+ cd4 t regulatory cells in infants exposed to malaria in utero sex differences in pediatric infectious diseases correlation between female sex, il28b genotype, and the clinical severity of bronchiolitis in pediatric patients sex differences in the blood transcriptome identify robust changes in immune cell proportions with aging and influenza infection sexual-dimorphism in human immune system aging sex differences in older adults' immune responses to seasonal influenza vaccination sex differences in immune responses that underlie covid-19 disease outcomes gender differences in patients with covid-19: focus on severity and mortality sex-specific clinical characteristics and prognosis of coronavirus disease-19 infection in wuhan, china: a retrospective study of 168 severe patients noncommunicable diseases country profiles western diet triggers nlrp3-dependent innate immune reprogramming the next innovation cycle in toxicogenomics: environmental epigenetics transgenerational effects of maternal diet on metabolic and reproductive ageing nutrition and epigenetics: an interplay of dietary methyl donors, one-carbon metabolism and dna methylation population differences in associations between c-reactive protein concentration and adiposity: comparison of young adults in the philippines and the united states diet and the epigenome effects of olive oil and its minor components on cardiovascular diseases, inflammation, and gut microbiota identification of hydroxytyrosyl oleate, a derivative of hydroxytyrosol with anti-inflammatory properties, in olive oil by-products olive phenolics increase glutathione levels in healthy volunteers effects of an isocaloric healthy nordic diet on insulin sensitivity, lipid profile and inflammation markers in metabolic syndrome -a randomized study (sysdiet) what is a healthy nordic diet? foods and nutrients in the nordiet study associations of the baltic sea diet with cardiometabolic risk factors-a meta-analysis of three finnish studies associations of the baltic sea diet with obesity-related markers of inflammation health effect of the new nordic diet in adults with increased waist circumference: a 6-mo randomized controlled trial a diet high in fatty fish, bilberries and wholegrain products improves markers of endothelial function and inflammation in individuals with impaired glucose metabolism in a randomised controlled trial: the sysdimet study influence of a prudent diet on circulating cathepsin s in humans healthy nordic diet downregulates the expression of genes involved in inflammation in subcutaneous adipose tissue in individuals with features of the metabolic syndrome healthy nordic diet modulates the expression of genes related to mitochondrial function and immune response in peripheral blood mononuclear cells from subjects with metabolic syndrome-a sysdiet sub-study eicosapentaenoic acid and prevention of thrombosis and atherosclerosis? marine omega-3 fatty acids and inflammatory processes: effects, mechanisms and clinical relevance omega-3 fatty acids and inflammatory processes: from molecules to man cardioprotective mechanism of omega-3 polyunsaturated fatty acids neuro-immune dysfunction during brain aging: new insights in microglial cell regulation n-3 polyunsaturated fatty acids (pufa) modulate the expression of functionally associated molecules on human monocytes polyunsaturated fatty acids inhibit the antigenpresenting function of human monocytes effects of omega-3-rich harp seal oil on the production of pro-inflammatory cytokines in mouse peritoneal macrophages dietary fish oil diminishes lymphocyte adhesion to macrophage and endothelial cell monolayers gpr120 is an omega-3 fatty acid receptor mediating potent anti-inflammatory and insulin-sensitizing effects human dendritic cell activities are modulated by the omega-3 fatty acid, docosahexaenoic acid, mainly through pparg:rxr heterodimers: comparison with other polyunsaturated fatty acids eicosapentaenoic acid prevents lps-induced tnf-a expression by preventing nf-kb activation docosahexaenoic acid induces an anti-inflammatory profile in lipopolysaccharide-stimulated human thp-1 macrophages more effectively than eicosapentaenoic acid eicosapentaenoic acid (epa) from highly concentrated n-3 fatty acid ethyl esters is incorporated into advanced atherosclerotic plaques and higher plaque epa is associated with decreased plaque inflammation and increased stability docosahexaenoic acid prevents dendritic cell maturation, inhibits antigen-specific th1/th17 differentiation and suppresses experimental autoimmune encephalomyelitis regulatory activity of polyunsaturated fatty acids in t-cell signaling n-3 pufa improves fatty acid composition, prevents palmitate-induced apoptosis, and differentially modifies b cell cytokine secretion in vitro and ex vivo effects of exogenous arachidonic, eicosapentaenoic, and docosahexaenoic acids on the generation of 5-lipoxygenase pathway products by ionophore-activated human neutrophils resolvin e1 and protectin d1 activate inflammation-resolution programmes resolvin e1 selectively interacts with leukotriene b 4 receptor blt1 and chemr23 to regulate inflammation resolvin e1 (rve1) attenuates atherosclerotic plaque formation in diet and inflammation-induced atherogenesis human cns immune senescence and neurodegeneration microglial senescence: does the brain's immune system have an expiration date? ageassociated changes in the content and fatty acid composition of brain glycerophospholipids the aging human orbitofrontal cortex: decreasing polyunsaturated fatty acid composition and associated increases in lipogenic gene expression and stearoyl-coa desaturase activity modulation of brain pufa content in different experimental models of mice dha-enriched phospholipid diets modulate age-related alterations in rat hippocampus docosahexaenoic acid-induced changes in phospholipids in cortex of young and aged rats: a lipidomic analysis from inflammation to sickness and depression: when the immune system subjugates the brain fatty acid composition of brain phospholipids in aging and in alzheimer's disease chronic administration of docosahexaenoic acid improves the performance of radial arm maze task in aged rats docosahexaenoic acid-rich phospholipid supplementation: effect on behavior, learning ability, and retinal function in control and n-3 polyunsaturated fatty acid deficient old mice dha improves cognition and prevents dysfunction of entorhinal cortex neurons in 3xtg-ad mice association between mediterranean diet and late-life cognition red blood cell omega-3 fatty acid levels and markers of accelerated brain aging dietary intake of eicosapentaenoic and docosahexaenoic acids is linked to gray matter volume and cognitive function in elderly cognitive aging, childhood intelligence, and the use of food supplements: possible involvement of n-3 fatty acids elevated levels of proinflammatory oxylipins in older subjects are normalized by flaxseed consumption dietary n-3 long chain pufa supplementation promotes a pro-resolving oxylipin profile in the brain systematic review of the association between chronic social stress and telomere length: a life course perspective the developmental origins of chronic physical aggression: biological pathways triggered by early life adversity psychological stress, immune response, and atherosclerosis the epigenome at the crossroad between social factors, inflammation, and osteoporosis risk epigenetic programming by maternal behavior the role of dna methylation in stress-related psychiatric disorders selective mobilization of cytotoxic leukocytes by epinephrine immune dysregulation and chronic stress among older adults: a review chronic stress and age-related increases in the proinflammatory cytokine il-6 depression, mood, stress, and th1/th2 immune balance in primary breast cancer patients undergoing classical massage therapy nuclear factor-kb is a critical mediator of stress-impaired neurogenesis and depressive behavior social signal transduction theory of depression inflammation as a psychophysiological biomarker in chronic psychosocial stress repeated social defeat activates dendritic cells and enhances toll-like receptor dependent cytokine secretion neuroinflammation caused by mental stress: the effect of chronic restraint stress and acute repeated social defeat stress in mice anger emotional stress influences vegf/vegfr2 and its induced pi3k/akt/mtor signaling pathway chronic unpredictable mild stress generates oxidative stress and systemic inflammation in rats stress and aging act through common mechanisms to elicit neuroinflammatory priming the link between chronic stress and accelerated aging psychological wellbeing and healthy aging: focus on telomeres toward a deeper understanding of a triad of early aging tired telomeres: poor global sleep quality, perceived stress, and telomere length in immune cell subsets in obese men and women alcohol and epigenetic changes: summary of the 2011 alcohol and immunology research interest group (airig) meeting methamphetamine decreases cd4 t cell frequency and alters proinflammatory cytokine production in a model of drug abuse exposure-dependent effects of ethanol on the innate immune system cocaine induced inflammatory response in human neuronal progenitor cells induction of innate immune genes in brain create the neurobiology of addiction the dissection of transcriptional modules regulated by various drugs of abuse in the mouse striatum histone deacetylase 5 epigenetically controls behavioral adaptations to chronic emotional stimuli decreased brain dopamine cell numbers in human cocaine users cocaine induces astrocytosis through er stress-mediated activation of autophagy immune system inflammation in cocaine dependent individuals: implications for medications development psychostimulant abuse and neuroinflammation: emerging evidence of their interconnection methamphetamine and its immune-modulating effects methamphetamine administration modifies leukocyte proliferation and cytokine production in murine tissues causes and consequences of methamphetamine and mdma toxicity modafinil abrogates methamphetamine-induced neuroinflammation and apoptotic effects in the mouse striatum methamphetamine-induced neuroinflammation and neuronal dysfunction in the mice hippocampus: preventive effect of indomethacin trends in substance use admissions among older adults elevated neutrophil to lymphocyte ratio in older adults with cocaine use disorder as a marker of chronic inflammation age-and sex-dependent effects of methamphetamine on cognitive flexibility and 5-ht2c receptor localization in the orbitofrontal cortex of sprague-dawley rats crack-cocaine dependence and aging: effects on working memory air pollution prevention and control policy in china air pollution and allergy: you are what you breathe air pollution associated epigenetic modifications: transgenerational inheritance and underlying molecular mechanisms biomarkers of the health outcomes associated with ambient particulate matter exposure the effects of exposure to air pollution on the development of uterine fibroids role of oxidative damage in toxicity of particulate mechanisms of heightened airway sensitivity and responses to inhaled so2 in asthmatics exposure scenario: another important factor determining the toxic effects of pm2.5 and possible mechanisms involved in vitro toxicity of particulate matter (pm) collected at different sites in the netherlands is associated with pm composition, size fraction and oxidative potential -the raptes project exposure to ultrafine particulate matter induces nf-kb mediated epigenetic modifications diesel exhaust particle exposure in vitro impacts t lymphocyte phenotype and function acute nitrogen dioxide (no2) exposure enhances airway inflammation via modulating th1/th2 differentiation and activating jak-stat pathway diesel exhausts particles: their role in increasing the incidence of asthma. reviewing the evidence of a causal link air pollution-derived pm2.5 impairs mitochondrial function in healthy and chronic obstructive pulmonary diseased human bronchial epithelial cells acute respiratory distress syndrome effects of pm2.5 exposure on the notch signaling pathway and immune imbalance in chronic obstructive pulmonary disease the impact on tregulatory cell related immune responses in rural women exposed to polycyclic aromatic hydrocarbons (pahs) in household air pollution in gansu, china: a pilot investigation pm 2.5 induced pulmonary fibrosis in vivo and in vitro blocking il-17a promotes the resolution of pulmonary inflammation and fibrosis via tgf-b1-dependent and -independent mechanisms effects of sub-chronic exposure to atmospheric pm2.5 on fibrosis, inflammation, endoplasmic reticulum stress and apoptosis in the livers of rats genetic and epigenetic alterations in normal and sensitive copd-diseased human bronchial epithelial cells repeatedly exposed to air pollution-derived effects of airborne pollutants on mitochondrial dna methylation prenatal particulate air pollution and dna methylation in newborns: an epigenomewide meta-analysis dose-and time-effect responses of dna methylation and histone h3k9 acetylation changes induced by traffic-related air pollution air pollution and dna methylation: effects of exposure in humans epigenetic response profiles into environmental epigenotoxicant screening and health risk assessment: a critical review air pollution, particulate matter composition and methylation-based biologic age air pollution stress and the aging phenotype: the telomere connection the effect of exposure time and concentration of airborne pm2.5 on lung injury in mice: a transcriptome analysis facing up to the global challenges of ageing coming of age: molecular drivers of aging and therapeutic opportunities find the latest version: review series introduction coming of age: molecular drivers of aging and therapeutic opportunities disability incidence and functional decline among older adults with major chronic diseases quality of life assessment instruments for adults: a systematic review of population-based studies comparative financing analysis and political economy of noncommunicable diseases the integration of inflammaging in age-related diseases scavenger receptor-a deficiency impairs immune response of microglia and astrocytes potentiating alzheimer's disease pathophysiology source of chronic inflammation in aging microglial cell dysregulation in brain aging and neurodegeneration aging and the immune system: an overview cellular senescence and alzheimer disease: the egg and the chicken scenario the epigenetics of inflammaging: the contribution of age-related heterochromatin loss and locus-specific remodelling and the modulation by environmental stimuli wandering along the epigenetic timeline myeloperoxidase as an active disease biomarker: recent biochemical and pathological perspectives the role of signaling pathways of inflammation and oxidative stress in development of senescence and aging phenotypes in cardiovascular disease oxidative stress and advanced lipoxidation and glycation end products (ales and ages) in aging and age-related diseases how the ageing microenvironment influences tumour progression unveiling the role of inflammation and oxidative stress on age-related cardiovascular diseases nf-kb-mediated neuroinflammation in parkinson's disease and potential therapeutic effect of polyphenols epigenetic upregulation of fkbp5 by aging and stress contributes to nf-kbdriven inflammation and cardiovascular risk nf-kb signaling in astrocytes modulates brain inflammation and neuronal injury following sequential exposure to manganese and mptp during development and aging neuroinflammation in frontotemporal dementia immunosenescence in aging: between immune cells depletion and cytokines up-regulation back to the future: epigenetic clock plasticity towards healthy aging immunity and inflammation: from jekyll to hyde update of inflammasome activation in microglia/macrophage in aging and aging-related disease aging of the immune system: focus on inflammation and vaccination inflammaging: a new immune-metabolic viewpoint for age-related diseases characterisation of an inflammation-related epigenetic score and its association with cognitive ability agerelated profiling of dna methylation in cd8+ t cells reveals changes in immune response and transcriptional regulator genes human aging-associated dna hypermethylation occurs preferentially at bivalent chromatin domains abnormal epigenetic regulation of immune system during aging do you remember mitochondria? mitochondrial turnover and aging of long-lived postmitotic cells: the mitochondriallysosomal axis theory of aging agerelated loss of cpg methylation in the tumour necrosis factor promoter dysregulation of c-x-c motif ligand 10 during aging and association with cognitive performance understanding intrinsic hematopoietic stem cell aging world health organization's global strategy on diet, physical activity and health: the process behind the scenes interleukin-10 responses from acute exercise in healthy subjects: a systematic review the physiological regulation of toll-like receptor expression and function in humans the influence of prolonged cycling on monocyte toll-like receptor 2 and 4 expression in healthy men exercise training inhibits inflammation in adipose tissue via both suppression of macrophage infiltration and acceleration of phenotypic switching from m1 to m2 macrophages in high-fat-diet-induced obese mice the anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease chronic low frequency/low volume resistance training reduces pro-inflammatory cytokine protein levels and tlr4 mrna in rat skeletal muscle exercise therapy downregulates the overexpression of tlr4, tlr2, myd88 and nf-kb after cerebral ischemia in rats neuroprotective effects of endurance exercise against high-fat diet-induced hippocampal neuroinflammation ten hacken nht. acute effects of cigarette smoke on inflammation and oxidative stress: a review exercise training reverses inflammation and muscle wasting after tobacco smoke exposure exercise but not dietinduced weight loss decreases skeletal muscle inflammatory gene expression in frail obese elderly persons role of toll-like receptor 2 and 4 signaling pathways on the inflammatory response to resistance training in elderly subjects 12 weeks of combined endurance and resistance training reduces innate markers of inflammation in a randomized controlled clinical trial in patients with multiple sclerosis efecto del ejercicio agudo sobre la expresioń del receptor tipo toll-4 y los mecanismos inflamatorios en corazoń de rata acute exercise activates myocardial nuclear factor kappa b exhaustive exercise increases inflammatory response via toll like receptor-4 and nf-kbp65 pathway in rat adipose tissue diclofenac pretreatment effects on the toll-like receptor 4/nuclear factor kappa b-mediated inflammatory response to eccentric exercise in rat liver diclofenac pretreatment modulates exercise-induced inflammation in skeletal muscle of rats through the tlr4/nf-kb pathway exercise-induced increase in serum inferleukin-6 in humans is related to muscle damage honokiol protects rats against eccentric exercise-induced skeletal muscle damage by inhibiting nf-kb induced oxidative stress and inflammation transcriptome analysis of neutrophils after endurance exercise reveals novel signaling mechanisms in the immune response to physiological stress exercise and inflammation-related epigenetic modifications: focus on dna methylation impact of aerobic exercise and fatty acid supplementation on global and genespecific dna methylation role of physical exercise in the regulation of epigenetic mechanisms in inflammation, cancer, neurodegenerative diseases, and aging process epigenetic regulation on gene expression induced by physical exercise regulatory molecules involved in inflammasome formation with special reference to a key mediator protein exercise effects on methylation of asc gene nfkb2 gene as a novel candidate that epigenetically responds to interval walking training inflammaging and anti-inflammaging: a systemic perspective on aging and longevity emerged from studies in humans role of tgf b signaling in the pathogenesis of alzheimer's disease age-dependent changes in the activation and regulation of microglia stress responses and innate immunity: aging as a contributory factor oxidative stress, inflamm-aging and immunosenescence dna damage response (ddr) and senescence: shuttled inflamma-mirnas on the stage of inflamm-aging emerging models and paradigms for stem cell ageing from inflamm-aging to immune-paralysis: a slippery slope during aging for immune-adaptation aging and parkinson's disease: inflammaging, neuroinflammation and biological remodeling as key factors in pathogenesis impact of stress on aged immune system compartments: overview from fundamental to clinical data the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © 2020 bachmann, bellalta, basoalto, goḿez-valenzuela, jalil, lépez, matamoros and von bernhardi. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord-254339-djmibi3a authors: griette, quentin; magal, pierre; seydi, ousmane title: unreported cases for age dependent covid-19 outbreak in japan date: 2020-06-17 journal: biology (basel) doi: 10.3390/biology9060132 sha: doc_id: 254339 cord_uid: djmibi3a we investigate the age structured data for the covid-19 outbreak in japan. we consider a mathematical model for the epidemic with unreported infectious patient with and without age structure. in particular, we build a new mathematical model and a new computational method to fit the data by using age classes dependent exponential growth at the early stage of the epidemic. this allows to take into account differences in the response of patients to the disease according to their age. this model also allows for a heterogeneous response of the population to the social distancing measures taken by the local government. we fit this model to the observed data and obtain a snapshot of the effective transmissions occurring inside the population at different times, which indicates where and among whom the disease propagates after the start of public mitigation measures. covid-19 disease caused by the severe acute respiratory syndrome coronavirus (sars-cov-2) first appeared in wuhan, china, and the first cases were notified to who on 31 december 2019 [1, 2] . beginning in wuhan as an epidemic, it then spread very quickly and was characterized a pandemic on 11 march 2020 [1] . symptoms of this disease include fever, shortness of breath, cough, and a non-negligible proportion of infected individuals may develop severe forms of the symptoms leading to their transfer to intensive care units and, in some cases, death, see e.g., guan et al. [3] and wei et al. [4] . both symptomatic and asymptomatic individuals can be infectious [4] [5] [6] , which makes the control of the disease particularly challenging. the virus is characterized by its rapid progression among individuals, most often exponential in the first phase, but also a marked heterogeneity in populations and geographic areas [7] [8] [9] . the number of reported cases worldwide exceeded 3 millions as of 3 may 2020 [10] . the heterogeneity of the number of cases and the severity according to the age groups, especially for children and elderly people, aroused the interest of several researchers [11] [12] [13] [14] [15] . indeed, several studies have shown that the severity of the disease increases with the age and co-morbidity of hospitalized patients (see e.g., to et al. [15] and zhou et al. [8] ). wu et al. [16] have shown that the risk of developing symptoms increases by 4% per year in adults aged between 30 and 60 years old while davies et al. [17] found that there is a strong correlation between chronological age and the likelihood of developing symptoms. since completely asymptomatic individuals can also be contagious, a higher probability of developing symptoms does not necessarily imply greater infectiousness: zou et al. [6] found that, in some cases, the viral load in asymptomatic patients was similar to that in symptomatic patients. moreover while adults are more likely to develop symptoms, jones et al. [18] found that the viral loads in infected children do not differ significantly from those of adults. these findings suggest that a study of the dynamics of inter-generational spread is fundamental to better understand the spread of the coronavirus and most importantly to efficiently fight the covid-19 pandemic. to this end the distribution of contacts between age groups in society (work, school, home, and other locations) is an important factor to take into account when modeling the spread of the epidemic. to account for these facts, some mathematical models have been developed [13, 14, 17, 19, 20] . in ayoub et al. [19] the authors studied the dependence of the covid-19 epidemic on the demographic structures in several countries but did not focus on the contacts distribution of the populations. in [13, 14, 17, 20] a focus on the social contact patterns with respect to the chronological age has been made by using the contact matrices provided in prem et al. [21] . while ayoub et al. [19] , chikina and pegden [20] and davies et al. [17] included the example of japan in their study, their approach is significantly different from ours. indeed, ayoub et al. [19] use a complex mathematical model to discuss the influence of the age structure on the infection in a variety of countries, mostly through the basic reproduction number r 0 . they use parameter values from the literature and from another study of the same group of authors [22] , where the parameter identification is done by a nonlinear least-square minimization. chikina and pegden [20] use an age-structured model to investigate age-targeted mitigation strategies. they rely on parameter values from the literature and do discuss using age-structured temporal series to fit their model. finally, davies et al. [17] also discuss age-related effects in the control of the covid epidemic, and use statistical inference to fit an age-structured sir variant to data; the model is then used to discuss the efficiency of different control strategies. we provide a new, explicit computational solution for the parameter identification of an age-structured model. the model is based on the siur model developed in liu et al. [23] , which accounts for a differentiated infectiousness for reported and unreported cases (contrary to, for instance, other sir-type models). in particular, our method is significantly different from nonlinear least-squares minimization and does not involve statistical inference. in this article we focus on an epidemic model with unreported infectious symptomatic patients (i.e., with mild or no symptoms). our goal is to investigate the age structured data of the covid-19 outbreak in japan. in section 2 we present the age structured data and in section 3 the mathematical models (with and without age structure). one of the difficulties in fitting the model to the data is that the growth rate of the epidemic is different in each age class, which lead us to adapt our early method presented in liu et al. [23] . the new method is presented in the appendix a. in section 4 we present the comparison of the model with the data. in the last section we discuss our results. patient data in japan have been made public since the early stages of the epidemic with the quarantine of the diamond princess in the haven of yokohama. we used data from the website covid19japan.com (https://covid19japan.com. accessed 6 may 2020) which is based on reports from national and regional authorities. patients are labeled "confirmed" when tested positive to covid-19 by pcr. interestingly, the age class of the patient is provided for 13,660 out of 13,970 confirmed patients (97.8% of the confirmed population) as of 29 april. the age distribution of the infected population is represented in figure 1 compared to the total population per age class (data from the statistics bureau of japan estimate for 1 october 2019). in figure 2 we plot the number of reported cases per 10,000 people of the same age class (i.e., the number of infected patients divided by the population of the age class times 10,000). both datasets are given in table 1 and a statistical summary is provided by table 2 . note that the high proportion of 20-60 years old confirmed patients may indicate that the severity of the disease is lower for those age classes than for older patients, and therefore the disease transmits more easily in those age classes because of a higher number of asymptomatic individuals. elderly infected individuals might transmit less because they are identified more easily. the cumulative number of death ( figure 3 ) is another argument in favor of this explanation. we also reconstructed the time evolution of the reported cases in figures 4 and 5 . note that the steepest curves precisely concern the 20-60-year old, probably because they are economically active and therefore have a high contact rate with the population. figure 1 . in this figure we plot in blue bars the age distribution of the japanese population for 10,000 people and we plot in orange bars the age distribution of the number of reported cases of sars-cov-2 for 10,000 patient on 29 april (based on the total of 13,660 reported cases). we observe that 77% of the confirmed patients belong to the 20-60 years age class. the model consists of the following system of ordinary differential equations: (1) this system is supplemented by initial data here t ≥ t 0 is time in days, t 0 is the starting date of the epidemic in the model, s(t) is the number of individuals susceptible to infection at time t, i(t) is the number of asymptomatic infectious individuals at time t, r(t) is the number of reported symptomatic infectious individuals at time t, and u(t) is the number of unreported symptomatic infectious individuals at time t. a flow chart of the model is presented in figure 6 . asymptomatic infectious individuals i(t) are infectious for an average period of 1/ν days. reported symptomatic individuals r(t) are infectious for an average period of 1/η days, as are unreported symptomatic individuals u(t). we assume that reported symptomatic infectious individuals r(t) are reported and isolated immediately, and cause no further infections. the asymptomatic individuals i(t) can also be viewed as having a low-level symptomatic state. all infections are acquired from either i(t) or u(t) individuals. a summary of the parameters involved in the model is presented in table 3 . our study begins in the second phase of the epidemics, i.e., after the pathogen has succeeded in surviving in the population. during this second phase τ(t) ≡ τ 0 is constant. when strong government measures such as isolation, quarantine, and public closings are implemented, the third phase begins. the actual effects of these measures are complex, and we use a time-dependent decreasing transmission rate τ(t) to incorporate these effects. the formula for τ(t) is the date d is the first day of public intervention and µ characterises the intensity of the public intervention. a similar model has been used to describe the epidemics in mainland china, south korea, italy, and other countries, and give reasonable trajectories for the evolution of the epidemic based on actual data [23, [25] [26] [27] [28] [29] . compared with these models, we added a scaling with respect to the total population size n, for consistency with the age-structured model (12) . this only changes the value of the parameter τ and does not impact the qualitative or quantitative behavior of the model. table 3 . parameters of the model. interpretation method t 0 time at which the epidemic started fitted s 0 number of susceptible at time t 0 fixed i 0 number of asymptomatic infectious at time t 0 fitted u 0 number of unreported symptomatic infectious at time t 0 fitted τ(t) transmission rate at time t fitted d first day of public intervention fitted µ intensity of the public intervention fitted 1/ν average time during which asymptomatic infectious are asymptomatic fixed f fraction of asymptomatic infectious that become reported symptomatic infectious fixed ν 1 = f ν rate at which asymptomatic infectious become reported symptomatic fixed rate at which asymptomatic infectious become unreported symptomatic fixed 1/η average time symptomatic infectious have symptoms fixed at the early stages of the epidemic, the infectious components of the model i(t), u(t) and r(t) must be exponentially growing. therefore, we can assume that the cumulative number of reported symptomatic infectious cases at time t, denoted by cr(t), is since i(t) is an exponential function and cr(t 0 ) = 0 it is natural to assume that cr(t) has the following special form: as in our early articles [23, [26] [27] [28] [29] , we fix χ 3 = 1 and we evaluate the parameters χ 1 and χ 2 by using an exponential fit to we use only early data for this part, from day t = d 1 until day t = d 2 , because we want to catch the exponential growth of the early epidemic and avoid the influence of saturation arising at later stages. once χ 1 , χ 2 , χ 3 are known, we can compute the starting time of the epidemic t 0 from (5) as : we fix s 0 = 126.8 × 10 6 , which corresponds to the total population of japan. the quantities i 0 , r 0 , and u 0 correspond to the values taken by i(t), r(t) and u(t) at t = t 0 (and in particular r 0 should not be confused with the basic reproduction number r 0 ). we fix the fraction f of symptomatic infectious cases that are reported. we assume that between 80% and 100% of infectious cases are reported. thus, f varies between 0.8 and 1. we assume that the average time during which the patients are asymptomatic infectious 1/ν varies between 1 day and 7 days. we assume that the average time during which a patient is symptomatic infectious 1/η varies between 1 day and 7 days. in other words we fix the parameters f , ν, η. since f and ν are known, we can compute computing further (see below for more details), we should have and by using the approach described in diekmann et al. [30] , van den driessche and watmough [31] , the basic reproductive number for model (1) is given by by using (8) we obtain in what follows we will denote n 1 , . . . , n 10 the number of individuals respectively for the age classes [0, 10[, . . . , [90, 100[. the model for the number of susceptible individuals s 1 (t), . . . , s 10 (t), respectively for the age classes [0, 10[, . . . , [90, 100[, is the following the model for the number of asymptomatic infectious individuals i 1 (t), . . . , i 10 (t), respectively for the age classes [0, 10[, . . . , [90, 100[, is the following . . . i 10 (t) = τ 10 s 10 (t) φ 10,1 (i 1 (t) + u 1 (t)) n 1 + . . . + φ 10,10 (i 10 (t) + u 10 (t)) n 10 − νi 10 (t). the model for the number of reported symptomatic infectious individuals r 1 (t), . . . , r 10 (t), respectively for the age classes [0, 10[, . . . , [90, 100[, is finally the model for the number of unreported symptomatic infectious individuals u 1 (t), . . . , u 10 (t), respectively in the age classes [0, 10[, . . . , [90, 100[, is the following in each age class [0, 10[, . . . , [90, 100[ we assume that there is a fraction f 1 , . . . , f 10 of asymptomatic infectious individual who become reported symptomatic infectious (i.e., with severe symptoms) and a fraction (1 − f 1 ), . . . , (1 − f 10 ) who become unreported symptomatic infectious (i.e., with mild symptoms). therefore we define in their survey, prem and co-authors [21] present a way to reconstruct contact matrices from existing data and provide such contact matrices for a number of countries including japan. based on the data provided by prem et al. [21] for japan we construct the contact probability matrix φ. more precisely, we inferred contact data for the missing age classes [80, 90[ and [90, 100[. the precise method used to construct the contact matrix γ is detailed in appendix b. an analogous contact matrix for japan has been proposed by munasinghe, asai and nishiura [32] . the contact matrix γ we used is the following where the ith line of the matrix γ ij is the average number of contact made by an individuals in the age class i with an individual in the age class j during one day. notice that the higher number of contacts are achieved within the same age class. the matrix of conditional probability φ of contact between age classes is given by (18) and we plot a visual representation of this matrix in figure 7 . . graphical representation of the contact matrix φ. the intensity of blue in the cell (i, j) indicates the conditional probability that, given a contact between an individual of age group i and another individual, the latter belongs to the age class j. the matrix was reconstructed from the data of prem et al. [21] , with the method described in appendix b. the daily number of reported cases from the model can be obtained by computing the solution of the following equation: in figures 8 and 9 we employ the method presented previously in liu et al. [29] to fit the data for japan without age structure. the model to compute the cumulative number of death from the reported individuals is the following where η d is the death rate of reported infectious symptomatic individuals and p is the case fatality rate (namely the fraction of death per reported infectious individuals). in the simulation we chose 1/η d = 6 days and the case fatality rate p = 0.286 is computed by using the cumulative number of confirmed cases and the cumulative number of deaths (as of 29 april) as follows p = cumulative number of deaths cumulative number of reported cases = 393 13744 . in figure 10 we plot the cumulative number of d(t) by using the same simulations than in figures 8 and 9 . figure 8 . cumulative number of cases. we plot the cumulative data (reds dots) and the best fits of the model cr(t) (black curve) and cu(t) (green curve). we fix f = 0.8, 1/η = 7 days and 1/ν = 7 and we apply the method described in liu et al. [29] . the best fit is d 1 = 2 april, d 2 = 5 april, d = 27 april, µ = 0.6, χ 1 = 179, χ 2 = 0.085, χ 3 = 1 and t 0 = 13 january. figure 9 . daily number of cases. we plot the daily data (black dots) with dr(t) (blue curve). we fix f = 0.8, 1/η = 7 days and 1/ν = 7 and we apply the method described in liu et al. [29] . the best fit is d 1 = 2 april, d 2 = 5 april, n = 27 april, µ = 0.6, χ 1 = 179, χ 2 = 0.085, χ 3 = 1 and t 0 = 13 january. in order to describe the confinement for the age structured model (12)-(15) we will use for each age class i = 1, . . . , 10 a different transmission rate having the following form the date d i is the first day of public intervention for the age class i and µ i is the intensity of the public intervention for each age class. in figure 11 we plot the cumulative number of reported cases as given by our model (12)-(15) (solid lines), compared with reported cases data (black dots). we used the method described in the appendix a to estimate the parameters τ i from the data. in figure 12 we plot the cumulative number of unreported cases (solid lines) as given by our model with the same parameter values, compared to the existing data of reported cases (black dots). figure 11 . we plot a comparison between the model (12)-(15) and the age structured data from japan by age class. we took 1/ν = 1/η = 7 days for each age class. our best fit is obtained for f i which depends linearly on the age class until it reaches 90%, with in order to understand the role of transmission network between age groups in this epidemic, we plot in figure 13 the transmission matrices computed at different times. the transmission matrix is the following where the matrix φ describes contacts and is given in (18) , and the transmission rates are the ones fitted to the data as in figure 11 τ during the early stages of the epidemic, the transmission seems to be evenly distributed among age classes, with a little bias towards younger age classes (figure 13a ). younger age classes seem to react more quickly to social distancing policies than older classes, therefore their transmission rate drops rapidly (figure 13b,c) ; one month after the start of social distancing measures, the transmission mostly occurs within elderly classes (60-100 years, figure 13d ). the recent covid-19 pandemic has lead many local governments to enforce drastic control measures in an effort to stop its progression. those control measures were often taken in a state of emergency and without any real visibility concerning the later development of the epidemics, to prevent the collapse of the health systems under the pressure of severe cases. mathematical models can precisely help see more clearly what could be the future of the pandemic provided that the particularities of the pathogen under consideration are correctly identified. in the case of covid-19, one of the features of the pathogen which makes it particularly dangerous is the existence of a high contingent of unidentified infectious individuals who spread the disease without notice. this makes non-intensive containment strategies such as quarantine and contact-tracing relatively inefficient but also renders predictions by mathematical models particularly challenging. early attempts to reconstruct the epidemics by using siur models were performed in liu et al. [23, [26] [27] [28] , who used them to fit the behavior of the epidemics in many countries, by including undetected cases into the mathematical model. here we extend our modeling effort by adding the time series of deaths into the equation. in section 4 we present an additional fit of the number of disease-induced deaths coming from symptomatic (reported) individuals (see figure 10 ). in order to fit properly the data, we were forced to reduce the length of stay in the r-compartment to 6 days (on average), meaning that death induced by the disease should occur on average faster than recovery. a shorter period between infection and death (compared to remission) has also been observed, for instance, by verity et al. [7] . the major improvement in this article is to combine our early siur model with chronological age. early results using age structured sir models were obtained by kucharski et al. [33] but no unreported individuals were considered and no comparison with age-structured data were performed. indeed in this article we provide a new method to fit the data and the model. the method extends our previous method for the siur model without age (see appendix a). the data presented in section 2 suggests that the chronological age plays a very important role in the expression of the symptoms. the largest part of the reported patients are between 20 and 60 years old (see figure 1 ), while the largest part of the deceased are between 60 and 90 years old (see figure 3 ). this suggests that the symptoms associated with covid-19 infection are more severe in elderly patients, which has been reported in the literature several times (see e.g., lu et al. [12] , zhou et al. [8] ). in particular, the probability of being asymptomatic (our parameter f ) should in fact depend on the age class. indeed, the best match for our model (see figure 11 ) was obtained under the assumption that the proportion of symptomatic individual among the infected increases with the age of the patient. this linear dependency of f as a function of age is consistent with the observations of wu et al. [16] that the severity of the symptoms increase linearly with age. as a consequence, unreported cases are a majority for young age classes (for age classes less than 50 years) and become a minority for older age classes (more than 50 years), see figure 12 . moreover, our model reveals the fact that the policies used by the government to reduce contacts between individuals have strongly heterogeneous effects depending on the age classes. plotting the transmission matrix at different times (see figure 13 ) shows that younger age classes react more quickly and more efficiently than older classes. this may be due to the fact that the number of contacts in a typical day is higher among younger individuals. as a consequence, we predict that one month after the effective start of public measures, the new transmissions will almost exclusively occur in elderly classes. the observation that younger ages classes play a major roles in the transmission of the disease has been highlighted several times in the literature, see e.g., davies et al. [17] , cao et al. [11] , kucharski et al. [33] for the covid-19 epidemic, but also mossong et al. [34] in a more general context. we develop a new model for age-structured epidemic and provided a new and efficient method to identify the parameters of this model based on observed data. our method differs significantly from the existing nonlinear least-squares and statistical inference methods and we believe that it produces high-quality results. moreover, we only use the initial phase of the epidemic for the identification of the epidemiological parameters, which shows that the model itself is consistent with the observed phenomenon and argues against overfitting. yet our study could be improved in several direction. we only use reported cases which were confirmed by pcr tests, and therefore the number of tests performed could introduce a bias in the observed data -and therefore our results. we are currently working on an integration of this number of tests in our model. we use a phenomenological model to describe the response of the population in terms of number of contacts to the mitigation measures imposed by the government. this could probably be described more precisely by investigating the mitigation strategies in terms of social network. nevertheless we believe that our study offers a precise and robust mathematical method which adds to the existing literature. we first choose two days d 1 and d 2 between which each cumulative age group grows like an exponential. by fitting the cumulative age classes [0, 10[, [10, 20[, . . . and [90, 100[ between d 1 and d 2 , for each age class j = 1, . . . 10 we can find χ j 1 and χ we choose a starting time t 0 ≤ d 1 and we fix and we obtain where χ i j ≥ 0, ∀i = 1, . . . , n, ∀j = 1, 2, 3. figure a1 . we plot an exponential fit for each age classes using the data from japan. we assume that cr 1 (t) = ν 1 1 i 1 (t), . . . where therefore we obtain i j (t) = i j e χ j 2 t (a3) where by assuming that the number of susceptible individuals remains constant we have . . . and if we assume that the u j (t) have the following form then by substituting in (a5) we obtain the cumulative number of unreported cases cu j (t) is computed as and we used the following initial condition: we define the error between the data and the model as follows . . . ε n (t) = i n (t) − τ n s n φ n1 i 1 (t) + u 1 (t) n 1 + . . . + φ nn i n (t) + u n (t) n n + νi n (t), or equivalently . . . ε n (t) = (χ n 2 + ν) i n e χ n 2 t − τ n s n φ n1 let the matrix φ be fixed. we look for the vector τ = (τ 1 , . . . , τ n ) which minimizes of min τ∈r n ∑ j=1,...,n define for each j = 1, . . . , n and h j (t) := s j φ j1 i 1 + u 1 n 1 e χ 1 2 t + . . . + φ jn i n + u n n n e χ n 2 t , the survey [21] presents reconstructed contact matrices for a number of countries including japan for the 5-year age classes [0, 5), [5, 10) , ..., [75, 80) at various locations (work, school, home, and other locations) and a compilation of those contact matrices to account for all locations. the precise description of the compilation is presented in the paper. note that this paper is a follow-up of mossong et al. [34] where the survey procedure is described (including the data collection protocol) for several european countries participating in the polymod study. the data is publicly available online (prem et al. [21] , supporting dataset, doi: https://doi.org/ 10.1371/journal.pcbi.1005697.s002) and is presented in the form of a zipped collection of spreadsheets, containing the data for several countries in columns x1 x2 ... x16. the columns stand for the average number of contact of one individual of the corresponding age class (0-5 years for x1, 5-10 years for x2, etc...), with an individual of the age class indicated by the row (first row is 0-5 years, second is 5-10 years etc...). since the age span covered by the study stops at 80, we had to infer the number of contacts for people over the age of 80. we postulated that most people aged 80 or more are retired and that their behaviour does not significantly differs from the behavior of people in the age class [75, 80). therefore we completed the missing columns by copying the last available information and shifting it to the bottom. we repeated the procedure for lines. we believe that the introduced bias is kept to a minimum since the numerical values are relatively low compared to the diagonal. because we use 10-year ages classes and the data is given in 5-year age classes, we had to combine adjacent columns to recover the average number of contacts. to combine columns together, we used the weighted average c i = n 2(i−1)+1 c 2(i−1)+1 + n 2(i−1)+2 c 2(i−1)+2 n 2(i−1)+1 + n 2(i−1)+2 , where the column c i corresponds to the average number of contacts of an individual taken at random in the [10(i − 1), 10i) and c i is the average number of contacts of an individual taken at random in the age class [5(i − 1), 5i). to combine two lines, we simply use the sum of the data l i = l 2(i−1)+1 + l 2(i−1)+2 . the matrix γ in (17) is the transpose of the array obtained by the former procedure applied to the "all locations" dataset. then φ is obtained by scaling the lines of γ to 1, i.e., who timeline-covid-19 world health organization. pneumonia of unknown cause-china. disease outbreak news clinical characteristics of coronavirus disease 2019 in china presymptomatic transmission of sars-cov-2-singapore transmission of 2019-ncov infection from an asymptomatic contact in germany sars-cov-2 viral load in upper respiratory specimens of infected patients clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study report of the who-china joint mission on coronavirus disease 2019 (covid-19). 2020. available online world health organization sars-cov-2 infection in children: transmission dynamics and clinical characteristics sars-cov-2 infection in children the effect of control strategies to reduce social mixing on outcomes of the covid-19 epidemic in wuhan, china: a modelling study age-structured impact of social distancing on the covid-19 epidemic in india temporal profiles of viral load in posterior oropharyngeal saliva samples and serum antibody responses during infection by sars-cov-2: an observational cohort study estimating clinical severity of covid-19 from the transmission dynamics in wuhan, china cmmid covid-19 working group. age-dependent effects in the transmission and control of covid-19 epidemics an analysis of sars-cov-2 viral load by patient age age could be driving variable sars-cov-2 epidemic trajectories worldwide modeling strict age-targeted mitigation strategies for covid-19 projecting social contact matrices in 152 countries using contact surveys and demographic data characterizing key attributes of the epidemiology of covid-19 in china: model-based estimations understanding unreported cases in the 2019-ncov epidemic outbreak in wuhan, china, and the importance of major public health interventions reference table for the year 2019: computation of population by age (single years) and sex-total population, japanese population estimating the last day for covid-19 outbreak in mainland china predicting the cumulative number of cases for the covid-19 epidemic in china from early data a covid-19 epidemic model with latency period a model to predict covid-19 epidemics with applications to south korea, italy, and spain predicting the number of reported and unreported cases for the covid-19 epidemic in china on the definition and the computation of the basic reproduction ratio r 0 in models for infectious diseases in heterogeneous populations reproduction numbers and subthreshold endemic equilibria for compartmental models of disease transmission quantifying heterogeneous contact patterns in japan: a social contact survey early dynamics of transmission and control of covid-19: a mathematical modelling study social contacts and mixing patterns relevant to the spread of infectious diseases acknowledgments: data from https://covid19japan.com. the authors declare no conflict of interest. author contributions: p.m. and o.s. designed the original study; q.g., p.m. and o.s. participated in the adaptation to the age-structured data; q.g. and p.m. wrote the computer code; all authors actively contributed to the initial version and revisions of the manuscript. all authors have read and agreed to the published version of the manuscript. and by settingremark a1. it does not seem possible to estimate the matrix of contact φ by using similar optimization method. indeed, if we look for a matrix φ = φ ij which minimizeswhenever φ is diagonal. therefore the optimum is reached for any diagonal matrix. moreover by using similar considerations, if several χ 2 j are equal, we can find a multiplicity of optima (possibly with φ not diagonal). this means that trying to optimize by using the matrix φ does not yield significant and reliable information.in the figure a2 below, we present an example of application of our method to fit the japanese data. we use the period going from 20 march to 15 april. key: cord-282839-3ii79g6j authors: moreno-fernández ayala, daniel j.; navas, plácido; lópez-lluch, guillermo title: age-related mitochondrial dysfunction as a key factor in covid-19 disease date: 2020-11-07 journal: exp gerontol doi: 10.1016/j.exger.2020.111147 sha: doc_id: 282839 cord_uid: 3ii79g6j sars-cov-2 causes a severe pneumonia (covid-19) that affects essentially elderly people. in covid-19, macrophage infiltration into the lung causes a rapid and intense cytokine storm leading finally to a multi-organ failure and death. comorbidities such as metabolic syndrome, obesity, type 2 diabetes, lung and cardiovascular diseases, all of them age-associated diseases, increase the severity and lethality of covid-19. mitochondrial dysfunction is one of the hallmarks of aging and covid-19 risk factors. dysfunctional mitochondria is associated with defective immunological response to viral infections and chronic inflammation. this review discuss how mitochondrial dysfunction is associated with defective immune response in aging and different age-related diseases, and with many of the comorbidities associated with poor prognosis in the progression of covid-19. we suggest here that chronic inflammation caused by mitochondrial dysfunction is responsible of the explosive release of inflammatory cytokines causing severe pneumonia, multi-organ failure and finally death in covid-19 patients. preventive treatments based on therapies improving mitochondrial turnover, dynamics and activity would be essential to protect against covid-19 severity. unbalanced immune response (yang et al., 2020) . anti-cytokine therapies have been proposed as therapeutic options to reverse hyper-inflammation and decrease severity (roshanravan et al., 2020) . further, t cell exhaustion associated with dendritic cell dysfunction has been also associated with the immunopathology of covid-19 (zheng et al., 2020a , zheng et al., 2020b and an active role of local sars-cov-2 infected neutrophils and macrophages in inflammatory reactions has been recently proposed (jafarzadeh et al., 2020) . the severity of covid-19 is associated with the dysfunction of the immune system found in aged individuals and recently, this aged immunity has been considered to exacerbate covid-19 (akbar and gilroy, 2020) . many of the age-associated diseases such as metabolic syndrome (ms), type 2 diabetes (t2d), obesity, hypertension and cardiovascular diseases (cvd) also aggravate the severity of covid-19 (pirola and sookoian, 2020, zheng et al., 2020c) . the deterioration of the immune system associated with aging is called immunosenescence (currie, 1992) , which is defined as the gradual deterioration of the immune system associated with the natural age progression (de martinis et al., 2007; pangrazzi and weinberger, 2020) . immunosenescence is key in the deteriorated immune response against viral infections. this restricted immune response prevents successful inhibition of viral spread at early stages of infection exacerbating morbidity and mortality in this population (jing et al., 2009 , montecino-rodriguez et al., 2013 . importantly, aging is also associated with a proinflammatory profile known as "inflammaging" (franceschi et al., 2017) . in inflammaging, activated cells such as microglia and macrophages or dendritic cells increase the activity of nuclear factor kappa light chain enhancer of activated b-cells (nf-κb), cyclooxygenase-2 (cox-2) and inducible nitric oxide synthase (inos), leading to the release of proinflammatory cytokines such as interleukin 6 (il6), il1β, and tumor necrosis factor alpha (tfnα) among others (dantzer et al., 2008 , agostinho et al., 2010 . this chronic inflammation has been associated with the inhibition of antigen-specific immunity and the low response of aged people to vaccines (akbar and gilroy, 2020; parmigiani et al., 2013) . deterioration of mitochondrial function is key in the progression of aging and age-related diseases . mitochondrial dysfunction is also involved in the deterioration of the immune system being a key factor in inflammaging, higher susceptibility to viral infections and impaired t cell immunity found in aged people and in age-associated diseases (mcguire, 2019) . in the present review, we show evidence indicating that mitochondrial dysfunction is a key factor for the severity of covid-19 disease and for triggering the cytokine storm associated with the devastating symptoms that collapse lungs and lead to death to covid-19 patients. improvement of mitochondrial activity in the elderly would serve as preventive therapy to improve the immune response and reduce mortality caused by this disease and other viral respiratory diseases such as influenza. the highest severity of covid-19 is found in aged male patients and suffering overweight or obesity (mauvais-jarvis, 2020). mitochondrial dysfunction is deeply associated with two of these factors, aging and obesity (lopez-lluch, 2017b) . mitochondria are essential for many key activities in cells involved not only in energy production but also in the synthesis of nucleotides, modification of membrane phospholipids and regulation of calcium homeostasis. further, dysfunctional mitochondria are the main sources of reactive oxygen species (mtros) that increase oxidative damage during aging and metabolic diseases (lopez-lluch et al., 2018) . the accumulation of damaged mitochondria by disruption or j o u r n a l p r e -p r o o f journal pre-proof malfunction of different nutrient sensor mechanisms in the cells is a hallmark aging and metabolic syndrome including obesity (lopez-lluch et al., 2018) . age-related mitochondrial dysfunction is also a consequence of the unbalance of mitochondrial dynamics, mito/autophagy and biogenesis, producing the accumulation of damaged mitochondria (lopez-lluch, 2017a, b; lopez-lluch et al., 2015) . defective autophagy is involved in aging progression and in the pathophysiology of many metabolic and age-related diseases affecting different organs and tissues (evans et al., 2017; lee et al., 2019b; lin et al., 2019; yamaguchi, 2019) . the accumulation of deficient mitochondria through a decrease in mitochondrial turnover has been associated with many age-related diseases including not only metabolic diseases (natarajan et al., 2020) , but also cardiovascular (shemiakova et al., 2020) and neurodegenerative diseases sarcopenia (shally and mcdonagh, 2020) or cancer (moro, 2019) among others. furthermore, many prolongevity effectors induce autophagy as a common denominator of their respective anti-aging effect (stead et al., 2019) . in the case of metabolic syndrome, a key factor in covid-19 severity (stefan et al., 2020) , mitochondrial dysfunction is key in the increase of insulin resistance associated with type 2 diabetes connected with the increase of mutations in mtdna, changes in atp levels, generation of ros and unbalanced mitochondrial turnover (skuratovskaia et al., 2020) . the metabolic inflexibility caused by the accumulation of damaged mitochondria in both, metabolic syndrome and aging, produces an inadequate metabolic substrate disposal affecting glucose and free fatty acid metabolism that is associated with a cluster of metabolic abnormalities that affects many organs and tissues including immune cells (chakravarthy and neuschwander-tetri, 2020 ). immunosenescence has been described as the aged-dependent deterioration of the immune system (currie, 1992) , and as the adaptation of the immune system to j o u r n a l p r e -p r o o f journal pre-proof deteriorative changes over the time (de martinis et al., 2007) . whatever it is, immunosenescence, as many other physiological dysfunctions in aging, has been partially associated with dysfunctional mitochondria (mcguire, 2019) . mitochondrial dysfunction associated with a defective mitochondrial turnover can specially affect t-helper cd4 + lymphocytes that control the whole immune response (bektas et al., 2019) . on the other hand, dysfunction of mitochondria produces deterioration of t-cell activity that, in a vicious cycle, increases senescence in many other tissues by activating cytokine storm (desdín-micó et al., 2020) . importantly, several inflammatory disorders associated with aging and mitochondrial dysfunction such as neurodegenerative diseases, diabetes and atherosclerosis among others, with a clear proinflammatory profile has been associated with the chronic aberrant nlrp3 inflammasome activation (kelley et al., 2019) . interestingly, the relationship of mitochondrial dysfunction with inflammation increases just after the fifth decade of life, just when covid-19 shows a rise in its severity and mortality (mcguire, 2019). thus, it seems clear that mitochondrial dysfunction is an important factor in the proinflammatory profile caused by the release of inflammatory cytokines produced by activation of nlrp3 inflammasome and other mechanisms over-activated in aging and in metabolic diseases. the response of the immune system is very complex and depends on the type of pathogen or agent to be blocked (justiz vaillant and jan, 2020) . many factors influence the immune response and one of them is mitochondria, that has been strongly associated with the activity of the innate response (sandhir et al., 2017) . inflammatory response depends on the innate immunity that is strongly affected by dysfunctional mitochondrial j o u r n a l p r e -p r o o f journal pre-proof activity (missiroli et al., 2020) (figure 1 ). many different pathogens are recognized through their repetitive molecular signatures by pattern recognition receptors (prrs). these receptors are present on the cell surface and in intracellular compartments of innate cells. their main receptors are toll-like receptors (tlrs), retinoic acid-inducible gene i-like receptors (rlrs), nucleotide oligomerization domain receptors (nlrs) and cytosolic dna sensors (cyclic gmp-amp synthase (cgas) and stimulator of interferon genes (sting)) ( thompson et al., 2011) . these receptors are activated by pathogen-associated molecular patterns (pamps) and also by damageassociated molecular patterns (damps) (tang et al., 2012) . pamps are found in pathogens, whereas damps are produced into the cells during stress, ros release, apoptosis or necrosis and mainly induce inflammatory response. in this response, nlrp3 (nlr family, pyrin domain containing 3) inflammasome triggers the activation of caspase 1 (casp1) and activates the secretion of proinflammatory cytokines such as il1β and il18 (zhao and zhao, 2020) . mitochondrial dysfunction plays an essential role in the activation of nlrp3 since damps can be released especially by damaged mitochondria (janeway and medzhitov, 2002) . to date, many mitochondrial damps have been identified: cardiolipin, n-formyl-peptides, mitochondrial transcription factor a (tfam), mitochondrial ros (mtros) and mitochondrial dna (mtdna) because they mimic bacterial structures (mcguire, 2019). these damps can also act independently of nlrp3. tfam activates immune cells through interaction with receptors of advanced glycation end products (rage) and tlr9 (julian et al., 2013) . the release of mtdna from dysfunctional mitochondria has been also associated with the rise of nlrp3-independent proinflammatory cytokines such as tnfα, j o u r n a l p r e -p r o o f journal pre-proof il6, regulatory upon activation, normal t-cell expressed and secreted (rantes, ccl5) or interleukin 1 receptor antagonist (il1ra) (pinti et al., 2014) . the release of mtros is key in the activation of the inflammatory immune response and in aging progression (de la fuente and miquel, 2009) . the increase of the release of mtros produced by mitochondrial dysfunction during aging can be responsible of the maintenance of a chronic state of inflammation that would reduce longevity and affect many of age-related diseases in a theory of aging known as oxi-inflammaging (de la fuente and miquel, 2009) . this increase in the oxidative damage produced in immune cells have been associated with immunosenescence, the deterioration of immune system during aging (garrido et al., 2019) . oxidative stress produced by mitochondrial dysfunction is an essential factor in the appearance of "inflammaging", the chronic inflammation profile associated with aging (franceschi and campisi, 2014) . this chronic inflammation profile is caused, at least in part, by the accumulation of damaged macromolecules during aging by both, the increase of oxidative stress and/or by inadequate elimination due to autophagy decline (franceschi and campisi, 2014) . the hallmarks of inflammaging are chronic and high levels of inflammatory biomarkers such as c-reactive protein or il6 (franceschi and campisi, 2014) . activated cells such as glia, macrophages or dendritic cells suffer the overactivation of nf-κb, cox-2 and inos leading to the release of proinflammatory cytokines such as il6, il1β, tnfα and also the release of mtros (agostinho et al., 2010) . as strategy, many prolongevity effectors that reduce the release of mtros would be used to reduce the inflammatory profile through improvement of mitochondrial activity (de la fuente et al., apart of the activation of nlrp3, high levels of mtros are also involved in other j o u r n a l p r e -p r o o f immunological mechanisms involved in inflammation such as hypoxia inducible factor 1 alpha (hif1α) and nf-κb (brunelle et al., 2005) . activation of hif1α by mtros can induce the expression of one of its gene targets, the cytokine il1β resulting in a proinflammatory phenotype (mcgettrick and o'neill, 2020; tannahill et al., 2013) . on the other hand, mtros induce nf-κb-dependent inflammation (herb et al., 2019) , although in a regulatory feedback, induction of nf-κb by mtros can also act as a signal to induce the removal of dysfunctional mitochondria that would reduce inflammation (zhong et al., 2016) . furthermore, the response of nk cells to il2 is defective in old individuals in an effect associated with the increase of oxidative stress caused by defective mitochondria (miranda et al., 2018) . on the other hand, many studies have shown the relationship of defective mito/autophagy processes with the inflammatory profile associated with aging. disruption of mitochondrial turnover contributes to the accumulation of damaged mitochondria and higher mtros production that aggravates proinflammatory processes contributing to the impairment of the progression of different age-related diseases (caruso et al., 2009 ) accordingly with the oxy-inflammaging theory. in the baltimore longitudinal study on aging, the accumulation of under-degraded mitochondria in autophagosomes of cd4 + t cells indicates the accumulation of dysfunctional mitochondria by deficiency of autophagy, which was associated with chronic inflammation in the elderly (bektas et al., 2019) . chronification of local inflammation in atherosclerosis has been also associated with defective mitophagy in aged individuals (orekhov et al., 2020) . on the contrary, several studies have demonstrated that improving mitochondrial turnover contributes to the decrease of inflammation and restoration of the activity of the immune system. restoration of mitochondrial turnover through induction of mito/autophagy, suppress the inflammatory response by inhibiting nlrp3 activation in different models of j o u r n a l p r e -p r o o f sepsis (kim et al., 2016) . removal of damaged mitochondria through activation of autophagy in murine macrophages protects against inflammation induced by alcohol in liver (liang et al., 2019) . in influenza infection, decrease of mtros reduced inflammation, neutrophils infiltration and virus load without affecting b and t cell activities . in a recent review, xu et al., (xu et al., 2020) summarize the accumulated evidence that implicates the elimination of dysfunctional mitochondria with the maintenance of the immune system during aging. therefore, we can speculate that the accumulation of dysfunctional mitochondria could be partially behind the high mortality rate by covid-19 in the elderly mainly due to mitochondrial insufficiency in senescent macrophages and lymphocytes that produce an exacerbated inflammatory response ( figure 2 ). mitochondrial dysfunction affects the activity of the immune system against virus infection. the release of interferon alpha (ifnα) and β (ifn type i (ifn-i)) is essential for antiviral response since these cytokines limit viral replication, improve antigen presentation and the activity of mavs depends upon intact mitochondrial membrane potential and oxphos activity (koshiba et al., 2011) suggesting that damaged mitochondria impair mavs activity. however, if this relationship is associated with the deficient response to viral infections during aging, especially to respiratory infections (haq and mcelhaney, 2014) , remains to be clarified, although some studies suggest a direct relationship. silencing mavs expression through rna interference abolishes the activation of nf-κb and irf3 in response to viral infection, permitting viral replication (seth et al., 2005) . further, aged monocytes showing impaired mitochondrial respiratory capacity (pence and yarbro, 2018) , suffer a decrease in the activation of irf3 and 7 suggesting a link between mitochondrial dysfunction, mavs malfunction and decrease of ifn-i release (molony et al., 2017) . recently, mavs-dependent signaling has been revised in deep in the immune response against emerging rna viruses such as ebola, zika, influenza a virus or sars-cov converting mitochondria as central hub of the response against these and other viruses (dutta et al., 2020) . another important process to be taken into consideration is that infection by virus also promotes mtros increase. as has been demonstrated in the previous section, mtros drive innate immune inflammation that exacerbates viral pathogenesis . this can be accompanied by the fact that many viruses produce modifications in mitochondrial activity that reduce the capacity of cells to induce ifn-i-dependent antiviral responses (anand and tikoo, 2013) . further, viruses show increased replication efficiency in senescent cells with low mitochondrial capacity, suggesting that accumulation of senescent cells, containing high levels of dysfunctional mitochondria, during aging and age-related diseases may promote the progression of virus infection (malavolta et al., j o u r n a l p r e -p r o o f 2020). in the case of covid-19, antivirus response of the immune system is compromised by a low release of type i and iii ifn accompanied by high expression of proinflammatory cytokines (blanco-melo et al., 2020) . this unbalanced response could be associated with the accumulation of damaged mitochondria in aging and obesity that strongly affect antiviral immunological response (tavernarakis, 2020) . t lymphocytes are key in the protection against virus infections. the activation of lymphocytes also depends on the mitochondrial activity. after t-cell receptor stimulation, substantial changes required for t-cell activation occurs in metabolism including mitochondrial oxphos activation (tarasenko et al., 2017) . t cell proliferation and activation require atp produced by mitochondrial activity to promote the increase of glycolysis (van der windt et al., 2013) and reprogrammation of the whole metabolism (chang et al., 2013) . this reprogrammation of the metabolism is essential to support tcr signaling and nucleic acid synthesis needed for the transition of quiescent t-cells to the proliferative state (ron-harel et al., 2016; weinberg et al., 2015) . oxphos activity is also essential in the reactivation of memory cd8 + t-cells. these cells have high respiratory capacity and high mitochondrial mass that allow them to rapidly reactivate after recognition of cognate antigens (van der windt et al., 2013) . the decline of oxphos in these cells is manifested as impaired immune memory (goronzy and weyand, 2017) and loss of capacity to quickly respond to secondary infections. it seems clear that mitochondrial activity is essential for the appropriate response of lymphocytes against virus infections and the accumulation of damaged mitochondria in these cells will impair defense against these infections. j o u r n a l p r e -p r o o f coenzyme q 10 (coq 10 ) is an essential component of the mitochondrial oxphos and antioxidant in cell membranes and its depletion is associated with severe mitochondrialdiseases (lopez-lluch et al., 2010) . it is known that levels of coq decrease in many tissues and organs during aging (kalen et al., 1989) . taken into consideration the important role of mitochondria in immunosenescence and inflammaging, a reduction of coq 10 levels in immune cells could impair the progression of immune system unbalance and increase the low grade inflammatory profile found in the elderly. the decrease of coq levels during aging also affects thymus (bliznakov et al., 1978) , and mitochondrial activity of coq 10 has been considered essential for the optimal function of the immune system (folkers and wolaniuk, 1985) . thus, we can postulate that this agerelated coq 10 decrease can be also partially responsible of the unbalance of the immune system found in immunosenescence and inflammaging. however, no studies have been performed to directly associate coq 10 depletion and inflammaging or immunosenescence although indirect studies seems to indicate a direct relationship (novoselova et al., 2009 ). coq 10 supplementation improves the activity of the immune system in infections. coq 10 as other natural occurring antioxidants such as α-tocopherol reduce the lps-induced inflammatory response in mice in a model of acute inflammation by modulating the activation of the nf-κb signaling pathway (novoselova et al., 2009 ). on the other hand, supplementation with coq 10 reduces the levels of the proinflammatory cytokine il17 and the levels of anti-inflammatory cytokines in a mice model of colitis . the effect was associated with the activation of the ampk and foxp3 regulatory pathways involved in mitochondrial turnover. the same anti-inflammatory response was found in graft vs. host disease (lee et al., 2016) . further, in a model of carrageenan-induced inflammation in the air pouch, coq 10 , in combination with the known immunomodulator βglucan, reduced leukocyte infiltration in lung, nitrite and proinflammatory cytokines il1α j o u r n a l p r e -p r o o f and β levels (vetvicka and vetvickova, 2018) . in humans, coq 10 supplementation significantly lower inflammation markers in individuals with metabolic syndrome (dludla et al., 2020) or with diabetic nephropathy (heidari et al., 2018) . coq 10 supplementation also reduces the proinflammatory marker, β-defensin 2 (hbd2) indicating a reduction in inflammatory status associate with diabetes (brauner et al., 2014) . on the other hand, a recent meta-analysis has demonstrated that coq 10 supplementation increases antioxidant defences although did not affect inflammatory cytokines in patients with coronary artery disease (jorat et al., 2019) . on the other hand, another systematic review and metaanalysis about the effect of coq 10 in markers of inflammation involving nine trials and 428 subjects, demonstrated that coq 10 supplementation significantly decreased tnfα although, in this case, did not affected il6 levels (zhai et al., 2017) . probably these discrepancies are mainly due to the type of disease and the supplementation procedures and further studies and clinical trials are needed to clarify the role of coq 10 supplementation in chronic inflammation. we have also found that coq 10 primary deficiency produces a change in the transcriptomic profile in cells, that acquire a defensive phenotype (fernandez-ayala et al., 2013) . among the gene ontology pathways repressed in primary coq 10 deficiency, many immune genes and immunity-related gene ontology pathways were found downregulated, like the cellular signaling mechanisms that respond to ifnα and, in general, to ifn-i. on the other hand, the mechanisms repressed were those associated with negative regulation of viral genome replication and viral reproduction, cytokine mediated signaling pathways and other pathways in immune system response (fernandez-ayala et al., 2013) . all these pathways indicate a key role of coq 10 in antiviral defense and have been associated with immunosenescence and with the severity of covid-19. all these studies indicate the importance of coq 10 in the activity of mitochondria and their effect on the immune system and on inflammation. for this reason, reduction of the levels of coq 10 in leukocytes during aging could be considered a key factor in age-related chronic inflammation and an important factor for the severity of covid-19. the study of the relationship of coq 10 levels in leukocytes and covid-19 severity and even other respiratory diseases such as flu could clarify this hypothesis and provide clues to use coq 10 as supplement to improve immune system activity in the elderly. the lethality of covid-19 depends of a systemic hyper-inflammation known as cytokine storm or macrophage activation syndrome (mas) (bektas et al., 2020) . the worst prognosis in the disease caused by sars-cov-2 virus occurs in patients with adult respiratory distress syndrome (ards) (grasselli et al., 2020) . although with some differences with the ards produced by sars-cov, an extremely powerful inflammation during the latter phase of the disease is the main cause of ards-mediated death (grasselli et al., 2020) in covid-19 as it was in the case of sars (de wit et al., 2016) . in cytokine storm, immune and non-immune cells release large amounts of proinflammatory cytokines that generates a great distortion in the immune response. to date, the proinflammatory activity of lung macrophages seems to be the main responsible of the trigger of cytokine storm in patients of covid-19 (pagliaro, 2020) . furthermore, the enormous release of proinflammatory cytokines is responsible of the exaggerated internal inflammatory processes suffered by survivors of the acute phase of the disease (bektas et al., 2020) . a persistent inflammation caused by over-activation of the innate immune system leads to j o u r n a l p r e -p r o o f cytokine storm and ards (teijaro et al., 2014) . in the case of covid-19, blood plasma shows significant high levels of proinflammatory cytokines such as il6, il1β, il1ra, il7, il8, tnfα, several chemokines such as cxcl9 and cxcl16, chemoattractant for t and nk cells, ccl8 and ccl4, which recruit monocytes/macrophages, and cxcl8, a classic neutrophil chemoattractant (proudfoot, 2002) . il2, il7, il10, tfnα, granulocyte colony(rahmani et al., 2020) . lower activity of ifn-i also correlates with the increase in the recruitment of inflammatory monocyte-macrophage populations, one of the hallmarks of the infection with sars-cov (channappanavar et al., 2016) and probably associated with the cytokine storm involved in covid-19. in fact, a study carried out in different covid-19 patients from different countries found a common denominator in a high proinflammatory signal from myeloid cells together with a low production of ifnα from dendritic cells (arunachalam et al., 2020) . in general, we can then consider that sars-cov-2 infection produces an unique and for coronaviruses, the key pattern recognition in macrophages depends on tlr7, which is activated by viral rna in endosomes (cervantesbarragan et al., 2007) . activation of tlr7 is needed for the production of infα (ifn-i), il12 and il6. this response is required for the production and activation of cd8 + t-cells, cd4 + and b lymphocytes (zhou et al., 2017) . another pathways involved in this response the rlrs, mda-5 and laboratory of genetics and physiology 2 (lgp2), which recognize cytosolic viral rna (zust et al., 2011) and the cgas-sting pathway, which recognizes cytosolic dna (sun et al., 2013) . activation of all these pathways induce a signaling cascade leading to the expression of ifn-i and other inflammatory cytokines. however, in the case of infection with coronaviruses, some papain-like proteases block tlr7 (li et al., 2016) and stingdependent signaling (sun et al., 2012) probably downregulating the activation of irfs and blocking the early transport of irfs to the nucleus (roth-cross et al., 2007; spiegel et al., 2005) . the importance of the tlr7 signal pathway has been very recently highlighted by the fact that several young patients suffering severed covid-19 and death showed lossof-function variants of the tlr7 gene affecting downstream ifn-i signaling (van der made et al., 2020). the same relationship has been found in patients with tlr3 and irf7 loss-of function mutations partially explaining the great differences in the response to the virus (zhang et al., 2020) . to this scenario, we have also to add the production of autoantibodies against different forms of ifn-i in some of the more severe covid-19 patients (bastard et al., 2020) indicating the importance of a correct ifn response in survival to this disease. importantly, cytotoxic cd8 + t-cells requires mitochondrial-mediated ifn-i signaling for optimal protection. activated naïve cd8+ t cells require the increase of mitochondrial mass and activation of mitochondria to produce il2 and tnfα, ifnγ (ifn-ii) and other mediators (fischer et al., 2018) . in a model of viral chorimeningitis infection in mice, the mitochondrial cyclophilin d was essential to produce ifn-i and maintain survival of cd8 + t-cells (condotta et al., 2020) . on the other hand, high il6 levels inhibit cd8 + cytotoxic tcells by blocking the secretion of ifnγ (ahmadpoor and rostaing, 2020) , paralyzing yet more the cell-mediated antiviral response during cytokine storm (velazquez-salinas et al., 2019). accumulation of abnormal mitochondria contributes to aging and age-related and metabolic diseases, including metabolic syndrome, cancer, neurodegenerative disease, type ii diabetes, etc (lopez-lluch, 2017b). covid-19 severity is linked to several previous pathological situations mainly, hypertension, diabetes and coronary heart disease, lung diseases, metabolic syndrome and obesity, and, importantly, older age (engin et al., 2020; zaki et al., 2020; zhou et al., 2020a) . in all these diseases, mitochondrial dysfunction maddaloni and buzzetti, 2020; mcmaster et al., 2015; prasun, 2020) . the direct relationship between mitochondrial dysfunction and comorbidities associated with covid-19 severity helps to understand the importance of maintaining mitochondrial health in the j o u r n a l p r e -p r o o f progression and severity of covid-19. following, we briefly summarize the relationship of these comorbidities with mitochondria and covid-19 progression. although the relationship between diabetes mellitus and severe complications in covid-19 are not completely clear, levels of proinflammatory cytokines in plasma in this disease have been associated with the severity of covid-19 infection (roy et al., 2020) . the phagocytic activity of professional phagocytic cells including macrophages and the innate cell-mediated immunity is impaired in diabetic patients (ma and holt, 2020) . diabetic patients also show elevated proinflammatory cytokines levels such as il1β, il6 and tnfα, the same cytokines induced by mitochondrial dysfunction (geerlings and hoepelman, 1999; maddaloni and buzzetti, 2020; pal and bhansali, 2020) . in these patients, mtros induces lysosomal dysfunction that impairs autophagic flux and contributes to m1 macrophage polarization to the inflammatory phenotype (yuan et al., 2019) . it seems clear that, mitochondrial dysfunction in diabetic patients contributes importantly to the low-grade inflammatory profile associated with this disease that is aggravated during aging and has been associated with higher severity in covid-19 infection. one of the main risk factors in covid-19 disease is obesity (kwok et al., 2020) . this relationship has been associated with a proinflammatory profile and metabolic dysregulation causing severe symptoms and complications such as hypercoagulopathy (pasquarelli-do-nascimento et al., 2020) . regarding mitochondrial activity, lipid challenge in obesity causes dysregulation of the immune response. high levels of fatty acids inhibit j o u r n a l p r e -p r o o f journal pre-proof the activity of cd4 + t-cells in an effect linked to the malfunction of autophagosome formation and mitochondrial degradation (guerrero-ros et al., 2020) . this disruption blocks mitochondrial turnover accompanied by the increase in mitochondrial ros and decrease in atp levels as hallmarks of mitochondrial dysfunction (guerrero-ros et al., 2020) . other studies have demonstrated that alterations in lipids and high-fat loading interfere in autophagic process and contribute to the accumulation of damaged mitochondria (koga et al., 2010; rodriguez-navarro et al., 2012) . hypertension is another main risk factors in covid-19 infection. in this relationship, inflammation also contributes importantly to the pathogenesis since inflammation impairs hypertension control (mischel et al., 2015) and hypertension induces the release of inflammatory cytokines in vascular tissues (mcmaster et al., 2015) . proinflammatory cytokines such as il17, il6, tnfα and ifnγ, are found in high levels in hypertensive patients (mcmaster et al., 2015) . in this process, mitochondrial dysfunction plays also a very active role. mitochondrial dysfunction in macrophage population strongly contributes to the m1/m2 unbalance favoring the activity of pro-inflammatory m1 macrophages. hypertension associated with obesity and other metabolic factors induces the unbalance of macrophage population increasing the amount and activity of m1 and decreasing the function of the anti-inflammatory and respiratory m2 macrophages (mouton et al., 2020) . on the other hand, improvement of mitochondrial activity reduces inflammation associated with hypertension. dehydrofolate reductase ko mice suffers hypertension and abdominal aortic aneurism after infusion with angiotensin ii. in these mice, scavenging of mtros completely abrogates the development of hypertension and aneurism indicating the importance of mitochondrial dysfunction in these processes (li et al., 2019) . moreover, j o u r n a l p r e -p r o o f mitochondrial sirt3 depletion induces vascular inflammation and oxidative stress in hypertension whereas its overexpression reduces vascular dysfunction (dikalova et al., 2020) . further, pharmacological restoration of mitophagy reduces hypertension-related stroke occurrence (forte et al., 2019) . all these studies indicate the importance of mitochondrial activity in the control of hypertension and probably in the response to covid-19. severity of covid-19 increases also in patients suffering metabolic syndrome (ms) (bansal et al., 2020) . ms is considered as the co-occurrence of obesity, dyslipemia and hypertension, main factors for covid-19 severity (zaki et al., 2020) . obesity and ms patients show a very compromised immune system (andersen et al., 2016) , even affecting lymphocytes populations (rodríguez et al., 2018) , that decrease the response of the organism to vaccines such as influenza and other viral infections (frasca and blomberg, 2020) . in ms, mitochondrial dysfunction contributes very importantly to oxidative stress and systemic inflammation (prasun, 2020) . mitochondrial abnormalities are also associated with cardiac contractile dysfunction occurring in obesity, type 2 diabetes and insulin resistance associated with ms (bugger and abel, 2008) . in this relationship, mitochondrial stress and unfolded protein response (mtupr) play a key role (hu and liu, 2011) . in fact, the use of therapies focussed to improve the capacity of mitochondria to reduce stress damage and decrease mtupr are considered an effective approach to avoid mitochondrial dysfunction associated with many of the physiological disorders associated with ms (hu and liu, 2011) . further, as strategy for the treatment of ms, enhancing j o u r n a l p r e -p r o o f mitochondrial biogenesis through pharmacological and non-pharmacological approaches and increase of antioxidant capacity has been recently proposed (prasun, 2020) . another of the main groups in risk for suffering severe covid-19 is composed of individuals suffering cardiovascular disease (cvd) (nishiga et al., 2020) . cvd is strongly aggravated by ms, hypertension, obesity and diabetes; therefore, all the indications above indicated for these diseases can be applied also to cvd. hypertrophy, fibrosis and inflammation are common denominators of aged cardiovascular system, and all of them are accompanied by the accumulation of dysfunctional mitochondria due to mito/autophagy decline among other factors (morciano et al., 2020) . accumulation of dysfunctional mitochondria in cvd by a shift or mitochondrial dynamics to fission indicates the importance of a right mitochondrial equilibrium in the progression of this disease (cooper et al., 2020) . on the other hand, induction of peroxisome proliferator-activated receptor gamma coactivator-1a (pgc1a), a widely known transcription factor that induces mitochondrial biogenesis and turnover, protects heart against oxidative stress, microcirculation and mitochondrial dysfunction (arad et al., 2020) . again, the relationship between inflammation and mitochondrial dysfunction seems to play an essential role in the progression and severity of cvd in elderly people (ferrucci and fabbri, 2018) . therapeutic agents and interventions targeting mitochondria decreasing mtros production have been extensively studied improving the progression of cvd (veloso et al., 2019) . cardioprotective signaling pathways seems to converge on mitochondria especially to prevent inflammatory injury associated with cvd (koenitzer and freeman, 2010) . further, mitochondrion-targeted antioxidants show cardioprotective effects linked to reduction of nf-κb signaling and reduction of the expression of j o u r n a l p r e -p r o o f inflammatory cytokines . supplementation with coenzyme q 10 plus selenium reduces the mortality by approximately 50% in patients with cvd in an effect associated to its bioenergetics, antioxidant and anti-inflammatory function (mantle and hargreaves, 2019). among the diseases associated with covid19 severity, lung diseases are the most important since massive bilateral pneumonia is one of the main symptoms of this disease (zhou et al., 2020b) . mitochondrial dysfunction has been also associated with many of the lung diseases such as ards, pneumonia, chronic lung diseases, or bronchial asthma among others (ten and ratner, 2020) . lung physiology is also affected during aging. ageassociated chronic obstructive pulmonary disease (copd) shows many of the hallmarks of aging including impaired autophagy/mitophagy, accumulation of damaged mitochondria and low grade chronic inflammation (barnes, 2019) . in lung dysfunction, peripheral blood mononuclear cells (pbmcs) and platelets actively participate in inflammation contributing to the severity and lethality of covid-19 (riou et al., 2020) . removal of dysfunctional mitochondria has been considered a key therapeutic process for the treatment of respiratory diseases (cloonan and choi, 2016) . activation of autophagy improves the initiation and the progression of lung diseases during aging reducing mitochondrial dysfunction and associated inflammation (nakahira et al., 2014) . however, other studies have indicated that autophagic clearance of mitochondria may aggravate the pathogenesis of copd by increasing cell death (ryter and choi, 2015) . interestingly, resveratrol (rsv), a polyphenol used in aging studies that promotes mitochondrial biogenesis and turnover (baur et al., 2006) , and also shows anti-inflammatory properties (tung et al., 2015) , has been recently considered as putative candidate to counteract lung j o u r n a l p r e -p r o o f and muscle impairments associated with copd (beijers et al., 2018) . furthermore, cr, the strongest non-genetic intervention in longevity, reverses several age-related changes in lung by reducing inflammation and improving mitochondrial turnover (hegab et al., 2019) . clearly, removal of damaged mitochondria plays, again, a key protective role in the progression of respiratory diseases associated with aging and risk factor for covid-19. prolongevity interventions can modulate the evolution of immunosenescence and inflammation in organisms (mau et al., 2020) . the most powerful interventions to delay aging are cr (lopez-lluch and navas, 2016), physical exercise (ciolac et al., 2020) and some dietary bioactive compounds or therapies based on the induction of mito/autophagy (lopez-lluch et al., 2018) and on maintenance of nad+ (braidy and liu, 2020) . caloric restriction (cr), delays t-cell senescence in non-human primates indicating its capacity to affect immunosenescence (messaoudi et al., 2006) . exercise improves immunological and anti-inflammatory response decreasing morbidity and mortality (turner, 2016) . prolongevity nutritional compounds such as polyphenols improve the immune function and reduce proinflammatory profiles in many model animals (olcum et al., 2020; tung et al., 2015) . the research about the influence of cr in humans is very complex and has not produced clear results to date, however, studies performed in aged long-lived nonhuman primates have demonstrated that cr delays t-cell senescence (messaoudi et al., 2006) . other studies in mice have demonstrated that cr improves cd4 + and cd8 + t-cells activity in the spleen, mesenteric lymph nodes, peripheral blood, thymus and salivary glands (jolly, 2004) . in mice, cr prevents thymic deterioration and improves the response of t-cells to j o u r n a l p r e -p r o o f il-2 (yang et al., 2009) . taken into consideration the importance of bioenergetics in the activity of t-cells (choi et al., 2017) and the effect of cr on mitochondrial activity and turnover (lopez-lluch et al., 2006) , the maintenance of mitochondrial activity in the immune system can be considered one of the main effect by which cr delays immunosenescence. exercise, a well-known anti-aging factor, also improves immunological and antiinflammatory response (turner, 2016) . physical activity in old mice (lee et al., 2019a) and in humans (sellami et al., 2018) improves immunological response. even in old patients showing cognitive dysfunction, aerobic exercise reduces the levels of the most significant age-related inflammatory cytokines, il6 and tnfα (stigger et al., 2019) . part of the positive effect of exercise can be due to a decrease of the amount of dysfunctional mitochondria by inducing mitochondrial biogenesis (lumini et al., 2008) . further, the immunomodulatory effect of exercise can be also associated with the stimulation of the synthesis of coq 10 improving both, mitochondrial and antioxidant activities (rodriguez-bies et al., 2015; rodriguez-bies et al., 2010) . bioactive compounds have shown positive effects of the immune function in many different models of immunological dysfunction such as ovariectomized mice (baeza et al., 2010) , normal aging (yuan et al., 2012) or in senescence accelerated mice (zhang et al., 2012) . in humans, the studies with natural extracts rich in bioactive compounds have shown conflicting results. in some experiments, extracts rich in bioactive compounds have demonstrated capacity to activate immune cells (tumova et al., 2017) , although with other extracts, no improvement was found (hunter et al., 2012) . on the other hand, high flavonoid cocoa supplements have recently demonstrated their capacity to reduce oxidative stress in plasma and inflammation in older subjects (munguia et al., 2019) . mediterranean diet, rich in plant foods, is associated with reduced risk of developing age-j o u r n a l p r e -p r o o f related chronic diseases by inducing protection against oxidative stress and improving mitochondrial activity that could be the cause of a reduced inflammation level (tosti et al., 2018) . among the most studied bioactive compounds, polyphenols have demonstrated their capacity to modulate mitochondrial physiology and reduce mitochondrial dysfunction (baur et al., 2006; tung et al., 2014) . polyphenols are nowadays considered potential antiaging agents because of their ability to modulate oxidative damage, inflammation, cell senescence and autophagy (russo et al., 2020) . rsv is not only useful reducing the levels of tnfα in aged animals (tung et al., 2015) , it also reduces the effect of tfnα in an in vitro model of uveitis in which reduces the response to tnfα and the release of proinflammatory cytokines (paladino et al., 2020) . a recent revision about the effect of different compounds on chronic low grade inflammation in humans and model animals indicated that rsv and metformin, a widely used pharmacological compound for t2dm treatment, show anti-inflammatory capacity and can be considered promising therapies for inflammation and frailty in the elderly . interestingly, metformin also inhibits the expression of nf-kb gene reducing the inflammatory response (kanigur sultuybek et al., 2019) through normalizing mitochondrial function through enhancing mitochondrial clearance by mito/autophagy (bharath et al., 2020) . in fact, metformin, has been recently proposed as pharmacological compound against sars-cov-2 infection through its anti-inflammatory property by modulating mitochondrial ros/ca + release (menendez, 2020) and by regulating mtor/ampk signaling involved in mitochondrial turnover (ramaiah, 2020) . another compound used as supplement that modulates several aspects of metabolism and mitochondrial mechanisms is coq 10 . low levels of plasma coq 10 have been associated with inflammation and mortality in cvd patients (shimizu et al., 2017) . furthermore, supplementation with coq 10 can prevent the processes related to j o u r n a l p r e -p r o o f journal pre-proof chronic oxidative stress and inflammation during aging (lopez-lluch, 2020; lopez-moreno et al., 2018) . many in vitro and clinical studies indicate that coq10 is a promising antiinflammatory molecule in metabolic and age-related diseases (schmelzer et al., 2010; shimizu et al., 2017; suárez-rivero et al., 2019; yubero-serrano et al., 2012) maintenance of nad + levels is important in aging (braidy and liu, 2020) . dysregulation of mitochondrial activity can affect nad + levels (chinopoulos, 2020) and introduce a new important factor in aging and the activity of the immune system (audrito et al., 2020) . decline in nad + has been reported in degenerative diseases associated with oxidative stress and inflammation (braidy and liu, 2020) . therefore, supplementation with nad + has been suggested as therapy for age-associated disorders reactivating defective dna repair and mitophagy, thus, avoiding accumulation of dysfunctional mitochondria (babbar et al., 2020) . decrease of the levels of the nad + precursor, nicotinamide mononucleotide (nmn) has been also associated with a proinflammatory profile in neurodegenerative diseases (yao et al., 2017) . this proinflammatory profile can be reversed by chronic supplementation with nicotinamide (nam), and other precursors of nad + , that improve bioenergetics and reduce inflammation in a dietary stress model in mice (braidy and liu, 2020; mitchell et al., 2019) . on the other hand, treatment with nmn improves cardiac muscle contractility and protects against inflammation in mice suffering cardiomyopathies (zhang et al., 2017) by improving mitochondrial function and reducing il6 and tnfα levels in many tissues (sims et al., 2018) . in general, it seems clear that many prolongevity effectors improve immune system in the elderly by regulating mitochondrial function and inflammation level. taken into consideration the importance of bioenergetics, mitochondrial activity and antioxidant j o u r n a l p r e -p r o o f protection in the immune response, we can speculate that maintenance of mitochondrial homeostasis by bioactive compounds or treatments that activate mitochondrial physiology, dynamics, removal and biosynthesis can be effective in the decrease of the inflammatory profile and in the immunosenescence associated with aging and age-associated diseases ( figure 3) . these treatments are shown as promising therapies to improve mitochondrial function and reduce inflammation in the elderly, and would protect them against viral respiratory infections that are more severe when patients show previous inflammatory conditions. sars-cov-2 causes a complex and rapid response that collapse lungs through the induction of a cytokine storm. the disease produced by sars-cov-2, covid-19, is highly severe in old patients and in persons showing previous risk factors that are related with age-dependent chronic diseases such as cvd, obesity, t2dm, ms or lung diseases. elderly people and patients suffering these chronic diseases show a low level of chronic inflammation that is associated with the dysfunction of mitochondria (parker et al., 2019) . induction of defective mitochondria removal through activation of the mito/autophagy process reduces the inflammatory profile (raz et al., 2017) and would improve the response to new pathogens such as sars-cov-2 even in old people. we postulate here that the maintenance of mitochondrial health through healthy life habits, pharmacological compounds o dietary supplements able to improve mitochondrial activity, dynamics and turnover would reduce the levels of inflammatory cytokines and the severity of covid-19 and other respiratory diseases such as seasonal flu. these and other "geroprotective" treatments must be used to treat or prevent covid-19 (promislow, 2020) . interventions and compounds able to improve mitochondrial health in the elderly would j o u r n a l p r e -p r o o f reduce or even eliminate the cytokine storm induced by sars-cov-2 infection and, therefore, reduce the grade of ards associated with covid-19. no existing effective treatment against covid-19 once cytokine storm and ards has started, prevention of the stronger effect induced by sars-cov-2 appears the most promising strategy. we think this strategy must be based in the improvement of the mitochondrial activity that would reduce the proinflammatory profile associated with aging and age-related diseases. aged mitochondria is also involved in the unbalance of immune system by increase of innate response and decrease of the adaptive response found in immunosenescence. mitochondrial dysfunction releases many damage signals to cytosol that end in the activation of inflammasome and the release of inflammatory cytokines that cause the chronic inflammation associated with aging and age-related diseases. neuroinflammation, oxidative stress and the pathogenesis of alzheimer's disease why the immune system fails to mount an adaptive immune response to a covid-19 infection. transplant international : official journal of the european society for aging immunity may exacerbate covid-19 mitochondria-nucleus shuttling fk506-binding protein 51 interacts with traf proteins and facilitates the rig-i-like receptor-mediated expression of type i ifn viruses as modulators of mitochondrial functions impact of obesity and metabolic syndrome on immunity national french survey of covid-19 symptoms in people aged 70 and over therapeutic approaches to diabetic cardiomyopathy: targeting the antioxidant pathway. prostaglandins & other lipid mediators systems biological assessment of immunity to mild versus severe covid-19 infection in humans nampt and naprt: two metabolic enzymes with key roles in inflammation mitophagy and dna damage signaling in human aging soybean and green tea polyphenols improve immune function and redox status in very old ovariectomized mice metabolic syndrome and covid 19: endocrine-immune-vascular interactions shapes clinical course pulmonary diseases and ageing autoantibodies against type i ifns in patients with life-threatening covid-19 resveratrol improves health and survival of mice on a high-calorie diet resveratrol for patients with chronic obstructive pulmonary disease: hype or hope? current opinion in clinical nutrition and metabolic care 21 a public health perspective of aging: do hyper-inflammatory syndromes such as covid-19, sars, ards, cytokine storm syndrome, and post-icu syndrome accelerate short-and long-term inflammaging? age-associated changes in human cd4(+) t cells point to mitochondrial dysfunction consequent to impaired autophagy metformin enhances autophagy and normalizes mitochondrial function to alleviate aging-associated inflammation imbalanced host response to sars-cov-2 drives development of covid-19 coenzyme q deficiency in aged mice nad+ therapy in age-related degenerative disorders: a benefit/risk analysis markers of innate immune activity in patients with type 1 and type 2 diabetes mellitus and the effect of the anti-oxidant coenzyme q10 on inflammatory activity oxygen sensing requires mitochondrial ros but not oxidative phosphorylation control of coronavirus infection through plasmacytoid dendritic-cell-derived type i interferon the metabolic basis of nonalcoholic steatohepatitis posttranscriptional control of t cell effector function by aerobic glycolysis dysregulated type i interferon and inflammatory monocyte-macrophage responses cause lethal pneumonia in sars-cov-infected mice role of aging and the immune response to respiratory viral infections: potential implications for covid-19 chronic low-grade inflammatory phenotype (clip) and senescent immune dysregulation acute sources of mitochondrial nad(+) during respiratory chain dysfunction nutrition and fasting mimicking diets in the prevention and treatment of autoimmune diseases and immunosenescence physical exercise as an immunomodulator of chronic diseases in aging mitochondria in lung disease cyclophilin d regulates antiviral cd8(+) t cell survival in a strategies to improve the functions and redox state of the immune system in aged subjects an update of the oxidation-inflammation theory of aging: the involvement of the immune system in oxi-inflamm-aging apoptosis remodeling in immunosenescence: implications for strategies to delay ageing sars and mers: recent insights into emerging coronaviruses t cells with dysfunctional mitochondria induce multimorbidity and premature senescence. science, eaax0860 mitochondrial deacetylase sirt3 reduces vascular dysfunction and hypertension while sirt3 depletion in essential hypertension is linked to vascular inflammation and oxidative stress coenzyme q(10) supplementation improves adipokine levels and alleviates inflammation and lipid peroxidation in conditions of metabolic syndrome: a meta-analysis of randomized controlled trials picking up a fight: fine tuning mitochondrial innate immune defenses against rna viruses. frontiers in microbiology 11 two important controversial risk factors in sars-cov-2 infection: obesity and smoking. environmental toxicology and pharmacology target acquired: selective autophagy in cardiometabolic disease survival transcriptome in the coenzyme q10 deficiency syndrome is acquired by epigenetic modifications: a modelling study for human coenzyme q10 deficiencies inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty early effector maturation of naïve human cd8(+) t cells requires mitochondrial biogenesis research on coenzyme q10 in clinical medicine and in immunomodulation pharmacological restoration of autophagy reduces hypertension-related stroke occurrence chronic inflammation (inflammaging) and its potential contribution to age-associated diseases the impact of obesity and metabolic syndrome on vaccination success oxidative-inflammatory stress in immune cells from adult mice with premature aging immune dysfunction in patients with diabetes mellitus (dm) successful and maladaptive t cell aging pathophysiology of covid-19-associated acute respiratory distress syndrome: a multicentre prospective observational study. the lancet. respiratory medicine the negative effect of lipid challenge on autophagy inhibits t cell responses ageing and respiratory infections: the airway of ageing calorie restriction enhances adult mouse lung stem cells function and reverses several ageing-induced changes mitochondrial reactive oxygen species enable proinflammatory signaling through disulfide linkage of nemo coenzyme q10 supplementation in aging and disease mitochondrial stress: a bridge between mitochondrial dysfunction and metabolic diseases? consumption of gold kiwifruit reduces severity and duration of selected upper respiratory tract infection symptoms and increases plasma vitamin c concentration in healthy older adults contribution of monocytes and macrophages to the local tissue inflammation and cytokine storm in covid-19: lessons from sars and mers, and potential therapeutic interventions innate immune recognition dietary restriction and immune function the effects of coenzyme q10 supplementation on biomarkers of inflammation and oxidative stress in among coronary artery disease: a systematic review and meta-analysis of randomized controlled trials mitochondrial transcription factor a, an endogenous danger signal, promotes tnfα release via rage-and tlr9-responsive plasmacytoid dendritic cells the nlrp3 inflammasome: an overview of mechanisms of activation and regulation sesn2/sestrin2 suppresses sepsis by inducing mitophagy and inhibiting nlrp3 activation in macrophages redox signaling in inflammation: interactions of endogenous electrophiles and mitochondria in cardiovascular disease altered lipid content inhibits autophagic vesicular fusion mitochondrial membrane potential is required for mavs-mediated antiviral signaling obesity: a critical risk factor in the covid-19 pandemic. clin obes, e12403 irf-3, irf-5, and irf-7 coordinately regulate the type i ifn response in myeloid dendritic cells downstream of mavs signaling voluntary exercise reverses immune aging induced by oxidative stress in aging mice coenzyme q10 exerts anti-inflammatory activity and induces treg in graft versus host disease coenzyme q10 inhibits th17 and stat3 signaling pathways to ameliorate colitis in mice β-cell autophagy: mechanism and role in β-cell dysfunction. molecular metabolism 27s, s92-s103 knockout of dihydrofolate reductase in mice induces hypertension and abdominal aortic aneurysm via mitochondrial dysfunction sars coronavirus papain-like protease inhibits the tlr7 signaling pathway through removing lys63-linked polyubiquitination of traf3 and traf6 murine macrophage autophagy protects against alcohol-induced liver injury by degrading interferon regulatory factor 1 (irf1) and removing damaged mitochondria autophagy in chronic kidney diseases ss31 ameliorates sepsis-induced heart injury by inhibiting oxidative stress and inflammation essential role of mitochondrial dynamics in muscle physiology mitochondrial activity and dynamics changes regarding metabolism in ageing and obesity coenzyme q in aging bioavailability of coenzyme q10 supplements depends on carrier lipids and solubilization mitochondrial dysfunction in metabolism and ageing: shared mechanisms and outcomes? calorie restriction induces mitochondrial biogenesis and bioenergetic efficiency calorie restriction as an intervention in ageing is coenzyme q a key factor in aging? mitochondrial responsibility in ageing process: innocent, suspect or guilty mediterranean diet supplemented with coenzyme q10 modulates the postprandial metabolism of advanced glycation end products in elderly men and women beneficial effects of exercise on muscle mitochondrial function in diabetes mellitus covid-19 and diabetes. diabetic medicine : a journal of the covid-19 and diabetes mellitus: unveiling the interaction of two pandemics. diabetes/metabolism research and reviews exploring the relevance of senotherapeutics for the current sars-cov-2 emergency and similar future global health threats. cells 9 coenzyme q10 and degenerative disorders affecting longevity: an overview life-span extension drug interventions affect adipose tissue inflammation in aging aging, male sex, obesity, and metabolic inflammation create the perfect storm for covid-19 the role of hif in immunity and inflammation mitochondrial dysfunction and the aging immune system inflammation, immunity, and hypertensive end-organ damage metformin and sars-cov-2: mechanistic lessons on air pollution to weather the cytokine/thrombotic storm in covid-19 delay of t cell senescence by caloric restriction in aged long-lived nonhuman primates deficient mitochondrial biogenesis in il-2 activated nk cells correlates with impaired pgc1-alpha upregulation in elderly humans (in)activity-related neuroplasticity in brainstem control of sympathetic outflow: unraveling underlying molecular, cellular, and anatomical mechanisms the role of mitochondria in inflammation: from cancer to neurodegenerative disorders daily fasting improves health and survival in male mice independent of diet composition and calories aging impairs both primary and secondary rig-i signaling for interferon induction in human monocytes mitophagy in cardiovascular diseases mitochondrial dysfunction in aging and cancer obesity, hypertension, and cardiac dysfunction: novel roles of immunometabolism in macrophage activation and inflammation high flavonoid cocoa supplement ameliorates plasma oxidative stress and inflammation levels while improving mobility and quality of life in older subjects: a double-blind randomized clinical trial autophagy: a crucial moderator of redox balance, inflammation, and apoptosis in lung disease mitochondrial dysfunction in age-related metabolic disorders covid-19 and cardiovascular disease: from basic mechanisms to clinical perspectives naturally occurring antioxidant nutrients reduce inflammatory response in mice phytochemicals and nlrp3 inflammasome inhibitory effects of phytochemicals on nlrp3 inflammasome activation: a review possible role of mitochondrial dna mutations in chronification of inflammation: focus on atherosclerosis is macrophages heterogeneity important in determining covid-19 lethality? medical hypotheses 143, 110073 covid-19, diabetes mellitus and ace2: the conundrum. diabetes research and clinical practice 162, 108132 resveratrol reverses the effect of tnf-α on inflammatory markers in a model of autoimmune uveitis t cells, aging and senescence age-related adverse inflammatory and metabolic changes begin early in adulthood impaired antibody response to influenza vaccine in hiv-infected and uninfected aging women is associated with immune activation and inflammation hypercoagulopathy and adipose tissue exacerbated inflammation may explain higher mortality in covid-19 patients with obesity. front endocrinol (lausanne) 11, 530 aging impairs mitochondrial respiratory capacity in classical monocytes circulating mitochondrial dna increases with age and is a familiar trait: implications for "inflamm-aging mitochondrial dysfunction in metabolic syndrome. biochimica et biophysica acta. molecular basis of disease a geroscience perspective on covid-19 mortality chemokine receptors: multifaceted therapeutic targets interferon β-1b in treatment of severe covid-19: a randomized clinical trial 2020. mtor inhibition and p53 activation, micrornas: the possible therapy against pandemic covid-19 activation-induced autophagy is preserved in cd4+ t-cells in familial longevity new insights into the implication of mitochondrial dysfunction in tissue, peripheral blood mononuclear cells, and platelets during lung diseases age-dependent effect of every-other-day feeding and aerobic exercise in ubiquinone levels and related antioxidant activities in mice muscle muscle physiology changes induced by every other day feeding and endurance exercise in mice: effects on physical performance inhibitory effect of dietary lipids on chaperone-mediated autophagy peripheral lymphocytes, obesity, and metabolic syndrome in young adults: an immunometabolism study mitochondrial biogenesis and proteome remodeling promote one-carbon metabolism for t cell activation targeting cytokine storm to manage patients with covid-19: a mini-review inhibition of the alpha/beta interferon response by mouse hepatitis virus at multiple levels the epidemiology and pathogenesis of coronavirus disease (covid-19) outbreak the association of cardiovascular diseases and diabetes mellitus with covid-19 (sars-cov-2) and their possible mechanisms mechanisms of aging and potential role of selected polyphenols in extending healthspan autophagy in lung disease pathogenesis and therapeutics mitochondria as a centrally positioned hub in the innate immune response. biochimica et biophysica acta. molecular basis of disease 1863 supplementation with the reduced form of coenzyme q10 decelerates phenotypic characteristics of senescence and induces a peroxisome proliferator-activated receptor-alpha gene expression signature in samp1 mice effects of acute and chronic exercise on immunological parameters in the elderly aged: can physical activity counteract the effects of aging? frontiers in immunology 9 identification and characterization of mavs, a mitochondrial antiviral signaling protein that activates nf-kappab and irf 3 the redox environment and mitochondrial dysfunction in agerelated skeletal muscle atrophy mitochondrial dysfunction and dna damage in the context of pathogenesis of low circulating coenzyme q10 during acute phase is associated with inflammation, malnutrition, and in-hospital mortality in patients admitted to the coronary care unit nicotinamide mononucleotide preserves mitochondrial function and increases survival in hemorrhagic shock mitochondrial destiny in type 2 diabetes: the effects of oxidative stress on the dynamics and biogenesis of mitochondria inhibition of beta interferon induction by severe acute respiratory syndrome coronavirus suggests a two-step model for activation of interferon regulatory factor 3 agephagy -adapting autophagy for health during aging obesity and impaired metabolic health in patients with covid-19 effects of exercise on inflammatory, oxidative, and neurotrophic biomarkers on cognitively impaired individuals diagnosed with dementia or mild cognitive impairment: a systematic review and meta-analysis international journal of molecular sciences 20 cyclic gmp-amp synthase is a cytosolic dna sensor that activates the type i interferon pathway coronavirus papain-like proteases negatively regulate antiviral innate immune response through disruption of sting-mediated signaling pamps and damps: signal 0s that spur autophagy and immunity succinate is an inflammatory signal that induces il-1beta through hif-1alpha cytochrome c oxidase activity is a metabolic checkpoint that regulates cell fate decisions during t cell activation and differentiation inflammation brakes mitochondrial metabolism in obesity mapping the innate signaling cascade essential for cytokine storm during influenza virus infection mitochondrial bioenergetics and pulmonary dysfunction: current progress and future directions pattern recognition receptors and the innate immune response to viral infection mitochondrial reactive oxygen species contribute to pathological inflammation during influenza a virus infection in mice health benefits of the mediterranean diet: metabolic and molecular mechanisms azorella compacta infusion activates human immune cells and scavenges free radicals in vitro modulation of endogenous antioxidant activity by resveratrol and exercise in mouse liver is age dependent anti-inflammatory effect of resveratrol in old mice liver is immunosenescence influenced by our lifetime "dose" of exercise cd8 memory t cells have a bioenergetic advantage that underlies their rapid recall ability the role of interleukin 6 during viral infections a mitochondrial approach to cardiovascular risk and disease combination therapy with glucan and coenzyme q10 in murine experimental autoimmune disease and cancer mitochondria in the regulation of innate and adaptive immunity mitochondrial dysfunction in neurodegenerative diseases and drug targets via apoptotic signaling emerging views of mitophagy in immunity and autoimmune diseases autophagy in the heart inhibition of thymic adipogenesis by caloric restriction is coupled with reduction in age-related thymic involution nicotinamide mononucleotide inhibits jnk activation to reverse alzheimer disease dietary intake of resveratrol enhances the adaptive immunity of aged rats mitochondrial ros-induced lysosomal dysfunction impairs autophagic flux and contributes to m1 macrophage polarization in a diabetic condition mediterranean diet supplemented with coenzyme q10 modifies the expression of proinflammatory and endoplasmic reticulum stress-related genes in elderly men and women association of hypertension, diabetes, stroke, cancer, kidney disease, and high-cholesterol with covid-19 disease severity and fatality: a systematic review effects of coenzyme q10 on markers of inflammation: a systematic review and meta-analysis decreasing pro-inflammatory cytokine and reversing the immunosenescence with extracts of pu-erh tea in senescence accelerated mouse inborn errors of type i ifn immunity in patients with life-threatening covid-19 short-term administration of nicotinamide mononucleotide preserves cardiac mitochondrial homeostasis and prevents heart failure nlrp3 inflammasome-a key player in antiviral responses nf-κb restricts inflammasome activation via elimination of damaged mitochondria clinical course and risk factors for mortality of adult inpatients with covid-19 in wuhan, china: a retrospective cohort study a pneumonia outbreak associated with a new coronavirus of probable bat origin post-translational regulation of antiviral innate signaling ribose 2'-o-methylation provides a molecular signature for the distinction of self and non-self mrna dependent on the rna sensor mda5 key: cord-003244-abs3tc3r authors: chong, ka chun; hu, pei; lau, steven; jia, katherine min; liang, wenjia; wang, maggie haitian; zee, benny chung ying; sun, riyang; zheng, huizhen title: monitoring the age-specificity of measles transmissions during 2009-2016 in southern china date: 2018-10-08 journal: plos one doi: 10.1371/journal.pone.0205339 sha: doc_id: 3244 cord_uid: abs3tc3r background: despite several immunization efforts, china saw a resurgence of measles in 2012. monitoring of transmissions of individuals from different age groups could offer information that would be valuable for planning adequate disease control strategies. we compared the age-specific effective reproductive numbers (r) of measles during 2009–2016 in guangdong, china. methods: we estimated the age-specific r values for 7 age groups: 0–8 months, 9–18 months, 19 months to 6 years, 7–15 years, 16–25 years, 26–45 years, and ≥46 years adapting the contact matrix of china. the daily numbers of laboratory and clinically confirmed cases reported to the center for disease control and prevention of guangdong were used. results: the peak r values of the entire population were above unity from 2012 to 2016, indicating the persistence of measles in the population. in general, children aged 0–6 years and adults aged 26–45 years had larger values of r when comparing with other age groups after 2012. while the peaks of r values for children aged 0–6 years dropped steadily after 2013, the peaks of r values for adults aged 26–45 years kept at a high range every year. conclusions: although the provincial supplementary immunization activities (sias) conducted in 2009 and 2010 were able to reduce the transmissions from 2009 to 2011, larger values of r for children aged 0–6 years were observed after 2012, indicating that the benefits of the sias were short-lived. in addition, the transmissions from adults aged between 26 and 45 years increased over time. disease control strategies should target children and adult groups that carry high potential for measles transmission. increased over time. disease control strategies should target children and adult groups that carry high potential for measles transmission. measles is a highly contagious acute viral disease. throughout the world, and most countries have set goals for its elimination. in 1978, the national expanded program on immunization (epi) in china started to implement a standard schedule for the routine administration of one dose of measles-containing vaccine (mcv1) among children between 8 and 24 months of age. subsequently, the mean annual measles incidence decreased from 355 per 100,000 in 1970-1979 to 53 per 100,000 in 1980-1989 [1] . in 1986, a two-dose routine measles immunization program was implemented for children aged between 8 months and 7 years. the age schedule for the second dose of mcv (mcv2) was shifted to 18-24 months in 2005. during 2000-2009, the number of measles cases showed a remarkable decrease but remained around 6.8 per 100,000 on average [2] . in 2006, the government of china set a goal to eliminate measles by 2012, for which purpose a series of programs was implemented, including strengthening routine immunization surveillance, supplementary immunization activities (sias), and casebased surveillance [2] . an sia is defined as the administration of a supplementary dose of a vaccine to a specific age population in a certain area during a short period, regardless of the recipients' previous vaccination histories. sias enhance routine immunization programs, including catch-up campaigns, follow-up campaigns, and outbreak-response immunization. the estimated coverage rate of routine immunization with mcv1 increased from 80.4% in 2000 to 91.1% in 2009, whereas the estimated coverage rate for mcv2 was <80% before 2005 and 84.3% in 2009 [1] . in september 2010, china conducted a synchronized, nationwide sia that targeted children aged 8 months to 14 years, covering 102 million children with a reported coverage rate of 97.5% [1] [2] [3] . although the annual measles incidence had dropped to 0.46 per 100,000 in 2012, it resurged to more than 1.96 per 100,000 in 2013 [3] . despite the implementation of two-dose routine vaccines since 2005, frequent outbreaks have occurred over the past years [4] [5] [6] . guangdong, a highly populated province with 108 million population in 2015, is located in the southernmost part of mainland china (fig 1) . the incidence of measles in guangdong dropped to a remarkable low in 2011 (0.30/100,000) after a series of sias targeting children aged 8 months to 14 years during 2009 and 2010. however, guangdong had the highest number of reported cases in china in 2012 and 2013, with incidences of 1.84 and 6.64 per 100,000, respectively [7] , even though the reported coverage of mcvs was kept above 98% every year after 2009. to this end, the guangdong government implemented some mop-up vaccination programs after 2012 targeting children aged 8 months to 6 years (fig 1) . monitoring the effectiveness of the measles control policy is done by surveillance. in china, measles is a category b infectious disease which indicates it is highly contagious and must be reported to the surveillance system within 24 hours after confirming the laboratory samples [8] . since 2004, china has a direct network reporting system and automatic warning information system for infectious diseases. the system focusses on the number of reported cases, but does not evaluate the transmissibility of measles. the effective reproduction number, r, is a key epidemiologic variable that summarizes the transmissibility of infectious diseases. it is defined as the expected average number of secondary cases produced by an infectious individual in a population in which not all the individuals are susceptible [9] . when r is larger than 1, an infectious individual is expected to infect more than one secondary case. when r is less than 1, an infectious individual tends to infect less than one secondary case, and the incidence will decrease. nevertheless, some infectious diseases have been shown to be strongly age-specific, for example, measles. age-specific r, defined as an average total number of secondary cases from all age groups generated by a single case with respect to his age group was recommended to study the differences in transmission potential taking account of social mixing [10] [11] [12] [13] [14] [15] . although a usual interpretation of age-specific r for gauging the control measures required to eliminate an infection is inappropriate [16, 17] , age-specific rs provide valuable information on the underlying heterogeneous transmission between and within different groups of individuals. for example, glass et al. estimated the rs of pandemic influenza a(h1n1) for children and adults and identified children had a higher transmission then adult cases. in china, the demography of measles infections has changed over time. while infants aged between 9 months and 18 months and young adults aged 16 to 25 years were the primary population of measles infections, children aged 0 to 8 months and adults aged 26-45 years became the primary sources after the national sia. apparently, the age specificity in measles transmissions could be affected by vaccination policies. chong et al. [18] showed that even though substantial decreases in the numbers of cases were observed after mass vaccination campaign, measles could still persist in a population given a high value of r. the majority of the relevant epidemiological studies conducted in china have been based on reported cases and have aimed to describe the incidence and characteristics of population distribution [19, 20] . however, the age specificity in measles transmissions had hardly been studied. in the present study, we compared the age-specific r of measles infections between different age groups by using laboratory and clinically confirmed data collected from 2009 to 2016. daily notifications of measles cases from january 1, 2009 to december 31, 2016 were collected from the national infectious disease monitoring information system (nidmis), as complied by the center for disease control and prevention (cdc) of guangdong province. for some of the cases with typical clinical symptoms, case notifications were sent to the person in charge of reporting by outpatient or resident doctors, and the cases were then recorded as "clinically confirmed". blood samples from these cases were sent to cdc clinical laboratories for confirmation, if laboratory capacity allowed. other cases with atypical clinical symptoms were recorded as "suspected cases," and the blood samples of these cases were subsequently transferred to a diagnostic laboratory to obtain a confirmed diagnosis. the test results were returned to the patients' doctors. if the test results were positive, the cases were relabeled as "laboratory-confirmed cases," and the person in charge of reporting was notified. if the results were negative, the cases were relabeled according to the specific disease that had been detected before handing over to the reporting personnel. for the (clinically confirmed or suspected) cases without laboratory confirmation, epidemiological investigations were conducted to determine whether the patients' infections had any linkage to other confirmed cases within 7-21 days before the onset of any symptom. the epidemiological investigations were performed through direct contacts in the relevant village, community, or school, or through direct contacts for mass gathering events. the clinically confirmed and laboratory-confirmed cases were both regarded as cases, and reporting personnel were required to report such cases to the nidmis within 6 hours. we divided the population into 7 age groups according to the age of onset: 0-8 months (pre-vaccination age), 9-18 months (received the first dose of the measles containing vaccine, mcv-1), 19 months to 6 years (received the second dose of the measles containing vaccine, mcv-2), 7-15 years (primary and secondary school students), 16-25 years (high school and college students/young adults), 26-45 years (mature adults), and !46 years (aged adults). this study was reviewed and approved by the medical ethics committee of the guangdong cdc. the application of the data in this study has been authorized by the guangdong cdc. all data were fully anonymized prior to access by any of the authors and does not involve patients' privacy prior collection. informed consents were exempt from the ethics committee in accordance to the cdc policy of continuing public health investigations of notifiable infectious diseases, in which the patient names, addresses, medical histories with infectious diseases, and their family information will not be disclosed to the public by guangdong cdc in any form. the data are available without restrictions (the link will be provided after the acceptance of the paper). the method for estimating the age-specific effective reproduction numbers suggested by white et al. [10] , which is a modification of the wallinga and teunis approach [21] , was adopted. let p d denote the probability of a serial interval of length d, (d = 1,2,. . .,d where d be the maximum serial interval length), n t;g i denote the frequency of symptom onset in age group g i (i = 1,2,. . .,g where g is the total number of age groups) on day t (t = 1,2,. . .,t where t is the length of the study period), r g i !g j denote the contact rate between two individuals from age group g i and age group g j (j = 1,2,. . .,g). the effective reproduction number of age group g i on day t, r t;g i , can be calculated by summing the expected number of individuals in each age group from t+1 to t+d infected by an individual in age group g i whose symptom onset was on day t: denote the relative probability that an individual in group g j on day t+d was infected by an individual in group g i on day t. in this study, there were 7 age groups (i.e., g = 7) and the maximum serial interval length d was set at 20. p d was generated from a gamma distribution with a mean of 7 days and standard deviation of 3 days [14] . r g i !g j was estimated by using the contact matrix of china, projected by the bayesian hierarchical model in prem et al [22] . the estimation formulas were implemented in microsoft excel. we extended the probabilistic method described in white et al. to generate the statistical uncertainty [15] . a parametric bootstrapping approach was employed to generate 1,000 realizations of fr t;g i g. in each iteration, we generated a new dataset by first simulating the total number of individuals in group g j (j = 1, 2, . . ., 7) infected by those in group g i (i = 1, 2, . . ., 7) with symptom onset of day t (t = 1, 2, . . ., t-1) from a poisson distribution with mean = n t;g i â x minðd;tà tþ d¼1 n tþd;g j â pði t;g i ! i tþd;g j þ, which can be interpreted as the estimated total number of individuals in group g j infected by all the individuals in group g i with symptom onset on day t, where n t;g i and pði t;g i ! i tþd;g j þ were directly obtained and calculated from the original dataset respectively. the simulated number was then distributed within the serial interval t + 1 and t + 20 according to a gamma distribution with a mean of 7 days and standard deviation of 3 days. the above procedure was repeated for all i,j, and t. the resulting data were used to calculate a realization of fr t;g i g and further averaged by months. the 95% credible intervals (ci) of the monthly estimates were obtained from the 2.5 th and 97.5 th percentiles over the 1,000 realizations. apart from china's contact matrix, contact matrixes from 8 other countries were employed to test the sensitivity of our results [23] . we also tried evaluating the estimates using 12 days and 3 days as the mean and standard deviation of the gamma distribution of the serial interval [24] . the r values estimated for children aged 7-15 years were low across the study period in general, even though the values also increased since 2012, indicating that primary and secondary school students had a limited contribution to measles transmissions. similarly, the results for the adults aged !46 years were extremely low across the study period, indicating that these persons were unlikely to infect more than a case on average. the for adults aged between 26 and 45 years, a clear seasonal pattern of r values was observed after 2012, which showed a similar trend to that observed in children. in 2014 and 2015, the estimated annual peaks of r were 1.24 (95% ci: 1.03 to 1.33) and 1.20 (95% ci: 1.01 to 1.39) respectively. given that the r peak of the entire population was significantly above unity in 2016, adults aged 26-45 years had the largest contribution to measles transmissions. s1 fig shows the sensitivity of the results to the use of contact matrices from other countries [23] . in general, the major findings were robust with the variation of contact patterns, for example, children aged 0-6 years still had a large contribution in measles transmissions after 2012. nevertheless, due to a difference in contact frequency, larger estimates were observed for children aged 0-8 months and 9-19 months when using the contact matrix of germany. moreover, while using poland's contact matrix drew a lower estimates for children aged 0-8 we also investigated using a different set of parameters for the distribution of the serial interval, and found that the results were generally consistent with the main analysis (s2 fig). the r values of children groups were slightly increased, whereas the r values of adult groups were slightly decreased. monitoring the age specificity of measles transmissions could provide information that would be valuable to officials who seek to develop adequate disease control strategies. for example, it could help to select appropriate age groups for supplementary vaccination. in this study, we compared the age-specific r of measles infections between different age groups, using laboratory and clinically confirmed data from 2009 to 2016 for guangdong province. according to the results, measles transmissions varied across most age groups before and after 2012 and the large values of r from the entire population indicated a persistence of measles in the population from 2012 to 2016. in general, children aged 0-6 years and adults aged 26-45 years had higher contributions in measles transmissions when comparing with other age groups after 2012. after 2013, while the peaks of r values for children aged 0-6 years dropped steadily by years, the peaks of r values for adults aged 26-45 years remained unchanged and kept at a high range every year, demonstrating the highest contributions in measles transmissions. the findings suggest that disease control strategies should target children and adult groups that carry a high potential for measles transmission. as has been previously noted, we found that children aged 0-6 years had r values that increased after 2012, even though sias targeted this population in 2009 and 2010. the increasing r values could have resulted from low mcv coverage in this cohort, for which the official reported coverage was usually over-estimated [25, 26] . an in-house survey of a similar cohort of children aged 24-47 months showed that mcv1 and mcv2 coverage rates were only 83% and 75%, respectively [25] , results that were inconsistent with the generally reported figure of >98% in china [27] . the geographic heterogeneity of vaccine coverage in china could be another explanation [28, 29] . a chinese study indicated that the measles antibody levels of children aged 2-10 years old were significantly lower for residents of rural areas than for residents of urban areas [28] . the primary reasons why rural children had missed their mcvs were because they were living far from the clinics and because they were unable to access vaccination information [30] . the incomplete immunization records of rural children also made it more difficult for public health officials to track them in order to administer the vaccine. we observed elevated transmissions in infants aged 0-8 months, which may primarily be attributed to the design of the immunization system, which regarded them as too young to be vaccinated by either routine immunization or sias. a longitudinal study of maternal measles antibody titers in infants in guangzhou (the provincial capital of guangdong province) showed that titers among infants decreased rapidly after 3 months of age, and were generally undetectable at 7 months of age [31] . several other studies reported similar results [32, 33] . hence, there was a remarkable immunity gap among children under 8 months old. some studies showed that only around 2.7% to 6.8% of infants are seropositive for measles at 6 months of age [34, 35] . nevertheless, even though infants aged 0-8 months were identified as a high transmissibility group, reducing the minimum age for receiving mcv-1 to 6 months is controversial. we also found that the transmissions from children aged 7-15 years were comparatively low, which was expected given that given that they were the main target of previous sias. moreover, many primary schools implemented screening of children's vaccination certificates and administered supplementary doses of the measles vaccine to fill immunity gaps before the annual entrance [36] . the values of age-specific r for adults aged between 26 and 45 years kept at a high range from 2013 to 2016 and it could be attributed to the lower efficacy of measles vaccines, the low vaccination coverages during 1980s and earlier, and the reduced chance of natural infections. persons aged 26-45 years at the time of the present study were thought to be the first recipients of the vaccination after the approval of routine immunization. liquid vaccines were used for immunization at that time. they had a lower effective dosage and may have resulted in the lower level or shorter protective duration of antibodies among the population. in addition, a functional cold chain, transportation, and communication system for the measles vaccine had not been established at that time; hence, the quality and efficacy of the vaccines could not be guaranteed. secondly, several parents knew nothing about the measles vaccine and underestimated the severity of measles, thereby resulting in a low vaccination rate and a high rate of unsure inoculation history. thirdly, secondary vaccine failure (i.e. measles onset after vaccination and successful seroconversion) due to waning immunity might have occurred among vaccinated adults. although our study could not identify secondary vaccine failure from other cases as serological evidence of previous successful vaccination were lacked, it has been concluded by who that waning immunity has not played a major role in the transmission of measles compared to the absence of initial immunity [37] . the proportion of cases attributable to secondary vaccine failure varied greatly across outbreaks [38] . in a cohort study (n = 2882) in zhuji county of zhejiang province, around 11-13% of those given with single doses of domestic vaccines would become sero-negative (measured by haemagglutination-inhibition tests) after 14 years, yet clinical measles cases rarely happened among them who had humoral immunity waned as they were still protected by secondary immune response [37, 39] . finally, the subsequent sias did not cover these persons; thus, the immunity gaps among people aged 26 to 45 years increased. on the other hand, the transmissions from individuals aged !46 years were the lowest among the age groups studied, even though there was almost no vaccination history in this group. we believe that the majority of these individuals acquired antibodies through natural infection, owing to the highly contagious nature of measles when they were young. moreover, many studies have shown that seropositivity after natural infection persists longer and generates a stronger response than the immunity acquired from vaccination [39] [40] [41] . given the increasing values of r for the entire population observed after 2012, some mopup vaccination campaigns in 2012 and 2013 appear to have had limited effectiveness, even though they aimed to control measles transmission. one reason for this is that rural families usually have a lower level of education and do not fully understand information regarding mop-up campaigns, which results in a lack of initiative to get the vaccine. moreover, some of the susceptibles were migrants, and officials reported difficulties tracking their vaccination histories. although door-to-door notifications, text messages, and telephone notifications have been used to inform migrant families to join mop-up campaigns [42] , it is often difficult to contact these families because of changes to their addresses or phone numbers. from a policy-making perspective, these results imply that for a successful measles control campaign, the public health department should carry out control measures for appropriate age groups. for children between 9 and 18 months old, it is necessary to take measures to improve vaccination coverage, including providing more publicity to improve parents' awareness about vaccination against measles, creating integrated multichannel notifications to inform parents of the vaccination, and strengthening the supervision of kindergartens. for adjustments to the immunization strategy, adult-specific vaccination programs should be considered to fill the immunity gaps among adults, especially for those aged between 26 and 45 years. one of the major limitations in this study is the quality of notification data. indeed, a proportion (~30%) of the notification data in the early phase study (2009) (2010) (2011) was only clinically confirmed which may lead to some misdiagnosis as well as an underestimate of the age-specific rs. nevertheless, more than 95% of cases were laboratory confirmed after 2011. particularly, the reliance on clinically confirmation was more in rural hospitals in which doctors may lack sufficient knowledge on measles diagnosis. the positive predictive value of a clinical definition would also be changed over time as measles has become rarer by time. to minimize the chance of misdiagnosis, the clinically confirmed cases were not only identified by clinical symptoms, but were also investigated with any potential epidemiological association with other laboratory-confirmed cases. moreover, the completeness of the data could be affected by underreporting as some of the parents might have regarded measles as a kind of skin disease or might have confused it with other diseases that involve skin rashes. apart from that, age-specific rs are common to be used as a metric to identify appropriate age groups most responsible for transmission as for a target of interventions [10, 12, 13] . however, when determining the effort required to eliminate an infection, the interpretation of an age-specific r is different from that of an overall r in a heterogeneous population as using the original threshold of unity could lead to an underestimation of target population for interventions [16, 17] . alternatively, roberts & heesterbeek [17] suggested a type-reproduction number which can single out particular subgroup rather than averaging over all subgroups. further works such as generalizability and statistical inference [16] on the alternative measures worth being investigated. in summary, we compared the age specificity in measles transmissions from 2009 to 2016 in guangdong province. although the provincial sias conducted in 2009 and 2010 were able to reduce the transmission rates from 2009 to 2011, larger effective reproductive numbers for children aged 0-6 years were observed after 2012, which indicates that the benefits of the sias were short-lived. in addition, the transmissions from adults aged between 26 and 45 years increased over time. based on the findings of the present study, we believe that disease control measures should strategically target those groups that carry a high potential for measles transmissions. monitoring progress towards the elimination of measles in china: an analysis of measles surveillance data beijing: world health organization china representative office world health organization. measles and rubella surveillance data investigation of a measles outbreak in china to identify gaps in vaccination coverage, routes of transmission, and interventions endemic and imported measles virus-associated outbreaks among adults new measles virus genotype associated with outbreak on the road to measles-free: where are we now? law of the people's republic of china on prevention and treatment of infectious diseases. database of laws and regulations definition and estimation of an actual reproduction number describing past infectious disease transmission: application to hiv epidemics among homosexual men in denmark determining the dynamics of influenza transmission by age estimating age-specific reproductive numbers-a comparison of methods. statistical methods in medical research estimating reproduction numbers for adults and children from case data pandemic influenza h1n1: reconciling serosurvey data with estimates of the reproduction number likelihood-based estimation of continuous-time epidemic models from time-series data: application to measles transmission in london estimation of the reproductive number and the serial interval in early phase of the 2009 influenza a/h1n1 pandemic in the usa. influenza and other respiratory viruses the type-reproduction number t in models for infectious disease control. mathematical biosciences a new method for estimating the effort required to control an infectious disease interpreting the transmissibility of measles in two different post periods of supplementary immunization activities in hubei epidemiological analysis of measles in china between changes of epidemiological characteristics of measles in beijing before and after supplementary immunization campaigns of measles vaccine in 2010 different epidemic curves for severe acute respiratory syndrome reveal similar impacts of control measures projecting social contact matrices in 152 countries using contact surveys and demographic data social contacts and mixing patterns relevant to the spread of infectious diseases the correlation between infectivity and incubation period of measles, estimated from households with two cases measles vaccine coverage estimates in an outbreak three years after the nation-wide campaign in china: implications for measles elimination investigation of a case of measles outbreak in a kindergarten in hubei province immunization: measles, 1st dose (mcv1) immunization coverage estimates by country comparison of measles antibody levels and trends of children aged 2-10 years between 2010 and 2015 in jiujiang area, jiangxi province analysis on the immunization of measles and its influencing factors among freshmen in elementary school and kindergarten in shenzhen city analysis of the influencing factors of measles vaccine leakage dynamic maternal measles antibody level in infants: a longitudinal study fetal, and neonatal outcomes associated with measles during pregnancy: namibia early waning of maternal measles antibodies in era of measles elimination: longitudinal study pre-vaccination evolution of antibodies among infants 0, 3 and 6months of age: a longitudinal analysis of measles, enterovirus 71 and coxsackievirus 16. vaccine measles antibodies in mother-infant dyads in tianjin notice on the implementation plan for checking the vaccination certificate before children's kindergarten and primary school enrollment in guangdong province world health organization. measles vaccines: who position paper identification of primary and secondary measles vaccine failures by measurement of immunoglobulin g avidity in measles cases during the 1997 são paulo epidemic duration of immunity following immunization with live measles vaccine: 15 years of observation in zhejiang province decreasing seroprevalence of measles antibodies after vaccination-possible gap in measles protection in adults in the czech republic immunoglobulin response in serum and secretions after immunization with live and inactivated poliovaccine and natural infection the influence of children's immunization leak replant measures on improving immunization vaccination rate we thank guangdong cdc for providing the data for analysis. we thank the two anonymous reviewers whose comments helped improve and clarify this manuscript. key: cord-306210-ny3vvu9h authors: clarfield, a. mark; jotkowitz, alan title: age, ageing, ageism and “age-itation” in the age of covid-19: rights and obligations relating to older persons in israel as observed through the lens of medical ethics date: 2020-11-12 journal: isr j health policy res doi: 10.1186/s13584-020-00416-y sha: doc_id: 306210 cord_uid: ny3vvu9h covid-19, the illness caused by the sars-cov-2 virus, has reached pandemic proportions. although the virus can cause disease in anyone, it is particularly dangerous for those with various “co-morbidities” such as heart disease, hypertension, diabetes, obesity and others. furthermore, advancing age (from about 60 on), even in those older persons without any accompanying illnesses, is a strong and independent risk factor for pneumonia, need for an icu bed and death from the virus. it is therefore essential to find ways to protect all at-risk persons (old or young) from the virus but at the same time not harming, more than absolutely necessary their essential freedoms as well as taking into account their social/psychological needs. compared with other oecd countries, israel’s population is still relatively young, with only 11.5% being over 65+ with a smaller proportion of older persons in long-term institutions than that found in most other comparable jurisdictions. these factors might explain a part of the country’s (so far) relatively low rates of serious disease and mortality compared to those seen in other developed countries. however there are still over a million older citizens at risk and the numbers of infected, hospitalized and seriously ill persons are rising once again. this is no time for complacency. an analysis of the effect of age on the disease as seen through the principles of medical ethics is followed by a proposal as to how best to balance these sometimes conflicting goals. this paper relates mainly to older persons in the community since the ministry of health early on in the pandemic initiated an effective program (magen avot) meant to protect those older persons in long-term care institutions. recommendations include the ministry of health publishing clear guidelines as to risk factors and offering sensible advice on how to practice physical (not “social”) distancing without exacerbating an older person’s sense of social isolation. in order to reduce the incidence of influenza (which can clinically be confused with covid-19) and the potentially disastrous consequences of a “double pandemic” this coming winter, a robust flu vaccination program needs immediate implementation. persons at all ages (but especially those 60+) should be encouraged and assisted to sign advance directives, especially those who do not wish to undergo invasive therapy. an individual older person’s wish to “make way” for younger people should be respected as an expression of his/her autonomy. as we enter the second wave, triage mechanisms and protocols need to be circulated in readiness for and well before a situation in which an acute imbalance develops between the availability for acute resources and the population’s need for them. the ministry of health, in cooperation with other relevant ministries and ngos, should take the lead in developing plans, ensuring that they are carried out in an orderly, timely and transparent manner. the blanket is indeed not large enough but we must place it as judiciously as possible in order as much as possible to protect, cover and keep warm the body politic. supplementary information: supplementary information accompanies this paper at 10.1186/s13584-020-00416-y. the sars-cov-2 virus can effect anyone at any age. as it continues to spread throughout the world it will clearly be with us for the foreseeable future. fortunately, at any age, almost all infected people (even older persons) will overcome this infection without serious sequelae. that being said, the waning immunological vigour of older persons and presence of risk factors ("co-morbidity") often accompanying older age (hypertension, increased bmi, diabetes, chronic lung disease, immunomodulation-immunosuppression, smoking, ischemic heart disease and cerebrovascular disease, etc.) make the disease a much more serious event for many older people. furthermore, it presents special challenges to their doctors and to the health care system (ref [1] ). for those infected, the incidence of severe disease rises inexorably and logarithmically with chronological age (beginning around age 60). comorbidity adds to the risk but does not replace age as an independent factor. some older patients will develop viral pneumonia and a relatively small subgroup will require icu and ventilator support. however, should these numbers grow too quickly, they can easily overwhelm the number of medical staff, hospital beds and ventilators available -a dire situation already observed in several places around the world. many of these acutely ill patients will die and the majority, even if they do survive, remain in the icu for many weeks. in this paper we address the issue of old age and how this particular coronavirus specifically effects older people with israel's experience being the framework for this exploration. in order to do so we first describe the country's demography briefly followed by a few words about formal jewish law (halacha) and its role (or surprising lack thereof) in framing health policy. next, the issue of aging itself is dissected: its role as a risk factor for and the influence of lockdown policies on older persons. as well we define "ageism", explaining the concept's relevance: what it is and what it is not as well as how ageism can adversely affect older persons during this crisis. we then analyze some of the trenchant dilemmas relating to covid-19 through the lens of medical ethics, examining the issues of triage and distributive justice, maximizing non-maleficence and how to ensure that older people's autonomy is facilitated while ensuring that they also remain safe (beneficence). given all of the aforementioned, we offer a specific program for how to move forward and help older persons and the health system to stay afloat as we try to ride the second wave of the pandemic without drowning. compared with most other industrialized countries, israel's population is still relatively young. this demographic pattern effects the expression of the pandemic in the country. see sidebar 1 for details. across the globe the reported case-fatality rate (ratio between confirmed deaths and confirmed cases) for covid-19 is around 2.8% (more than 10 times that for influenza), but this number can vary widely by locationas high as 9.7% (italy) to less than 0.3% (iceland) (https://ourworldindata.org/grapher/coronavirus-cfr; accessed 17 oct., 2020). in israel, at least so far (as of late october, 2020), this rate is still relatively low at 0.7% and despite the very sharp recent rise in confirmed cases it has held reasonably steady over the past few months. examining another ratio (again, as of late october, 2020), 231 per million population have died here compared with 637 in the uk or 672 in the us, although the rate in israel may rise given the recent increase in new cases observed. (see https://www.worldometers.info/coronavirus/ accessed october 17, 2020) . for various reasons, early on, in the spring of 2020, the country coped quite well -with a very low infection rate, few severe cases and a very low death rate. however, coinciding with (or because of) a too rapid release from the lockdown, the figures have deteriorated over the past few months, especially recently (late october). for example, according to the ministry of health's (hebrew language) dashboard (see https://datadashboard.health.gov.il/covid-19/?utm_source=go.gov.il& utm_medium=referral; accessed 17 oct., 2020) the number of new confirmed cases almost doubled in the last week of august 2020 and the number of severe and ventilated cases has gone up by 20% in the last week of august. as of late september the government had reclosed the country more or less hermetically after a failed policy of quarantining "hot" cities or neighbourhoods with particularly high rates of infection -most of these being haredi (ultra-orthodox) or arab municipalities. as such, beginning just before judaism's most holy day of atonement (yom kippur) the country has once again been hermetically closed down for a planned two week (at least) period. this after the failure of localized urban quarantines which failed to dampen the epidemic -most of these being in haredi (ultra-orthodox) or arab municipalities. this picture can hardly be considered successful policy management even if there remains legitimate argument about the variance caused by each of the many steps taken (or not) to date. clearly, these numbers express a moving target and it is not easy nor often possible to tease out the exact cause and effect for rising or falling rates which may be affected by many variables such as change in or extent of testing policy and others. furthermore, improved treatment protocols have brought the pressure for icu/ventilator resources down somewhat. equally important, with respect to a possible exhaustion of the health system through care seeking, the number of hospital beds, trained personnel etc. may be much more important than the number of ventilators. overall, given the larger number of asymptomatic people than those identified as infected, the overall death rate for those actually infected may be even lower than that reported. however, we do not yet know if all those who do survive serious illness will return to their premorbid state of health and function. there is some doubt that this will be the case, with a prediction that a significant minority may suffer serious long-term sequelae subsequently requiring rehabilitation (ref [2] ). in israel, in response to this pandemic, as has been the case in many countries, initially broad and very strict social distancing measures were enacted for the whole population. however, after the number of cases fell precipitously in may these strictures were loosened. unfortunately, despite warnings by relevant professionals, this release was allowed to take place much too quickly and in a rather haphazard manner, with a resultant recrudescence of cases. not surprisingly, many older people found these lockdown steps very difficult to tolerate as a result of being almost totally cut off from family and friends, not to speak of having to look after themselves with minimal help from outside. there is concern that the dangers of social isolation for older people may equal or even outweigh its benefits (ref [3] ). as such, some have called for a useful change in terminology from "social" to "physical" distancing. furthermore, some older people in israel were skeptical of the government's motives and felt that they were being "sacrificed" to keep the medical system functioning in order to favour younger citizens. for their part, many younger people continue to express skepticism relating to the dangers of sars-cov-2 as a result of their low chance of suffering a complication should they become infected and in part because of their understandable lack of faith in the present government and its actions. although we are dealing with a fast and erratically moving target, with the present situation in mind this paper will elucidate relevant issues and offer policy recommendations germane to when and how older persons can minimize risk and at some point in the future return to their pre-covid-19 routine in israel. the general approach taken is that of a "soft utilitarianism" (i.e. what promises the greatest good to the greatest number) while at the same time we make every effort to minimize damage to individual human rights and to ensure that the scourge of ageism does not manifest itself. against the odds, if the epidemic once again quickly subsides, the issues addressed herein will be much less relevant. however, this paper is meant to deal with the much more probable scenario in which sars-cov-2 will be with us for months, perhaps years to come, and especially as we now suffer a second wave more severe than the first. and as was the case in the 1919/20 influenza epidemic, we may even have to endure a third wave. around the world, as a first and necessary step, blanket physical distancing has proven itself, as it did in previous influenza pandemics (both 1918 and 2009). along with heightened personal hygiene, hand washing, and especially the use of face masks, this blunt instrument had until very recently (mid-june) largely reduced and delayed peak attack rates in many countries as well as reducing mortality and the number of very sick persons requiring hospital care (ref [4] ). in israel and elsewhere, but unfortunately not everywhere (see northern italy ref [5] and spain), this tool helped save many lives as well as reducing pressure on acute and icu hospital beds, of which israel is lacking. as well, this step has helped at least so far to preserve precious icu/ventilator beds for the use of young and old alike. along with the whole population so far, at least physically, older persons have benefitted from these drastic measures, although the national economy is taking a severe blow adding not surprisingly to social and political instability. as the country locks down again, the question arises once more as to what approach should be taken. an excellent overview of how to manage such a challenge can be found in tomas pueyo's much cited article "the hammer and the dance" in which the "hammer" refers to the lockdown resulting in abrupt social distancing meant to flatten the curve and the "dance" to how we can get out of lockdown with the least possible loss of life whilst making every effort to maintain the economy (https://medium. com/@tomaspueyo/coronavirus-the-hammer-and-thedance-be9337092b56). explaining the hammer in an interview pueyo stated, "i wanted to create a very strong metaphor ….that could represent the idea of something aggressive early on and then something less aggressive afterwards." he termed the next phase a dance …because it is a much more fluid phase. you need to know the steps of the dance and really apply them as if it were choreography. (see: https://abc7news.com/society/viral-hammer-and-thedance-influences-reopening-amid-pandemic/6199923/ accessed 3 sept., 2020). with respect to older persons, however much it reduces risk, there is justifiable concern over the real health costs involved in physical distancing by keeping older persons confined too strictly and for too long to their homes. these include ill effects, both medical and psychological, especially on those of low socio-economic status (https://www.nytimes. com/2020/06/08/opinion/coronavirus-elderly-suicide.html). furthermore, there is some early anecdotal evidence from both here and abroad that many people have delayed clinic or er visits for non-coronavirus conditions, putting their overall health at risk. it is also not clear under lockdown how many isolated older persons have been able to manage their day to day affairsgroceries, medications, household cleaning and repairs. all this is especially problematic when these people cannot avail themselves of the help of their children and/or neighbours. without this aid it is difficult for such older persons to cope with social isolation and resulting loneliness. in order to analyze this complex issue, whilst taking a morally defensible ethical stance, the approach herein attempts to balance the sometimes conflicting principles of medical ethics, namely: autonomy, beneficence (doing good), non -maleficence (not doing evil) and distributive justice. with 80% of its population being jewish and given the country's unique history, it will come as no surprise that jewish law and traditions will sometimes influence both israel's norms and laws. (see sidebar 2.) biological ageing: what is it? the phenomenon of ageing does not necessarily lead to disease but it does gradually reduce the human organism's ability to withstand stress and is thus relevant to considerations re the effects of the sars-cov-2 virus on older persons. (see sidebar 3). just as for many other diseases, there are "risk factors" for developing covid-19, this term refers not to the disease per se but as something that increases a person's chances of developing one. for example, cigarette smoking is a risk factor for lung cancer, as is the metabolic syndrome for heart disease. however, having a risk factor does not guarantee that one will inevitably develop the illness in question. it just makes the disease more likely. for its part, chronological age (even when controlling for other characteristics) is clearly one of the most significant risk factors for covid-19 pneumonia, the need for ventilator support and above all for death (ref [6] ). why this is and what implications this fact might have for relevant policies will now be addressed. fortunately, for reasons not yet clear, young people (especially children 1-9 years old) seem hardly to be affected by this coronavirus. although they are indeed very efficient spreaders to adults for influenza, it appears that with the coronavirus this may fortunately not be the case. furthermore, although further work needs to be done to reach a firm conclusion, it is possible that young children may actually not constitute a significant danger to their teachers, parents or grandparents. however, at the other end of the spectrum, as alluded to above, increasing age is most definitely an independent risk factor for complications and death once a person is infected (ref [6] ). for example, an intensive care audit from the uk showed a very poor covid-19 pneumonia icu survival rate for those over 70 of less than a quarter (only 24.3%) versus more than three quarters survival (75.7%) for those 16-49 years of age (ref [7] ). a more recent study from northern italy indicated an equally dire prognosis for older men admitted to icu with a death rate of 40% for those 71-80 years old and 52% for those 80-90 (ref [8] ). the numbers were even higher if the patient had hypertension. there are similar figures from israeli icus and elsewhere across the world. tragically, although treatment protocols have indeed increased the chance of survival at all ages, the bottom line is that older persons who become ill enough to require ventilator support are very unlikely to survive. an understandable point has been made that not all older persons are the same. for example, it has been argued that one can find an 85 year old who by a combination of good fortune, favourable genetics and careful lifestyle choices, is in better health than an individual 75 year old with none of these three characteristics. in other words, the "biological" age of a particular 85 year old may well be less than the chronological age of an individual younger by a decade or even two. while this may occasionally be the case, it would be very difficult to assess this phenomenon in any accurate or scientific way within an age cohort (e.g. 65-80 or 80+). and unfortunately, despite the wishful thinking of many older persons and some mistaken authorities, the facts show that the older one is, the higher the risk even when controlling for various relevant co-morbidities. one study indicated that an 80 + year old with no known diseases still has fewer years left to live than does an 60-69 year old with 5 (!) co-morbidities (ref [9] ). sadly, these facts put to rest the attractive myth that a heathy older person can be at lower risk from covid-19 than younger people with co-morbidities. to this end, the renowned american centers for disease control (cdc) provide a simple guidance, listing two rubrics for risk: 1) older adults -even without comorbidity and 2) those with underlying conditions -at any age. (see: https://www.cdc.gov/coronavirus/2019ncov/need-extra-precautions/people-at-increased-risk. html; accessed 25 sept., 2020). so too did the canadian geriatrics society make similar recommendations using age 60 + (unrelated to the presence or absence of risk factors) as the number at which risk begins to rise (see: https://cgjonline.ca/index.php/cgj/article/view/443/507; accessed 25 sept., 2020). patients in nursing homes have been and likely will continue to be a particularly hard hit group, as has been observed in europe (https://www.theguardian.com/world/2 020/apr/13/half-of-coronavirus-deaths-happen-in-carehomes-data-from-eu-suggests), canada and in the us (https://www.nytimes.com/2020/04/17/us/coronavirusnursing-homes.html). in israel, although the absolute numbers remain low relative to many other countries, institutionalized residents still make up about one-third of the covid-19 victims. this is of course bad news but fortunately we have not witnessed the terrible scenes of neglect observed abroad. fortunately, early on in the pandemic, the moh published and at least partially enforced comprehensive guidelines as to how to deal with this sector (https://govextra.gov.il/media/16435/elderlycare-covid19.pdf; accessed 25 sept., 2020) with a special team dedicated to dealing with this situation. "lockdown" policies: ageism or age-protective? in israel, despite some protest, chronological age has been considered as one of the first criteria for social isolation or "stay at home directives", and ultimately considered the last to be released from lockdown. there are several reasons to support such a consideration as well as counter arguments. these are addressed now, followed by a possible solution which attempts to balance the main conflicting considerations. such guidelines need to be scientifically valid, transparent, workable, and insofar as possible, fair so that most in society will be able and agree to buy into it. however before moving on, one must address the complex issue of "ageism". it was the late, great gerontologist dr. robert butler who first defined the term, which according to the who constitutes " … the stereotyping, prejudice, and discrimination against people on the basis of their age [alone]. ageism is widespread and an insidious practice which has harmful effects on the health of older adults. for older people, ageism is an everyday challenge. overlooked for employment, restricted from social services and stereotyped in the media, ageism marginalizes and excludes older people in their communities." (see: https://www.who.int/ageing/ageism/en/ accessed 25 sept., 2020). clearly, the use of someone's chronological age to stereotype and discriminate (in the social sense of the word) is completely unacceptable. for example, age cannot be a criterion for a job for which it is not relevant (e.g. accounting, childcare or academic promotions, etc.). but some well-accepted regulations do use chronological (not even "biological") age as an inclusion and exclusion criterion for certain types of work. common sense is called upon here. for example, it is unlikely that most passengers, even the most gerontophilic, would feel completely comfortable watching two otherwise healthy 90 year old pilots enter the cockpit to preside over a 12 h trans-atlantic flight. in recognition of this logic, even though one could claim it is an expression of ageism, most authorities restrict commercial airline pilots' license to those younger than 65. even then they must also prove that they are healthy (https://www.easa.europa.eu/sites/default/files/ dfu/easa_rep_resea_2017_1.pdf). in contrast, a situation in israel where sadly ageism is still definitely at work can be found in the agemandatory retirement laws governing academia and the civil service. in our view these policies are wrongheaded but this issue is beyond the purview of this paper. on a more positive note, chronological age is used to entitle a universal pension or rights for certain services (e.g. in israel, homemaker hours according the nursing care act, etc.). age also confers discounts on public transport to wealthy older persons rather than poorer younger onesa case of "reverse ageism?" more trivial perhaps, but still relevant to this discussion, there seems to be no serious societal objection to older person receiving discounts to films, concerts and even municipal taxes, simply on the basis of age alone. one could even argue that we use age to discriminate to a significant degree against younger people, e.g. forcing (almost) all israeli youth to register for the military draft at age 17 and obligating most of them to serve their country and possibly endangering themselves to protect their elders for at least 2-3 and sometimes many more years during their own early and formative years, returning to serve in the reserves for many subsequent years. might this not be considered another example of "reverse ageism"? writing recently in the bmj, one british authority pointed to a disturbing phenomenon. "what is undoubtedly ageist is a collective fear of ageing and death in our societal and media values, meaning that appearing old is seen as being diminished, invisible, and unvalued by society. this in turn leads to older people themselves 'othering' any older people they see as being vulnerable, different from their more youthful and active selves. this can lead to 'grey on grey' ageism." (ref [10] ). true, but even worse in our view has been society's lack of preparedness for how this virus could affect older persons that constitutes the true expression of discrimination against older personsboth in israel and abroad. for those older persons who, despite knowing the facts, might chose to take risks and expose themselves to this virus, some will argue against an ageist "paternalism" that would prevent them from exercising their human rights. this means that a person at risk at any age must be free to make an individual decision as to whether he/ she is willing to go back out into society, take the risk of falling ill with covid-19 and accept the consequences, however dire they may be. this claim, in contrast to the one re the older airplane pilot falling ill and endangering all passengers, assumes that older persons are only endangering themselves were they end up needing hospitalization or an icu bed. indeed, should this second wave respond to steps being taken and wane quickly and israel be assured that we have enough icu beds to manage any surge, this claim will be valid and the older person or anyone with other risk factors must be free to take their chances. however, as we are now riding a second wave, this argument (supporting autonomy) seems much less valid in that it will be also be crucial to protect the stock of hospital and icu beds so that they would be available for as many as possibleyoung and old. in such a case it may well become necessary to be stricter in regulations taking distributive justice into account by enforcing isolation of all high risk groups, older persons among them. for its part, the israel gerontology association (long the lead in many important age advocacy initiatives) joining a coalition with four other organizations, have mobilized in the direction of protecting the autonomy of older persons against what they view as an ageist paternalism. they argue that using chronological age as a sole criterion discriminates against some older healthy persons who they claim may even be at less risk than younger sicker people. recently this coalition responded to the joint questionnaire of special procedures mandate of older persons sent out by the un (see: https://www. ohchr.org/en/hrbodies/sp/pages/joint-questionnaire-covid-19.aspx; accessed 25 sept., 2020). the coalition did make some important points, warning for example of the dangers posed by ageism to israel's older population brought on by the covid-19 crisis (personal communication prof yitzhak brick). unfortunately, the coalition members also made the incorrect claim that chronological age is not an independent risk factor for covid-19 complications, despite the clear evidence that it is. for example, in error they offer that, "[f] irst, it was clear that there is no difference between old and young people with regard to infection. secondly, most of the older persons who died from the disease suffered from co-morbidities and severe health risk factors. 40% of the people who died from the covid-19, came from long term facilities." their statement goes on, claiming, " … .that the chronological age cannot be the sole criterion [as to who needs to stay at home], as some people at high age are fit and healthy and others who are younger can be sick and frail, old persons are not all the same. policy makers should not depend on the chronological age when they decide about who has the right to go out of his home or not, and the decision should be made by the person himself [italics ours]." this error of fact, the claim that chronological age is not an independent risk factor, does no service to the elderly and will in fact mislead those who need to make difficult decisions in the weeks and months ahead. others, such as the british society of gerontology have made similar claims (ref [11] ). there is also a growing protest movement among some older people in israel (ref [12, 13] ) as well as in europe (https://www.wsj.com/ articles/older-europeans-reject-calls-to-remain-in-isolation-as-lockdowns-ease-11589112002; accessed 25 sept., 2020) arguing against the justification of such strictures. beyond the issue of ageism, this argument rejects any offer of beneficence, adducing autonomy as the highest ethical value. however, most liberal democracies do put a limit on such considerations in other relevant domains and most citizens will accept these restrictions as reasonable. for example, at any age, one must wear a seat belt when driving. societies demand such steps not only to protect the individual and his/her family (principle of beneficence, aka "paternalism") but also in order to preserve the commons (principle of distributive justice). in the absence of such strictures, society would be more likely to lose the productive years left to an individual who is killed or badly injured in a car accident. in the spirit of both beneficence and distributive justice, lowering the costs to society of premature death or the subsequent rehabilitation of those who survive a car accident seems a reasonable consideration which justifies the (partial) curtailment of a citizen's autonomy. closer to the elder pilot argument is the dire effect that too many people (at any age) simultaneously falling ill with covid-19 would have on hospital servicesparticularly but not exclusively icu/ventilator beds (principle of distributive justice). although we are still not (yet) in that dire situation in israel, this is not just a theoretical argument as we have seen examples from around the developed world of health services becoming overwhelmed or coming very close to doing so as a result of too sudden and heavy a surge on bed and personnel availability (ref [5, 14] ). according to this argument, it is not only in the personal interest of high risk people (older persons as well as younger people with co-morbidity) to make every effort to avoid infection. as well, the argument goes, they should do so in order to help maintain the viability of a health system given that this organization needs to be capable of looking after them should they (or their children or other younger persons) fall ill. of interest is the sense that despite the recent relaxation of formal strictures, preliminary data from israel's largest health fund (clalit) suggest that older persons seem to be voting with their feet to protect themselves. they seem to be voluntarily observing stricter behaviours than those demanded by the israeli government. as pointed out in the times of israel on 12 july, 2020, though israel's infection rate has soared to some 1200-1400 new cases a day in recent days, the percentage of serious cases has been far lower. for example, at the height of the first wave in mid-april, some 180 of a total 9800 active cases were considered serious, or about 1.8%. on saturday [11 july, 2020], 134 of 18,296 cases were considered serious, or about 0.7%. (see: https:// www.timesofisrael.com/at-risk-groups-less-hard-hit-in-2 nd-wave-causing-fewer-serious-cases-analysis/; accessed 25 sept., 2020). against the claim of "ageism" and in the spirit of supporting both "distributive justice" and intergenerational solidarity, others feel that especially in a situation of a critical imbalance between demand and icu resources, it is indeed justified to use chronological age as a criterion (among others of course) for the allocation of scarce resources. for example, a noted american medical ethicist franklin miller (himself 71 years old) offered, "if demand for ventilators keeps growing and further outstrips supply, i believe it could be justifiable as a matter of policy to forgo mechanical ventilation for all patients 70 years of age and older who have a medical condition that puts them at elevated risk of death, such as chronic renal disease, cardiovascular disease, diabetes, and chronic lung disease" (ref [15] ). another authority, larry churchill went even further offering ("as i approach my 75 year") his own personal ethical approach which would give priority to a younger person (ref [16] ). closer to home, a.b. yehoshua one of israel's foremost writers and thinkers, expressed himself in a similar vein (ref [17] ). not all will accept nor support this stance but it does seem to be a position taken by at least some older persons. of interest, colleagues from the field of social gerontology have objected that even such self-sacrifice is in their view still ageist. obviously, none of the three abovementioned distinguished older persons would agree. undoubtedly they would hold that not allowing one to take this approach constitutes an unjustified attack on their autonomy. should the present second wave tower high enough to threaten to overwhelm israel's limited supply of icu and ventilator stock (as was observed in italy, spain and ny state several months ago), the need for difficult choices will inevitably arise. much has been written about the vexed subject of ventilator triage (ref [18] [19] [20] ). relevant statements have also been published by the israel geriatrics society in hebrew on the website of the israel medical association (ref [21] ) and in a modified english version in a geriatrics journal (ref [22] ) as well as by a public commission set up by the moh (ref [23] ). should they wish, and we believe many might elect to do so, a significant number of older persons could voluntarily avoid ending up a triage case or at least ensure clarity relating to their wishes should they reach such a fork in the road. in a thoughtful piece in the nejm, aronson recently offered, "i know many happy engaged elders in their 70s, 80s, 90s, and 100s … who would not want to be put on a respirator … patients and [the us] health care system would be better served if all adults and elders use some of the spare time created by our new, home-confined lives to discuss and document their care preferences, whether the goal is aggressive, supportive or palliative care." (ref [24] ). unfortunately, israel is still quite far behind other industrialized countries in this domain, only recently beginning any discussions on the possibility of "a good death" (ref [25] ). even worse, it is still very difficult and expensive to legally appoint someone an enduring power of attorney which is another way to reduce conflict and misunderstandings over this fraught issue. furthermore, problems of cognitive decline, impaired vision and hearing, not to speak of linguistic mismatch between health care personnel and their older patients (not uncommon in israel), could interfere with an older persons' understanding their situation and expressing their relevant wishes. aronson bemoans the dire effects of the absence of such planning (for any reason) which " … increases the suffering at the end of life …" with the presence of such documents helping " … people with serious or lifelimiting illness to live and die according to their personal preferences" (ref [24] ). relevant efforts must swiftly be made to avoid the maleficence that might follow from ignoring this urgent need. for various reasons related to history and culture, israeli elders, even those with a very short life span (including people with advanced cancer or severe dementia) are often subjected to far more aggressive treatment than would be the case in other western countries. sadly, this phenomenon is observed even when such interventions are clearly futile and painful (ref [26, 27] ). as such, in many cases, when an older person falls acutely ill in israel, he/she may be subjected to invasive procedures and an admission to icu etc. this despite the fact that had the older person really understood what was actually involved, they may well not have agreed to such an intervention. it is thus society's solemn duty to ensure that older persons clearly understand what the automatic fallback options are should they not have made their prior wishes known. furthermore, as addressed above, it is essential that older persons understand the fact that age is an independent risk factor for covid-19 complications and death. suggesting otherwise, despite the clear evidence that it is, does them a terrible disservice in that they may act to endanger themselves by thinking that as a "healthy" older person they are at lower risk than they actually are. how to manage this second wave? as israel enters its second lock-down (in late september coinciding with the day of atonement [yom kippur]) it is worth studying the approach by pueyo alluded to above (ref https://medium.com/@tomaspueyo/coronavirus-the-hammer-and-the-dance-be9337092b56). but the truth is that at this stage, no-one has yet choreographed either a perfect "hammer" or "dance". all agree that it is economically and socially unsustainable to keep most of the population locked down and laid off indefinitely, even at the cost of more covid-19 deaths. without health, there is no wealth; but the opposite is also true. as such we must open up our societies as quickly but as we safely can. all of the suggestions offered below, in order to be humane (encouraging beneficence and maximizing nonmaleficence) and fair (distributive justice) and in part to compensate older citizens for having to wait until the younger ones are first "released", will require that society take some important steps in parallel. these would include ensuring that during the hammer and even for some time afterwards, older housebound persons would have their daily needs metmaterial, medical and psychological. space does not allow us to go into detail but an example would be special "older hours" for food stores, facilitated home delivery, availability of handymen, plumbers and electricians who would be on call via a central number, etc. and other relevant supports. all of these suggestions require that the moh, along with other relevant government agencies, keeps its finger on the pulse of the epidemicopening the faucet, testing and opening or closing it further depending on the results of extensive and focused testing. a step-by-step proposal 1) with respect to the at-risk populations (those with relevant medical illnesses and older age), so far, even though the number of infected person is rising once again, at the date of writing (late october, 2020) the program recommended herein is still voluntary. this however could change should the situation worsen significantly. one hopes that relevant professional organizations (such as the ministry of health and the israel geriatrics society) ngos such as joint-eshel and lay bodies will use their influence to convince older people and others at high risk to voluntarily follow these guidelines, as they are both in their own individual interest and that of society'swith or in the absence of a lockdown. many of these steps have been taken previously but we are aiming at a rapidly moving target. however, should we reach a catastrophic situation of overwhelmed emergency rooms, insufficient ventilators (and/or the team members needed to manage them), mandatory lockdown of all high risk persons of any age might be required. 2) save lives and protect the system (in that order). although it should be obvious by now, the three essential steps are physical distancing, wearing a face mask and frequent hand washing. and it is indeed distressing to observe how few young people in israel (and others around the world) seem to have internalized the need for such simple but efficacious behaviours. there are even a few world leaders who demonstrably refuse to cover their offending upper airways although fortunately this is largely not the case in israel. to this end, the state needs to more aggressively ensure the promulgation, explication and enforcement of relevant regulations and the supply of appropriate kit in public spaces. here we would expect the moh to lead the way with public health announcements supported by the media, neither of which have as yet excelled in this domain. 3) it is critically important that public personalities, cultural figures, athletes and above all politicians follow and are seen to follow the rules. it is particularly difficult to ask the populace to act in a compliant manner especially when at least three of israel's leaders (all over age 70), prime minister benjamin netanyahu, president ruby rivlin, and most egregious of all, the then minister of health (!) rabbi yacov litzman all shamelessly broke the moh rules over the recent passover holiday. and in early july the newly appointed minister of health yuli edelstein also flouted his own ministry's regulations. we are not alone, as many leaders from around the world have acted in a similar irresponsible way, but in this domain all politics are local. of interest is the welcome public apology recently offered by pres rivlin for his un-leader-like behaviour during the last major jewish/national holiday of passover (see: https://www.timesofisrael. com/as-lockdown-set-to-begin-rivlin-apologizes-forleaders-virus-failures/#gs.gk20fz accessed 19 sept,2020). however, to the best of our knowledge, he is the only miscreant who has offered any such contrition. 4) all of the steps outlined herein are mutually supportive. sensible physical distancing must be explained and defined so that older persons aren't unnecessary "imprisoned" in their apartmentsin other words, needlessly distanced socially. for example there is very little risk involved in meeting children and grandchildren outside in a park or garden strictly separated by 2 m and wearing masks, etc. overly stringent, contradictory and irrational guidelines offered by the moh characterized the first wave and caused significant and entirely unnecessary suffering among older persons, especially but not only in sheltered housing (diur mugan). 5) in the fall and early winter it will also be especially important to ensure a robust influenza vaccination program with wide availability of anti-flu medications (e.g. oseltamivir [tamiflu] ) given that the rise in flu cases which usually begins in november will be superimposed on the ongoing covid-19 pandemic. in this vein health personnel must be encouraged and perhaps even legislated to take a mandatory flu vaccine, given the disappointingly low rates of uptake by this crucial sector in israel in past years. further clinical guidance must be offered to older persons and physicians in the field as to how to handle a patient presenting with nonspecific "flu-like" symptoms from nov-marchswabbing, an algorithmic strategy if positive or negative for flu or sars-cov-2, etc. 6) all persons over age 60, even without co-morbidity, must clearly understand that they are at increased risk for complications and death should they become infected; the older, the greater the danger. this is the case even for an otherwise robust older person. comorbidity adds risk to chronological age; patients and their doctors must understand this clearly. despite pushback by some ill-informed pollyanna's, this message must be forceful and clear. here ngos such as the israel association of gerontology and joint-eshel could help spread the evidence-based word. 7) many who fall seriously ill may elect to be hospitalized and if necessary ventilated (see above). however, there will be those who do not wish to undergo this procedure, instead opting for a more palliative approach. in order to exercise their autonomy, all adult citizens (especially those with any relevant co-morbidity and all those > 60 years) should sign an advance directive. these are available on line from the moh (see https://www.health. gov.il/services/citizen_services/dyingpatientlaw/ pages/dyingpatientrequest.aspx). as well, it is advisable to prepare an enduring power of attorney ( ‫י‬ ‫י‬ ‫פ‬ ‫ו‬ ‫י‬ ‫כ‬ ‫ו‬ ‫ח‬ ). it is most unfortunate that in israel this process is so complex and expensive and the ministry of law shares responsibility for this dire situation. hopefully in the near future, it will be simplified and further encouraged. in the true interest of their older clients, relevant groups such as the israel association of gerontology, joint-eshel and other members of the abovementioned "coalition" should lobby to simplify these procedures and to convince more citizens to take this essential step in order to protect the exercise of their autonomy. in the absence of such guidelines, faced with a patient ill with covid-19, clinicians will find it difficult to know what the individual patients' wishes are re ventilation. from the legal point of view in israel, family members have no formal say in such decisions unless they are the legal guardian ( ‫א‬ ‫פ‬ ‫ו‬ ‫ט‬ ‫ר‬ ‫ו‬ ‫פ‬ ‫ו‬ ‫ס‬ ) of an older person or have the enduring power of attorney mentioned above. strain, israel's hospitals are still just able to cope with the influx of covid-19 patients. however, this balance could change rapidly and should a severe mismatch between needs and resources develop, one would seriously have to consider the need for triage (see above). in this domain much has been written about chronological age alone not being a relevant consideration but most understand that this factor cannot be ignored. furthermore, adding a moral twist to the debate, doing so may be considered by some as practicing ageism. however, in our view, while age alone should not be used as a factor in triage decision making, common sense and the fact that mortality goes up logarithmically with age as well as the chance of coming off a ventilator becomes vanishingly small, it cannot be ignored. the moh would do well to introduce these guidelines into the legal regulations where relevant. 9) those persons with significant comorbidity (at any age) are considered as belonging to the older person (60+) category. under present conditions they should be advised, insofar as is possible, to stay "shielded". however, using similar logic to that pertaining to ventilator triage, should the situation worsen significantly, in the spirit of maximizing distributive justice, consideration would be given to enforcing such behaviour. 10) returning to all older persons (60+), depending on the results of the steps described above, if the situation once again allows, they should be encouraged to return to normal function -but only gradually and carefully. this would pertain to all "vulnerable" persons at any age with serious underlying health conditions (as previously outlined) and those whose immune system is compromised such as by chemotherapy for cancer and other conditions requiring such therapy. 11) unfortunately much poor (and confusing) advice was disseminated to older persons during the initial lockdown with the moh failing to provide timely and accurate advice re prevention and health promotion. as we have now entered a new lockdown, the following recommendations would pertain. even now these guidelines are relevant to all older persons and any younger people at high risk. i. although not always easy to do so accurately, each person can try to determine his/her own risk from the coronavirus and make decisions accordingly. the moh should help by providing simple evidence-based guidance to people, taking into account one's risk profile, medical history and, if necessary, consultation with the individual's family doctor. the moh has published a schema on their website, but it is difficult to find, confusing and not known to most older persons. ii. even in the event of a strict "lockdown", persons of any age should still get out of their apartment and enjoy as much physical exercise as possible. there is no good medical rationale to prevent people at any risk not to walk, jog, outdoor yoga /tai chi, etc. -as long as masking and physical distancing are maintained. iii. re essentials (health, shopping, essential services), people at risk should get as much help as possible from delivery services, friends, family and the local authorities in order to minimize going out for these needs. some people will need assistance from the state/municipality to manage. examples of sensible social engineering taken in other countries include having supermarkets maintain certain hours for high risk persons and directing shoppers through aisles in a "one way" direction while also enforcing the two meter rule. to the best of our knowledge, none of this exists today the health funds (kupot haholim) will need to be ready to provide adequate medical services at home and/or at specially configured clinics at specific hours in the day. iv. all persons at risk need to maintain strict physical (not social) distancing including from family members (especially those aged 10+). with any outside contact, masks must be worn by all and no physical contact is allowed, including for example, passing plates of food back and forth. family visits outside in a private garden or public park should be allowed as long as everyone stays more than 2 m apart. v. some older people may choose, in the spirit of maximalising distributive justice and out of a sense social solidarity towards the younger generation (as for example expressed by a. b yehoshua among others alluded to above ref [15] [16] [17] ) and out of concern regarding their individual risk, to maintain even stricter social isolation as well as to give priority to younger persons. this decision should be neither minimized nor mocked. whatever one's thoughts about ageism, this choice is to be honoured and respected as a legitimate expression of the at-risk person's autonomy. we live in a society where certain younger age and occupational groups sacrifice for the health, safety and security of those older than them and this must be a bidirectional phenomenonespecially between consenting adults. vi. as addressed above, all older persons should be encouraged and if necessary helped to make and document decisions about advanced directives so that their wishes can be respected should their health suddenly deteriorate. this expression of autonomy is of paramount importance, especially in times of crisis and uncertainty and given the default option of aggressive icu and ventilation measures too often taken in this country. should a triage situation develop,clarification of this domain will also help reduce family uncertainty as well as decreasing unnecessary pressures on the health care system. 12) as alluded to in sidebar 1, israel enjoys a population of approximately 1.1 million citizens over 65 years, 97.6% of whom live in the community. all of these recommendations refer primarily to older persons dwelling in the community however, they would not be as applicable to the 22% of older persons receiving homemaker care according to the nursing law ( ‫ח‬ ‫ו‬ ‫ק‬ ‫ס‬ ‫י‬ ‫ע‬ ‫ו‬ ‫ד‬ ) or who had an authorization for a personal attendant (usually a foreign worker). such people will be much frailer than the usual older person, exhibiting even a higher prevalence of co-morbidity and cognitive decline. another vulnerable sector would also not be included in this schema, that is persons in institutions for older persons (approximately 23,600, that is 2.6% of the elderly) with the possible exception of those more independent elders living in sheltered housing ( ‫ד‬ ‫י‬ ‫ו‬ ‫ר‬ ‫מ‬ ‫ו‬ ‫ג‬ ‫ן‬ ). as mentioned above, the moh has designed an ongoing mechanism (magen avot) meant to protect this extremely vulnerable population. among other things, this program ensures an adequate supply of ppe as well frequent as pcr testing of both residents and staff. after a rocky start this program now seems to be working quite well and offers area example of what israel got right during the pandemic (ref [28] ). 13) planning needs to consider a sensible exit strategy from the ongoing second wave. these recommendations should be instituted gradually: releasing first those 60-69 years old; then 70-84 and finally all 85+. although such age categories are admittedly arbitrary, they clearly represent the increasing risk of the average person in each group from covid-19 (less clinical reserve, higher likelihood of co-morbidity and shorter life expectancy, etc.) as one climbs the age scale. 14) outreach is needed to populations which traditionally have less access and/or trust in the healthcare system such as citizens from arab and ultra-orthodox communities where infection rates are increasing more than in the general population. this can be done by having citizens from those communities actively involved in the decision making process and encouraging local leadership to take an active role in disease prevention and management. in this paper we have tried to address the vexed issue of age; how a society such as israel's should make every attempt to meet the needs of older persons during the pandemic while taking into account those of the wider society as well as the sometimes conflicting principles of medical ethics. space does not allow us to deal with all relevant issues and for some we can only outline the topic. please see sidebar 4. a final (personal) word from the older author (amc) even today and especially as we ride and try to balance on the second wave without plunging into the roiling seas, this proposal puts much onus on israel's senior citizens, many of whom have not had an easy life. this will be the case whether or not these guidelines are statutory or voluntary. just as they may have begun to enjoy retirement, hobbies, their grandchildren etc., older persons are once again to be restricted (at least partially) by this terrible pandemic. it must however be kept in mind that it is the virus, not society which is responsible. this proposal asks a heavy price of older persons, i.e. to wait inside and struggle relatively alone for longer than younger people. but it is logical and meets the criterion of soft utilitarianism alluded to above (the greatest good to the greatest number.) i am almost 71 and, according to this proposal, will have to wait my turn until i am allowed and/or allow myself more freedom -perhaps for quite a while. as are the two older medical ethicists and a.b. yehoshua quoted above (ref [15] [16] [17] ), i am willing to do so because i believe in the science, logic and moral approach of this "dance". in addition, in social solidarity with younger people, i am willing to take these steps for the sake of my children and their generation which is the one which will drive the economic, defense and social engines of our society out of this crisis. and in the end, as an older israeli, i (and i know of others) am willing to do this for the sake of our society. while many infected persons are asymptomatic and most survive the sars-cov-2 virus, covid-19 can be a serious disease, especially for those with co-morbidity and for many older persons, even without. the sars-cov-2 virus has caused illness and death and wrought severe socio-economic disruption for people at all ages across the globe (see https://www.economist.com/international/2020/09/26/the-pandemic-is-plunging-millionsback-into-extreme-poverty). given the iron laws of biology, on average healthy older persons are at higher risk than younger, even unhealthy people. as such, society pathophysiology, transmission, diagnosis, and treatment of coronavirus disease 2019 (covid-19): a review the stanford hall consensus statement for post-covid-19 rehabilitation the silent danger of social distancing from mitigation to containment of the covid-19 pandemic; putting the sars-cov-2 genie back in the bottle facing covid-19 in italy -ethics, logistics and therapeutics on the epidemic's front line estimating excess 1-year mortality associated with the covid-19 pandemic according to underlying conditions and age baseline characteristics and outcomes of 1591 patients infected with sars-cov-2 admitted to icus of the lombardy region covid-19 -exploring the implications of long-term condition type and extent of multimorbidity on years of life lost: a modelling study what the pandemic measures reveal about ageism the price of continued isolation for older persons -a social disaster. maariv (online-hebrew) sheltered housing in the days of corona -worse than a prison why i support age-related rationing of ventilators for covid-19 patients. the hastings center on being an elder in a pandemic ready to die if that will be instead of a younger person ventilator triage policies during the covid-19 pandemic at u.s. hospitals associated with members of the association of bioethics program directors the toughest triage -allocating ventilators in a pandemic fair allocation of scarce medical resources in the time of covid-19 israel ad hoc covid-19 committee: guidelines for care of older persons during a pandemic joint commission of the israel national bioethics council, the ethics bureau of the israel medical association and representatives from the ministry of health age, complexity, and crisis -a prescription for progress in pandemic death is inevitable -a bad death is not; report from an international workshop ethical issues in end-of-life geriatric care. the approach of three monotheistic religions: judaism, catholicism and islam enteral feeding in end-stage dementia: a comparison of religious, ethnic and national differences in canada and israel publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations acknowledgements none. received: 2 july 2020 accepted: 14 october 2020 needs to protect all of those particularly susceptible to this virusboth from the disease as well as from the ill effects of the necessary constraints on their freedoms necessitated by this worldwide emergency. but equally important, governments must act transparently and solely in the interests of citizens. finally, they need to ensure a fair distribution of resources -especially if society is faced with an acute shortage. the trick will be in getting the balance right. supplementary information accompanies this paper at https://doi.org/10. 1186/s13584-020-00416-y. we alone are responsible for the whole text. the authors read and approved the final manuscript.funding none.availability of data and materials not relevant.ethics approval and consent to participate not applicable.consent for publication not relevant. author details key: cord-309161-ceahghs1 authors: epel, elissa s. title: the geroscience agenda: what does stress have to do with it? date: 2020-09-28 journal: ageing res rev doi: 10.1016/j.arr.2020.101167 sha: doc_id: 309161 cord_uid: ceahghs1 geroscience offers a counterpoint to the challenged pursuit of curing diseases of aging by focusing on slowing the biological aging process for extended healthspan earlier in life. remarkable progress has led this field toward animal trials and the next challenge lies with translation to humans. there is an emerging number of small human trials that can take advantage of new models integrating behavioral and social factors. understanding dynamic aging mechanisms, given the powerful social determinants of aging (crimmins, 2019) and human variability and environmental contexts (moffitt, 2019), will be critical. behavioral and social factors are intrinsic to aging. toxic stressors broadly defined can lead to stress-acceleration of aging, either directly impacting aging processes or by shaping poor behavioral health, and underlie the socioeconomic disparities of aging. in contrast, hormetic stressors, acute intermittent stressors of moderate intensity, can produce stress resilience, the ability for quick recovery and possibly rejuvenation of cells and tissues. although health research usually examines static biomarkers, aging is reflected in ability to recover from challenges pointing to new interventions and targets for examining mechanisms. a fuller model incorporating stress resilience provides innovative biobehavioral interventions, both for bolstering response to challenges, such as covid-19, and for improving healthspan. circumstances and substances. hormesis traditionally described a cells or organisms bi-phasic response to an external chemical or stressor. there is indeed overlap between stress processes and aging processes, and two become intertwined with the concept of hormesis. toxic stress includes traumatic or ongoing adversity for months on end, and the psychological responses--chronic high perceived stress, burnout, or depression. many large scale studies demonstrate that traumatic or chronic psychosocial adversity, including low socioeconomic status, predict higher allostatic load, whereas high levels of psychosocial resources are associated with lower allostatic load, with small but reliable effects (danese & mcewen, 2012; wiley et al., 2017) , described further under "reserve capacity" (section 3). homeostasis to allostatic load. stress research started with examination of the acute stress responses to acute stressors in rodents. cannon's stress studies led to the popular concept of homeostasis (cannon, 1932) but a simple linear model of homeostasis does not explain the range of human stress responses, and there have been many elaborations of this concept. selye described the continuum from acute stress to chronic stress (selye, 1956) . acute stress can be hormetic when there is quick recovery back to homeostasis. given the complexity of physiological regulation, and that our body mounts a response in mere anticipation of threat, sterling and colleagues have described allostasis as a more encompassing description of the body's regulation-the constant fluctuations to meet expected demands (schulkin & sterling, 2019) which in biogerontology has been called "homeodynamics." chronicity of stressor exposure reveals a "fragility in homeostasis" (ramsay & woods, 2014) when physiological signs of 'exhaustion' appear, such as, in rodents, damage in organs. mcewen and colleagues have labeled this cost of adaptation--the dysregulation and damage across systems--as allostatic load (mcewen, 2004) . the concept of allostatic load, whether it is at a systemic or cellular level, gives us an intermediate phenotype of aging, an early step toward development of diagnosable disease. this is a critical concept to geroscience, and in fact many of the actual measures of allostatic j o u r n a l p r e -p r o o f load used in from the psychology and public health literature are actually indices of aging (entringer & epel, 2020) . geroscience leaders have started to identify the biomarkers important in geroscience trials, as those that can predict aging outcomes and mortality, and are responsive to interventions, and this short list includes glucose control and inflammation (justice et al., 2018) . thus, there is potentially great overlap between geroscience biomarkers and the stress-related allostatic load markers described in section 3 (cellular, multi-system, and measures of recovery), and these fields can inform each other. 1. an integrative model of stress and aging. stress acceleration (toxic stress) and stress rejuvenescence (hormetic stress). given the important role of social stress in aging, we need a deeper understanding of types of stress exposures. an overarching model explains the range of stress exposures, from toxic stress to acute hormetic stress, and our body's diverging responses to these exposures. our stress responses are not typically thought of as basic mechanisms of aging but indeed they are actively shaping rate of aging. as shown in figure 1 , the dose and intensity of the stressor determines in part whether the organism responds with positive physiological changes or impairments in aging processes (modified from franceschi et al., 2018) . the exact timing of stressor exposure is an important consideration of a hormetic or pre-conditioning effect, as some stressors lead to sensitization across stressors, rather than habituation (i.e., belda et al., 2016) and this may differ by species, stage of development, and stressor paradigm. therefore, a general model cannot determine the exact parameters of intensity and dose for hormetic stressors. it is important area of future research to identify the boundary conditions and inflection points for the range of potentially hormetic stressors . moderate stressor exposure can lead to both housecleaning in the cells, making them appear younger or rejuvenated, as well as growth of new neural pathways. over time, the accumulation of hormetic stress can promote slowing of aging processes. j o u r n a l p r e -p r o o f 1.1 hormesis is a form of stress resilience. this paper brings together the hormesis literature with the broader stress resilience literature. the cellular biology of hormetic responses is well mapped, and has general common responses as well as stressor specific responses. the acute stress response has a common pathway of creating calcium influx, oxidative stress, and energetic stress. this increases transcription factors such as nrf-2, foxos, creb, and nf-kb, leading to many hormetic effectors, such as chaperone proteins (eg, heat shock proteins which help fold proteins efficiently and prevent protein aggregation), er stress, endogenous antioxidants (sod, glutathione), growth factors, and mitochondrial proteins (mattson, 2008a) . after moderate doses, the cells become resistant to many other types of stressors (heat, uv, oxidative stress, metals), and to death (murakami et al., 2003) . hormesis is a universally observed phenomena across types of cells and types of stressors, including psychological stress. in model organisms, short manageable stressors lead to improvements in aging, although this depends on types of stressor and species (lagisz et al., 2013; rattan, 2008) . for example, low dose gamma radiation over time can extend average lifespan up to 30% in mouse studies (calabrese & baldwin, 2000) . in humans, there is evidence of hormetic stress, such as the effects of exercise, although this is not typically labeled as hormesis. hormesis naturally applies to humans-not just to cells but to physiological and psychological regulation. a typical example is vaccinationwhich leads to enhanced immune responses later. here we expand the definition of hormetic stress to include the positive stressors that humans engage in-such as short term bodily stressors like exercise and temperature stress, but also novel challenging experiences that expand coping resources, knowledge, generativity, and feelings of accomplishment, described further below (section 1.2). since hormetic stress has traditionally been applied to cellular physiology, we use the larger concept of 'stress resilience' as the widest umbrella term for describing when humans recover quickly, in any system, from various exposures. as shown in the appendix, there are many j o u r n a l p r e -p r o o f overlapping terms that relate to the concept of stress resilience. just as the term "stress" is a multi-level construct that needs to examination in a sophisticated interdisciplinary manner, stress resilience is also a multi-level concept that encompasses the full range of human exposures, responses, and inter-related systems. the term stress resilience thus subsumes psychological resilience, physiological resilience/enhanced allostasis, and social resilience. this model of stress resilience can thus be applied to most processes--at the cellular level, physiological level, and psychosocial level. psychosocial stress resilience here refers to the dynamic recovery in psychological, behavioral and social processes and related physiological processes. high stress resilience is reflected by quick physiological and affective recovery from psychological stressors. the neurochemistry of psychological resilience has also been described, based on rodent models (cathomas et al., 2019) . whether a stressor leads to a hormetic or toxic response is not solely determined by the chronicity of the stressor. it is also determined in part by the psychological appraisals, which is shaped by the context, culture, personal history and personality of the individual. when one feels demands exceed resources, in any situation, this creates a physiological and emotional stress response (folkman et al., 1986) . if it is perceived as a threat they cannot cope with, this repeated stress response over time will last longer and be more wearing. in contrast, if they view it as positive challenge that they have the resources for, they will have a profile of quicker recovery, as summarized elsewhere . thus the appraisal of the stressor codetermines the physiological response. it is not just stress responses to major events that matter. our frequent daily stress responses have cumulative effects: the tendency to have slower recovery of negative mood or greater loss of positive mood after a daily stressor predicts inflammation and long term disease and mortality mroczek et al., 2015; piazza et al., 2013; sin et al., 2015) . short term manageable stressors, such as physical or cognitive challenge that can promote growth, learning and development can lead to protective responses. an example of this is found in studies of the experience corps. exposing elderly retired people who are often isolated to a job mentoring at-risk youth in schools is often viewed as stressful but leads to feeling more purpose in life. in men, it has been linked to better health and increases in hippocampal volume gruenewald et al., 2015; varma et al., 2015) . in the case of coping with chronic stressors, most people (around 80%) recover to baseline levels of well being after a loss or disaster (galatzer-levy et al., 2018) . resilience may develop over time, leading to more mastery, purpose, faith, self esteem, and thus more resilient responses to future stressors. in contrast, toxic exposures accumulate over a lifetime, promoting "stress-acceleration of aging" processes. chronic stressors for decades, multiple shorter term exposures over years, and stressors embedded early in life, can all have toxic effects when there is insufficient resources to cope, and nor opportunities to fully recover. developmental factors are critical for understanding when stressors can be hormetic vs. toxic. we do not know precise developmental trajectories for differential effects of toxic stress on mental and physical health and even less is known about hormesis across the human lifespan. with aging, there is a decrease in both the reproductive and anabolic hormones that are part of a salutary acute stress response (epel et al., 1998) , and also a reduction in aspects of molecular hormesis, such as a lower heat shock response to stressors (calabrese et al., 2014; epel, 2008) . we know most about the developmental impact of toxic stressors. while there are myriad individual patterns of exposures, traumatic stress or material deprivation have larger effects early in life than when they occur at later periods; early life adversity is predictive of a range of poor outcomes, including poor mental health, health behaviors, biomarkers of aging, and earlier disease onset (deighton et al., 2018; hughes et al., 2017) although plasticity is still possible (mcewen & morrison, 2013) . given the sensitive period j o u r n a l p r e -p r o o f of pregnancy, it is not surprising there is evidence of transgenerational effects of stress and pregnancy complications on systems regulating aging like telomeres and epigenetics (epel, 2020; girchenko et al., 2017; ross et al., 2020) . a careful meta-analysis of the effects of early adversity points to psychological threat, rather than material deprivation, as the factor underlying accelerated biological aging such as early puberty, telomere shortening, and brain development (colich et al., 2020) . for trauma and abuse, the earlier in life, prenatal and pre-pubertal, when the brain is most rapidly developing, the larger the imprint of lifelong effects on mental and physical health (agorastos et al., 2018) . there are many examples of early adversity with accelerated biomarkers of aging in children: in prepubertal children, early life adversity leads to greater inflammatory acute stress response, and basal inflammation several years later (slopen et al., 2014) . in prepubescent youth, exposure to violence is associated prospectively with telomere shortening (shalev et al., 2013) , and telomere shortness in early childhood predicts carotid artery thickness several years later, and during puberty (barraclough et al., 2019; skilton et al., 2016) . early adversity may accelerate aging in part through inducing early puberty which in turn is linked to earlier onset of metabolic disease (gur et al., 2019; sun et al., 2017) . early adversity may also initiate a trajectory of early aging through lower reserve capacity such as low optimism and higher stressful events in adulthood (surachman et al., 2019) . early adversity also predicts poor health behaviors such as sedentariness, smoking and substance use in youth (wiehn et al., 2018) and these habits appear to persist long into adulthood . the pillars of mammalian aging, represent fundamental and related pathways such as genomic instability, telomere attrition, epigenetic alterations, loss of proteostasis, metabolic pathways such as deregulated nutrient sensing, mitochondrial j o u r n a l p r e -p r o o f dysfunction, cellular senescence, stem cell exhaustion, and altered intercellular communication, macromolecular damage, chronic low-grade inflammation, and adaptation to stress (kennedy et al., 2014; lópez-otín et al., 2013) . other hallmarks of cellular aging are being identified in the brain (mattson & arumugam, 2018) . molecular pathways are often not closely related to each other, pointing to the use of algorithms, for better prediction of outcomes, described below. several of these basic mechanisms in immune cells have been associated with aspects of social stress, including systemic inflammation and shorter telomeres (epel et al., 2004; kiecolt-glaser et al., 2011; miller et al., 2008) poor mitochondrial function (picard et al., 2018) , and accelerated epigenetic aging (park et al., 2019; wolf et al., 2018) . these associations with lifespan stress demonstrate there is no closed system of intrinsic aging, and even at these most molecular levels our aging rate is influenced by our life exposures. we cannot rule out the possibility that some of these observations are from transgenerational effects. a new practical approach already used in humans is to measure a panel of biomarkers of aging that reflect cumulative damage across regulatory systems (e.g., metabolic, immune, stress related), and reducing this a composite measure. the first of these measures was allostatic load (seeman et al., 2001) , and there are newer algorithm measures like 'pace of aging' (belsky, caspi, et al., 2017) , and lack of normal covariation among regulatory systems (belsky, huffman, et al., 2017) . these measures serve as a barometer of biological aging across the lifespan, linked to early experience, and may be useful to examine the effect of interventions (moffitt, this issue). so far, the markers used have been chosen out of convenience of availability, but there is exciting potential to develop further translational measures based more directly on the basic mechanisms of aging. this admittedly requires high intensity collaboration between basic and clinical scientists (eg, assessments of mtor activity, senescent cells, mitochondrial functioning). 2.3 speed of recovery as a novel measure of latent aging at any age. geroscience recognizes that physiological adaptation to stress stands out as a common phenotype of aging j o u r n a l p r e -p r o o f across model systems of aging. stress resilience, and its impairment, is partly an outcome of the social hallmarks of aging, and a common underlying process that in part regulates the cellular hallmarks of aging. snapshot one-time measures of aging based on blood have inherent limitations in that they do not directly test how a person responds to an acute stressor. recovery from challenge is a critical measure of stress resilience that may be important, as it assesses the latent homeostatic capacity of a system. speed of recovery is thought of as intrinsic homeostatic capacity, a latent capacity that reflects biological aging. recovery is such an important marker of aging that it is central to the emerging areas of 'physiological geroscience" and "translational geroscience." naturalistically, acute events often precede a rapid decline in function, reflecting lack of stress resilience. for example, 50% of new disabilities develop after an acute accident or illness and hospitalization (gill et al., 2004) . there are many examples of paradigms measuring recovery that have validated the importance of using a challenge, and measuring functional or biological recovery from the challenge. frailty is a measure of advanced biological age that reflects loss of stress resilience due to age related decline in physiological reserve (hoogendijk et al., 2019) . however, frailty is a final common pathway, one that is probably not reversible. stress resilience interventions will need to target people earlier in life long before frailty sets in. in contrast physiological resilience, which refers to ability to bounce back from a stressor, is measurable at any age (whitson et al., 2016 (whitson et al., , 2018 . stress resilience depends in part on the pre-existing level of reserve capacity, the positive protective factors of an organism, as well as the immediate adaptive psychological response to stressors (cognitive appraisals). in the stress literature, reserve capacity has been defined as j o u r n a l p r e -p r o o f combination of personal resources such as optimism and sense of control, and social factors such as social support. high psychosocial reserve capacity appears to buffer those from low ses backgrounds from developing cardiovascular disease (matthews et al., 2008) . in geroscience, reserve capacity refers to a broader set of resources of or buffers, social, psychological or physiological including cognitive function (e.g., high iq), physiological (e.g., aerobic fitness, sleep), and psychological assets (e.g., high optimism or positive affect). high reserve capacity increases the likelihood that one will have a hormetic protective response to a stressor. as shown in figure 2 , after diverse types of stressors (eg, chemical, physiological or psychological), an organism reacts and recovers to baseline with different speeds and this is moderated by baseline reserve capacity. for example, in response to a hip replacement surgery, the biggest predictor of good recovery was reporting good physical function at baseline (colón-emeric et al., 2019) . in response to general anesthesia, predictors of protection from dementia and other cognitive outcomes was measures of cognitive reserve such as education and vocabulary ability (cizginer et al., 2017) . indices of reserve capacity in functional abilities (such as ability to stand, gait speed, level of fitness), and glucose-insulin response to a glucose load, predict time to mortality, as reviewed elsewhere (seals & melov, 2014) . one of the most well-developed areas of reserve capacity comes from examination of individual dispositions of temperament, typically called personality traits. there are many psychological assets in adulthood that are associated with both better recovery from stressors, and with health and mortality. these include optimism, positive affect, mindfulness, coping with stress with cognitive reappraisal or active coping, high presence of social support or seeking support, purpose in life, and quality relationships. many of these assets have been associated with indices of good health, such as self-reported health and higher heart rate variability (carnevali et al., 2018) . these positive assets are both shaped by genetics and life experience. will promote further positive responses to future stressors, and may help slow the rate of aging in humans, as shown in figure 1 . how can we best translate hormetic interventions to humans? there are many potential interventions that may improve stress resilience, listed in table 1 . lifestyle interventions, such as exercise, caloric restriction, intermittent fasting, challenging cognitive activities, and response to phytochemicals in vegetables and fruits, are thought to work in part through hormesis (mattson, 2008b; radak et al., 2017) . at least one group is pilot testing a cocktail of stressors in humans to examine rejuvenation effects, using intermittent cold, heat, fasting and hypoxia, together with phytochemicals (pruimboom et al., 2016) . the hypoxic preconditioning effect demonstrates protection of neurons and cardiac cells, and is a potential area of translation (li et al., 2017 ). an interesting novel intervention inducing acute stress (through exposure to intermittent hypoxia and cold) appears to improve immune response to endotoxin at least in a small initial study, with a replication underway (kox et al., 2014) . at ucsf we are testing a similar protocol to see if it improves autonomic and neuroendocrine response profiles (including a quicker recovery from acute stress). another dramatic way to increase stress resilience is to enter periods of fasting, or fasting mimicking with low calories. in rodents, this leads to stress resistance and regeneration and rejuvenation processes through hormesis, in part by down regulating gh, igf-1. mtor, and pka signaling (longo, 2019; rangan et al., 2019) . reserve capacity is built during formative developmental experiences, such as level of education, attachment relationships, and stress exposures that shape the neural architecture of stress responding, narratives of optimism, and foster positive challenge mindsets. one can build reserve capacity by increasing physiological buffers (fitness, or antioxidant diet), or psychological stress resilience, through psychological trainings that might decreasing chronic stress arousal and bolster one's mental filter so they j o u r n a l p r e -p r o o f habitually perceive less threat. interventions that build psychological positive assets like optimism, mastery, and purpose in life need to be further developed and refined. mind-body interventions have a strong empirical base for improving self-reported wellbeing (creswell, 2017) with mixed effects on basal inflammation (bower & irwin, 2016) . mindfulness training may lead to changes in heart rate variability and telomere biology, although the evidence again varies by population and study (rådmark et al., 2019) (conklin et al., 2019) and appears stronger with clinical samples-those with high stress or early disease. there is emerging evidence that mind-body interventions improve physiological acute stress reactivity, changing stress appraisals and physiology to more of a positive challenge profile with a strong peak and faster recovery (daubenmier et al., 2019; lindsay et al., 2018) health behaviors regulate healthspan. the social hallmarks of aging shape health behaviors from an early age, which track throughout life. adverse health behaviors, such as diet, physical activity, sleep, and smoking are shaped by social stress. chronic stress both biologically drives toxic nutrition choices (sugar, fast food), impairs sleep, and promotes addictions, an indirect pathway in stress-acceleration of aging. the converse is also true, health behaviors lead to stress-slowing of aging. seventh day adventist who practice lifelong positive health behaviors, and lack the adverse behaviors of substance use, tend to have optimal longevity, living at least four years longer than the average us life expectancy and thus being the only blue zone in the us (fraser & shavlik, 2001) . exercise is the prototypical hormetic intervention. it increases the odds of healthy aging by 39% (daskalopoulou et al., 2017) . the mechanisms at the cellular level are becoming well explicated, as it can enhance mitochondrial health, telomere biology glucose, v02 max, oxidative stress, no) and upregulation stress resistance pathways, such as autophagy, and creating the opportunity for a long healthspan for all (health equity) requires improving economic and social factors. social factors are intrinsic to aging, our rate of aging depends on our social context and conditions. material deprivation and poor neighborhood quality confer psychological stress and risk of poor mental and physiological health (brisson et al., 2020) . for example, food insecurity is associated with over two fold risk of clinical anxiety or depression in adults, and confers even higher risk in college students (arenas et al., 2019; leung et al., 2020) . we now have a better understanding of how social threats lead to toxic stress. the primary motivational forces shaping human behavior are seeking safety and connection with others, and avoiding danger and anxiety. our mind is constantly seeking cues for safety or danger, even when we are not aware of this, and these social signals are transduced to biological signals, including patterns of autonomic activity and gene expression that are linked to inflammation. it is thought that exposure to or perception of frequent social threats (such as social rejection, discrimination, violence, and lack of safety) creates higher chronic systemic inflammation and sympathetic arousal, even while sleeping, and greater risk of affective disorders (brosschot et al., 2017; o'donovan et al., 2013; slavich, 2020; slavich et al., 2010) . conversely, social support, and social capital including perceived safety in neighborhoods, may be stress buffering, and are often associated with less inflammation and longer telomeres (brown et al., 2020; rentscher et al., 2020; thames et al., 2019) (geronimus et al., 2015; m. park et al., 2015) . social support and social networks can bolster healthspan interventions: our stress, emotional and physiological, is contagious to close others (carnevali et al., 2020; engert et al., 2019) , and conversely positive emotion and positive health behaviors are also socially influenced (christakis & fowler, 2013; kim et al., 2015) . the geroscience interventions that may work in mice will not be useful if they cannot be translated well to humans, taking into account our need for support and the significant challenges we have with adherence to exercise and other lifestyle changes. poor behaviors can override effects of protective pharmaceuticals. a common example of this is that people still develop diabetes while taking metformin due to overeating a western junk food diet. improving health behaviors can best be prioritized and implemented in the context where basic social needs are met. creating a supportive built environment and positive social environment are critical to promoting long-term behavior change. the science of behavior change, including the nih initiative focusing on this (nielsen et al., 2018) , has dramatically raised the sophistication of the research in this area, using the experimental medicine model to identify and manipulate the behavioral and social factors that facilitate adherence to health behaviors. behavioral or health interventions that work beyond the individual level, that can decrease loneliness and improve support will be more successful. the covid-19 pandemic demonstrates well the role of social factors in resilience to mental health disorders and infection. the pandemic led to dramatic increases in mental health disorders in the us and other countries (xiong et al., 2020) but this was not equally distributed. those with low education, income, minority status, loneliness, or low social support have significantly higher rates of mental health disorders from pandemic stress (arafa et al., 2020; holingue et al., 2020; palgi et al., 2020) . these vulnerable groups also tend to have higher rates of covid severity (adhikari et al., 2020; webb hooper et al., 2020) . any policies that improve social equity are also 'stress reducing' health policies that may contribute to healthspan, and can be incorporated into the geroscience agenda. geroscience is now more important than ever, both to our aging global demography but also to the health challenges we face going forward. in our new era we have dramatically increasing temperature extremes, wildfires and small particle pollution, and new zoonotic viruses to contend with intermittently. thus reducing social disparities, improving stress resilience and bolstering immune function have become critical public health goals. the vulnerability to covid-complications, while still largely unknown beyond older age and pre-existing diseases, clearly depends on ability of the immune system to respond robustly. the relevance of immune senescence in covid-lethality has stimulated many hypotheses about geroscience-related prevention and treatment (barzilai et al., 2020; salimi & hamlyn, 2020; sargiacomo et al., 2020) . while vaccination is essential for traditional prevention, it is not a universal solution: the elderly have poorer antibody responses to vaccination, there are many strains of the current virus, and there are expected to be many proliferations of future viral strains novel to the human body, due to climate change. therefore, geroscience interventions have unique universal importance across time. pharmacological interventions have been suggested for covid such as rapalogs, senoytics, nicotinamide adenine dinucleotide nad+, and metformin for anti-inflammation, telomere stability, or to boost vaccination response (omran & almaliki, 2020) . those with diabetes appear to benefit from metformin, which has hormetic properties, to prevent covid-related mortality (luo et al., 2020) . beyond pharmacological treatments, it is likely some of the interventions for boosting stress resilience in table 1 may enhance resistance to viral infections, from common cold to novel viruses. the malleable lifestyle behaviors like fitness, nutrition, sleep quality, and stress reduction, are important ways to reduce insulin resistance and comorbidities, and thus may help prevent immune senescence and covid complications. one pathway through which stress resilience interventions could impact immunity is through stabilizing telomere length. short telomeres predict greater vulnerability to rhinovirus infection, acute respiratory syndrome disorders, and mortality from sepsis (cohen et al., 2013; liu et al., 2020) . chronic psychological stress shortens telomeres in animal studies and impairs viral immunity (cohen et al., 1991 (cohen et al., , 1998 . short telomeres indicate lower ability to mount a robust replicative t cell response, and this may be a critical or even fatal j o u r n a l p r e -p r o o f limitation in the face of covid related lymphopenia (aviv, 2020) . in short, covid-19 presents a potent example of the potential for using indices of aging as predictors of disease and targets of intervention. the goal of geroscience is to slow aging to improve healthspan. in the next generation of research, we will benefit greatly from incorporating the large malleable factors that impact human aging-biobehavioral and social factors. the nia's intervention and testing program, a multi-institutional infrastructure to study biological agents for healthspan in animals is a model that can be extended to human trials that takes into account the social and behavioral factors (moffitt, this issue). the social hallmarks of aging shape rate of aging, in part through toxic stress processes. the understanding of toxic stress and hormetic stress as factors shaping aging will have implications for interventions. stress resilience, the ability to recover quickly and turn on rejuvenative processes, is an important dynamic endophenotype of healthy aging. it remains to be seen how much resilience is merely a characteristic of healthy aging or a causal factor, although much evidence reviewed here suggests it is at least partly causal. a better understanding of how to measure stress resilience, and to promote stress resilience at the cellular, physiological and psychosocial levels will lead to important gains in slowing aging. the science of stress is an integral part of geroscience, and offers insights on how to harness stress for optimal longevity, and implications for how to conduct the most effective interventions incorporating these stress processes as both target mechanisms and outcomes. by having an integrative paradigm that can be examined across levels, we can reduce the gap between physiological stress research in model organisms and human research on stress, resilience and adaptation. there are many ways to measure biological aging in humans that can serve as a barometer of change for interventions. this includes cellular level markers, multi-system composites, and ways of examining dynamic stress resilience, as reviewed. this j o u r n a l p r e -p r o o f can include recovery from a medical event in the elderly, but also recovery to standardized challenges, and to naturalistic stressors. geroscience offers an exciting opportunity for high feasibility impact interventions. this integrative paradigm can shape the next generation of researchers. the training models need to change to bridge the many fields as outlined by pioneers in geroscience (newman et al., 2019) . models which are focused on pharmacological interventions must expand to be inclusive of both social and behavioral interventions, the current 'big levers.' lastly, this field, like all of science, needs to actively encourage and support young investigators from diverse and underprivileged backgrounds to enter this important and growing field which has the potential to minimize socioeconomic and ethnic/racial health disparities not just for equity but for the improved science that results with diverse life experiences and perspectives. frameworks for proof of concept trials related to loss of physiological resilience have been initially outlined (justice et al., 2016) , and there are many geroscience trials in the field. these human trials can draw on the rich insights from decades of biobehavioral basic and intervention research. the science of behavior change initiative at nih is supporting the development of more effective behavioral and social interventions using the experimental medicine model using the same attention and rigor as pharmaceutical studies. by working across disciplines, with an understanding the role of lifespan experiences, and complexity of human environments, the geroscience framework has tremendous potential for breakthrough innovations in increasing healthspan. there has been a proliferation of terms from related disciplines that overlap and are differentiated here. the discipline most often using the term is noted, but these terms could be used to describe all levels of analysis, including cellular, physiological/organ systems, or psychological, behavioral and social processes. resilience has also been applied ast the systems level, to organizations, communities, societies, and ecosystems. how systems change in response to stressors, typically referring to level of hermetic or a protective adaptive responses in cell such as heat shock protein increases. (mattson) . mild stressors induce adaptive capacities that protect an organism for a short while from future stressors and may improve the physiological state of that organisms. preconditioning is a case of hormesis where exposure to a chemical agent leads to a 30-60% stronger adaptive response to subsequent exposures, across cell types and stressors (calabrese, 201) . in psychology, the tem 'stress inoculation' is used in a similar way. in terms of psychological stressors, under-exposure to the typical daily and major life events can lead to lack of development of stress buffering resources, and poor ability to quickly recover from stressors. biologically the lack of acute stressors prevents the intermittent episodes of cellular 'housecleaning' activities that slow aging. ideal exposure to sufficient numbers of manageable challenges throughout life stimulate cognitive growth, coping skills, and emotion regulation skills, as well as the need for supportive social networks. biologically, ideal exposure to acute stress can have hormetic effects, leading to rejuvenescence-functioning that is enhanced (or "younger") compared to baseline. overexposure to stress without sufficient resources (toxic stress) can lead to maladaptive neural pathways of overresponding to stress, depression, and stress related acceleration of aging from cells to regulatory systems. this figure is adapted from francheschi et al, 2018. in response to acute stressors, individuals have a kinetic trajectory of responses across psychological and physiological regulatory systems that lead to reactivity and recovery profiles. resilient stress responses (typically rapid high peak and rapid recovery) often have hormetic effects at the cellular or systemic levels. high levels of reserve capacity predict more rapid recovery, and this may lead to a positive feedback loop promoting higher reserve capacity. level of stress resilience is multiply determined by the social context and individual reserve capacity. together the latent homeostatic capacity of the organism to have resilient stress responses serves as an indicator of biological age and over time may influence the speed of aging. assessment of community-level disparities in coronavirus disease 2019 (covid-19) infections and deaths in large us metropolitan areas socioeconomic inequalities in health. no easy solution early life stress and trauma: developmental neuroendocrine aspects of prolonged stress system dysregulation psychological impacts of the covid-19 pandemic on the public in egypt a systematic review and metaanalysis of depression, anxiety, and sleep disorders in us adults with food insecurity ischemic preconditioning improves performance and accelerates the heart rate recovery the geroscience hypothesis: is it possible to change the rate of aging? telomeres and covid-19 early and late childhood telomere length predict subclinical atherosclerosis at age 14 yrs. -the cardiocaps study geroscience in the age of covid-19 targeting aging with metformin (tame) critical features of acute stress-induced crosssensitization identified through the hypothalamic-pituitary-adrenal axis output impact of early personal-history characteristics on the pace of aging: implications for clinical trials of therapies to slow aging and extend healthspan change in the rate of biological aging in response to caloric restriction: calerie biobank analysis mind-body therapies and control of inflammatory biology: a descriptive review a systematic review of the association between poverty and biomarkers of toxic stress exposed to events that never happen: generalized unsafety, the default stress response, and prolonged autonomic activity social regulation of inflammation related gene expression in the multi-ethnic study of atherosclerosis the effects of gamma rays on longevity stress biology and hormesis: the yerkes-dodson law in psychology-a special case of the hormesis dose response preconditioning is hormesis part i: documentation, dose-response features and mechanistic foundations building biological shields via hormesis sex hormonal regulation and hormesis in aging and longevity: role of vitagenes the wisdom of the body impact of the baltimore experience corps trial on cortical and hippocampal volumes autonomic and brain morphological predictors of stress resilience the contagion of social defeat stress: insights from rodent studies neurobiology of resilience: interface between mind and body the wear and tear of daily stressors on mental health social contagion theory: examining dynamic social networks and human behavior the cognitive reserve model in the development of delirium: the successful aging after elective surgery study types of stressors that increase susceptibility to the common cold in healthy adults psychological stress and susceptibility to the common cold association between telomere length and experimentally induced upper respiratory viral infection in healthy adults biological aging in childhood and adolescence following experiences of threat and deprivation: a systematic review and meta-analysis resiliency groups following hip fracture in older adults meditation, stress processes, and telomere biology mindfulness interventions adverse childhood experiences, allostasis, allostatic load, and age-related disease physical activity and healthy ageing: a systematic review and meta-analysis of longitudinal cohort studies a randomized controlled trial of a mindfulness-based weight loss intervention on cardiovascular reactivity to social-evaluative threat among adults with obesity biomarkers of adverse childhood experiences: a scoping review increased expression of telomere-regulating genes in endurance athletes with long leukocyte telomeres relationships between positive psychological constructs and health outcomes in patients with cardiovascular disease: a systematic review embodied stress: the physiological resonance of psychosocial stress the stress field ages: a close look into cellular aging processes psychological and metabolic stress: a recipe for accelerated cellular aging? hormones can childhood adversity affect telomeres of the next generation? possible mechanisms, implications, and next-generation research accelerated telomere shortening in response to life stress more than a feeling: a unified view of stress measurement for population science stress biology and aging mechanisms: toward understanding the deep connection between adaptation to stress and longevity embodying psychological thriving: physical thriving in response to stress stress, telomeres, and psychopathology: toward a deeper understanding of a triad of early aging repeat remote ischaemic pre-conditioning for improved cardiovascular function in humans: a systematic review appraisal, coping, health status, and psychological symptoms the continuum of aging and age-related diseases: common mechanisms but different rates ten years of life: is it a matter of choice? trajectories of resilience and dysfunction following potential trauma: a review and statistical evaluation depression increases the risk of mortality in patients with heart failure: a meta-analysis race-ethnicity, poverty, urban stressors, and telomere length in a detroit community-based sample hospitalization, restricted activity, and the development of disability among older persons associations between maternal risk factors of adverse pregnancy and birth outcomes and the offspring epigenetic clock of gestational age at birth substantial health and economic returns from delayed aging may warrant a new focus for medical research the baltimore experience corps trial: enhancing generativity via intergenerational activity engagement in later life burden of environmental adversity associated with psychopathology, maturation, and brain behavior parameters in youths mental distress during the covid-19 pandemic among us adults without a pre-existing mental health condition: findings from american trend panel survey frailty: implications for clinical practice and public health the effect of multiple adverse childhood experiences on health: a systematic review and meta-analysis. the lancet frameworks for proof-of-concept clinical trials of interventions that target fundamental aging processes a framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the tame geroscience: linking aging to chronic disease childhood adversity heightens the impact of later-life caregiving stress on telomere length and inflammation social network targeting to maximise population behaviour change: a cluster randomised controlled trial voluntary activation of the sympathetic nervous system and attenuation of the innate immune response in humans a randomized control trial to establish the feasibility and safety of rapamycin treatment in an older human cohort: immunological, physical performance, and cognitive effects life extension after heat shock exposure: assessing meta-analytic evidence for hormesis psychobiological factors of resilience and depression in late life the long arm of childhood experiences on longevity: testing midlife vulnerability and resilience pathways understanding the cumulative burden of basic needs insecurities: associations with health and academic achievement among college students preconditioning in neuroprotection: from hypoxia to ischemia acceptance lowers stress reactivity: dismantling mindfulness training in a randomized controlled trial peripheral blood leukocyte telomere length is associated with j o u r n a l p r e -p r o o f survival of sepsis patients programmed longevity, youthspan, and juventology the hallmarks of aging metformin treatment was associated with decreased mortality patients with diabetes in a retrospective analysis association between socioeconomic status and metabolic syndrome in women: testing the reserve capacity model. health psychology: official journal of the division of health psychology hormesis defined hormesis and disease resistance: activation of cellular stress response pathways hallmarks of brain aging: adaptive and pathological modification by metabolic states protection and damage from acute and chronic stress: allostasis and allostatic overload and relevance to the pathophysiology of psychiatric disorders the brain on stress: vulnerability and plasticity of the prefrontal cortex over the life course remote ischemic perconditioning to reduce reperfusion injury during acute st-segment-elevation myocardial infarction: a systematic review and meta-analysis a functional genomic fingerprint of chronic stress in humans: blunted glucocorticoid and increased nf-kappab signaling exercise, autophagy, and apoptosis emotional reactivity and mortality: longitudinal findings from the va normative aging study multiplex stress resistance in cells from longlived dwarf mice exercise-induced mitohormesis for the maintenance of skeletal muscle and healthspan extension creating the next generation of translational geroscientists the nih science of behavior change program: transforming the science through a focus on mechanisms of change exaggerated neurobiological sensitivity to threat as a mechanism linking anxiety with increased risk for diseases of aging influence of nad+ as an ageing-related immunomodulator on covid 19 infection: a hypothesis the loneliness pandemic: loneliness and other concomitants of depression, anxiety and their comorbidity during the covid-19 outbreak stress, epigenetics and depression: a systematic review where you live may make you old: the association between perceived poor neighborhood quality and leukocyte telomere length affective reactivity to daily stressors and long-term risk of reporting a chronic physical health condition a mitochondrial health index sensitive to mood and caregiving stress influence of a 10-day mimic of our ancient lifestyle on anthropometrics and parameters of metabolism and inflammation: the "study of origin aerobic exercise lengthens telomeres and reduces stress in family caregivers: a randomized controlled trial -curt richter award exercise, oxidants, and antioxidants change the shape of the bell-shaped hormesis curve a systematic review and meta-analysis of the impact of mindfulness based interventions on heart rate variability and inflammatory markers clarifying the roles of homeostasis and allostasis in physiological regulation fasting-mimicking diet modulates microbiota and promotes intestinal regeneration to reduce inflammatory bowel disease pathology hormesis in aging relationship closeness buffers the effects of perceived stress on transcriptomic indicators of cellular stress and biological aging marker p16ink4a epigenetic age and pregnancy outcomes: grimage acceleration is associated with shorter gestational length and lower birthweight association of optimism with cardiovascular events and all-cause mortality: a systematic review and metaanalysis covid-19 and crosstalk with the hallmarks of aging the genetics of human personality covid-19 and chronological aging: senolytics and other anti-aging drugs for the treatment or prevention of corona virus infection allostasis: a brain-centered, predictive mode of physiological regulation translational geroscience: emphasizing function to achieve optimal longevity allostatic load as a marker of cumulative biological risk: macarthur studies of successful aging the stress of life exposure to violence during childhood is associated with telomere erosion from 5 to 10 years of age: a longitudinal study affective reactivity to daily stressors is associated with elevated inflammation. health psychology: official journal of the division of health psychology childhood asthma prevention study group telomere length in early childhood: early life risk factors and association with carotid intima-media thickness in later childhood social safety theory: a biologically based evolutionary perspective on life stress, health, and behavior black sheep get the blues: a psychobiological model of social rejection and depression childhood adversity, adult neighborhood context, and cumulative biological risk for chronic diseases in adulthood childhood social disadvantage and pubertal timing: a national birth cohort from australia life course socioeconomic status, daily stressors, and daily well-being: examining chain of risk models experienced discrimination and racial differences in leukocyte gene expression experience corps baltimore: exploring the stressors and j o u r n a l p r e -p r o o f rewards of high-intensity civic engagement heritability of personality: a meta-analysis of behavior genetic studies covid-19 and racial/ethnic disparities physical resilience: not simply the opposite of frailty physical resilience in older adults: systematic review and development of an emerging construct how adverse childhood experiences relate to single and multiple health risk behaviours in german public university students: a crosssectional analysis relationship of psychosocial resources with allostatic load: a systematic review traumatic stress and accelerated dna methylation age: a meta-analysis impact of covid-19 pandemic on mental health in the general population: a systematic review the impact of changes in population health and mortality on future prevalence of alzheimer's disease and other dementias in the united states crimmins, steve austad, and edward calabrese. key: cord-313218-4rbxdimf authors: narushima, miya; kawabata, makie title: “fiercely independent”: experiences of aging in the right place of older women living alone with physical limitations date: 2020-09-09 journal: j aging stud doi: 10.1016/j.jaging.2020.100875 sha: doc_id: 313218 cord_uid: 4rbxdimf this study explores the experience of aging among older canadian women with physical limitations who live by themselves. while aging in place has been a policy priority in rapidly greying canada, a lack of complementary public supports poses challenges for many older adults and their family members. employing a qualitative methodology, and drawing from the notion of aging in the right place, we collected personal narratives of 12 women (aged 65 to 92) in two geographic areas in ontario, including residents of regular houses, apartments, condominiums, assisted living and community housing for seniors. through thematic analysis, we identified four overarching themes: 1) striving to continue on “at home”, 2) living as a “strong independent woman”, 3) the help needed to support their “independence”, and 4) social activities to maintain self. our findings illustrate how, despite their mobility limitations, older women can change their residential environment and their behavior by deploying the coping strategies and resources they have developed over time. however, we also found that older women are largely silent about their needs, and that experiences varied depending on life histories, health conditions, and the availability of supports in their wider environment (home care, alternative housing options, accessible transportation, opportunities for social and physical activities). we hope these findings will incite further studies and discussion to help make aging in the right place a real choice for anyone who wishes to do so. population aging in canada will keep accelerating over the next decade. the ratio of "senior citizens" (aged 65 years and older) is expected to grow from 17.5% in 2019 to 22.7% by 2031 (statistics canada, 2019) . "old-old" canadians in their late 90s and above are among the fastest growing age group (hudon & milan, 2016) . like many countries, canada's policy response to this demographic change is the promotion of aging in place, generally understood as being able to remain in familiar homes or communities for as long as possible. the premise is to promote independent living in later life, while shifting care for the older adults from institutions to home and community (dalmer, 2019; lehning, nicklett, davitt, & wiseman, 2017) ; a shift long criticized by social gerontologists for being part of the devolution of aging and long-term care policies. policy makers have largely supported this strategy as a cost-effective long-term care alternative. more than anyone, however, it is older adults themselves who are in favor of the idea. aging in place has become common in canada. comparing the 2011 and 2016 censuses, the ratio of people aged 65 and older living in "collective dwellings" (e.g., assisted living, supportive housing, retirement residences, seniors' apartments, continuum care facilities, and nursing homes) has dropped from 7.9% to 6.9% (garner, tanuseputro, manuel, & sanmartin, 2018; statistics canada, 2012) . given the increasing numbers of older canadians, one would expect this number to grow, not decline. the 2016 census found only 5.0% of seniors had moved in the past year, a much lower rate than the general population (13.0%). this should not, however, be assumed to reflect older adults' satisfaction with their housing. in fact, almost a quarter of seniors reported their housing as "below standard" in terms of either affordability, adequacy, or suitability (federal/provincial/territorial ministers responsible for seniors, 2019). although health status among older adults is heterogeneous, chronic diseases and physical limitations increase with advancing age. more than three-quarters of canadians aged 65 and older reported having at least one chronic condition, and one quarter reported three or more. one out of four of those aged 85 and over reported a need for support in instrumental activities of daily living (iadl), while one in ten needed support in activities of daily living (adl). like the rest of the world, older women are disproportionately represented in these groups (canadian institute for health information, 2011) . older women in general are more likely to face challenges since women live longer and are more likely spend their later years with mobility problems and pain (bushnik, tjepkema, & martel, 2018) and nearly twice as likely to live alone than their male counterparts. the 2016 census found 26.0% of seniors lived alone, 68.0% of who were women (tang, galbraith, & truong, 2019) . in addition, women living alone comprised 57.0% of seniors with "core housing needs" (federal/ provincial/territorial ministers responsible for seniors, 2019). given these demographic, health, and socio-economic trends, more research on the experience of aging in place among older women, especially those living alone with physical limitations, is needed (gonyea & melekis, 2018) . from "aging in place" to "aging in the right place" the conceptual development of aging in place began when american environmental gerontologists (lawton & nahemow, 1973) introduced the "ecological model of aging" to examine the relationship between people and their environments. in this model, an older person's functioning is determined by the "fit" between "personal competences" (e.g., physical, psychological, and social functions) and "environmental characteristics" (e.g., the immediate and wider environments). as changes happen in either or both, older adults can try to adapt their physical and social environments to find a comfort zone by deploying their resources (greenfield, 2011; lawton & nahemow, 1973; peace, holland, & kellaher, 2011; stafford, 2016) . this theoretical framework helps us to understand aging in place as a dynamic process of personenvironment interactions. wahl, iwarsson, and oswald, and their collogues in germany and sweden have extended this framework to, "maintaining the highest autonomy, well-being, and preservation of one's self and identity as possible, even in the face of severe competence loss" (wahl, iwarsson, & oswald, 2012, p.310 ). this process is influenced by two concepts: "belonging" and "agency". belonging involves an older person's sense of connection with others and the environment and preserved identities over time. agency refers to sufficient control of their environment to maintain autonomy. belonging grows in importance as people get older, especially when they develop functional impairments (oswald, wahl, schilling, & iwarsson, 2007; wahl et al., 2012) . this model reminds us of the benefits of taking a life-course perspective to understand the experience of aging in place. in the same vein, golant (2011 golant ( , 2015 , an american environmental gerontologist, has put forward the notion of aging in the right place. pointing to the unequal capabilities and resources among older adults, golant (2008 golant ( , 2015 criticizes how aging in place has been promoted as a cultural imperative in america, emphasizing an individual's self-reliance in sustaining a healthy active lifestyle. even when older adults have chronic health problems, disabilities, or cognitive deficits, he argues, if they are offered "enabling residential and care opportunities that strengthen their coping skills to achieve their evolving needs and goals", they can still "age successfully" (golant, 2015, p.353 ). golant thus advocates shifting public discourse, and older adults' thinking, from aging in place to aging in the right place, which includes expanding the various alternative housing options being consideredsuch as group housing, active adult communities, senior apartments, assisted living residences, continuum care, and the like. in this model, regardless of residential type, older adults can achieve "residential normalcy" where they feel comfortable, competent, and in control. older adults may use various coping strategies when their residential normalcy becomes incongruent. moving to alternative housing such as assisted living, active adult communities, and nursing homes can be seen as adaptive responses to aging. golant (2015) also noted that enriched coping strategies are products of the resilience of both older persons and their environments. despite this theoretical development, the public discourse surrounding aging in place in canada seems to have stagnated. for example, in a public guide issued by the federal government, "aging in place" is defined as "having access to services and the health and social supports and services you need to live safely and independently in your home or your community for as long as you wish and are able" (federal/provincial/territorial ministers responsible for seniors, 2015, p.1). the guide also notes that an individual can achieve this goal through early planning in such areas as home, community, transportation, care and support services, social connection, healthy lifestyle, finance, and information. as dalmer (2019) has noted, such neoliberal rhetoric frames aging in place as "a matter of choice" that can be responsibly managed by individuals. given the lack of affordable housing alternatives and the unmet need for long-term home care services for many older canadians, however, this so-called choice is often illusory. as mentioned, according to the 2016 census, only 6.8% of canadians aged 65 years and older lived in "collective dwellings," including nursing homes (the most common) and other alternative senior residences such as assisted living and retirement homes. this suggests that moving to alternative housing, as advocated by aging in the right place, is still uncommon in canada. this is partly due to a lack of affordable senior residences. in ontario, the average monthly rent for a standard space for a resident without high-level care needs was $3758 canadian in 2018 (canada mortgage and housing corporation, 2019). given seniors' average annual income -$48,800 for men and $34,900 for women (statistics canada, 2020) -alternative housing is unaffordable for most older canadians, especially women. as more and more older adults age in place, their homes and communities increasingly become locations for health and social care services (hereafter "home care"). since long-term home care is not universally insured under the canada health act, older adults who don't qualify need to resort to community agencies that often require a co-payment or privately hire help (armstrong, zhu, hirdes, & stolee, 2015; gilmour, 2018; government of ontario, 2019; johnson et al., 2018; lee, barken, & gonzales, 2018) . according to the 2015/2016 canadian community health survey, over one-third (35.4%) of people with home care needs did not have their needs met, especially among those with home support services for maintenance of daily living (gilmour, 2018) . the current policy of aging in place needs more complementary public supports to reduce the challenges facing many older adults and their families. it is within this context that we explore the experiences of aging in place among older canadian women with physical limitations who live alone. our research questions include: 1) what is it like to live at "home" alone for older women with physical limitations? 2) what support do they receive and how? and 3) what are the enabling and disabling factors for their independent living? this study employed a qualitative research methodology (merriam & tisdell, 2016) , more specifically, combining personal narrative analysis (maynes, pierce, & laslett, 2008) with a narrative gerontology approach (de medeiros, 2014) . a qualitative approach lets us explore inductively how older women construct and make sense of their experience of aging in place (merriam & tisdell, 2016) , connecting their individual experience and life trajectories with broader cultural and social forces (maynes et al., 2008) . this reinforces what narrative gerontology advocates: listening to older people's lives as stories to understand their social world -personal, interpersonal, structural and cultural (de medeiros, 2014) . this study is part of a larger study, and ethics clearances were obtained from the research ethics boards of both researchers' universities. we recruited participants in two areas (a large metropolitan area and a medium sized city) in southern ontario. the criteria for inclusion were: women 65 years and older, who lived by themselves at home with chronic physical conditions, and who were using or had used home care services. following the notion of aging in the right place, we included both regular house, condominium, and apartment, as well as alternative housing such as assisted living and community housing for seniors. we created a flyer, noting we were "looking for participants in a research study to learn their experience of and opinions about living with chronic physical conditions." approximately 70 flyers were either posted in their residences or directly delivered to potential participants through personal support workers (psws) in collaboration with five different community organizations. recruitment was harder than we had expected. since only two participants voluntarily called back, we asked our participants, colleagues, and friends to deliver the flyer to whoever might meet the criteria. eventually, we had 15 interviewees. although every interview will be used in our larger study, 12 participants met all the criteria for this study. the 12 participants ranged between 65 and 92 (the average age was 83), and lived in various residential types in varying states of health. all have been given pseudonyms (see participants' profiles in table 1 ). the data collection was conducted in the spring and summer of 2017. the first author and a student research assistant conducted all interviews together. eleven interviews were conducted in participants' homes and one was in a public space. visiting their residences let us observe their daily living and neighborhood environments. each interview lasted from 90 to 120 min. we began by asking participants to tell us their life histories, followed by questions about their daily and weekly routines, current physical condition, strategies and challenges for managing their independent living, the support they receive, and their opinions about aging in place in general. since one chinese immigrant participant (hong, 90) had difficulty speaking english, her daughter (lin, 64) joined the interview as a translator, also providing some of her own insights as a family carer. following each interview, we provided a gift card of $30 with a thank you note. then the two interviewers debriefed each other, recording what they had noticed in the field notes. all interviews were audio recorded, transcribed verbatim, and sent to participants to check accuracy and to modify if requested.the twelve transcripts comprised 281 pages in total. following the steps of thematic analysis (merriam & tisdell, 2016) , we started open coding by reading the first participant's data set (transcript and field notes), then underlined any segments that might be meaningful and attached labels (i.e., code and themes). next, we moved to axial coding by sorting these codes and themes into more comprehensive groups (i.e., categories). then, we created a matrix to display the categories, themes, and supporting quotations for the first participant transcript. we went through the same procedures for the second data set, and compared the two matrices to create a master list of crosscase categories and themes. this master list was used as a basis for analyzing the other participants' data. comparing all 12 participants' matrices, we generated four overarching themes as findings. to increase trustworthiness, our design included data triangulation, member checking of interview transcripts, a reflexive journal, and peer debriefing with research team members (creswell, 2013; merriam & tisdell, 2016) . we found the following four overarching themes: 1) striving to continue on "at home", 2) living as a "strong independent woman", 3) the help needed to support their "independence", and 4) social activities to sustain self. these overarching themes contain several subthemes. the first theme involves our participants' efforts to live in their homes comfortably and safely. as shown in table 1 , many participants had lived in the same residence for decades, while a quarter had moved in the past four years due to changes in their mobility or marital status. in any event, all participants seemed comfortable in their residence, which they called "home". the first thing that we noticed was that these homes preserve their personal histories and identities. their well-kept living rooms were stuffed with vintage furniture, family photos, art, crafts, books, instruments, souvenirs, plants, pets, etc. participants four participants mentioned they might have to move in the future when they could no longer take care of themselves. yet their narratives suggested the difficulty of moving to alternative housing. certainly, i couldn't afford one of these fancy private assisted retirement homes. i've been to one of them to visit a friend of mine. she pays about $3500 a month for one room. i cannot afford that on my pension (dorothy, 83). my mom [hong, 90] is on the waiting list. well, it's been 10 years already since she registered. it's one of the chinese long-term care homes. […] oh, yes, it's common. they say it normally takes over 10 years! (lin, 64). these comments underline the lack of affordable alternative housing many older adults face. during our visit, we were also impressed by their efforts to control their home environment to live safely. all participants had at least one chronic health condition. however, their biggest challenges were mobility issues -especially difficulty in walking, falls, and the fear of falling. despite their use of mobility aids (e.g., cane, walker, wheelchair), many participants talked about their occasional falls. all had made some home adaptations by installing safety features (e.g., staircase railing, grab bar, special chair and non-slip mat for bathrooms). they were also using assistive devices. ten of 12 participants carried an emergency alert pendant or had installed an alert system with pull cord for their bathrooms. this was a lifesaver for some. valerie, 92, who has had multiple falls, related: i've used it twice. one time, they were able to get in through the kitchen window. the other time, i was doing christmas decorations when my daughter phoned, and when i turned, i fell. my daughter phoned a friend's husband to come, but before he arrived, i phoned the emergency alert and asked them if there was a particular way he should pick me up. they immediately sent somebody and got me on the chair. valerie's story suggested how unexpectedly and easily falls can happen at home, and how the assistive device helps in those instances. many participants were also using other technologies to help increase their sense of control and autonomy. half used a tablet or a computer for frequent communication with their families, reading news, and searching information. a participant with vision problems showed us a sight enhancement reading machine. one had a mobile chair lift for the staircase. the most advanced case of impairment was renelsa, who at 84 spent most of her day in bed due to her frailty, but she could still live alone in her one-bedroom apartment in community housing. her building had a security camera to screen visitors, and her apartment door could be opened with a remote control beside her bed. we had no idea about how limited her mobility was until she greeted us in her bedroom. participants in assisted living appreciated similar safety features in their units, and the railings in the hallways and elevators. in addition, mei lien, 68, explained how her residence gave her "peace of mind": "last year, in the middle of night, i had to call somebody, and they [staff] came up. i don't have family in canada, so at least you know somebody is there if you call". margaret, 84, who was recently widowed, reflected on her decision to move from her house to a seniorfriendly condo: the very last thing i wanted to do was move into this building… do i want to live here? no! but should i live here? absolutely! … if you think your health is going to be the same tomorrow as it is today, you are wrong. we all progress to some extent from day to day … i did not know the presence of a garbage disposal in the hallway was so convenient. so in the big picture, it was a very wise thing. in this way, each participant was negotiating their own physical and social conditions, and actively managing to control their home environment as best they could. the second theme involves our participants' distinctive shared character. although their life histories and current conditions varied, we were struck by their positive, spirited, and persevering attitudes. contrary to our expectation, participants rarely brought up their needs. we thus had to ask if there was anything to complain about. dorothy, 83, who had just recovered from a fall on ice, laughed and said: well, i think, oh, god, i ache, i ache, i ache, but i shouldn't complain, especially when i see other people… at least, i can still walk around, i can still look after myself, and do my own thing in my own house. so you know, i would say i'm fortunate. […] well, you have to make the choices yourself, don't you? you either sit there and wither away, or you get involved and do something. luisa, 78, mentioned that she had learned it from her role model: i am a contented person. i am not always looking for what i don't have. i learned that from my mother. she independently lived in her own apartment until 93, climbed stairs to the fourth floor, and always baked and cooked for visitors. you know, she never complained about her situation. she was fiercely independent. as these comments imply, many of our participants held to a similar principle in their lives. in fact, participants commonly described themselves as brave, independent women. their life stories were full of personal and historical events: the great depression, world war ii, immigration, marriage, divorce, separation, accident, the deaths of spouses, children, and friends, and their own health problems. every participant had an occupation at some point, and many repeatedly used the word "independent" to describe themselves. as hannah, 88, who had immigrated from germany with her husband after world war ii, put it: i was always this independent (laughter). i was married, and i was independent. i became a widow at the age of 42, and raised three children. when my husband got sick, i had a job [a lab aid in a hospital] and i took a year of absence to take care of him at home. but i needed the money, so i cleaned houses, took in other people's clothes. i wanted my children to have a better education. i never went on welfare, i worked and all my children went to university. if you came from a different country, you help yourself, you don't rely too much on the country. it's my job to look after the family. a former university professor, margaret, who was mourning her husband's death and managing her own health problems, described her efforts to be a strong role model for others at 84 years old: i am very strong-willed person. i was always a determined youngster. even as a girl, i was an independent child (laughter). even now, i just have to get really strong to be a good role model for women. i always try to be, because who is going to be the one to make me look and feel strong? me! you will only be strong if you work to be that way. […] i just live today, that's exactly how i think. i believe you stay the strongest person you can be each day you are alive. as these comments suggested, our participants' self-identity as strong independent women developed through various life experiences, sustains them in the face of the challenges of later life. nevertheless, we also learned that participants' "independent" lifestyles were supported by many other people in a mix of formal and informal care. due to our recruitment criteria, all participants had had an experience of publicly funded "formal" home care. however, at the time of our interview, only four were eligible for long-term home care, receiving 30 min to 1.5 h a day. for the other eight participants, publicly funded home care ended two to three months after a hospitalization. once this post-acute care was over, they were back on their own. the four participants who could afford it hired a paid housekeeper a few hours a week. two more, thanks to their retirement benefits, continued regular physiotherapist visits at home or attended weekly exercise classes through community agencies. compared to those living in regular houses or apartments, participants in assisted living had an advantage in the availability of and accessibility to long-term home support services right in their own buildings. however, some expressed hesitation to use additional support services due to their worry about the additional cost: "if you need the extra service, you have to pay. it depends if you or your family can afford it. so you just hope and pray you won't need more services" (mei lien, 68). like mei lien, many participants saw cost as a barrier to longer-term formal home care. as mentioned before, however, none explicitly advocated a more affordable publicly supported long-term home care system. in contrast, participants talked much more openly about informal care and support -their reliance on their family members, friends, and neighbors for regular help for transportation and household chores. ten out of 12 participants, regardless of residential type, had at least one close family member nearby. while most participants still managed to clean their homes, do laundry, and cook simple meals, carrying groceries and to taking public transportation were getting harder. family members were the primary source for a wide range of household chores. luisa, 78, described the support from her son's family: it helps me a lot that my son and daughter-in-law live here [in the same city]. i've been calling them to do things. he installed the railing on the basement stairs, because i've had three falls since last december. it just makes me feel more secure. and my daughter-inlaw takes me to a rheumatologist in another city, because i don't drive highways anymore. for participants whose family members lived far away, friends and neighbors were crucial sources of social support: "i have a good friend who takes me grocery shopping and to doctors' appointments" (hannah, 88); "when i had the cancer, i had radiation 28 times in december. every morning i told my friends, i cannot do it one more day, but i did thanks to them" (elizabeth, 92). as these comments suggest, most participants were grateful for the informal support and care provided by family members, friends and neighbors. clearly, these provided crucial instrumental and emotional support to all participants. overall, participants' narratives suggested an imbalance between formal and informal home care and support. even for participants receiving publicly funded long-term home care, that was not enough to live alone at home with disability and frailty, due to the limited time and tasks performed by the personal support workers (psws). for example, although psws help renelsa three times a day for a total of 1.5 h, it is her brother who brings over meals twice a week to store in her freezer. for hong (90), who speaks limited english, communication with the psw is challenging. as her daughter said, "the agency working in this building has no psw who speaks chinese. for showering, communication is very important. that's why i need to translate. otherwise, i could be preparing breakfast during that time" (lin, 64). participants in assisted living also reported regular informal support from their family members. katharine, 88, who no longer cooks for herself, mentioned: "i can have dinner at the dining hall downstairs, but my niece and nephew do weekly shopping for my breakfast and lunch." compared with participants living in houses, however, those in assisted living did not have to rely family and friends for daily personal care. overall, regardless of residential type, our participants' narratives suggest their independent life was unattainable without support from many others. the fourth theme involves the benefits of opportunities for continued social participation. despite noticeable physical discomfort, most participants kept trying to maintain the activities and the relationships that they valued, which were clearly an important part of their social identity. three participants living in houses were still earning a small income. many participants also kept volunteering in their communities. in particular, participants in assisted living had many opportunities within their own buildings. for example, tami, 65, a master of 3d origami, taught it to her fellow residents while volunteering at a nursing home once a week. as she explained: in 2010, when i got this problem [a rare and progressive degenerative disease], i started volunteering. the volunteer work makes me happy. sometimes, it's just sitting and talking to them [the residents in a nursing home]. but if i talk to them, they smile. they are losing their smile all day, so i want to make them smile. smile … like cheeks up. their smiles make me happy. like tami, many participants mentioned their joy at making themselves useful to others, despite, or possibly because of, their own mobility and health challenges. tami also appreciated the wheel-trans system that made her volunteering possible. most participants also stayed active in the groups to which they belong. elizabeth, 92, a former entrepreneur, described her monthly routine: "i go to church on sundays, probus club and torch club once a month…i also go to all sorts of classes". although elizabeth had no family members in canada, her long-term involvement in her local community had helped her develop a circle of good friends who she could rely on. renelsa, 84, a former nurse and devoted christian once nicknamed "the sister in the operating room", could no longer attend church, so three fellow congregants visited her twice a month: "on sunday, we have church right here in my apartment! i really look forward to when they come". many residents in assisted living had an even busier schedule of social, cultural, and physical activities. emily, 85, showed us her monthly calendar on which she had circled her activities. on some weekdays, her schedule is packed from 7:30 am to 3 pm! we also noticed a notable difference in the accessibility for exercise between those living in their own house and apartment and those in assisted living. most participants in assisted living continued to attend using their canes and walkers, while those living in their own houses stopped going to exercise classes in their communities due to a lack of transportation and coverage for long-term physiotherapy. participants' narratives make it clear that these opportunities for civic engagement and social and physical activities give them a routine to leave their "homes" to socialize, and enable them to keep playing a social role in their communities. moreover, older women mutually support each other in various ways by giving rides, bringing soups, etc. they not only receive support from others, they kept providing support to each other. overall, our study's findings illustrate how older women living alone with physical limitations can, with support from others, manage to maintain their independence in places where they feel "at home". all were achieving "residential normalcy" (golant, 2015) in "homes" that were "uniquely their individual domain" (kontos, 1998, p.286) , where they could feel comfort, autonomy, security, self-identity, and continuity of self (golant, 2015; stones & gullifer, 2016; wiles, leibing, guberman, reeve, & allen, 2012a) . their familiar belongings-what coleman and wiles's (2020) termed their "objects of meaning"-symbolically connected their past, present, and perhaps future selves. this also overlaps with the concept of "belonging". as wahl et al. (2012) noted, familiarity, routines, and emotional attachment developed over time help preserve identity and enable aging well in the right place. despite their physical discomfort, all were "fiercely independent", a phrase used by two participants (elizabeth, 92; louisa, 78) . as prescribed by aging in place policy, they strove to alter their home environment to live as independently and safely as possible, deploying the strategies and resources available and affordable in their contexts. they practiced problem-focused "assimilative coping", but many also used emotion-focused "accommodative coping" by accepting and being content with what they have (golant, 2015, p.102) . these conscious behaviors exhibit our participants' "competences" (lawton & nahemow, 1973) and "agency" (wahl et al., 2012) , another enabler in person-environment interactions. one unexpected finding is their emphasis on being strong-willed "independent women". this self-image, developed over their life course, provides a psychological resource to cope with challenges in later life. clearly, they are "resilient" people (golant, 2015, p.118) who are motivated and confident, with the physical capabilities, mental stamina, and flexibility to find appropriate solutions to the environmental obstacles they face. yet, based on their life stories, we suspect that their resilience is not an innate personality trait so much as an ability to "adapt well" learned and developed over time in relation to others and to their environments ( van kessel, 2013; wiles, wild, kerse, & allen, 2012b) . we found this learning process to be resilient operating even among very old and frail participants. this supports peace et al.'s (2011) finding that, while frailty and decline of personal competence are related, they are not synonymous. older adults can confront challenges by bringing their life experiences to their person-environmental interactions. despite their limited mobility, many stayed involved in social and volunteer activities, using their skills and sustaining and developing relationships. importantly, our participants did not passively receive care. they also actively provided it to others. this finding overlaps with the concepts of "vitality and agency in frailty" for preserving selfidentity and continued self-development in later life (bjornsdottir, 2018; latimer, 2012) . it also highlights the crucial role of opportunities for social participation, meaningful and reciprocal contribution, and relationship building to aging in place. a recent increase in innovative community-based participatory approaches to aging in place, such as the naturally occurred retirement community (norc), for example, includes this reciprocal exchange of support and care by creating resourceful community environments (greenfield, scharlach, lehning, & davitt, 2012; sixsmith et al., 2017) . nonetheless, our findings also suggest some disabling factors. the constant "balancing act" (golant, 2015, p.355) person-environment interactions in later life demands was difficult for some, especially for those with severe mobility limitations, multiple comorbidities, few close family members and friends, and low income. also, the quality of our participants' aging in place was influenced by local environments, including the availability of affordable home care services, physical activities, and safe and reliable public transportation (e.g., wheel-trans). most notably, our participants were facing the challenges of pain and balance: falling posed a real threat, as found in previous studies (e.g., bushnik et al., 2018) . nevertheless, for many participants -especially those living in houses and apartments without transportation and private home care insurance -regular exercise classes, physiotherapy, and fall prevention programs were neither affordable nor accessible. given the proven benefits of interventions for falls and fear of falling (e.g., whipple, hamel, & talley, 2018) , it is essential to develop strategies to make those programs more available. policies in aging, health, and social services should support greater collaboration between community-based formal and informal care (ryser & halseth, 2011) . in the current discourse surrounding aging in place, independent living tends to refer to an autonomous lifestyle achieved through the personal efforts of individuals. in reality, however, as our findings show, aging in place for older women with physical limitations inevitably requires a view of "independent living" which promotes reciprocity and interdependence between individuals and their communities, including both formal and informal supports. in other words, as golant (2015, p.356 ) advocated, we need to adopt an "it takes a village" perspective. nevertheless, consistent with previous studies (johnson et al., 2018; kadowaki, wister, & chappell, 2015) , publicly supported long-term home care -especially for maintenance and prevention purposes, such as home support services and physiotherapy -was still unavailable for many of our participants. our study adds further contextual evidence to canada's need for the publicly supported long-term home care system many have advocated over the past decade (canadian home care association, 2016; gilmour, 2018; kadowaki et al., 2015; special senate committee on aging, 2009; turcotte, 2014) . overall, the findings of our study support the notion of aging in the right place proposed by golant (2015) . they suggest that, despite their tireless individual efforts to be independent in a place of their own, older women can reach a point where the changing balance between personal competence and environmental pressure requires a new strategy to maintain self-identity, what peace et al. (2011) term "option recognition" (p.751). participants who could afford it or were eligible for public subsidy often moved into assisted living to regain control. given the lack of a universal long-term home care system in canada, moving to assisted living helps reduce the heavy burden placed on some older adults and their family members (ryser & halseth, 2011) . at the same time, our participants' narratives reaffirm that alternative senior residences -such as active adult communities, assisted living, and continuum care retirement communities -are not a readily available or affordable option for many middle-income older canadians (dalmer, 2019) . finally, the most unexpected finding in our study is the collective silence of older women, the so-called "shadow story" (de medeiros & rubinstein, 2015) , about their unmet need for more formal and structural support reported in previous studies (e.g., canadian home care association, 2016; gilmour, 2018; turcotte, 2014) . this may be partly because the interviewers were "others" (dorothy, 83), making it hard for participants to reveal their true feelings, and partly because respondents wanted to present themselves as role models for their interviewers, who were of their daughter's and granddaughter's generation. complaining and demanding that their needs be met contradicted their core principle of "being independent". finally, adopting the neoliberal rhetoric of being self-reliant and autonomous model citizens, older women may see their growing care need for daily activities as an individual matter that they should take care of themselves, rather than a structural issue connected to the long struggle over public policy. further study is required to clarify these points and investigate how a "sociological imagination," as coined by c. wright mills (1959) , might be used to collectively empower older women and inform public policies alike. this study has several limitations. due to our small number of selfselected participants who are resilient and have positive outlooks, our findings reflect more the experiences of older women who are successfully aging in the right place, despite their physical conditions. the voices of older adults who live with cognitive impairment, depression, and social isolation, or whose lack of resources make them more vulnerable, are missing. furthermore, the data was collected before the covid-19 pandemic, which has likely altered older women's perceptions and experiences. all these areas are important, and deserve further study. despite these limitations, our research provides a valuable window into experiences of aging in the right place of an understudied groupolder women living on their own with physical challenges in canada. no matter how fiercely and successfully independent older women try to be, framing aging in place as a matter of individual efforts alone is misguided. it is crucial that more structural supports and improved community-based care that is informed by recipients themselves become an integrated part of public policy. the shifting of public perceptions from aging in place to aging in the right place has the potential to foster subjectively-defined aging well among older adults with different needs and resources. we hope these findings will encourage further studies and the political will to make aging in the right place a real option for older adults in canada and far beyond. this study was funded by a grant from the japan society for the promotion of science (#15k13083). none. rehabilitation therapies for older clients of the ontario home care system: regional variation and client-level predictors of service provision holding on to life': an ethnographic study of living well at home in old age health reports. health-adjusted life ex seniors' housing report -ontario better home care in canada: a national action plan health care in canada, 2011: a focus on seniors and aging being with objects of meaning: cherished possessions and opportunities to maintain aging in place qualitative inquiry and research design: choosing among five approaches a logic of choice: problematizing the documentary reality of canadian aging in place policies narrative gerontology in research and practice shadow stories" in oral interviews: narrative care through careful listening thinking about your future? plan now to age in place -a checklist report on housing needs of seniors transitions to longterm and residential care among older canadians unmet home care needs in canada commentary: irrational exuberance for the aging in place of vulnerable low-income older homeowners the quest for residential normalcy by older adults: relocation but one pathway women's housing challenges in later life: the importance of a gender lens using ecological frameworks to advance a field of research, practice, and policy on aging-in-place initiatives a conceptual framework for examining the promise of the norc program and village models to promote aging in place senior women. women in canada: a gender-based statistical report. catalogue no.89-503-x. ottawa: statistics canada no place like home: a systematic review of home care for older adults in canada influence of home care on life satisfaction, loneliness, and perceived life stress resisting institutionalization: constructing old age and negotiating home home care and frail older people: relational extension and the art of dwelling ecology and the aging process utilization of formal and informal home care: how do older canadians' experiences vary by care arrangements social work and aging in place: a scoping review of the literature telling stories: the use of personal narratives in the social sciences and history qualitative research: a guide to design and implementation housing-related control beliefs and independence in activities of daily living in very old age option recognition' in later life: variations in ageing in place informal support networks of low-income senior women living alone: evidence from fort st ageing well in the right place: partnership working with older people. working with older people canada's aging population: seizing the opportunity aging and place: clarifying the discourse census in brief no. 4: living arrangements of seniors statistics canada catalogue no. 98-312-x2011003. ottawa, on: statistics canada the daily. canada's population estimates: age and sex income of individuals by age group, sex and income source, canada, provinces and selected census metropolitan areas at home it"s just so much easier to be yourself': older adults' perceptions of ageing in place living alone in canada. insights on canadian society canadians with unmet homecare needs the ability of older people to overcome adversity: a review of the resilience concept aging well and the environment: toward an integrative model and research agenda for the future fear of falling among community-dwelling older adults: a scoping review to identify effective evidence-based interventions the meaning of "aging in place" to older people resilience from the point of view of older people the sociological imagination we would like to send our heartfelt thanks to all participants in this study for generously sharing their life experiences and insights. our appreciation also goes to the organizations and their staff members, our colleagues and friends, who assisted in our recruitment, and ms. jessica wong and ms. ramesha ali for their assistance in data collection. we extend our acknowledgement to dr. beard and two anonymous reviewers for their encouraging and constructive feedback. key: cord-007084-4niom5mw authors: popplewell, philip y.; butte, john; azhar, salman title: the influence of age on steroidogenic enzyme activities of the rat adrenal gland: enhanced expression of cholesterol side-chain cleavage activity(*) date: 1987-06-01 journal: endocrinology doi: 10.1210/endo-120-6-2521 sha: doc_id: 7084 cord_uid: 4niom5mw the ability of isolated adrenocortical cells to secrete corticosterone in response to acth challenge declines as rats age, but the site or mechanism(s) of this impairment is still unknown. to test the functionality of steroidogenic capacity per se, we measured the key enzyme activities involved in corticosterone biosynthesis. we also measured the mitochondrial cytochrome p-450 content and nonsteroidogenic enzymes specific for subcellular fractions. mitochondria and microsomal fractions were isolated from the adrenals of 2-, 12-, and 18month-old animals and used for various enzyme measurements. mitochondrial side-chain cleavage enzyme activity (nanomoles per min mg protein(-1)) increased from a mean of 0.43 ± 0.06 in 2-month-old rats to 1.26 ± 0.11 and 1.51 ± 0.06 in 12and 18-month old rats, respectively. after incubation with 5cholesten-3j8,25-diol (25-hydroxycholesterol; 25 μg/ml) sidechain cleave activity rose to 5.0 ± 0.6, 12.4 ± 1.2, and 16 ± 1.4 nmol min(-1) mg protein(-1) in adrenal mitochondrial fractions from 2-, 12-, and 18-month-old rats, respectively. in contrast, mitochondrial cytochrome p-450 content did not vary with advancing age. microsomal δ(5)-3β-hyroxysteroid dehydrogenase-δ(5)-δ(4)isomerase activities were similar in 2and 12-month-old rats, but 21-hydroxylase (nanomoles per min mg protein(-1)) activity was significantly increased in 12-month-old rats (2-month-old, 5.2 ± 0.2; 12-month-old, 7.7 ± 0.5). finally, mitochondrial 11βhydroxylase was comparable in both age groups. in addition, activities of mitochondrial nonsteroidogenic enzymes, such as monoamine oxidase, amytal insensitive nadh cytochrome c reductase, cytochrome c oxidase, succinate dehydrogenase, and malate dehydrogenase, did not change with age. it appears from the evidence presented that the activities of the steroidogenic enzymes are not responsible for the diminished capacity in corticosterone production seen with aging in the rat. (endocrinology120: 2521–2528,1987) i t has been reported previously from this laboratory that the steroidogenic capacity of adrenocortical cells declines as rats age (1) . furthermore, this defect seems to be due to biochemical events distal to binding of acth to its receptor and stimulation of camp production (1) . although the exact mechanism of this defect is yet to be defined, the possibility that this phenomenon may represent a direct effect on the steroidogenic process per se is quite appealing. in rat adrenals, steroid (corticosterone) biosynthesis involves the active participation of cholesterol side-chain cleavage, a 5 -3/?-hydroxysteroid dehydrogenase-a 5 " 4isomerase (3/3-hsd), 21-hydroxylase, and 11/3-hydroxylase activities (2) (3) (4) (5) (6) (7) (8) . among these, cholesterol side-chain cleavage (cytochrome p-450 scc ) catalyzes the first step in corticosterone biosynthesis (i.e. the conversion of cholesterol to pregnenolone) and is generally considered to be the rate-limiting step in steroidogenesis (2) (3) (4) (5) (6) (7) (8) . furthermore, the levels of various steroidogenic enzyme activities have been shown to be influenced and/or regulated by acth (2) (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) . therefore, the age-related decline in corticosterone secretion would be expected to have a profound effect on the activity of some or all steroidogenic enzymes. moreover, this age-related defect may, in fact, result from alterations in the key enzyme(s) involved in corticosterone biosynthesis. the present studies were conducted, therefore, to examine the effects of aging on steroidogenic enzymes responsible for the production of corticosterone. additionally, changes in mitochondrial cytochrome p-450 were compared with the activity of cholesterol side-chain cleavage. finally, to assess nonspecific age-related effects, the activities of several unrelated enzymes associated with specific compartments of mitochondria were also measured. [7-14 c] benzylamine hydrochloride (sa, 50-60 mci/mmol) and [l,2-n3 h]deoxycorticosterone (sa, 35-60 ci/mmol) were obtained from amersham corp. (arlington heights, il). fatty acid-free bsa, glucose-6phosphate, adenine nucleotides, sodium succinate, and cytochrome c were the products of sigma chemical co. (st. louis, mo). all unlabeled steroids were supplied by research plus laboratories (denville, nj). 5-cholesten-3j8,25-diol (25-hydroxycholesterol) was purchased from steraloids, inc. (wilton, ny). all other reagents used were of analytical grade. male retired breeder sprague-dawley rats [crl:cobs cd (sd)br], 9-10 months of age, were obtained from charles rivers breeding laboratories (wilmington, ma) and allowed to age to 12 and 18 months in our facility for aging animals, which is isolated from the general animal quarters in this v.a. center. two-month-old rats of the same strain were obtained from the same source. the rats were housed under conditions of controlled light (constant light from 0600-1800 h each day) and temperature (22-24 c) and given free access to purina laboratory chow (no. 5012, ralston-purina, st. louis, mo) and water. the animals in this colony are routinely monitored for the following viruses and infectious agents: pneumonia virus of mice (pvm), rev-3 virus, encephalomyelitis virus (gd-v11), sendai virus, kilham rat virus, rat corona virus/sialodacryoadenitus (rcv/sda), and mycoplasma pulmonis. occasional animals tested positively for pvm, h-1 virus and rev/sda, but all animals were negative for the remaining agents. routine diagnostic necropsies were not performed. in addition, animals were checked for gross pathology before use. those with visible tumors or apparent defects were discarded. preparation of mitochondria. rats were killed by cervical dislocation, and the adrenals were rapidly removed and trimmed of excess fat and external connective tissue. adrenal mitochondria were isolated by a slightly modified procedure of toaff et al. (16) , as described previously (17, 18) . briefly, adrenals from four to six rats were homogenized in 5 times their wet weight of ice-cold buffer containing 0.25 m sucrose, 1 mm edta, 25 mm hepes (ph 7.0) and 10 mg/ml fatty acid-free bsa (buffer a). the homogenate was then centrifuged at 600 x g (ja 20 rotor, beckman j21, palo alto, ca) for 10 min to remove intact cells, nuclei, and debris. the supernatant was then subjected to centrifugation at 8700 x g for 10 min to sediment mitochondria. the pellet (sedimented mitochondria) was resuspended in buffer a and centrifuged at 600 x g for 10 min, and mitochondria were resedimented at 8700 x g for a further 10 min. the resulting pellet was resuspended in buffer b (0.2 m sucrose, 20 mm kc1,5 mm mgcl 2 , and 25 mm tris-hcl ph 7.4) to a desired protein concentration and immediately used for enzyme measurements. preparation of microsomal fraction. the 8,700 x g supernatant was centrifuged at 15,000 x g for 15 min, and the pellet was discarded. the supernatant fraction was next centrifuged at 105,000 x g for 60 min (60-ti rotor, beckman lm 8 ultracentrifuge) to sediment microsomal fraction. the pellet was washed in buffer a (without bsa) and again collected at 105,000 x g for 60 min. the sediment was resuspended in buffer c (0.25 m sucrose, 1 mm edta, and 10 mm potassium phosphate, ph 7.0) and immediately used for enzyme assays. assay for cholesterol side-chain cleavage activity. the enzyme activity was measured by a slight modification of the procedure of toaff et al. (16) , as described by mori and marsh (17) . the incubation medium in a final volume of 1 ml contained 0.2 m sucrose, 10 mm kc1, 5 mm mgcl 2 , 0.2 mm edta, 10 mm potassium phosphate, 25 mm tris-hcl (ph 7.4), 1 mg/ml bsa (essentially fatty acid free), 3 mm sodium succinate, 6 ftm cyanoketone, and a suitable aliquot of mitochondrial preparation (50-100 ^tg protein/ml) in the presence or absence of 25hydroxycholesterol (25 /ng/ml). after incubation at 37 c for 5-10 min, the reaction was terminated by quick freezing at -60 c. the reaction product, pregnenolone, was extracted from the incubation mixture with hexane (three times, 2 ml each) and assayed by specific ria (19) . cyanoketone was included to inhibit further metabolism of pregnenolone to progesterone. all assays were run in triplicate. the cholesterol side-chain cleavage activity is expressed as nanomoles of pregnenolone formed per min mg protein" 1 . assay for 3/3-hsd. 3/3-hsd activity was determined by measuring the conversion of [ 3 h]pregnenolone to [ 3 h]progesterone as described by shaw et al. (20) . briefly, incubation medium in a final volume of 1.0 ml contained 50 mm potassium phosphate buffer (ph 7.4), 50 nm [ 3 h]pregnenolone (400 dpm/pmol), 0.5 mm nad + , and a suitable aliquot of microsomal fraction. the reaction, maintained at 37 c for 15-30 min, was initiated by the addition of [ 3 h]pregnenolone (dissolved in 30 n\ dimethylsulfoxide). the reaction was stopped by the addition of 0.1 ml 1 n naoh, and unlabeled pregnenolone (50 ng) and progesterone (50 fig) were added in addition to [ 14 c]progesterone (5000 dpm) to monitor recovery. the steroids were extracted two times with 5 ml diethyl ether, and pooled diethyl ether extracts were dried under n 2 . pregnenolone and progesterone were separated by ascending tlc on silica gel h using chloroformdiethyl ether (5:1, vol/vol) as a solvent system. the radioactivity associated with progesterone was measured by liquid scintillation spectrometry (beckman ls3801 scintillation counter). the purity of the [ 3 h]progesterone was determined by repeated recrystallization. all enzyme assays were carried out in triplicate. 3/3-hsd activity is expressed as nanomoles of progesterone produced per min mg protein" 1 . assay for 21-hydroxylase activity. enzyme activity was determined by measuring the formation of [ 14 c]deoxycorticosterone from [ 14 c]progesterone according to the procedure of menard et al. (21) . all incubations were performed at 37 c for 15-20 min. the : incubation medium in a final volume of 0.4 ml contained 50 mm tris-hcl (ph 7.4), 0.6 mm nadph, 10 mm glucose-6-phosphate, 1 u/ml glucose-6-phosphate dehydrogenase, 5 mm mgcl 2 , 1 mm [ 14 c]progesterone (10,000 dpm/nmol in 2.5% propylene glycol), and a suitable aliquot of the micro-somal fraction. the reaction was initiated by the addition of microsomal fraction and stopped by the addition of 0.04 ml 1 n naoh. fifty micrograms each of progesterone and deoxycorticosterone (containing 5000 dpm [ 3 h]deoxycorticosterone to monitor recovery) were added to each tube, and steroids were extracted with dichloromethane. steroids were separated by tlc (silica gel f254 plates) using dichloromethanebutyl alcohol (1:1, vol/vol) as a mobile phase. the radioactivity associated with deoxycorticosterone was measured by liquid scintillation spectrometry, as described above. all assays were carried out in triplicate. the enzyme activity is expressed as nanomoles of deoxycorticosterone formed per min mg protein" 1 . assay for llfi-hydroxylase. the enzyme activity was measured by following the conversion of [ 3 h]deoxycorticosterone to [ 3 h] corticosterone, as described by churchill et al. (22) . briefly, incubation medium in a final volume of 0.5 ml contained 50 mm tris-hcl (ph 7.4), 1 mm mgcl 2 , 1 mm [ 3 h]deoxycorticosterone (20,000 dpm/nmol in 2.5% propylene glycol), 0.25 m sucrose, 4 mm sodium succinate, and a suitable aliquot of mitochondrial preparation. all incubations were carried out at 37 c for 15-20 min. the reaction was initiated by the addition of mitochondrial suspension and terminated by the addition of 0.05 ml 1 n naoh. fifty micrograms each of deoxycorticosterone and corticosterone were added to each tube, and steroids were extracted with dichloromethane. steroid were separated by tlc using silica gel f 254 plates and dichloromethane-butyl alcohol (1:1, vol/vol) as a solvent system. the plates were run three times in same solvent system, and the corticosteronecontaining areas were isolated, eluted, and counted for radioactivity by liquid scintillation spectrometry, as described above. all enzyme assays were carried out in triplicate. the enzyme activity is expressed as nanomoles of corticosterone formed per min mg protein" 1 . measurement of cytochrome p-450. mitochondrial cytochrome p-450 was measured according to the method of omura and sato (23) . the extinction coefficient of 91 cm" 1 mm" 1 was used to calculate the cytochrome p-450 concentration from the absorbancy difference between 450 and 490 nm. miscellaneous enzyme assays. succinate dehydrogenase activity was measured according to the method of pennington (24) . the activity is expressed as nanomoles of 2-(p-iodophenyl)3-(pnitrophenyl)5-phenyltetrazolium reduced per min mg protein" 1 . malate dehydrogenase was assayed by a modification of the procedure of ochoa (25) , as described by vardanis (26) , with activity expressed as nanomoles of nadh oxidized per min mg protein" 1 . the radiochemical procedure of mccaman et al. (27) was used to quantitate monoamine oxidase, with activity expressed as nanomoles of benzaldehyde produced per min mg protein" 1 . amytal-insensitive nadh cytochrome c reductase was measured by a combination of the procedures of sottocasa et al. (28) and privalle et al. (29) . the enzyme activity is expressed as nanomoles of cytochrome c reduced per min mg protein" 1 . cytochrome oxidase activity was measured according to the methods of cooperstein and lazarow (30) , with activity expressed as nanomoles of cytochrome c oxidized per min mg protein" 1 . the protein content of all fractions was measured by the modified procedure of lowry et al. (31) , as described by markwell et al. (32) . statistical analyses. the results are expressed as the mean ± se. the results were analyzed by analysis of variance. the analysis used the general linear models procedures of sas (sas institute, cary, nc) when giving a significant f value; scheffe's posttests were used to determine differences between any two age groups. p < 0.05 was considered statistically significant. cholesterol side-chain cleavage enzyme activity, the rate-limiting enzyme in corticosterone biosynthesis, was measured in adrenal mitochondria isolated from 2-, 12-, and 18-month-old male sprague-dawley rats. all assays were carried out in the presence and absence of 25hydroxycholesterol (25 /ug/ml). the enzyme-catalyzed reaction product, pregnenolone, was quantitated by a specific ria. results presented in figs. 1 and 2 show incubation time-and enzyme concentration-dependent pregnenolone formation by the adrenal mitochondria isolated from 2-and 12-month-old rats. under basal conditions, the rate of pregnenolone formation was low and exhibited a biphasic response (fig. 1, inset) . in contrast, addition of oxygenated sterol (25-hydroxycholesterol) greatly enhanced pregnenolone production, and again this effect was biphasic. furthermore, at each time point studied, mitochondria from senescent rats synthesized 2-3 times more pregnenolone compared to corresponding values from young control groups. similarly, the rate of pregnenolone formation was linear with protein concentration up to 100 /kg/ml in both age groups examined (fig. 2) . like time-course studies, enzyme concentration studies also revealed enhanced steroidogenic capacity of mitochondria from 12-month-old rats, and this effect was potentiated in the presence of 25-hydroxycholesterol. we next examined the side-chain cleavage enzyme activity in mitochondria isolated from rats 2, 12, and 18 months of age, and the results are presented in fig. 3 . under basal conditions (without 25-hydroxycholesterol), cholesterol side-chain cleavage activity (expressed as nanomoles of pregnenolone produced per min mg protein" 1 ) increased (p < 0.001) from a mean (±se) of 0.43 ± 0.06 in 2-month-old rats to 1.26 ± 0.11 and 1.51 ± 0.06 in the 12-and 18-month-old rats, respectively. similarly, mitochondria isolated from 12-and 18-month-old rats showed significantly higher activity in the presence of more polar exogenous substrate (25-hydroxycholesterol) compared to the 2-month-old groups (18-month-old, 16 ± 1.4; 12-month-old, 12.4 ± 1.2; 2-month-old, 5.0 ± 0.6). all of these enzyme assays were carried out under a nearlinear range of time and enzyme protein concentration. thus mitochondria isolated from the 12-or 18-monthold rats exhibited an enhanced capacity to synthesize pregnenolone compared to mitochondria from control groups. moreover, addition of 25-hydroxycholesterol produced a further substantial increase in pregnenolone formation in mitochondria isolated from older animals, and levels were significantly higher than those in mitochondria from control groups. in contrast to progressive changes in side-chain cleavage activity, mitochondrial cytochrome-p450 contents did not change with age (table 1). a comparison of the activities of other steroidogenic enzymes, 3/3-hsd 21-hydroxylase, and 11/miydroxylase, in microsomal and mitochondrial fractions of adrenals from 2-and 12-month-old animals is shown in table 2 . no significant age-related changes were noted for 3/3-hsd (29.8 ± 1.2 nmol min" 1 mg protein" 1 in 2-monthold rats us. 29.5 ± 2.2 nmol min" 1 mg protein" 1 in 12month-old rats; p = ns). similarly, mitochondrial 110hydroxylase activity was comparable in both age groups examined (1.21 ± 0.15 nmol min" 1 mg protein" 1 in 2month-olds us. 1.19 ± 0.09 nmol min" 1 mg protein" 1 in 12-month-olds; p = ns). in contrast microsomal 21hydroxylase activity was slightly but significantly (p < 0.001) increased in 12-month-old rats (7.7 ± 0.5 nmol min" 1 mg protein" 1 ) compared to that in 2-month-old animals (5.2 ± 0.2 nmol min" 1 mg protein" 1 ). mean activities (±se) of monoamine oxidase, amytalinsensitive nadh cytochrome c reductase, succinate dehydrogenase, cytochrome oxidase, and malate dehydrogenase are presented in table 3 . monoamine oxidase (33, 34) and amytal-insensitive results are the mean ± se. the number of experiments is given in parentheses. "expressed as nanomoles of progesterone produced per min mg protein" 1 . 6 expressed as nanomoles of deoxycorticosterone produced per min mg protein" 1 . c expressed as nanomoles of corticosterone produced per min mg protein" 1 . results are the mean ± se of eight separate experiments. 0 expressed as nanomoles of benzaldehyde produced per min mg protein" 1 . 6 expressed as nanomoles of cytochrome c reduced per min mg protein" 1 . c expressed as nanomoles of iodonitrotetrazolium reduced per min mg protein" 1 . d expressed as nanomoles of cytochrome c oxidized per min mg protein" 1 . e expressed as nanomoles of nadh oxidized per min mg protein" 1 . nadh cytochrome c reductase (18, 28, 29, 35) are located on the outer mitochondrial membrane and were chosen for study to serve as a control for the increase in sidechain cleavage activity associated with preparation of mitochondrial fractions. succinate dehydrogenase and cytochrome oxidase are conventional markers of the inner mitochondrial membrane (26) and were chosen as a control for the possibility that age leads to a generalized change in the activity of adrenal enzymes. malate jdehydrogenase is a classical marker for mitochondrial matrix (26, 29) and was employed to serve as a control for mitochondrial integrity. the fact that the activity of none of these enzymes changed as rats grew older provides support for the relative specificity of the age-related increase in cholesterol side-chain cleavage activity. the ability of isolated adrenocortical cells to respond to acth declines with advancing age (1, 36) . we have shown previously that this aging defect lies distal to both binding of acth to its receptor and the consequent production of its secondary messenger camp (1) . in the present studies the possible relationship between steroidogenic enzyme activities and steroidogenesis in rat adrenals during aging was explored. accordingly, we measured cholesterol side-chain cleavage, 3/3-hsd, 21-hydroxylase, 11/3-hydroxylase activities, and cytochrome p450 contents in appropriate mitochondrial and microsomal fractions of adrenals from 2-, 12-, and 18-month-old rats. an unexpected finding was that cholesterol side-chain cleavage activity showed a progressive increase with advancing age. a slight but significant increase in the activity of 21-hydroxylase was also noted in adrenal microsomal fractions from senescent rats. in contrast, activities of 3/3-hsd and 110hydroxylase were insensitive to the aging process. interestingly, the current results have clearly indicated that adrenal side-chain cleavage enzyme activity increased at a time when acth-induced cellular steroidogenesis has been more than 60% depressed (1, 36) . several mechanisms might account for the stimulatory effect of aging on cholesterol side-chain cleavage activity. one possibility is an augmentation of enzyme synthesis. in addition, if degradation of cholesterol side-chain cleavage enzyme protein were to proceed at a lower rate than in young rats, the levels of this enzyme would be expected to be higher, since the steady state level of any given protein is achieved by its relative rates of synthesis and degradation. a second possibility may be that an increased activity represents cellular adaptive changes to deal with the diminished capacity of the adrenal gland to mobilize and use cholesterol esters for steroidogenesis. indeed, we have recently shown that cholesterol ester content increases with age and that this defect was related to specific changes in neutral cholesterol esterase (popplewell, p. y., and s. azhar, submitted). thus, an increase in cholesterol side-chain cleavage activity can be viewed as a compensation on the part of the enzyme to the elevated cholesterol esters levels. that is, mitochondrial side-chain cleavage enzymes increase in activity in order to effectively use that cholesterol which becomes available from the stored cholesterol ester. however, the fact that the adrenal steroidogenic response is still blunted in senescent rats demonstrates this to be a partially successful compensation. another possibility of equal importance is that the observed increase in cholesterol side-chain activity may be in response to vastly elevated levels of plasma acth, previously reported in senescent rats (37) . this hyperstimulation hypothesis is supported by the observations that the cholesterol side-chain cleavage step is the rate-limiting step in steroidogenesis and, as such, activated/regulated by acth (2, 4, 5) . finally, evidence has recently been presented to support the idea that adrenal mitochondria contain more than one cholesterol side-chain cleavage system (38) (39) (40) . thus, it is conceivable that elevated levels represent stimulation of only one isoenzymic form which may or may not actively participate in steroidogenesis under in vivo situations. obviously more rigorous experimental approaches are needed to sort out these various possibilities. such investigations are currently in progress in our laboratory. we were unable to document any age-related changes in mitochondrial cytochrome p450 levels. these results point to a dissociation between cytochrome p450 levels and cholesterol side-chain cleavage enzyme activity. this discrepancy could be attributed to a variation in the relative compositions of various forms of cytochrome p450 in total mitochondrial preparations from young and senescent rat adrenals (41, 42) . in addition, a pool of cytochrome p450 not associated with steroidogenic enzymes (i.e. cytochrome p450 8cc or cytochrome p450 u/ 3) may exist (12) , which, in turn, could mask a real age effect on specific cytochrome p450 8cc . the above hypothesis is of interest in view of the previous finding demonstrating a dissociation in half-lives of 21-hydroxylase and cytochrome p450 (4.5 vs. 2.9 days) in rat adrenals after hypophysectomy (12) . additional evidence for this hypothesis is the recent finding of naumoff and stevenson (43) , who observed a delayed developmental maturation pattern for cholesterol side-chain activity compared to cytochrome p450 in rat ovaries after gonadotropin treatment. in view of these observations, it is not unreasonable to speculate that levels of cytochrome p450 and side-chain cleavage are modulated differentially as rats grow old. finally, demonstration of any specific age effect on cytochrome p450 8cc will require the purification of a side-chain cleavage enzyme system from adrenals of young and old rats. results of the present study also suggest that the decline in steroidogenesis observed in adrenocortical cells isolated from senescent rats is not related to a reduction in cholesterol side-chain cleavage activity or other steroidogenic responses, as measured in vitro in isolated subcellular components. these in vitro results do hot exclude the possibility, however, that side-chain cleavage activity is reduced (or blunted) in intact cells or in vivo. furthermore, the possibility that the aging process directly affects the performance (in vivo) of recently identified regulator (29, (44) (45) (46) (47) (48) (49) (50) (51) (52) (53) (54) (55) of the side-chain cleavage enzyme activity should also be considered. previous reports indicate that the aging process in mouse and rat adrenals is associated with changes in 3/3-hsd (55, 56) . we realize that our inability to demonstrate an age effect on this enzyme are in conflict with earlier studies (55, 56) . several technical/physiological differences in the experimental approach to the problem may account for the observed incongruent findings. for instance, the earlier studies were carried out with female rats or mice, as opposed to male rats employed in the present studies. additionally, variations in the assay mixture and other experimental conditions may account for the observed discrepancy. likewise, alterations in nutritional status, animal strain, or other physiological factors could also contribute significantly. finally, since this enzyme is not rate limiting, even a modest decline in its activity should have very little adverse effect on the overall steroidogenic capacity of the adrenal gland. significant changes in some steroidogenic enzymes in other steroid-producing tissues have been demonstrated in senescent rats. for example, testicular 30-hsd activities have been shown to decline with advancing age (57) (58) (59) . similarly, other researchers have reported significant age-related loss of this enzyme activity in rat ovary (60) (61) (62) . likewise, other researchers have presented evidence that activities of 17a-hydroxylase (57, 59, 63) , c17-20 lyase (63), as well as microsomal cytochrome p-450 (63) are depressed in testes from aged rats. however, comparison of data from different steroidogenic tissues suggests that changes in enzyme activities that occur with aging in one steroid-producing tissue may not necessarily be applicable to other steroid-producing tissues. in conclusion, the results of the present study suggest that the impairment of corticosterone secretion in adrenocortical cells isolated from senescent rats is probably not related to a reduction in the activity of steroidogenic enzymes, as measured in vitro. however, since the transport of cholesterol to cytochrome p450 scc rather than the activity of cytochrome p450 scc per se limits the rate of steroidogenesis, it is possible at this time to at least speculate that the age-related decline in steroidogenesis is related to a decrease in the transport of cholesterol to the mitochondria. the roles of microtubules (44), microfilaments (44) , phospholipids (40, (45) (46) (47) 52) , sterol carrier proteins (48) (49) (50) (51) , and other factors (28, 53, 54) have all been described as playing a part in cholesterol transport. failure of or changes in any of these mechanisms with age would reduce the amount of cholesterol substrate available for steroidogenesis within the mitochondria, and we are presently studying the possibility that cholesterol transport is also altered with age. differential effects of aging on acth receptors, adenosine 3',5' cyclic monophosphate response and corticosterone secretion in adrenocortical cells from sprague-dawley rats on the mechanism of action of acth adrenal gland cholesterol side-chain cleavage, cytochrome p450, and the control of steroidogenesis cholesterol metabolism in the adrenal cortex regulation of the adrenal and gonadal microsomal mixed function oxygenases of steroid hormone biosynthesis the roles of cytochrome p450 in the synthesis and metabolism of steroids a heuristic proposal for understanding steroidogenic processes the mechanism of action of adrenocorticotropic hormone: the role of mitochondrial cholesterol accumulation in the regulation of steroidogenesis evidence that the cyclohexamide-sensitive site of adrenocorticotropic hormone action is in the mitochondrion: changes in pregnenolone formation, cholesterol content, and the electron paramagnetic resonance spectra of cytochrome p-450 regulation of cytochrome p-450 supported 11-/3-hydroxylation of deoxycortisol by steroids, oxygen and antioxidants in adrenocortical cell cultures life time of adrenal cytochrome p450 as influenced by acth mechanism of induction of a 5 -3/miydroxysteroid dehydrogenase-isomerase activity in rat adrenocortical cells by corticotropin steroidogenic enzyme activities in cultured human definitive zone adrenocortical cells: comparison with bovine adrenocortical cells and resultant differences in adrenal androgen synthesis in vitro spontaneous and adrenocorticotropin dependent maturation of the steroidogenic pathway of ovine fetal adrenal cells relationship of cholesterol supply to luteal mitochondrial steroid synthesis the site of luteinizing hormoe stimulation of steroidogenesis in mitochondria of the rat corpus luteum oxygen dependence of adrenal cortex cholesterol side chain cleavage': implications in the rate-limiting steps in steroidogenesis radioimm'unoassay of serum and ovarian pregnenolone in immature rats synergistic effect of follicle-stimulating hormone and luteinizing hormone on testicular a 5 -3/3-hydroxysteroid dehydrogenase-isomerase: application of a new method for the separation of testicular compartments spironolactone and cytochrome p-450: impairment of steroid 21-hydroxylation in the adrenal cortex topological studies of the steroid hydroxylase complexes in bovine adrenocortical mitochondria the carbon-monoxide binding pigment of liver microsomes. i. evidence for its homoprotein nature biochemistry of dystrophic muscle: mitochondrial succiniate tetrazolium reductase and adenosine triphosphatase malic dehydrogenase from pig heart protein kinase activity at the inner membrane of mammalian mitochondria microdetermination of monoamine oxidase and 5-hydroxytryptophan decarboxylase activities in nervous tissues an electron-transport system associated with the outer membrane of liver mitochondria: a biochemical and morphological study regulation of intramitochondrial cholesterol transfer to side-chain cleavage cytochrome p-450 in rat adrenal gland a microspectrophotometric method for the determination of cytochrome oxidase protein measurement with the folin phenol reagent a modification of the lowry procedure to simplify protein determination in membrane and lipoprotein samples the submitochondrial localization of monoamine oxidase-enzymatic marker for the outer membrane of rat liver mitochondria utilization of intramitochondrial membrane cholesterol by cytochrome p-450 dependent cholesterol side-chain cleavage reaction in bovine adrenocortical mitochondria: steroidogenic and non-steroidogenic pools of cholesterol in the mitochondrial inner membranes localization of l-lactate dehydrogenase in mitochondria aging of the rat adrenocortical cells: response to acth and cyclic amp in vitro the neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis cytochrome p-450 of adrenal mitochondria: steroid binding sites of two distinguishable forms of rat adrenal mitochondrial cytochrome p-4508c c evidence suggesting that more than one sterol side chain cleavage system exists in mitochondria from bovine adrenal cortex effects of phospholipid and detergent on the substrate specificity of adrenal cytochrome p-450scc: substrate binding and kinetics of cholesterol side-chain oxidation purification and characterization of mitochondrial cytochrome p-450 associated with cholesterol side-chain cleavage from bovine corpus luteum inhibition of cholesterol side chain cleavage by active site directed antibody to corpus luteum cytochrome p450 the differential development of mitochondrial cytochrome p-450 and the respiratory cytochromes in rat ovary intracellular movement of cholesterol in rat adrenal cells: kinetics and effects of inhibitors on the mechanism whereby acth and cyclic amp increase adrenal polyphosphoinositides: rapid stimulation of the synthesis of phosphatidic acid and derivatives of cdp ~ diacylglycerol phosphoinositide metabolism and hormone action adrenocorticotropic hormone-mediated changes in rat adrenal mitochondrial phospholipids sterol carrier protein 2 : delivery of cholesterol from adrenal lipid droplets to mitochondria for pregnenolone synthesis sterol carrier protein 2 : identification of adrenal sterol carrier protein 2 and site of action for mitochondrial cholesterol utilization intramitochondrial movement of adrenal sterol carrier protein with cholesterol in response to corticotropin scallen tj 1985 phospholipid, sterol carrier protein 2 and adrenal steroidogenesis polyphosphoinositide activation of cholesterol side chain cleavage with purified cytochrome p-4508cc brownie ac i983 cholesterol side-chain cleavage in the rat adrenal cortex: isolation of a cycloheximide-sensitive activator peptide modulation of the kinetics of cholesterol side-chain cleavage by an activator and by an inhibitor isolated from the cytosol of the cortex of bovine . adrenals aging and adrenal a 5 -3-/3-hydroxysteroid dehydrogenase in female mice aging and adrenal a 6 -3/3-hydroxysteroid dehydrogenase in female rats the effect of vasectomy on steroid metabolism by the seminiferous tubules and interstitial tissue of the rat testis: a comparison with the effects of aging effect of age on testis a 6 -3j8-hydroxysteroid dehydrogenase in the rat testicular function and sexual activity in senescent mice ovarian a 5 -3/3-hydroxysteroid dehydrogenase in aging rats aging and ovarian a 5 -3j8 hydroxysteroid dehydrogenase in rats aging and ovarian a 5 -3/3-hydroxysteroid dehydrogenase in the pregnant mouse an analysis of the age-related decline in testicular steroidogenesis in the rat key: cord-020694-zoy49483 authors: baig, ulfat; laxmi, vidhya; ojha, akanksha; watve, milind title: geriatric infections: decreased immunity or evolved opportunists? date: 2020-04-10 journal: j biosci doi: 10.1007/s12038-020-0025-x sha: doc_id: 20694 cord_uid: zoy49483 in host–parasite co-evolution, parasites are assumed to have an advantage owing to their shorter generation time. evolution of pathogens within the lifetime of a host individual is implicated as a strong selective force in the evolution of sex and aging in the host. however, this assumption or its testable predictions have not been examined empirically. we classified infectious bacteria and viruses into those that can have continued long-term existence on the host body (group 1) versus those that have only a short-term interaction during an active infection (group 2). we surveyed the literature for age-specific incidence data about infections from both the groups. the age trends of the two groups show contrasting patterns. the incidence of infections by all group 1 pathogens showed a 2.28to 28-fold increase in older ages. in group 2, 6 out of the 9 pathogens showed a significant declining trend in incidence with age. in both groups, there was greater mortality or morbidity among the infected in the old-age classes. these patterns are better explained by pathogen evolution than by age-related decline in immunity. electronic supplementary material: the online version of this article (10.1007/s12038-020-0025-x) contains supplementary material, which is available to authorized users. the incidence of a number of infections appears to increase in old age (yoshikawa 2000; schneider 1983; gardner 1980; yoshikawa and norman 2017; bender 2003; meyers 1989) . there are three possible causes for this pattern. although there is substantial literature on immunosenescence in several species of animals (papp et al. 2012; sidler et al. 2013; youngman et al. 2011; zerofsky et al. 2005) , the assertion that immunosenescence forms the foundation for infectious disease in elderly humans, according to schneider (1983) , '…lacks a firm scientific foundation'. although over the last four decades, substantial literature on the molecular and cellular aspects of immunosenescence has been added, many fundamental questions about the evolution of these mechanisms, its relevance to aging and health, even a precise definition of immunosenes-cence are under substantial haze and debate (fulop et al. 2018; pawelec 2018 ). alternatively, it is possible that a decline in the overall physiological capacity increases morbidity and mortality at the same level of infection. the third possible cause, largely overlooked by medicine, is that the opportunistic pathogens associated with the body evolve within the lifetime of an individual to overcome its resistance mechanisms. evolutionary biologists have recognized this imbalance in the host-parasite co-evolution. pathogens have an upper hand in the host-parasite co-evolution owing to their faster rate of evolution. pathogen evolution within the lifetime of an individual is recognized to play a role in the evolution of sex (hamilton 1980 ) and the evolution of host aging (ulfat et al. 2017) . the three hypotheses are not mutually exclusive and it is difficult to quantify their relative importance. nevertheless, it is possible to make and test specific differential predictions from the different causal hypotheses. at least under certain conditions, these predictions allow us to differentiate between the competing hypotheses: (i) if decline in general immunity is the main cause, the incidence of all types of infections is expected to increase in old age although not to the same extent. the body is exposed to opportunistic pathogens more often than to externally acquired infections. therefore, the incidence of opportunistic infections is expected to increase substantially more than that by externally acquired pathogens. however, since there are alternative explanations for an increase in opportunistic infections (hypothesis (iii) stated below), they cannot be taken to support this hypothesis. a significant increase in the incidence of externally acquired infections is required to support this hypothesis. (ii) agerelated physiological deterioration is expected to increase the morbidity and mortality among the infected population. alternatively, a significantly greater increase in the morbidity-mortality in comparison with the increase in incidence can be taken as a support to this hypothesis. (iii) if evolution of opportunistic pathogens is the major cause, the incidence of opportunistic infections should specifically increase in old age without affecting the incidence of externally acquired infections. it is likely that all three play a role in geriatric infections and it may not be possible to resolve between the three hypotheses under every condition. nevertheless, an exploration into the competing hypotheses and an attempt to falsify one or more of them can certainly be attempted. we searched the literature on age-related trends in incidence to see whether there are consistent trends across studies and whether one or more of the above hypotheses can be falsified or supported using them. in order to compare the age specific incidence of opportunistic versus non-opportunistic infections, we selected pathogens that are sufficiently common globally, for whom there is good background epidemiological information including whether and with what frequency they inhabit the host body under normal conditions, whether a long-term carrier state is known, and whether they confer long-term immunity. known childhood infections, sexually transmitted infections, zoonotic and vector borne infections were excluded. the infectious agents selected were divided in to two groups (table 1): group 1 comprising pathogens that can exist on or within a host body for prolonged period either as a part of normal microbiota, long-term carrier state or silent subclinical existence; and group 2 comprising pathogens that do not constitute the normal body flora and do not have long-term (1e year being used as a cutoff here) association with individual host bodies. pathogens from group 1 have the opportunity to evolve to overcome the specific defence mechanisms of an individual host, whereas group 2 pathogens do not have this opportunity owing to a short-term association with any host individual. we searched pubmed and google scholar for individual published reports giving age-class-specific incidence, in addition to available online data from centers for disease control bureau of statistics. for infections such as urinary tract infections that can be caused by many different pathogens, only studies with confirmed identification of pathogens were included (supplementary table 1) . for many pathogens more than one datasets were available. where the reported age classes matched and the age trends were comparable, we pooled the data. incidence data were pooled only for looking at the quantitative trends (figure 1). wherever the reported age classes were different or the trends were contradicting, we did not pool the data but plotted them separately. for significance testing, the data were not pooled but individual trends were tested separately using the selected statistical methods (see below). the systematic review design followed preferred reporting items for systematic reviews and meta-analyses guidelines. age-specific incidence of clinically diagnosed infections for each of the selected pathogens was calculated as the number of cases per 100,000 age-group-specific population. data could be used as reported from papers in which the age-normalized incidence was given. wherever the reported data was in terms of the number of cases, age normalization was done by accessing age structure demographic data of the specific country (bangladesh bureau of stastitics, 2017; pakistan bureau of statistics, 2017; directorate of census operation, tamil nadu, 2017). alternatively, we requested unreported demographic data from authors wherever required. the age grouping in different data sources was often different and could not be matched exactly. in order to enable a comparative analysis, we considered the incidence in the age group covering the age 20 as unit incidence, and incidence in all other age groups was expressed as multiples of this unit. this normalization allowed comparison across pathogens with widely differing incidences. the significance of the trend in each of the individual datasets was tested using non-parametric correlations since the trends were typically nonlinear. data on the same population but at different years were considered as different sets. if male/female incidence was reported separately, they were analysed separately. we avoided the childhood data (age \20) in analysing trends so as to avoid complications due to childhood immunity. the consistency in the age trend was analysed using spearman's rho correlation using excel 2007 and prism 5. in addition to considering the significance of individual rho at the significance level of 0.05, we also looked at how many datasets had positive or negative rho values to test consistency in the trends across datasets. this was particularly important since in some datasets: only two age classes were recognized, and so individual rho calculations were meaningless. for example, in opportunistic e. coli infections the data by flasche et al. (2011) had only two age groups but there were 5 such datasets and all of them had an increasing trend. therefore, although we could not test individual trends for significance, the consistency across datasets was tested to be non-random by a chi square test. at the third level, we also looked at the total number of negative and positive trends in group 1 versus group 2 pathogens. this analysis, being non-parametric, does not give a quantitative idea of the fold increase in incidence with age. the fold change in incidence in the pooled data was represented in age trend diagram (figure 1) and calculated as the ratio of the incidence per 100,000 in the age class over 60 s to the incidence in the age class covering the age 20. for testing the physiological decline hypothesis, we looked for publications reporting age-specific mortality rates among the infected individuals. alternatively, we compared age trends in the population mortality with those in incidence wherever available. according to the inclusion and exclusion criteria, we obtained 176 datasets from 20 pathogen species. the monotonicity of trends of incidences with age groups in every individual dataset was tested using non-parametric correlations (supplementary table 2). trends in the age-specific incidence clearly fell into two types of patterns (figure 1). in one, consisting of 10 species of pathogens and 14 pooled datasets, the incidence invariably increased with age. between the age groups covering the 20s and over-60s, the increase was remarkable ranging from 2.28-fold to 28-fold. in the other pattern followed by 8 species and 12 pooled datasets, there was a significant negative trend in 6 with a 50% to 95% decrease in incidence between the 20 and over-60 age groups. the two patterns corresponded very closely with the two groups in table 1. all pathogens of group 1 showed a positive incidence trend with age. for two datasets, data on only two age groups relevant to our question was available. here we could not perform any statistical analysis for the trend in individual datasets, but in both the groups the incidence was higher in the higher age class in every dataset examined. the statistical significance of the trends was tested non-parametrically. the spearman's rho is a good indicator of monotonic trends even if they are nonlinear. for all datasets that had more than three adult age groups, we tested the significance of individual trends. in group 1 pathogens, 116 out of 118 trends were positive, out of which 88 were individually significant. only two rho values were negative and they were not significant. for every group 1 pathogen, either individual positive trends or the consistency across trends was significant. out of 58 datasets for group 2 pathogens, 46 trends were negative, 32 being individually significant. out of the 12 positive trends, only 3 were individually significant. out of 9 pathogens, 6 had significantly decreasing age incidence curves. influenza had a mixed trend (8 negative and 7 positive rho values), cholera had 1 significant negative and 4 nonsignificant positive rho values, and coronavirus had 3 negative trends but none significant. thus, collectively group 1 pathogens, having opportunity to evolve on the host body, had a predominantly increasing age incidence trend, and group 2 pathogens, not having such opportunity, had predominantly decreasing one. this can be best viewed collectively in the frequency distribution of all rho values which lie on the positive extreme for group 1 pathogens and mostly on the negative side for group 2 (figure 2). although the incidence trends in group 2 pathogens were predominantly declining, we examined whether the trends in mortality and morbidity were also different. the specific case of influenza is demonstrated in figure 3 , which shows that in contrast to the incidence trend, the hospitalization rate as well as mortality rate clearly increased with age (cdc influneza vaccine activity, us, 2012-2014; dávila et al. 2014 ; cdc prevention and control of influenza with vaccines, 2010). the contrast in the incidence and morbidity-mortality trends supports the physiological decline hypothesis more than the immunity decline hypothesis since the latter predicts rise in incidence as well. a remarkable consistency was observable in the age trends for any given pathogen. for any pathogen for which we had multiple sources of data, the trends were very similar across populations, gender and years, with the only possible exception of influenza and cholera. the predominant trends of these 20 pathogen groups are consistent with the pathogen evolution hypothesis. as an alternative to evolution on individual host body, one can possibly argue that some of the opportunistic pathogens induce immunosenescence in the host (aguilera et al. 2018) , and therefore their incidence increases with age. however, if they induce general immunosenescence, the host susceptibility to all kinds of infections should increase. the failure to increase the incidence of externally acquired pathogens makes this interpretation unlikely. the prediction specific to the declining immunity hypothesis that the incidence of externally acquired infections should also increase with age failed to obtain generalized support in epidemiological data. this result needs to be interpreted carefully because age-related decline in immunity is a widely held belief in the field of medicine. studies on individual components of immunity appear to support this hypothesis. for example, reduction in antibody response to vaccines in old age has been demonstrated (goodwin et al. 2006) . however, incidence patterns should be the ultimate marker of immunity to infections. in clinical research, often pathway intermediates or surrogate markers are used for the risk of a disease, such as ldl cholesterol for cardiovascular disease. although such markers make early inferences possible, the ultimate test is the real end point. in many drug trials, a reduction in ldl was not accompanied by a reduction in cardiovascular events (aim-high investigators 2011). similarly, normalization of blood sugar failed to arrest complications of diabetes in many trials (nice trial 2008; accord 2008) . similarly, it is likely that a decline in immunity with old age is apparent when looking at certain mechanisms or surrogate markers, but the ultimate test needs to be based on the actual incidence of disease. incidence of infection depends upon exposure to pathogen propagules and it might be argued that for certain infections exposure may decline with age. we excluded sexually transmitted infections and vectorfigure 2 . frequency distribution of spearman's rho reflecting incidence trends with age. note that for group 1 pathogens, the rho values are predominantly close to ?1; for group 2 they are mostly negative with a few exceptions. borne infections where a change in exposure with age is more likely. for airborne pathogens, the exposure is expected to be more homogeneous in a population but we do not see any consistent age-related increase in such infections. quantitatively, we see a 10-to 30-fold rise in the incidence of 5 to 6 group 1 pathogens, for equal number of group 2 pathogens, there is a decline up to one-tenth in the incidence (figure 1). if the difference in exposure was to account for it, a 100-to 300-fold difference in exposure is required. in the absence of data on exposure level, this explanation remains weak although it might explain a small part of the trend. the epidemiological patterns do not falsify the immunosenescence hypothesis but show that immunosenescence is not strong enough to overpower the other age-related factors that might decrease the age-specific incidence. in a nutshell, epidemiological analysis suggests that evolution of opportunistic pathogens to overcome resistance mechanisms of individual hosts is likely to be the major contributor to geriatric infections. although decreased immunity can increase infections by opportunistic pathogens, it should also show at least some increase in externally acquired infections. the fact that there is a significant decrease in most group 2 infections undermines the generalization of declined immunity. while physiological deterioration appears to contribute to increased morbidity and mortality among the infected, the signature of generalized immunosenescence did not appear to be very strong in the epidemiological data. pathogens are rapidly evolving and the rate of evolution is orders of magnitude faster than that of the host. this imbalance in the host-parasite co-evolution is thought to be a major selective force in the evolution of sex and that of aging (hamilton 1980; ulfat et al. 2017) . however, evolution of any member of the microbiota within the lifetime of an individual has not yet been demonstrated. we give epidemiological evidence in support of within host lifetime evolution for the first time. a corollary of increased incidence of opportunistic infections is that evolving opportunistic pathogens contribute to the aging process itself both in physiological time and in evolutionary time, and many mechanisms involved in aging are triggered by opportunistic infections (aguilera et al. 2018; ulfat et al. 2017) . thus, the cause-effect relationship might actually be inverted. it may not be old age causing infections but the evolving pathogens causing aging. it may not be a coincidence that after the use of antibiotics, which can disturb the course of evolution of the opportunistic pathogens, human life expectancy started increasing dramatically. a more systematic exploration of the evolution of pathogens within the lifetime of a host has the potential not only to understand the mystery of aging but also to improve infection management at a global level. chronic infections: a possible scenario for autophagy and senescence cross-talk bangladesh bureau of statistics 2017 government of the people's republic of bangladesh infectious disease risk in the elderly basic medical microbiology (little brown) centers for disease control, prevention (us), national center for prevention services (us) prevention and control of influenza with vaccines a textbook of microbiology substantial morbidity and mortality associated with pandemic a/h1n1 influenza in mexico, winter 2013-2014: gradual age shift and severity directorate of census operation long term trends introduce a potential bias when evaluating the impact of the pneumococcal conjugate vaccination programme in england and wales immunosenescence and inflamm-aging as two sides of the same coin: friends or foes? the effect of aging on susceptibility to infection antibody response to influenza vaccination in the elderly: a quantitative review sex versus non-sex versus parasite infectious diseases in the elderly: an overview a role for skn-1/nrf in pathogen resistance and immunosenescence in caenorhabditis elegans age and immunity: what is ''immunosenescence sherris medical microbiology infectious diseases in the elderly immunosenescence is associated with altered gene expression and epigenetic regulation in primary and secondary immune organs ub was supported by the maharashtra gene bank programme during the study period. there was no other funding support for the study. corresponding editor: ng prasad key: cord-007088-yfdb594k authors: coleman, gerald l.; barthold, stephen w.; osbaldiston, george w.; foster, sumner j.; jonas, albert m. title: pathological changes during aging in, barrier-reared fischer 344 male rats(1) date: 1977-05-17 journal: j gerontol doi: 10.1093/geronj/32.3.258 sha: doc_id: 7088 cord_uid: yfdb594k pathology, microbiology, and selected serum chemistries were evaluated in 144 male fischer rats from 4 to 33 mo of age. the rats were reared and maintained under barrier conditions, which successfully excluded the introduction of major infectious disease agents throughout the entire study, including mycoplasma pulmonis. a wide variety of pathology was found and tabulated, and many lesions were found to increase in severity and incidence with age. there was a high correlation of renal disease severity with increasing age. serum total protein and albumin decreased with age, while alpha-1 globulin and cholesterol increased. r p he choice of a laboratory animal for a par-x ticular study should be based on the best information available. for example, male f344 rats have a high incidence of testicular interstitial cell tumors (jacobs & huseby, 1967) . this fact may make these rats valuable for some studies and useless for others. without baseline information, choosing a strain of animal could waste time and money. furthermore, lack of information about more subtle changes affecting certain organ systems could influence interpretation of data. once an animal is selected, it must be free of most infectious diseases and must be maintained under controlled environmental conditions to minimize introduction of life-limiting variables. these influences become especially important when life-span studies are contemplated. this report details data obtained from specific pathogen free f344 male rats. parameters for this study included morphological alterations of major organs and measurement of selected serum chemicals. the effort was not to relate findings to the aging process per se, but rather to obtain data that may be of value to investigators using f344 rats. in order to obtain meaningful information, the rats had to be free of significant infectious disease. thus, serological and microbiological monitoring was a major aspect of the study. the study also provided information on the feasibility of maintaining rats free of major intercurrent infection throughout their life-span in a commercial breeding environment and of shipping aged rats to investigators without significant mortality or stress. rats. -fischer 344 rats were obtained by hysterectomy and were raised axenically in flexible film isolators. rats from this nucleus stock were inoculated orally with a mixed broth bacterial culture containing a modification of the schaedler formula (schaedler, dubos, & costello, 1965) . breeding stock derived from the nucleus colony were maintained under barrier husbandry conditions in a standard commercial production building at the charles river breeding laboratories, wilmington, ma. at the time of birth, large litters were reduced to 8 young. when weaned, the sexes were separated, and male rats were maintained at 5 per cage until 6 mo of age then at 3 per cage without additions or recombinations thereafter. the rats were housed in shoebox type cages, 13" x 12" by 7" with heat-sterilized hardwood bedding. they were fed a commercial diet ad libitum (charles river 4rf rat-mouse formula), which contained a minimum of 26% protein, 5% fat, and a maximum of 5.0% fiber. the diet was pasteurized (225f for 15 min) but was not sterilized. statistical analysis. -inter-relationships were sought between age and nephropathy severity index, age and serum chemistry values, nephropathy and serum chemistry values, and between selected serum chemical parameters, using correlation coefficients. coefficients greater than 0.30 were considered significantly correlated (p = 0.99), based on the sample size. when a correlation between 2 parameters was found, the linear regression formula was calculated. calculations and determination of probability levels were performed by established methods (steel & torrie, 1960) . pathology. -a wide variety of lesions occurred. the type and incidence of lesions in various organs are tabulated in tables 1 through 19 and are discussed below. all rats had one or more lesions, and a majority of dead or moribund rats had some form of neoplasia or advanced renal disease. rats selected as "unhealthy" also had some form of neoplasia, and 2 had posterior paresis of undetermined origin. neoplasms: a few tumors were seen in rats less than 18 mo of age, but most occurred after that point (table 1) . the most common tumor types were testicular interstitial cell tumors, 'microbiological associates. bethesda, md. pituitary chromophobe adenomas, and a form of mononuclear cell leukemia. the incidence of other tumors was low. a total of 103 rats had some form of neoplasia. thirty-five of the affected rats had 2, 30 rats had 3, 6 rats had 4, 2 rats had 5, and 1 rat had 6 types of neoplasia at one time. the tumors are discussed under the individual organ categories below. although leukemia is generally rare in rats, there is an unclassified mononuclear cell leukemia that has reached an incidence of up to 25% in the wistar-furth (w-fu) and fischer rat strains (davey & moloney, 1970; jacobs & huseby, 1967; moloney, boschetti, & king, 1968 . twenty-three rats in this study (16%) had leukemia of this type. the highest incidence was 29.8% in the 24-to 30-mo age group. fourteen rats were clinically ill prior to necropsy and the remainder were asymptomatic. hemograms on 9 of these rats revealed a total leukocyte count range of 68,400 to 323,000 cells//u.l (average 143,190) . the cells were morphologically identical to those described by others . minimal organ changes, related to the leukemia, were present. twenty rats had spleens ranging from 4 to 20 times normal size. splenomegaly was due to sequestration of erythrocytes and neoplastic mononuclear cells in the sinuses of the red pulp. there was effacement of the white pulp, a the numbers a (b) indicate: a = # of cases within the age group c, d, e b = % incidence within the age group c = # of randomly selected rats with lesion d = # of "unhealthy" rats with lesion e = # of dead or moribund rats with lesion refer to appropriate organ system table for group size and over-all incidence within individual age group. 1 with transformation to squamous cell carcinoma and metastases to lung. by tumor growth in only 3 of these rats. infiltration of leukemic cells occurred irregularly in other organs: lung, 4; liver, 8; kidney, 1; adrenal gland, 7; pancreas, 1; skeletal muscle, 1; lymph node, 2; and bone marrow, 9. seven of the 23 rats had no evidence of organ infil-tration. this pattern of variable organ involvement was similar to that described by others except the incidence of hepatic and pulmonary involvement in this study was much lower (davey & moloney, 1970; moloney et al., 1970) . respiratory system: the most frequent finding was small lymphocytic aggregates in or just beyond the walls of major bronchi ( table 2 ). the incidence of these increased with age until 12 mo, then remained steady until 30 mo, and then declined. mild perivascular lymphocytic infiltrates were found in most rats less than 6 mo of age, and the incidence decreased steadily with age. there were several cases of mild focal chronic interstitial pneumonia, characterized by small foci of alveolar septal fibrosis with sparse infiltrates of lymphocytes and macrophages. these were generally adjacent to peribronchial lymphocytic aggregates. one rat had focal interstitial fibrosis without leukocytic infiltrates. the most severe pulmonary lesion was a mild focal atypical hyperplasia (innes, garner, & stookey, 1967) which occurred in a few rats over 24 mo of age. alveoli were lined by cuboidal to columnar epithelial cells, with variable amounts of interstitial fibrosis. three rats had medial hypertrophy, and 3 had medial calcification of the pulmonary artery, both of which are considered to occur frequently in rats (wilens & sproul, 1938) . a few rats in the oldest age group had focal intraalveolar collections of foamy macrophages primarily in subpleural regions. this has been considered a normal finding in rats (beaver, ashburn, & mcdaniel, 1963) . none of the lungs had lesions suggestive of chronic respiratory disease, a disease associated with mycoplasma pulmonis (jersey, whitehair, & carter, 1973) . no primary pulmonary neoplasms were detected. four rats with a mononuclear cell leukemia had mild alveolar septal infiltrates, and 1 rat had pulmonary metastases of a squamous cell carcinoma arising in the ear canal. other common findings, not tabulated in this study, were dilatation and atrophy of tracheal glands and mineralization of tracheal cartilage. cardiovascular system: cardiac lesions were common and appeared to be influenced (table 3) . mild to moderate focal chronic interstitial myocarditis occurred frequently in rats less than 6 mo old and then decreased in incidence with increasing age. it was characterized by focal aggregates of large mononuclear leukocytes and scattered phagocytic cells which separated myocardial fibers. myocardial degeneration occurred with or without inflammation and was characterized by focal regions of shrunken or vacuolated myocardial fibers. these two lesions were not always coincidental, but one or both appeared to be the predecessor of interstitial fibrosis, >vhich was first seen at 6 to 12 mo, and increased in incidence and degree with age. this lesion has been well reviewed by others (berg, 1967; fairweather, 1967) . the fibrosis appears to be closely related to early degenerative and inflammatory changes, rather than based on a vascular origin. only a few vascular or valvular lesions were found, which seemed to have no correlation to age. none of the lesions noted were considered of sufficient severity to impair cardiac function. vascular lesions, which occurred rarely, are discussed under the organ system involved. urinary system: all but one of 144 rats examined had some degree of renal pathology (table 4 ) and that rat was less than 6 mo old. the lesion common to all rats was a complex of chronic changes that have been given a variety of names such as nephritis, nephrosis, glomerulosclerosis, glomerular hyalinosis, nephropathy, and chronic progressive nephrosis (andrew & pruett, 1957; berg, 1965; couser & stilman, 1975; durand, fisher, & adams, 1964; elema & arends, 1975; elema, koudstaal, lamberts, & arends, 1971; foley, jones, osborn, & kimeldorf, 1964; gray, weaver, & purmalis, 1974; lalich & allen, 1971; lalich, faith, & harding, 1970; saxton & kimball, 1941; simms & berg, 1957) . the term "chronic nephropathy" was chosen in this study as the best descriptive term for this disease, since the lesion was chronic, was more complex than the aforementioned specific terms imply, and involved the entire nephron. the pathogenesis, histopathology, and ultrastructural pathology of the nephropathy have recently been well described (couser & stilmant, 1975; elema & arends, 1975; gray etal., 1974) . chronic nephropathy was graded 1 to 4, with an additional, end stage, category for severely affected kidneys. grade 1 kidneys had thick-ened glomerular capillary basement membranes and slight mesangial thickening in some glomeruli. a few cortical tubules were shrunken, had thickened, wrinkled basement membranes, and were lined by enlarged cells containing basophilic cytoplasm and large nuclei. in addition, grade 2 kidneys had scattered dilated tubules lined by atrophic epithelium with occasional hyalin casts, particularly at the corticomedullary junction. protein casts became prominent in grade 3 kidneys, and appeared within cortical, medullary, and papillary tubules. the glomerular lesion was more pronounced with atrophy of capillary tufts, sclerosis, thickening of bowman's capsule, and tubular basement membranes. these finding's were pronounced in grade 4 kidneys, which commonly had adhesions of glomerular tufts to bowman's capsule and both enlarged nuclei in the tunica media and proliferation of adventitial connective tissue in afferent arterioles of the severely affected glomeruli. endstage disease had no normal parenchyma remaining, with widespread glomerular sclerosis, marked tubular dilation, atrophy and hyalin cast formation, and interstitial fibrosis. cytoplasmic tubular epithelial lipochrome pigment increased with age and first appeared at 150 days. in severe cases, it was accompanied by hemosiderin granules. scattered aggregations of interstitial mononuclear leukocytes (chronic interstitial nephritis) were frequently found throughout the cortex but could not be correlated with the severity of nephropathic change. the incidence and severity of chronic nephropathic changes are presented in table 4 and plotted against age in fig. 1 . there was a highly significant correlation between aging and severity of the renal disease (correlation coefficient = +0.80, n = 144 rats). other renal lesions occurred sporadically. one rat had a large infarct of unknown cause. tumor metastases occurred in several rats and included: reticulum cell sarcoma, lymphosarcoma, and mononuclear cell leukemic infiltration. a pheochromocytoma had invaded the perirenal tissue of 1 rat. urinary bladder lesions consisted of two cases of suppurative cystitis and one of transitional cell papilloma. cystitis occurred concurrently with pyelonephritis in a 600-day-old paralyzed, moribund rat, apparently secondary to neurogenic atony. splenic lesions: lesions were absent in rats less than 18 mo old, except for reticuloendothelial hyperplasia in 1 rat in the 12-to 18-mo group (table 5) . chronic passive congestion was evident in spjeens of rats with severe bile duct hyperplasia. circulatory embarrassment, related to hepatic portal fibrosis, was thought to be the cause of the splenic congestion. in 20 rats with mononuclear cell leukemia, splenic congestion was exacerbated by infiltration of the hepatic sinusoids by leukemic cells, in addition to primary leukemic involvement of the spleen. marked leukemia-associated splenomegaly has been noted by others (davey & moloney, 1970; jacobs & huseby, 1967; moloney et al., 1969 moloney et al., , 1970 . infiltration of white pulp occurred in only three cases. in 5 rats with passive congestion, there was reticuloendothelial hyperplasia. the spleens of 6 rats in the two oldest age groups had recent or old infarcts, possibly related to chronic passive congestion. excessive extramedullary hematopoiesis occurred secondary to anemia in 5 rats. endocrine system: adrenal cortical changes were not evident before 6 mo. in rats with neoplasms, especially chromophobe adenomas of the pituitary, there was diffuse or focal fatty change in the inner cortex (table 6 ). cortical adenomas were found in 2 rats of the 24-to 30-mo group. two rats in the older age group also had hyperplastic nodules in the zona fasiculata, and 1 rat had diffuse cortical hypertrophy. telangiectasis of cortical vessels was present in 6 rats more than 12 mo old. two rats table 7 . pancreatic lesions. had inflammatory lesions. one had a focal pericapsular suppurative process, and 1 had periarteritis of a capsular artery. adrenal medullary changes did not appear in rats less than 18 mo old. thereafter, only a few lesions were found. five rats had pheochromocytomas, one of which had spread to perirenal tissues, and another of which occurred concurrently with a thyroid medullary carcinoma. two rats had thrombosed adrenal medullary vessels, and in 1 rat, thrombosis was associated with hyperplasia of medullary cells. one case of focal medullary hyperplasia occurred without a demonstrable cause. focal mononuclear cell leukemic infiltrates occurred in the cortex of 7 rats and medulla of 1 rat. pancreatic islet lesions occurred in low incidence (table 7) and are discussed under digestive system. hypophyseal lesions were restricted to the adenohypophysis (table 8) . chromophobe adenomas were commonly diagnosed after 18 mo but one case was found in the 6-to 12-mo group. the tumors were of papillary, sinusoidal, diffuse and mixed types (russfield, 1968) . compression atrophy of the overlying brain occurred in 6 rats. nodular hyperplasia was seen in 1 rat. chromophobe adenomas are common in some strains of rats (ito, moy, kaunitz, kortwright, clarke, furth, & meites, 1972) . sinusoidal dilatation occurred in 5 rats, and 1 rat had multiple colloid cysts lined by low cuboidal epithelium, and which contained basophilic, hyalin material. only a few changes were found in the thyroid and parathyroid glands (table 9 ). one rat had diffuse hypertrophy, 1 had an adenoma, and 3 had medullary carcinomas of the thyroid. a higher incidence of thyroid tumors in fischer and sprague-dawley rats has been reported (jacobs & huseby, 1967; thompson, huseby, fox, davis, & hunt, 1961) , but unless rats are fed low iodine diets, thyroid tumors are otherwise considered rare (axelrad & leblond, 1955; isler, leblond, & axelrad, 1958) . the adenoma seen in this study was of the gamma type (axelrad & leblond, 1955; isler et al., 1958) . two rats over 30 mo old had parathyroid hyperplasia. one had end stage, and the other had grade 3 nephropathy. two cases of fibrous osteodystrophy were seen but neither were in rats with demonstrable parathyroid hyperplasia. digestive system: hepatic lesions were common (table 10 ). the most frequent lesion was bile duct hyperplasia, which increased in incidence and severity with age. this lesion has not previously been described, which suggests an environmental influence was present in this study. the affected livers were brown, firm, and rough-surfaced. beginning at about 6 mo, increased numbers of bile ducts were seen in some portal tracts. the numbers of ducts per portal area and the number of portal areas affected increased with time until the incidence in 18-mo-old rats was greater than 98%. basement membranes of bile ducts became thickened and sclerosed. bile ductal epithelium underwent hyperplasia and squamoid metaplasia. eventually, these changes led to obliteration of portal structures, including blood vessels. the portal lesion was considered to be an antecedent of the nodular regenerative changes seen in older rats. the latter were first seen in a 720-day-old rat and were accompanied by a hepatocellular carcinoma. nine other rats had regenerative nodules without evidence of neoplastic transformation. other hepatic lesions were generally mild and sporadic and included mild focal or diffuse ''the numbersa (b) indicate: a = # of cases within the age group c.d.e b = % of cases within the age group c = # of randomly selected rats with lesion d = # of "unhealthy" rats with lesion e = # of dead or moribund rats with lesion fatty change, hydropic degeneration, and hepatocellular atrophy. the incidence of acute hepatocellular coagulative necrosis increased slightly but steadily with age. variably sized foci of cystic sinusoidal dilatation were seen in older age groups. this lesion appeared to result from hepatocellular atrophy and/or necrosis, with retention of the reticular framework to form the walls of the cystic spaces. a similar lesion has been described in old wag/rij rats (boorman & hollander, 1973) . eight rats with mononuclear cell leukemia had hepatic sinusoidal infiltration of leukemic cells. an apparently much higher incidence of hepatic infiltration was reported elsewhere . one diaphragmatic hernia (presumably congenital), one reticulum cell sarcoma, and two cases of lymphosarcoma were seen. the gastrointestinal tract was remarkably free of lesions (table 11 ). there were six cases of focal glandular dilation of gastric mucosa, and 1 rat had focal chronic gastritis. metastatic enteric mineralization occurred in 1 rat. two rats had focal nonsuppurative sialoadenitis. one moribund rat had acute colitis. mesenteric lipomas in 2 rats were the only form of neoplasia found. the most frequent pancreatic lesion was islet cell adenoma which occurred in 9 rats (table 7) . a review of other studies indicated a much lower incidence than the 6% seen in this study (rowlatt, 1967) . this is probably because all tumors occurred in rats over 18 mo old, with the highest incidence (30%) occurring at 30 or more months of age. the next most frequent lesion was pancreatic lobular atrophy, which occurred in 6 rats more than 18 mo old. this has been reported to be a common finding in the aging rat (andrew, 1944; berg, 1967) . acinar and ductal ectasia were found in a small number of rats without associated lobular atrophy. a few rats with evidence of previous hemorrhage, resolved pancreatitis, alpha cell degeneration, thrombosis, and lymphosarcoma were seen. two rats had periarteritis nodosa of the pancreatico-duodenal artery which is a common location for this lesion (berg & harmison, 1955; skold, 1961; yang, 1965) . reproductive system: lesions of the testes and accessory sex glands were common (tables 12& 13). the earliesttesticular change was epithelial degeneration of scattered seminferous tubules in a 150-day-old rat. by 300 days, many testes had nodular interstitial (leydig) cell hyperplasia. this appeared to precede interstitial cell neoplasia, since hyperplasia was not found after 520 days, and interstitial cell tumors began to appear at 510 days; tumors sharply increased in incidence in the 18-to 24-mo group and reached an incidence of 100% by 30 mo. a high incidence of this type of tumor in fischer rats, but not other rat strains, has been noted by others (davey & moloney, 1970 , jacobs & huseby, 1967 . no metastases were seen. the only other type of tumor seen was papillary mesothelioma, arising from mesothelium of the tunica albuginea, in 3 rats. one table 11 . digestive system lesions. rat had epithelial hyperplasia of the ductus efferentes. the incidence of testicular atrophy increased with age. atrophy of the seminiferous tubules was first noted in 2 rats in the 6-to 12mo group, then increased to 100% incidence by 18 mo. two rats in the oldest age group had focal dystrophic mineralization of seminiferous tubules. the onset of interstitial cell tumors was coincidental with the onset of seminiferous tubular atrophy, but a few rats had testicular atrophy without tumors. concurrent with testicular atrophy, the seminal vesicles became shrunken with decreased secretory activity. one case of prostatic atrophy was found. inflammatory lesions of the prostate, but not seminal vesicles, were common. both nonsuppurative and suppurative lesions were found. central nervous system: lesions of the brain and spinal cord were present in only 1 rat before 18 mo (table 14) . the rat had protrusion of an intervertebral disk, with secondary degeneration of the spinal cord and resulting posterior paresis. all other central nervous system lesions were restricted to the brain. six rats with pituitary adenomas had secondary compression atrophy of overlying brain. scattered single instances of hemorrhagic necrosis, ischemic malacia, atherosclerosis, and hemorrhage were present in other rats. well defined, nonstaining vacuoles, adjacent to or within neurons or within the neuropil of the cerebellar white matter and brain stem were encountered with increasing age (garner, innes, & nelson, 1967) , and reached 80% incidence in the oldest group. two rats had posterior paralysis of undetermined cause. the cauda equina or peripheral nerves were not examined for radiculoneuropathy (berg, wolf, & simms, 1962) , but myelin degeneration was not seen in the upper lumbar spinal cord. musculoskeletal system: lesions of the musculoskeletal system were rare and did not appear until after 18 mo, except in the rat with intervertebral disk protrusion (tables 15 & 16) . focal muscular dystrophy was present in 2 rats, dystrophic mineralization occurred in a few muscle fibers of the quadriceps femoris of 1 rat, and 4 rats had diffuse muscular atrophy. one case each of subscapular rhabdomyosarcoma, lymphosarcoma infiltration, and mononuclear cell leukemic infiltration was found. several skeletal lesions occurred in addition to the inter vertebral disk protrusion previously discussed. two rats had mild proliferative synovitis of the knee, and 2 rats with end-stage nephropathy had fibrous osteodystrophy. bone marrow lesions included three cases of myeloid or erythroid hyperplasia and focal areas of myelofibrosis in 2 rats. nine of 23 rats with mononuclear cell leukemia had bone marrow involvement. epiphyseal plates (distal femoral and proximal tibial) remained open for the life-span of the rats. ocular lesions: lesions of the eye and surrounding structures were uncommon (table 17) . focal nonsuppurative harderian dacryoadenitis occurred in 4 rats, and 4 rats had similar changes in the meibomian glands. one rat had suppurative panophthalmitis, and 4 rats had chronic keratitis. two rats had atherosclerosis of ocular arteries, 4 had focal scleral mineralization, 5 had nuclear cataracts, and 3 had diffuse retinal degeneration (dowling & sidman, 1962) . skin and adnexae: there was a moderate incidence of lesions in the skin and cutaneous adnexae, most of which were neoplasms which occurred in middle and older age groups (table 18) . with the exception of five epidermal inclusion cysts and one sebaceous nevus, the remaining lesions were neoplasms, which began to appear at 300 days. among the most frequent tumors were preputial gland sebaceous adenomas with squamous differentiation. they were often cystic and contained desquamated epithelial debris. the tumors had a fine connective tissue matrix, a thick collagenous capsule, and were invariably benign. fibromas occurred in equal frequency. most were subcutaneous, but one was intradermal. they were highly collagenous, hypocellular, and often mineralized. three rats had subcutaneous lipomas. tumors of the auditory sebaceous glands (zymbal's glands) occurred in 4 rats. a similar low spontaneous incidence of this tumor type has been reported by others (schardein, & kaump, 1966; snell, 1965; tannenbaum, vesselinovich, maltoni, & mitchell, 1962) . these tumors were all sebaceous with squamous differentiation. the squamous component in 1 rat gave rise to a squamous cell carcinoma with pulmonary metastases. squamous papillomas were found in 2 rats, one on the lip and the other on the back. three rats had basal cell tumors, 1 had squamous and follicular differentiation, and 2 had trichoepitheliomas. a single rat had a subcutaneous capillary angioma. nonneoplastic lesions included 1 rat with focal suppurative epidermitis, due to selfinflicted trauma of the eyelid overlying a chronic meibomian adenitis, and 1 rat with acute necrotizing posthitis. mammary lesions (table 19 ) consisted of nine cases of gynecomastia, one case of pyogranulomatous mastitis, and three cases of adenofibromatosis. only 4 rats with gynecomastia had concurrent pituitary lesions, despite evidence of association of these 2 lesions (ito et al., 1972) . clinical chemistry. -significant age-related changes in total protein, albumin, alpha-1 globulin, and cholesterol concentrations 21) were observed. the same parameters had a significant relationship with the degree of chronic nephropathic change (fig. 6-9 and tables 20, 22). interrelationships between serum constituents independent of age and renal disease were sought, but no relationships were found. total protein concentration progressively decreased with increasing age and renal lesion severity (fig. 2 & 6) . this change was due primarily to a progressive decrease in serum albumin concentration (fig. 3 & 7) . this has previously been shown to be due to urinary loss associated with nephro-pathy rather than a decrease in serum half-life or rate of production (salatka, kresge, harris, edelstein, & ove, 1971 ). globulin concentration increased with age and renal disease due to increases in the 11.0 alpha-1 globulin fraction ( fig. 4 & 8) . an increase in alpha globulin concentration with age has been reported (uebel, 1956 ) but the mechanisms responsible for this change have not been established. other studies with rats (berg, 1965; salatka, 1965 salatka, , et al., 1971 ubell, 1965) has shown a progressive increase in gamma globulin with age, but this was not seen in this study. since serum levels of gamma globulin reflect primarily the host's immune response to antigenic stimuli, direct comparison of results from different studies is not possible. cholesterol levels in individual rats of all age groups were widely variable but there was a consistent increase with advancing age and renal disease (fig. 5 & 9 ). hypercholester t olemia has been reported in young rats with renal disease, suggesting a causal relationship (berg, 1965) . the mechanism for this change is unknown. the wide range of cholesterol values at each age group was an unexpected finding, since the rats in this study were an inbred strain in a reasonably controlled environment and fed the same diet. serum sodium and potassium were not significantly altered with age and severity of kidney disease. creatinine, another index of renal impairment, showed no relationship to age or renal damage. only 1 rat had an elevated creatnine of 2.3 mg/dl. serum urea nitrogen was measured only in rats in the older age groups, which had more advanced pathology. several rats had levels exceeding 40 mg/dl, up to 87 mg/dl in 1 animal. no correlation occurred between creatinine and urea nitrogen levels. microbiology. -all of the rats sampled throughout the course of the study were free of mycoplasma pulmonis, salmonella, ectoparasites, and endoparasites. occasional rats were found to have p. aeruginosa in their nasopharynx and/or cecum, with no evidence of associated pathology. other rodent pathogenic bacteria were not isolated from any of the rats. serology. -a consistent pattern of antibodies to pvm, sendai virus, and mvm was noted at the onset of the study and persisted throughout the study. approximately 90% reacted to pvm (1:20-1:320), 70% reacted to sendai virus (1:10-1:80), and 30% reacted to mvm (1:20-1:80). a limited number (10%) reacted weakly to mhv (1:10-1:20), and even fewer reacted to rcv (1:10-1:20). antibodies to mhv most probably represent cross reactivity to a rat coronavirus rather than to mhv (bhatt, percy, & jonas, 1972; parker, cross, & rowe, 1970) . the pattern was identical in all age groups with the exception of mvm, to which only rats greater than 18 mo of age reacted. no chemical or histological evidence of clinical infection was noted. this study further characterized the fischer 344 male rat through its natural life-span. in order to obtain meaningful life-span information, the environment was stabilized in every way practicable. all animals "were housed behind a barrier to minimize possible disease outbreaks. other factors, such as food, water, heating, ventilation, caging, and bedding were kept reasonably uniform throughout the study. with these controls, the 50% mean survival was 29 mo. maximum survival to 35 mo was observed. mortality was negligible until about 20 mo, at which time the curve dropped rapidly, with a shouldered slope. cause of death of animals found dead or moribund was not evaluated in detail, since cause was not always apparent. as a generalization, most deaths were related to neoplasia or advanced renal disease. dead or dying rats often had lesions equal in severity to their living cohorts. clinical chemical parameters of live aged rats showed renal compensation, despite the severity of the lesion. it seemed probable that many rats died acutely following decompensation, but the chemistries are not available to prove this presumption. a commercial breeder was chosen to evaluate the feasibility of maintaining and shipping aged rats to scientists. the results clearly demonstrate that maintaining aged rats free of major overt infectious disease is possible, as monitored by microbiological, serological, and pathological methods. the study demonstrates the efficacy of barrier facilities. of note was the absence of chronic respiratory disease, associated with mycoplasma pulmonis. the facility remains in operation, free of m. pulmonis, 6 years after its establishment. the only contaminant since tabulating these data has been syphacia obvelata (pinworm). hundreds of rats have been shipped from this colony to investigators. no untoward effects have been observed or reported, indicating the practicality of raising aging animals at one location and distributing them to users. others (flynn, poole, & tyler, 1971 ) have provided detailed documentation that aged animals could be successfully shipped by air across the country. pathology data in this study should be interpreted with caution. there was.a variety of pathology found, but all animals, including man, develop lesions with increasing age. these data cannot be compared directly with data on other rat strains, since other strains have not been examined as critically as the aging male f344 rat used in this study. the male fischer rat appeared to have a relatively low incidence of malignant solid tumors, an extremely low incidence of pulmonary disease of any type, and a low prevalence of a wide range of benign tumors. testicular leydig cell tumors were in virtually all aged male fischer rats. nonneoplastic lesions were varied and found as expected in almost all organs with advancing age. renal disease, as previously mentioned, was suspected as a contributor to the cause of death of many of the rats and was shown to affect serum chemical parameters with age. the hepatic bile ductal hyperplasia and sclerosis was interpreted as the result of an environmental insult rather then a natural progressive lesion associated with aging per se. analysis of feed is in progress to detect the presence of a possible hepatotoxic component in the diet, and the lesion is being further studied. summary pathology, microbiology, and selected serum chemistries were evaluated in 144 male fischer rats from 4 to 33 mo of age. the rats were reared and maintained under barrier conditions, which successfully excluded the introduction of major infectious disease agents throughout the entire study, including mycoplasma pulmonis. a wide variety of pathology was found and tabulated, and many lesions were found to increase in severity and incidence with age. involution of the reproductive system, myocardial degeneration and fibrosis, chronic renal disease, sclerosing bile ductal hyperplasia, and chronic passive splenic congestion were the most frequent nonneoplastic lesions seen. testicular interstitial cell tumors, mononuclear cell leukemias, and pituitary adenomas were the most frequent tumors found, with a large number of other types occurring in low incidence. there was a high correlation of renal disease severity with increasing age. serum total protein and albumin decreased with age, while alpha-1 globulin and cholesterol increased. no changes were seen in serum sodium, potassium, urea, creatinine, or other protein components. senile changes in the pancreas of wistar institute rats and of man with special regard to the similarity of locule and cavity formation senile changes in the kidneys of wistar institute rats induction of thyroid tumors in rats by a low iodine diet lipid deposits in the lungs of germ-free animals spontaneous nephrosis, with proteinuria, hyperglobulinemia and hypercholesterolemia in the rat longevity studies in rats: ii. pathology of aging rats blood pressure and heart size in aging rats degenerative lesions of spinal roots and peripheral nerves in aging rats characterization of the virus of sialodacryoadenitis of rats: a member of the coronavirus group chronic nephritis in rats fed high protein diets spontaneous lesions in the female wag/rij (wistar) rat mesangial lesions and focal glomerular sclerosis in the aging rat postmortem observations on fischer rats with leukemia and other disorders. laboratory investigation inherited retinal dystrophy in the rat histology in rats as influenced by age and diet. i. renal and cardiovascular systems focal and segmental glomerular hyalinosis and sclerosis in the rat spontaneous glomerulosclerosis in the rat cardiovascular disease in rats long distance airtransport of aged laboratory mice a renal lesion associated with diuresis in the aging sprague-dawley rat pathology of laboratory rats and mice ultrastructural observations of chronic progressive nephrosis in the sprague-dawley rat respiratory disease in rats influence of age and of iodine uptake on the production of thyroid tumors in the rat incidence and character of the spontaneous pituitary tumors in the strain cr and w/fu male rats neoplasms occurring in aged fischer rats with special reference to testicular, uterine and thyroid tumors mycoplasma pulmonis as the primary cause of chronic respiratory disease in rats protein overload nephropathy in rats with unilateral nephrectomy. ii. ultrastructure study protein overload nephropathy: in rats subjected to unilateral nephrectomy the pathogenesis of dietary nephritis in the rat observations on leukemia in wistar/furth rats. cancer research spontaneous leukemia in fischer rats rat coronavirus (rc v): a prevalent, naturally occurring pneumotropic virus of rats. archivfiir die gesamte virusforschung pancreatic neoplasms of rats and mice endocrine pathology. williams & wilkins rat serum protein changes with age relation of nephrosis and other diseases of albino rats to age and to modifications of diet the development of the bacterial flora in the gastrointestinal tract of mice auditory canal structures in rats as altered by aging and by the administration of tris (p-aminophenyl) carbonium pamoate longevity and the onset of lesions in the male rats chronic arteritis in the laboratory rat spontaneous lesions of the rat principles and procedures of statistics multipotential carcinogenecity of urethan in the sprague-dawley rat spontaneous tumors in the sprague-dawley rat uber altersabhangige verschiebungen der serumieweisskorper bei wistarraten determination.of creatine, creatinine, arginine, guanidionacetic acid, guanidine and methyl guanidine in biological fluids spontaneous cardiovascular disease in the rat. ii. lesions of the vascular system polyarteritis nodosa in laboratory rats. laboratory investigation a new method for the direct determination of cholesterol journal of laboratory key: cord-005097-6xkx9a56 authors: herndler-brandstetter, dietmar; cioca, daniel p.; grubeck-loebenstein, beatrix title: immunizations in the elderly: do they live up to their promise? date: 2006 journal: wien med wochenschr doi: 10.1007/s10354-006-0267-8 sha: doc_id: 5097 cord_uid: 6xkx9a56 in the 21st century, public health is not only challenged by newly emerging and re-emerging infectious diseases but also by demographic developments that are taking place in many countries. importantly, infections in the elderly are more frequent, more severe and have distinct features with respect to clinical presentation and treatment. this is due to a decline in the functions of the immune system referred to as immunosenescence. the most important age-related changes affect the t cell system. although this derogates the protective effect of some vaccines, vaccinations are still considered the most cost-effective medical procedure for preventing morbidity and mortality caused by infectious diseases. the present article aims at outlining the impact of infectious diseases on the elderly and summarizing the progress made in the field of vaccinations of the elderly and how age-related changes within the immune system contribute to the decreased efficacy of vaccines. improved public health measures and standards of living, together with medical advances such as immunizations and antibiotics, contributed substantially to the reduction of mortality and morbidity caused by infectious diseases in the 20th century. in particular, the implementation of large-scale vaccination strategies led to the eradication of smallpox in 1980 [1] and to a drastic reduction of poliomyelitis, tetanus, diphtheria, measles, pertussis and meningitis. at the beginning of the 21st century, vaccinations are still considered the most cost-effective medical procedure for preventing morbidity and mortality caused by infectious diseases. to date, approximately 26 different infectious diseases can be prevented by vaccinations and 61 vaccines are being developed according to a 2004 survey by the pharmaceutical research and manufacturers of america [2] . the new candidate vaccines are intended to provide protection against diseases caused by rotavirus, herpes zoster and papilloma virus and will be commercially available in one to two years (table 1) . moreover, improved vaccines against influenza, meningitis, pneumonia and tuberculosis are currently being tested in clinical trials (table 1) . immunizations in the elderly: do they live up to their promise? dietmar herndler-brandstetter, daniel p. cioca and beatrix grubeck-loebenstein 1 modern immunology is using vaccines to either selectively suppress or enhance the immune response thus making it also applicable for the treatment of non-infectious diseases such as allergy, autoimmunity, alzheimer's disease and cancer but also to prevent nicotine drug dependency by anti-nicotine vaccination [3] . recent progress in the development of vaccines against the human papilloma virus that can cause cervix cancer (table 1 ) and vaccination with dendritic cells loaded with tumor antigen [4] exemplify the potential of these novel approaches. furthermore, research activities of the last decade have shown that the chronic inflammatory background apparent in elderly persons may exacerbate the functional pathology and disease course of age-related disorders, such as arteriosclerosis [5] , rheumatoid arthritis [6] and alzheimer's disease [7, 8] . thus, future immunotherapeutic approaches may take advantage of the recent research progress in identifying the underlying immunological mechanisms of these diseases. nevertheless, infectious diseases represent a major challenge to human progress and survival as they are still responsible for approximately 20 % of all deaths in the world. this is of course not only related to microbial and viral factors but also to social and environmental determinants [9] . however, the resurgence of several infectious diseases was supported by the increased occurrence of multiple drug-resistant microorganisms such as staphylococcus aureus, mycobacterium tuberculosis, escherichia coli and streptococcus pneumoniae. this situation inflicts an enormous economic burden on health care systems all over the world. however, public health is not only challenged by newly emerging and re-emerging infectious diseases, but also by the demographic revolution that is proceeding in developed countries leading to a dramatic change of the age structure. today, people in austria and every other country of the european union are living longer than at any other time in recorded history. in austria, life expectancy at birth has increased from 66.5 (1970) diseases in geriatric patients are becoming an increasingly important issue, especially because infections in the elderly are not only more frequent and more severe, but also have distinct features with respect to clinical presentation, microbial epidemiology, treatment and infection control. urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, infective endocarditis, bacterial meningitis, tuberculosis and herpes zoster appear to have a higher prevalence in elderly persons. in developed countries like the united states, pneumonia, influenza and septicemia are still ranked among the ten major causes of deaths in people aged 65 years and older. the causations for increased susceptibility to infectious diseases include epidemiological elements, immunosenescence and malnutrition, as well as age-associated anatomical alterations. the present article intends to outline the impact of infectious diseases on the elderly and to summarize the current progress in the field of vaccinations of the elderly, what and how vaccines are being improved and how agerelated changes within the immune system contribute to the decreased efficacy of vaccines. the attention of humankind is regularly directed to the outbreak of deadly infectious diseases such as ebola, marburg or sars and to the worldwide spread of aids and hepatitis c that are currently affecting together more than 210 million people [10] . recently, outbreaks of avian influenza in russia and kazakhstan alerted the world, because of the fear that the highly pathogenic h5n1 virus may mutate and facilitate human-to-human transmission. however, public attention to diseases that cause substantial morbidity and mortality among the elderly population is less prominent. the most frequent infectious diseases in the elderly include invasive streptococcus pneumoniae infection, influenza, urinary tract and skin infections [11] . moreover, old individuals may also fail to respond sufficiently to therapy and frequently suffer from opportunistic infections, recurrent infections with the same pathogen or reactivation of latent diseases, such as those caused by mycobacterium tuberculosis and varicella zoster virus. there are no vaccines available for many infectious pathogens that are frequent in the elderly and existing vaccines are underused and do not assure such an effective protection as in the young. elderly persons for instance, typically have a decreased immune response to pathogens with which they have previously not been in contact, such as rabies and yellow fever virus, or new influenza virus strains. the following paragraphs will now deal with the most important infectious diseases that threaten the elderly population and will present data on their occurrence, vaccine availability and efficacy, vaccination coverage and current health authority recommendations. influenza is one of the most important infectious diseases and was responsible for the death of 20 million people after the first world war. in austria, it is estimated that between 1.000 and 6.000 people die during an epidemic influenza outbreak. especially elderly people and persons that are chronically ill or otherwise immunocompromised are at enhanced risk. for instance, during influenza epidemics, barker and mullooly reported two deaths per 100.000 among healthy people below 65 years of age compared with 797 per 100.000 in those over 65 with two or more high-risk conditions [12] . in contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic variation and possess an animal reservoir. thus, new epidemics and pandemics are likely to occur in the future, and eradication of the disease will be difficult to achieve. only recently, specific antiviral therapy has become available by the implementation of two neuraminidase inhibitors (oseltamivir ® and zanamivir ® ). for instance, oseltamivir ® decreases the duration and severity of disease up to 40 % when given within the first 36 hours after symptoms have occurred [13, 14] . nevertheless, active immunization remains a vital element in the prophylaxis of influenza disease, although the frequently occurring antigenic drift requires an annual modification of the vaccine components according to the recommendations of the who. thus, vaccination has to be repeated annually to ensure protection against the circulating influenza strains (fig. 1) . however, compared with other european countries, influenza vaccination coverage in austria ranges in the lowest third, with only 15 % of elderly people being vaccinated. in contrast, vaccination coverage in the united states is about 70 % among people aged 65 and above [15] . although several vaccines are available, the efficacy of many vaccines in preventing influenza disease in elderly persons is only around 56 % [16] . especially very old and frail persons show a decreased response to influenza vaccines [17] . the reduced vaccine efficacy is due to low levels of iga and igg antibodies, delayed peak antibody titers and shortened maintenance of titers after vaccination. nevertheless, immunization in elderly people has been shown to be safe, cost-effective and associated with reduced rates of hospitalization and influenzarelated deaths [18, 19] . in particular, the efficacy of influenza vaccination in reducing mortality in elderly people is greater after repeated annual vaccinations than after first administration [20] . at present, influenza vaccines can be classified in split-protein, subunit, virosomal and live-attenuated vaccines ( table 2) . split-protein vaccines have been used since the 1980ies, are cheap and offer a good protection. recently, subunit vaccines with new adjuvants have been developed (fluad ® , addigrip ® ) that show an increased immunogenicity, a favorable safety profile and may be more suitable for the vaccination of elderly people [21] . inflexal v ® , a virosomal vaccine, displays the highest immunogenicity. furthermore, new live-attenuated and subunit influenza vaccines are currently in clinical trials and promise to have an increased efficacy of protection (table 1) . especially live-attenuated influenza vaccines are considered to elicit strong t cell responses and should therefore increase the antibody levels after vaccination (fig. 2) . additionally, non-injectible application devices (nasal, oral, transcutaneous) may increase the patient's compliance, especially as the vaccination has to be repeated annually. infections due to streptococcus pneumoniae -along with influenza -are the most frequent cause of death in industrialized countries among vaccine-preventable diseases. in austria, up to 18.000 persons acquire pneumonia each year whereof around 10 % die. an existing primary disease, such as diabetes mellitus or a chronic heart disease may even increase lethality up to 30 %. moreover, 80 to 90 % of deaths associated with streptococcus pneumoniae infection occur in people aged 60 and older. thus, antibiotic therapy has to be initiated as soon as possible to reduce the risk of complications due to pneumonia, meningitis or sepsis. nonetheless, fifty percent of all deaths occur within the first 48 hours despite adequate antibiotic therapy. this is mostly due to the increased occurrence of multiple drug-resistant pneumococcal strains. all-important, people are not necessarily immune after a pneumococcal infection, because there are about 90 different streptococcus pneumoniae strains and immunity will be guaranteed only to the strain that has caused the infection. in austria, pneumococcal polysaccharide vaccines are available including 23 strains that cause almost 90 % of the disease (table 2) . these vaccines offer protection against invasive pneumococcal disease in 65 % of the general elderly population [22, 23] . in high risk elderly persons, the protective effect of vaccination seems 133 to be only moderate. above all, vaccination coverage among the elderly population is only around 10 to 15 %. this may be due to the high costs of the vaccine and its unsatisfying efficacy in elderly people. but more immunogenic vaccines are currently in different phases of clinical trials (table 1 ) and promise to be more efficient in old age. elderly people also represent the largest target population for tuberculosis (tb) which is still a global health problem as there are 8 million new tb cases and 1.6 million deaths each year. in austria, the number of tb cases decreased from 1.364 in 1998 to 1.079 in 2002 but it is more prevalent in people aged 55 and over. moreover, tuberculosis often has an atypical manifestation in old age and is therefore frequently diagnosed with delay. this may lead to increased morbidity and mortality and to a spreading of the disease, in particular within institutionalized elderly persons [24] . moreover, most infected individuals develop a latent infection that can be reactivated in about 10 % of the patients at any time during their life. further difficulties include the increased emergence of new, multiple drug-resistant strains with higher transmissibility, the poor efficacy of bcg vaccine in protecting adults and elderly people from pulmonary infection [25] and the increased risk of tb co-infection in hiv positive patients [26] . yet, the bcg vaccine is not recommended for general use in many countries, such as austria and the united states, because the vaccine displays adverse side effects and low efficacy in adults, and interferes with skin test screening. however, new tb vac-134 fig. 2 . schematic representation of the adaptive immune response to a pathogen. the immune system is the body's major defense mechanism against exogenous pathogens and even the slightest alterations of immune function may have deleterious effects on human welfare. whenever a pathogen invades the human host, the innate (unspecific) and the adaptive (specific) arms of the immune system will be activated. first, the pathogen gets phagocytosed by antigen presenting cells (apc), such as monocytes and dendritic cells. the proteins of the pathogen will be cut into small peptides followed by a vesicular transport of these peptides to the cell surface where they are presented on so-called major histocompatibility complex (mhc) molecules. these peptide-mhc complexes on the cell surface of an apc can now be recognized by a specific t cell receptor (tcr) expressed on t cells. the process of pathogen recognition leads to activation of the t cell that will consequently initiate various effector functions. however, one has to distinguish between two types of t cells that mediate different functions. cd4 + (helper) t cells can stimulate b cells that consequently differentiate into plasma cells and produce antibodies. on the other hand, cd8 + (cytotoxic) t cells mediate killing of tumor cells and host cells that have been infected by a pathogen. the activation of cd4 + and cd8 + t cells is also a prerequisite to form long-lasting immunological memory. cine candidates have now entered phase i clinical trials (table 1) . they may have a more favorable safety profile and may be able to induce strong cellular immune responses, necessary to protect against an intracellular pathogen such as mycobacterium tuberculosis. herpes zoster is another disease that predominantly occurs in the elderly and is caused by the reactivation of the varicella zoster virus. primary infection with varicella zoster virus (vzv) has the clinical manifestation of chickenpox and usually occurs in children. the virus then remains latent in human ganglia until its reactivation in the course of an immune suppression or deficiency [27] . the reactivation of vzv results in the clinical manifestation of shingles and post-herpetic neuralgia and is associated with a progressive decline in cell-mediated immunity to vzv, thus rendering older adults more susceptible to vzv. in the near future, routine vaccination of children in austria will include a new tetravalent vaccine that protects against measles, mumps, rubella and varicella (table 1) . however, these pediatric vzv vaccines are not adequate in boosting t cell responses in older adults. fortunately, a vaccine that prevents herpes zoster virus reactivation is currently in phase iii clinical trials. this live-attenuated vzv vaccine, which is 14-times more potent than the currently available vaccines that prevent chickenpox, has specifically been developed to protect the reactivation of herpes zoster in elderly people [28, 29] . this is of particular importance, because older adults were not vaccinated against vzv and may have been infected by vzv. for instance, 95 % of canadians have had chickenpox by the age of 15. thus, reactivation of herpes zoster and its clinical manifestations will remain a serious health threat to the growing elderly population. but new and more potent candidate vaccines may have a beneficial effect by reducing morbidity and mortality due to boosting t cell responses in older adults. another herpes virus, the cytomegalovirus (cmv), has also been shown to persist throughout life until its reactivation due to immune suppression or deficiency. depending on the geographic area, 60 to 100 % of the adult population is infected by cmv [30] . although immunocompetent persons mostly do not recognize infection as it causes no or few relatively unspecific symptoms, recent research results suggest that cmv favors an accelerated aging of the immune system, because the organism continuously has to warrant immunity to this chronic viral infection [30] [31] [32] . this is due to the fact that the virus has evolved numerous mechanisms to continuously escape the host's immune defense [33] and to persist throughout life within the infected organism. this leads to a re-configuration of t cell immunity due to the accumulation of dysfunctional, virus-specific cells that fail to be eliminated from the system. the accumulation of dysfunctional cd8 + t cells has been associated with a lack of antibody production following influenza vaccination in elderly people [34] . in order to prevent cmv infection, especially to protect hiv-infected patients from cmv co-infection, new candidate vaccines against cmv are now being tested in phase i clinical trials (table 1) . beyond, these candidate vaccines could also prevent cmv-associated aging of the immune system and its consequences when applied in early life. although tetanus and diphtheria vaccines have been used for routine immunization over decades, few studies exist that document their efficacy in elderly people. there is still evidence that the vaccination coverage among elderly persons is low and even around 40 % of appropriately vaccinated elderly persons do not have protective tetanus-specific antibody concentrations [35] [36] [37] [38] [39] . therefore, austrian public health authorities have recommended 5-instead of 10-year booster vaccination intervals for people aged 60+, using a combined vaccine against tetanus, diphtheria and pertussis (fig. 1) . moreover, strategies have to be developed to draw public attention to the problem of vaccination in the elderly and increase vaccination acceptance. whooping cough (pertussis) is a highly contagious respiratory system infection caused mainly by the bacterium bordetella pertussis. pertussis can last for several weeks and affects approximately 700 to 1000 austrian people annually. due to the implication of routine childhood vaccination using acellular pertussis vaccines, the high mortality rate among young children has been reduced. although most infants are being immunized against pertussis, this immunity usually fades during adolescence. concordantly, a significant increase in reported pertussis incidence among adolescents and adults has been observed [40] . still, the reported pertussis cases in adults and elderly people are likely to be underestimated because symptoms of disease may be characterless and make clinical diagnosis difficult. there is also evidence that the attack rate of pertussis is high among nonvaccinated elderly people (53 %) [41] . moreover, 10 % of these elderly people died from intracranial bleeding, while they were symptomatic for pertussis. thus, regular booster immunizations for adults and elderly persons ( fig. 1 ) are indispensable to provide sustained levels of antibodies against pertussis. this is so much the worse as elderly people have a higher risk of severe manifestations of tbe. on that account, it will be necessary to increase vaccination coverage among elderly people as well as to assure that they follow the 3-year booster intervals currently recommended (fig. 1) , as they have a more rapid decline in protective antibody levels, too [36] . regular booster injections in adult life will guarantee the maintenance of a long-lasting humoral immune response [43] and will decrease the risk of immunization failures in elderly people. due to increased mobility, elderly persons are also at an enhanced risk of encountering new antigens (e. g. typhoid and yellow fever virus, hepatitis a, rabies virus). for instance, in 1980 only 5 % of austrians aged over 60 were traveling to a developing country whereas in 1995 this number has reached 15 % and is still increasing. this is a problem, as elderly persons must rely on a limited t cell repertoire that does not necessarily include full responsiveness to new antigens (see chapter 2 for details). hepatitis a vaccination is currently recommended when traveling to tropical and subtropical countries that carry an enhanced risk of infection. for instance, the risk of hepatitis a infection of travelers to developing countries was estimated to be 3 to 20 cases per 1000 persons per month of stay, varying with destination, living conditions and age [44, 45] . remarkably, improved sanitary standards in developed countries have reduced the risk of environmental exposure to hepatitis a virus and have lowered the overall incidence of infection. paradoxically, susceptibility to the virus has nevertheless increased because of the decrease in natural immunity. thus, less than 20 % of persons born after 1945 have a natural immunity against hepatitis a virus [44] . furthermore, increasing age represents an enhanced risk of severe infection and mortality rates are about two percent for persons older 40 years of age [44] . there is also some evidence of lower antibody titers associated with advancing age. for instance, the seroconversion rates 8 months after two doses of havrix ® were found to be 85 % and 60 % for adults ≤ 35 years and >35 years, respectively [46] . after following a recommended immunization schedule with twinrix ® , seroprotection was 92 % and 63 % for adults < 40 years and >60 years, respectively [47] . considering these results, it may be useful to determine hav antibodies in elderly persons, as in the case of vaccination failure boosters have shown themselves to be effective [47] . it is further recommended that the vaccine is given at least 3 to 4 weeks before travel due to a slower onset of the antibody response observed in older people [48] . another important travel vaccine is directed against yellow fever, which is endemic in sub-saharan africa and central south america and is caused by a mosquito-borne flavivirus. neonates and older adults are both at increased risk of severe disease, and mortality rates after infection are highest in these age groups. yet, there is no specific treatment against yellow fever. vaccination is the only way to protect persons traveling to regions where yellow fever is endemic. the only vaccine currently available contains a live-attenuated 17d strain virus (table 2) and has been shown to be safe and highly potent [49] . however, the high sensitivity to temperature makes it necessary that the vaccination is only carried out at specific, who-approved institutions. due to the increased use in international travelers, it has become evident that advanced age may be a risk factor for serious adverse effects [50] . compared with persons aged 25-44 years, individuals aged ≥75 had an 18-fold greater risk of experiencing serious adverse events after vaccination. the rate of systemic illness requiring hospitalization or leading to death after yellow fever vaccination was reported to be 3.5 per 100.000 among people 65 to 75 years of age and 9.1 per 100.000 for people over 75 years. moreover, there are no systematic studies available evaluating the efficacy of the vaccine in elderly persons. to strengthen the vaccine's fundamental role in disease prevention and control, efforts to maximize its safety and to ensure its efficacy in elderly persons should be accelerated. a wide range of age-related changes in immune system development and function have been identified and are referred to as immunosenescence (table 3) . immunosenescence is a complex remodeling of the immune system that may contribute significantly to morbidity and mortality in the elderly. it is the consequence of continuous attrition caused by chronic antigenic stress and it has emerged in combination with the extension of lifespan in the 20 th century. although both cellular and humoral immune responses are modified with advancing age, much of the decrease in immunoresponsiveness seen in elderly people is associated with changes in t cell responses. hence, the first and most striking age-dependent alteration affecting the immune system is thymic involution, which starts soon after puberty and is complete by the age of 50 [51, 52] . the thymus, the central lymphoid organ, is responsible for the maturation and eventual selection of fully functioning t cells, so-called naive t cells, derived from the bone marrow. consequently, thymic involution leads to a dramatic decline in the output of naive t cells and to severely decreased naive t cell counts. there is also evidence that the remaining naive t cells in the periphery may get exhausted as they undergo accelerated homeostatic proliferation in order to -in the end unsuccessfully -fill the immunological space and may thus restrict the naive t cell repertoire and impair the organ-isms' capability to respond to a broad panel of new pathogens [53] [54] [55] . nevertheless, no age-related changes in the total number of t cells are observed [56] . this is due to an increase in the number of antigen-experienced t cells [57] . these antigen-experienced t cells can be divided into memory and effector t cells. the latter cell type includes a substantial proportion of senescent cells that accumulate in elderly people and are responsible for maintaining t cell counts to compensate the loss of naive t cell regeneration. however, senescent effector t cells display phenotypic changes (loss of co-stimulatory molecules such as cd28 and cd40l) as well as functional changes (lack of the production of important cytokines, decreased proliferative response, shortened telomeres, increased resistance to programmed cell-death and restricted t cell diversity) [58, 59] . of particular importance, the cd8 + cd28effector t cell population displays a distinct cytokine profile, as it produces large amounts of the pro-inflammatory cytokine gamma interferon (ifnγ), but does not produce interleukin 2 (il-2) and the anti-inflammatory, b cell stimulating cytokine il-4 [34] . in a recent publication [30] , we demonstrated that aging as well as cmv infection lead to a decrease in the size of the naive and early memory cd8 + t cell pool, but to an increase in the number of dysfunctional, ifnγ-producing cd8 + cd28effector t cells. the accumulation of effector t cells has been shown to be associated with insufficient efficacy of vaccines to induce antibody production in old age [34, 60] and to predict higher mortality [61] . further, the production of pro-inflammatory cytokines by accumulating effector t cells leads to ubiquitous chronic inflammatory responses in old age ("inflamm-aging"; [62] ), which consequently support the development of age-related chronic diseases, such as arteriosclerosis [5] , rheumatoid arthritis [6] and alzheimer's disease [7, 8] . importantly, elderly people who respond well to influenza vaccination also have high numbers of early memory cd8 + t cells [63] . thus, the early memory cd8 + t cell population, which is a crucial source of il-2 and il-4 production and represents a reservoir of great diversity, is an important prerequisite for intact immune responses in elderly persons [64] . as a result, impaired t cell-mediated immunity as well as defects in antigen presentation by apc, substantially contribute to the decline in b cell specific functions [65] . although aged individuals have normal numbers of circulating b cells, have no decrease in serum immunoglobulin (ig) levels and are capable of mounting robust humoral responses, the antibodies produced are generally of lower affinity and are less protective than those produced by young persons [66] . the process of aging leads to both quantitative and qualitative alterations in the peripheral b cell developmental system and includes the shifts in antibody specificities from foreign to autoantigens and in antibody isotypes from igg to igm. furthermore, it is reported that b cells from aged subjects are stimulated 70 % less efficiently by the follicular dendritic cells than the b cells from young subjects [67] , suggesting a correspondingly reduced maintenance of functional memory cells. the result of all these dynamic modifications in the b cell compartment is a reduction of both t cell-independent and t cell-dependent b cell responses [68] . to summarize, the cytokine environment, the t cell repertoire as well as molecules responsible for cell to cell interactions between t and b cells, are major determinants for intact antibody production in old age. thus, decreased numbers of cd28 + and cd40l + t cells and a lack of cytokines such as il-2 and il-4, are both likely to endanger normal t cell / b cell communication, b cell klrg-1, killer cell-lectin-like receptor g1; tnfα, tumor necrosis factor α growth, differentiation, and antibody production in the elderly. there is a tremendous need to increase the protective effect of vaccines in the elderly. research of the last decade has provided new insights into the molecular mechanisms of the aging immune response, which can be now used for the development of potent vaccines. actually, there is already a gradual shift from the original focus on humoral immunity to a focus that includes the cellular and innate immune components. in particular, effective vaccines against chronic diseases, such as hiv, hepatitis c, tuberculosis and cancer require strong t cell responses, to attack virus-infected cells and to protect against disease. currently, several strategies are being pursued to increase immunogenicity, to minimize adverse side effects and to increase vaccine acceptance by introducing needle-free injection devices. proven and promising vaccine technologies are used to design conjugate, subunit, live vector, dna and live-attenuated vaccines [69] . while live-attenuated vaccines stimulate numerous immune components and display enhanced immunogenicity, conjugate and subunit vaccines are often supplemented with adjuvants to ensure their protective effect. generally, adjuvants can be divided into antigen delivery systems (cationic microparticles, proteasomes and viruslike particles) and immune potentiators (e. g. cytokines). these adjuvants may overcome the proposed age-related functional decline of innate immune responses by targeting pattern-recognition receptors, such as the recently identified toll-like receptors or nucleotide-binding oligomerization domain proteins [70] . the enhanced activation of the innate immune system may also improve antigen processing and presentation leading to more potent t and b cell responses. furthermore, vaccines supplemented with the dna of a cytokine (e. g. il-2 or il-15) may boost immune responses by generating more and long-lived memory t cells [71, 72] . additional to improving vaccine efficacy, a modification of vaccination strategies for elderly people has been supported by the results of several vaccination trials. a decreased response and a shortened duration of protective immunity following booster immunizations are characteristic features of old age [37] . therefore, austrian health authorities have recommended shorter vaccination intervals for tetanus, diphtheria, pertussis and tbe (fig. 1) . thus, increased public awareness of regular booster vaccinations in adults should be enforced, as these immunization regimes are essential to maintain the ability to respond to recall antigens in old age. recent results of our laboratory further indicate that long-lasting protection and a good booster effect after a long time can be expected when a live-attenuated vaccine is used for primary immunization (unpublished observation). these findings favor a heterologous prime-boost immunization regime, using potent live-attenuated vaccines at the beginning and continue with inactivated, less immunogenic compounds. consistent with the increased emergence of infectious diseases and the current demographic development in many countries, infectious diseases in geriatric patients are becoming an increasingly important issue. the frequent occurrence and severity of infectious diseases seen in the elderly is mostly related to an age-related decline in the functions of the immune system that also negatively influences the production of protective antibody levels after vaccination. as a result, immunization regimes have been adjusted for elderly individuals and the need to develop more immunogenic vaccines specifically addressing the elderly population has been recognized by manufacturers. alternative routes of administration should further contribute to an increased vaccine acceptance and a consequent rise in the vaccination coverage among elderly people. a successful eradication campaign. global eradication of smallpox survey: new medicines in development for infectious diseases anti-nicotine vaccination: where are we? dendritic cells as therapeutic vaccines against cancer artherosclerosis as an infectious, inflammatory and autoimmune disease immunosenescence, autoimmunity, and rheumatoid arthritis role of the immune system in the pathogenesis, prevention and treatment of alzheimer's disease how chronic inflammation can affect the brain and support the development of alzheimer's disease in old age: the role of microglia and astrocytes social and environmental risk factors in the emergence of infectious diseases ageing and infection pneumonia and influenza deaths during epidemics: implications for prevention efficacy and safety of the oral neuraminidase inhibitor oseltamivir in treating acute influenza: a randomized controlled trial. us oral neuraminidase study group effectiveness of oseltamivir in preventing influenza in household contacts: a randomized controlled trial influenza and pneumococcal vaccination coverage among persons aged > or =65 years and persons aged 18-64 years with diabetes or asthma-united states the efficacy of influenza vaccine in elderly persons. a meta-analysis and review of the literature immunity and immunization in elderly the efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization reduction in mortality associated with influenza vaccine during 1989-90 epidemic evidence of increased clinical protection of an mf59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in italy the 23-valent pneumococcal polysaccharide vaccine. part i. efficacy of ppv in the elderly: a comparison of meta-analyses impact of pneumococcal vaccination on morbidity and mortality of geriatric patients: a case-controlled study tuberculosis in the elderly efficacy of bcg vaccine in the prevention of tuberculosis. meta-analysis of the published literature co-infection with hiv and tb: double trouble stress-induced subclinical reactivation of varicella zoster virus in astronauts vaccination boosts adult immunity to varicella zoster virus a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults long-term cytomegalovirus infection leads to significant changes in the composition of the cd8+ t-cell repertoire, which may be the basis for an imbalance in the cytokine production profile in elderly persons human immunosenescence: is it infectious? dysfunctional cmv-specific cd8(+) t cells accumulate in the elderly cytomegalovirus misleads its host by priming of cd8 t cells specific for an epitope not presented in infected tissues lack of antibody production following immunization in old age: association with cd8(+)cd28(-) t cell clonal expansions and an imbalance in the production of th1 and th2 cytokines vaccination against tetanus in the elderly: do recommended vaccination strategies give sufficient protection vaccine protection in the elderly: are austrian seniors adequately protected by vaccinations? insufficient protection for healthy elderly adults by tetanus and tbe vaccines no immunity for the elderly a population-based serologic survey of immunity to tetanus in the united states the epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of bordetella pertussis infection an epidemic of pertussis among elderly people in a religious institution in the netherlands tbe vaccination and the austrian experience immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation epidemiology and prevention of hepatitis a in travelers hepatitis a and hepatitis b: risks compared with other vaccine preventable diseases and immunization recommendations immunogenicity of an inactivated hepatitis a vaccine in dutch united nations troops immunogenicity of combined hepatitis a and b vaccine in elderly persons the effect of age and weight on the response to formalin inactivated, alum-adjuvanted hepatitis a vaccine in healthy adults murphy k (1981) persistence of neutralizing antibody 30-35 years after immunization with 17d yellow fever vaccine advanced age a risk factor for illness temporally associated with yellow fever vaccination thymic involution in aging thymic involution with ageing: obsolescence or good housekeeping? homeostasis and the age-associated defect of cd4 t cells postthymic in vivo proliferation of naive cd4+ t cells constrains the tcr repertoire in healthy human adults age-related dysregulation in cd8 t cell homeostasis: kinetics of a diversity loss in vivo ldl receptor and hmg-coa reductase regulation in human lymphocytes and its alterations during aging marked increase with age of type 1 cytokines within memory and effector/cytotoxic cd8+ t cells in humans: a contribution to understand the relationship between inflammation and immunosenescence the aging of the immune system cd8 t cells and aging value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals expansions of peripheral blood cd8 t-lymphocyte subpopulations and an association with cytomegalovirus seropositivity in the elderly: the swedish nona immune study inflamm-aging. an evolutionary perspective on immunosenescence il-4-producing cd8+ t cells with a cd62l++(bright) phenotype accumulate in a subgroup of older adults and are associated with the maintenance of intact humoral immunity in old age cd25-expressing cd8+ t cells are potent memory cells in old age ineffective humoral immunity in the elderly ageing, autoimmunity and arthritis: senescence of the b cell compartmentimplications for humoral immunity age-related depression of fdc accessory functions and cd21 ligand-mediated repair of co-stimulation age-related defects in cd4 t cell cognate helper function lead to reductions in humoral responses vaccine development strategies for improving immunization: the role of modern immunology targeting the innate immune response with improved vaccine adjuvants augmentation and suppression of immune responses to an hiv-1 dna vaccine by plasmid cytokine/ig administration coimmunization with an optimized il-15 plasmid results in enhanced function and longevity of cd8 t cells that are partially independent of cd4 t cell help expression of cd57 defines replicative senescence and antigen-induced apoptotic death of cd8+ t cells update the influence of age on t cell generation and tcr diversity resistance to apoptosis in human cd8+ t cells that reach replicative senescence after multiple rounds of antigen-specific proliferation b cells in the aged: cd27, cd5, and cd40 expression age-related loss of naive t cells and dysregulation of t-cell/b-cell interactions in human lymph nodes age-associated changes in the cellular composition of the human adenoid the effect of age on the bcell repertoire effect of age on humoral immunity, selection of the b-cell repertoire and b-cell development the authors thank ddr. wolfgang maurer for comments and critical reading of the manuscript. we would also like to express our thanks to prof. ddr. e. huber † who unfortunately died last may. he and the austrian green cross have generously supported our work for many years and are therefore responsible for some of the results our group referred to in this article. key: cord-018387-ci5wx26t authors: di benedetto, svetlana; müller, ludmila title: aging, immunity, and neuroinflammation: the modulatory potential of nutrition date: 2019-07-31 journal: nutrition and immunity doi: 10.1007/978-3-030-16073-9_14 sha: doc_id: 18387 cord_uid: ci5wx26t aging influences an organism’s entire physiology, affecting functions at the molecular, cellular, and systemic levels and increasing susceptibility to many major chronic diseases. the changes in the immune system that accompany human aging are very complex and are generally referred to as immunosenescence. the factors and mechanisms of immunosenescence are multiple and include, among others, defects in the bone marrow, thymic involution, and intrinsic defects in the formation, maturation, homeostasis, and migration of peripheral lymphocytes. aging affects both the innate and adaptive arms of the immune system. the process of aging is commonly accompanied by low-grade inflammation thought to contribute to neuroinflammation and to many age-related diseases. numerous attempts to define the role of chronic inflammation in aging have implicated chronic oxidative stress, mitochondrial damage, immunosenescence, epigenetic modifications, and other phenomena. several lifestyle strategies, such as intervening to provide an adequate diet and physical and mental activity, have been shown to result in improved immune and neuroprotective functions, a decrease in oxidative stress and inflammation, and a potential increase in individual longevity. the studies published thus far describe a critical role for nutrition in maintaining the immune response of the aged, but they also indicate the need for a more in-depth, holistic approach to determining the optimal nutritional and behavioral strategies that would maintain immune and other physiological systems in elderly people. in this chapter, we focus first on the age-related changes of the immune system. further, we discuss possible deleterious influences of immunosenescence and low-grade inflammation (inflammaging) on neurodegenerative processes in the normally aging brain. finally, we consider our current understanding of the modulatory potential of nutrition that may mediate anti-inflammatory effects and thus positively affect immunity and the aging brain. it is now clear that a variety of genetic and environmental factors impact upon health in old age, including effects on immunity. however, the relative contribution of these factors to immunosenescence will have to be more accurately established. these variables clearly include nutrition (micro and macro), physical activity, mental well-being, as well as gender and ethnicity, genetic background, psychosocial parameters (including stress), socioeconomic status, earlylife events, and different chronic infections [1, 2] . contributing to immune competence, since undernutrition impairs the immune system, suppressing immune functions that are fundamental to host protection. undernutrition leading to an impairment of immune function can be due either to insufficient intake of energy and macronutrients or to specific deficiencies in some particular micronutrients, although often these occur in combination [4] . among other micronutrients, zinc, for instance, has an essential significance to health; its deficiency is responsible for various diseases. zinc is one of the most important trace elements in the organism, with three major biological roles, as a catalyst, structural, and regulatory ion. it plays a critical role in organism homeostasis, in immune function, in oxidative stress, in apoptosis, and in other physiological activities [2, 5] . thus, zinc deficiency may adversely affect the immunological status, increase oxidative stress, lead to the generation of inflammatory cytokines, and influence the progression of many chronic diseases, including atherosclerosis, neurological disorders, autoimmune diseases, age-related degenerative diseases, and various malignancies [5] . zinc deficiency is known to decrease innate immune function. it particularly impairs the lytic activity of natural killer (nk) cells, reduces natural killer t (nkt)-cell cytotoxicity and immune signaling, influences the neuroendocrine-immune pathway, and alters cytokine generation in mast cells [6, 7] . however, excessive amounts of some nutrients may also impair immune function. overnutrition, combined with an inactive lifestyle and sedentary behavior, promotes the accumulation of visceral fat and leads to obesity. accumulating evidence indicates that obesity causes chronic low-grade inflammation and the development of systemic metabolic dysfunction that appears to be aetiologically associated with obesity-linked disorders [2, 8] . adipose tissue acts as a key endocrine organ by releasing bioactive substances, known as adipokines, that may have either pro-or anti-inflammatory activities [9] . the production of pro-inflammatory adipokines, such as tumor necrosis factor (tnf), leptin, retinol-binding protein 4, lipocalin 2, il-6, il-18, and angiopoietin-like protein 2, in expanding fat tissue increases, while the concentrations of anti-inflammatory cytokines are reduced [9] . this process is accompanied by an infiltration of adipose tissue with pro-inflammatory mediators and the induction of a low-grade inflammatory state, which is characterized by elevated levels of circulating inflammation markers, such as il-6, tnf, and c-reactive protein (crp). adipose tissue is infiltrated with macrophages in two separate polarization states: m1, which produces pro-inflammatory cytokines, and m2, which produces anti-inflammatory cytokines. therefore, it has been proposed that in the adipose tissue, a phenotypic switch takes place toward the macrophages of m1-phenotype, promoting the inflammatory state. this low-grade systemic inflammation is known to be associated with the development of atherosclerosis, neurodegeneration, insulin resistance, and the promotion of tumor growth [10] . it was also demonstrated that diet-induced obesity recruits monocytes from the periphery to the brain following herpes simplex virus (hsv)-1 latency in mice [11] , leading to an exaggerated neuroinflammatory response and the promotion of neurodegeneration. while these phenomena are not limited to the elderly, they often tend to be exacerbated in older people who, for one reason or another, exercise less than the young [2] . thus, many chronic and neurodegenerative diseases can be prevented by changing lifestyle and behavioral habits, particularly dietary habits, and exercise. for example, a positive effect of a 3-month regimen of comprehensive lifestyle changes (plant-based diet, moderate exercise, stress management, and improved social support) on increased telomerase activity was demonstrated in men with low-risk prostate cancer. after a 5-year follow-up, relative telomere lengths of lymphocytes were increased in the lifestyle intervention group and decreased in the control group [12] . according to the findings of another study on more than 23,000 adults, a healthy lifestyle alone lowered the risk of developing chronic diseases with known inflammatory etiology by 78% [13] . although such changes are thought to be beneficial, more investigations are needed to confirm whether this is really the case, and the full biological implications remain to be determined in large rcts [2, 14] . thus, recent studies indicate the need for a more in-depth, holistic approach to determine the optimal nutritional and behavioral strategies that would maintain immune and other physiological systems in the elderly people. superimposed on chronological age alone, the remodeling of immunity as a result of interactions with the environment over the life course is instrumental in shaping immune status in later life. in addition to interactions with pathogens, host microbiome and nutrition, exercise and stress, and many other extrinsic factors are crucial modulators of this immunosenescence process [2] . in the next sections, we briefly describe the observed agerelated changes in the immune system and then outline the possible contribution of inflammaging and immunosenescence to neuroinflammation and finally discuss the modulatory potential of nutrition and active lifestyle thereon. human immune aging represents a universal and multifaceted process characterized by progressive immunodeficiency, chronic inflammation, and autoimmunity [15, 16] . the complex regulatory circuits required for maintaining appropriate physiological homeostasis may become compromised with aging [17, 18] . age-related immune dysfunction (in combination with other mechanisms) may at least in part explain the process of aging itself [19] , as originally proposed by walford in 1969 [20] . in the course of aging, our immune system undergoes an imprecisely defined process of immunosenescence that affects both adaptive and innate immune systems. the most marked changes in adaptive immunity are decreased numbers of peripheral naïve t cells and the concomitant accumulation of late-stage differentiated memory t cells [18, [21] [22] [23] [24] [25] [26] [27] [28] with reduced antigen receptor repertoire diversity [26, [29] [30] [31] (figs. 14.1 and 14.2). this phenomenon results from poorly understood age-related impairments in the hematopoietic stem cell (hsc) compartment which generates fewer t-cell precursors in adult and later life, on the one hand, and thymic involution at puberty which markedly reduces the production of mature t cells from their precursors, on the other hand [32] . the hsc compartment (fig. 14.1 ) is negatively modulated and functionally affected by aging [33] and is increasingly substituted by adipose tissue [18, 34, 35] . age-related modification within the hsc compartment may be partly due to the "intrinsic cellular aging" of hscs themselves. aged hscs demonstrate more accumulated dna damage, telomere attrition, and epigenetic deregulation, often in combination with an increase in intracellular reactive oxygen species (ros) [2, 36] . such events may also lead to progressive myeloproliferative disorders and the malignant transformation of hscs. in addition to such "intrinsic" hsc age effects, the extracellular and stromal matrix of the aging bone marrow (which normally nurtures and drives stem cell production) also undergoes dramatic structural changes in terms of the numbers of stromal cells and osteoblasts and reduced production of il-7 ( fig. 14.1 ). the aged pool of hscs is often characterized by a marked shift in lymphoid and myeloid lineage output. such age-associated myeloid skewing of the differentiation potential, together with decreased homing efficiency, contributes to changes in the cellular composition of the hsc compartment and is believed to be an important contributor to the decline of immune competence in the elderly [2, 37, 38] . given the age-associated alterations at the level of immune cell production in the bone marrow and the skewing toward myeloid differentiation in the cells exported to the periphery, it is not surprising that immune functioning also changes with age. not only are fewer b cells produced and fewer t-cell progenitors, but in the case of the latter, their development in the thymus is compromised by the universal process of thymic involution ( fig. 14.1 ). although this may be viewed as a developmental event and not truly a senescence effect, it is thought to have dramatic consequences for immunity over the lifespan [18] . both extrinsic and intrinsic factors are considered ( fig. 14.1 ) to be involved in causing thymic involution, including the thymic microenvironment as well as the impaired development of aged thymocytes themselves [39] . during this ongoing process, beginning even before puberty, as in the bone marrow, a progressive replacement of lymphoid tissue by fatty tissue takes place, accompanied by a reduction of the active areas of thymopoiesis [40] . most elderly people do retain some residual thymic function, which may act to provide a continuous low-level input of new naïve t cells (fig. 14.1 ) to the periphery [41] at least until extreme old age [18] . the end result of thymic involution is that the individual is equipped with a set of naïve t cells early in life, but which are not constantly replaced at the same level throughout life. thus, elderly people have vanishingly small numbers of naïve t cells and accumulations of memory t cells (figs. 14.1 and 14.2), mostly specific for the pathogens that they have previously encountered [18] . aged individuals have decreased protection against newly arising infections as well as difficulties in controlling endogenous persistent viral infections [42] . according to a current paradigm, the age-associated shrinkage of compartment size and diminution in t-and b-cell receptor diversity ( fig. 14 .1) appears to be responsible for the impaired protective ability of the immune system to respond to a universe of antigens [25, 26, 42] . particularly, dramatic changes with age are seen in the repertoire diversity that declines dramatically [29, 31] . lifelong exposure to different pathogens (figs. 14.1 and 14.2) is regarded as a major driving factor of the phenotypic changes in the distribution of t-cell subsets over the life course. for unclear reasons, especially a latent infection with cytomegalovirus (cmv), but not with any other herpes viruses, with recurrent episodes of reactivation has been found to promote memory t-cell "inflation" and drive t cells to a late stage of differentiation. in aged individuals, oligoclonally expanded cd8 + t cells show an increased expression of late-stage differentiation markers. the accumulation of these highly differentiated t cells, at least some of which may be truly senescent, contributes to the age-associated increased production of pro-inflammatory cytokines and low-grade inflammation and could thus possibly also contribute to age-related morbidity and mortality [24, [43] [44] [45] [46] [47] . regulatory t cells (tregs) play a central role in immune regulation ( fig. 14. 1), providing a delicate balance between protective and pathothe aging immune system. the hsc compartment is negatively modulated and functionally affected by aging (a). age-related modification within the hsc compartment may be partly due to "intrinsic cellular aging" of hscs themselves, with accumulated dna damage, telomere attrition, and epigenetic deregulation. the extracellular and stromal matrix also undergoes dramatic structural changes in terms of the numbers of stromal cells and osteoblasts and the reduced production of il-7. the aged pool of hsc shows a marked shift in lymphoid and myeloid lineage output. thymic involution (b) involves both extrinsic and intrinsic factors, including the thymic microenvironment as well as the impaired development of aged thymocytes themselves. a progressive replacement of lymphoid tissue by fatty tissue takes place, accompanied by a reduction of the active areas of thymopoiesis. the end result of thymic involution is vanishingly small numbers of naïve tc and accumulations of memory tc (c), mostly specific for the pathogens that they have previously encountered. age-affected tregs (d) can induce chronic inflammation, an increased risk of autoimmunity, but also be responsible for diminished immunity. elevated inflammatory immune mediators, sars (e), are responsible for the activation of self-reactive memory bc, producing increased levels of auto-ab (f), which are frequent in aged individuals as a result of tissue damage and apoptosis. repetitive antigenic challenges over the lifetime (g) may stimulate pro-inflammatory cytokines, contributing to the maintenance of persistent chronic inflammation. self-reactive b and t cells (h) recognize a self-antigen and differentiate into memory and effector cells due to a breakdown of the control of autoreactivity. chronic inflammation additionally resulting in tissue injury and apoptosis attracts dcs, which in elderly people have impaired the ability to take up apoptotic cells (i). instead, they induce a vicious circle with a further pro-inflammatory response and increased reactivity to self-dna, which may be more immunogenic in the elderly. additionally, damps (i), present in proteins released during cell necrosis, promote sterile inflammation. ecm, extracellular matrix; hsc, hematopoietic stem cell; tec, thymic epithelial cells; adpc, adipocytes; ob, osteoblasts; dc, dendritic cells; fb, fibroblasts; bm, bone marrow; bc, b cells; tc, t cells; auto-tc, autoreactive t cells; tregs, regulatory tc; mdscs, myeloid-derived suppressor cells; apoptb, apoptotic bodies; dna, deoxyribonucleic acid; damps, damage-associated molecular patterns; sasp, senescence-associated secretory phenotype; il, interleukin; auto-ab, autoantibodies. (modified from müller and pawelec [18] ) genic immune responses [18] . early data indicated that younger and older people possessed phenotypically identical tregs but that suppressive function waned in the latter [48] . more recent data confirm that aging significantly affects the generation, homeostasis, diversity, and functional competence of tregs. a decline of thymic function disturbs the thymic treg production and also seems to be compensated for through the peripheral expansion of pre-existing tregs and/or through the conversion of conventional t cells into tregs [49] , as had been demonstrated using t-cell clonal culture models much earlier [50] . thus, due to the leading role of tregs in immune homeostasis, an age-related deterioration of tregs ( fig. 14. 1) might induce either excessive immunity (impacting a chronic inflammation as well as increasing the risk for autoimmunity) or, conversely, an age-related increase of treg activity might result in failing immunity (raising the risk of malignancies and infectious diseases) in the elderly [49, 51, 52] . as we age, the maintenance of homeostatic conditions may become compromised [18] . the consequence of this imbalance may be that immunity is redirected toward the innate immune responses, characterized by increased levels of systemic inflammatory molecules -a phenomenon dubbed as inflammaging [44] . large epidemiologic studies commonly report about elevated levels of inflammatory factors such as crp, il-6, and tnf in the peripheral blood of elderly people [53] . elevated inflammatory immune mediators ( fig. 14.1 ) are thought to be involved in most age-related chronic and neurodegenerative diseases as well as carcinogenesis. over the life course, inflammatory stimuli from pathogen sources are likely to become increasingly entangled with endogenous stimuli. one possible source of this endogenous "noise" is the senescence-associated secretory phenotype (sasp) characterizing the accumulating "senescent" cells in the elderly that can affect the behavior of neighboring cells [54, 55] . the sasp is a spectrum of pro-inflammatory proteins and cytokines secreted by such cells, which have permanently exited the cell cycle and are known to accumulate in the periphery to significant numbers with advancing age [56, 57] . this process is also associated with the activation of self-reactive memory b cells, producing increased levels of autoantibodies ( fig. 14.1) , which are frequent in aged individuals as a result of tissue damage and apoptosis [58] . repetitive antigenic challenges over a lifetime (figs. 14.1 and 14.2) may stimulate pro-inflammatory cytokines, contributing to the maintenance of persistent chronic inflammation [59] . such persistent age-related chronic inflammation represents an extreme stress factor for the immune system, causing eventual exhaustion. autoimmunity is associated with what could be considered premature immune aging, demonstrating the relationship between chronic immune stimulation and progressive immunosenescence [18, 60] . according to the current paradigm, autoimmunity develops when self-reactive b and t cells (fig. 14.1 ) recognize a self-antigen and differentiate into memory and effector cells due to the breakdown of the control of autoreactivity [15] . it can occur by a selection of t cells with an elevated affinity for self-antigens or latent viruses, which are at the same time also pro-inflammatory. the chronic inflammation additionally resulting in tissue injury and apoptosis attracts dendritic cells (dc), which in elderly people have an impaired ability to take up apoptotic cells (fig. 14.1) . instead, they induce a vicious circle with a further pro-inflammatory response and increased reactivity to self-dna, which may be more immunogenic in the elderly due to increased hypomethylation [16] . additionally, damageassociated molecular patterns (damps), present on proteins released during cell necrosis and promoting sterile inflammation, also become more frequent with advancing age [17, 18] . it has been suggested that aging is associated with chronic innate immune activation and significant changes in the functions of monocytes and macrophages, which may have implications for increased low-grade chronic inflammation and for the development of age-related diseases [61] . monocytes are known to be mediators of the inflammatory response and comprise at least three different subsets, namely, classical, intermediate, and nonclassical monocytes. an age-related increase in frequencies of intermediate and nonclassical monocytes has been reported [62, 61] . our results from the berlin aging study ii confirmed these findings, where we also found an age-related increase in frequencies of intermediate and nonclassical monocytes [63] . together with age-related macrophage activation, inflammatory monocytes contribute to the subclinical chronic inflammatory process [44, 64, 65] . the immune and central nervous systems represent two adaptive physiological systems of the body, which extensively communicate with each other throughout the lifespan. given the multifaceted interactions between these systems and their tight interdependency, it is to be expected that peripheral immunosenescence and inflammaging contribute to neuroinflammation. peripheral low-grade inflammation may promote inflammatory processes in the aged brain ( fig. 14. 2) by modulating glial cells toward a more active pro-inflammatory state, leading to the loss of neuroprotective function, to neuronal dysfunction, and to the accumulation of brain tissue damage [65] [66] [67] . systemic inflammation may, therefore, increase the risk of developing cognitive impairment, neurological disorders, and neurodegeneration [68] [69] [70] . in the next section, we will have a closer look at how inflammaging may contribute to the process of neuroinflammation during aging. human aging is characterized by an impairment of cognitive abilities. although no agreement exists on the basic mechanisms involved in this process, neuroinflammation appears to be the main contributor that links together many factors associated with cognitive aging [65, 71] . as we age, we experience greater susceptibility to memory impairments following an immune challenge that is characterized by an increased and prolonged production of pro-inflammatory cytokines in the otherwise healthy aged brain [65, 72] . it is widely established that both aging and stress can affect the neuroendocrine system, activate the hypothalamic-pituitary-adrenal (hpa) axis to release corticotropin-releasing hormone (crh) from the paraventricular nucleus of the hypothalamus, and cause the anterior pituitary gland to secrete adrenocorticotropin (acth) (fig. 14.3) . this, in turn, induces the release of glucocorti-coids from the adrenal gland into the circulation [73] . cortisol affects the immune system in different ways by regulating the expression of cytokines [74] , chemokines, and adhesion molecules and by affecting immune cell migration, maturation, and differentiation [65, 72, 75] . high levels of cortisol can negatively influence hippocampal neurogenesis directly or indirectly through the regulation of the expression of cytokines and their receptors on the brain and immune cells. recent ultrastructural analyses have uncovered a new player in the age-related remodeling of neuronal circuits, especially at the synapse level, that is rare under homeostatic conditions but becomes abundant during aging, neurodegeneration, and chronic stress [76] . these hyperactive "dark microglia" (fig. 14. 3) frequently reach into synaptic clefts with their highly ramified and thin processes, extensively encircle axon terminals and dendritic spines, and engulf them [76, 77] . aging and neurodegeneration are characterized by dysregulated interactions with synapses, resulting in neuronal loss, which, in turn, represents the best pathological correlate of cognitive decline [77] . these conditions can sensitize the aged brain to produce an exaggerated response following exposure to a stressor or to the presence of an immune stimulus in the periphery [78] . altered microglia profiles together with impairments in key regulatory systems can lead to prolonged neuroinflammation and age-related neurobehavioral complications [65, 79] . on the systemic level, peripheral immunosenescence and inflammaging lead to age-related changes in the blood (fig. 14. 3) [65] . chronic exposure to inflammatory mediators may disrupt the endothelial barrier and allow for the transfer of immune cells and numerous pro-inflammatory cytokines into the brain parenchyma that, in turn, can modulate microglial phenotype and reactivity and drive low-grade brain inflammation. brain cells, such as microglia, astrocytes, and neurons, as well as peripheral immune cells, such as t cells, monocytes, and macrophages, participate in inflammation (fig. 14.3) . it would provide an inflammatory milieu that is populated by all these resident and additional infiltrating immune cells that participate in a complex interfig. 14.3 the aging brain and neuroinflammation. aging and stress activate the hpa axis to release crh from the paraventricular nucleus of the hypothalamus and cause the anterior pituitary gland to secrete acth. this, in turn, induces the release of glucocorticoids from the adrenal gland into the circulation. high levels of cortisol can negatively influence hippocampal neurogenesis directly or indirectly through the regulation of an expression of cytokines and their receptors on the brain and immune cells. peripheral immunosenescence and inflammaging lead to age-related changes in the blood. chronic exposure to inflammatory mediators may disrupt the endothelial barrier and allow for the transfer of immune cells and numerous pro-inflammatory cytokines into the brain parenchyma that, in turn, can modulate microglial phenotype and reactivity and drive low-grade brain inflammation. activated microglia and astrocytes change their morphology and function and produce pro-inflammatory cytokines, such as il-1 β, il-6, and tnf. macrophages change their protective m2-phenotype to the pro-inflammatory m1-phenotype, thus contributing to further neuroinflammation. this overproduction of proinflammatory mediators disrupts the delicate balance needed for ltp induction, impairs synaptic plasticity, and reduces the production of bdnf and igf-1, thus having detrimental consequences for neural precursor cells as well as for the normal neuronal functioning. hpa, hypothalamic-pituitary-adrenal axis; crh, corticotropin-releasing hormone; acth, adrenocorticotropin; il, interleukin; ifn, interferon; tnf, tumor necrosis factor; ltp, long-term memory potentiation; bdnf, brainderived neurotrophic factor; igf, insulin-like growth factor. (modified from di benedetto et al. [65] . https:// doi.org/10.1016/j.neubiorev.2017.01.044) play between secreted inflammatory modulators and activated cell surface receptors, such as tolllike receptors (tlrs) [65] . these receptors are primarily expressed on cells that play central roles in inflammatory response, including macrophages and microglia [80] . activated microglia and astrocytes change their morphology and function and produce proinflammatory cytokines such as il-1β, il-6, and tnf [65] . recent work suggests that microglia undergo a process of senescence, similar to the one in peripheral immune cells. senescent and hyperactive microglia have been detected in the aged and diseased brain [81] . the aging brain, in turn, is apparently able to modulate the immune system and to support the recruitment of immune cells from the periphery, thereby contributing further to immunosenescence and neuroinflammation [82] . in addition, macrophages change their protective m2-phenotype to the proinflammatory m1-phenotype, thus contributing to further neuroinflammation [65] . as the aged brain is already "primed" to respond to inflammatory stimuli, additional stress or infection may induce more detrimental changes in the cognitive functioning of aged individuals [78, 83] . furthermore, the age-related concurrent reduction of anti-inflammatory molecules also contributes to a sensitization to extrinsic and intrinsic stressors. t cells produce less il-4 and il-10 and more interferon gamma (ifn-γ), thereby promoting microglial activation. this has detrimental consequences for neural precursor cells, leading to a decrease of neurogenesis (fig. 14. 3) as well as increased decrements in learning and memory [84, 85] . taken together, the overproduction of proinflammatory mediators in the periphery may induce a progressive increase in neuroinflammation, characterized by increased glial activation, elevated steady-state levels of inflammatory cytokines, and a decreased production of antiinflammatory molecules, even in neurologically intact aged individuals [65] . in the next section, we consider the modulatory potential of nutrition in its ability, in combination with physical activity, to mediate anti-inflammatory effects and thus positively influence immunity and the aging brain. evidence that long-term behavioral changes, including nutritional intervention and reduced energy intake together with physical activity, may prevent, improve, or even reverse age-related impairments in immune function continues to accumulate [2] . lifestyle factors, such as diet and exercise, have been established as playing an important role in immunosenescence, and the practice of "healthy" behavior may minimize the age-associated decline of immune function (figs. 14.4 and 14.5). accumulating data strongly suggest that inflammation and oxidative stress are the main inducers of cellular aging (fig. 14.5) . the cross talk between oxidative stress and inflammation is a complex process, and there are studies reporting that ros can stimulate inflammation via the activation of inflammasomes and the production of cytokines such as il-1β and il-18, which subsequently trigger inflammatory responses [86] . at least in the context of adiposity and inflammation mentioned above, as well as via multiple other postulated physiological effects, caloric restriction (cr) in humans might have beneficial effects in terms of lowering metabolism, a reduction of visceral fat, and weight loss [2] . cr has been shown to delay signs of immunosenescence in animals and is considered today as the only known method to prolong median as well as maximal lifespan in several tested species, from invertebrates to rodents and even including nonhuman primates [32, 87] . thus, in rodents and nonhuman primates, cr leads to an attenuation of the age-related shift from naïve to memoryphenotype t cells and maintains a higher number of naïve t cells in aged animals [88] . furthermore, the age-associated rise of pro-inflammatory cytokines, such as il-6, ifn-γ, and tnf, and the resulting pro-inflammatory state of an aged immune system can be reversed by cr. it has been reported that the age-related decrease in the proliferative capacity of t cells (due to the shift from naïve to memory-phenotype t cells) can be reversed by cr [2, 32] . nevertheless, there are still many open questions concerning cr, which has been shown to be effective in improving the immune response in unchallenged animals, although it might compromise the host's defense against pathogenic infection and result in higher morbidity and mortality outside the laboratory. moreover, cr has been shown to delay immunosenescence in animals, but this effect needs to be verified in humans. furthermore, short-term cr may well be feasible, whereas long-term dietary restriction might have detrimental psychological and other effects in humans, especially in the older population, making its practicality questionable [2, 89, 90] . nevertheless, the recent results from a multicentered, randomized clinical trial have demonstrated that long-term moderate cr without malnutrition induces a significant and persistent inhibition of inflammation in young and middle-aged healthy nonobese adults without impairing the cell-mediated immunity [91] . the optimization of nutrition may represent one of the first and theoretically easiest and cheapest strategies that can be employed to preserve health during aging [2] . the development of "elderly specific," functional foods, containing probiotics and/or prebiotics, may help in preventing the age-related disruption of the gut environment [92] . in fact, it has been demonstrated that the maintenance of a "healthy" gut microbiota during aging could help to delay or prevent the inflammaging process [93] . immunostimulatory properties, such as the modulation of cytokine production or adjuvant effects on t-lymphocytes and nk activity, have been demonstrated for various health-promoting lactobacillus and bifidobacterium strains [94] [95] [96] . it has been shown that 3-and 6-week interventions in elderly people can have positive effects, such as measurable increases of nk cells, tumoricidal activity, and monocyte phagocytic capacity [97] . a probiotic yogurt supplementation tested on elderly persons affected intestinal bacterial overgrowth. this intervention was able to normalize the response to endotoxin and modulate inflammatory markers in blood [98] as well as decrease the incidence of infections in this group of elderly people. furthermore, a significant increase of phagocytosis, nk-cell activity, and production of il-10 was also demonstrated following the probiotic supplementation in the elderly as well as the reduced production of the proinflammatory cytokines il-6, il-1β, and tnf [92, 99] . boge et al. showed in two clinical trials that the consumption of a probiotic drink (containing l. casei) by elderly subjects for several weeks before and after an influenza vaccination led to a significant increase in the influenza-specific antibody titer, demonstrating the potential of probiotics in improving the protective efficacy of vaccination in the elderly population, in which it is usually considerably reduced [100, 101] . a seminal advance has been the realization that probiotic supplementation is likely to require "tailor-made" mixtures of different bacteria in order to achieve the desired effect. atarashi et al. identified 17 strains of bacteria preferentially inducing colonic tregs which reduced symptoms in models of colitis and allergic diarrhea in mice [102] . thus, supplementation with tailor-made mixtures of probiotics may be effective in modulating immune responses where the use of single strains is ineffective. this may be one reason why the results of the many human probiotics supplementation trials have often been equivocal since mostly a single strain was used even if it was the "right" strain [2] . the mechanism of action of the mixed bacterial strains is the induction of cd4 + cd25 + foxp3 + tregs by bacterial antigens, which in turn stimulate the intestinal epithelial cells to produce tgf-ß1, but not inflammatory il-6, and tnf. fecal samples from patients with inflammatory bowel disease and atopy have been reported to contain relatively low amounts of some of the same bacterial strains, suggesting their relevance to human disease as well as in the animal model. in the context of supporting the "right" balance of gut bacteria, reversing our nutritional habits "back to mother nature" might represent an additional solution for the modulation of agerelated inflammatory status and associated chronic and neurodegenerative diseases [2] . the accumulating data from in vitro, animal, and clinical studies provide evidence that a greater consumption of fruits, cereals, vegetables, legumes, and spices is associated with a lower risk of many diseases [103] [104] [105] [106] [107] [108] . consumption of diets consisting of natural foods can also raise the amounts of plant-based nutraceuticals in the body, such as antioxidants and anti-inflammatory agents. these nutraceuticals are known to cope with free radicals and to modulate the inflammatory signaling pathways in cells, suppressing the onset of age-related chronic conditions [2, 107, [109] [110] [111] . several studies demonstrate that dietary polyphenols are able to repress inflammation by the inhibition of nuclear factor kappa-light-chain enhancer of activated b-cell (nf-κb) signaling [112] [113] [114] [115] [116] . remarkably, plant extracts from strawberry, mulberry, and blueberry were shown to contain antioxidants that are able to activate the antioxidant defense system and to counter the deleterious effects of irradiation by reducing oxidative stress and inflammation [117] . a significant decrease in the levels of inflammatory cytokines was demonstrated by the administration of the diet supplements containing pomegranates, figs, or dates [118] . nutritional intervention including micronutrients and vitamins has also been recognized as a practical, cost-effective approach to attenuate age-associated declines in immune function, vaccination efficiency, and resistance to infectious and neoplastic diseases. the importance of micronutrients, trace elements, and vitamins in proper immune functioning is clear, and deficiencies in one or more of these nutrients may impair practically all forms of immunity [2] . among them, zinc is an essential element of which the significance to health is indisputable, as discussed above [119] . it has been shown that zinc supplementation enhances the innate immune responses by increasing phagocytosis and t-cell functionality [120] . an increase in serum zinc concentration was associated with an increase in the number of t cells [119] . zinc supplementation was also able to improve the generation of nk cells from cd34 + cell progenitors through the increased expression of the gata-3 transcription factor [7] . vitamin c has also been found to positively modulate immunosenescence and inflammaging, representing two main hallmarks of human aging. moreover, it has been shown to epigenetically regulate genome integrity and stability, indicating a key role of vitamin c in healthy aging [121] . vitamin e supplementation has been demonstrated to improve immune responsiveness in healthy elderly individuals by the enhancement of cell-mediated immunity [122] . it was also able to reverse many of the t-cell age-associated defects, including reduced levels of phosphorylation of critical signaling proteins, as well as to improve defective immune synapse formation. vitamin e also enhances the production of il-2, the expression of several cell cycle control proteins, and t-cell proliferation [123] . intake of vitamin e above recommended levels has been shown to enhance t-cell function in aged animals and humans. this effect is believed to contribute to an improved resistance to influenza infection and to a reduced incidence of upper respiratory infections in elderly people [1, 124] . here, we can provide only a few examples, limited to spices and fruits and their bioactive components, known to modulate different stages of tumorigenesis, including tumor cell survival, proliferation, invasion, and angiogenesis. the anticancer activities of spices are mediated primarily through the suppression of inflammation. bioactive components of spices, such as eugenol and 6-gingerol, prevent the release of tnf and il-1β [125] in vitro stimulated macrophages [126] . curcumin has been shown to suppress the inflammatory mediators nf-κβ and cox-2 [127] , anethole inhibits nf-κβ activation and cytokine production [128] , and cinnamaldehyde blocks the age-related activation of nf-κβ and targets inflammatory cox-2 as well as induces nitric oxide synthase (nos) [129] . ursolic acid, which is present in many fruits, including apples, pears, plums, bearberries, loquat, jamun, and rosemary, has been found to exert antitumor activity against colon cancer [130] , breast cancer [131] , nonsmall cell lung cancer [132] , pancreatic cancer [105] , melanoma [133] , multiple myeloma [134] , cervical cancer [135] , and prostate cancer [108] . also, several other nutraceuticals have been shown to exert antitumor and anti-inflammatory activities. since oxidative stress and inflammation are two of the major triggers of age-related pathologies and neurodegeneration, the consumption of phytochemicals from fruits, vegetables, herbs, and spices may exert relevant immunomodulatory and anti-inflammatory activities also in the context of the aging brain [86] . compelling evidence has shown that dietary phytochemicals, particularly polyphenols, have properties that may suppress neuroinflammation and prevent toxic and degenerative effects in the brain. the mechanisms by which polyphenols exert their action are not fully understood, but it is clear that they have a direct effect through their antioxidant activities. they have also been shown to modulate intracellular signaling cascades, including the pi3k-akt, mapk, nrf2, and mek pathways. polyphenols also interact with a range of neurotransmitters, illustrating that these compounds can promote their health benefits in the brain through a direct, indirect, or complex action [136] . approaches with multiple antioxidant nutrients to block the oxidative stress related to the systemic and brain inflammation pathways may, therefore, prevent or delay the cognitive impairments by preventing microglia aging [137] . as a framework of balanced multicomponent diet strategy, adherence to a mediterranean diet enriched with fruits, vegetables, nuts, and unsaturated fatty acids promotes neuroprotection by decreasing inflammation, restoring cerebral blood flow and volume, inhibiting neurodegeneration, and enhancing neural plasticity by increasing neurogenesis [138] . flavonoids, plant polyphenolic compounds, which are abundant in fruits and vegetables, exhibit a wide variety of biological effects, including antioxidant, free-radical scavenging, and anti-inflammatory properties. luteolin, a flavonoid found in high concentrations in celery and green pepper, has been shown to reduce the production of pro-inflammatory mediators and to inhibit the jnk and ap-1 signaling pathway in mice [139] . it was therefore suggested that luteolin may inhibit neuroinflammation and improve cognition in the otherwise healthy aged by constraining brain microglia [140] . phenolic acids, an important class of polyphenols, are abundantly present in berries, nuts, coffee, tea, and whole grains. they exert their antioxidant and anti-inflammatory activities by the attenuation of microglial activation; the significant inhibition of the production of tnf, il-6, il-1β, and no; and the reduction of mrna and protein levels of cox-2 and inos [141] . also, retinoids and carotenoids are known as potent antioxidants and anti-inflammatory agents having neuroprotective properties [142] . sesamol, a phenolic lignan from sesame supplementation, prevents systemic inflammation-induced memory impairment [143] . recently, much interest has focused on the suggested anti-inflammatory and neuroprotective effects of dietary-derived polyphenols and the long-chain n-3 polyunsaturated fatty acids (pufa), eicosapentaenoic acid (epa), and docosahexaenoic acid (dha), rendering these molecules as potential candidates for use in preventative and therapeutic strategies to reduce the risk of age-related chronic neurodegenerative diseases [144] [145] [146] . both dha and epa can reduce neuroinflammation and cognitive decline. in particular, it has been demonstrated that epa positively influences mood disorders and dha maintains normal brain structure [147] . supplementation with epa may attenuate neuroinflammation by inhibiting microglial activation and microgliaproduced pro-inflammatory cytokines and by enhancing the expression of astrocyte-produced neurotrophins and their receptors [148] . in general, many studies with animal models support the protective effects of n-3 pufa supplementation under different conditions. however, studies to demonstrate clear benefits on human subjects toward a particular disease have not been conclusive, probably due to heterogeneous dietary habits and the population being in different demographic conditions. since many botanical polyphenols can also up-and downregulate the same pathways, future studies may need to include testing for combined effects of dha and these polyphenols [149] . thus, more clinical studies are needed to determine the amounts of dietary agents needed to delay aging and agerelated diseases and to investigate their effects on different age groups [107] . furthermore, when identifying dietary approaches to promote healthy brain aging, a holistic approach should be considered, including nutrition, exercise, and lifestyle factors, which not only target the brain but also overall cardiovascular, immune, and metabolic health [144] . several interventions, including different types of exercises, have been proposed to restore immune and neural functions in elderly people. physical exercise and physical activity in later life might target modifiable risk factors of aging, such as low-grade inflammation, inducing immunoprotective and neuroprotective functions (fig. 14.5) [150, 151] . numerous studies have revealed the anti-inflammatory and antioxidative effects following physical activity (figs. 14.4 and 14.5), which potentially exert beneficial effects on neuroplasticity, affect the expression of neurotrophins, and therefore help to maintain normal neuronal functions [152] . barrientos and colleagues observed an inhibition of neuroinflammation (caused by infection) in rats performing exercises and an increased induction of bdnf mrna in the brain of otherwise sedentary animals [153] . further studies with aged mice revealed that wheel running inhibits the proinflammatory state of microglia and their ability to proliferate, thus inducing a pro-neurogenic phenotype [154] . certainly, the anti-inflammatory effects of exercise are mediated through multidirectional pathways. some of them are exerted on adipose tissue, skeletal muscles, immune system cells, and the cardiovascular system (figs. 14.4 and 14.5). these effects include the modulation of anti-inflammatory and pro-inflammatory cytokine profiles, redox-sensitive transcription factors, and antioxidant and prooxidant enzymes and repair proteins [155] . regular physical activity combined with nutritional interventions can reduce the size of adipocytes and attenuate inflammation in adipose tissue by phenotype switching from pro-inflammatory m1-type to anti-inflammatory m2-type macrophages (fig. 14.4) . in addition, a reduction in the numbers of circulating pro-inflammatory-type monocytes and an increase in the numbers of tregs were found in the peripheral blood of individuals following physical activity [156, 157] . recent evidence suggests that contracting muscles release myokines [2, [158] [159] [160] [161] [162] , which affect the synthesis of bdnf in the dentate gyrus of the hippocampus [162] . physical activity may have a buffering role on the hormonal stress-responsive systems (fig. 14.4) , such as the hpa axis and the sympathetic nervous system [163] , thus maintaining immunoprotective and neuroprotective functions. it has been also shown that regular exercise is associated with an improved immune responsiveness to influenza vaccination in older adults. the exercise-related increase in the antibody titer, t-cell function, macrophage response, improvement of the th1/th2 cytokine balance, the level of pro-inflammatory cytokines, and changes in naive/ memory cell ratio have also been reported [164] . taken together, one might conclude that nutritional intervention in combination with physical activity activates and/or modulates the release of hormones, myokines, and cytokines as well as modulate the expression of various immune-reactive molecules, which all contribute to anti-inflammatory effects and the possible attenuation of immunosenescence and neuroinflammation. around the world, especially in many european countries, the older segment of the adult population is growing in size and proportion [165] . in dealing with this demographic change, what people make of the added years of their lives will be the most important aspect but will only be advantageous to the individual and to society at large if people can remain active participants in daily life and work [65] . maintaining immunological and cognitive functions will be paramount, but their performances are known to decrease with increasing age, even in overtly healthy individuals. preventing and/or attenuating immunosenescence and inflammation and delaying cognitive decline are probably the most effective measures for postponing the point of time at which individuals are no longer able to lead an independent life [65] . effective pharmacological treatments, especially for cognitive but also for the immune decline, remain unavailable. therefore, we will need a more holistic view of the aging process, where the dynamics of the interaction between environment, intestinal microbiota, and host must be taken into consideration. we should also take into account the age-associated physiological changes in the gastrointestinal tract as well as age-related modifications in lifestyle, nutritional behavior, and impaired functionality in the immune system of the elderly population [2, 65] . some modifiable lifestyle factors, such as poor diet and physical and cognitive inactivity, have been identified as being associated with an increased risk of cognitive and immune decline [166] . encouragingly, exercise can have a protective effect, even if initiated in advanced old age [2, 65, 167] . the intake of antioxidant nutrients reduces both systemic inflammation and neuroinflammation during aging [168] . due to the fact that diet component targets are different, combining different nutrients acting on convergent antiinflammatory pathways may result in an increased anti-inflammatory efficacy [144, 169, 170] . in this chapter, we have described the potential basic processes underlying age-related decline, namely, immunosenescence and a progressive increase in neuroinflammation characterized by an increased glial activation, elevated steady-state levels of inflammatory cytokines, and a decreased production of neurotrophic molecules as well as potential positive effects of nutrition and physical exercise. it is our hypothesis, as partly summarized here, that a judicious combination of dietary interventions and exercise, cognitive training, and a pharmacological manipulation of immunosenescence and inflammatory processes will eventually deliver an optimal individualized regime for the maintenance of the best possible immune and cognitive functions over the lifespan of every individual. the role of nutrition in enhancing immunity in aging aging and immunity -impact of behavioral intervention probiotics and prebiotics and health in ageing populations the immune system: a target for functional foods? zinc and human health: an update metallothioneins/ parp-1/il-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. effect of zinc supply zinc improves the development of human cd34+ cell progenitors towards nk cells and increases the expression of gata-3 transcription factor in young and old ages anti-inflammatory nutrition as a pharmacological approach to treat obesity adipokines in inflammation and metabolic disease the anti-inflammatory effects of exercise: mechanisms and implications for the prevention and treatment of disease diet-induced obesity prolongs neuroinflammation and recruits ccr2(+) monocytes to the brain following herpes simplex virus (hsv)-1 latency in mice increased telomerase activity and comprehensive lifestyle changes: a pilot study healthy living is the best revenge: findings from the european prospective investigation into cancer and nutrition-potsdam study effect of comprehensive lifestyle changes on telomerase activity and telomere length in men with biopsy-proven low-risk prostate cancer: 5-year follow-up of a descriptive pilot study the janus head of t cell aging -autoimmunity and immunodeficiency inflammation & autoimmunity in human ageing: dendritic cells take a center stage inflammation, ageing and chronic disease as we age: does slippage of quality control in the immune system lead to collateral damage? on the immunological theory of aging the immunologic theory of aging. copenhagen: munksgaard differences between naive and memory t cell phenotype in malawian and uk adolescents: a role for cytomegalovirus? impact of age, sex and cmv-infection on peripheral t cell phenotypes: results from the berlin base-ii study the role of immunity in elderly cancer immunosenescence in vertebrates and invertebrates diversity and clonal selection in the human t-cell repertoire mechanisms shaping the naive t cell repertoire in the elderly -thymic involution or peripheral homeostatic proliferation? naive and memory cd8 t cell pool homeostasis in advanced aging: impact of age and of antigen-specific responses to cytomegalovirus peripheral blood t-cell signatures from high-resolution immune phenotyping of gammadelta and alphabeta t-cells in younger and older subjects in the berlin aging study ii a population biological approach to understanding the maintenance and loss of the t-cell repertoire during aging the influence of age on t cell generation and tcr diversity t cell ageing: effects of age on development, survival & function gain and loss of t cell subsets in old age-age-related reshaping of the t cell repertoire the ageing haematopoietic stem cell compartment bone marrow and bone: a functional unit immunosenescence of ageing stem cells and aging in the hematopoietic system stem cells and the aging hematopoietic system the aged thymus shows normal recruitment of lymphohematopoietic progenitors but has defects in thymic epithelial cells the effect of age on thymic function lymphostromal interactions in thymic development and function direct evidence for thymic function in adult humans age-related changes in cd8 t cell homeostasis and immunity to infection chronic inflammation (inflammaging) and its potential contribution to ageassociated diseases inflamm-aging. an evolutionary perspective on immunosenescence inflammation and reactivation of latent herpesviruses in older adults role of cmv in immune senescence senescence of the human immune system functional assay for human cd4+cd25+ treg cells reveals an agedependent loss of suppressive activity the impact of aging on regulatory t-cells acquisition of suppressive activity and natural killer-like cytotoxicity by human alloproliferative "helper" t cell clones regulatory t cells and the immune aging process: a mini-review age-related autoimmunity inflammatory markers in population studies of aging four faces of cellular senescence the senescence-associated secretory phenotype: the dark side of tumor suppression t-cell immunity in the aging human cellular senescence and the senescent secretory phenotype: therapeutic opportunities immune receptor signaling, aging and autoimmunity human t cell aging and the impact of persistent viral infections telomere dysfunction, autoimmunity and aging aging is associated with chronic innate immune activation and dysregulation of monocyte phenotype and function monocyte phenotype and polyfunctionality are associated with elevated soluble inflammatory markers, cytomegalovirus infection, and functional and cognitive decline in elderly adults the modulatory effect of age, gender and cytomegalovirus (cmv) persistence on peripheral blood immune cell subsets in participants of the berlin aging study ii inflammaging and antiinflammaging: a systemic perspective on aging and longevity emerged from studies in humans contribution of neuroinflammation and immunity to brain aging and the mitigating effects of physical and cognitive interventions inflammaging as a prodrome to alzheimer's disease agingdependent changes of microglial cells and their relevance for neurodegenerative disorders neuroinflammation and ageing: current theories and an overview of the data brain structures implicated in inflammation-associated depression peripheral immune signatures in alzheimer disease neuroinflammation and cognitive aging neuroinflammation in the normal aging hippocampus aging-related changes in neuroimmune-endocrine function: implications for hippocampal-dependent cognition quality and timing of stressors differentially impact on brain plasticity and neuroendocrine-immune function in mice inflammation as a psychophysiological biomarker in chronic psychosocial stress dark microglia: a new phenotype predominantly associated with pathological states microglia across the lifespan: from origin to function in brain development, plasticity and cognition neuroinflammation associated with aging sensitizes the brain to the effects of infection or stress microglial priming and enhanced reactivity to secondary insult in aging, and traumatic cns injury, and neurodegenerative disease the role of the immune system in neurodegenerative disorders: adaptive or maladaptive? immune aging, dysmetabolism, and inflammation in neurological diseases t cell recruitment in the brain during normal aging inflammation, neurodegenerative diseases, and environmental exposures role of neuroinflammation in neurodegenerative diseases (review) inflammation in schizophrenia: a question of balance dietary phytochemicals in neuroimmunoaging: a new therapeutic possibility for humans? the caloric restriction paradigm: implications for healthy human aging mice and flies and monkeys too: caloric restriction rejuvenates the aging immune system of non-human primates is dietary restriction beneficial for human health, such as for immune function? lifespan-extending caloric restriction or mtor inhibition impair adaptive immunity of old mice by distinct mechanisms long-term moderate calorie restriction inhibits inflammation without impairing cell-mediated immunity: a randomized controlled trial in non-obese humans the inflammatory status of old age can be nurtured from the intestinal environment aging of the human metaorganism: the microbial counterpart through ageing, and beyond: gut microbiota and inflammatory status in seniors and centenarians probiotics and immune response immunologic effects of yogurt effects of a fermented milk drink containing lactobacillus casei strain shirota on the human nk-cell activity the inflammatory status of the elderly: the intestinal contribution modulation of the fecal microflora profile and immune function by a novel trans-galactooligosaccharide mixture (b-gos) in healthy elderly volunteers a probiotic fermented dairy drink improves antibody response to influenza vaccination in the elderly in two randomised controlled trials antibody response to influenza vaccination in the elderly: a quantitative review treg induction by a rationally selected mixture of clostridia strains from the human microbiota raw and cooked vegetables, fruits, selected micronutrients, and breast cancer risk: a case-control study in germany are vitamin and mineral deficiencies a major cancer risk? structure-dependent inhibition of bladder and pancreatic cancer cell growth by 2-substituted glycyrrhetinic and ursolic acid derivatives black soy peptide supplementation improves glucose control in subjects with prediabetes and newly diagnosed type 2 diabetes mellitus age-associated chronic diseases require age-old medicine: role of chronic inflammation ursolic acid overcomes bcl-2-mediated resistance to apoptosis in prostate cancer cells involving activation of jnk-induced bcl-2 phosphorylation and degradation molecular targets of dietary agents for prevention and therapy of cancer anti-inflammatory diets neuroprotective effect of natural products against alzheimer's disease nutritional modulation of age-related changes in the immune system and risk of infection the beneficial role of anti-inflammatory dietary ingredients in attenuating markers of chronic low-grade inflammation in aging inflammasomes, hormesis, and antioxidants in neuroinflammation: role of nrlp3 in alzheimer disease a unique combination of micronutrients rejuvenates cognitive performance in aged mice diet and inflammation: possible effects on immunity, chronic diseases, and life span resveratrol attenuates hypoxia-induced neurotoxicity through inhibiting microglial activation long-term dietary supplementation of pomegranates, figs and dates alleviate neuroinflammation in a transgenic mouse model of alzheimer's disease effect of zinc supplementation on serum zinc concentration and t cell proliferation in nursing home elderly: a randomized, double-blind, placebo-controlled trial zinc influences innate immune responses in children with enterotoxigenic escherichia coli-induced diarrhea vitamin c, aging and alzheimer's disease vitamin e supplementation enhances cell-mediated immunity in healthy elderly subjects vitamin e, signalosomes and gene expression in t cells age-associated changes in immune function: impact of vitamin e intervention and the underlying mechanisms eugenol suppresses cyclooxygenase-2 expression in lipopolysaccharide-stimulated mouse macrophage raw264.7 cells effect of 6-gingerol on pro-inflammatory cytokine production and costimulatory molecule expression in murine peritoneal macrophages curcumin (diferuloylmethane) down-regulates cigarette smoke-induced nf-kappab activation through inhibition of ikappabalpha kinase in human lung epithelial cells: correlation with suppression of cox-2, mmp-9 and cyclin d1 anethole blocks both early and late cellular responses transduced by tumor necrosis factor: effect on nf-kappab, ap-1, jnk, mapkk and apoptosis suppression of age-related inflammatory nf-kappab activation by cinnamaldehyde ursolic acid inhibits proliferation and stimulates apoptosis in ht29 cells following activation of alkaline sphingomyelinase inhibitory effect of ursolic acid on b16 proliferation through cell cycle arrest proliferative inhibition, cell-cycle dysregulation, and induction of apoptosis by ursolic acid in human non-small cell lung cancer a549 cells ursolic acid induces apoptosis through mitochondrial intrinsic pathway and caspase-3 activation in m4beu melanoma cells ursolic acid inhibits stat3 activation pathway leading to suppression of proliferation and chemosensitization of human multiple myeloma cells proteomic analysis of ursolic acid-induced apoptosis in cervical carcinoma cells are polyphenols strong dietary agents against neurotoxicity and neurodegeneration? nutrients, microglia aging, and brain aging a dietary treatment improves cerebral blood flow and brain connectivity in aging apoe4 mice luteolin reduces il-6 production in microglia by inhibiting jnk phosphorylation and activation of ap-1 dietary luteolin reduces proinflammatory microglia in the brain of senescent mice the neuroprotective effects of phenolic acids: molecular mechanism of action molecular antiinflammatory mechanisms of retinoids and carotenoids in alzheimer's disease: a review of current evidence sesamol supplementation prevents systemic inflammation-induced memory impairment and amyloidogenesis via inhibition of nuclear factor kappab nutrition for the ageing brain: towards evidence for an optimal diet neuroinflammatory processes in cognitive disorders: is there a role for flavonoids and n-3 polyunsaturated fatty acids in counteracting their detrimental effects? the role for dietary omega-3 fatty acids supplementation in older adults omega-3 polyunsaturated fatty acids and oxylipins in neuroinflammation and management of alzheimer disease dietary eicosapentaenoic acid normalizes hippocampal omega-3 and 6 polyunsaturated fatty acid profile, attenuates glial activation and regulates bdnf function in a rodent model of neuroinflammation induced by central interleukin-1beta administration docosahexaenoic acid (dha): an essential nutrient and a nutraceutical for brain health and diseases physical activity and cognitive function in individuals over 60 years of age: a systematic review physical exercise and cognitive performance in the elderly: current perspectives exercising the worry away: how inflammation, oxidative and nitrogen stress mediates the beneficial effect of physical activity on anxiety disorder symptoms and behaviours little exercise, big effects: reversing aging and infection-induced memory deficits, and underlying processes wheel running attenuates microglia proliferation and increases expression of a proneurogenic phenotype in the hippocampus of aged mice physical activity and high-sensitivity c-reactive protein the multi-ethnic study of atherosclerosis exercise-induced myokines and their role in chronic diseases exercise training-induced lowering of inflammatory (cd14+cd16+) monocytes: a role in the anti-inflammatory influence of exercise? deletion of the type-1 interferon receptor in appswe/ps1deltae9 mice preserves cognitive function and alters glial phenotype exercise and the immune system: regulation, integration, and adaptation the anti-inflammatory effect of exercise neuroprotective effects of physical activity on the brain: a closer look at trophic factor signaling aging and inflammation: directing traffic through physical activity reversing age-associated immunosenescence via exercise it's never too late human cognitive aging: corriger la fortune? leisure-time physical activity from mid-to late life, body mass index, and risk of dementia neurological effects of honey: current and future prospects the combination of vitamins and omega-3 fatty acids has an enhanced antiinflammatory effect on microglia dietary polyphenols as modulators of brain functions: biological actions and molecular mechanisms underpinning their beneficial effects acknowledgment this research was supported by the max planck society. key: cord-016903-z2vqfq98 authors: herndler-brandstetter, dietmar; grubeck-loebenstein, beatrix title: the efficacy of vaccines to prevent infectious diseases in the elderly date: 2007 journal: immunosenescence doi: 10.1007/978-0-387-76842-7_10 sha: doc_id: 16903 cord_uid: z2vqfq98 infectious diseases still represent a major challenge to human progress and survival. especially elderly persons are more frequently and severely affected by infectious diseases and they display distinct features with respect to clinical presentation and treatment. although vaccinations are considered a vital medical procedure for preventing morbidity and mortality caused by infectious diseases, the protective effect of vaccinations is abrogated in elderly persons. this is due to a decline in the functions of the immune system referred to as immunosenescence. the first part of this chapter will therefore summarize the status quo of the efficacy of vaccines in preventing morbidity and mortality caused by typical infectious diseases in the elderly, such as influenza, pneumonia and tuberculosis. the second part will then elucidate the underlying age-related mechanisms which may contribute to the decreased efficacy of vaccines. based on the complex mechanisms involved in immunosenescence, strategies will be outlined which may be succesfful in enhancing protective immune responses following vaccination in elderly persons. with respect to the current demographic development in many countries, including the european union and the united states of america, infectious diseases in geriatric patients are becoming an increasingly important issue. infections in elderly persons are not only more frequent and more severe, but they also have distinct features regarding clinical presentation, microbial epidemiology and treatment. urinary tract infections, lower respiratory tract infections, skin and soft tissue infections, infective endocarditis, bacterial meningitis, tuberculosis and herpes roster appear to have a higher prevalence in elderly persons. in developed countries like the united states, pneumonia, influenza and septicemia are ranked among the ten major causes ofdeaths in people aged 6s years and older. 1 the reasons for the increased susceptibility to infectious diseases include epidemiological elements, imrnunosenescence, malnutrition and age-dependent anatomical alterations. infectious diseases still represent a major challenge to human progress and survival as they are responsible for about 20% ofall deaths in the world. this is not only related to microbial and viral factors but also to social and environmental determinants, such as social upheaval, urbanization, air travel, natural disasters and climate change.' newly emerging infectious diseases include acquired immune deficiency syndrome (aids), hepatitis c, several hemorrhagic fevers, severe acute respiratory syndrome (sars) and avian influenza. the resurgence ofseveral other infectious diseases is supported by the increased occurrence ofmultiple drug-resistant microorganisms such as staphylococcus aureus, mycobacterium tuberculosis, escherichia coli and streptococcuspneumoniae. *corresponding author: beatrix grubeck-loebenstein-institute for biomedical aging research, austrian academy of sciences, rennweg 10, 6020 innsbruck, austria. email: beatrix.grubeck-loebenstein@oeaw.ac.at immunosenescence, edited by graham pawelec. ©2007 landes bioscience and springer science+business media. altogether, this represents an enormous economic burden on health care systems all over the world. for instance, the annual costs ofmedical care for treating infectious diseases in the united states alone is about $120 billion and for treating antimicrobial-resistant infections it may be as high as $5 billion. ' a great success story was the implementation oflarge-scale vaccination strategies that led to the eradication of smallpox in 1980 4 and to a drastic reduction ofpoliomyelitis, tetanus, diphtheria, measles, pertussis and meningitis. presently, vaccinations are still considered the most cost-effective medical procedure for preventingmorbidity and mortality caused by infectious diseases. 26 different infectious diseases can be prevented by vaccinations and 61 vaccines are being developed according to a 2004 survey by the pharmaceutical research and manufacturers ofamerica," the new candidate vaccines are intended to provide protection against diseases caused by rotavirus, herpes zoster and papilloma virus and will be available from 2007 onwards ( table 1) . but also improved vaccines against influenza, pneumonia and tuberculosis are currently being tested in clinical trials ( table 1 ). this chapter now outlines the relevance ofvaccines to fight infectious diseases in old age and how age-related changes within the immune system contribute to the decreased efficacy of vaccines. it also discusses the progress made in the development of vaccines with improved immunogenicity in elderly persons. outbreaks of deadly infectious diseases such as ebola, marburg, sars or the h5nl avian influenza regularly alert the world, whereas there is not much public attention paid to infectious diseases that cause substantial morbidity and mortality among the elderly population. for instance, influenza, invasive streptococcus pneumoniae infection, urinary tract and skin infections have a higher prevalence in elderly persons," old individuals may also fail to respond sufficiently to therapy and frequently suffer from opportunistic infections, recurrent infections with the same pathogen or reactivation oflatent diseases, such as those caused by mycobacterium tuberculosis or the varicella zoster virus. there are no vaccines available for many infectious pathogens that are frequent in elderly subjects and existing vaccines are underused and often do not assure such an effective protection as in young subjects. the following paragraphs will highlight the most important infectious diseases which threaten the elderly population and will provide information on epidemiology, vaccine availability and efficacy,vaccination coverage and general health authority recommendations. influenza is a highly contagious, acute viral respiratory disease that causes significant morbidity and mortality. the annual outbreaks affect approximately 5-20% ofthe population worldwide with 3-5 million cases ofsevere illness and up to one million deaths each year. especially elderly people and persons that are chronically ill or otherwise immunocompromised are at enhanced risk. for example, during influenza epidemics, barker and mullooly reported two deaths per 100,000 healthy people below 65 years ofage compared with 797 per 100,000 in those over 65 with two or more high-risk conditions? in contrast to measles, smallpox and poliomyelitis, influenza is caused by viruses that undergo continuous antigenic variation and possess an animal reservoir. therefore, we are recognizingannual epidemics that have been interruptedby three pandemics (spanish influenza, hinl, 1918-1919; asian influenza, h2n2, 1957-1958 andhongkonginfluenza,h3n2, 1968), caused by new influenza virus strains with increased virulence. influenza viruses are enveloped viruses containing eight single-stranded rna segments which encode for viral proteins, such as hemagglutinin (ha), neuraminidase (na), matrix protein (ml) and nucleoprotein (np) (fig. 1) . influenza viruses belong to the family orthomyxoviridae and are divided into three genera, influenza virus a, b and c, based on antigenic differences in two oftheir structural proteins, m and np. disease symptoms caused by influenza c are rare whereas influenza b often causes sporadic outbreaks, especially in residential communities like nursing homes. influenza a viruses are further divided into subtypes according to the antigenicity oftheir major envelope glycoproteins, ha and na. with at least is different hemagglutinin and 9 different neuraminidase subtypes, there is con siderable antigenic variation among influenza viruses. the human influenza viruses are currently limited to three hemagglutinin (h i, h2 and h3) and two neuraminidase subtypes (n 1 and n2), whereas birds are the predominant hosts for the other subtype strains. ha initiates viral infection by binding to sialic acid residues on the carbohydrates ofglycoproteins present on epithelial cells ofthe respiratory trace. therefore, high-affinity iga and igg antibodies against ha may preven t infection from influenza virus. in contrast, na cleavesthe sialic acid from viral and cellular proteins to promote the release of newly synthesized influenza viruses from the infected host's plasma membrane. although antiviral drugs with moderate efficacy are available, active immunization represents the most vital element in th e prophylaxis ofinfluenza disease. however, the frequently occurring antigenic driftrequires an annual modification ofthe vaccinecomponents according to the recommendations ofthe who. therefore, vaccination has to be repeated annually to ensure protection against the circulating influenza strains. but vaccination coveragediffers largelywithin european countries. in 2002, the rate ofvaccinedistribution washighest in spain, belgium,the netherlands, united kingdom and germany (between 18.1 and 20.3%) and lowest in poland, czech republic, lithuania and latvia (between 1.9 and 7.1%). canada and the united states had the highest rate ofvaccine distribution, being 32.8 and 28.9%, respectively. remarkably,70% ofus citizens aged 65 and abovehave been vaccinated against influenza."although there are severalvaccinesavailable, the efficacyofmanyvaccinesin preventing influenza diseasein elderlypersons isonly around 56%.9 especiallyveryold and frail persons show a decreased response to influenza vaccines.p'ihe reduced vaccine efficacyis due to low levelsofiga and iggantibodies, delayed peak antibody titers and shortened maintenance of titers after vaccination. nevertheless, immunization in elderly people has been shown to be safe,cost-effective and associated with reduced rates ofhospitalization and influenza-relateddeaths.i1,12in particular, the efficacyofinfluenzavaccination to reduce mortality in elderlypeople is greater after repeated annual vaccination than after first administration. 13presently, influenza vaccines can be classifiedin split-virus, subunit, virosomal and live-attenuated vaccines ( table 2 ). split-virus vaccines are used since the 1980s, are cheap and offer a good protection for children above 6 months of age and adults. recently, subunit vaccines with new adjuvants have been developed (fluado, addigrip') that show an increased immunogcnicity, a favorable safety profile and may be more suitable for the vaccination of elderly persons.'! additionally, invariant antigens, such as m 1 and np, may also play an important role in protection and could be used in vaccines to induce long-lasting immunity to a variety of different influenza strains. another strategy to enhance immunogenicity may the use ofvirosomes that are nontoxic , biodegradable lipid-basedantigen-presentation systems." virosomal influenzavaccines, such asinflexalv', infiuvac plus'and invivac'have been on the market in several european countries for a number of years. they display a high immunogenicity and a similar safety profile in elderly persons compared with inactivated influenza vaccines.f" furthermore, new live-attenuated and subunit influenza vaccines ate currently in clinical trials that promise to have an increased efficacy ofprotection (table 1) . especially live-attenuated influenza vaccines ate believed to elicit strong tcel! responses and should be able to enhance antibody levels after vaccination. importantly, before administration of live-attenuated vaccines to elderly or immunocompromised persons, an acceptable safety profile has to be demonstrated. irrespective ofthe improvement ofinfluenza vaccines for elderly persons, vaccination of children is clinically effective'" and high vaccination coverage among pupils has demonstrated to induce herd immunity and to reduce mortality in older adults. streptococcus pneumoniae is an important cause of invasive clinical manifestations such as bacterial pneumonia, meningitis and septicemia, particularly in young children and the elderly. 80 to 90% ofdeaths associated with streptococcus pneumoniaeinfection occur in people aged 60 years and above. several further groups at higher risk ofinvasive pneumococcal disease have been defined, including individuals with splenic dysfunction, immunosuppression, chronic pulmonary or cardiac disease, diabetes mellitus and chronic liver disease. generally, antibiotic therapy has to be initiated as soon as possible to reduce the risk ofcomplications due to pneumonia, meningitis or sepsis. nonetheless, 50% ofall deaths occur within the first 48 hours despite adequate antibiotic therapy. this may be due to the increased occurrence of multiple drug-resistant pneumococcal strains. in 2002, the proportion ofpenicillin-resistant streptococcus pneumoniaewas reported to be 53% in france and more than 25% in israel, poland, romania and spain." after recovering from pneumococcal infection, people are not necessarily immune, because there are about 90 different serotypes and immunity will be guaranteed only to the strain that has caused the infection. currently, pneumococcal vaccines are available that include up to 23 strains which are responsible to cause disease in almost 90% ofall cases ( table 2 ). these vaccines offer protection against invasive pneumococcal disease in 65% of the general elderly population 22.23whereas in elderly persons with high risk factors, the protective effect of vaccination seems to be only moderate. although many european countries recommend the administration of pneumococcal vaccines to all those >65 years ofage, vaccination coverage among the elderly population is very low. this may be due to the high costs ofthe vaccine and its unsatisfying efficacy in elderly people. but more immunogenic vaccines are currently in different phases ofclinical trials (table 1 ) and promise to be more efficient in old age. additionally, implementing pneumococcal vaccination for children may decrease the incidence ofpneumococcal disease in the elderly by reducing transmission and possibly accomplishing herd immunity.-" each year, about 8 million people are infected worldwide with the tubercle bacillus mycobacterium tuberculosis and 1.6 million ofthem die. the eu25 has a tuberculosis (tb) burden ofmore than50,000 new casesper year,with the highest incidences in latvia, lithuania and estonia (50-100 cases/ 100,000). the risk ofdeveloping a disease following tb infection is about 5-10% during lifetime and individuals above 65 years ofage have a four-fold increased risk ofdeveloping tb than the average population," tb is also frequently diagnosed with delay due to an atypical manifestation in old age. this may lead to an increased morbidity and mortality and to a spreading ofthe disease, in particular within institutionalized elderly persons.p further difficulties include the increased emergence of new, multiple drug-resistant strains with higher rransmissibiliry," the poor efficacy of the current bacille calmette guerin (bcg) vaccine in protecting adults and elderly people from pulmonary infection" and the increased risk oftb co-infection in hiv positive patients." however, in the past few years, several tb vaccine candidates have entered phase i clinical trials, including adjuvanted subunit vaccines as well as improved live recombinant strains of the current bcg vaccine (table 1 ). all these vaccine candidates are supposed to induce an effective and sustainable cellular immune response which is thought to be crucial to protect the host from an intracellular pathogen such as mycobacterium tuberculosis. 30 primary infection with the varicella zoster virus (vzv) causes chickenpox which is usually a mild disease in childhood. the virus then persists in a latent form in sensory ganglia until its reactivation which results in the clinical manifestation of herpes zoster (shingles). between 13 and 26% ofpersons with herpes zoster develop complications, such as postherpetic neuralgia." postherpetic neuralgia also increases with age with a prevalence of 50% in people aged 70 years and above. the incidence and severity ofherpes zoster increase with age, because vzv reactivation is associated with a progressive decline in cell-mediated immunity to vzvy.·33 routine vaccination ofchildren using a tetravalent vaccine that protects against measles, mumps, rubella and varicella will soon be available (table 1 ) and may reduce the incidence of chickenpox as well as the reactivation ofvzv in later life. since 1995, a live-attenuated oka strain vzv vaccine is on the market that has shown clinical efficacy in preventing children from chickenpox." however, the currently available vzv vaccines have not been proven to adequately boost t-cell responses in older adults and to prevent reactivation ofherpes zoster. recently, a vaccine that may prevent herpes zoster virus reactivation has been submitted for registration. this live-attenuated vzv vaccine has been developed to prevent reactivation of herpes zoster in the elderly.3s.36this is of particular importance, because the elderly population has not been vaccinated against but may have been frequently infected by vzv. for instance, more than 90% ofadults in the united states have had chickenpox. as a consequence, it is estimated that up to 800,000 people in the united states suffer from shingles each year and the incidence is expected to increase as the population ages. thus, reactivation ofherpes zoster and its clinical manifestations represents a serious health burden to the growing elderly population and could be counteracted by potent vaccines. the cytomegalovirus (cmv), a b-herpesvirus, has also been shown to persist throughout life until its reactivation as a result ofimmune suppression or deficiency. cmv infection is quite common and affects 60-100% ofthe adult population, dependingon the area. the cmvis transmitted via person-to-person contacts but immunocompetent subjects mostly do not recognize infection as it causes no or few unspecific symptoms. however, a cmv infection represents a severe health problem in immunocompromised persons (e.g.,due to immunosuppressive disease, chemotherapy or transplantation) or in a fetus as a result of congenital infection. research results over the past decade suggest that cmv favors an accelerated aging of the immune system as cmv infection is chronic and the organism is forced to continuously prevent virus reactivation.f'" despite the high frequency of cmv-specific cd8+ tscells, the virus usually can not be eliminated by the immune system. this is because the virus has evolved several mechanisms to escape the host's immune defense." for instance, cmv encodes for a type ofproteins called immunoevasins that modulate the presentation ofviral peptides or directly suppress cellular immune responses. hence, the accumulation of cmv-specific t-cells substantially constricts the diversity of the t-cell repertoire" and leads to the production ofproinflammatory cytokines, such as gamma interferon and tumor necrosis factor alpha.'? this imbalance in the cytokine production profile may not only promote the pathogenesis of age-related diseasesf but leads to a decreased production of antibodies following influenza vaccination in elderly persons.fa few antiviral substances including ganciclovir, valganciclovir, foscarnet and cidofovir are available to prevent cmv infection in immunocompromised patients. but antiviral therapy is limited by its severe adverse reactions, such as neutropenia, nephrotoxicity, hypocalcemia and seizures. another strategy is the adoptive transfer ofdonor-derived cmv-specific cd4+ and cd8+ t-cells that may restore the host's immunity against cmv. 44 despite the need ofa safe and potent vaccine that prevents cmv disease, no vaccine candidate has yet entered the market. a few vaccines against cmv are currently in phase iiii clinical trials (table 1) . active immunization against cmv could reduce the incidence ofneonatal infections as well as complications in immunocompromised persons and may prevent cmv-associated premature aging ofthe immune system when applied early in life. pertussis (whooping cough) is a highly contagious respiratory system infection caused by the bacterium bordetella pertussis and rarely by b.parapertussis, b. bronchiseptica or other pathogens. each year, more than 20 million cases ofpertussis are reported worldwide, 90% ofwhich occur in developing countries, with an estimated 200,000 to 300,000 fatalities. the implementation of routine childhood vaccination against pertussis has reduced the high mortality rate among children. although most infants are being immunized against pertussis in industrialized countries, immunity usually fades during adolescence. consequently, a significant rise in pertussis incidence has been noticed in adolescents and adults." however, the reported pertussis cases in adults and elderly people are likely to be underestimated because symptoms ofdisease may be characterless and make clinical diagnosis difficult. among nonvaccinated elderly people the attack rate ofpertussis is high (53%) and up to 10% ofelderly persons may die from intracranial bleeding while they are symptomatic for pertussis." regular booster immunizations should thus be considered for adults and elderly persons, which is indispensable to remain protected from disease. tetanus is acquired via environmental exposure to the spores of clostridium tetani,which are present in soil worldwide. the disease is caused by a potent neurotoxin produced by the bacterium in dead tissue, e.g.,dirty wounds. diphtheria is a bacterial disease caused by corynebacterium diphtheriac and is transmitted from person to person through close physical contact. the public health burden ofboth diseaseshas been low in developed countries due to routine immunization. however, outbreaks ofdiphtheria have been reported in the independent states ofthe former soviet union, algeria, china, iraq, sudan, thailand and other countries. thus, maintaining high vaccination coverage is important to prevent the outbreak of new diphtheria epidemics. although vaccines that prevent from tetanus and diphtheria have been used for routine immunization for a long time all over the world, few studies exist that document their efficacyin elderly people. the vaccination coverage among elderly subjects is decreasing in several european countries and up to 40% of appropriately vaccinated elderly persons do not have protective tetanus-specific antibody concentrations. 47-49therefore, public health authorities ofsome european countries have recommended five instead often year booster vaccination intervals for people over 60 years ofage. additionally, strategies should be developed to draw public attention to the problem ofimmunizations in the elderly, to inform general practitioners and to increase vaccination acceptance. the increasing mobility ofelderly persons recognized worldwide is accompanied by an enhanced risk to encounter new antigens. this may be ofconcern because elderly persons possess a limited t-cell repertoire that may not guarantee full responsiveness to a wide variety ofnew antigens (see below for details). nevertheless, in vitro experiments have demonstrated that naive t-cells from elderly persons can still be stimulated by neoantigens, at least to the recombinant etr protein of tbe virus and rabies virus." based on an assessment of the risks for travel-related diseases, including the destination, the type of journey and the duration, vaccination is recommended to protect from typhoid and yellow fever, hepatitis a and b, japanese encephalitis, tick-borne encephalitis (tbe) or rabies. but elderly persons should also check whether they have followed the recommended booster intervals of routine immunizations, e.g., against tetanus, diphtheria, poliomyelitis, measles or influenza. tbe is caused by a virus that is primarily transmitted to humans by infected ticks. there are three genetically closely related subtypes of the tbe virus known (european, siberian and far eastern subtype). tbe is among the most dangerous neuro-infectious diseases in europe and asia and is responsible for up to 12,000 casesoftbe annually, most ofthem occurring in russia, czech republic and the baltic states." up to 30% ofadults with clinically confirmed tbe infection develop meningitis or meningoencephalitis and the lethality oftbe in europe is up to 1%.yet,there is no specific therapy available and, therefore, active immunization with inactivated whole virus provides the only efficient protection from tbe disease ( table 2 ).52 importantly, more and more tbe cases are reported in people over 50 years ofage and vaccination coverage in this population is lower than average. therefore, future strategies should increase the vaccination coverage among elderly persons and assure that they stick to regular booster intervals. anyhow, regular boosters should be given throughout life as this may favor the maintenance oflong-lastinghumoral immunity against tbe53and may decrease the risk ofimmunization failures in the elderly. hepatitis a is an acute disease ofthe liver caused by the hepatitis a virus (hay), a nonenveloped virus belonging to the picornaviridae family. each year, an estimated 1.5 million cases ofhepatitis a occur worldwide. hay infection induces life-long immunity and is usually asymptomatic in young children, whereas adults frequently experience symptomatic disease. hay is acquired directly from infected persons by close contact or by the consumption ofcontaminated drinking water, vegetables, fruits or shells. hay vaccination is recommended when traveling to tropic and subtropic countries that have an increased risk of infection. for instance, the risk ofhepatitis a infection ofpersons traveling to developing countries was estimated to be 3 to 20 cases per 1000 persons per month ofstay,varying with destination, living conditions and age." improved sanitary standards in developed countries have reduced the opportunity for environmental exposure to hay and have lowered the overall incidence ofinfection. paradoxically, susceptibility to the virus increased because of the decrease in natural immunity. consequently, less than 20% ofpersons born after 1945 have a natural immunity against hay'54 in contrast to hepatitis b and c that may lead to the manifestation of a chronic infection, clinical illness after hepatitis a infection is usually mild in young individuals. but increasing age represents an enhanced risk ofsevere infection and mortality rates are about 2% for persons over 40 and 4% for those over 60 years ofage." several vaccines against hepatitis a are available (table 2 ) and a study of773 adults showed that immunogenicity and safety profiles between 'iwinrix' and havrix' are comparable.56 but there is some evidence oflower antibody titers with advanced age. for instance, the seroconversion rates 8 months after two doses ofhavrix' were found to be 85% and 60% for adults < 35 years and >35 years, respectively.57after the recommended immunization schedule with twinrix'.seroprotection was 92% and 63% for adults <40 years and >60 years, respectively.58 therefore, it may be useful to measure hay antibodies in elderly persons, as in the case ofvaccination failure, boosters have shown to be effective." it is further recommended that the vaccine is given at least 3 to 4 weeks before travel due to a slower onset ofthe antibody response in elderly individuals. 59 another travel vaccine is directed against yellow fever (yf), which is endemic in tropic regions ofafrica and south america. yf is transmitted by the bite ofinfective aedes aegypti and other mosquitoes that bite during daylight hours in regions below 2500 meters ofaltitude. most infections lead to an acute illness characterized by fever, muscular pain, headache, anorexia, nausea and/or vomiting, often with bradycardia. after a few days, about 15% ofpatients progress to a second phase, with resurgence offever,development ofjaundice, abdominal pain and haemorrhagic manifestations. halfofthese persons die 10-14days after the onset ofillness. the who estimates that a total of200,000 cases ofyf occur each year, with about 30,000 deaths. 6oyf also represents a significant risk to more than 3 million travelers that visit yf-endemic areas each year. neonates and elderly individuals demonstrate the highest mortality when infected by the yf virus. as there is no specific antiviral treatment against yf available yet, vaccination is the only way to protect persons from yf disease. the currently available vaccine contains a live-attenuated 17d strain virus ( table 2 ) and has been shown to be safe and highly potent." however, due to the increased use in international travelers, it has become evident that advanced age might be a risk factor for serious adverse effects and even deam. 62 compared with persons aged 25-44 years, individuals aged <75 had an 18-fold greater risk to experience serious adverse events after vaccination. the rate for systemic illness requiring hospitalization or leading to death after yf vaccination was reported to be 3.5 per 100,000 among people 65 to 75 years of age and 9.1 per 100,000 for people more than 75 years. furthermore, there are no studies available that demonstrated the efficacy of the yf vaccine in elderly persons. accordingly, recommendations and manufacturing standards have been modified to increase vaccine safety in elderly persons. although the benefit-risk ratio still favors the vaccination ofpeople at high risk for infection and outlines the vaccine's fundamental role in disease prevention and control, efforts to improve safety and to ensure vaccine efficacy in elderly persons are ofurgent need. the term immunosenescence refers to a complex remodeling ofthe immune system in old age and may contribute significantly to morbidity and mortality in the elderly. thymic involution, telomere shortening, t-cell signal transduction changes, alterations in the interaction of the innate and adaptive immune response, impaired dna repair and antioxidant mechanisms as well as persistent antigenic stress may all be factors contributing to immunosenescence. although perturbations ofinnate immune system components have been described, much ofthe decrease in immunoresponsiveness seen in elderly people is associated with changes in t-cell responses. this is due to the continuous loss offunctional thymic tissue with increasing age. 63.64the thymus, the central lymphoid organ, is responsible for the maturation and selection ofso-called naive t-cells that regenerate the peripheral tcell pool and retain the capability ofthe immune system to respond to a variety ofdifferent pathogens. in old age, the number ofnaive t-celis decreases while the number ofantigen-experienced 'tcells increases. 65 .66 these antigen-experienced t-celis include a substantial proportion of senescent memory-effector t-cells that accumulate in elderly persons. senescent memory-effector tcelis display phenotypic (loss ofcostimulatory molecules such as cd28 and cd40l) as well as functional changes (altered cytokine production profile, decreased proliferative response, shortened telomeres, increased resistance to programmed cell-death and restricted t-cell diversity).67.68ofparticular importance, the senescent cd8+cd28-memory-effector t-cell population predominantly produces the pro-inflammatory cytokine gamma interferon (ifny), but does not produce interleukin 2 (il-2) and the anti-inflammatory, b-cell stimulating cytokine il-4. 43 recent data also support the hypothesis that chronic infection with the cytomegalovirus, ã -herpesvirus, may lead to a decrease in the size ofthe naive and early memory cd8+ t-cell pool, but to an increase in the number of dysfunctional, ifny-producing cd8+cd28-memory-effector tvcells (fig. 2) , 37 one clinical consequence of the accumulation of cd8+cd28-t-cells is an impaired generation of protective antibody levels after vaccination. 43.69 furthermore, the age-dependent increase in the level ofpro-inflammatory cyrokines may lead to ubiquitous chronic inflammatory responses in old age 42 and may therefore support the development of age-related chronic diseases, such as atherosclerosis," rheumatoid arthritis" and alzheimer's disease. 72, 73 although individuals maintain a relatively constant total number ofperipheral b-celis during aging, each b-cell subset comprises severeperturbations in size,dynamics and repertoire. the alterations affecting the bvcell subsets are due to a decreased generation ofb-cell precursors, such asearly lymphoid precursors and pro-bvcells, cell-intrinsic as well as micro-environmental disturbances are both likely to contribute to the decreased output ofpro-bscells. furthermore, alterations in environmental factors also impair overall v(d)j recombinase activity among pro-bvcellst'whlch accounts for the limited b-cell repertoire frequendy detected in elderly persons." although no decrease in overall serum immunoglobulin levels have been observed during aging, the antibodies generated in old age are oflower affinity due to a shift in antibody isotypes from igg to igm,76 of particular importance, b-celis from elderly individuals are stimulated 70% less efficiendy by follicular dendritic cells than bvcells from young subjects," suggesting loss ofb-cell function, in part due to the decreased expression ofcostimulatory molecules, such as cd40 or cd27,78 impaired t-cell-mediated immunity as well as defects in antigen presentation by antigen presenting cells there is a tremendous need to increasethe protective effect ofvaccines in the elderly. research of the last decade has provided new insights into the molecular mechanisms ofthe immune response in old age, which can now be used for th e development of potent vaccines. in the past, vaccines were primarily designed to elicit a strong humoral immune response . however, vaccines in elderly persons may be more effective ifthe stimulate innate immune components and the generation of long-lived memory t-cells. currently,severalstrategies are being pursued to increase immunogeniclry, to minimize adverse side effects and to increase vaccine acceptance by introducing needle-free injection devices. proven and promisingvaccine technologies are used to design conjugate, subunit, live vector, dna and live-attenuated vaccines (table 3) .80 while live-attenuated vaccines (e.g.• against varicella, measles or yellow fever) stimulate numerous immune components and display enhanced immunogenicity, conjugate and subunit vaccines (e.g., against influenza) are often supplemented with adjuvants" to ensure their protective effect. generally, adjuvants can be divided into antigen delivery systems (cationic microparticles, proteasomes and virus-like particles) and immune potentiators (e.g.• cytokines). these adjuvants may overcome the proposed age-related functional decline ofinnate immune responses by targeting pattern-recognition receptors, such as the recently identified toll-like receptors or nucleotide-bindingoligomerization domain proteins." the enhanced activation ofthe innate immune system may also improve antigen processing and presentation leading to more potent t and b-cell responses and to sustained immunological memory. vaccines supplemented with the dna of cytokines (e.g., il-2 , il-? il-i2, il-is or il-21 ), chemokines or costirnulatory molecules may magnify immune responses by generating more and long-lived memory t_ceiis83-85and may overcome immunodominance.'" in addition to improve vaccine efficacy, a modification of vaccination strategies for elderly persons has been supported by the results of several vaccination trials. for instance, a decreased response and a shortened duration ofprotective immunity following booster immunization is a characteristic feature of old age. 87thus , several european health authorities have recommended five-year vaccination intervals for tetanus, diphtheria, pertussis and pneumonia. increased public awareness of regular booster vaccinations in adults should be enforced, as these immunization regimes may be essential to maintain the ability to respond to recall antigens in old age. recent result s also indicate that long-lasting protection but also a good booster effect can be expected even a long time after the last vaccination, when a live-attenuated vaccine (e.g., polio vaccine) is used for primary immunization in early life. new delivery systems that make use oftiny micro-needles or non-injectable application devices (nasal , oral, transcutaneous) may further increase vaccination acceptance, especially in the case of influenza as this vaccination has to be repeated annually. infectious diseases in elderly persons are becoming an increasingly importan t issue. an utmost need represents the development ofmore immunogenic vaccines for the elderly. the improvement of specific vaccine types regarding immunogenicity and tolerability, th e addition of adjuvants. the design ofnew delivery systems as well as specific immunization regimes should all contribute to an enhanced efficacy ofvaccines in elderl y persons. further improvements may comprise the adjustment ofvaccination intervals in old age, the increase in vaccine acceptance and vaccination coverage as well as raising people's awareness to stick to the recommended booster vaccination intervals throughout life. in the distant future, vaccines may also play an important role in treating non-infectious diseases such as allergy, autoimmunity, alzheimer's disease and cancers. deaths: leading causes for 2002 social and environmental risk factors in the emetgence of infectious diseases a successful eradication campaign. global eradication of smallpox survey: new medicines in development for infectious diseases ageing and infection pneumonia and influenza deaths during epidemics: implications for prevention influenza and pneumococcal vaccination coverage among persons aged> or =65 years and persons aged 18-64 years with diabetes or asthma-united states the efficacy of influenza vaccine in elderly persons. a meta-analysis and review of the literature immunity and immunization in elderly the efficacy and cost effectiveness of vaccination against influenza among elderly persons living in the community influenza vaccination programs for elderly persons: cost-effectiveness in a health maintenance organization reduction in mortality associated with influenza vaccine during 1989-90 epidemic evidence of increased clinical protection of an mf59-adjuvant influenza vaccine compared to a non-adjuvant vaccine among elderly residents of long-term care facilities in italy immunogenicity of new virosome influenza vaccine in elderly people immunogenicity of trivalent subunit versus virosome-formulated influenza vaccines in geriatric patients randomized study to compare the immunogenicity and reactogenicity of an influenza split vaccine with an mf59adjuvanted subunit vaccine and a virosome-based subunit vaccine in elderly clinical experience with inactivated, virosomal influenza vaccine inactivated influenza virus vaccines in children the japanese experiencewith vaccinating schoolchildren against influenza the 23-valent pneumococcal polysaccharide vaccine. part 1.efficacyof ppv in the elderly: a comparison of meta-analyses impact of pneumococcal vaccination on morbidity and mortality of geriatric patients: a case-controlled study changing epidemiology of invasivepneumococcal disease among older adults in the era of pediatric pneumococcal conjugate vaccine. lama stead ww: tuberculosis tuberculosis in the elderly antitb drug resistance in the world efficacy of bcg vaccine in the prevention of tuberculosis. meta-analysis of the published literature colnfection with hiv and tb: double trouble lnununology of tuberculosis population-based study of herpes zoster and its sequelae varicella-zoster virus: pathogenesis, immunity and clinical management in hematopoietic cell transplant recipients stress-induced subclinical reactivation of varicella zoster virus in astronauts live attenuated varicella vaccine vaccination boosts adult immunity to varicella zoster virus a vaccine to prevent herpes zoster and postherpetic neuralgia in older adults long-term cytomegalovirus infection leads to significant changes in the composition of the cd8+ t-cell repertoire, which may be the basis for an imbalance in the cyrokine production profile in elderly persons human immunosenescence: is it infectious? dysfunctional cmv-specific cd8 +t-cells accumulate in the elderly cytomegalovirus misleads its host by priming of cd8 tvcclls specific for an epirope not presented in infected tissues cytomegalovirus seropositivity drives the cd8 t-cell repertoire toward greater clonaliry in healthy elderly individuals inllamm-aging. an evolutionary perspective on immunosenescence lack of antibody produ ction following immunization in old age: association with cd8 +cd28' t-cell clonal expansions and an imbalance in the production of thl and th2 cyrokines restoration of viral immunity in immunodeficient humans by the adoptive transfer oft-cell clones the epidemiology of pertussis: a comparison of the epidemiology of the disease pertussis with the epidemiology of bordetella pertussis infection an epidemic of pertussis among elderly people in a religious institution in the netherlands vaccination against tetanus in the elderly: do recommended vaccination strategies give sufficient protection no immunity for the elderly a population-based serologic survey of immunity to tetanus in the united states t-cells from elderly persons respond to neoantigenic stimulation with an unimpaired il-2 production and an enhanced differentiation into effector cells epidemiology and ecology of tbe relevant to the production of effectivevaccines tbe vaccination and the austrian experience vaccine immunogenicity and safety of a booster vaccination against tick-borne encephalitis more than 3 years following the last immunisation epidemiology and prevention of hepatitis a in travelers hepatitis a and hepatitis b: risks compared with other vaccine preventable diseases and immunization recommendations a prospective,randomized, comparative us trial of a combination hepatitis a and b vaccine (twinrix) with corresponding monovalent vaccines (havrix and engerix-b) in adults immunogenicity of an inactivated hepatitis a vaccine in dutch united nations troops immunogenicity of combined hepatitis a and b vaccine in elderly persons the effect of age and weight on the response to formalin inactivated, alum-adjuvanted hepatitis a vaccine in healthy adults district guidelines for yellow fever surveillance persistence of neutralizing antibody 30-35 years after immunization with 17d yellow fever vaccine advanced age a risk factor for illness temporally associated with yellow fever vaccination thymic involution in aging thymic involution with ageing: obsolescence or good housekeeping? age-related loss of naive t-cells and dysregulation of t'-cell/ b-cell interactions in human lymph nodes marked increase with age of type 1 cytokines within memory and effector/cytotoxic cd8+ t-cells in humans: a contribution to understand the relationship between inflammation and immunosenescence the aging of the immune system cd8 t-cells and aging value of immunological markers in predicting responsiveness to influenza vaccination in elderly individuals artherosclerosis as an infectious, inflammatory and autoinunune disease role of the immune system in the pathogenesis, prevention and treatment of alzheimer's disease how chronic inflammation can affect the brain and support the development of alzheimer's disease in old age: the role of microglia and astrocytes bone marrow microenvironmental changes underlie reduced rag-mediated recombination and bvcell generation in aged mice the effect of age on the b-cell repertoire ageing, autoimmunity and arthritis: senescence of the b-cell compartment -implications for humoral immunity age-related depression of fdc accessory functions and cd21 ligand-mediated repair of costimulation b-cells in the aged: cd27, cds and cd40 expression ineffective humoral immunity in the elderly vaccine development strategies for improving immunization: the role of modem immunology survey of human-use adjuvants targeting the innate immune response with improved vaccine adjuvants augmentation and suppression of immune responses to an hiv-l dna vaccine by plasmid cytokine/ig administration coimmunization with an optimized il-15 plasmid results in enhanced function and longevity of cd8 t-cells that are partially independent of cd4 t-cell help il-21 influences the frequency, phenotype and affinity of the antigen-specific cd8 t-cell response adjuvant il7 or il-15 overcomes immunodominance and improves survival of the cd8+ memory cell pool insufficient protection for healthy elderly adults by tetanus and tbe vaccines immunizations in the elderly: do they live up to their promise the authors wish to acknowledge the support ofthe austrian science fund and the austrian green cross society for preventive medicine. key: cord-002005-35c6mak0 authors: parker, philip d.; jerrim, john; anders, jake title: what effect did the global financial crisis have upon youth wellbeing? evidence from four australian cohorts date: 2016-02-08 journal: dev psychol doi: 10.1037/dev0000092 sha: doc_id: 2005 cord_uid: 35c6mak0 recent research has suggested significant negative effects of the global financial crisis (gfc) on mental health and wellbeing. in this article, the authors suggest that the developmental period of late adolescence may be at particular risk of economic downturns. harmonizing 4 longitudinal cohorts of australian youth (n = 38,017), we estimate the impact of the gfc on 1 general and 11 domain specific measures of wellbeing at age 19 and 22. significant differences in wellbeing in most life domains were found, suggesting that wellbeing is susceptible to economic shocks. given that the gfc in australia was relatively mild, the finding of clear negative effects across 2 ages is of international concern. the influence of macrolevel events and conditions on psychological variables is of central interest within the social sciences (fletcher, 2015) . in particular, there is growing interest in the influence of shifts in local and global economic conditions on personality (bianchi, 2014) , mental illness (sargent-cox, butterworth, & anstey, 2011) , and wellbeing (di tella, macculloch, & oswald, 2006; yang, 2008) . estimating the impact of such factors, however, has proven to be difficult. this is due to the use of cross-sectional designs that make it difficult to separate the influence of development (the degree to which there are changes in wellbeing that correspond to particular developmental stage) and period (cultural and economic conditions or events unique to a particular historical period ; fletcher, 2015; schoon, 2006; yang, 2008) . in this article, we took a multidisciplinary approach, using literature and methodological approaches from psychology, sociology, and economics to estimate the impact of the global financial crisis (gfc) on the multidomain wellbeing of australian youth. to do this we used four cohorts of the longitudinal study of australian youth (lsay) with wellbeing measured in 12 domains. unlike previous research, we used longitudinal data from multiple birth-cohorts to estimate the effects of a unique and pervasive economic crisis. we also used wellbeing measured across most major life domains. this is in contrast to most research to date, which has focused on a single general domain. furthermore, we leveraged the unique opportunities afforded by the lsay to estimate these effects at two distinct ages (19 and 22 years of age). to do this we used statistical models, rarely used in previous research, to provide counterfactual estimates of the effect of the gfc (morgan & winship, 2014) . there has been growing interest in recent years of the effects of macrocontext (national or international conditions or events) on individual factors in psychology (fletcher, 2015) . however, the idea that dramatic changes in the global environment can have meaningful influence on individual psychology is not a new one. c. wright mills (1959 mills ( /2000 3) laid the groundwork for this area of inquiry, stating "neither the life of an individual nor the history of a society can be understood without understanding both". in a pioneering study, glen elder's (1999) research on children growing up in the great depression prompted consideration of not only the influence of macrolevel conditions on progress and frustration in development, but also how such effects filter through to young people via links with local institutions, social ties, and family networks. elder (1999) noted effects of the great depression on social wellbeing, psychological health, and hope and optimism for the future; particularly among those who were younger and thus less cognitively developed. in addition, elder drew attention to the effect of economic downturns on populations of youth as a whole, in addition to those suffering abject and persistent deprivation (see elder & caspi, 1988) . thus, one needs to consider the effects of economic downturns on factors such as wellbeing across whole cohorts (jahoda, 1988) . recent research by di tella et al. (2006) found that a country's economic position has significant effects on wellbeing. indeed, di tella et al. indicated that rising unemployment that results from economic hardship has a critical effect not only on those who lose their job, but for the population as a whole. these effects were observed across a range of macroeconomic events including recessions, changes in gdp, inflation, and the relative generosity of the welfare system. schoon (2006) considered cohorts of british people born in 1958, thus growing up in a golden age of economic stability and prosperity, and those born in 1970, thus growing up in more economic vulnerable times. schoon reported that growing up in times of economic prosperity seems to be a protective factor against psychological distress and promotes wellbeing. conger, rueter, and conger (2000) , studying the effects of the severe economic downturn in the rural midwest of the united states found that economic distress affected young people's wellbeing via its impact upon parents' mood and parenting behavior. finally, forkel and silbereisen (2001) considered the effect of the reunification of germany on development. using a family stress model framework, they found that economic uncertainty had an effect on child wellbeing via parents depressed mood in the west, but less so in the more significantly altered society in the east. in relation to the gfc, a review by clark and heath (2014) found dips in trends in happiness and social wellbeing, including trust and experiences of prosocial behavior in the united kingdom and the united states. in australia, sargent-cox et al. (2011) focused on the influence of the gfc on australian seniors, suggesting that this group was at particular risk due to vulnerability in retirement savings as well as fear spread by the australian media. they also found significant increases in depression and anxiety. likewise the recent unicef innocenti report (fanjul, 2014) found that in 29 of the 41 oecd and non-oecd eu countries wellbeing decreased and experience of everyday stress increased from 2007 to 2013. they attributed this impact as likely due to the gfc. taken together, the literature to date suggests three important considerations. first, changes in macrocontexts, and economic conditions in particular, can have meaningful impacts on wellbeing. second, these may have an impact upon everyone (i.e., those directly and indirectly affected). third, consideration of general wellbeing should be supplemented by consideration of domain specific measures within multiple life domains, given findings that social domains of life appear to be vulnerable to economic conditions. although elder (1999) focused on the effect of the great depression on youth, recent research has tended to focus on the elderly as a group of particular vulnerability. although the elderly were particularly exposed to the gfc (e.g., sargent-cox et al., 2011) , there are important reasons to also consider the develop-mental period ranging from the transition from high-school to the mid-20s. here we explore the biological, social, and economic reasons for this. steinberg (2009 steinberg ( , 2013 has highlighted convincing biological, behavioral, and neurological evidence to extend the definition of adolescence up to mid-20's. steinberg's (2014) argument is both social, noting that youth are now becoming financially and socially independent at later ages, and biological, with evidence of continued and significant brain plasticity well into the mid-20s. steinberg noted that this malleability means that young people are particularly vulnerable to toxic contexts that can lead to lifelong negative impacts. cummins (2014) likewise noted that wellbeing is particularly volatile during adolescence due to heightened biosocial change. this is consistent with the work of elder (1999) who noted that age was negatively related with impact of the great depression, hypothesizing that ongoing cognitive development meant that hardship had a more severe and long lasting impact. socially, not only is the post-high-school period defined by identity formation and uncertainty in social and occupational roles (arnett, 2000) but it is a period in which developmental transitions are both plentiful and of considerable importance to long-term status attainment (guo, parker, marsh, morin, 2015; parker, lüdtke, trautwein, & roberts, 2012; parker, thoemmes, duinveld, & salmela-aro, 2015) . the life span theory of control indicates that those making the transition from formal schooling to tertiary education or the labor market are particularly at risk of contextual events and influences (heckhausen, wrosch, & schulz, 2010; heckhausen & schulz, 1995 ; see also dietrich, parker, & salmela-aro, 2012) . such a period is defined by the convergence of developmental tasks from multiple life domains (educational, occupational, social, family, romantic, and values) and, as such, is one of the most critical developmental periods (zarrett & eccles, 2006) . from the perspective of life span theory of control (heckhausen & schulz, 1995) the particular danger of macroeconomic events, like the gfc, would be the potential to knock youth off a typical developmental track; delaying transitions, interfering with increasing independence from parents, and extending periods of career and educational uncertainty. for example, research on transition delays provides evidence that even a relatively short delay can have ongoing consequences for status attainment well into adulthood (see haase, heckhausen, & köller, 2008; heckhausen & tomasik, 2002; parker et al., 2015) . economically, not only is unemployment particularly high during this developmental period, but in australia, the united kingdom, and the united states the jump in unemployment levels during the gfc for those aged 16 to 24 was notably larger than for the working population as a whole; youth unemployment in australia jumped from 8.9% to 13.8%, whereas overall unemployment grew from 4% to almost 6%, in the period of 2008 to 2011 (our calculations are based on australian bureau of statistics data). as noted above, both unemployment and the risk of unemployment has a particularly detrimental effect on wellbeing (clark, georgellis, & sanfey, 2001) . the risk of unemployment can cause young people to make different choices about their educational and occupational plans than they otherwise would, which can put them at a distinct disadvantage when competing with their near age peers who entered this developmental period at a more economically advantageous time (see kahn, 2010) . finally, at the posthigh-school transition young people are increasing independence via entry into the labor market or tertiary education, yet they also remain strongly connected to parents (parker, lüdtke et al., 2012) . as such, the wellbeing of young people may suffer from both their own exposure to economic downturns but also that of their parents as suggested from a family stress model perspective (conger et al., 2000) . psychologists, economists, and sociologists have all been interested in the influence of both micro-and macrolevel conditions on wellbeing. a common thread across much of this research is general or aggregated wellbeing (e.g., life satisfaction). there is, in contrast, relatively little attention given to how such events might differentially affect multiple life domains. part of the reason is that it is difficult to determine how many and which life domains to cover. as cummins (1996) noted, if every human action is considered a life domain, true multidimensional measurement becomes impossible. derived from the work of cummins and colleagues, however, youth surveys of the australian population have covered between 12 to 14 life domains focusing on achievement, social life, community engagement, perspectives on the future, and living stan-dards. these domains are derived from empirical research on what most participants consider to be important and have been used over long periods of time, across countries, and age groups. this provides strong evidence of validity and utility of multiple dimensional measures of wellbeing in these areas (see cummins, 2014; tomyn, fuller tyszkiewicz, & cummins, 2013 , for a review). as cummins (2014) noted, there is value in a parsimonious multidomain approach, and the domains that are used here capture the domains that are relevant for the majority of young people (tomyn et al., 2013) . thus, taking a multidimensional perspective, we consider the degree to which there are differential impacts of events like the gfc on wellbeing measured in different domains. as noted above, there is some evidence to suggest that social wellbeing and optimism for the future is particularly at risk during economic hard times (clark & heath, 2014; elder, 1999; lau et al., 2008) , yet research in this area has been relatively limited in the number of domains explored. empirical research suggests economic conditions can lead to significant changes in wellbeing. this literature, however, has note. age is the average age at the first wave in the analysis. social class based on the erickson-goldthorpe-portocarero schema. three letter codes used for australian states. all figures use population weights. tended to use cross-sectional studies without the ability to follow individuals over time. here we make use of the unique opportunities afforded by the lsay datasets, which follow young people from four birth cohorts for up to 10 years. the nature of the lsay data, four birth cohorts measured roughly three years apart, allows us to compare the influence of the gfc at two distinct ages in the post high-school transition period (i.e., age 19 and 22). as can be seen in table 1 , the 19-year-old age group captures much of the movement of young people from high-school to tertiary education or the labor market. at age 22, young people appear to have mostly made this transition. the comparison of these age groups is opportunistic (i.e., due to the possibilities afforded by the data), however, and thus we have little evidence on which to assume the gfc would have differential effects. on this basis, we put forward the following hypotheses: hypothesis 1: the gfc will have a negative impact upon young people's wellbeing across the major domains of importance to late adolescents. we expect the influence of the gfc to differ by life domain, with particular impact on domains related to social life and long-term prospects. hypothesis 3: as existing research base is not yet large enough on which to make a strong hypothesis, we do not anticipate that there will be differences in the size of the effect of the gfc at age 19 compared to 22. four cohorts of the lsay database were used. two of those cohorts did not go through the gfc during the time period covered in the study: birth cohorts 1981 (n ϭ 9,738; ages covered 17-25) and 1984 (n ϭ 9548; ages covered 17-26). two cohorts did experience the gfc during the study: birth cohorts 1987 at age 22 (n ϭ 9,378; ages covered 17-26) and 1990 at age 19 (n ϭ 9,353; ages covered 17-23). the cohorts are named after the modal birth year. the structure of the data is represented in figure 1 . the 1981 and 1984 cohorts reflect representative samples of australian year nine students with wellbeing data collected 2 years later. the 1987 and 1990 cohorts represent longitudinal extensions of the programme for international student assessment (pisa), a representative sample of 15-year-olds where wellbeing data was collected a year later. harmonization was based on modal grade in school rather than age in years. as a result there is a difference of several months in the average age of the cohorts for the waves of interest with the average age gradually increasing from 1981 to 1990 cohorts. this may be due in part to differences in how data was collected, but may also reflect a growing preference for later school intake ages by parents (see edwards, taylor, & fiorini, 2011) . population weighted demographics for each cohort can be found in table 1 . all cohorts used a two-stage sampling procedure. the primary sampling unit was schools, selected with probability proportional to size. a random sample of students was then selected from within each school. weights are provided that aim to account for (a) particular design effect including the disproportionate sampling of schools and (b) participant attrition (marks & long, 2000) . thus the sample weights aim to provide unbiased estimates of the population consistently across the waves of the study. wellbeing. wellbeing was assessed using a measure similar to the personal wellbeing index (pwi) originally developed by cummins and colleagues (e.g., cummins, eckersley, pallant, van vugt, & misajon, 2003) . versions of this measure have been used in a number of large-scale panel studies in australia and beyond, including in all lsay cohorts. as such it provides a critical insight into historical trends in wellbeing of australian youth. there are 12 domains covered by this instrument. two additional domains relating to the economy and the way in which the country is being run were excluded due to not being present at critical waves of the study. all variables begin with the stem "how happy are you with [domain]" (see below for suffixes), with response scales varying from 1 (very happy) to 4 (very unhappy). to aid interpretation, these answer points were reverse scored such that higher scores reflected greater happiness. an additional response point was included representing "can't say/don't know." this choice was selected by less than 1% of the sample on average and never more than 4% for any question in any wave. this response was coded as missing for the purposes of the current study. abbreviations will be used for the 12 wellbeing variables (exact item suffix in brackets) as follows: general (your life as a whole), living (your standard of living), home (your life at home), future (your future prospects), career (your career prospects), work (the work you do, at study, at home or in a job), money (the money you get each week), leisure (what you do in your spare time), location (where you live), social (your social life), people (how you get on with people in general), and independence (your independence; being able to do what you want). gfc. the gfc is generally considered to have begun during 2008. however, the impact on australia and the individuals in the study likely came later. sargent-cox et al. (2011) made the case that the impact of the gfc on australians, and particularly the psychological impact, should be dated to 2009. we thus consider the gfc to have occurred when participants were aged 19 in the 1990 cohort and 22 for the 1987 cohort. marking the gfc at 2009 is both consistent with previous research, captures both the dramatic jump in unemployment levels that centered on this period and the zenith of media reporting on the gfc where there was a particular environment of heightened "panic, anxiety, and insecurity" (sargent-cox et al., 2011 , p. 1105 ). age-period-cohort effects. a long running concern in developmental psychology has been how to disentangle the effects of age, period, and cohort (see baltes & nesselroade, 1970; schaie & strother, 1968) . age effects are concerned with how old an individual is, cohort effects are concerned with the shared experiences of those who grow up in a similar historical context, whereas period effects are concerned with the impact of particular events that occur at a given time in history (see schoon, 2006; yang, 2008) . it is these period effects, and in particular changes in wellbeing that occurred after 2009 that are the focus of the current research. such research is limited by the requirement of having multiple cohorts of data that cover at least part of the life span. even when such data are available, there are concerns about identifying such effects given they are confounded (e.g., age ϭ period-cohort). to account for this we consider age as fixed (e.g., we only ever compare 19-year-olds to other 19-year-olds). second, we aim to minimize the influence of cohort by making statistical comparisons between cohorts who were born closest in time thus ensuring that they share much of the same historical context (see figure 1 ). thus, when considering the influence of the gfc at age 19, we compare the 1990 cohort (as the exposed group) to the earlier 1987 cohort (as the nonexposed group). when considering the effect of the gfc at age 22, we compare only the 1987 cohort (as the exposed group) to the earlier 1984 cohort (as the nonexposed group; see figure 1 ). counterfactual reasoning. in addition to concerns relating to isolating period effects, we were also concerned with providing estimates of the effect of the gfc that were as close to causal as the data would allow. to do this, we aimed to find counterfactual conditions that serve as an indication of what would have occurred to a variable of interest had a given event not occurred (morgan & winship, 2014) . put simply, in the case of the current research, we ask the question "what if the gfc never happened?" in the current research a birth cohort that experienced the gfc at a particular age serve as the exposed group (i.e., experienced the gfc at age 19 or 21) and the closest earlier cohort at the same age serves as the nonexposed group (i.e., did not experience the gfc at age 19 or 21). to increase our confidence that the control group acts as a sufficient counterfactual for the treatment group we used two approaches common in sociology and economics; namely a matching and a difference-in-differences (did) technique. propensity score matching. matching aims to find strategic subsamples of individuals in the exposed and nonexposed groups that either match participants across groups exactly on a small number of critical confounding variables, match approximately on a large number of confounding variables, or some combination of the two (morgan & winship, 2014) . in the current research we used a mixture of exact and approximate matching via a propensity score matching (psm) approach. here participants in the exposed and nonexposed groups were matched exactly on exogenous demographic variables (gender, state of residence, social class [erickson-goldthorpe-portocarero schema; ericson, goldthorpe, & portocarero, 1979] , and indigenous status) and postschool pathway variables (number of years of high-school completed, labor market status [employed, unemployed, not in labor market], and tertiary education status [enrolled, completed, dropped out, not relevant] measured at age 18 for the 19-year-old comparison and 21 for the 22-year-old comparison). participants were also propensity matched on age in days and all wellbeing variables up to the year prior to the gfc. the aim of psm is to create samples of exposed and nonexposed individuals who are similar (or balanced) on a wide range of potentially biasing covariates. initial analysis consisted of modeling the relationship between the covariates and presence in either the exposed or nonexposed groups. we used logistic regression to estimate the propensity score and, based on these scores, we used nearest neighbor matching with matches allowed when participants were within .20 of the standard deviation of the logit of the propensity score. as noted above, exact matching was used for several demographic, educational, and occupational status variables. one-to-one matching was used, without replacement (see stuart, 2010; thoemmes & kim, 2011 , for a review). propensity score estimation and matching were done with the matchit package in r (ho, imai, king, & stuart, 2011) and regression with clustered standard errors for school membership was conducted with the survey package (lumley, 2011) . hypotheses were tested using equation 1. here ␥ represented the effect of the wellbeing variable pre_y before the gfc (age 18 for the 19 year-old comparison and 21 for the 22-year-old comparison), ␤ is the parameter of interest-the difference in y between the gfc exposed cohort (coded 1) and control cohort (coded 0). subscript j was the school that individual i was in at wave 1. importantly, psm allowed us to match participants on both grade in school and age in days, thus ensuring participants were similar in both biological and social developmental stage at the comparison point. did. as a robustness check, and to provide population estimates, we also adapted the logic of did to estimate the gfc influence across cohorts. a did approach estimates trends in a variable of interest in an exposed and nonexposed group. it assumes that both trends are essentially parallel and would remain so had an event of interest (e.g., the gfc) not occurred. a did approach estimates the shift from parallel trends at the exposure point (see figure 2 ). the assumption is that this discontinuity in parallel trends provides an estimate of the effect of exposure to a given event (angrist & pischke, 2014 , provide a number of applied examples). typically this model is used to explore the potential effect of a treatment in two or more contemporaneous groups; one in which the treatment is present and one where it is not. for the gfc, however, young people either went through the historical period at a particular developmental stage or they did not. the multiple cohorts of lsay, however, allow us to extend the logic of the did approach to noncontemporaneous groups, given that the same measures were collected using the same survey collection procedure on participants of approximately the same age. as noted above, we thus make the assumption that cohort effects are negligible. following, angrist and pischke (2014) we fitted two sets of models. the first was a basic did model specified in equation 2: where ␤ is the first order estimate of cohort on the wellbeing variable y, ␥ is the first order estimate of the gfc and ␦ is the parameter of interest (i.e., whether there was a shift in trend for the gfc exposed cohort at the time of the gfc; see figure 2 ). the subscripts t refer to individual observations at a given time wave, i refers to individual participants under which observations were nested, and j relates to the primary sampling unit which, in our case, was the school the individuals were in at the first wave of data collection. exploiting the fact that we had more than two waves of data, we also tested a model in which the assumption of common trends was partially relaxed. this second model was estimated using equation 3: in equation 3, and are included to relax the assumption of common trends, and allow for cohort specific linear trends. all other terms remain consistent with equation 1. missing data and survey design. as noted above the lsay database has a complex design. to account for this a series of weights were applied to ensure estimates were representative of the australian population. finally, even with the use of attrition weights there remains missing data holes where participants have failed to complete a particular item within a given wave. to account for this various complexities we (a) provide clustered standard errors for individual observations nested within participants who were themselves nested within schools; (b) apply sample and attrition weights; and (c) multiply impute wave specific missing data. imputation was achieved using a bootstrapped expectation maximization approach (honaker, king, & blackwell, 2011) . given that nonattrition related missing data was generally small (ͻ5%), five imputations was considered sufficient. the means and confidence intervals for each cohort were plotted in the following manner (see figure 2 , e.g., plot). first, all cohorts were plotted on a single graph with solid lines representing observations that occurred before the expected impact of the gfc (i.e., 2009 -2010). second, two close-up plots for each wellbeing domain were created, highlighting particular comparisons of interest. these close-up plots also provide insights into the comparisons of interest for the psm and did models. the first close-up compares the 1990 and 1987 cohorts at ages 17 to 21. the second compares the 1990 and 1984 cohorts at ages 20 to 24. given space restrictions, we provide an example plot for general wellbeing only (see figure 3 ). however, all graphs, means and 95% confidence intervals, and an interactive graph are available from the paper website at https://pdparker.github.io/gfcweb/. microdata is available by application from the australian data archive (https://www.ada.edu .au/). a visual inspection of all the graphs suggested that the 1987 and 1990 cohorts had similar (or slightly higher) levels of wellbeing across domains than the earlier cohorts before the gfc. however, a relatively large gap emerges between the earlier and later cohorts, starting at age 19 for the 1990 cohort and age 22 for the 1987 cohort. thus, results were consistent with the hypothesis that the gfc had a negative impact on wellbeing. interestingly, there was some evidence of recovery in 2011 (ages 21 for the 1987 cohort and 24 for the 1990 cohort), where in many cases the wellbeing levels returned to those of the other cohorts before again diverging and growing progressively larger. finally, the first wave of the 1984 cohort was well below trend and may represent an outlier for consideration in later models. the close-up graphs provide strong evidence for the negative impact of the gfc with most of the relevant contrasts displaying overlapping confidence intervals in the years prior to the gfc before diverging. it was on this basis that we explored the hypotheses using psm and did models. two sets of psm models were estimated; one comparing the 1990 with the 1987 cohort at age 19 and one comparing the 1987 to the 1984 cohort at age 22. matching was done exactly on gender, social class, state of residence, and indigenous status; as well as labor market status, university status, and number of years of high-school completed. propensity matching was done on age in days and all pre-gfc wellbeing variables. negative effects indicate that the gfc exposed cohort was lower on wellbeing than the comparison cohort (see table 2 for results). matching suggested that the 1990 and 1987 cohorts were very similar with only 3% of the 1,365 assessed terms indicating a prematching difference of greater .20 of a standard deviation. after matching no term displayed a difference of greater than .12 standard deviation units. prematching the sample size was 12,390. after matching this was only reduced to a balanced sample of 7,604. table 2 displays the differences in wellbeing at age 19 for the 1990 and 1987 cohort controlling for pre-gfc levels. unsurprisingly, given the similarity between the two groups, matched and unmatched results were similar. in particular, the only factor that gfc exposure did not predict was satisfaction with money. furthermore, nine of the 12 wellbeing domains had cohen's d differences greater than .10. in order of effect-sizes these were social life, independence, general, living standards, career prospects, leisure time, future prospects, and home life. matching for the 1987 and 1984 cohorts revealed a greater prematching difference with 1% of the 3,402 assessed terms displaying a cohen's d differences of .20 or greater and 7% of terms greater than .25. after matching, no term had a cohen's d difference greater than .16. this matching resulted in a decline in sample size from 9,632 cases to a balanced sample of 5,572. matching did result in a decline in the size of effects and the number that were statistically significant. however, eight out of 12 wellbeing factors remained significant, and of those only three had effects sizes greater than .10; namely career prospects, home life, and people in general (in order of effect size). importantly, however, these results tended to be smaller than the comparison at age 19 but generally not significantly so. indeed, z tests suggested only satisfaction with living standards, independence, and social life had significantly larger effects at age 19 that 22. as a robustness check to the psm results we ran a series of did models. in this case two sets of models were estimated. first, we compared the 1990 cohort (who went through the gfc at age 19) to the 1987 cohort. second, we compared the 1987 cohort (who experienced the gfc at age 22) with the 1984 cohort. negative did estimates represent the disadvantage of the gfc exposed cohort over the comparison cohorts in terms of wellbeing. for the did at age 19, we found significant results for 11 wellbeing variables when we assumed a common trend (satisfaction with money was not significant) and all 12 were significant when we controlled for cohort specific trends. of these, nine had effect sizes larger that .10. in order of effect size these were satisfaction with leisure time, social life, future prospects, independence, work, career prospects, home life, general, and people in general. interestingly, the gfc appeared to have a small positive effect on satisfaction with money. at age 22, results not controlling for trend were significant in all domains but only two domains when controlling for cohort specific trends (satisfaction with career prospects and work; see table 3 ). as we noted above, the first time point for the 1984 cohort was considerably off trend and thus likely exerted considerable leverage on the linear trends. thus, we also estimated these models excluding the first wave. this resulted in seven out of 12 significant results, with only career prospects having an effect size of the gfc greater than .10. using z tests, the gfc had significantly larger effects for 19-year-olds than 22year-olds in terms of satisfaction with leisure time, where you live, social life, living standards, and future prospects (ordered in terms of size of difference). impact of the gfc on multidimensional wellbeing by taking advantage of the unique opportunities provided by the lsay data. we were able to overcome limitations in previous research via the use of multiple cohorts of longitudinal data to explore the influence of the gfc at two different ages in one general and 11 domain specific measures of wellbeing. exploration of graphed means suggested significant divergence in wellbeing for the gfc cohorts in year 2009 to 2010. of most concern, while there was evidence of recovery in 2011 in both the 1990 and 1987 cohorts, this gap reopened and grew larger. using the logic of psm and did models, these findings were also examined statistically. there was consistent evidence of a negative impact of the gfc in most domains at age 19 with the exception of satisfaction with money; which was generally not significant and occasionally positive. the effect at age 22 was more ambiguous, though generally suggested significant effects for over half the wellbeing domains. taken together, these results suggest significant though small differences at age 22 than at age 19 for wellbeing in at least three life domains. the current research across multiple models, using multiple comparisons, and across multiple domains suggested that the gfc did have a significant negative impact on the wellbeing of young people in australia. such a result is important, as the gfc had a much milder influence in australia than it did elsewhere. indeed, although youth unemployment jumped from 8.9% to 13.8% during the gfc in australia, it rose from under 10% to almost 18% in the united states (our calculation) during the same period. thus, although research in other countries is needed, it is likely that the results in countries such as the united states and the united kingdom, let alone greece, italy, ireland, and spain, was considerable. importantly, given our focus on the population as a whole, unmoderated by individual exposure, the effect sizes of above .10 standard deviation units, and often above .15, were concerning given effects of unemployment of .50 (lucas, clark, georgellis, & diener, 2004) . this suggests that for particularly vulnerable groups, for example those who experienced the largest relative loss in status or income or became unemployed, the findings may have been considerably more dramatic. an interesting effect present in the trend plots for wellbeing was a drop in wellbeing in 2009, consistent with our hypothesis, before a recovering during 2010 and then a step decline again from 2011 to 2013. although we did not provide a hypothesis for this pattern, exploration of the unemployment rates provides a potential explanation (di tella et al. (2006) . in particular the pattern of decline and recovery is consistent across both wellbeing and unemployment. namely, unemployment rose sharply from 2008 to 2009 before recovering just as rapidly. from 2011 unemployment then increased steadily to levels worse than those at the initial impact of the gfc (see figure 4 ). although it would be naïve to suggest that wellbeing naturally follows unemployment rates, it is fair to suggest that they do provide a proxy for general economic conditions in a country over a given time period. relatively little research has considered the differential effects of macro or micro contextual events on multiple domains of wellbeing. when such a comparison is made it is often done in relatively few domains. our research was one of the few to comprehensively test the impact of events like the gfc across a wide spectrum of youth's lives. previous research has suggested that social domains are particularly at risk. there was some evidence that this was the case with effects on satisfaction with social life, at age 19, and getting along with people in general at age 22 being particularly affected. for both age groups, social domains, general life satisfaction, and satisfaction with career or future prospects appeared to be most strongly affected. such results are consistent with the developmental challenges these two groups face. in particular, these transition periods are primarily focused on the developmental tasks of developing new friendship networks and renegotiating existing relationships (tanner, 2006) . likewise, making appropriate transitions into higher education or the labor market are crucial during these age periods (dietrich et al., 2012) . importantly, these findings are also consistent with previous research on the gfc and the great depression where wellbeing in social domains and optimism for the future were particularly at risk (elder, 1999; clark & heath, 2014) . importantly, the findings suggest that the gfc had a significant impact across most life domains indicating that this event touched most aspects of young people's lives. importantly, the finding of small, nonsignificant results of the gfc on satisfaction with money suggests that results across domains were not merely a poisoned well effect (i.e., negative effects from one domain flooding through to all other domains). as such these findings indicate that economic hard times have a pervasive negative effect on the wellbeing of young people. although the type of domain effects across 19-and 22-year-olds were similar, a consistent finding was that effects were routinely smaller in the older age group. this difference, however, was only consistently significant in three cases; social life, independence, and living standards. these particular domains may be associated table 3 standardized did estimates comparing 1990 and 1987 cohort (age 19) with the many upheavals that occur during the post high-school transition (see dietrich et al., 2012) . as can be inferred from table 1 , the gfc hit 19-year-olds at the end of high-school and in a period where most of the sample was establishing themselves in either university or the labor market. restructuring of old relationships and forming of new friendship circles after high-school is common during this period (see tanner, 2006) , which may explain why satisfaction with social life was affected more for 19-yearolds. likewise, during this transition young people are expected to considerably increase their independence from parents (parker, lüdtke et al., 2012) . although not the focus of this study, it may be that the gfc meant that 19-year-olds had less financial independence and were thus less able to establish greater independence either within the family home or by moving out. the older 22year-olds transitioned from high-school some 3 years earlier and were thus able to at least begin the developmental tasks associated with restructure old and establish new relationships and gaining independence from parents during a more prosperous period. di tella et al. (2006) suggested that a payment of $330 u.s. ($448 u.s. in 2009 dollars; all conversions done using williamson, 2015) to the population in general may be sufficient to offset the effects of an economic recession on wellbeing. they do note, however, such a payment may not be sufficient for dramatic changes to economic conditions. the australian context provides a means of exploring this hypothesis given that the government provided payments of up to $900 aud ($597 u.s. in 2009 dollars) to 80% of the working age population and 90% of families (hyslop, 2014) . although not the main focus of the current research, satisfaction with money was the one domain to be largely unaffected by the gfc, suggesting a positive effect of the payment may have occurred. however, any potential effect of this payment appeared to be constrained to this domain only. there is some tension between the degree to which macroforces represent shared or qualitatively different experiences for different sectors of the community (elder, 1999) . here we focused on the population as a whole. although most research in psychology does focus on average treatment effects, exploring effects within particular strata is an important line for future research. this was difficult in the current case, however, where we had no data on individual exposure to the gfc, which would likely be the strongest moderator of any gfc effect (e.g., sargent-cox et al., 2011) . importantly, although we used rigorous designs by borrowing from the logic of did and psm regression in our research, the extent to which they represent causal effects is dependent on the degree to which the comparison cohorts represent true counterfactual counterparts to the gfc exposed cohorts. as we noted above we make the assumption that cohort effects are negligible. although we aimed to design our models as close to ceteris paribus comparisons as possible, readers should consider the potential biasing effect of birth cohort differences. finally, it should be noted that we used single-item measures for wellbeing in each life domain. multi-item measures would have allowed for latent variable modeling and thus a control for measurement error. the current article was concerned with whether the gfc had an effect on young people's wellbeing across multiple life domains. we focused on an age group that was undergoing a large number of developmental tasks at a critical period of life that has implications across the life span (dietrich et al., 2012) . we found that all domains were significantly affected in at least one case, with effect sizes often above .10 for those who were aged 19 during the gfc. given that we were focused on a country in which the impact of the gfc was less sever than in the european union or the united states, these effects are of international concern. as conger et al. (2000) suggested, we cannot typically predict large-scale changes like the gfc; however, a better understanding of how such events impact young people is critical for marshaling an appropriate response. mastering metrics: the path from cause to effect emerging adulthood. a theory of development from the late teens through the twenties multivariate longitudinal and cross-sectional sequences for analyzing ontogentic and generational change: a methodological note entering adulthood in a recession tempers later narcissism scarring: the psychological impact of past unemployment hard times: the divisive tool of the economic slump the role of economic pressure in the lives of parents and their adolescents: the family stress model the domains of life satisfaction: an attempt to order chaos understanding the wellbeing of children and adolescents through homeostatic theory developing a national index of subjective wellbeing: the australian unity wellbeing index phase-adequate engagement at the post-school transition the macroeconomics of happiness who gets the "gift of time" in australia? exploring delayed primary school entry children of the great depression: social change in life experience economic stress in lives: developmental perspectives intergenerational class mobility in three western european societies: england, france and sweden children of the recession: the impact of the economic crisis on child wellbeing in rich countries does entering adulthood in a recession affect narcissism? robust evidence is still needed family economic hardship and depressed mood among young adolescents from former east and west germany achievement, motivation, and educational choices: a longitudinal study of expectancy and value using a multiplicative perspective goal engagement during the school-work transition: beneficial for all, particularly for girls a life-span theory of control get an apprenticeship before school is out: how german adolescents adjust vocational aspirations when getting close to a developmental deadline a motivational theory of life-span development matchit: nonparametric preprocessing for parametric causal inference amelia ii: a program for missing data the distributional effects of the australian cash bonus payments response to the global financial crisis economic recession and mental health: some conceptual issues the long-term labor market consequences of graduating from college in a bad economy the sars (severe acute respiratory syndrome) pandemic in hong kong: effects on the subjective wellbeing of elderly and younger people unemployment alters the set point for life satisfaction complex surveys: a guide to analysis using r. hoboken weighting the 1995 year 9 cohort sample for differential response rates and sample attrition: technical paper no. 15. lsay technical reports the sociological imagination counterfactuals and causal inference personality and relationship quality during the transition from high school to early adulthood achievement, agency, gender, and socioeconomic background as predictors of postschool choices: a multicontext study i wish i had (not) taken a gap-year? the psychological and attainment outcomes of different post-school pathways the global financial crisis and psychological health in a sample of australian older adults: a longitudinal study the effect of time and cohort differences on the interpretation of age changes in cognitive behavior risk and resilience: adaptations in changing times should the science of adolescent brain development inform public policy? the influence of neuroscience on us supreme court decisions about adolescents' criminal culpability age of opportunity: lessons from the new science of adolescence matching methods for causal inference: a review and a look forward recentering during emerging adulthood: a critical turning point in life span human development a systematic review of propensity score methods in the social sciences the personal wellbeing index: psychometric equivalence for adults and school children seven ways to compute the relative value of a u.s. dollar amount, 1774 to present an age-period-cohort analysis. american sociological review the passage to adulthood: challenges of late adolescence key: cord-142389-t5swlp04 authors: linden, matthias; dehning, jonas; mohr, sebastian b.; mohring, jan; meyer-hermann, michael; pigeot, iris; schobel, anita; priesemann, viola title: the foreshadow of a second wave: an analysis of current covid-19 fatalities in germany date: 2020-10-12 journal: nan doi: nan sha: doc_id: 142389 cord_uid: t5swlp04 a second wave of sars-cov-2 is unfolding in dozens of countries. however, this second wave manifests itself strongly in new reported cases, but less in death counts compared to the first wave. over the past three months in germany, the reported cases increased by a factor five or more, whereas the death counts hardly grew. this discrepancy fueled speculations that the rise of reported cases would not reflect a second wave but only wider testing. we find that this apparent discrepancy can be explained to a large extent by the age structure of the infected, and predict a pronounced increase of death counts in the near future, as the spread once again expands into older age groups. to re-establish control, and to avoid the tipping point when tti capacity is exceeded, case numbers have to be lowered. otherwise the control of the spread and the protection of vulnerable people will require more restrictive measures latest when the hospital capacity is reached. a second wave of sars-cov-2 is unfolding in dozens of countries. compared to the first wave, this second wave manifests itself strongly in newly reported cases, but less so in death counts. however, already the increasing case numbers put the mitigation strategy at risk, because with case numbers being too high, local tipping points are crossed, which makes the control increasingly difficult, impedes the targeted protection of the vulnerable people, and leads to self-accelerating spread [1, 2] . importantly, a tipping point is reached when case numbers surpass the test-trace-and-isolate (tti) capacity of the local health authority, thus potentially long before hospitals are overwhelmed [1] : when tti breaks down, testing and tracing can only be carried out insufficiently and with considerable delay, which leads to more and more missed chains of infections. thereby increasingly more sars-cov-2 carriers remain unnoticed, and thus transmit the virus inadvertently -also to people at risk. as unaware carriers are strong drivers of the spread of sars-cov-2, the case numbers start to rise more quickly, and the spread spills over to the vulnerable population. in the following, we present evidence for a second wave and the crossing of this tipping point. in germany, as in many other countries, the emergence of the second wave has been questioned, because only the case numbers have been rising since july, while hospitals were not overwhelmed and death numbers stayed almost constant (fig. 1) . we investigated this apparent discrepancy using age-stratified case and death reports [3] , and an age-dependent infection fatality rate (ifr). the ifr is derived from a meta-analysis of seroprevalence studies and extensive pcr tracing programs [4] . approximately, the ifr increases by a factor of 10 for every 20 years of age, being about 10% at age 82. from this age-dependent ifr we predict the temporal evolution of the covid-19associated deaths by delaying each age group's observed weekly cases by two weeks and multiplying by the ifr (see supplementary material). (left) , and the number of predicted and actual covid-19-associated deaths are displayed for each age group (middle). the observed number deaths (black) in each age group matches well the predicted deaths calculated from the case numbers (color) using an age-dependent infection-fatality rate from a metaanalysis [4] . despite a rise in total reported cases since mid july (bottom), cases in the older age groups only started to rise in september (blue arrows). as a consequence, a rise in deaths is expected to unfold soon (right). the forecast scenarios a and b (gray, right column) predict a further increase in case numbers and deaths. the recent rise of infections in the older age groups together with the overall rise in cases clearly indicates a loss of control over the spreading and the start of a second wave. the temporal evolution of the predicted covid-19associated deaths (color) matches the actually observed ones (black) well in each age group (fig. 1, right) . even the absolute numbers match, suggesting a low fraction of unobserved sars-cov-2 infection chains. this agestratified analysis plausibly resolves the apparent discrepancy between the total reported infections and deaths: the rise in reported cases has been mainly driven by younger generations (younger than 60), who contribute only little to the absolute death counts, whereas the elderly (60+ years) managed to maintain low case numbers until recently. however, in september cases among the elderly started to increase steeply. this finding is not confounded by increased testing, because the test numbers in that age group stayed almost constant [3] . this spill-over to the elderly strongly suggests a failure to protect the vulnerable people due to an increased number of unaware sars-cov-2 carriers. moreover, this loss of control over the spread is also marked by the increase of the reproduction number r since begin of october (table i ). the spill-over and the increase of r are clear signatures of crossing the tipping point to uncontrolled spread. during summer 2020, the age groups 60+ apparently were protected well: if the virus had been spreading independently equally among all age groups, an estimated 1.3% to 2.0% of the infected would have died (calculated from the ifr in [4] ). however, the case fatality rate cfr was only 0.39% in august (table i) . now, with the strongly increasing number of infections among the elderly (fig. 1) , the cfr will most likely increase soon. this indicates that protecting the people at risk might be possible whilst case numbers are low, but likely fails under high covid-19 incidence. for the coming two weeks, the already reported cases clearly predict that the number of weekly deaths will almost double. beyond two weeks forecasts are difficult, because the death counts depend on the not-yet-reported cases. to account for this uncertainty, we display two future scenarios, where in (a) we assume a linear increase, and in (b) an exponential increase in cases (see supplementary material). the resulting forecasts range between 500 and 800 weekly deaths in early november, but case numbers might even grow faster in case the second wave fully unfolds. if the test-trace-and-isolate (tti) system is overwhelmed and stops to function as a powerful means of control, mitigation of the spread breaks down and the rise of case numbers accelerates [1] . thus, the current development in germany puts the past successful management of the pandemic seriously at risk. to re-establish control and to avoid crossing the tipping point when the tti capacity is exceeded, case numbers have to be lowered without further delay. otherwise the control of the spread and the protection of vulnerable people will inevitably require much more restrictive measures -at latest when the hospital capacity is reached. a. data sources for germany, the age-stratified data used in this document was retrieved from the national health agency, the robert koch institute (rki): both the number of reported sars-cov-2 cases and the number of deaths are available in age groups of ten years [3] , and the reported cases are also available with 5-year stratification up to the age of 80 from [5] . it was verified that the number of cases in the two sources matches. the time points of the case and death numbers correspond to their reporting dates, and not necessarily to the actual testing or date of death. the population age distribution of germany was retrieved from the united nation's database [6] . b. ifr calculation the overall goal is to estimate death numbers from past reported cases per age group and compare them to the observed number of deaths. we used an age-dependent infection-fatality rate (ifr) equation, following recent meta-studies [4, 7] : let a be the age of an infected person. then the infection fatality rate for this age is estimated as this equation formalizes that at 82 years, the ifr is 10% and decreases by a factor of 10 every 20 years. the age group 100+ is treated separately as 60%, in accordance with the supplementary calculations in [4] . in our analysis, we omit cases below the age of 20, as the weekly reported death numbers in that group are too low for any meaningful analysis. the equation (1) is very close to the published one [4] , but has been rounded to integers for simplicity. for comparison see table ii. as reported cases are available with 5-year stratification, equation (1) was evaluated centered in the respective age group. for instance, the ifr of the age group 40-44 is approximated as: one has to distinguish this ifr calculation from the cfr calculation which we calculate by simply dividing the number of deaths by the observed cases two weeks before, as discussed in more detail in paragraph h. c. estimating the number of deaths from the reported sars-cov-2 cases the number of deaths is estimated by multiplying the published weekly number of reported cases in 5-years-wide age groups by the associated ifr (equation (2)). to obtain the time point of the expected number of deaths, we delayed the number of reported cases by two weeks. this accounts for a one week delay between infection and case reporting, and a three weeks delay between infection and death. thus, the total delay of two weeks between reported case and death amounts to the difference between the infection-case and infectiondeath delay. in addition, two weeks matches a median delay of 10 days, which can be derived from individual case histories supplied by the rki's publicly available database [8] . an alternative approach would have been to take those case histories, infer a delay-distribution between reporting and death with a one-day temporal resolution and predict daily deaths. unfortunately, the age-groups of this dataset are between 20 and 25 years wide, compared to 5 year groups with weekly temporal resolution [5] . due to the strong age-specificity of the ifr we opted for smaller age-groups. the observed number of deaths is only available in 10-years-wide age groups. thus, to match the coarser stratification, we summed the corresponding two 5-yearswide age groups for all the plots. d. uncertainties of predictions our estimations features a number of uncertainties: the ifr probably decreased over the course of the pandemic because of better treatments. this leads to some overestimation of the ifr as reported by levin et al [4] , which uses data from early in the pandemic. a fraction of cases remains unobserved, and people at risk may protect themselves better than earlier in the pandemic. moreover, the assumed two-week delay between case detection and death is an approximation, the observed delay of individual cases features a wider distribution. overall however, the evidence indicates that in germany half or more of all cases are currently detected [9] . in relative numbers across age-groups, uncertainties are smaller, because systematic errors in the ifr and the delay approximations are expected to effect all age groups similarly. e. accounting for non-matching age groups if reported cases are not available with a 5-year stratification, but only coarser , we distribute the reported cases of the coarser age groups in 5-years-wide age groups, proportional to the population-age distribution of the respective country [6] . this approach is necessary for ages above 80 years for germany, where only 10-years-wide age groups are available: 80-89, 90-99 and 100+. f. prediction we consider two distinct scenarios for the future spread of the virus. scenario a is a linear extrapolation fitted to the reported cases in the respective age groups over the last 5 weeks, which we chose since linear growth can reflect the local and heterogeneous spreading of sars-cov-2. furthermore, scenario b is an exponential forecast using the reproduction rate r 0 = 1.2 given by the rki [3] in early october and represents a worser scenario. for the forecast, the corresponding weekly increase of 37.5% is applied to the latest week of age-stratified case numbers. g. effective infection fatality rate the effective infection fatality rate ifr eff is defined as the infection fatality rate given the age distribution of reported cases. it is calculated by weighting the ifr of the age groups (eq. (2)) by the number of current reported cases. this approach to calculate the effective ifr accounts for varying case distributions within the age groups, which therefore leads to a time-dependence of the effective ifr. note that this ifr eff is not a case-fatality rate, because only the age distribution of reported cases is used to weight the ifr(a) in each age group appropriately; this is different from the case-fatality rate, which corresponds to the ratio of observed deaths to reported cases. we used this definition of an effective ifr to calculate the effective ifr for germany assuming eq. (2) and a case distribution proportional to the population's age distribution: ifr de mix = 1.83. with equal spread across all age groups, 65% of deaths would originate from the 80+ age group (tabl. ii). with values from [4] for the age-specific ifr (instead of eq. (2) h. case fatality rate in order to compare the theoretical effective infection fatality rate to the actual reported deaths, we calculated a case fatality rate. the approach was to divide the number reported deaths occurring two weeks later by the reported cases. this doesn't take into account the wide distribution of delays between infections and deaths. we mitigate the errors introduced by this simple assumption by using at least 2 weeks of data (tab. i). i. testing the steep increase in the number of cases throughout all age-groups starting in october is not driven by increased testing activity: between the end of june and the end of september, the rate of positive tests stayed below 1% except for the age group 15-34, which stayed between 1-1.5% [10] . until mid-september, it even remained below 0.5% in the age groups 60-79 and 80+. in conjunction with a consistently high number of tests of 600-700 per 100000 in the age group 80+, well above the 300-400 tests per 100000 in the other groups, we assume adequate coverage of that age group, and as a result a constant low number of undetected cases. the twofold increase in overall testing from beginning to end of august, 500000 to 1 million tests per week [3] , was driven by tests in the age groups < 60, temporarily lowering the fraction of positive tests in those groups until mid-september. from then on the number of tests continues to be around 1 million tests per week, leading to our conclusion that the increase of cases since september is not driven by increased test activity. [4] evaluated at the center of the age group alongside 95% confidence interval bounds. the second column list the ifr values used in the analysis, which are calculated using eq. (2). the right half displays the predicted and observed percentage of deaths in each age group, cumulatively summing over all preceding age groups. for the estimated percentage for germany, the age-specific ifr from the 3rd column is multiplied with the fraction of population in the age group. the observation refers to deaths in weeks 31-40 [3] . the observed fraction of deaths was almost twice as large as the estimated one in the age group up to 60 years (last two columns), reflecting that the virus spread more among the younger people than expected. these columns also show that 5.23 % (10.1%) of all deaths are expected among the age group up to 60, thus almost 95 % (90 %) of all deaths are expected to originate from the age groups 60+ assuming age-independent (or age-dependent) spreading. eine zweite welle von sars-cov-2 breitet sich in dutzenden von ländern aus. die zweite welle zeigt sich zwar stark in neu gemeldeten fällen, aber im vergleich zur ersten welle weniger in der zahl der todesfälle. jedoch gefährden bereits diese steigenden fallzahlen die eindämmung von covid-19, denn bei zu hohen fallzahlen werden lokal kipppunkteüberschritten, was die kontrolle erschwert, den gezielten schutz von risikogruppen behindert und zu einer selbstbeschleunigenden ausbreitung führt [1, 2] . ein kipppunkt wird erreicht, wenn die täglichen neuinfektionen die kapazität einer lokalen gesundheitsbehördeübersteigen, so dass sie nicht mehr effektiv testen und kontakte nachverfolgen können (tti, test-traceisolate). diese situation kann eintreten lange bevor die krankenhäuserüberlastet sind, und ist daher besonders kritisch [1] : wenn das tti zusammenbricht, können tests und rückverfolgung nur unzureichend oder mit großen verzögerungen durchgeführt werden, wodurch infektionsketten zunehmend nicht erkannt werden. dadurch bleiben mehr sars-cov-2-träger unentdeckt und können das virus unbeabsichtigterweiseübertragen -auch auf risikogruppen. da die unentdeckten träger die ausbreitung entscheidend vorantreiben, steigen die fallzahlen immer schneller und ansteckungen breiten sich auch in vorher effektiv geschützten risikogruppen aus. im folgenden präsentieren wir hinweise für eine zweite welle und dië uberschreitung dieses kipppunktes. in deutschland, wie in vielen anderen ländern, ist die entstehung einer zweiten welle in frage gestellt worden, da nur die fallzahlen seit juli gestiegen sind, während die krankenhäuser nichtüberlastet waren und die todesfälle nahezu konstant blieben (abb. 2). wir untersuchten diese offensichtliche diskrepanz anhand von altersstratifiziertn fall-und sterbezahlen [3] und einer altersabhängigen infektionssterblichkeitsrate (ifr, infection fatality rate). die ifr basiert auf einer metaanalyse von seroprävalenzstudien und umfangreichen pcr-tracing-programmen [4] . die ifr steigt für jedes 20. lebensjahr etwa um den faktor und beträgt im alter von 82 jahren rund 10%. aus dieser altersabhängigen ifr prognostizieren wir die zeitliche entwicklung der covid-19-assoziierten todesfälle, indem wir die wöchentlich beobachteten fälle jeder altersgruppe um zwei wochen verzögern und mit der entsprechenden ifr multiplizieren. weitere informationen und ergebnisse finden sich in den "supplementary material". der zeitliche verlauf der vorhergesagten covid-19assoziierten todesfälle (farbig) stimmt mit den tatsächlich beobachteten (schwarz) in jeder altersgruppe gutüberein (abb. 2, rechts). selbst die absoluten zahlen stimmen uberein, was auf einen niedrigen anteil unbeobachteter sars-cov-2-infektionsketten hindeutet. unsere altersstratifizierte analyse löst die scheinbare diskrepanz zwischen den insgesamt gemeldeten infektionen und todesfällen plausibel auf: der anstieg der fig. 2. die anzahl der wöchentlichen covid-19-fälle (links) sowie die anzahl der prognostizierten und beobachteten covid-19-assoziierten todesfälle werden für jede altersgruppe (mitte) angezeigt. die vorhersage der anzahl der todesfälle anhand der fallzahlen (farbig) stimmt mit den gemeldeten todesfällen (schwarz) in jeder altersgruppe guẗ uberein, wobei eine altersabhängige infektionsfatalitätsrate basierend auf einer meta-analyse [4] zugrunde gelegt wurde. trotz eines anstiegs der gesamtzahl der gemeldeten fälle seit mitte juli (unten) stiegen die fälle in denälteren altersgruppen erst seit september an (blaue pfeile). infolgedessen erwarten wir, dass bald ein deutlicher anstieg der todesfälle beobachtet werden kann. die prognoseszenarien a und b (grau, rechte spalte) sagen einen weiteren anstieg der fallzahlen und todesfälle voraus. der jüngste anstieg der infektionen in denälteren altersgruppen zusammen mit dem gesamtanstieg der fälle weist eindeutig auf einen kontrollverlustüber die ausbreitung und den beginn einer zweiten welle hin gemeldeten fälle wurde hauptsächlich von den jüngeren generationen (jünger als 60 jahre) verursacht, die nur wenig zu den absoluten todesfällen beitragen, während es bei denälteren menschen (60+ jahre) bis vor kurzem gelang, die fallzahlen niedrig zu halten. im september stiegen die fälle beiälteren menschen jedoch steil an. diese beobachtung lässt sich nicht auf die zunahme der durchgeführten tests zurückführen, da die anzahl der tests in dieser altersgruppe nahezu konstant blieb [3] . diesesüberschwappen aufältere menschen legt nahe, dass es aufgrund der wachsenden zahl unbemerkter sars-cov-2 infizierter nicht gelungen ist, die risikogruppen zu schützen. darüber hinaus ist dieser kontrollverlust seit anfang oktober auch durch einen anstieg der reproduktionszahl r gekennzeichnet (tabelle iii). das uberschwappen auf dieältere generation und die zunahme in r sind beides klare zeichen dafür, dass der kipppunkt zur unkontrollierten ausbreitungüberschritten wurde. im sommer 2020 waren die altersgruppen 60+ offenbar gut geschützt: hätte sich das virus unabhängig und gleichmäßigüber alle altersgruppen verbreitet, wären schätzungsweise 1,3% bis 2,0% der infizierten gestorben, wenn man von der in [4] berichteten ifr ausgeht. die todesfallrate (cfr, case fatality rate) lag im august jedoch nur bei 0,39% (tabelle iii) . jetzt, mit der stark zunehmenden anzahl der infektionen unterälteren menschen (abb. 2), wird die cfr höchstwahrscheinlich bald ansteigen. dies weist darauf hin, dass ein schutz der risikopersonen möglich ist, solange die fallzahlen niedrig sind, aber wahrscheinlich bei hoher covid-19-inzidenz scheitert. für die kommenden zwei wochen kann alleine aufgrund der bereits gemeldeten fälle der letzten zwei wochen vorhergesagt werden, dass sich die zahl der wöchentlichen todesfälle fast verdoppeln wird. prognosenüber mehr als zwei wochen hinaus gestalten sich als schwierig, da die zahl der todesfälle von den noch nicht gemeldeten fällen abhängt. um diese unsicherheit einzugrenzen, setzen wir zwei zukunftsszenarien an, wobei wir in (a) einen linearen anstieg und in (b) einen exponentiellen anstieg der fälle annehmen (methoden in den "supplementary material"). die sich daraus ergebenden vorhersagen bewegen sich zwischen 500 und 800 wöchentlichen todesfällen anfang november. die fallzahlen könnten jedoch noch schneller ansteigen, falls sich die zweite welle voll entfaltet. wenn die kapazitätsgrenze für testung und kontaktnachverfolgung (tti)überschritten ist, brechen die eindämmungsmaßnahmen dieses kontrollsystems zusammen und der anstieg der fallzahlen beschleunigt sich [1] . die aktuelle entwicklung in deutschland bringt somit die in der vergangenheit erfolgreiche bewältigung der pandemie ernsthaft in gefahr. um die kontrolle wieder zu erlangen und um einüberschreiten des kipppunktes beiüberlastung der tti-kapazität zu vermeiden, müssen die fallzahlen unverzüglich gesenkt werden. andernfalls werden die eindämmung der ausbreitung und der schutz der risikogruppen zwangsläufig sehr viel restriktivere maßnahmen erfordern -spätestens wenn die krankenhauskapazität erreicht ist. the challenges of containing sars-cov-2 via test-trace-andisolate together we can do it: each individual contribution protects health, society, and the economy rki tuesdays' situation reports assessing the age specificity of infection fatality rates for covid-19: systematic review, meta-analysis, and public policy implications. medrxiv survstat@rki 2.0 api united nations world population database assessing the age-and gender-dependence of the severity and case fatality rates of covid-19 disease in spain rki) dl-de/by 2-0. arcgis database of the rki's covid-19 dashboard reconstructing the early global dynamics of under-ascertained covid-19 cases and infections rki laborbasierte surveillance sars-cov-2 report of 2020 key: cord-007303-wuuhlowd authors: valkonen, tarmo title: the finnish pension system and its future challenges date: 2020-04-01 journal: inter econ doi: 10.1007/s10272-020-0877-1 sha: doc_id: 7303 cord_uid: wuuhlowd a specific feature in the finnish pension system is rule-based preparation for mortality change. the earned pension capital is adjusted to life expectancy and the lowest age limit of the flexible retirement age will be adapted so that the ratio of expected years in employment and retirement is fixed after year 2030. forum return on funds is low, and the amount of excess is saved to support the funding. the pension scheme is run by private pension companies and other pension institutes, which are individually liable for the pre-funded part of the pensions, but mutually responsible for fi nancing the payas-you-go part. public sector schemes have buffer funds that aim to smooth contribution rates. as an outcome, about a third of the accrued earnings-related pension rights are pre-funded. the main challenge of the pension system is population ageing, which is escalating in finland due to the recent large fall in fertility. if the number of children remains low and net migration does not increase markedly, there will be a growing need to increase contribution rates. moreover, the life expectancy adjustment of pensions lowers replacement rates if mortality rates fall as expected. it will be compensated partly by longer working careers, but full compensation would require a faster-than-projected increase in employment rates. other risks that may infl uence the sustainability of the pension system include lower growth in employment and wages due to technological development as well as lower pension fund yields than expected. this review fi rst provides a brief outlook on the various development stages of the finnish pension system that are still visible in its basic structure and the logic of the current version. the subsequent section illustrates with some key indicators how the current system has succeeded in reaching its goals and shows its risk-sharing properties. this is followed by a discussion of how the pension system is prepared to cope with future challenges that are common to pension schemes across industrialised countries. the concluding section suggests changes that could make the finnish system even more resilient. the history of finnish old age pensions dates to pensions of the civil servants in 19th century, but a fi rst scheme with substantial coverage was established in 1939, when the national pension system was introduced. this earnings-related scheme was based on fully funded individual accounts. the negative experiences of war-time infl ation and political resistance led to the 1957 pension reform that included abandonment of pre-funding, equalisation of pensions, introduction of income-and wealth-tested the finnish pension system has succeeded in gaining high social, and reasonable fi nancial sustainability. the balance between reaching the ambitious redistribution goals and minimising labour supply distortions is achieved with tax-fi nanced, income tested basic pensions, income-tested basic pensions and a strong link between wage income and accrued pensions for middle-and high-income workers in the earnings-related schemes. these well-governed fi rst-pillar schemes have high coverage and similar benefi t rules. second pillar occupational pensions are rare in finland. one of the secrets of its success has been the capacity to make extensive reforms when required. by law, the earnings-related pension scheme follows the defi ned benefi t rule, where contribution rates adjust to shocks that weaken the contribution base or increase expenditures. in practice, however, an outlook of a strongly increasing contribution rate has often triggered a reform process. both the negotiations and the full implementation of the reforms have taken time, but the outcomes have been largely accepted. a specifi c feature in the finnish pension system is rulebased preparation for mortality change. the earned pension capital is adjusted to life expectancy and the lowest age limit of the fl exible retirement age will be adapted so that the ratio of expected years in employment and retirement is fi xed after year 2030. postponed withdrawal of pensions is rewarded in an actuarially fair way. this set of rules generates strong incentives to extend working life when life expectancy increases. hence, the rules promote adequacy of pensions and fi scal sustainability. another non-standard element is the partial pre-funding of the fi rst-pillar earnings-related benefi ts. the share of contributions that is pre-funded in the dominating private sector pension scheme (tyel) is small, but the required forum creased the investments in stock and foreign markets. the public sector pension institutes started buffer-type pre-funding of the contributions in the late 1990s. an extensive and radical pension reform took place in 2005. the reformed rules form the backbone of the current pension system. key elements were the harmonisation of the benefi t rules of different earnings-related schemes, a tighter link between earned income and accruals, introduction of fl exible old age retirement, gradual abolishment of several early retirement schemes and the introduction of a link between life expectancy of the retiring cohort and the pensions. pension accrual starts from an earlier age and smaller amounts of wages are counted. a pensionable wage is determined by the whole working career. pensions are fully portable allowing job and sector changes without losses in accrued amounts. the maximum replacement rate was abolished. the accrued pension rights are indexed to average wages and consumer prices with weights 80/20 during working years. for the pensions in payment, the ratio is 20/80. some pensions accrue also during periods of unemployment, child care, sick leave and studies. the possibility to withdraw the pension was separated from the decision of retiring from work. the only remaining link was that postponement of pension withdrawal was rewarded with a higher accrual rate only when working life continued. flexible retirement allowed retirement between the ages 62 and 67, but withdrawal at age 62 caused a marked loss in the pension if the person was not unemployed long term. one of the ideas behind the fl exible retirement age was that the expected future decline in pensions due to increasing longevity could be compensated by extending voluntarily working careers. it turned out, however, that old age retirement concentrated at age 63 and there was the risk of a continuously falling replacement rate. the observed reluctance to extend voluntarily working lives and a continued rise in projected life expectancy generated the need for a new pension reform. it was understood that the low retirement age endangered both adequacy of pensions and fi nancial sustainability of the general government. the reform, implemented in 2017, introduced a stepwise increase in the lower age limit of the fl exible pension age until it reaches age 65 in 2027 and establishes a link between life expectancy and the lowest retirement age in 2030. the link is calibrated so that for each additional year of life expectancy, the lower age limit goes up by eight months. the link is also applied to basic pensions and early retirement pensions except disability pensions. the upper age limit of the fl exible retirement age will be raised from 68 to 70 years. supplementary allowance and tax fi nancing. in 1996, the basic part of the pension was abolished and only the income-tested part of the national pension remained. the guarantee pension, which defi nes the minimum amount of pension income, was introduced in 2011. disability pensions were part of the system from the beginning. the general earnings-related private sector pension scheme was introduced in 1962. while based on law, it was an outcome of negotiations between labour market parties. since then, the social partners have had a decisive role in the preparation of pension reforms and strong representation in the governing bodies of the pension funds. different sectors prepared their own laws during the 1960s and ended up with a different set of rules. the low retirement ages and high accrual rates of the public sector schemes particularly stuck out. the private sector schemes and the national pension scheme had a retirement age of 65 years. during the next two decades, benefi ts were expanded. in the 1970s, the accrual rates were raised markedly, and the initially low pensions were topped up with discretionary increases. the unemployment pension was introduced for the long-term unemployed who were at least 60 years of age. the eligibility age for these pensions was lowered to 55 years in the 1980s. several new early retirement schemes were introduced in 1986. the popularity of early retirement surprised policy planners. the deep recession in the beginning of the 1990s and the continuous increase in life expectancy initiated a period of retrenchments. first, the liability to pay pension contributions, previously solely on employers, was partially shifted to employees. more importantly, it was agreed that the future increases in contributions are distributed on a 50/50 basis. the true incidence of the hikes in the employers' contribution rates had always been mainly on wages because they were agreed by the central labour market parties, but this reform further strengthened the responsibilities of the labour unions. also, a long process of limiting access to early retirement schemes started. the investment policies of pension funds changed radically during the 1990s. in times of undeveloped fi nancial markets, pension wealth was an important source of liquidity and investment funding for domestic fi rms. the real rate of return on pension funds was often negative due to a high infl ation rate and the use of investment income exceeding the required return to lower contributions. the development of the fi nancial markets and the alleviation of investment regulations of the funds promoted by striving for higher returns and more diversifi cation rapidly in-forum does not capture the growth of real wages. when the gap between purchasing power of basic pensions and earnings-related pensions became large enough, political reality required discretionary increases in the level of these pensions. the importance of the income-tested basic pensions has declined strongly during recent decades because the maturing of the earnings-related pension schemes has reduced the number of eligible pensioners with suffi ciently small earnings-related pensions. pension income represents about 85% of all incomes of pensioners. the rest comprises mainly labour and capital income. the disposable income of pensioners is also infl uenced by strongly progressive taxation, which leaves pension income from national pensions untaxed. the poverty rate among pensioners is 13% (when the criterion is 60% of the median disposable income), which is the same as the average rate in the total population and somewhat lower than the eu average. living standards of pensioners are also supported by the extensive underpriced public health and long-term care services. the finnish centre for pensions provides long-term projections on pensions, total expenditure and contribution rates (tikanmäki et al., 2019) . the outlook, based on the 2019 population projection of statistics finland, shows that the ratio of average total pensions to average wages is expected to decline by around ten percentage points in 65 years mainly because of the life expectancy adjustment of pensions. the outlook of the fi nancial sustainability of the earningsrelated pension system strongly depends on the time period studied. the passing of the baby boomer generation starts to bring down the ratio of expenditures to gdp in the 2030s. low fertility and extending longevity turn the trend when approaching the middle of the century. the main private sector pension scheme can keep the contribution rates stable until the 2050s, but after that there will be a strong and continuous increase. if the scheme aims to smooth development of contributions until 2085, it should raise the contribution rate immediately by 2.6 percentage points (tikanmäki et al., 2019) . this means that the scheme is not fi nancially sustainable. in the public sector, the current very high costs are expected to converge in the long term towards the same level as in the private sector, which allows a minor decline in the ratio of contributions to wages. the pension reforms, together with improved education and health of the retiring cohorts have increased the employment rates of elderly persons dramatically in finland. the gain in the 60-64 age group has been more than 20 percentage points since the 2005 pension reform, which the higher accrual rate earned from work after the lowest retirement age was replaced by a reward for postponing withdrawal of the pension. the reform also included two minor changes in early retirement schemes. the generous part-time pension scheme was replaced by the actuarially fair possibility of drawing part of the old age pension from age 61. the second new element is a years-of-service pension, which can be drawn from age 63 if a stressful working career has continued for at least 38 years and the working capacity of the individual has declined. the years-of-service pension remains unpopular because access to benefi ts is complicated and uncertain and it is smaller than the disability pension. the goal of higher employment periods near retirement has been supported by shortening the period of earnings-related unemployment benefi ts paid before reaching the lowest eligibility age for old age pensions. private sector pensions are fi nanced by contributions collected from employers and employees. contributions are deductible in income taxation, pensions are taxable, and there is no tax on the yields of the funds during the savings period (exempt-exempt-taxed principle). entrepreneurs have similar benefi t rules, but they have fl exibility in declaring the amount of labour income and thereby can infl uence the paid contributions and accrued benefi ts. in addition, government supports their pensions. the key features of the current earnings-related pension system are universality and uniformity. policy changes are effective, because the rules apply to almost everyone, and the fi rst-pillar benefi ts cover a large share of the incomes of the retired population. for those whose earnings-related pensions are small, the pensions-tested tax-fi nanced national pension tops up the income. guarantee pensions ensure the minimum level of income. low-income pensioners are also eligible for a housing allowance. the assessment of the performance of the pension system requires a characterisation of its goals. in an agreement on the main features of the 2017 pension reform, the social partners set a smooth development of the contribution rates, long-term protection of the benefi ts and ensured fi nancing as the targets (social partners, 2014). this statement refl ects the reality well: even though the system is based on the principle of defi ned benefi ts, the goals of constant contributions and fair burden sharing between generations have high priority. the aims of the basic pensions are harder to clarify. national pensions and guaranteed pensions are indexed to consumer prices, which means that their development forum government permanently. fertility risks are less important for schemes with individual or cohort-specifi c pre-funding. another, more controversial possibility would be to add a link between the number of children raised and the amount of pension accrued at the individual level (sinn, 2005) . another trend that possibly weakens the tax and contribution bases is the potential fall in labour income caused by technological development. robotisation and digitalisation infl uence the relative use of labour and capital in production, factor income shares and possibly also unemployment (acemoglu et al., 2020) . a related trend that is already observable in the finnish labour market is the polarisation of jobs and wages. even though there are large uncertainties about the future development of these trends, their potential infl uence on wages and pensions may be signifi cant. an essential issue in fi nancial sustainability of a pay-asyou-go fi nanced pension system is the link between labour income and accrued pensions. if it is tight, a fall in the total wage bill also reduces pension accruals and finally pension expenditure. the challenge is to fi nance the pensions in payment during the time gap between the immediate realisation of lower contribution income and the future decline in paid pensions. third topic that has recently received renewed attention is the interaction of old age pensions and socio-economic differences in life expectancy. well-educated people, who have higher wage income and larger pensions, live longer and benefi t from old age pensions more. moreover, an increase in the statutory retirement age means that the share of one's lifetime as pensioner declines more for the less educated. this is seen as unfair (sánchez-romero et al., 2019) . the average working careers of less-educated workers, on the other hand, end earlier, and there is often a period of disability or unemployment before old age retirement. therefore, the realised redistribution depends strongly on the income available after early retirement compared to the old age pension. in the case of finland, a simulation study showed that the average welfare of the less educated does not decline when the retirement age increases (lassila et al., 2015) . more generally, the main emphasis should be put on reducing the life expectancy differences instead of requiring poorly specifi ed socio-economically adjusted retirement ages. a fourth recent trend, which infl uences especially prefunded pension schemes, is the low interest rate of lowrisk government bonds. in pre-funded defi ned contribu-is almost three times higher than the improvement in the total employment rate. it is very likely that the growth will continue at a rapid pace due to the rising statutory retirement age. the real rate of returns to pension funds has been reasonably high after the investment policies were liberalised (4% in 1997-2018) . the low riskless interest rate has boosted asset values and risk premiums have grown, compensating the decline in interest income in recent years. the returns have been somewhat higher in the public sector buffer funds, where risk-taking is not restricted by solvency rules. history shows that demographic development is diffi cult to project in the long term. as population projections are important for the sustainability of pay-as-you-go fi nanced defi ned benefi t pensions, it is useful to assess the uncertainty involved. analysis performed using the stochastic population projections as inputs in an economic model shows that the finnish idea of linking both pensions and the retirement age to life expectancy can manage longevity uncertainty very well. longer working life helps to mitigate the replacement rate decline at the same time as the fi nancial sustainability of both the pension system and the general government is improved (lassila and valkonen, 2018) . the other demographic and economic risks are carried by the contribution rate in finland, at least if their realisation does not trigger pension reforms. the decreased contribution base requires that the contributions remain higher until the generations that have accrued less pension rights retire. therefore, an observed reduction in the sum of wages and salaries is more problematic with a higher interest rate and lower future growth of contributions. realisation of the risks related to the yield of the pension funds tend to increase contribution rates when the funds are used to pay pensions. the hottest topic of the current pension discussion in finland is the rapid fall of the fertility rate during the past ten years. as there has been no decline in the amount of public resources used to support families by income transfers and services, and the employment rates of the young adults have improved, the reasons behind the declining number of births is not likely to be economic. lack of information about the underlying causes means that there is also large uncertainty about the recovery of fertility and the effi ciency of possible policies to promote it. the policy makers must consider the possibility that the fall in fertility weakens the fi nances of the pension scheme and general the main lesson to be learned from the history and the performance of the finnish pension system is that resiliency can be achieved in two ways. one is a preparedness to make pension reforms, whenever fi nancial or social sustainability are at risk. another is to agree beforehand on rules that redistribute the outcomes of the risks in a way that is acceptable. in finland, the increased weight on fi nancial sustainability and intergenerational fairness in the decisionmaking of the social partners has enabled implementation of balanced reforms, where excessively generous early retirement schemes have been abolished and the link between the wages earned and pensions accrued is strengthened. a key feature is also the new rules that promote longer working lives as a response to increased life expectancy. in general, optimal risk sharing between generations is diffi cult to defi ne. we observe the outcome of the interaction of current pension rules and realised demographic and economic risks but know little about the alternatives. one way of investigating risk sharing is to use stochastic simulations, which describe the outcomes of the current and alternative rules in hundreds of demographic and economic futures. this method provides a set of choices for policymakers. if the pension system is reformed when required instead of investing in risk sharing rules, the system would benefi t from a practice that triggers automatic adjustments to benefi ts and contributions until a reformed scheme takes effect. such a rule would speed up the adjustments processes. tion schemes, the low yield means that the adequacy of pensions is at risk. in pre-funded defi ned benefi t schemes, the contributions are increased either immediately due to solvency issues, or later when the funds are used to pay pensions. the finnish private sector pension institutes have a unique solvency rule that allows a decline in the pre-funded share of the accrued pension liability when stock market prices fall. it has been suggested that this share should be enlarged to allow a riskier investment policy as a response to the low interest rates. this would improve the average return on the funds and mitigate potential problems because of solvency requirements (such as the forced sale of risky assets during recessions), but it increases the variation in the contribution rate, when the funds are used to pay pensions. the covid-19 crisis weakened the fi nancial sustainability of the pension system markedly, but is not expected to result in an abandonment of the system's basic principles. the social partners reacted to the crisis by suggesting a temporary 2.6 percentage point cut in the employer's pension contribution rate. this was accepted by the government. the reduction will be compensated during the 2022-2025 period by higher contributions. the finnish pension system has yet to solve some issues related to effi ciency and risk sharing, yet it has many features that serve as an example of a well-defi ned and robust way to ensure old age security at reasonable costs. the most urgent challenge is to share the fi scal consequences of lower fertility fairly between generations. the current pre-funding alleviates the problems somewhat, but the risk of a large jump in contribution rates is too high. a rules-based way of improving intergenerational fairness would be to establish a link between the prefunding rate and the fertility rate. a more precise instrument would be a link between the accrual of pensions and the fertility rate of a cohort. there is some room for diminishing pension expenditure by removing poorly justifi ed elements. accrual of earnings-related old age pensions from periods when the individual does not pay contributions is one of them. it is the manifestation of a tendency to introduce redistribution in all parts of the tax and benefi t system, also benefi tting those who are well-off in terms of lifetime income. another discretionary policy that would support overall fi nancial sustainability would be to increase the lowest retirement age before implementing the link to longevity. competing with robots: firm-level evidence from france työeläkeuudistus 2017: vaikutukset työuriin, tulonjakoon ja julkisen talouden kestävyyteen, publications of the government´s analysis longevity, working lives and public finances redistributive effects of different pension systems when longevity varies by socioeconomic status europe's demographic defi cit a plea for a child pension system sopimus vuoden 2017 työeläkeuudistuksesta statutory pensions in finland: long-term projections 2019, finnish centre for pensions key: cord-029015-rn62sbfm authors: guyonnet, sophie; rolland, y.; takeda, c.; ousset, p.-j.; ader, i.; davezac, n.; dray, c.; fazilleau, n.; gourdy, p.; liblau, r.; parini, a.; payoux, p.; pénicaud, l.; rampon, c.; valet, p.; vergnolle, n.; andrieu, s.; de souto barreto, p.; casteilla, l.; vellas, b. title: the inspire bio-resource research platform for healthy aging and geroscience: focus on the human translational research cohort (the inspire-t cohort) date: 2020-07-10 journal: j frailty aging doi: 10.14283/jfa.2020.38 sha: doc_id: 29015 cord_uid: rn62sbfm background: the geroscience field focuses on the core biological mechanisms of aging, which are involved in the onset of age-related diseases, as well as declines in intrinsic capacity (ic) (body functions) leading to dependency. a better understanding on how to measure the true age of an individual or biological aging is an essential step that may lead to the definition of putative markers capable of predicting healthy aging. objectives: the main objective of the institute for prevention healthy aging and medicine rejuvenative (inspire) platform initiative is to build a program for geroscience and healthy aging research going from animal models to humans and the health care system. the specific aim of the inspire human translational cohort (inspire-t cohort) is to gather clinical, digital and imaging data, and perform relevant and extensive biobanking to allow basic and translational research on humans. methods: the inspire-t cohort consists in a population study comprising 1000 individuals in toulouse and surrounding areas (france) of different ages (20 years or over — no upper limit for age) and functional capacity levels (from robustness to frailty, and even dependency) with follow-up over 10 years. diversified data are collected annually in research facilities or at home according to standardized procedures. between two annual visits, ic domains are monitored every 4-month by using the icope monitor app developed in collaboration with who. once ic decline is confirmed, participants will have a clinical assessment and blood sampling to investigate markers of aging at the time ic declines are detected. biospecimens include blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. nasopharyngeal swabs and cutaneous surface samples are collected in a large subgroup of subjects every two years. feces, hair bulb and skin biopsy are collected optionally at the baseline visit and will be performed again during the longitudinal follow up. expected results: recruitment started on october 2019 and is expected to last for two years. bio-resources collected and explored in the inspire-t cohort will be available for academic and industry partners aiming to identify robust (set of) markers of aging, age-related diseases and ic evolution that could be pharmacologically or non-pharmacologically targetable. the inspire-t will also aim to develop an integrative approach to explore the use of innovative technologies and a new, function and person-centered health care pathway that will promote a healthy aging. electronic supplementary material: supplementary material is available for this article at 10.14283/jfa.2020.38 and is accessible for authorized users. aging is an important risk factor for several adverse health outcomes, particularly chronic and metabolic diseases and intrinsic capacity (ic) decline. since chronological age differs from biological aging, operationally defining biological aging is an essential aspect to understand the interplay between aging and health outcomes. individuals progress differently in the aging process ("normal" aging vs "accelerated" aging), which means, biological aging is a heterogeneous process. in this context, we need to develop researches to identify biomarkers of aging and healthy aging, and know how to measure biological aging. according to the geroscience field, understanding aging and the links with age-related diseases would contribute to prevent and/or delay the onset of various diseases and the decline in ic domains, in particular in the six operational ic domains crucial for independent living defined by the world health organization (who) (mobility, cognition, psychological, vitality, hearing and vision capacities) (1-3). the who has recently published the integrated care for older people, icope handbook guidance, to support healthy aging and to propose to health-care providers appropriate approaches to detect and manage declines in ic. with this integrated and individualized approach, who aims to reduce the number of dependent people by 15 million worldwide by 2025 (4) (5) (6) (7) . studying concomitantly biomarkers of aging and the natural history of ic evolution in people of different ages and functional status is to date very challenging to understand the relation between biological aging and health outcomes. in this context, the inspire program was built to foster research in the field of geroscience and healthy aging. inspire is a research program dedicated to biological and healthy aging, aimed at constituting a bio-resource platform going from animals to humans, from cells to individuals, from research to clinical care. inspire will provide clinical, biological and technological resources for research and development on aging. the resources will be open to both academic and industry worlds in order to promote healthy aging and prevent dependency. it is a public-private initiative that brings together internationally recognized experts from basic and translational science (in particular, in the fields of immunology, metabolism, neurosciences and mesenchymal stem/stroma cells), clinical gerontology (i.e., researchers, but also physicians and nurses involved in clinical care), primary care and public health (8) . one of the main challenges of inspire is to identify markers capable of determining biological aging with the implementation of human and animal cohorts. the inspire human translational cohort (inspire-t cohort) will recruit about 1000 individuals of several chronological ages (from 20 years to 100+) and functional capacity levels (from robust to frail, and even disabled) with baseline and follow-up biological, clinical, imaging and digital data over 10 years. these data should allow us to explore and identify a set of biomarkers of aging, age-related diseases and ic evolution. in addition, the inspire-t cohort aims: i/ to test the feasibility and acceptability of a new app for smartphone and tablet developed to monitor the six ic domains (locomotion, cognition, vision, hearing, vitality/nutrition, psychological status) according to the who recommendations; and ii/ to explore the development of digital markers of aging. this paper describes the study design of the inspire-t cohort. the inspire-t cohort, started in october 2019, is a 10-year observational study. the study population will consist of 1000 subjects recruited in the city of toulouse and surrounding areas, south-western france, and covering the age range of 20 years and over (no upper limit for age). several follow-up visits will be regularly scheduled during the 10-year period of this study. additional visits will be conditioned by the remote monitoring of ic and the onset of other major clinical conditions. at baseline, and then once a year, diversified data (clinical, digital, imaging) and biospecimens (blood, urine, saliva and dental plaques) are collected following standardized procedures. data collection is performed in the clinical research center (crc) of the gerontopole -chu toulouse. it can also be performed in participants' home (for more frail and disabled volunteers), or in selected gerontopole's collaborating centers by a mobile research team trained by the crc. participants are assessed by appropriately trained clinical research members. between yearly waves of data collection, participants are asked to record major clinical information, including adverse events (e.g. new diagnosis, sars cov-2 diagnosis, influenza, fracture…), medical consultations, hospitalizations, and changes in the drug prescription every 4-months. they also have the six ic domains monitored (with or without the help of a caregiver) (icope program step 1) (4, 7) in either the application developed in collaboration with who (icope monitor app) or a web platform; or through a phone call by a gerontopole's trained research nurse. when declines are detected in the icope step 1, a phone call is organized by the research nurse within one week to confirm this decline and to investigate the causes in collaboration with the medical research team. once an ic decline is confirmed, participants have a thorough clinical assessment following the recommendations of the icope step 2 (4,7) and blood sampling (data are collected by research nurses in a home visit or at the research facility). such information will enable us to investigate the response of some markers of aging at the time declines are detected. the clinical assessments and biomarkers' exploration also allow us to propose a personalized prevention care plan to maintain function according to the recommendations from the who icope program for usual care (icope step 3) (4,7). participants are trained to monitor their ic during the baseline visit by the gerontopole' research team. the remote monitoring of ic will last the whole length of this research study, i.e., up to ten years. the figure 1 shows schematically the study procedures over one year. table 1 describes the study flow chart with all data collected at each time point during the follow-up. to ensure quality of data collected, standard operating procedures are implemented covering subject's recruitment, biobanking, remote monitoring of ic, clinical assessments and digital data collection. all data are collected in the inspire-t database. preventive strategies to limit errors like miscoding, missing values, are applied before data entry to ensure the validity and quality of the performed data analysis. tools will be implemented for data exploration and data sharing between inspire consortium researches and later on with external scientists. the main objective of the inspire-t cohort is the appropriate data collection of key variables and biospecimens for at least 1000 people at baseline and 800 people with at least four years of follow-up (i.e. four yearly post-baseline assessments) over the 10-year study. the key variables are clinical data on all six ic domains (locomotion, cognition, vo²max with blood sampling / maximal aerobic power b √ √ the cognitive composite score will be realized only in people lower than 70 years; b. other examinations are proposed to a limited number of participants in a volunteer basis vision, hearing, vitality/nutrition, psychological status), and the collection of blood, urine, saliva and dental plaque samples. secondary objectives include: i/the identification of (a set of) biomarkers of aging through the constitution of a comprehensive biobank; ii/the assessment of the feasibility and acceptability of the icope monitor app used to measure and monitor intrinsic capacity; iii/ the study of the evolution of ic domains over time and its association with health outcomes; and finally, iv/ the study of the correlation between digital biomarkers to biological/imaging biomarkers and ic domains ( figure 1 , online consultation). a mouse cohort in mirror of the human inspire-t cohort is being built in order to cross the results of translational research found in humans on aging animal models, and vice versa (8) . the main objective of the inspire animal cohort is to define the relationship between the molecular mechanisms of cell premature senescence and frailty/accelerated aging (8) . we will recruit about 1000 subjects, men and women, aged 20 years-old or over (no upper limit for age), and affiliated to a social security scheme. people having a severe disease compromising life expectancy at 5 years (or at 1 year for subjects living in nursing homes) and people deprived of their liberty by administrative or judicial decision, or under guardianship, are excluded. recruitment is stratified per 10-year age groups, oversampling older people in order to be able to investigate major clinical events (e.g., declines on ic, onset of age-related diseases). due to the heterogeneity of biological aging, we opted for no too stringent eligibility criteria. by diversifying our recruitment sources and monitoring key risk factors for accelerated aging (e.g., age, obesity, frailty, and activities of daily living), we will be able to recruit participants with different trajectories of aging. sample size calculation was not relevant as many objectives of the inspire-t cohort are exploratory. we therefore considered an approach based more on the potential of the inspire-t cohort in terms of the ability to obtain parameter estimates with sufficient precision with a recruitment of 1000 subjects that corresponds to the maximum number of subjects that can be recruited and monitored with the funding provided. in case of evident underpowered population (for a particular subgroup of subjects), a reasoned additional recruitment of subjects may be considered in a second phase. to limit the attrition rate, subjects will be monitored by both active (visits, telephone calls) and passive ways (monitoring of several functions using new technologies via mobile phones or other connected devices). from all subjects enrolled, investigations include data collection at baseline and during follow-up visits (annual visits and additional visits planed in case of decline in ic). upon written informed consent, the following set of information is obtained by using a standardized questionnaire: inspire-t study procedures over one year. the remote monitoring of intrinsic capacity will last the whole length of this research study, i.e., up to ten years other examinations are proposed to a limited number of participants (all age ranges and functional status) in a volunteer basis: dual energy x-ray absorptiometry (dxa) for body composition assessment; whole body and brain magnetic resonance (mri); cardiorespiratory fitness (maximum oxygen consumption (v02 max) with blood sampling before and after the effort, and maximal aerobic power), and isokinetic muscle strength. these examinations are proposed annually for the dxa and, every two years for the other tests (mri, vo2 max, isokinetic muscle strength). participant-reported outcome for sarcopenia (sarqol) (25) is completed for volunteers who perform cardiorespiratory fitness exploration. innovative digital assessments are also planned to be tested, such as home sensors (e.g., for measuring walking speed and its variability in daily environment), automated video analysis of mobility, and 3d facial images for the detection of digital markers of aging. a subgroup of 100 patients monitored by ambient sensors at home or sensors worn on the wrist over the long term will allow to remote and continuous monitoring of the trajectories of the ic domains (especially mobility, sleep parameters and nutrition) (cart/smarthome research ancillary study, legal authorizations in process). this sub-study, developed in partnership with the cart research project team in united states (orcatech team, oregon health and science university, or, usa; pi, jeffrey kaye; www.ohsu. edu) will allow us to detect subtle changes that are not clinically perceptible, well before the appearance of signs and symptoms and therefore determine innovative digital biomarkers and decision thresholds. these digital biomarkers will be correlated with clinical data but also biological and imaging biomarkers. biospecimens are collected during the inspire-t cohort for the creation of a biobank. biospecimens, including blood, urine, saliva, dental biofilm, are collected from all subjects at baseline and then, annually (the genotyping sample will be collected only at the baseline visit). nasopharyngeal swabs and cutaneous surface samples are collected from all subjects every two years. feces, hair bulb, and skin biopsy, are collected optionally at baseline visit (see table 2 ). aliquots of biological material are stored at -80°c (dental biofilm, saliva, serum, plasma and urine) or at -196° c liquid nitrogen (pbmc) at the central lab (crb tbr, chu toulouse/ ifb purpan, toulouse, france). analysis will be either performed in toulouse by the local biological teams involved in the inspire project or by any third party not yet determined. the modality of laboratory data transfer from the central lab to other parties will be defined at a later stage. samples from the biobank may be moved to other us and european countries if required. the inspire-t biobank is supervised by the crb tbr where all measures are taken to ensure a quality service based on appropriate resources and adequate safety procedures: observance of good laboratory practice guidelines (the crb tbr is certified afnor since 2015), fully-equipped premises, appropriate, approved and safe equipment (17 freezers -80°c eppendorf cryocube, 2 liquid nitrogen tanks with manual and documented filling, vigitemp probes provide metrological tracking), qualified personnel, safety test and system implementation, sample traceability (all of biological collections are tracked in a specific software (td biobank), and chu servers are daily backed up). all freezers are equipped with an alarm system. equipments are monitored three times per day. every failure is reported in the kalilab software as non-compliance statements. all the participants will be tested for sars cov-2 infection via serological tests from blood collection when these latter will be available. all biological samples are processed within 110 min following a protocol elaborated for inspire purpose and split into smaller aliquots at the inspire-t biobank (figures 2 &3, for blood collection, all subjects are asked to donate blood (60 ml) by venipuncture after overnight fasting. the blood sample is processed to obtain whole blood, plasma, red blood cells, serum and peripheral blood mononuclear cells (pbmc). for whole blood and serum, samples are immediately shipped after collection at room temperature to the crb tbr for the preparation of whole-blood and serum aliquots for freezing at -80° in the inspire-t biobank. for pbmc, blood samples are immediately transported to the crb tbr at room temperature and treated within 24 hours from time of collection. pbmc are collected after density gradient-based separation, counted and frozen at 8-14 millions/ cells per vial. frozen vials will be stored in liquid nitrogen. for plasma and rbc (edta/lithium heparin/bdp100 blood), aliquots are immediately prepared after collection in the crc and stored at -80°c until their shipment to the inspire-t biobank. when visits are organized by the mobile research team, some blood samples are not performed to limit quality procedures deviations (it concerns the lithium heparin tube, the 2 whole blood edta tubes and the bd p100 blood tube). participants are asked to collect at least 20 ml urine in a sterile screw-top container. the obtained volume is transferred into two vacutainer tubes of 10 ml each and directly shipped at room temperature to the crb tbr where urine aliquots of 1 ml are prepared and stored at -80°c in the inspire-t biobank. participants are asked to collect 10 ml saliva in 50 ml falcon tube (at least 30 min after a meal). the falcon tube is immediately shipped at room temperature to the crb tbr where saliva aliquots of 1 ml are prepared and stored at -80°c in the inspire-t. biofilm sampling consists in recovering the biofilm from the external surfaces of the teeth (from natural teeth in priority, from prosthetic teeth if not possible), at the juxta-gingival level by curettage at 4 sites distributed over the dental arches: a sample from the upper anterior teeth, a sample from the upper posterior teeth, a sample from the lower anterior teeth, a sample from the lower posterior teeth. the product of each curettage is individualized in a sterile 1 ml cryotube. the four cryotubes are frozen at -80° in the crc after the collection and regularly shipped to the crb tbr. nasopharyngeal swab will be addressed to the institute of biology of the chu toulouse within 4 hours from time of collection for their analysis (detection and identification of multiple respiratory viral and bacterial nucleic acids). residuals samples will be stored at -80° to the crb tbr in the inspire-t biobank. swab samples are done on a skin exposed area (posterior face of the forearm) and a non-exposed area (lower back). specimens are stored immediately at -80°c in the crc. frozen tubes are regularly shipped to the crb and stored at -80°c in the inspire-t biobank. in addition, two 14 mm diameter d-squames are applied successively on the exact same area of the posterior face of the forearm: the first one is discarded and the second one is stored in a 2 ml tube. the same procedure is performed on the lower back. both tubes are regularly shipped to the crb and stored at -80°c in the inspire-t biobank. feces are collected at the first visit and immediately stored at -80°c. if it is not possible, the participant can return to the research facility within one week with its frozen sample in a coproculture pot, placed in a cool box. the frozen feces samples are regularly shipped to the crb tbr and stored at -80°c in the inspire-t biobank. twenty hairs are taken with the bulb and immediately stored after the collection in a sterile 2 ml cryotube in the crc until their shipment to the inspire-t biobank. a 4 mm skin biopsy is obtained by using a punch. skin samples are prepared according two different procedures: half of the samples are immediately rinsed, dried and stored at -80°c until its shipment to the crb tbr; the other are immediately placed in a cryotube with pbs for cells cultures to organize a biobank of skin fibroblasts. a biobank scientific committee will be set up, in the aim of determining the scientific directions and research priorities, of evaluating ongoing projects and their state of progress, and of resolving any methodological and ethical concerns raised by the studies. it shall i/examine the relevance, feasibility and conditions of implementation of the propositions concerning any analyses; ii/ ensure that national and international partnerships are made formal; iii/ control use of data, especially sample use, and iv/ ensure that participants rights are protected. the data disclosed will be made anonymous (coded, traceable data). since the primary outcome measure of the inspire-t cohort is related to reaching prespecified numbers for recruitment and retention, we will use numbers and percentages. hypothesis-testing statistics will be employed for some of the secondary outcome measures and the new hypothesis arising through the 10 year duration of the inspire program. specific statistical analysis plan (sap) will be written to answer each research question. big data methods of analysis will be considered when examining the large and diversified amount of data that will be gathered from clinical and paraclinical evaluations, biospecimens, and digital assessments. significance will be set at p ≤ 0.05. analyses will be performed using stata (v14, statacorp), sas (v9.4, cary, nc, usa), and r (v3.5.2). statistical analyses will be done by researchers of the inspire program and professional statisticians. analyses by gender will be conducted. the inspire-t cohort is carried out in accordance with the declaration of helsinki, which is the accepted basis for clinical study ethics, and must be fully followed and respected by all engaged in research on human beings. the inspire-t cohort protocol has been approved by the french ethical committee located in rennes (cpp ouest v) in october 2019. this research has been registered on the site http://clinicaltrials.gov (id nct04224038). the first participant was recruited on october 16 2019. our objective is to recruit at least, 1000 people at baseline (500 during the first year and 500 during the second year of the project) from 20 onwards, including robust, prefrail and frail older adults, as well as disabled people, to be able to better understand the biology of aging across age-ranges and functional status. all the recruiting work is currently carried out by the toulouse gerontopole research team on a single site; a mobile clinical research team is also currently active to recruit frailer population (e.g. people unable to come to research facilities) in toulouse and surrounding areas. current inclusion rates are 4 participants per day. this rate will allow us to reach our objective of 1000 inclusions in 2 years. two hundred and forty participants have been included by march 13 2020 (137 women / 103 men; mean age: 74.6 years), and 400 new inclusions are planed until september 2020. among the 240 enrolled participants, 168 are robust, 60 prefrail and 6 frail with fried criteria (9). all participants gave their consent for the complete biobanking, 112 participants have accepted the skin biopsy, 231 hair bulb collection and 216 feces collection. all subjects have accepted the dxa, and 211 vo2 max and muscle strength assessment. the sub-study on mri is planned to start on september 2020. however, recruitment has been temporarily suspended during the covid-19 pandemic. our first plans were to recruit a representative sample of users of primary care services, by inviting people to participate using patients' list of several family physicians in different areas (with different deprivation levels) of toulouse (all patients aged 20 years or over being invited to be screened for participation). however, this recruitment approach proved to be unfeasible, mainly because many physicians have been very busy taking care of several viral pathologies during winter 2019-2020 (including covid-19 from february 2020) (26, 27) . consequently, we decided to diversify the sources of recruitment. current recruitment relies mainly on the following strategies: flyers, community outreach strategies, media coverage, newspaper advertising, posters, online promotion, mass mailing, presentations at public events, conferences, study website, dissemination through institution newsletters, identification of participants from previous studies or existing registries, onsite recruitment /medical records review (by investigators/clinical research assistants), dissemination through health care providers : coordination with primary care, memory centers, hospital outpatient clinics, medical centers, physicians (site investigators, primary care physicians), specialists, hospital inpatient lists, private clinics, and finally, dissemination through residential homes, and nursing homes. the recruitment channels of the participant included (and planed over the next 6 months) is detailed in table 3 . applied strategies are constantly followed and adapted if necessary throughout the recruitment study period (weekly meeting with investigators and study staff). a mobile research team was implemented in january 2020 to recruit frailer population by collaborating with residential homes, long-term care facilities and post-acute and rehabilitation facilities. next collaborations are considered with the crct in oncopole-toulouse (an institution dedicated to cancer research and care) and a private clinic focused on the management of obese people. retention strategies are implemented in parallel. it consists of participant-centered values and strategies including (but not limited to) identify proxy contacts, minimize waiting time during study visits, facilitate transportation from and to research facilities, adapt comfortable waiting room facilities, build relationships with study participants; remind nonresponsive participants (contact via phone or email, make phone calls during optimal hours; offering regular feed-back during the follow-up (mailing study updates); offering regular gadgets during the follow up and postcards. the inspire-t cohort will gather clinical, biological (including imaging), and digital data for subjects of several chronological ages and functional capacity status regularly followed over up to 10 years. one of the most innovative aspects of the inspire-t cohort is that, through a close monitoring of participants with the icope monitor app, we will obtain clinical and biological data at the moment declines in ic come up. the cohort will provide us the needed resources to improve our understanding of the biological mechanisms of aging and the natural history of loss of ic leading to dependency during aging. by following and monitoring the ic of participants over time, this study will provide information about a new, function-centered healthcare pathway, which would agree with who recommendations for an integrated care for older people. at the medium term, this data may inform the development of a pragmatically interventional study testing the effects of this new healthcare pathway on clinical outcomes in older people; this healthcare pathway may be integrated in daily practice in healthcare systems, becoming thus the usual care. innovative digital solutions (including sensors) proposed in the inspire-t cohort are a promising way to remotely collect and analyze real-life and continuous health related data and thus longitudinal trajectories over time. it makes it possible to detect subtle variation in the ic before a clinical event. the inspire-t cohort will also perform relevant and extensive bio banking to allow basic and translational research in humans in the field of geroscience and healthy aging. the inspire-t biobank might lead to improving our understanding about molecular and physiological mechanisms involved in healthy aging, interacting with changes linked to specific chronic diseases. this may contribute to establish a set of biomarkers, that could be pharmacologically or nonpharmacologically targetable, and that would characterize biological aging and, then, permit to identify an accelerated aging phenotype. in their recent paper, ahadi s et al (28) have defined different types of aging patterns in different individuals, termed "ageotypes", on the basis of the types of molecular pathways that changed over time in a given individual. according to the authors, "ageotypes" may provide a molecular assessment of personal aging, reflective of personal lifestyle and medical history that may ultimately be useful in monitoring and intervening in the aging process". one of the inspire approach: an integrative view of biological aging the main objectives of the inspire-t cohort is to identify biological markers that could detect the inter-individual variability of biological processes before it becomes clinically perceptible (29) . the identification of biomarkers of aging may help us to identify individuals who are with a high risk of developing age-associated diseases, decline in ic or disability, and to propose personalized strategies, including innovative therapeutics, to prevent or restore impaired functions. our clinical and biological data will give the opportunity to explore the interaction between changes with aging on inflammation, metabolism, gerosciences in general, and neurodegenerative process leading to alzheimer's disease (30, 31) or physical frailty (32), two major causes of loss of functions. the inspire-t cohort will benefit from the availability of plasma neurodegenerative biomarkers (plasma amyloid beta 42/40, neurofilaments, plasma phospho tau) (31) . the development of biological markers of frailty is also required to improve the treatment of frail individuals. the etiology of frailty is complex. proposed biomarkers of frailty include markers of inflammation. as recently proposed by the icsfr task force perspective on biomarkers for sarcopenia and frailty, «machine learning and information technology innovation could thus be used to develop risk scores that could be used in clinical and research settings. other technologies, such as induced pluripotent stem cells (ipscs) or skin fibroblasts, could be used to study markers of senescence and could also enable a move towards personalized medicine» (32). interventions to promote healthy aging will be more effective in people with a risk of decline (29) . hallmarks of aging are under scrutiny in particular dna alteration, epigenetics, unusual protein production, senescent cells secreting pro-inflammatory factors and others. new therapies aim to target senescent cells or their secretory proteins (the senolytic molecules) and therefore promote healthy ageing are presently under development (33) (34) (35) (36) . finally, the inspire-t cohort gives us the opportunity to federate clinical and biological research teams in toulouse and occitania region to build a research platform of gerosciences discovery to explore mechanisms of aging, and to implement comprehensive translational projects towards the goal of preventing the consequences of aging for a healthy, and long-lived society (37) . the animal cohort, generated to "mirror" the human translational cohort, will facilitate the translation of results from basic research to humans and to the clinics. the identification of markers of aging will take advantage of three complimentary approaches to look for the best markers of aging: without a priori approaches (transcriptomics, proteomics, metabolomics); semi a priori approach (metabolism, inflammation, cell cycle, mitochondrial network…); and targeted approach (pre-identified targets such as (but not limited to) growth differentiating factor 15 (gdf-15), apelin, senescent cells, amyloid protein in plasma) (38) . from a biological viewpoint, the function-centred approach recommended by who represents a challenge due to the multidimensionality that characterizes ic' trajectories during aging. we will develop an integrative view of biological aging ( figure 2 ). three classes of parameters transversal to the whole organism, present in all organs, strongly interrelated and crucial in tissue homeostasis have been selected: i) inflammation and immunity that represents both a warning signals and the house keeping guard of tissue integrity, ii) mesenchymal stem/ stroma cells (msc) allowing support for all function and their adaptation and iii) metabolism that controls any cell decision and the fate of most of them. for all these transversal components, senescence mechanisms will be carefully investigated. due to the covid19, teleconsultation has been added for the pre-inclusion and some of the assessment, we will be able also to assess the" stay at home order" on the inspire-t cohort subjects (39) . in conclusion, the inspire-t cohort, nested in the inspire platform, will contribute to healthy aging and dependency prevention. the inspire-t cohort will foster discoveries of human markers (i.e., biological, clinical, digital) of healthy aging capable of predicting functioning and resilience. challenges and opportunities for geriatric medicine measring biological aging in humans : a quest editorial: linking geroscience and integrated care to reinforce prevention who | who guidelines on integrated care for older people (icope) geneva: world health organization; 2017. integrated care for older people: guidelines on community-level interventions to manage declines in intrinsic capacity editorial: who guidelines on community-level interventions to manage declines in intrinsic capacity: the road for preventing cognitive declines in older age? older people and the implementation in the inspire care cohort andrieu s et al for the inspire program group. the inspire research initiative: a program for geroscience and healthy aging research going from animal models to humans and the healthcare system frailty in older adults: evidence for a phenotype studies of illness in the aged. the index of adl : a standardized measure of biological and psychosocial function assessment of older people: self-maintaining and instrumental activities of daily living mini-mental state'. a practical method for grading the cognitive state of patients for the clinician screening for dementia by memory testing wechsler adult intelligence scale-revised formal and semantic lexical evocation in normal subjects. performance and dynamics of production as a function of sex assessing the nutritional status of the elderly: the mini nutritional assessment as part of the geriatric evaluation adherence to the french programme national nutrition santé guideline score is associated with better nutrient intake and nutritional status evidence-based protocol: oral hygiene care for functionally dependent and cognitively impaired older adults the phq-9: validity of a brief depression severity measure a short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission development and validation of criterion-referenced clinically relevant fitness standards for maintaining physical independence in later years. the gerontologist assessment of muscle function and physical performance in daily clinical practice : a position paper endorsed by the european society for clinical and economic aspects of osteoporosis, osteoarthritis and musculoskeletal diseases (esceo) the utility of the cognitive function instrument (cfi) to detect cognitive decline in non-demented older adults validation of the sarqol®, a specific health-related quality of life questionnaire for sarcopenia. j cachexia sarcopenia muscle editorial : covid-19 and older adults editorial : geriatric medicine in italy in the time of covid-19 personal aging markers and ageotypes revealed by deep longitudinal profiling revisiting the hallmarks of aging to identify markers of biological age editorial: geroscience and the role of aging in the etiology and management of alzheimer's disease plasma biomarkers of ad emerging as essential tools for drug development: an eu/us ctad task force report icfsr task force perspective on biomarkers for sarcopenia and frailty senescent cells: an emerging target for diseases of ageing targeting senescent cells in translational medicine the role of cellular senescence in ageing and endocrine disease creating the next generation of translational geroscientists a framework for selection of blood-based biomarkers for geroscience-guided clinical trials: report from the tame biomarkers workgroup. geroscience impact of the covid-19 outbreak on the clinical and research activities of memory clinics: an alzheimer's disease center facing the covid-19 the inspire program is supported by grants from the region occitanie/pyrénées-méditerranée (reference number: 1901175), the european regional development fund (erdf) (project number: mp0022856), msd avenir and the inspire chairs of excellence funded by: alzheimer prevention in occitania and catalonia (apoc), edenis, korian, pfizer, pierre-fabre.conflict of interest: all authors of the paper "the inspire research initiative: a program for geroscience and healthy aging research going from animal models to humans and the healthcare system" declare no conflicts of interest related to this manuscript.open access: this article is distributed under the terms of the creative commons attribution 4.0 international license (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons license and indicate if changes were made. key: cord-274009-ew4diub5 authors: emerson, kerstin gerst title: coping with being cooped up: social distancing during covid-19 among 60+ in the united states date: 2020-06-29 journal: rev panam salud publica doi: 10.26633/rpsp.2020.81 sha: doc_id: 274009 cord_uid: ew4diub5 objectives. this study examined the impact of sheltering in place and social distancing among adults aged 60 and older during the 2020 outbreak of covid-19 in the united states. methods. using convenience sampling respondents were asked to complete a web-administered survey to explore impact of social distancing on loneliness, stress, and behavioral changes. the analytic sample consisted of 833 responses of persons aged 60 and older. results. a large portion reported being stressed (36%), and/or being lonely (42.5%). nearly 1/3 stated that their sense of loneliness increased during the time of social distancing. respondents reported engaging in more solitary activity (and fewer in-person activities), using email and text messages more than usual, and spending more time on computers/tablet than usual. approximately 2/3 reported using more social media than usual. these differed significantly by younger (age 60-70) and older (71+) respondents. additionally, changes in physical activity, drinking, recreational drug use and sleeping pattern changes differed by age. conclusions. social distancing has significant consequences on loneliness and health behaviors among adults in the united states, many of which differ by age group. results have implications for continued shelter in place practices, but also for any older adult that may be homebound for other reasons. the worldwide spread of covid-19 has created a pandemic unlike any seen in a century, and it is disproportionately affecting older adults (1) . global data, including those from the united states, consistently show higher death rates among older adults and those with underlying conditions (2) . to curb disease transmission and risk of infection, the us began recommending restrictions of social interactions for these most vulnerable populations. specifically, on march 5, 2020, the centers for disease control (cdc) warned that older adults were particularly vulnerable to the covid-19 and encouraged older adults to take extra precautions (2) . recommended precautions included social distancing and sheltering in place. social distancing is a public health practice to reduce disease transmission by preventing people with an illness from coming into close contact with non-infected people (3) . similarly, sheltering in place is aimed at reducing transmission rates by remaining at home except for essential travel. adhering to these recommendations means many older adults in the us have been at home with minimal outside contact for an extended period of time. little is known about how this extended period of sheltering in place has impacted older adults. however, researchers are concerned that current public health safety measures pose a risk of loneliness, even among those that are living with other family members (1) . social interaction is integral to human well-being, and the impact of not having ones social needs met (aka loneliness) can be wide ranging. loneliness has been connected to both morbidity and mortality (4, 5) . loneliness can be a particularly important concern for older adults, who may have additional risk factors, such as physical and cognitive impairment, death of loved ones, and decreases in economic resources (6, 7) . sheltering in place and social distancing may be adding additional risk factors for loneliness as older adults lose many potential outlets for social interaction, such as going to religious services, seeing friends and family, shopping, and group exercise classes. while data on the impact of social distancing for covid-19 is not yet available, research on prior quarantining events suggests that one unintended consequence of such measures is psychological distress. most recently, research on the impact of mandated quarantine during the severe acute respiratory syndrome (sars) outbreak in canada showed a high level of psychological distress among respondents (8) . the purpose of this study was to explore how adults aged 60 and older in the us are coping with social distancing and sheltering in place during the covid-19 pandemic. specifically, the survey hoped to answer two main questions: 1) what have been the effects of social distancing on adults aged 60 and older, and 2) what have been behavioral and social communication changes since social distancing started? the answers can shed light on challenges experienced by those social distancing, and can guide potential public health interventions strategies. survey instrument. we conducted a web-based survey in qualtrics, which consisted of 28 questions. a web-based format was chosen due to budget and time constraints; it was important to reach those practicing social distancing during the event to avoid recall bias (8) . the survey was open for two weeks, beginning on march 30 th and concluding on april 12 th , 2020. the sampling of the survey was a convenience sample, with links sent out on social media and gerontology listservs. only persons aged 60 and older were asked to respond. each respondent was asked to forward the survey on to other persons aged 60 and older. the study was approved by the university of georgia institutional review board (irb# 00002133). analytic sample. 922 persons initiated the survey, but only 843 (91.4%) completed the survey. an additional 10 responses were not included in the analytic sample because they did not provide their age or because they were not in the united states. the final sample size was 833 respondents living in the us, aged 60 and older. variables. the survey collected socio-demographic data, including age (top-coded at 85), sex (male, female, other), race (white, black/african american, american indian/alaska native, asian, native hawaiian/pacific islander, other), ethnicity (hispanic or latino as defined by the us census (14)), employment status (part-time, full-time, not employed), and household size (continuous). additionally, respondents were asked to estimate how many people they continue to be in contact with in person, but outside of the home (no one else, 1, 2-3, 4 or more). respondents were also asked about the type of home they live in (apartment, house, nursing home, assisted living, other). loneliness was determined by asking respondents: "since you started socially distancing, have you felt lonely?" (yes, most of the day/yes, some of the day/no, never). for analyses all respondents who answered most or some were coded as lonely. respondents were then asked a follow up loneliness question: "do you feel more, less, or the same level of loneliness compared to the time before you were socially distancing?". stress was measured by self-report response to the prompt: "stress means a situation in which a person feels tense, restless, nervous or anxious or is unable to sleep at night because their mind is troubled all the time. do you feel this kind of stress these days?" (answer choices were a 5-point likert scale). for analyses the five answer choices were collapsed into three groups (1=a great deal/a lot, 2=moderate amount, 3-a little/not at all). relationships was determined by the question: "do you feel like you have close relationships that bring you emotional security and well-being?" (answer choices were yes, definitely/yes, somewhat/no, not at all). self-rated health was measured by a 5-point likert scale ranging from poor to excellent. finally, respondents were asked to choose all that apply from a range of behavioral and communication changes since beginning social distancing. these included doing more or less: sleeping, engaging in physical activity, smoking, drinking alcohol, using recreational drugs, eating, solitary activities, engaging in in-person activities, making/receiving phone calls, using social media, emailing, ending/receiving text messages, and spending time on the computer/tablet/phone. analyses. data are presented in descriptive format. means were calculated to summarize continuous variables. for categorical variables, group proportions were calculated. to explore differences by age, the results were divided into younger (ages 60-70) and older (ages 71+). because sample cell sizes were small, all statistical comparisons by age are conducted using fisher's exact test. stress, loneliness, and relationship responses were examined by whether respondents lived alone, using pearson chi-square tests. a p-value of < 0.05 was considered to be significant for all analyses. all analyses were conducted using spss v21. description of the sample. the sample age range was 60 to 85+(top-coded), with 62.8% in the younger (aged 60-70) category (table 1) . a majority (80.5%) of the sample was female, white (96%), and not hispanic (97.9%). race/ethnicity did not differ by age of respondents, though the younger age group was significantly more likely to be female (84.3%) compared to the older age group (74.1%). who is social distancing and what does their household look like? the average number of days spent practicing social distancing for this sample was 16.95 (range 2-65 days, sd 5.8). this did not differ significantly by age. for context, the survey opened 25 days after the official cdc recommendations were published for older adults and ended 39 days after the recommendations. about 85% of survey respondents lived in a house, 8.6% lived in an apartment, and 5.7% lived in other locations, such as condos, or townhomes. a majority of respondents were living either with one other person (64.3%) or living alone (21.3%). approximately two-thirds (67.7%) of respondents were not employed, although this differed significantly by age. the older age group had higher rates (86.7%) or not working, compared to 56.5% of younger age group. of those that were employed, 28-30% usually work from home and continue to work from home (across both age groups). among the older respondents 48.6% usually worked outside the home, but were now working from home because of covid-19, compared to 61.6% of the younger group. what social contacts do people have? more than half (51.2%) of respondents saw no one else outside their household, 15.3% saw only one person, 21.9% saw 2-3 people, and 11.6% saw four or more people. most (94.5%) respondents spoke with someone on the phone at least once a day, and 56.4% spoke to someone using video calling (e.g. facetime/skype) at least once a day. video calls were significantly more common among the younger respondents, with nearly 53.8% of older respondents saying the never used video calls, compared to 37.6% of younger respondents. nearly all respondents (98.8%) reported having at least some close relationships that bring them emotional security and well-being. how are people feeling? respondents rated their health fairly highly, with 94.4% rating their health as good, very good, or excellent. approximately 43% of respondents reported feeling lonely some or most days. for about two-thirds (65.6%) of the respondents their level of loneliness had not changed, though 30.9% stated that they are more lonely now compared to before they were socially distancing. about 3.5% felt less lonely. over one-third (36.9%) of the sample reported being moderately to a great deal stressed. this differed significantly by age. older respondents reported higher rates of being only a little or not at all stressed out (74.2%) compared to younger respondents (56.5%). analyses stratified by living alone. some health measured differed significantly by whether or not respondents lived alone ( table 2 ). those living alone had much higher rates of current loneliness (59.3%) compared to those that lived with others (38.4%). those living alone were also significantly more likely to report that their loneliness had increased since social distancing (42.4%) compared those living with others (27.9%). those living alone were less likely to report having a close relationship that brings them emotional security and well-being, where 3.6% said they didn't have this at all, and 20.4% said they had it somewhat. this was compared to 0.0% for not at all and 12.7% for somewhat among those living with others. stress, having close relationships, and physical health did not differ significantly by living alone. table 3 . health behaviors. sleep patterns were impacted for a little over 1/3 of the sample, with 27.1% reporting more sleep than usual, and 15.8% reporting less sleep. younger respondents were significantly more likely to report sleeping less. physical activity levels changed as well, in both directions. about one-quarter (24.6%) of respondents engaged in more physical activity, while 37.3% engaged in less physical activity than usual. younger respondents were significantly more likely to increase their physical activity, whereas older respondents were significantly more likely to decrease their physical activity. alcohol intake increased for 12.2% of the sample, but decreased for 4.4% of the sample. increase in alcohol consumption was significantly higher for the younger age group (14.9%) compared to younger respondents (7.7%). smoking and recreational drug use both had smaller changes, with 1.3% smoking more than usual and 1.1% smoking less than usual, and 1.4% taking more recreational drugs and 1.0% taking fewer drugs. less use of recreational drugs than usual was significantly more common among older adults, though sample sizes are small. since social distancing, over one-third (35.4%) of respondents report eating more than usual, and 11.1% ate less than usual. this differed significantly by age, where younger people were more likely to report eating more, and older respondents were more likely to report eating less. a majority of respondents (56.4%) engaged in more solitary activities, and 1.2% engaged in fewer of those activities. a larger proportion of older respondents reported engaging in solitary activities (61.6%) compared to younger respondents (53.3%). while some (1.1%) have engaged in more in-person activities than usual, more (48.4%) report less in person activities. communication. among respondents, 4.6% make/receive fewer phone call, 1.3% use social media less, 3.1% email less, 1.9% send/receive fewer text messages, and 0.5% spend less time on their computer/tablets/or phones. however, for a much larger group of respondents, each of these styles of communication increased. among respondents, 45.3% make/receive more phone calls, 66.3% use social media more, 40.2% email more than usual, 60.6% send/receive more text messages, and 67.2% spend more time on their computer/tablet/or phones than usual. several of these communication styles different significantly by age. the younger respondents were significantly more likely to increase their social media use compared to older respondents (73.2 vs. 54.5%, respectively). younger respondents also indicated an increased use of text messages (64.2%) compared to older respondents (54.5%) alternatively, the older respondent group reported increased use of email (44.2% vs. 37.9%). while social distancing is not a new phenomenon (13) , it was never as sustained in the us or as prevalent as it has been since the covid-19 outbreak. while the cdc provided guidance for older adults and adults with high-risk conditions, for most people the process of sheltering in place and social distancing is asking them to create a new normal with little to no precedent to lean on. one potential concern is the higher risk of loneliness as we decrease social contacts. this may be particularly concerning for older adults, who have more risk factors for loneliness. the goal of this survey was to see how people aged 60 and older are doing given the recommendations to practice social distancing. the survey results showed that some respondents are adjusting well and not feeling lonely or stressed. however, a significant portion of adults reported experiencing at least some distress. over a third (36%) of respondents reported feeling moderate to a great deal of stress during this time. those over age 70 were less likely to report stress, however. this stress and age pattern follows previous data showing decreases in stress by age (9) . it is not clear from this cross-sectional data if this age pattern is a cohort effect (reflecting history and life experiences born around the same time) or a difference in individuals' circumstances. additionally, a large portion of respondents (43%) noted being lonely. loneliness rates did not differ significantly by (10) , suggesting that this sample had relatively high rates. rates of loneliness were significantly higher among those living alone (59.4%). however, even those living with others had relatively high rates of loneliness (41.7%). this supports previous research that simply living with others does not erase the risk of loneliness (11) . perhaps most notable is that many respondents (31%) stated that their sense of loneliness increased during the time of social distancing. this suggests that social distancing practices are having an impact on a portion of those aged 60 and older. respondents who lived alone were more likely to report an increase in loneliness. this indicates that those living alone are a particularly vulnerable group to increased loneliness during periods of quarantine. not surprisingly, a large portion of respondents reported engaging in more solitary activity (and fewer in-person activities). respondents also reported using email and text messages more than usual and spending more time on computers/tablet than usual. two-thirds of respondents reported using more social media than usual. some of these behaviors differed significantly by age. for the older age group, adults they were more likely to engage in less physical activity, and to eat less. while participating in less physical activity is probably not a healthy behavior, it is unclear whether eating less is healthy or not. this likely depends on the individual's weight and health, as well as in the nutritional changes made with eating less. unlike their younger counterparts (aged 60-70), older respondents were not drinking more alcohol (in fact, they were more likely to report lower alcohol intake, though this difference was only marginally significant). more older adults reported less recreational drug use (though this was a very small response rate). younger respondents were more likely to report sleeping less. while there is no one clear overall pattern by age, the data suggest that those in the younger age category may be engaging in less healthy behaviors during covid-19. in this sample, younger people are more stressed, drinking more alcohol, sleeping less, and eating more. they are, however, engaging in more physical activity, which for many is assumed to be a healthy behavior. communication also differed by age. while both age groups reported using social media more than usual, those in the younger age group reported this much more often than those aged 70 and older (73% vs. 55%, respectively). the younger group also used texts more often. those in the older age category reported more email use instead. this suggest that intervention and public health communication strategies may need to differ by age category. these results have implications for continued shelter in place practices, but also for how to intervene with any population of older adults that may be homebound for any number of reasons (e.g. health issues, transportation). the high level of engagement with social media suggests that for all groups social media can play an important role in interventions. this is especially the case for those aged 60-70. doing media-based interventions through platforms such as facebook live may be an effective way to reach this population. interventions could include social activities, live exercise activities, or social media public health messaging campaigns. on the other hand, those in the older age category were more likely to use the phone and email. it may be better to target interventions through phone or email for this population. examples include connecting people to hotline/ warmline services such as the institute on aging's friendship line, which provides free telephone support for older adults that are lonely (12). while interventions should certainly be targeted to those living alone, it is important not to ignore those that are living with others. these data show that those living with others are still vulnerable to loneliness. this study had some limitations. the survey was a convenience sample of a relatively small number of adults compared to the total number of adults that are actively practicing social distancing in the us. in fact, since the survey was online, a specific subset of adults were likely not reached with this survey. this includes, but is not limited to, rural elders with limited internet access. it is also possible that a self-selection effect may have occurred (8) , where those who either felt the greatest or the least effects of social distancing chose to complete the survey. therefore, the results are not generalizable and should be interpreted with caution. additionally, the survey was fielded in the first 2-3 weeks of the social distancing, which likely only captures the immediate impact of social distancing. future research should explore the impact of a longer duration of social distancing. in conclusion, this survey provides a first glimpse into the lives of adults aged 60 and older living through the unprecedented public health situation caused by the covid-19 pandemic. the results can increase awareness of potential stress, loneliness and health behavior changes for public health officials, as well as point towards the communication methods that may be most effective for interventions. managing mental health issues among elderly during covid-19 pandemic people who are higher risk for severe illness what is social distancing? social relationships and mortality risk: a meta-analytic review loneliness: a sourcebook of current theory, research and therapy. perspectives on loneliness loneliness as a public health issue: the impact of loneliness on health care utilization among older adults older adult loneliness: myths and realities sars control and psychological effects of quarantine don't worry, be 80: worry and stress decline with age loneliness and health in old er adults: a mini-review and synthesis social isolation, loneliness, and living alone: identifying the risks for public health social distancing in the times of coronavirus pandemic about hispanic origin disclaimer. authors hold sole responsibility for the views expressed in the manuscript, which may not necessarily reflect the opinion or policy of the rpsp/pajph and/or paho. objetivos. evaluar el impacto de la indicaciã³n de quedarse en casa y el distanciamiento social en los adultos de 60 aã±os o mã¡s durante el brote de covid-19 en los estados unidos en 2020. mã©todos. utilizando un muestreo de conveniencia, se solicitã³ a los destinatarios que completaran una encuesta administrada por internet para explorar el impacto del distanciamiento social respecto de la soledad, el estrã©s y los cambios de comportamiento. la muestra analizada consistiã³ en 833 respuestas de personas de 60 aã±os o mã¡s.resultados. una proporciã³n importante de la muestra informã³ experimentar estrã©s (36%) o soledad (42,5%). en alrededor de un tercio de los casos se informã³ que la sensaciã³n de soledad aumentã³ durante el perã­odo de distanciamiento social. los encuestados informaron que realizaban mã¡s actividades solitarias y menos actividades presenciales, utilizaban el correo electrã³nico y los mensajes de texto mã¡s de lo habitual y pasaban mã¡s tiempo que lo habitual con sus computadoras o tabletas. aproximadamente dos tercios de las personas que respondieron informaron que utilizaban las redes sociales mã¡s que lo habitual. se observaron diferencias significativa entre los encuestados mã¡s jã³venes (60-70 aã±os) y los mayores (>71). los cambios en la actividad fã­sica, el consumo de alcohol y de drogas recreativas y los cambios en los patrones de sueã±o tambiã©n difirieron segãºn la edad. conclusiones. el distanciamiento social tiene consecuencias significativas respecto de la soledad y los comportamientos que afectan a la salud en los adultos mayores de los estados unidos, muchas de los cuales varã­an segãºn el grupo etario. los resultados tienen implicaciones respecto de la indicaciã³n sostenida de quedarse en casa, asã­ como para otros adultos mayores que deban estar confinados a su hogar por razones distintas a la pandemia. key: cord-035015-slgywe0c authors: nunn, alistair v. w.; guy, geoffrey w.; brysch, wolfgang; botchway, stanley w.; frasch, wayne; calabrese, edward j.; bell, jimmy d. title: sars-cov-2 and mitochondrial health: implications of lifestyle and ageing date: 2020-11-09 journal: immun ageing doi: 10.1186/s12979-020-00204-x sha: doc_id: 35015 cord_uid: slgywe0c infection with sars-cov-2 displays increasing fatality with age and underlying co-morbidity, in particular, with markers of the metabolic syndrome and diabetes, which seems to be associated with a “cytokine storm” and an altered immune response. this suggests that a key contributory factor could be immunosenescence that is both age-related and lifestyle-induced. as the immune system itself is heavily reliant on mitochondrial function, then maintaining a healthy mitochondrial system may play a key role in resisting the virus, both directly, and indirectly by ensuring a good vaccine response. furthermore, as viruses in general, and quite possibly this new virus, have also evolved to modulate immunometabolism and thus mitochondrial function to ensure their replication, this could further stress cellular bioenergetics. unlike most sedentary modern humans, one of the natural hosts for the virus, the bat, has to “exercise” regularly to find food, which continually provides a powerful adaptive stimulus to maintain functional muscle and mitochondria. in effect the bat is exposed to regular hormetic stimuli, which could provide clues on how to resist this virus. in this paper we review the data that might support the idea that mitochondrial health, induced by a healthy lifestyle, could be a key factor in resisting the virus, and for those people who are perhaps not in optimal health, treatments that could support mitochondrial function might be pivotal to their long-term recovery. the risk of severe morbidity associated with infection by sars-cov-2 rises with age and underlying comorbidities, which indicate that up to 1.7 billion people, or 22% of the global population, could be at severe risk; the increased risk seems to be largely associated with an imbalanced and/or an excessive inflammatory response [1] . one suggestion is that the severity could be related to a failure of inflammation resolution, leading to pulmonary hyper-inflammation and "cytokine storms" [2] . with increasing age there is often an exaggerated innate immune response to respiratory infections [3] and rising inflammatory tone [4, 5] . overall, it seems that susceptibility to the virus is related to an age-related loss of adaptive immunity combined with an increased innate immune response [6] . this "inflammaging" seems to be associated with t-cell immunosenescence and thymic atrophy; critically, exercise seems to be protective [7] . the protective effect of exercise is informative, as the pathological severity of sars-cov-2 infection seems to be associated with many obesity-related co-morbidities, such as diabetes [8] [9] [10] , in contrast, physical fitness is emerging as a preventative strategy against the virus [11] . this suggests that as well as age, lifestyle could be important in determining susceptibility to the virus. we have suggested that a modern sedentary lifestyle has effectively removed exogenous hormetic stimuli, such as physical activity, which is leading to an accelerated ageing phenotype [12] . in short, a modern lifestyle could be accelerating the process of "inflammaging": obesity is associated with a pro-inflammatory state, increased inflammatory macrophages and altered t-cell homeostasis [13] . in contrast, exercise is largely anti-inflammatory, which is thought to explain its many benefits [14, 15] . a key player in this adaptation is the mitochondrion, as mitochondrial stress enhances mitochondrial function not only in muscle, but in multiple other organs with myokines playing a key role [16, 17] . for example irisin, which protects mitochondria, can protect against ischaemia/reperfusion (ir) injury in the lung [18] . irisin has also been found to favourably alter genes in adipocytes that are affected by the sars-cov-2 [19] and to modulate macrophage reactive oxygen species (ros), displaying anti-oxidant and anti-inflammatory properties [20] . critically, exercise can enhance mitochondrial function and capacity in peripheral blood mononuclear cells (pbmcs) [21] . as mitochondria are pivotal in the immune response and many viruses in turn modulate mitochondria [22, 23] , it is possible that altered mitochondrial function may explain at least some of the variance in responses to sars-cov-2. as most cells in the body contain mitochondria, including immune cells, this would be expected and is now embraced by the concept of "immunometabolism". this is perhaps most clearly seen in the clinical phenotype of subjects with inherited mitochondrial defects who often display immunodeficiency and a much higher rate of infectionshighlighting the reliance of the immune system on mitochondria [24, 25] . although this is relevant to resistance to the virus, it is also perhaps relevant to the efficacy of vaccines; thacker and colleagues, using gene expression assays of pbmcs, have shown that there is an age-related decrease in response to influenza vaccines, which appears to be linked to decreased mitochondrial function [26] . in short, compromised mitochondrial function, either due to genetic factors, extreme age, or lifestyle, could have a bearing on both resistance to the virus and the ability to mount an effective response to a vaccine. it therefore seems that maintaining "mitochondrial health" is vital, which probably correlates with an effective mitochondrial reserve induced by factors like physical activity, such that when the system is "stressed" (e.g., by a virus), it can cope. although the virus may only infect certain cells, the immune response is global and dependent on mitochondrial function in multiple tissues and organs. what is clear is that severity is associated with the hyperinflammation syndrome and involves dysregulation of many different cell types [27] . this is to be expected, as throughout evolution, viruses have evolved to manipulate the immune system to hide from it, and can invoke immunosuppression, which in itself can become pathological, for instance, by modulating t-cells [28, 29] . it now seems that the spike protein of sars-cov-2 can bind to t-cell receptors (tcrs), acting as a superantigen and causing excessive activation of the adaptive immune systempotentially resulting in the hyperinflammatory syndrome [30] . this is perhaps relevant as persistent antigenic stimulation can lead to t-cell exhaustion, which is associated with decreased oxidative phosphorylation and loss of mitochondrial function despite enhanced glycolysisbut can be reversed using anti-oxidants [31] . data is now showing that covid-19 patients do have populations of t-cells displaying mitochondrial dysfunction, as well as altered mitochondrial markers in monocyteshinting that immune-metabolic phenotyping could be used to understand disease pathogenesis and possible treatments; this could include targeting mitochondria [32] . in short, the immune system itself could well be a target for this virus. apart from the virus targeting the tcr as a super antigen, there is evidence that other than it binding to the angiotensin converting enzyme (ace) as its main receptor, it may also bind receptors on immune cells, such as cd147 and cd26 [33] , or neuropilin-1 (nrp-1) [34, 35] . we have structured this paper to first review the now established data on general mitochondrial function and health in relation to "inflammaging", followed by the evidence suggesting that the sars-cov-2 virus itself manipulates mitochondrial function and what we might learn from batswhich are thought to be its natural host. from this we propose that a poor lifestyle accelerates "inflammaging" which is associated with mitochondrial ill-health, and in some populations this predisposes them to a worse outcome. in the second part of the paper we discuss the implication of this idea in relation to current and suggested drug-based treatments and vaccine efficacy, the "long-covid" syndrome, as well as how environmental factors may make some people more vulnerable. understanding these concepts may help inform clinical strategy. circulating extracellular vesicles (evs) derived from immune cells seem to have emerged as a means of studying immunosenescence. in particular, they show an agerelated decline in mitochondrial functionwhich could be related to dysfunctional mitophagy [36] . in fact, mice engineered to have dysfunctional t-cell mitochondria display accelerated senescence and "inflammaging", highlighting the point that t-cells can determine organismal fitness and lifespan [37] . this does support data indicating the importance of a healthy t-cell response in defending against the virus [38, 39] . the underlying aetiology for "inflammaging" has long thought to be associated with mitochondrial dysfunction as suggested by nick lane in 2003 in his "double agent" theory [5] , and is now receiving renewed interest, for instance, in how decreasing mitochondrial function can reduce t-cell function and enhance immune senescence, as mitochondria are pivotal in metabolic reprogramming towards the warburg effect [40] . indeed, as mitochondrial dysfunction can lead to "inflammaging", the observed increase in older people of mitokines could be an attempt by the system to restore homeostasis as many are anti-inflammatory. unfortunately, for many, this response doesn't fully compensate [41] . this is why "exogenous" factors, such as physical activity or calorie restriction seem to be required to optimise function; these were normal factors during evolution, but are not in our modern sedentary and obesogenic environment. one aspect of ageing is a failure to remove damaged components, for instance, dysfunctional mitochondria via mitophagy, which could lead to immune dysfunction [42] . it has been suggested that imbalances in mitochondrial mass could be responsible for ageing-related t-cell subset dysfunction [43] , which would suggest a failure of mitophagy. indeed, activation of mitophagy/autophagy is thought to be a pivotal mechanism in slowing ageing and inhibiting inflammation during calorie restriction (cr) [44] : cr/intermittent fasting has been suggested as a defence against the sars-cov-2 as it is antiinflammatory [45] . in contrast, a modern sedentary lifestyle is also contributing to "inflammaging", which acts as a common mechanism linking sarcopenia, obesity, cardiomyopathy and dysbiosis, with over-activation of nod-like receptor pyrin family domain containing 3 (nlrp3) inflammasomes and mitochondrial dysfunction playing key roles [46] . overall, this all seems to support a close link between immunosenescence, inflammaging and failing mitochondrial function. does sars-cov-2 modulate mitochondrial function, either indirectly or directly, and if so, in what cells? the above suggests that there is a close link between mitochondrial dysfunction and immunosenesence, which could lead to an increased chance of an imbalanced immune response to sars-cov-2. this could take the form of both an inability to clear it, but also an exaggerated pro-inflammatory response and a "cytokine storm". however there could also be another factor, and that is that the virus is modulating mitochondrial function to help it replicate. one clue to this possibility is that many viruses do appear to manipulate bioenergetics towards aerobic glycolysis (the "warburg effect"); this is a highly energydependent process to help generate substrates to build new virus particles [47] . aerobic glycolysis does require healthy mitochondria, and is a normal process in multiple cell types, including immune cells [48] . perhaps tellingly, data suggest that successful clonal expansion of vaccine-elicited t-cells is heavily depending on mitochondrial function [49] . what this suggests is that any cell forced to produce new viruses, if its mitochondria are not functioning optimally, could rapidly become energy deficient and be more likely to die, and depending on its type and location, could either enhance inflammation and/or compromise the immune response. what are the sars-cov-2 receptors and where are they found? the direct impact of the virus will depend on which cells it infects. to date, most evidence points towards ace2 being the primary receptor for this virus. early data suggested ace2 is predominantly expressed in pulmonary alveolar type 2 progenitor (at2) and respiratory epithelial cells, but is also expressed in myocardial, illium and oesophagus, as well as some kidney cellswith little expression in immune cells [50] . elevated ace2 expression has also been found in the olfactory neuroepithelium, potentially explaining the anosmia that some patients have suffered [51] . more recent data has suggested that ace2 may be primarily expressed in bronchial transient secretory cells [52] . perhaps of relevance to the increased risk associated with obesity is that high ace2 expression has been found in both visceral and subcutaneous adipose tissue; this is important as adipose tissue in obesity is well known to secrete higher levels of angiotensin 2, an inflammatory component of the renin-angiotensin aldosterone system (raas), which is key in driving many of the pathological complications associated with this condition [53] . critically, obesity also seems to be associated with increased expression of ace2 in the lung, and enhanced inflammatory markers and dysregulated lipogenesis; viruses are well known to hijack lipid metabolism as part of their life cycle [54] . although ace2 is not highly expressed in immune cells, it is possible that other proteins expressed on immune cells could be acting as sars-cov-2 receptors, such as cd26 (also known as dipeptidyl peptidase 4, dpp4) or cd147 (also called basigin). cd147 can be activated by cyclophilins, which are inhibited by cyclosporine a. critically, the expression of these potential receptors changes with age, as well as with co-morbid conditions, such as obesity and hypertension [33] . thus both cd147 and cyclophilin a have been suggested as potential targets for treating the virus. for example, cyclosporine is very effective against corona viruses; however, its immunosuppressive actions would limit its usefulness [55] . cd147 and ace2 expression is often increased in lung disease, resulting in excessive activation of the raas and enhancing damage, which could, in part, explain the origins of the cytokine storm. it has been suggested that melatonin, a potent natural anti-oxidant, could suppress the cd147 inflammatory pathway and help in treating covid-19 patients [56] . in silico binding studies do seem to support the possibility that the virus does indeed use cd147 as a receptor, and could, potentially, explain why lymphopenia is associated with severity of covid-19 and a loss of t-cell subsets [57] . data is indicating that this virus may also bind to neuropilin-1 (nrp-1); this protein is expressed on many cells, including those in the central nervous and immune systems, and is also a receptor for vascular endothelial growth factor a (vegf-a) [34, 35, 58] . apart from suggesting it can thus potentially infect the central nervous system (cns), it also appears that sars-cov-2 can induce analgesiawhich could aid in increased disease transmission in asymptomatic individuals [59] . nrp-1 is also a focus for immunotherapy treatments in oncology, as it is expressed on subsets of regulatory t-cells [60] . there is also data indicating it is expressed in the cardiovascular system; if its expression is reduced, it results in cardiac mitochondrial dysfunction as it controls the master mitochondrial regulator, peroxisomal proliferator-activated receptor γ coactivator 1α (pgc1α), as well as peroxisomal proliferating activating receptor γ (pparγ) [61] . this data does suggest that the virus not only modulates essential components of the raas affecting inflammatory balance via ace2, but if it is also modulating the t-cell response directly, for instance, via cd147, or the tcr, or even, nrp-1. in sars-cov-1 the open reading frame-9b (orf-9b) encodes for a protein that locates to the mitochondrion. here it induces fusion by triggering degradation of dynamin-like protein 1 (drp-1), while inhibiting mitochondrial anti-viral signalling proteins (mavs). this is thought to underlie its ability to suppress the anti-viral interferon response. it can also induce autophagy and activate nf-κb [62] . mavs are small proteins that on detection of double stranded rna (dsrna) oligomerise on mitochondria to form a signalling platform and initiate interferon signalling, as well as cell death [63, 64] . it also seems that mavs can act as adaptor proteins for nlrp3, forming a complex with mitochondria, although the inflammasome can also be activated in a way that doesn't induce an interferon response, but can induce the interleukin beta (il-β) response [65] . with regards sars-cov-2, protein interaction mapping shows that it shares a great deal of homology with sars-cov-1, but significantly, several of its proteins are also predicted to directly interact with mitochondria, such as non-structural proteins (nsps) 4 and 8, and orf9c, as well as components of the interferon and nf-κb pathways [66] . this, because of the well described role of viruses in manipulating mitochondrial function, has led to other groups suggesting that indeed, mitochondrial "hijacking" by sars-cov-2 could be a key factor in the pathogenesis of this virus [67] . many viruses also use viroporin proteins that can oligomerise to help viral entry and release, as well as control intracellular signalling ions, such as calcium or potassium. they can also, via direct protein interaction, manipulate signalling pathways. the host cell detects these as changes in ions levels and ros, and via, for instance, the nlrp3 inflammasome, activates cellular defence [68] . sars-cov-1 has at least three viroporins, two of which are essential for replication and virulence [69] ; the e protein, in particular, not only seems to trigger p38 mapk activity, but also seems to modulate calcium flux by acting as a permeable ion channel in endoplasmic reticulum-golgi intermediate compartment (ergic)/golgi membranes, activating the inflammasome [70] . sars-cov-2 seems to have a similar e viroporin that induces ionic imbalance [71] . from the calcium and ros signalling perspective this is particularly important, as mitochondria are not only pivotal in calcium buffering and signalling, but are also controlled by calcium [72] . data suggest that many viruses form viral "factories", which are constructed from host cell membranes, and are often tightly coupled to mitochondria to provide precursors and energythis includes the coranoviridae [73, 74] . emerging data is now suggesting that t-cell mediated immunity may be playing a powerful role in protecting against the virus, as many asymptomatic people, or those who have only had mild symptoms, show low levels of anti-sars-cov-2 antibodies but a strong t-cell mediated response against the virus. in contrast, more severe disease is associated with more rapid seroconversion and the presence of inflammatory markers, such as creactive peptide (crp) [75, 76] . in fact, it now appears that the severity of infection positively correlates with a decreased type 1 interferon (ifn1) response, but an exaggerated inflammatory response, characterised by high levels of interleukin 6 (il-6) and tumour necrosis factor alpha (tnfα)possibly related to excessive activity of nuclear factor kappa b (nf-κb). this latter finding could be related to an auto-inflammatory loop in the lungs [77] . it does seem that in some people that the transcriptional response to sars-cov-2 is imbalanced, with a less than optimal interferon-i and -iii response, but an exaggerated chemokine one; this may represent an evolved manipulation of the immune system by the virus that worsens the outcomes for older patients with comorbidities as they cannot clear the virus properly [78] . data from autopsies of deceased covid-19 patients show that tissue inflammation and organ dysfunction do not map to the cellular distribution of the virus, hinting at tissue-specific tolerance. in fact, severe inflammatory changes seem to be largely restricted to the lungs and the reticulo-endothelial system. this suggested that covid-19 related deaths were due to immunemediated, rather than pathogen-mediated organ inflammation and injury [79] . it may therefore be relevant that ifn1 can also have some anti-inflammatory actions, modulating for instance, nlrp1/3 inflammasomes and inhibiting interleukin-1 (il-1) production [80] . type 1 interferons are key in modulating t-cell responses and resistance to viruses [81, 82] . it had been suggested that as the virus uses ace2 as a receptor on the cell surface it could trigger activation of the renin-angiotensin-aldosterone system (raas), which in turn, leads to hyperactivation of the nlrp3 inflammasome and pyroptosis, a form of cell death that results in inflammatory amplification [81] . data does now seem to support this and has been shown in various types of human stem cellswhich could potentially affect tissue regeneration [83] . ace2 cleaves angiotensin ii to generate angiotensin (1-7), which is largely anti-inflammatory and protective [84] . critically, mitochondria have a functional angiotensin system [85] , and ace2 seems to be mitochondrially protective [86] . potentially of interest here is that a product of ace2, angiotensin-(1-9), seems to inhibit mitochondrial fission in the heart, enhancing mitochondrial fusion and calcium buffering and protecting against cardiac hypertrophy [87] . it is thus possible, by binding to ace2, the virus may suppress a counterbalancing anti-inflammatory pathway that affects mitochondrial function. so why would sars-cov-2 do this? one possible explanation is that the virus affects the most prevalent immune cells in the lungs, monocytes/macrophages, inducing them to shift metabolically to aerobic glycolysis, which favours viral growth. the infection, in the presence of oxygen, seems to achieve this by triggering mitochondrial reactive oxygen species (ros) production, stabilising the hypoxia-inducible factor-1α (hif-1α), which in monocytes, consequently inhibits t-cell responses and lung epithelial cell death. it seems that high glucose levels induce viral replication [88] . furthermore, the inflammasome can also modulate glycolysis; in macrophages, this may be a key process in metabolic reprogramming [89] . critically, inflammasome activation can be inhibited by nuclear factor, erythroid 2-like 2 (nfe2l2/nrf2), which is pivotal in enhancing antioxidant defences and suppressing inflammation [90] ; it therefore counterbalances nf-κb, which is also redox activated, but central to the immune response [91] . another key factor is that the sars-cov-2 genome encodes proteins that can target the nf-κb pathway [66] . sars-cov-2 therefore seems to induce a warburg shift (aerobic glycolysis), which is a tactic that many other viruses, and cancer cells, use [47] . it is thus of relevance that that the metabolic reprogramming induced by sars-cov-2 can be suppressed by melatonin [92] , which is a powerful antioxidant that protects mitochondria [93] . in fact sars-cov-2 also seems to induce activation of pathways like p38 mitogen activated protein kinase (mapk), which results in cell cycle arrest, inhibition of apoptosis, and results in a feed-forward inflammatory loop [94] ; the systems it targets therefore do seem have much in common with those that are altered in cancer [95] . critically, mapks also modulate mitochondrial function, for instance, interacting with the voltage dependent anion channel 1 (vdac1) [96] . this seems to add up to the virus manipulating several pathways to invoke aerobic glycolysis, which must involve mitochondrial function. diabetes is also associated with activation of p38 mapk via ros generated by glucose induced mitochondrial dysfunction that can be offset by targeted mitochondrial antioxidants [97, 98] . not only is diabetes a risk factor for a worse outcome when infected with sars-cov-2, but the virus itself may induce a worsening of the condition [99] [100] [101] . indeed, it now seems that fasting blood glucose is a predictor of mortality for covid-19 patients [102] . overall, prediabetes and/or type 2 diabetes (t2d) itself is embraced by the concept of the metabolic syndrome in which insulin resistance, mitochondrial dysfunction and inflammation are all components [12] . metformin, which modulates mitochondrial function, is a key treatment for t2d [103] and has shown some benefit in covid-19 patients [104, 105] . in contrast, evidence indicates that the inflammatory effect of the western diet may induce activation of the nlrp3 inflammasome [106] . in light of the emerging data, this could only worsen the potential for an exaggerated inflammatory response. it is therefore likely that sars-cov-2 does modulate mitochondrial function. so it could be surmised, for instance, that this virus could ensure close tethering of mitochondria, and via calcium flux, stimulate their function. clearly, if this process was too overwhelming, or the mitochondria were already functionally compromised, this would rapidly lead to mitochondrial stress. with regards this, singh and colleagues have highlighted an interesting link with viruses and the production of mitochondrially-derived vesicles (mdvs), which are normally part of a system to remove damaged components from the mitochondrion [67] . if, like sars-cov-1, this new virus also does this, and also induces mitochondrial fusion, it hints at an interesting ability to prevent apoptosis, as well as mitophagy, but stimulate a mechanism to move virus particles around. if it is also inhibiting mav activity, then the mitochondrion might not initiate interferon signalling, but might still continue, potentially by producing higher than normal levels of ros, to stimulate inflammasome activity and metabolic reprogramming towards glycolysis. in effect, the virus repurposes the normal inflammatory metabolic reprogramming towards aerobic glycolysis, which involves modulation of mitochondrial function, but manages to suppress the normal anti-viral interferon response. in many tissues, the system may manage to stay in balance and not cause an overt over activation of the immune system, but in the lungs, it seems that in some people, this balance is lost. figure 1 summarises this. as indicated, if the virus is modulating mitochondrial function in a variety of cell types, either directly, or indirectly, then the more robust the mitochondrial system, fig. 1 viruses like sar-cov-2 manipulate cellular metabolism leading to the potential for a feed-forward inflammatory loop. viruses have evolved to usurp their host's cellular machinery to make more viruses. one common mechanism is to suppress apoptosis and manipulate the immune system to inhibit specific anti-viral programmes, which usually means interferons, while stimulating a shift towards aerobic glycolysis to provide precursors to build new viruses. however, this latter ability repurposes pathways that are often involved in generalised immunity that both increase the production of pro-inflammatory mediators, while metabolically reprogramming immune cells. in the case of sars-cov-2 this may well result in a feed-forward pro-inflammatory loop in the lungs, which seems to be driven by monocytes/macrophages switching to aerobic glycolysis and is driven my mitochondrial ros and stabilisation of hif-1α; in turn, this metabolic shift suppresses t-cells and the interferon response [88] . this process is accentuated as the virus may well stimulate inflammasome activation [81] , while if it is similar sars-cov-1, it could also suppress mavs formation and activate nf-kb [62] ; protein interaction mapping does suggest this is the case [66] . as it is likely that inflammasome activation can also invoke glycolysis [89] , then the evolutionary rationale seems sound. of particular importance here is also the balance between nf-kb and nrf2, which more or less seem to counter-balance each other, as nrf2 is pivotal in suppressing excessive oxidative stress [91] . for more detailed reviews of the role of mitochondria in the immune response see [22, 107] the greater the chance of the system being able to resist the virus. in general, hormetic factors, such as exercise, seem to be necessary to maintain mitochondrial health throughout the body; this phenotype is associated with a more balanced immune response and minimisation of "inflammaging". in this section we review why this is, and look at why one of the natural hosts of the virus, the bat, may be able to resist. a robust mitochondrial system and effective immune system may rely on hormesis a key component of effective immunity is now thought to be a healthy mitochondrial system [107] , while an underlying unifying element to both the ageing process and conditions associated with a poor lifestyle is a degradation in overall mitochondrial function/reserve and a rise in oxidative stress and inflammation [4, 5] . an important factor in the maintenance of mitochondrial function is hormesis where low levels of stress induce an over-compensatory response that induces positive adaptations, enabling an organism to better tolerate the stressor next time they encounter it. for example, an effective hormetic response can be induced by sub-lethal doses of physical activity, calorie restriction and many plant polyphenols [12] , with mitochondrial stress being a key trigger [108] . this results in an enhanced respiratory reserve and anti-oxidant capacity, and a greater ability to manage the atp/ros ratio when placed under stress [109] . certainly, small, long-lived species like bats and sparrows, when compared to comparatively much shorter lived species like mice, do demonstrate lower levels of mitochondrial hydrogen peroxide release [110] . given that mitochondrial dysfunction is strongly correlated to immune dysfunction and chronic inflammation [111] , then inflammation resolution is probably going to be best achieved by ensuring healthy mitochondrial function as it ensures that ros release does not get out of control. the concept of hormesis suggests that it is important to constantly stimulate the renewal and maintenance of a large population of healthy mitochondria. it may therefore be possible to learn something from one of the natural hosts of sars-cov-2, bats [112] . bats are the only true flying mammal and are exceptionally long-lived for their size. this could be because the evolution of flight has required a whole host of adaptations, including maintaining a large pool of mitochondria that produce very little ros while maintaining a high atp output. this appears to have gone hand-in-hand with changes in the immune system to prevent excessive inflammatory activation by stressed mitochondria, for instance, by dampening nlrp3 inflammasome activity. the net result is that many bats can tolerate high levels of viruses, like the coronaviridae family [113] [114] [115] [116] and do show a reduced antibody and inflammatory response, hinting they are using another part of their immune system to control the virus [117] . the inflammasome may thus be important, as its activation can lead to pyroptosis, an inflammatory form of apoptosis, and can be triggered by excessive mitochondrial stress [118] . it may well be an essential component in "inflammaging" [42] . there is some evidence that at least in some species of bat, mitochondrial health, despite bursts of oxidative stress, is maintained by stringent mitochondrial quality control mechanisms, like mitophagy [119] . mitophagy is in fact a negative regulator of nlrp3 inflammasome activity, so although mitochondrial damage can activate the inflammasome, it can also activate counter-balancing mitophagy to prevent excessive inflammation [120] . in short, it seems that powered flight has required the co-evolution of both mitochondria that tightly control ros, and a co-adapted immune system. critically, there is evidence that sars-cov-2 inhibits autophagy [121] , suggesting it might also inhibit mitophagy. if this virus does indeed induce mitochondrial fusion, as sars-cov-1 may do [62] , then this would fit, as mitochondrial fusion can inhibit mitophagy, and can inhibit cell death and ensure energy production, although prolonged fusion can also initiate cell death in some circumstances [122] . this latter point suggests another innate anti-viral mechanism. overall, modulation of the inflammasome could be one element in how the virus could result in an "inflammaging" phenotype. the effects of hormesis, certainly for humans, are perhaps most clearly seen in response to exercise training, in particular, aerobic training, where both mitochondrial capacity and function is increased in young and old [123, 124] . this is matched by increased survival and healthier ageing in cohorts who undertake plenty of physical activity [125] . active muscle is generally inflammatory, but commensurately induces counterbalancing powerful anti-inflammatory and anti-oxidant mechanisms throughout the body. exercise thus appears to show a biphasic dose response and the evidence is building that as long as it is not done excessively, in particular, allowing time for recovery, it is highly beneficial: over time the adaptive over-compensation includes an improved anti-inflammatory and anti-oxidant feedback (25) (26) (27) (28) [126] . muscle has now been shown to have other functions, like harbouring and supplying anti-viral stem t-cells, hence, antagonising t-cell exhaustion and protecting proliferative potential during inflammation [127] . in contrast white adipose tissue plays a key role in adaptive immunity, and in excess, contributes to the altered immune function and chronic inflammation often associated with obesity [128] . in particular, excessive visceral adipose tissue (vat), seems to play a pivotal role in obesity-related pathogenesis; critically, its volume is decreased by exercise [129] . furthermore, not only does type 1 interferon unlock dormant adipocyte inflammatory potential [130] , but exercise reduces adipose expression of nlrp3 [131] . it therefore seems that adipose tissue and muscle play a yin-yang role in the immune response, whose set point will thus be determined by an individual's fitness and calorie balance, and overall mitochondrial capacity and health, and thus, reserve. in short, mitochondrial reserve, and thus spare respiratory capacity, is pivotal in enhancing the "healthspan", and is greatly improved by exercise [109] . the key here is that stress can be signalled from mitochondria in any tissue to the rest of the body by way of "mitokines"; muscle activity is a prime inducer of mitochondrial stress [132] . it therefore seems that control of inflammation is associated with tight control of mitochondrial ros, which is itself dependent on "mitohormesis" by factors such as exercise, plant compounds in the diet, and calorie restriction [108, 133] . the basis for this is that life is based on redox and compartmentalised production of ros as part of a signalling system [134, 135] . this has led to redox theories of disease and ageing, focussing on the mitochondrion [136] and their role in generating an agerelated rise in inflammatory tone [5] , which supports the pivotal role of mitochondria in the immune system [137] and in resistance to infections including viruses [138] . in support of this, there is increasing evidence that mitochondria can also act as net sinks of ros and this is linked to lifespan. for instance mitochondria from the long lived naked mole rat (nmr) produce less ros than comparable shorter lived animals [139, 140] . furthermore the mitochondria in nmr, and bats, also appear to be able to maintain a depolarisation of the inner membrane for much longer during their life cycle, which is a key mechanism to reduce ros production during ageing [141] . a key idea that relates to this is the redox-optimised ros balance (r-orb) hypothesis, which stipulates that mitochondrial emission of ros will reach a nadir when respiratory rate reaches a maximumin effect, mitochondria will maximise atp production and minimise ros as they evolved to work at an intermediate redox state [142, 143] . thus having a good mitochondrial reserve might suggest that this nadir can be maintained when the system is put under stress. an essential component of mitochondrial control is uncoupling. this is a process whereby the proton gradient in the mitochondrion is uncoupled from atp production, and it initially seemed to be a key process to reduce ros production, as well as generating heat. it was therefore thought to act as a very good safety valve for mitochondria and play a fundamental role in survival and prevention of oxidative damage. in fact, 20% or more of the energy captured by electron transport is dissipated. however, uncoupling can also be associated with an increase in ros, hence, it is a key component of redox signallingand has led to updated versions of the "uncoupling to survive" hypothesis. it may therefore play a key role in mitohormesis, resulting not just in cell autonomous adaptations, but also systemic adaptation from signals, for instance, sent out from stressed skeletal muscle via mitokines. uncoupling also controls calcium signalling. it now seems that mild uncoupling can, indeed, lead to increased longevity [144] . it is thus perhaps relevant that a mitochondrial uncoupling protein, ucp2, can negatively control the inflammasome [145] , and in general, seems to suppress immune activity [146] . uncoupling thus plays an important role in mitochondrial efficiency, which can either be defined as the respiratory control ratio (rcr -ratio of mitochondrial respiration supporting atp synthesis to that required to offset the proton leak) or the atp/oxygen ratio (the amount of atp generated per unit of oxygen consumed) this can lead to some confusion, as it can lead to opposite conclusions about efficiency. however, whichever metric is used, it does describe the capacity to convert resources into atp, and in effect, the coupling efficiency [147] . in fact a study has shown that skeletal muscle mitochondria in obese, sedentary and insulin resistance women somewhat paradoxically show reduced mitochondrial coupling, but a higher production of mitochondrial hydrogen peroxide. in effect, despite a degree of uncoupling, their mitochondria were showing signs of oxidative stress; this might have been due to nutrient overload. however, an exercise training programme corrected this, and was correlated with an improvement of mitochondrial function, in particular, an enhanced ability to undertake beta oxidation of fats and restoration of metabolic flexibility, the ability to switch between carbohydrate and fat as energy sources, and better insulin sensitivity [148] . the apparent increase in uncoupling could be part of a homeostatic response to reduce excessive ros production, as ucps can be activated by oxidative stress [149] . this would further support evidence that exercise induces an adaptive response that enabled the mitochondrial system to cope better. finally, it is perhaps worth emphasising the link between mitochondrial reserve and ability to control oxidative stress. mitochondria can generate ros and are closely linked to nrf2, which is a master transcription factor controlling antioxidant responses [150] . this suggests that exercise will not only induce greater mitochondrial reserve, but greater anti-oxidant capacityand perhaps, a greater reserve ability to uncouple to manage oxidative stress. as previously indicated, like the original sars virus, this new virus also seems to induce worse outcomes in patients who are older, have hypertension and cardiovascular disease, and induces a phenotype characterised by raised inflammatory and coagulation markers, multiorgan failure, as well as neurological complications and myocardial injury [151] . in short, most things we identify with the ageing process and the metabolic syndrome, both of which are associated with declining mitochondrial function [152, 153] . it thus pertinent that the rate of ageing can be modified by lifestyle and disease, and that epigenetics are making it possible to determine, with some degree of accuracy, the biological age and compare it with the chronological age through dna methylation (dnamage), and predict the likelihood of future mortality [154, 155] . although mitochondria obviously play a role in this, and reduced mitochondrial dna copy number (mtdnacn) does appear to be a proxy for mitochondrial buffering capacity, and is negatively correlated with dnamage, the precise relationship with biological age is still unclear. for instance, evidence does indicate a clear role for mitochondria in ageing-related disease and mortality, but not necessarily chronological age [156] . however, data does suggest that inducing mitochondrial dysfunction alone in t-cells can induce premature senescence, driving "inflammaging" and a tendency towards a cytokine storm [37] . one well known concept in ageing is the idea of declining organ reserve, which at the molecular level, is related to a loss of excess metabolic capacityin particular, bioenergetics and mtdna, as well excess telomere capacity [157] . in this respect, it could be argued that the immune system could be viewed as an organ, and is also subject to declining reserve. as the immune system ages there is a subclinical accumulation of pro-inflammatory factors, as well as decreased numbers of circulating respiring mitochondria found in extracellular vesicles (evs), which are derived from immune cells [36] . coupled to this, there is also evidence that with increasing age the monocyte inflammasome-mediated inflammatory response is altered. for instance, this response to influenza a is retained but the anti-viral interferon response declines [158] . furthermore, ageing is also associated with a gradual loss of anti-oxidant capability that is associated with a decrease in the t helper 1 (th1) anti-viral response, which might underlie some of the anti-viral activity of glutathione and other anti-oxidants [159, 160] . this is certainly commensurate with reduced immune system reserve. however, there is still a lot that is not understood about ageing, which is why it has led some authors to categorise it using several separate hallmarks, with mitochondrial function only being one of several integrated systems as the precise cause is still not fully understood [161] . however, many authors continue to focus on the mitochondrionmainly because it represents an ancient nexus that arose from the endosymbiotic event between a prokaryote and archaean that gave rise to eukaryotes, and understanding this does provide insight into the immune system and inflammation, and the ageing process [152, 162] . some have suggested that ageing is actually related to the loss of mitochondrial respiratory reserve capacity [109] . this, we suggest, does have a great deal of merit, and in relation to resistance to viruses, could be viewed from a reduction in bioenergetic/redox capacity of the immune system as people age. tellingly, reduced skeletal muscle mtdnacn is associated with symptoms of the metabolic syndrome, whereas exercise increases mtdnacn and is negatively associated with markers of the metabolic syndrome and enhanced aerobic capacity [163] . thus although certainly not the entire story, ageing is associated with declining mitochondrial function, which is likely to be related to reduced immune "reserve" and flexibility. hence, as a proxy for potential severity when infected, mitochondrial function does have its place in the ageing process. the lessons for humans are thus fairly clear: exercise is part of our evolutionary heritage, and plays key role in maintaining optimal mitochondrial health and immune balance (fig. 2) . as is becoming clear, maintaining good health, in particular, optimal levels of aerobic fitness and muscle/fat balance is a good preventative strategy, in effect, the results of living a healthy lifestyle. a retrospective study following the hong kong influenza outbreak in 2008 found that physical activity was protective and displayed a "u" shaped dose-response curve [165] . high aerobic fitness is associated with reduced morbidity and mortality [166, 167] and physical activity, if not overdone, is generally anti-inflammatory in the longer term [15, 168] and results in an enhanced anti-oxidant status [169] . equally, calorie restriction, which is associated with improved lifespan, is also anti-inflammatory [170, 171] , as is a diet high in polyphenols and probiotics [172] . however, there are still many people, who, for various reasons are not living a particularly healthy lifestylethe effects of which become worse with age. this therefore raises the question, would enhancing/supporting mitochondrial health help in this population if they become infected and would understanding the role of mitochondria help in deciding treatment regimens? there are a number of possibilities, ranging from suppressing the auto-inflammatory loop (e.g., direct targeting of inflammatory pathways, with, say antibodies, or kinase inhibitors), to mitochondrial protection, enhancing mitochondrial turnover and renewal and preconditioning, to direct management of redox. in fact, it seems that many established drugs probably already do modulate mitochondrial function, which may provide us with further insight. the other main strategy and one perhaps with the greatest potential preventative benefit in the long run, is vaccination. the implications of mitochondrial health here could be extremely important in whether or not a vaccine is successful in particular populations, for instance the elderly and those with co-morbidities. many of the compounds now being studied may influence mitochondrial function. for instance research on immunomodulation during influenza infections has fig. 2 resistance to sars-cov-2: mitochondrial and redox reserve, hormesis and the metabolic/inflammatory see-saw. data strongly support that people who are aerobically fit, and follow a healthy lifestyle, tend to have a greater metabolic and anti-oxidant reserve related to training-induced mitochondrial adaptation; this is associated with less disease and a longer "healthspan". the underlying principle that leads to this is described by hormesis and is the product of humans having evolved, along with most other animals, in an environment where this adaptation was constantly induced due to the need to move, and food was less available. as a phenotype, they tend to have greater muscle to fat ratio, and exhibit few, if any symptoms of the metabolic syndrome, such as increased liver fat and visceral adipose tissue (vat) volume, insulin resistance, or markers of chronic inflammation. in this context, data suggest that muscle, as an organ, tends to be anti-inflammatory when used regularly, whereas adipose, in particular, in vat is inflammatory if it becomes overloaded. as the virus seems to induce oxidative stress [164] and aerobic glycolysis to enhance its own replication, it could be argued that in a person with poor mitochondrial and anti-oxidant reserve, infection will tend to tip towards chronic inflammation and incomplete resolution. in this scenario, it is important to suppress either inflammation itself, or provide extra anti-oxidant power to damp down the potential for a feed-forward inflammatory spiral looked at corticosteroids, peroxisomal proliferating activated receptors (ppar) agonists, cyclooxygenase (cox) inhibitors, adenosine monophosphate kinase (ampk) activators, direct antioxidants, and natural products [173] . all of these can modulate mitochondrial function [174] [175] [176] [177] [178] . non-steroidal antiinflammatory drugs (nsaids) in general, to varying degrees, affect mitochondrial function [179] . critically, network-based drug repurposing has recently identified several candidates, such as irbesartan, paroxetine, sirolimus, melatonin and quinacrine, amongst others [180] . it has been suggested that angiotensin receptor blockers (arbs) are mitochondrially protective [181] , while anti-depressants, such as paroxetine, can inhibit mitochondrial function [182] . sirolimus, or rapamycin, is actually one of the best studied calorie restriction mimetics as it modulates mammalian target of rapamycin (mtor); it is anti-inflammatory and modulates mitochondrial function, and could play a key role in mitohormesis [183] . it can, in fact, increase mitochondrial respiration and reduce production of hydrogen peroxide [184] . critically, data does suggest that this new virus can indeed inhibit autophagy and the mtor pathway [121] . this might suggest that it can enhance atp production while reducing ros, which would obviously benefit it (by at least, initially, suppressing immune activation). overall, it could be argued that compounds that do inhibit mitochondrial function might have a number of effects, such as inducing mitohormesis, so activating mitochondrial turnover and renewal, but they could also disable mitochondrial support for viral replication, and perhaps, enhance apoptosis. however, this has to be balanced with the possibility that they could cause too much damage, and potentially, worsen the situation. one group of drugs that has been investigated as a possible treatment for sars-cov-2 are the antimalarial aminoquinolones, which have been investigated for decades as immunomodulators and anti-virals. their basic mode of action involves proton capture and deacidification of the lysosomal/endosomal compartment, which interferes with viral replication, autophagy and inflammatory pathways, but they also affect the plasma membrane, map kinases, calcium signalling, as well as dna [185] . they can also modulate mitochondrial function [186] [187] [188] and have been shown to have antioxidant activity [189] . paradoxically, they can also induce oxidative stress, which has raised concerns about their use in covid-19 treatment due to the hypoxia associated with the acute respiratory distress syndrome (ards); one suggested mechanism is increased ros generated by mitochondriaas well as possible direct effects on mitochondria [190] . a meta-analysis has shown that hydroxychloroquine used in treatment of covid-19 resulted in a 2.5 times greater mortality compared to control groups, whereas its use was associated with a 1.2 times improvement in patients with mild to moderate symptoms compared to a control group [191] . a pharmacovigilance study also found that the use of hydrochloroquine/chloroquine for treatment of covid19 was associated with higher rates of cardiovascular side effects [192] . interestingly, in another study, although hydroxychloroquine and chloroquine were not associated with any significant effect on mortality, hydroxychloroquine, but not chloroquine, was associated with a significant reduction in transfer to the intensive care unit of patients admitted to hospital [193] . critically, a recent review of the literature show these molecules to have biphasic/hormetic effects in multiple models, for instance, they can both stimulate or inhibit cancer cell and virus growth depending on dose [194] . this not only highlights the role of dose, but also, potentially, the induction of oxidative stress and the patient's underlying health, and whether or not these compounds enhance risk or benefit. another very old anti-inflammatory drug, colchicine, is also being investigated for efficacy in covid-19 patients, as it seems to inhibit the nlrp3 inflammasome, perhaps by suppressing the transport of mitochondria [195] . interestingly, sars-cov-2 does seem to modulate many proteins related to the cytoskeleton, and can induce filopodial protusions [94] . colchicine is often used to study autophagy, as it depolarises microtubules, so inhibiting the process. it has now been shown that it can result in impairments in skeletal mitochondrial function, increasing ros, and in older animals, this can result in insulin resistance [196] . this all suggests that many of these drugs, especially those that might affect mitochondrial function, either directly, or indirectly, and could have an age-dependent effect -especially those that might affect autophagy. an important class of drugs are the mapk inhibitors, many of which have been developed as anti-cancer agents. as indicated previously, mapks can modulate mitochondrial function. they have been proposed as potential treatments as the virus seems to upregulate p38 activity and inhibit counter-regulatory pathways. although this may well help in viral replication, it can also result in excessive inflammation in some patients [197, 198] . interestingly, vemurafenib, a mapk inhibitor, has been shown to inhibit dynamin-related protein 1 (drp1) phosphorylation, reversing excessive mitochondrial fission in melanoma cells and resulting in hyper-fusion and enhancing oxidative phosphorylation and reversal of aerobic glycolysis [199] . this again highlights the parallels between cancer and viral infection in the sense that both induce extensive metabolic reprogramming and manipulation of the cell cycle, often towards aerobic glycolysis with modulation of mitochondrial function, as well as attenuating/modifying immune responses. data also suggest that cyclophilin inhibitors, such as cyclosporine a, which apart from being immunesuppressants, could also inhibit the replication of related corona viruses. data has already shown that some transplant patients receiving immunosuppressants seemed to have some protection against the virus, although these were observational studies and other factors, such as good hygiene, could be important. but in vitro data does hint at efficacy, especially on other corona viruses, such as middle east respiratory syndrome coronavirus (mers), as does evidence around the importance of the cyclophilins in aiding viral replication. the mode of action is thought to involve inhibition of the calcineurin and suppression of the nuclear factor of activated t cells (nfat) (reviewed in [200] ). in mice infected with mers-cov, it seems that cyclosporine induces a robust interferon gamma response, which is associated with inhibition of viral replication and release [201] . mavs are a key component of resistance to viruses, and can activate both interferon and nf-kb pathways, putting mitochondria centre stage in viral defence [202] ; data indicate that immunophilins are regulators of mavs [203, 204] . given the importance of cyclophilin d, a wellknown target of cyclosporine that modulates mitochondrial permeability transition [205] , it would be interesting to speculate that apart from the well described immunophilin targets of compounds like tacrolimus and cyclosporine, a role for modulation of mitochondria could not be ruled out. in this light, the effectiveness of the pan-cyclophilin inhibitor, alisporivir, which does not have immunosuppressive effects, is potentially interesting as it has high potency against sars-cov-2. it has been suggested that its ability to inhibit cyclophilin d, and thus control mitochondrial permeability, maybe of importance in preventing lung damage [206] . finally, some very promising preliminary data from the recovery trial suggests that low dose dexamethasone could help prevent death of up to 30% of ventilated patients [207] . on the 18th september 2020, the european medicines agency endorsed the use of dexamethasone in covid-19 patients on oxygen or mechanical ventilation (ema/483739/2020). the most well-known effect of glucocorticoids is to suppress inflammation, largely through the glucorticoid receptor (gr), but with chronic use they do have side effects, as they are catabolic [208] . the key point here is that glucocorticoids are generally induced by stress, and in the short term, are highly protective. it is thus relevant that grs also transfer to the mitochondrion and control mitochondrial gene transcription, and have biphasic actions [209] . it is thus relevant that dexamethasone has been shown to both induce mitochondrial uncoupling and increase oxidative phosphorylation [210] , but also cause mitochondrial dysfunction [211] . this is hardly surprising as mitochondria are central to both steroid biosynthesis and action, and thus, stress management [174] . although it might be surmised that the predominant effect in the recovery trial is through direct suppression of inflammatory pathways, it is not impossible that effects on mitochondria could not be ruled out. a further approach that has been suggested is suppression of oxidative stress by using compounds that are anti-oxidants. direct anti-oxidants, for example n-acetyl cysteine, which, although it has shown some efficacy, has met with limited success due to dose issues [212] . however vitamin c, which is now known to concentrate in mitochondria and act as a ros scavenger [213] , could be useful. a retrospective analysis of data has suggested that vitamin c can both reduce the time in the intensive care unit and the time on ventilators, particularly for very ill patients [214, 215] . it is now being suggested that it is used in combination with quercetin, which also seems to have efficacy in viral infections [216] : quercetin is a natural product that has anti-oxidant properties and concentrates in mitochondria and can induce mitochondrial biogenesis [217, 218] . another important principle is that many plant compounds seem to have anti-viral properties, as well as anti-cancer properties, and modulate calcium signalling and mitochondrial functionwith common targets, such as vdac. plants suffer both from viral infection and cancer, so it could be that there is some cross over in function from plants to animals [219] . as viruses seem to hijack their host's cellular machinery, including mitochondrial function, then partially inhibiting mitochondrial function could be an evolved strategy to defeat the virus, especially if it induces apoptosis and/or upregulates mitophagy and mitochondrial renewal and anti-oxidant systems. a good example of this is perhaps salicylic acid, which is a major plant defence signalling compound [220] and modulates mitochondrial function, both inhibiting the electron transport chain and acting as an uncoupling agent [221, 222] , as well as regulating vdac expression [223] . some plant viruses produce proteins that can inhibit the oxidative burst and salicyclic-acid dependent autophagy [224] . there is thus, potentially, useful insight provided by the observation that some medicines that are derived from plant (or other organism) defence compounds, also appear to have some benefit in human viral infections. indeed, gurbel and colleagues have suggested that aspirin could be used against sars-cov-2, for instance, by reducing its activation of nf-κb [225] . there is also interest in the potential for compounds such as cannabidiol (cbd) in helping covid-19 patients, as the cannabinoids do seem to have some antiviral activity, and are anti-oxidant and anti-inflammatory [226] . cbd, amongst its many identified targets [227] , does seem to directly modulate mitochondrial function, for instance, it has been shown to bind to vdac1 and inhibit the electron transport chain [228, 229] . there is also evidence that it can inhibit inflammasome activation [230] . one key mechanism is that many plant compounds activate nrf2 and are thus hormetic [231] . furthermore, as many manufactured drugs were developed from defence compounds found in plants and other organisms, this principle could be extended to include them. another example of this could be the statins, which also inhibit mitochondrial function [232] [233] [234] , and one study has indeed shown they can reduce mortality of covid-19 patients [235] . another ubiquitous antioxidant molecule, melatonin, which also protects mitochondria [236] , is also being investigated as an adjuvant to protect against a cytokine storm in sars-cov-2 infection [237] . interestingly, it has been shown to reverse the warburg effect in immune cells, potentially having an anti-inflammatory effect, and providing a justification for its use in covid-19 patients [92] . likewise, glutathione is also showing promise, in particular, as it seems to help redress the age related th1/th2 imbalance [160] . of potential relevance is the observation that a modified vitamin e derivative that concentrates in mitochondria has shown benefits in a model of cardiac inflammation induced by sepsis. it seems to do this by suppressing mitochondrial dna damage and its subsequent release [238] ; mtdna is a potent activator of the inflammatory system [239] . also of interest here is vitamin d, which has been suggested as a potential adjuvant treatment for patients with the virus, as it may restore immune function. in particular, it may enhance anti-inflammatory cytokine production and so limit the possibility of a cytokine storm. analyses do seem to show that it can have some benefit in people who have low levels of this vitamin [240] . critically, it modulates mitochondrial function, having diverse affects depending on the tissue; it can stimulate muscle mitochondrial function [241] , but may also enhance lipid storage and adipogenesis [242] . interestingly, it has been suggested that covid-19 morbidity increases with northerly latitude, suggesting a link with ultraviolet light and vitamin d [243] . vitamin b3 has also been shown to have some protective effects in mitochondrial myopathy models [244] , and has been suggested that it could help prevent lung injury in covid-19 patients [245] . finally, artificial mitochondrial anti-oxidant molecules, such as mitoq and skq1 could also provide benefit [246] . there are also compounds like luminol derivatives, which only become ros scavengers in areas of high oxidative stress and are showing some promise in modulating redox-driven inflammation [247] [248] [249] . however, unlike mitoq and skq1, it is likely that luminollike compounds act outside the mitochondrion [250] . the age related decline in immune function is well described, although not well understood, and affects virtually all components and has a big impact on the success of vaccinationwhich has led to a constant drive to improve vaccines for the older generation, in particular against influenza [251] . it is, however, recognised to be modifiable by many factors, ranging from exercise, to stress, and chronic infections [252] . critical in these responses is metabolic flexibility, for instance, the ability to switch between oxidative phosphorylation and glycolysis, and how this effects different sub-populations of cells and the pro-inflammatory/anti-inflammatory balance. for instance, aged b-cells lose oxidative phosphorylation capacity, and rely more on glycolysis and generate more ros. they also infiltrate adipose tissue, heightening inflammation in a process involving the nlrp3 inflammasome. in relation to the b-cell response, which is key purpose of vaccination, it seems that obesity, and the metabolic syndrome, accelerates immunosenescence and reduces the ability to produce antibodies [253] . a primary research area is on the development of vaccines for the elderly against influenza; on average, over the age of 65 years, the efficacy drops off rapidly. to study this, immunosenescence related markers in the blood have been correlated with outcome. interestingly, t-cell responses have been found to be a stronger correlates of protection than antibodies. although the biology is immensely complex, and may require a system level "vaccinomics" approach, dysregulated metabolism is clearly part of the problemand it has been suggested that treatments to correct dysregulated metabolic or other physiological processes may be required before administration of vaccines [254] . it would therefore seem that in order to improve the efficacy of vaccines, it is either necessary to tailor the vaccine to the particular immunosenescence profile a patient shows, or, perhaps to reduce their epigenetic age by ensuring they live a healthy lifestyle and so enhance their immune system. there are a number of factors to consider from this. if, as seems to be the case, this virus is modulating mitochondrial function, and thus, mitochondrial health is important, there are a number of intriguing possibilities. does mitochondrial function explain why morbidity may be greater among men than women? there are obviously confounding behavioural factors, but statistically, men seem to have higher rates of mortality than women when infected with the coronavirus [255, 256] . mitochondria in females may be more robust, which could explain why females tend to live longer than males [257] . would pollution lower resistance to the virus? nitrogen dioxide is oxidative and can induce pulmonary inflammation and reduce function [258] , oxidise mitochondrial cytochrome c [259] , while acute inhalation can cause mitochondrial dysfunction in the brain [260] . data from the united kingdom is now suggesting that high levels of pollution are linked to increased covid-19 lethality [261] . linked to this is the very disturbing evidence that iron-rich nanoparticles, largely derived from motor vehicles, are now being found in cardiac mitochondria in the very young, and are causing oxidative stress [262] . the renin-angiotensin-aldosterone system (raas) and mitochondrial function the coronavirus binds to ace2 [263, 264] and mitochondria have their own angiotensin system [85] . ace2 cleaves angiotensin ii to produce antiinflammatory molecules and protects mitochondria [84, 86] . this suggests ace1/2 polymorphisms will be a factor in reaction to the virus [265] . arbs, acei and statins may enhance ace2 activity. their role in treatment is thus debated [266, 267] . during hypoxia, mitochondrial function is inhibited, but then becomes a source of ros during reperfusion. could damaged mitochondria in the lung and/or heart lead to an exacerbation of symptoms if too much oxygen is given to a patient? this is clearly a difficult clinical conundrum, but does suggest that supplementary oxygen should only be used where absolutely necessary. compounds such as melatonin, cbd and curcumin have shown some protective effects ischaemic-reperfusion models [268] [269] [270] curcumin is an uncoupling agent [271] . cbd modulates mitochondria [228] . key in this is emerging data that hypoxic preconditioning requires a drop in the mitochondrial proton motive force [272] . management of etc uncoupling is thus vital for life to control oxidative stress [273] . ppars may play a key role in controlling uncoupling [274] . furthermore there is much evidence that anaesthetics can modulate mitochondrial function and could play a role in both preand post-ischaemia protection, and some can act as uncoupling agents [275] [276] [277] . two recent structure-docking studies have indicated that several phytochemicals could inhibit the sars-cov-2 protease [278, 279] . as many phytochemicals can also modulate mitochondrial function [280] , and primarily evolved to protect the plant, it could be surmised that they are multi-functional and modulate multiple pathways to achieve this. long term effects -"long covid" it is becoming clear that following recovery from the primary infection with sars-cov-2, many people are suffering from long term effects, such as fatigue and mental health problems, as well as more obvious lung problems. this has resulted in the formation of a national uk consortium and the launch of the phosp-covid study to investigate the long terms effects on health of this virus (see https://www.phosp.org/) [281] . one possible consequence of viral infection could be longer term mitochondrial dysfunction, which could lead to a variety of symptoms. mitochondrial function, and their relationship to immunity, is again becoming a focus for research in the chronic fatigue syndrome, which is still not completely understood [282] . this has been further supported by evidence of mitochondrial dysfunction in pbmcs of people with chronic fatigue syndrome [283] . can we test the hypothesis that mitochondrial health = immune health and enhanced resistance to the virus? in terms of testing and/or looking for evidence that mitochondria could help explain some of the pathophysiology of this virus, there are several potential ways to look for this relationship, ranging from laboratory based to population studies. this work could be carried out in vitro with cultured cells and/or isolated mitochondria prepared from control and infected individuals. in particular, using imaging to look for co-localisation in "virus factories". it could be predicted that those populations exhibiting the lowest levels of optimal health and the highest levels of the metabolic syndrome and "diabesity", will show the highest susceptibility. for example, it might be revealing to map the case fatality rate to the latest trends in obesity/ diabetes after the necessary confounders are taken into account [284] . in support of this, the emerging data from new york in relation to sars-cov-2 infection is that obesity is strongly correlated with critical illness [9] . in contrast, would those populations showing the highest fitness levels and functioning be more resistant? for instance, would measured vo 2 max show an inverse relationship with morbidity? individuals with known mitochondrial dysfunction are well known to show abnormal susceptibility to infections [25] . is there a link between mitochondrial haplotype and resistance? there is certainly evidence for different mtdna haplotypes amongst different populations [285] . although there is an emerging disparity in morbidity between black people and other minorities in the usa, it is thought it may be more to do with socio-economic imbalances and higher rates of lifestyle induced comorbidities [286] . blood-derived mitochondrial markers of reduced function may correlate with disease severity before, during and after infection. data now show it is possible to determine someone's epigenetic age and compare it with their chronological age. there is a close correlation with this ratio and coexisting morbidity [287] . thus, would blood-derived epigenetic markers of metabolic age correlate with disease severity before, during and after infection? the main conclusion from this review is that as immune function is dependent on mitochondrial function, and although this does decline with age, the rate it does so can be modified by lifestyle. this is perhaps best highlighted by the link between ageing, mitochondrial function and the metabolic syndrome. this implies that both resistance to the virus, and the effectiveness of a vaccine, will be linked to the mitochondrial health of the individual. furthermore, as evidence indicates that many viruses, which most likely include sars-cov-2, modulate bioenergetics and redox in both the immune system and other cells they infect to enhance their own replication, they could potentially induce excessive stress in these systems if their mitochondria are already sub-optimally functional. this would suggest that in patients experiencing severer symptoms, mitochondrial support could be a strategy, which could take many forms, both direct (e.g., mitochondrial anti-oxidants), or indirect (anti-inflammatories, inhibitors of viral replication etc.). this viewpoint becomes apparent when one considers that mitochondria are a central nexus and have many functions, ranging from supplying energy, anabolites for new growth, controlling intracellular redox, calcium signalling, detection of viruses and activation of anti-viral mechanisms, as well as ultimately controlling the life and death of the cell. global, regional, and national estimates of the population at increased risk of severe covid-19 due to underlying health conditions in 2020: a modelling study inflammation resolution: a dual-pronged approach to averting cytokine storms in covid-19? role of aging and the immune response to respiratory viral infections: potential implications for covid-19 mitochondrial dysfunction and oxidative stress activate inflammasomes: impact on the aging process and age-related diseases a unifying view of ageing and disease: the double-agent theory remodeling of the immune response with aging: immunosenescence and its potential impact on covid-19 immune response contributions of age-related thymic involution to immunosenescence and inflammaging lifestyle risk factors for cardiovascular disease in relation to covid-19 hospitalization: a community-based cohort study of 387,109 adults in uk. medrxiv factors associated with hospitalization and critical illness among 4,103 patients with covid-19 disease obesity and impaired metabolic health in patients with covid-19 a preventive role of exercise across the coronavirus 2 (sars-cov-2) pandemic lifestyle-induced metabolic inflexibility and accelerated ageing syndrome: insulin resistance, friend or foe? obesity-associated t-cell and macrophage activation improve partly after a lifestyle intervention the anti-inflammatory effect of exercise the role of exercise-induced myokines in muscle homeostasis and the defense against chronic diseases exercise modulates oxidative stress and inflammation in aging and cardiovascular diseases exercise-released myokines in the control of energy metabolism irisin protects mitochondria function during pulmonary ischemia/reperfusion injury irisin modulates genes associated with severe coronavirus disease (covid-19) outcome in human subcutaneous adipocytes cell culture irisin as a multifunctional protein: implications for health and certain diseases lowintensity exercise stimulates bioenergetics and increases fat oxidation in mitochondria of blood mononuclear cells from sedentary adults mitochondria as molecular platforms integrating multiple innate immune signalings mitochondrial functions in infection and immunity vulnerability of pediatric patients with mitochondrial disease to vaccinepreventable diseases the emerging role of immune dysfunction in mitochondrial diseases as a paradigm for understanding immunometabolism agingdependent alterations in gene expression and a mitochondrial signature of responsiveness to human influenza vaccination immunopathology of hyperinflammation in covid-19 mechanisms of virus-induced immune suppression virally induced immunosuppression superantigenic character of an insert unique to sars-cov-2 spike supported by skewed tcr repertoire in patients with hyperinflammation mitochondrial oxidative phosphorylation is linked to t-cell exhaustion mitochondrial induced t cell apoptosis and aberrant myeloid metabolic programs define distinct immune cell subsets during acute and recovered sars-cov-2 infection distribution of ace2, cd147, cd26, and other sars-cov-2 associated molecules in tissues and immune cells in health and in asthma, copd, obesity, hypertension, and covid-19 risk factors neuropilin-1 facilitates sars-cov-2 cell entry and provides a possible pathway into the central nervous system neuropilin-1 is a host factor for sars-cov-2 infection immune cell extracellular vesicles and their mitochondrial content decline with ageing t cells with dysfunctional mitochondria induce multimorbidity and premature senescence antigen-specific adaptive immunity to sars-cov-2 in acute covid-19 and associations with age and disease severity robust t cell immunity in convalescent individuals with asymptomatic or mild covid-19 mitochondrial dysfunction and the aging immune system immunosenescence and inflammaging: a role for mitokines? semin immunopathol fueling inflamm-aging through mitochondrial dysfunction: mechanisms and molecular targets mitochondrial mass governs the extent of human t cell senescence control of inflammation by calorie restriction mimetics: on the crossroad of intermittent fasting, a possible priming tool for host defense against sars-cov-2 infection: crosstalk among calorie restriction, autophagy and immune response inflammaging as a common ground for the development and maintenance of sarcopenia, obesity, cardiomyopathy and dysbiosis oncogenic virus-induced aerobic glycolysis and tumorigenesis the emerging facets of non-cancerous warburg effect clonal expansion of vaccine-elicited t cells is independent of aerobic glycolysis single-cell rna-seq data analysis on the receptor ace2 expression reveals the potential risk of different human organs vulnerable to 2019-ncov infection elevated ace2 expression in the olfactory neuroepithelium: implications for anosmia and upper respiratory sars-cov-2 entry and replication sars-cov-2 receptor ace2 and tmprss2 are primarily expressed in bronchial transient secretory cells association of high level gene expression of ace2 in adipose tissue with mortality of covid-19 infection in obese patients regulation of angiotensin converting enzyme 2 (ace2) in obesity: implications for covid-19 cyclophilin a and cd147: novel therapeutic targets for the treatment of covid-19 role of melatonin in the treatment of covid-19; as an adjuvant through cluster differentiation 147 (cd147) molecular basis of the potential interaction of sars-cov-2 spike protein to cd147 in covid-19 associated-lymphopenia in silico identification and validation of inhibitors of the interaction between neuropilin receptor 1 and sars-cov-2 spike protein sars-cov-2 spike protein co-opts vegf-a/neuropilin-1 receptor signaling to induce analgesia regulation of antitumour cd8 t-cell immunity and checkpoint blockade immunotherapy by neuropilin-1 cardiomyopathy and worsened ischemic heart failure in sm22-alpha cre-mediated neuropilin-1 null mice: dysregulation of pgc1alpha and mitochondrial homeostasis sars-coronavirus open reading frame-9b suppresses innate immunity by targeting mitochondria and the mavs/traf3/traf6 signalosome mavs polymers smaller than 80 nm induce mitochondrial membrane remodeling and interferon signaling mavs forms functional prion-like aggregates to activate and propagate antiviral innate immune response the adaptor mavs promotes nlrp3 mitochondrial localization and inflammasome activation a sars-cov-2 protein interaction map reveals targets for drug repurposing decoding sars-cov-2 hijacking of host mitochondria in pathogenesis of covid-19 pathophysiological consequences of calcium-conducting viroporins role of severe acute respiratory syndrome coronavirus viroporins e, 3a, and 8a in replication and pathogenesis. mbio severe acute respiratory syndrome coronavirus e protein transports calcium ions and activates the nlrp3 inflammasome structural proteins in severe acute respiratory syndrome coronavirus-2 calcium transport and signaling in mitochondria virus factories: biogenesis and structural design virus factories: associations of cell organelles for viral replication and morphogenesis robust t cell immunity in convalescent individuals with asymptomatic or mild covid-19 dynamics of igg seroconversion and pathophysiology of covid-19 infections impaired type i interferon activity and inflammatory responses in severe covid-19 patients imbalanced host response to sars-cov-2 drives development of covid-19 tissue-specific tolerance in fatal covid-19 type i interferon inhibits interleukin-1 production and inflammasome activation sars-cov-2 infection and overactivation of nlrp3 inflammasome as a trigger of cytokine "storm" and risk factor for damage of hematopoietic stem cells regulation of effector and memory t-cell functions by type i interferon sars-cov-2 entry receptor ace2 is expressed on very small cd45(−) precursors of hematopoietic and endothelial cells and in response to virus spike protein activates the nlrp3 inflammasome identification and characterization of a functional mitochondrial angiotensin system exosome-mediated transfer of ace2 (angiotensin-converting enzyme 2) from endothelial progenitor cells promotes survival and function of endothelial cell angiotensin-(1-9) prevents cardiomyocyte hypertrophy by controlling mitochondrial dynamics via mir-129-3p/pkia pathway elevated glucose levels favor sars-cov-2 infection and monocyte response through a hif-1α/glycolysis-dependent axis the nlrp3 inflammasome modulates glycolysis by increasing pfkfb3 in an il-1beta-dependent manner in macrophages the crosstalk between nrf2 and inflammasomes basic principles and emerging concepts in the redox control of transcription factors melatonin inhibits covid-19-induced cytokine storm by reversing aerobic glycolysis in immune cells: a mechanistic analysis melatonin and mitochondrial function the global phosphorylation landscape of sars-cov-2 infection the landscape of human cancer proteins targeted by sars-cov-2 a new paradigm for mapk: structural interactions of herk1 with mitochondria in hela cells mitochondria-targeted antioxidant attenuates high glucose-induced p38 mapk pathway activation in human neuroblastoma cells high glucose induces phosphorylation and oxidation of mitochondrial proteins in renal tubular cells: a proteomics approach new-onset diabetes in covid-19 diabetes and covid-19: evidence, current status and unanswered research questions mounting clues suggest the coronavirus might trigger diabetes fasting blood glucose at admission is an independent predictor for 28-day mortality in patients with covid-19 without previous diagnosis of diabetes: a multi-centre retrospective study role of mitochondria in the mechanism(s) of action of metformin metformin treatment was associated with decreased mortality in covid-19 patients with diabetes in a retrospective analysis observational study of metformin and risk of mortality in patients hospitalized with covid-19 western diet triggers nlrp3-dependent innate immune reprogramming the essential functions of mitochondrial dynamics in immune cells sublethal mitochondrial stress with an attendant stoichiometric augmentation of reactive oxygen species may precipitate many of the beneficial alterations in cellular physiology produced by caloric restriction, intermittent fasting, exercise and dietary phytonutrients: "mitohormesis" for health and vitality is there a link between mitochondrial reserve respiratory capacity and aging? examining the mechanisms responsible for lower ros release rates in liver mitochondria from the long-lived house sparrow (passer domesticus) and big brown bat (eptesicus fuscus) compared to the short-lived mouse (mus musculus) mitochondrial dysfunction and damage associated molecular patterns (damps) in chronic inflammatory diseases. mitochondrion the proximal origin of sars-cov-2 going to bat(s) for studies of disease tolerance novel insights into immune systems of bats comparative analysis of bat genomes provides insight into the evolution of flight and immunity dampened nlrp3-mediated inflammation in bats and implications for a special viral reservoir host bat tolerance to viral infections stressing out the mitochondria: mechanistic insights into nlrp3 inflammasome activation population level mitogenomics of long-lived bats reveals dynamic heteroplasmy and challenges the free radical theory of ageing mitophagy: a balance regulator of nlrp3 inflammasome activation analysis of sars-cov-2-controlled autophagy reveals spermidine, mk-2206, and niclosamide as putative antiviral therapeutics mitochondrial network structure homeostasis and cell death in vivo assessment of muscle mitochondrial function in healthy, young males in relation to parameters of aerobic fitness enhanced protein translation underlies improved metabolic and physical adaptations to different exercise training modes in young and old humans hormetic effects of reactive oxygen species by exercise: a view from animal studies for successful aging in human skeletal muscle antagonizes antiviral cd8(+) t cell exhaustion adaptive immunity and adipose tissue biology the effect of exercise on visceral adipose tissue in overweight adults: a systematic review and meta-analysis type i interferon sensing unlocks dormant adipocyte inflammatory potential the nlrp3 inflammasome instigates obesity-induced inflammation and insulin resistance systemic effects of mitochondrial stress how increased oxidative stress promotes longevity and metabolic health: the concept of mitochondrial hormesis (mitohormesis) the cell cycle is a redox cycle: linking phasespecific targets to cell fate redox signaling through compartmentalization of reactive oxygen species: implications for health and disease redox theory of aging mitochondria in innate immune signaling mitochondria and viruses the exceptional longevity of the naked mole-rat may be explained by mitochondrial antioxidant defenses h2o2 metabolism in liver and heart mitochondria: low emitting-high scavenging and high emitting-low scavenging systems mild depolarization of the inner mitochondrial membrane is a crucial component of an anti-aging program redox-optimized ros balance: a unifying hypothesis redox-optimized ros balance and the relationship between mitochondrial respiration and ros mitochondrial uncoupling and longevity -a role for mitokines? uncoupling protein 2 modulation of the nlrp3 inflammasome in astrocytes and its implications in depression uncoupling protein ucp2: when mitochondrial activity meets immunity the rcr and atp/o indices can give contradictory messages about mitochondrial efficiency defects in mitochondrial efficiency and h2o2 emissions in obese women are restored to a lean phenotype with aerobic exercise training mitochondrial uncoupling proteins: subtle regulators of cellular redox signaling regulatory crosstalk between the oxidative stress-related transcription factor nfe2l2/nrf2 and mitochondria clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study the role of mitochondria in aging mitochondrial dysfunction in metabolic syndrome new targeted approaches for epigenetic age predictions the epigenetic clock as a predictor of disease and mortality risk: a systematic review and meta-analysis mitochondria and aging in older individuals: an analysis of dna methylation age metrics, leukocyte telomere length, and mitochondrial dna copy number in the va normative aging study organ reserve, excess metabolic capacity, and aging mx1 reveals innate pathways to antiviral resistance and lethal influenza disease intracellular redox state as target for anti-influenza therapy: are antioxidants always effective? glutathione increase by the n-butanoyl glutathione derivative (gsh-c4) inhibits viral replication and induces a predominant th1 immune profile in old mice infected with influenza virus the hallmarks of aging the vital question: why is life the way it is? great britain: profile books ltd mitochondrial dna copy number associates with insulin sensitivity and aerobic capacity, and differs between sedentary, overweight middle-aged males with and without type 2 diabetes highlights of covid-19 pathogenesis. insights into oxidative damage is exercise protective against influenza-associated mortality? association of cardiorespiratory fitness with long-term mortality among adults undergoing exercise treadmill testing dose-response associations between accelerometry measured physical activity and sedentary time and all cause mortality: systematic review and harmonised meta-analysis inflammatory effects of high and moderate intensity exercise-a systematic review the antioxidant effect of exercise: a systematic review and meta-analysis caloric restriction reprograms the single-cell transcriptional landscape of rattus norvegicus mitochondria--a nexus for aging, calorie restriction, and sirtuins? cell health relevance of the modification of low grade inflammation in ageing (inflammageing) and the role of nutrition the cytokine storm of severe influenza and development of immunomodulatory therapy an energetic view of stress: focus on mitochondria mitochondria and pgc-1alpha in aging and age-associated diseases inhibition of mitochondrial complex i by various non-steroidal anti-inflammatory drugs and its protection by quercetin via a coenzyme q-like action quantitative in vivo proteomics of metformin response in liver reveals ampk-dependent and -independent signaling networks polyphenols as mitochondria-targeted anticancer drugs effects of the nonsteroidal anti-inflammatory drug celecoxib on mitochondrial function network-based drug repurposing for novel coronavirus 2019-ncov/sars-cov-2 enhancing mitochondrial health to treat hypertension editor's highlight: therapeutic concentrations of antidepressants inhibit pancreatic beta-cell function via mitochondrial complex inhibition the role of mitochondria in mtor-regulated longevity rapamycin increases mitochondrial efficiency by mtdna-dependent reprogramming of mitochondrial metabolism in drosophila immune modulation as a therapeutic option during the sars-cov-2 outbreak: the case for antimalarial aminoquinolines treatment with antimalarials adversely affects the oxidative energy metabolism in rat liver mitochondria platinum (ii)-chloroquine complexes are antimalarial agents against blood and liver stages by impairing mitochondrial function mitochondrial oxidative phosphorylation and mitophagy in myocardial ischaemia/reperfusion: effects of chloroquine antioxidant action of antimalarials oxidative stress, proton fluxes, and chloroquine/ hydroxychloroquine treatment for covid-19 a meta-analysis on the effects of hydroxychloroquine on covid-19 cardiovascular adverse events associated with hydroxychloroquine and chloroquine: a comprehensive pharmacovigilance analysis of pre-covid-19 reports early hydroxychloroquine but not chloroquine use reduces icu admission in covid-19 patients chloroquine commonly induces hormetic dose responses the greek study in the effects of colchicine in covid-19 complications prevention (grecco-19 study): rationale and study design colchicine treatment impairs skeletal muscle mitochondrial function and insulin sensitivity in an age-specific manner molecular insights into sars cov-2 interaction with cardiovascular disease: role of raas and mapk signaling p38 mapk inhibition: a promising therapeutic approach for covid-19 targeting mitochondria in melanoma: interplay between mapk signaling pathway and mitochondrial dynamics cyclosporine and covid-19: risk or favorable? cyclophilin inhibitors restrict middle east respiratory syndrome coronavirus via interferon lambda in vitro and in mice regulation of mavs expression and signaling function in the antiviral innate immune response mitochondria-nucleus shuttling fk506-binding protein 51 interacts with traf proteins and facilitates the rig-i-like receptor-mediated expression of type i ifn cyclophilin aregulated ubiquitination is critical for rig-i-mediated antiviral immune responses cyclophilin d: an integrator of mitochondrial function inhibition of sars-cov-2 infection by the cyclophilin inhibitor alisporivir (debio 025) covid-19: low dose steroid cuts death in ventilated patients by one third, trial finds anti-inflammatory glucocorticoid action: genomic insights and emerging concepts stress and glucocorticoid receptor regulation of mitochondrial gene expression adenine nucleotide translocator promotes oxidative phosphorylation and mild uncoupling in mitochondria after dexamethasone treatment dexamethasone-induced mitochondrial dysfunction and insulin resistance-study in 3t3-l1 adipocytes and mitochondria isolated from mouse liver redox regulation of inflammation: old elements, a new story vitamin c: update on physiology and pharmacology vitamin c may reduce the duration of mechanical ventilation in critically ill patients: a meta-regression analysis vitamin c can shorten the length of stay in the icu: a meta-analysis quercetin and vitamin c: an experimental, synergistic therapy for the prevention and treatment of sars-cov-2 related disease (covid-19) mitochondria accumulate large amounts of quercetin: prevention of mitochondrial damage and release upon oxidation of the extramitochondrial fraction of the flavonoid quercetin induces mitochondrial biogenesis through activation of ho-1 in hepg2 cells from sunscreens to medicines: can a dissipation hypothesis explain the beneficial aspects of many plant compounds? plant immunity: danger perception and signaling mitochondrial-derived reactive oxygen species play a vital role in the salicylic acid signaling pathway in arabidopsis thaliana salicylic acid is an uncoupler and inhibitor of mitochondrial electron transport vdac2 involvement in the stress response pathway in arabidopsis thaliana viral protein suppresses oxidative burst and salicylic aciddependent autophagy and facilitates bacterial growth on virus-infected plants can an old ally defeat a new enemy? cannabinoids and the coronavirus molecular targets of cannabidiol in neurological disorders direct modulation of the outer mitochondrial membrane channel, voltagedependent anion channel 1 (vdac1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death cannabinoid-induced changes in respiration of brain mitochondria cannabidiol modulates the immunophenotype and inhibits the activation of the inflammasome in human gingival mesenchymal stem cells cellular stress responses, hormetic phytochemicals and vitagenes in aging and longevity mitochondrial impairment by ppar agonists and statins identified via immunocaptured oxphos complex activities and respiration statindependent modulation of mitochondrial metabolism in cancer cells is independent of cholesterol content statin treatment decreases mitochondrial respiration but muscle coenzyme q10 levels are unaltered: the lifestat study in-hospital use of statins is associated with a reduced risk of mortality among individuals with covid-19 melatonin and mitochondrial dysfunction in the central nervous system covid-19: melatonin as a potential adjuvant treatment mitochondrial ros induces cardiac inflammation via a pathway through mtdna damage in a pneumonia-related sepsis model mitochondrial dna in inflammation and immunity evidence that vitamin d supplementation could reduce risk of influenza and covid-19 infections and deaths 25-dihydroxyvitamin d3 regulates mitochondrial oxygen consumption and dynamics in human skeletal muscle cells spotlight on vitamin d receptor, lipid metabolism and mitochondria: some preliminary emerging issues perspective: vitamin d deficiency and covid-19 severity -plausibly linked by latitude, ethnicity, impacts on cytokines, ace2, and thrombosis (r1) effective treatment of mitochondrial myopathy by nicotinamide riboside, a vitamin b3 covid-19 infection: the perspectives on immune responses mitochondria-targeted drugs neuroprotective effects of the drug gvt (monosodium luminol) are mediated by the stabilization of nrf2 in astrocytes monosodium luminol reinstates redox homeostasis, improves cognition, mood and neurogenesis, and alleviates neuro-and systemic inflammation in a model of gulf war illness p-173 -mp1032 -a novel anti-inflammatory drug ameliorates the progression of autoimmune diseases detection of mitochondria-derived reactive oxygen species production by the chemilumigenic probes lucigenin and luminol immunosenescence and challenges of vaccination against influenza in the aging population factors that may impact on immunosenescence: an appraisal the impact of obesity and metabolic syndrome on vaccination success immunosenescence-related transcriptomic and immunologic changes in older individuals following influenza vaccination gender-specific coronavirus-infections in the light of evolution gender differences in patients with covid-19: focus on severity and mortality mitochondria: a central target for sex differences in pathologies effects of personal nitrogen dioxide exposure on airway inflammation and lung function nitrogen dioxide oxidizes mitochondrial cytochrome c acute nitrogen dioxide inhalation induces mitochondrial dysfunction in rat brain links between air pollution and covid-19 in england iron-rich air pollution nanoparticles: an unrecognised environmental risk factor for myocardial mitochondrial dysfunction and cardiac oxidative stress cryo-em structure of the sars coronavirus spike glycoprotein in complex with its host cell receptor ace2 structural basis for the recognition of the sars-cov-2 by full-length human ace2 the combination of ace i/d and ace2 g8790a polymorphisms revels susceptibility to hypertension: a genetic association study in brazilian patients covid-19, ace2 and the cardiovascular consequences hypothesis: angiotensin-converting enzyme inhibitors and angiotensin receptor blockers may increase the risk of severe covid-19 melatonin protects cardiac microvasculature against ischemia/reperfusion injury via suppression of mitochondrial fission-vdac1-hk2-mptp-mitophagy axis curcumin: novel treatment in neonatal hypoxic-ischemic brain injury cannabidiol protects against hepatic ischemia/reperfusion injury by attenuating inflammatory signaling and response, oxidative/nitrative stress, and cell death uncoupling of oxidative phosphorylation by curcumin: implication of its cellular mechanism of action optogenetic control of mitochondrial protonmotive force to impact cellular stress resistance mitochondrial electron transport chain, ros generation and uncoupling (review) the integration of lipid-sensing and antiinflammatory effects: how the ppars play a role in metabolic balance mitochondrial targets for volatile anesthetics against cardiac ischemia-reperfusion injury effects of general anaesthetic procedures on mitochondrial function of human skeletal muscle mitochondrial depolarization underlies delay in permeability transition by preconditioning with isoflurane: roles of ros and ca2+ structural basis of sars-cov-2 3cl(pro) and anti-covid-19 drug discovery from medicinal plants potential phytochemicals as efficient protease inhibitors of 2019-ncov mitochondria in neuroprotection by phytochemicals: bioactive polyphenols modulate mitochondrial apoptosis system, function and structure covid-19: what do we know about "long covid mitochondria and immunity in chronic fatigue syndrome a swat h-ms analysis of myalgic encephalomyelitis/chronic fatigue syndrome peripheral blood mononuclear cell proteomes reveals mitochondrial dysfunction worldwide trends in body-mass index, underweight, overweight, and obesity from 1975 to 2016: a pooled analysis of 2416 population-based measurement studies in 128.9 million children, adolescents, and adults bioenergetics in human evolution and disease: implications for the origins of biological complexity and the missing genetic variation of common diseases covid-19: black people and other minorities are hardest hit in us publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none.authors' contributions an wrote and edited the manuscript after discussion with gwg, while all other authors contributed equally to critiquing the original drafts and the concepts therein, and approved the final manuscript. no specific source of funding supported this paper.availability of data and materials not applicable.ethics approval and consent to participate none required. all authors have approved the paper for publication. professor geoffrey guy is the founder and chairman of gw pharmaceuticals; professor alistair nunn is a scientific advisor to gw pharmaceuticals; dr. wolfgang brysch is the chief executive officer of metriopharm ag. the remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. key: cord-263650-jxkjn8ld authors: andruske, cynthia lee; o'connor, deborah title: family care across diverse cultures: re-envisioning using a transnational lens date: 2020-10-20 journal: j aging stud doi: 10.1016/j.jaging.2020.100892 sha: doc_id: 263650 cord_uid: jxkjn8ld in an increasingly globalized world, the importance of developing a more culturally complex understanding of family care has been clearly identified. this study explored family care across three different cultural groups chinese, south asian, and latin american living in a metropolitan, pacific-west, canadian city. in-depth qualitative interviews were conducted with 29 family members from one of the three family groups exploring how they practiced ‘care’ for their aging, often frail, relatives. the importance of conceptualizing family care as a transnational, collective undertaking emerged from the outset as critical for understanding care practices in all three cultural communities. three themes identified contributed to this conceptualization: the need to broaden the understanding of family care; the centrality of geographic mobility, and the need to rethink the location of aging and consider its relationship to mobility; and the use of technology by extended family networks to facilitate continuity and connection. an over-riding notion of ‘flow’ or fluid movement, rather than a fixed, static arrangement, emerged as critical for understanding family care. this perspective challenges the dominant approach to studying family care in gerontology that generally conceptualizes family care practice as one local primary caregiver, often female, with some support from other family members. understanding family care from a transnational lens builds support for the importance of a feminist ethics of care lens and has important implications for policy and service delivery practices. canada, like many other western countries, reflects an increasingly globalized world with almost a quarter of adults living in canada selfidentifying as an immigrant (stats canada, 2019) . of these, 15% are over age 65 (stats canada, 2019) , and if they came after 1990, they likely belong to a culturally diverse community, including 48% from asia and the pacific region and 10% from south and central america (citizenship and immigration, canada, 2009) . a majority of older immigrants have come to the country under canada's reunification policy and are more likely to be living with and/or supported by family for at least 10 years after their arrival (mcdonald, 2011) . the need to understand the implications of this culturally diverse world on the aging experience (phillipson, 2015; torres, 2015) and the provision of family care (bryceson, 2019; chappell & hollander, 2011; keating & de jong gierveld, 2015; kirkland et al., 2015; roberto & anderson et al., 2002; guo, kim, & dong, 2019; pinquart & sorensen, 2003) and the differential uptake of support, both formal and informal (greenwood, habibi, smith, & manthorpe, 2015) . however, many questions remain. in particular, two gaps in this body of knowledge limit its usefulness. first, at a general level, the strong focus of the stress/burden model has tended to assume one fixed primary caregiver and resulted in an incomplete understanding of the role of the rest of the family in providing care and support (sims-gould & martin-mathews, 2007) . second, in considering ethnicity and/or culture in family care, this body of knowledge has rarely focused on finding a meaningful way to examine the significant role that immigration and acculturation may have in implicating family care practices (guo et al., 2019) . a second body of research, found largely outside of the gerontological literature, has focused more explicitly on the role of transnationalism and migration in family care. this body of work has explored intergenerational care across the life-span including a small but growing body of research examining care of aging parents. 'care' in this body of research has generally been extended to capture a diversity of caring arrangements and activities as proposed by finch (1989) and fisher and tronto (1990) . seminal work by a western australian research group (baldassar, baldock, & wilding, 2007 ; see also baldassar & merla, 2014) has been particularly influential as a foundation for considering transnationalism as it relates to family care in the field of aging. their work has explored how care for an aging parent is accomplished and negotiated between family members living far apart and in different countries. during one of their first ethnographic studies, they interviewed 100 australian immigrant families -about two thirds were of european descent with the remainder from new zealand (8), singapore (14), iraq (9), and afghanistan living in iran (21). to capture the experiences of both the immigrant adult children and older parents in their home countries, the researchers interviewed the immigrants in australia and the parents and other family members still remaining in the home countries. interviews included family and immigration histories, types of communication used, travel, and reciprocal care for care receivers and care givers based on finch's (1989) typology of family care exchange (financial, emotional, personal, practical, and accommodation) . additionally, the researchers observed and recorded how families organized space, tools, and other artifacts used for communication exchanges . the work of this research group has made important contributions for understanding transnational care. in particular, they highlighted the diversity and complexity of how care arrangements were negotiated and managed, drawing attention to issues such as how obligation may be culturally mediated, the impact of the migration process on establishing care capacity, and the importance of technology in these care arrangements. a small literature base has built on this body of knowledge as it relates to aging family care especially in europe (see for example, kordasiewicz, radziwinowiczówna, & kloc-nowak, 2018; miette sagbakken, spilker, & ingebretsen, 2018; zechner, 2008) . findings continue to demonstrate the complexity of understanding these family processes, and miette sagbakken et al. (2018) concluded by recognizing the importance of considering both the availability of kin members but also their understanding of obligation and reciprocity and how that might reflect their embeddedness in more than one society. despite its promise, however, this body of literature is only rarely addressed in the broader gerontological work on family care and a 'substantial void' in the caregiving literature remains in relation to understanding cultural values and processes (lee, chaudhuri, & yoo, 2015) , especially in relation to examining the experiences of non-western immigrants (dhar, 2011b; wilding & baldassar, 2018; zhou, 2012 zhou, , 2015 . this current study bridges these two, somewhat disparate, bodies of research. specifically, drawing on a broad understanding of care that is consistent with fisher and tronto (1990) ; also tronto, 2013) , the purpose of our study was to explore and compare the relationships between culture and informal family care practices across three diverse ethno-cultural groups: chinese, south asians, and latin americans living in vancouver, british columbia, canada. although transnationalism was not considered at the outset of the study, all three of these groups have unique immigration trajectories, with the latin americans representing a relatively recent group immigrating for political and economic reasons from south and central america while the south asians and chinese have much longer histories in canada. we explored the following questions: 1) what are the cultural interpretations and meanings of caring for an older family member within select ethnic minority communities? 2) how do cultural meanings of relationships influence the care process? this qualitative study drew on constructivist grounded theory (charmaz, 2014 (charmaz, , 2017b charmaz, 2017a) to explore the process and meanings of family care across non-western cultural groups. the constructivist approach is designed to facilitate development of a framework to better understand the processes individuals create around their experiences and ways of being in the world. in keeping with this, the interview was designed iteratively; the researchers began with a few broad questions in order to develop a deeper and richer exploration and understanding of concepts through reflection and theoretical interviewing. throughout the research process, it is important to acknowledge the reciprocity that exists between the participants and researchers as well as the expertise of the participants (charmaz, 2014 (charmaz, , 2017b charmaz, 2017a) . this also helps diffuse power imbalances between participants and researchers. adults self-identifying as chinese, south asian, and latin american, and providing unpaid, informal care or support to someone over the age of 65 needing some level of assistance with activities of daily living, were invited to participate. drawing on the work of finch (1989) and fisher and tronto (1990; tronto, 2013) , we conceptualized care as a "multifaceted complex social phenomenon, entailing both emotional and material (instrumental) aspects" (kordasiewicz et al., 2018, p. 77 )this encapsulated notions of caring for, caring about, providing care, and caring with (fisher & tronto, 1990 ) -and left it up to participants to describe what they meant by providing informal care or support. participant recruitment initially took place through researchers' personal networks, ads, and organizations in each of the chinese, south asian, and latin american communities. as the study progressed, snowball sampling was utilized, and participants were purposefully selected to ensure cultural, gender, and relational diversity. the final number of adults included 29 participants: nine (9) chinese (2 males and 7 females) from china, hong kong, and burma. ten (10) south asians (3 males and 7 females) originated from india, east africa, and england. the ten (10) latin american participants (2 males and 8 females) immigrated from chile, colombia, argentina, el salvador, and venezuela. table 1 provides an overview of the family members consenting to participate. with signed informed consent, up to three personal, semi-structured, audio taped interviews were conducted with each of the 29 individuals in the language of their choice. to capture cultural meanings and connotations and ensure carers' comfort and ease of expression, all but four individuals chose to be interviewed in their native language (cantonese, hindi, punjab, or spanish). the interviews were designed as an iterative process where three experienced researchers (each fluent in the respective group's native language/s) began with broad questions focused on family members' experiences and perceptions of providing informal care or support to an older adult, and then developed a deeper and richer exploration of concepts through reflection and theoretical interviewing. topics included exploring how each defined giving care in terms of their own cultural beliefs and backgrounds, and how -from their perspectives -these influenced the assistance or support they provided. consistent with a constructivist grounded theory approach, interview questions were honed and refined throughout the data generation process to explore emerging concepts and understandings. follow up interviews, ranging between a couple of weeks to a month after the first interview per the accessibility and schedule of participants, were conducted, and for some a third meeting, focused on expanding and verifying insights. at the end of the final interview, a demographic questionnaire was completed orally with each participant to collect information about both the carer and care receiver (for example, age, education, health status, financial resources, time in canada, citizenship, and others). ethical approval was obtained through the ethical review board from the university of british columbia. table 2 below provides a picture of care receivers as described by their relatives. each family was caring for or assisting at least one parent, spouse, or relative ranging in age from 65 to 100. some care receivers were healthy and independent while others had severe health problems such as alzheimer's, heart problems, or other diseases. in keeping with canada's family reunification program (mcdonald, 2011) , 27 of the 29 older adults had immigrated to canada to reunite with their families. although only two latin americans still resided in south america, visiting their adult children only when economically possible and based on immigration policies, they planned on immigrating at a later date. furthermore, the 27 care receivers had lived in canada for 10 years or more and in some cases, even for 30 to 39 years (10). also, most care receivers (22) either lived with the carer or a family member. data analysis was a collaborative (team), iterative process using a strategy consistent with the constant comparative method. first, all taped interviews were translated verbatim, (to capture cultural meanings), into english by the respective research associate who conducted it. next, a three-stage process began with the research associate affiliated with each of the three groups analyzing several interviews and coding them. then, associates with the principal researcher in vancouver met to discuss the interviews to analyze meanings, initial codes, and compare these among the three cultural groups. using these team decisions and codes, a code book was developed. it was then used to conduct a line-by-line coding of each transcript. atlas-ti facilitated this coding process. once data was coded, the research team began looking for links among codes to develop categories, for creating broader themes as they began to emerge. these were then refined and developed through subsequent interviews with the participants and by returning to the data. data revealed a process of family care that was complex and dynamic across all three cultural groups. specifically, a sense of flow and fluidity created a picture of care as a shared phenomenon -across family members and geography -that was highly dependent upon communication technology. hence, a significant theme that emerged across all three groups was the importance of conceptualizing family care as a transnational, collective undertaking underpinned by three themes: broadening the conception of 'family care'; locating family care as transnational; and increasing reliance on technology. in this study, consistent with existing research dhwan, 1998; flores, hinton, barker, franz, & velasquez, 2009; guo, li, liu, & sum, 2015; hsueh, hu, & clarke-ekong, 2008; pharr, francis, terry, & clark, 2014) , family care emerged as a normative cultural expectation in all three groups. however, each labelled and described the concept differently. for example, for the chinese (ch) participants, this revolved around the language of filial piety and/or 'ganqing' based on a relational sense of moral duty and responsibility, resulting from confucianism. these values were generally volunteered spontaneously and explicitly: it is our "culture" to "look after" the elder. it's more emphasized in our education from when we were kids....although my parents never said: 'you have to take care of me,'… but from a young age when we were "brought up," you know "ganqing" [you feel you] have to take care of him/her… especially those with alzheimer's (an 1 -ch daughter caring for mother, age 80, with alzheimer's). supporting this perception as a culturally expected norm, sing mei, caring for her chinese parents, noted: 'i see my other friends, they also doing the same thing to their parents, to take carce of their parents' (sing mei -ch daughter caring for parents, ages 75+). south asian (sa) participants also positioned family care as a normative cultural expectation, but they were more likely to draw upon a religious understanding: describing caring for seniors and others as part of their religion where caring for others is an ingrained culturally expected religious responsibility to serve god and, thus, others. for instance, depicting this link between 'seva' or religious service and 'farz' note: ⁎ the two chinese caregivers worked outside of canada longer than they resided inside of canada. ⁎⁎ originally, 10 chinese agreed to participate. however, one male dropped out. ⁎⁎⁎ two of the south asians indicated that another person was also the "primary" caregiver with them. ⁎⁎⁎⁎ nr -= no response to request for age ⁎⁎⁎⁎⁎ one wife was also a daughter-in-law to one of the male la participants. of la americans, 2 were only children. or cultural responsibility, kavya, a south asian wife, caring for her husband and living with their daughter stated: 'culture, we are so religious from inside that we are taught from the beginning culture and religions, they are the same, and they run parallel.' kavya explained further: our foundation is such right from the start; serving others is like our religion. it is like serving god when we look after someone who is sick. we are told from childhood to look after sick people. what our children are doing…is part of our culture. in our culture, we teach to share. we shared with them; they are returning it to us. (kavya -sa wife caring for husband, age 70+) although religion is an important underlying value for the latin american (la) participants in this study, they described and explained caring for elders, family, and friends as 'deber' or duty. here, "family obligation" was based on the notion of collective loving family relationships and loyalty to family cultural values that extended beyond duty to immediate family into the community of friends. sandra, a previously paid health care provider, recently retired to care for her aging chilean mother, captured latin american cultural caring as collective and communal: as a family member, there is the affective aspect. never would i leave a parent, a very good friend, godmother, or whatever, if they don't have a family member or a person close to them. i feel that it is my "deber" (duty and obligation) for feelings for sentiments. i feel it is my "deber" to take care of/be concerned with that person, pay attention to them. (sandra -la daughter caring for mother, age 94) caring for elders as a social expectation of being a 'good' son, daughter, or family member in the kin relationship network, then, was consistent across all three cultural groups. these cultural expectations also extended to friend networks described by many participants from all three groups. moreover, participants explained this care was a reciprocal act embedded within the social fabric of the culture. subtle differences in the foundations for understanding these expectations emerged, however. caring obligations appeared to be linked explicitly to religion for south asian participants, but it seemed more related to the teachings of political philosopher, confucius, for the chinese whereas latin americans tended to describe caring as a more collective sense of family extending beyond blood relationships. importantly, across all three cultural groups, this notion of family care was communal, embedded in a loose definition of the extended family network that included friends, blood relatives, and relational family. to illustrate, in our study, carers did not define a primary caregiver, but they discussed caring in terms of networks and relationships. even only adult children like argentinian rossana pointed out that she had created networks from her family (husband, daughter, and grandchildren, among others) and paid companions as well as her 92-year-old mother's long-time friends to provide support and care. another argentinian, 50-year-old casimiro, an only adult son, drew on his partner and extended family, like his female cousin living in seattle to provide support and companionship for his aging mother living independently. casimiro commented: my cousin, andrea, who is like my sister, comes from seattle every two months, and sometimes she stays for a week with my mother to keep her company. when i am here at my breaking point, she comes. she takes over. she releases me. for example, she came last week, and she cooked for two weeks. she leaves things prepared. she cares for my mother all the weeks. she takes her; she brings her back. she gives me license… (casimiro -la son, only child, assisting mother, age 81) thinking further about his support network, casimiro explained: when i have problems with her [my mother], andera, my cousin, and daniel, my partner, are the two people who assist me…ahhh. i have a very good friend of hers in the [spanish community] group also…. that woman is very, very good also, and she helps me too… yes…she knows her [my mother] very well. she is from ecuador, and she knows the latin culture very well, so she cheers me up. (casimiro -la son, only child, assisting mother, age 81) care was often described in terms of friend networks that provided support. for example, yoyi, a colombian business woman and daughter-in-law noted: 'in my country, (laughs) if someone is sick, 20 people arrive to care for them' (yoyi -la daughter-in-law coordinating care for mother-in-law, age 89) while a sa daughter, aaliyah, commented, 'my white friends get very surprised that my friends come right away when i need them.' furthermore, aaliyah (sa) explained that friendship was much more: 10-19 = 7 2 = 85-89 1 = diabetes2 = prostate 4 = mothers 1 = independently 20-29 = 1 2 = glaucoma2 = hard of hearing ⁎⁎⁎ 1 = father 30-39 = 2 40 = 0 south asians (13 ⁎ ) ⁎⁎ 2 = 70-74 2 = 65-69 2 = alzheimer's 8 = mothers 7 = with caregiver ⁎⁎⁎ 1-9 = 0 1 = 70-74 1 = bedridden 3 = fathers 4 = independently 10-19 = 7 2 = 75-79 2 = 75-79 1 = brain hemorrhage 1 = wife 1 = care home 20-29 = 2 2 = 80-84 9 = no health issues reported 2 = husbands 1 = with cg's brother 30-39 = 4 1 = 85-89 1 = mother-in-law 40 += 0 1 = 100+ latin americans (11 ⁎ ) 2 = 75-79 2 = 65-69 3 = alzheimer's 7 = mothers 5 = with caregiver ⁎⁎⁎⁎⁎⁎⁎ 1-9 = 0 1 = 75-79 1 = pace maker ⁎⁎⁎ 1 = father 3 = independently 10-19 = 2 2 = 80-84 2 = diabetes 1 = husband 3-nursing homes 20-29 = 1 1 = 85-89 1 = prostate cancer 1 = daughter-in-law 30-39 = 4 3 = 90-94 1 = stroke 1 = aunt 40 = 2 ⁎⁎⁎⁎⁎ 3 = old age 2 = visit c& live in south america 2 = healthy note: ⁎ number of care receivers is greater because some caregivers are caring for more than one person. ⁎⁎ one south asian caregivers was also a care receiver. ⁎⁎⁎ 2 chinese indicated 2 health issues; 2 chinese indicated 3 health problems; 2 latin americans reported 2 illnesses ⁎⁎⁎⁎ although some of the south asians indicated that the cr lived with them, in actuality, a number would live part-time with others in the family assisting with care. ⁎⁎⁎⁎⁎ one cr was a canadian by birth but had lived outside of canada for a number of years. ⁎⁎⁎⁎⁎ one latin american cr was born in south american but resided in the us ⁎⁎⁎⁎⁎⁎⁎ some started out living independently and then lived with cg or returned to independent lving, or started out living with cg and then moved o a nursing home. i went to india after 16 years, believe it or not, my friend kept my mother with her for a full month. who would do that? i can't imagine. my mother was very happy. if she [friend] hadn't, we couldn't have gone to india. we both had to go, me and my daughter, we couldn't have thought of it. we didn't worry at all. it is our culture. if there is anything, i know that my friends are here, i don't have family, but my friends will be there. (aaliyah -sa daughter caring for mother, age 80+) in essence, two types of friend networks emerged during conversations with participants: friends of carers (as pointed out above) and friends of care receivers. although care receiver friend networks may not have provided direct care for their aging friends, they offered different types of support. this 'care' was more supportive and reinforcing companionship. five of the la participants spoke directly to the importance of this support: for example, rossana, an only child, maintained: [my 92-year-old mother] has two friends, well, she had. she has another friend who telephones her every so often…..sometimes she goes to visit her, but only once a month, but my mother counts on that. my mother has a little book where she has everyone's telephone number written down, and she calls… she asks people to call for her because she can no longer dial because she has lost her dexterity, so someone dials for her, and so she can talk. (rossana -la daughter, only child, caring for mother, age 92) the deeply embedded cultural values, perceptions, and actions held by these three ethnic groups regarding family care created tensions within the canadian context for some, especially for those individuals dealing with relatives suffering from alzheimer's or severe illness. for instance, a recently retired chinese daughter, an, whose mother with alzheimer's lived with her and her retired chinese husband recognized the stress of this tension as she talked about how she had visualized her retirement quite differently: …after i retired, i was hoping to live the life of a retiree, hoping to do some traveling and enjoying life in retirement, doing more activities. but because i have to take care of an elderly [80-year-old] person with "alzheimer," i can't do what i want to do personally. (an -ch daughter caring for mother, age 80, with alzheimer's) for an, even though caring for her aging mother was causing stress in her marriage, as a chinese wife and daughter, pointed out: this situation is -…because she's my mother, and she's very afraid of going into a seniors' home, and i can't -my heart myself -basically i'm chinese, so "until" she really cannot "manage" one day, i mean when i cannot "handle" her "at home," i cannot bear to send her away to a seniors' home. (an -ch daughter caring for mother, age 80, with alzheimer's) other participants from the three cultural groups articulated views about cultural tensions between the canadian context and embedded cultural values of their elders. according to abhijeet, a retired south asian son, caring for his 100-year-old mother, 'there is culture in us,…a 30-year culture…we brought with us [when we immigrated to canada], …still alive in us. we know, it is not for us, we know…elders from india, after 60, when their life is almost over, they cannot change' (abhijeet -sa son caring for mother, age 100). sandra, the la retired health care worker, addressed the necessity of balancing canadian beliefs and way of life with her cultural values since she has a canadian born son and her 94-year-old chilean mother living with her. sandra was clear, however, that she would ensure that her chilean mother's cultural family caring beliefs would be respected and honored despite what others might say. the doctor told me, "…well… there are institutions where you can put your mother." i said, "forget it! forget it! my mother is never going to be in an institution either." because the doctor is also chilean, and he would say, "forget what i said. forget it." because i would just look at him, "do you really think my mother would accept going there?". (sandra -la daughter caring for her mother, age 94) nevertheless, as a 17-year immigrant to canada, sandra's changing values were reflected in her views of her own future old age in canada. i say to my son, "forget it. i am canadian now. the day that i begin to fail, in front of my house, there is a nursing home, you don't have to do any more than cross the street, and you put me there" (laughs). because my son is canadian, and he's going to marry a canadian girl, so then i must accept that the canadian family is different so his wife might think, ya the woman [mother-in-law sandra] is very slow, and there [nursing home] she will be very calm. (sandra -la daughter caring for mother, age 94) other participants expressed similar change s in their values the longer time they spent in canada. participants despite some accepting the changes in cultural values, abhijeet, retired south asian son and husband, a long-time resident (17 years) of canada, expressed the tensions that emerged in all three groups in this way: my parents, my father, her [wife] parents, my grandfathers, these are their pictures. when they were aged, they were looked after. at that time, the culture was different. now, it has changed. people over here are westernized, who bothers? go and leave your mother there [nursing home]. we'll pay money there. your attachment?. (abhijeet -sa husband and son caring for wife, age 68, and mother, in summary, family, kin, and friend care networks often were bounded, at least loosely, along cultural lines in their beliefs, intentions, perspectives, and actions. participants across all three cultural groups in this study drew firmly upon cultural beliefs about family care to make sense of their actions and responsibilities. for many, cultural perspectives about family care helped them explain their own sense of responsibility. importantly, however, cultural values also set the foundation for caring arrangements that were much more communal and relational. the sense of responsibility, however, could create tensions as participants experienced perceived cultural clashes regarding the understanding and meaning of familial care. a surprising theme to emerge early in this study was related to the relevance of geography and mobility to the flow of care. care processes were fluid, often transcending national, international, and geographical boundaries. mobility involved all members of the care network, including the person being cared for. geographical flow of care often consisted of the care receiver being cared for or supported across multiple households and geographical borders -both within the immediate locality as well as across different countries. furthermore, individuals providing some type of support or 'care' varied in terms of the type of relationship (immediate family; extended family; or friend networks) and location. one description of the mobility of the flow and fluidity of care between households by the immediate family was explained by chaaya, a south asian daughter, sharing care of their mother with her sister: mummy, from the time she came from india, first she lived with me, and later my sister moved out, and now she lives with my sister. half the week she lives here, and the other half she lives with my sister, and she has a very flexible schedule, and we are happy to keep her with us. there is joy in the house, that there is an elder in the house. (chaaya -sa-daughter caring for mother, age 67) while the movement of this flow of care often occurred with immediate families at the local level, particularly for frail care receivers, surprisingly, mobility of care receivers took place fluidly across transnational borders. it was not uncommon for older adults, particularly if health allowed, to spend time (often months) with family members either between different households locally or dispersed throughout north america and/or transnationally in a former country of origin. often, it was difficult to determine what country or geographic location was 'home' to the older adult care receiver given the frequency and regularity of these mobile relocations. although some chinese and south asian individuals were mobile locally and nationally, this transnational movement phenomenon tended to be more frequent among latin americans. what was clear in the data was the complexity of facilitating this geographical movement. to illustrate the intricate and complicated support arrangements created by extended families, margarita, chilean only daughter, caring for her 90-year-old mother later diagnosed with alzheimer's, described: i have a cousin who lives in los angeles. she is my mother's niece, and she called me one day and said, "i'm going to chile. do you want me to take my aunt?" i said, "yes," so that we bought her a ticket so that she could go to chile, and so that afterwards she would be able to go to brazil. i have a son in brazil. we bought her the ticket. i, my boyfriend, and my mother travelled to los angeles where my cousin lives, and from there my cousin took her to chile, and, initially, she was going to stay with her brother there, but it didn't work out, and before she left, we looked for another arrangement, and a distant relative, said that she could have her in the house, and for a reasonable amount of money so much so that she went there for a month, and after a month, she went to my son's house in brazil. (margarita -la only daughter caring for mother, age 90, with alzheimer's) as explained above, planning trips was extremely cumbersome. participants not only had to take into account the complicated nature of planning travel for their aging parents, but they needed to account for other factors influencing movement across international and national borders. for example, ignacio, the youngest son of three colombian brothers, explained that although his 68-year-old mother was independent and able-bodied, she is afraid of airplanes, so she cannot come alone. she is very frightened of airplanes, [and] she speaks absolutely nothing of english, or rather, for her to come alone is not an option either…" to counteract these issues, "we need to go there and bring her here, …" and then accompany her back when she returns to colombia. (ignacio -la son assisting mother, age 68) ignacio pointed out the importance of revising immigration, airline, and health policies, and programs to facilitate travel for aging immigrant parents: 'if they [policymakers, healthcare professionals, airline owners, or others] would simplify the way to bring parents, that way they would not have to become permanent residents or citizens.' he described ways travel could be facilitated and more accessible for older as well as frail adults. ….a program,…, where someone could bring them [older adults], and one wouldn't need to go and bring them here, rather that there would be a system where someone could bring various at a time, accompanying them in the airplane and helping them with running around for immigration. that would exist a way in that they could have tickets, a discount on the air fares….in the future an easier and faster way would exist that if the children are here, and the parents are alone there to make the immigration process faster because the time that they are there alone, well, it could become a risk that they experience other inconveniences because they are alone. (ignacio -la youngest son assisting mother, age 68) finally, not only was the older adult mobile, carers also travelled within or between cities nationally or internationally to help provide care for aging relatives. jasmine, a chinese canadian daughter, stated: [when i was] away in toronto for a brief period, about a bit more than a year, my sister came to live with her' [their mother]. …, my sister, my brother-in-law, and my father were with my mother. in the end, they left, went back to hong kong. in 2002, i came back from toronto to be with my mother. (jasmine -ch daughter caring for mother, age 80+, with alzheimer's) a prevalent theme underpinning the data from all three ethnic family networks indicated the importance of technology for facilitating an approach to family care that promoted a geographically fluid caring experience. in its least sophisticated form, technology included regular telephone contact -both locally and transnationally -with other family members and the care receiver. however, it also involved taking advantage of 'newer' technologies such as email and skype. the importance of telephone connection was highlighted by many: 'comfort was just a phone call away,' noted chaaya, a counselor and sa daughter. it enabled sibling and kin caring for older adults to be in 'communication all the time, absolutely, all the time, so that, well, or rather directly with her and through my sisters…' (chaaya -sa daughter sharing care with her sister of their mother, age 67). low cost international calling was relied upon extensively. regular phone contact -sometimes daily -was maintained between family networks. this ensured all members were involved in daily life and decision making for the senior and family. it also helped reduce stress for those currently providing hands-on care and ensured all family members had an understanding of the older adult's care needs. this allowed each family member to contribute to care decisions as they emerged daily based on each person's abilities and time to assist with and participate in the care and support process. meiling, 73-year-old chinese wife, caring for her 77-year-old husband with dementia e pointed out: our daughter came two years ago to see her daddy, but she has work and children and family, so they can't come every year….they have to wait for the right time, the children's summer holidays, to come over. so we rely on telephoning. they call 1, 2, or 3 times a week to talk with us. it's good. at least with the phone call, you get to know the situation. you can talk…now, they ask how's life with daddy, how he's deteriorating, get to know his conditions, that can help me reduce my stress [laughs heartily]. (meiling -ch wife caring for husband, age 77, with dementia) illustrating the many ways phone calls were used strategically, one son, ignacio, − a physician working in canada as a researcher -telephoned not just to keep his mother in colombia close to him but also to assist in monitoring her health: in actuality, we do it [call] once a week, and i ask her how her health is, if she has had medical appointments. i always find out what happened during the medical appointment, what medicines, what exams they ask for, what prescriptions she is taking, how she is feeling. perhaps, her health is the most important thing that i am aware of in addition to that, her emotional state. (ignacio -la son assisting mother, age 68) while not a replacement for actual physical contact and recognizing the complexity and financial cost associated with travel, phone calls were helpful. much of the calling was, not unexpectedly, between members of the family kin network, but the potential value of using telephone contact with health professionals strategically to keep family aware and involved, was also raised. thinking about his mother, ignacio suggested: -to find a way that the doctors there [in colombia] can communicate with the children here [in canada]…one could send them an email or tell them…a communication bridge to tell them how he found my mother, what needs to be done, because my mother goes to the doctor, and the doctor explains a mountain of things in medical terms that she is not going to understand. she goes home, and i ask her how it went, and she tells me fine. (ignacio -la son assisting mother, age 68) frequently, telephone calls were used to share news, keep in touch, and communicate -often daily. usually, these calls dealt with the mundaneness of daily living and celebrations. some extreme examples demonstrated the importance of contact as a lifeline. for instance, one venezuelan niece, leila, described how a visa problem limited her ability to travel, so she had to rely on an international call to talk with her dying aunt. previously, leila had cared for her aunt for more than 15 years in the us. devastated that she could not be by her aunt's side in her last moments, leila remembered saying as she listened over the phone to her aunt's labored breathing: little aunt, you are with god. never be afraid because god is with you. you will see that you are going to be super well. god loves you. i don't know how much. i love you so much, you know. (leila -la niece caring for aunt, age 75, with alzheimer's) leila recognized the importance of emotional caring by an extended family member as a fundamental aspect of care. the warmth of family caring could not be replaced by professional caregiving -and her simple use of telephone contact allowed leila to continue providing loving, heartfelt, emotional support, connection, and comfort. not being able to be there…, it was like disappearing from her life. before that…, we talked, and all, but……it was that i was there at every moment for her [when she had been caring for her aunt with alzheimer's on a daily basis in the us]. the woman [professional caregiver] she had was excellent, but it was not the same quality, or rather the love, or rather the quality of care could have been very special, very professional, and all, and…very affectionate, latina, …, quality, but nothing like the love of the family. (leila -la niece caring for aunt, age 75, with alzheimer's) despite its utility and importance for emotional support, comfort, and communication, technology had some downsides. even with reduced costs of international calling cards, daily international calls still remained expensive. moreover, telephone calls could be intrusive to one's personal life as explained by casimiro, argentinian son, an only child: if she [my mother] needed something, she would call me a number of times. i tell you that because if not, she becomes another of the things; this …is very interesting. with her, one must have balance because i visit her every day. she becomes very possessive, and afterwards, she thinks i have the obligation! at the same time, when i answer the telephone every time, but i do not answer one time, she says to me, "why didn't you answer the telephone!" …i say, "mami, i am working. i am doing business. sometimes, i cannot attend to you. leave me a message, and i will answer you." it is something very interesting. it is like an education…if i answer her immediately every time, sometimes when i do not answer, it is "oh, lala!" (laughs). (casimiro -la son, only child, assisting mother, age 81) beyond the telephone, other types of technology -for example, skype -emerged as an important facet for facilitating more traditional views of collective caring and played a key role in uniting local, national, international, and transnational 'carers.' it brought family members at a distance closer together in terms of proximity, particularly for some latin american participants. a vivid illustration of how technology facilitated day-to-day involvement was offered by antonia. despite residing a continent away, this 37-year-old female doctoral candidate described the continued closeness between her two sisters living in venezuela, her mother, and herself in canada. antonia pointed out that through technology, she, as the youngest daughter, was in constant communication with her mother in order to be part of and share experiences with her mother's daily life: by…using skype, we also see each other. then, if she goes saturday to have lunch at my sister's, my nieces turn on the computer. i say, mami, get on so that i can show you the little flower that bloomed on the plant. then, i show her through the house with the computer showing her the little flower, and it is so wonderful…it feels wonderful because she knows… as if she had come to actually see how it is doing, what the house is like here, and if the plant, and if it grew or if it didn't grow. i show her how…i hung a few new pictures. then, through skype, i can see the paintings. this makes it easier. (antonia -la youngest daughter supporting mother, age 66) technology played an important role in facilitating and fostering the fluidity and flow of care for cultivating a sense of closeness, proximity, and presence of family, kin, and friend networks caring for and involved in the life of the older person and family. as described by all three family cultural groups, technology spanned local, national, and geographical distance and transnational borders to bring comfort, support, presence, closeness, and involvement in decision making while allowing family, extended kin, and friends to participate in seniors' daily lives and experiences at a distance. recognizing the importance of culture within a context of informal family care, the research team for this study sought to better understand the process of family care within three ethnic communities in vancouver, bc, canada. a broad understanding of giving care was adopted, allowing participants to self-identify their role in the care process from their cultural perspectives. this, perhaps, set the stage for the importance of fundamentally challenging conventional ideas associated with the study of family care in north america that has often focused on one 'primary' caregiver. specifically, across all three cultural groups, our findings support an understanding of family care as truly occurring within broader family kin (and friendship) networks that tended to be culturally bounded, often loosely, but not geographically constrained. this meant that in all three cultural groups, but especially with the latin american participants, it was often difficult to name a 'primary' caregiver since even only children, like rossana and casimiro, created extended kin and friend support networks that aided in the provision of support and care. consistent with this approach, none of the family carers identified themselves as the 'primary' caregiver. the notion of a primary carer was further disrupted by the mobility and use of extended travel by both the older adult to live with other family members and/or by family members spending time with the older adult making it difficult to even determine the location where primary care was being provided. our participants described complex negotiated decisions made by kin networks as a collective family undertaking about how, when, where, why, and by whom care and support would be provided to aging seniors. care was fluid and flowing throughout individuals, networks, time, space, distances, and ages. this suggests to us the need to extend ideas about aging in place -a term that commonly directs policies and practice -to consider more specifically the notion of 'aging-across-place' (r. beard, personal communication, august 17, 2020) as a relevant concept for understanding care within culturally diverse, immigrant groups. these findings position family care using a lens that is far broader and relational than the narrow focus on the provision of instrumental care that has typically dominated understanding of family care within conventional gerontological literature. hence, our findings support the much more inclusive and complex approach to care offered by scholars, such as finch (1989) and tronto (2013) . tronto has developed the concept into an ethics of care framework. grounded in feminist relational theory, an ethics of care lens captures the reciprocity of care in that we are all interdependent, both receiving and giving care throughout our lives. in this framework, tronto identifies five principles to guide the provision of care: attentiveness, responsibility, competence, responsiveness, and solidarity. these correspond to five phases of care: 'caring about,' 'caring for,' 'care giving,' 'care receiving,' and 'care with.' these phases are fluid and can operate simultaneously and sometimes contradictorily, across different relationships. pragmatically, the phases and corresponding principles capture the complexity of the caring process and provide a useful lens for exploring relationships: purpose, needs, emotions, and power. this framework lens may be especially important for understanding the interface between the experiences of family and formal care, particularly within ethnically diverse communities where underutilization of formal supports has, in many cases, been identified as a problem. second, our findings raise questions about how place of residence may be re-interpreted and understood as a more fluid concept than is typically assumed with movement occurring at the local, national, and international levels. in raising these insights, the study contributes to the understanding of family care as a transnational global phenomenon and bridges two important bodies of research. as identified in the introduction, migration scholars introduced the importance of a transnational perspective to describe and conceptualize relationships individuals and communities develop and sustain across geographical distances and national borders (baldassar, 2007; horne & schweppe, 2017) . with few exceptions (baldassar, 2016; baldassar et al., 2007; merla, 2014) , this lens has rarely been applied to the study of aging and/or understanding family care of older adults (amin & ingman, 2014; horne & schweppe, 2017; näre, walsh, & baldassar, 2017; zechner, 2008) , especially related to non-western cultural groups (dhar, 2011b; torres, 2015; wilding & baldassar, 2018; zhou, 2012 zhou, , 2015 . this lens did not initially inform our research. however, the importance of it emerged early on in the data generation phase, and, consistent with a grounded theory approach, was used to help question, refine, and develop understanding. for example, we began to explore the fluidity and flow of care, role of technology, and describe how some ethnic older adults experience this notion of aging across different geographical places. our research suggests that this lens has much to offer to the study of family care in gerontology and supports findings by baldassar et al. (2007, baldassar, and merla, 2014 ) that family care does not need to be proximate in order to be effective. a transnational lens draws attention to a number of areas that require further exploration and development. first, consistent with the work of baldassar, nedflcu, merla, and wilding (2016) ; wilding, 2006; wilding & baldassar, 2018) , and others (see for example, ahlin, 2020; lee, lee et al., 2015) , the promises and challenges of information communication technology (ict) for facilitating a more holistic understanding and enactment of 'family care' emerged as a critical aspect of family care that requires further examination. our findings lend texture to wilding's (2006) suggestion that technologies blur lines of imagined proximity and physical separation as families creatively incorporate diverse types of technologies into their provision of care to meet cultural, social expectations, and health needs in these contexts that tend to be particular to specific points in time. it supports the value of ict for 'enacting everydayness' (ahlin, 2020) , p. 76 as a key theme related to 'good care at a distance.' one powerful example of the blurring of distance and time in this study was the graduate student, antonia, having lunch with her mother daily via skype. an understanding of the importance of ict also highlights ways of re-visioning the provision of formal support. for example, family conferences using supportive technology may help ensure that the entire family -irrespective of geographic location -has the necessary information to provide quality care and support, particularly for ethnic collective cultures. ensuring both the availability and uptake of effective communication technology infrastructures and digital literacy for older adults and their families will be an important area for research and service development. this is especially urgent in these times of covid 19. our study also supports the works of bryceson (2019), wilding and baldassar (2018) , and zhou (2012 zhou ( , 2015 that focused on the need to better understand how structural issues may impede the process of family care. transnational care or 'distant care' has received little recognition in the area of policy development (baldassar & merla, 2014) , and yet, as identified by at least one participant, ignacio, in our study, policies and practices, for instance around travel, may deter families from being able to care and provide culturally appropriate support in the way that they want while residency requirements may act as barriers for use of health and social care support services. future research is needed to understand how diverse health and social policies in both the home country as well as the country of immigration impact family care ( lee et al., 2015) . finally, attention to the notion of care as fluid and flowing for both able-bodied as well as those who are frail or ill emerged from our study as an important finding. 'flow of care' related to the presentation of negotiated, reciprocal, and shared family collective informal care was based on ability, availability, and capacity to care, occurring in motion, fluidly, through time and space as the care receivers transitioned and moved geographically to be with family as they aged and/or family moved to be with them. in addition to being consistent with an ethics of care framework, this notion develops further the work related to the circulation of care being developed by baldassar and merla (2014) ; . the concept of care circulation offers a broad view on transnational care through its focus on 'the reciprocal, multidirectional, and asymmetrical exchange of care that fluctuates over the life course and within transnational family networks subject to the political, economic, cultural, and social contexts of both sending and receiving societies' (baldassar & merla, 2014, p. 25) . in some of their work, they have examined how the older adult contributes in this circulation of care: an important limitation of our study is that we did not explicitly explore the role of the older person in the family care process except in relation to receipt of care. further research is needed to broaden and deepen the picture of family care, addressing more explicitly the role of reciprocity within the process. through this study, we explored the process of providing informal care to a family member within three diverse, non-western cultural immigrant communities. findings highlight the importance of recognizing family care as more communal and geographically fluid, supported by the innovative use of technology. the study suggests the need for a reframing of our understandings of family care -for example broadening moving from a notion of 'aging in place' to one of aging across geographical locations -and the need for policies and practices that can accommodate a different way of providing family care. we need to reinterpret care as flowing freely and fluidly throughout family, kin, and friend networks of informal, collective, and communal care through space, time, and distances locally, nationally, transnationally, and globally. no conflict of interest existed by the authors. good care" with icts in indian transnational families eldercare in the transnational setting: insights from bangladeshi transnational families in the united states transnational families and aged care: the mobility of care and the migrancy of ageing de-demonizing distance in mobile family lives: co-presence, care circulation and polymedia as vibrant matter families caring across borders: migration, aging and transnational caregiving transnational families, migration and the circulation of care: understanding mobility and absence in family life ict-based co-presence in transnational families and communities: challenging the premise of face-to-face proximity in sustaining relationships comments about a concept in the text of a manuscript from the editor of the research and dementia, caring and ethnicity: a review of the literature transnational families negotiating migration and care life cycles across nation-state borders an evidence-based policy prescription for an aging population constructivist grounded theory the power of constructivist grounded theory for critical inquiry special invited paper: continuities, contradictions, and critical inquiry in grounded theory transnational caregiving: part 1, caring for family relations across nations transnational caregiving: part 2, caring for family relations across nations caregiving stress and acculturation in east indian immigrants caring for their elders issues of race, ethnicity and culture in caregiving research: a 20 year review family obligations and social change toward a feminist theory of caring beyond familism: a case study of the ethics of care of a latina caregiver of an elderly parent with dementia. health care for women international barriers to access and minority ethnic carers' satisfaction with social care services in the community: a systematic review of qualitative and quantitative literature sense of filial obligation and caregiving burdens among chinese immigrants in the united states family relations, social connections, and mental health among latino and asian older adults transnational aging: toward a transnational perspective in old age research acculturation in filial practices among us chinese caregivers a 10 year portrait of theorizing in family gerontology: making the mosaic visible families and aging: from private troubles to a global agenda mining a unique canadian resource: the canadian longitudinal study on aging ethnomoralities of care in transnational families: care intentions as a missing link between norms and arrangements caring from afar: hib migrant workers and aging parents theorising about ageing, family and immigration la circulación de cuidados en las familias trasnacionales (the circulation of care in transnational families) concluding reflections: 'care circulation' in an increasingly mobile world: further thoughts dementia and migration: family care patterns merging with public care services ageing in transnational contexts: transforming everyday practices and identities in later life culture, caregiving, and health: exploring the influence of culture on family caregiver experiences placing ethnicity at the centre of studies of later life: theoretical perspectives and empirical challenges differences between caregivers and non-caregivers in psychological health and physical health: a meta-analysisanalysis at the intersection of culture: ethnically diverse dementia caregivers' service use diverse family structures and the care of older persons theorizing in family gerontology: new opportunities for research and practice family caregiving or caregiving alone: who helps the helper? immigration and ethno-cultural diversity highlight tables. immigrant status and period of immigration, 2016 counts, both sexes, age (65 years and over), canada, provinces and territories, 2016 census -25% sample data expanding the gerontological imagination on ethnicity: conceptual and theoretical perspectives caring democracy: markets, equity and justice virtual' intimacies? families communicating across transnational contxts ageing, migration and new media: the significance of transnational care care of older persons in transnational settings space, time, and self: rethinking aging in the context of immigration and transnatonalism time, space and care: rethinking transnational care from a temporal perspective we would like to thank dr. daniel lai (formerly of the university of calgary and now the hong kong polytechnic university) and acknowledge his leadership for this project.we would like to thank research assistants sonia andhi, msw for her work with the south asian interviewees and dr. sing mei chan for her assistance with the chinese participants as well as their help during the research process. a special thank you goes to, vancouver public librarian marilyn macpherson for her help in locating some of the statistics canada data.we are especially grateful to the chinese, south asian, and latin american participants and their families for sharing their experiences of caring and supporting their elderly relatives. this research was made possible by a canadian institutes health research grant (cihr #178845 -npi: dr. daniel lai) canada. this research was approved by the ethics committees from the university of calgary (calgary, ab) and the university of british columbia (vancouver, bc). key: cord-016301-vqmqnipq authors: winnick, aaron m.; karabicak, ilhan; distant, dale a. title: elderly transplant recipients date: 2011-01-25 journal: principles and practice of geriatric surgery doi: 10.1007/978-1-4419-6999-6_98 sha: doc_id: 16301 cord_uid: vqmqnipq while the total number of organs transplanted in this country has increased over the years, there is still an ever-widening gap between the need for organs and our capacity to meet that need as the overall waiting list continues to grow. this is due in part to significant advances in transplant techniques and outcomes such that americans with organ failure now seek transplants in greater numbers. additionally, life-expectancy gains in the united states are creating an aging population who are more likely to suffer organ failure than younger americans. the national transplant waiting list has continued to shift toward older candidates. the scientific registry of transplant recipients (srtr) reported that at the end of 2007, 59.7% of all 97,248 candidates on the waiting list for all organs were 50 years old or older, and 14.9% were 65 years or older. these percentages are substantially higher than they were in 1998 (41.5 and 8.1%, respectively) [1]. sn is an 84-year-old african-american male who developed renal failure after undergoing a triple-vessel coronary artery bypass graft (cabg) following a myocardial infarction in 2004. he has a history of hypertension and has been stable on hemodialysis via an av fistula. he has excellent exercise tolerance, a normal ejection fraction on cardiac catheterization, and was asymptomatic with regard to his coronary artery disease. he is fully functional and living independently since he retired from his job as a bus operator. he was placed on the waiting list for renal transplant in 2007. he received a zero mismatch offer from a 75-year-old deceased donor in august 2008. the donor was a 125 lb woman with no significant medical history who died from a cerebrovascular attack (cva). her serum creatinine was 0.7 mg/dl and postprocurement biopsy revealed minimal glomerulosclerosis. both kidneys were pumped and then implanted ipsilaterally in a 4½-h operation. he exhibited good immediate function and mild troponin elevation, but no other complications. he received induction therapy with three doses of thymoglobulin (1.5 mg/kg/dose), prograf, and steroids. he was discharged to home 5 days later with a creatinine of 2.0 mg/dl. no hospital readmissions occurred, and 1 year following transplantation, his creatinine level was 1.2 mg/dl. he is currently being maintained on prograf 2 mg twice daily and prednisone 5 mg daily. he remains quite active working as a producer for a local radio station, and he travels extensively visiting family. loss and death, and the degree and type of immunosuppressive therapy. this discussion focuses primarily on deceaseddonor organ transplants into the elderly, since fewer live-donor transplants are performed in the aged (670 transplants in 2008) . the kidney being the most frequently transplanted solid organ offers the most data in older patients and is therefore a primary focus of this chapter. no consensus exists as to what age defines "elderly" or "geriatric" within the transplant literature, and therefore, no attempt is made to offer such a definition; rather, the studies and data are examined with regard to the issues to be examined and the principles to be applied to older transplant candidates. older americans are an increasingly important consumer of end stage renal disease services in the united states. the u.s. renal data system (usrds) collects and provides national demographic information about patients with kidney disease treated with either dialysis or transplantation. the average age of the dialysis patient continues to increase each year, with nearly half of patients undergoing regular dialysis now over 65 years of age, and the mean age of those beginning treatment is now greater than 60 years [2]. there are currently 48,773 patients on the waiting list for a kidney, with 7,800 (16%) over the age of 65. in 2007, nearly 17,000 kidney transplants were performed in the united states, with 2,377 (14%) going to patients over the age of 65 [1] . kidney transplantation has been shown to improve quality of life and length of life compared with those remaining on dialysis [3] . in one longitudinal study of mortality, investigators evaluated data collected over 6 years on 228,552 patients who were receiving dialysis as treatment for their end-stage renal disease. of these, 46,164 were deemed healthy enough to be placed on the waiting list for transplantation, and 23,275 received a first deceased-donor kidney transplant. the mortality ratio for the patients on dialysis who were awaiting transplantation was 38-58% lower than that for all patients on dialysis (annual death rates of 6.3 and 16.1 per 100 patient-years, respectively). the long-term mortality rate was 48-82% lower among transplant recipients than patients on the waiting list (annual death rate 3.8 per 100 patient-years). recipients over the age of 60 demonstrated significant benefit in mortality after transplantation, with annual death rates per 100 patient-years at risk for all patients on dialysis, patients on the waiting list, and transplant recipients being 23.2, 10, and 7.4, respectively. it is estimated that, among those over the age of 60, projected remaining years of life are approximately 6 and 10 years for those who remain on a waiting list or undergo renal transplant, respectively [4] . multiple studies over the past 10 years have confirmed that patients older than 60 years of age have longer life expectancy with deceased-donor kidney transplantation when compared to patients of the same age group on the waiting list. post-kidney transplant recipients report a better quality of life, from mental well-being to physical functionality and social functioning. in addition, after adjusting for comorbidities, there is no significant difference in graft failure compared to younger patients [5] [6] [7] [8] . as with all organ transplants, the risks and benefits must be carefully weighed, especially in the elderly. will this organ improve the patients' overall survival and quality of life? will an older patient be able to survive the operation, manage the medications, endure the potential side effects of immunosuppression, and have the social and financial support necessary to recover and maintain rigorous doctor appointments? current success in transplanting kidneys into older recipients has quieted misconceptions within medical communities and the general public, among them the erroneous belief that advanced age alone prevents a successful surgical outcome, that the elderly patient with esrd has a very limited life expectancy, and thus cannot receive a transplant, and that older recipients have poor results based upon outdated information from the previous era of transplantation and immunosuppression. older recipients, however, do have a higher risk of cardiovascular events, infection, and malignancy after kidney transplantation compared to younger patients [9] . also, they are more prone to drug side effects and toxicity [10] . the absolute gain in survival provided by a donor kidney varies considerably depending on recipient factors, such as age and comorbid illnesses. although overall graft failure rates are not higher for elderly recipients, death with a functioning graft does occur more often which shortens the lifespan of the donated kidney (especially from a young donor) [10] . clearly, a younger recipient would more likely experience more years of allograft function with the same kidney. with ever-increasing organ shortages, the ethical dilemma of including age as a potential allocation factor has been raised. the argument pits the increased survival and quality of life for the older transplant recipient against the population gain in allograft survival by transplanting kidneys preferentially into younger recipients. what is the best way to deal with these competing allocation philosophies, namely, giving everyone an equal chance to receive an organ vs. getting the maximum benefit from each organ transplanted? in the u.s., the united network for organ sharing (unos) provides regulatory oversight and balances these ethical principles in an effort to achieve socially acceptable allocation policy. an alternate strategy to maximize the benefit of donor organs matches kidneys with lower expected graft survival time (principally older donors) to patients with lower expected longevity (principally older recipients). the current allocation of expanded criteria donor (ecd) kidneys attempts to do this. these kidneys are procured from donors older than 60 years of age or donors aged 50-59 years with at least two of the following conditions: cerebrovascular accident as cause of death, a history of hypertension, or a serum creatinine > 1.5 mg/dl [11] . while ecd kidneys carry a relative risk of graft failure greater than 1.7 compared to a reference group of donors aged 10-39 years without any of the above three conditions, elderly recipients of ecd kidneys were found to have a survival benefit compared with waiting-list candidates (rr = 0.75; 95% ci 0.65-0.86; p < 0.0001) [8] . the benefits (shortening of waiting time) and risk (impaired long-term graft function) associated with the use of ecd kidneys should be addressed on an individual basis. as with all recipients, elderly patients do best with an ideal donor kidney; however, the ecd policy achieves a compromise that enhances the donor pool and provides good alternative to dialysis. another option for increasing the number of organs and decreasing the waiting period for renal transplantation is to perform a dual kidney transplant. both kidneys from an older donor, which individually would be considered marginal or inadequate for transplantation, are transplanted into a single recipient. this expands the use of kidneys that otherwise would not be used. there is a misconception that dual kidney transplantation involves the transferring of an inferior organ; on the contrary, it is just a different type of organ transplant. for all kidneys being evaluated for donation, the creatinine clearance is calculated. if it is greater than 65 ml/min, each individual kidney may be transplanted into two different recipients. if it is below 40 ml/min both kidneys are usually deemed unsuitable for transplant. the area in between, 40 and 65 ml/min, constitutes the range to use two kidneys together to give recipients the function of one kidney. this allows for the transplantation of as much kidney function as, if not more than, a standard single transplant from a nonexpanded criteria donor. with careful selection, the amount of kidney function that is being transplanted with dual kidney is comparable to a single kidney transplant [12] . prior to transplantation of any organs, the prospective recipient has to be carefully evaluated to detect and treat any coexisting illnesses that may affect patient and graft survival after transplantation. in the elderly, this is imperative for two reasons: graft loss in the elderly is related primarily to patient death, and the main causes of morbidity and mortality following transplantation are infection and cardiovascular disease [13, 14] . regardless of the age of the recipient, a thorough medical, surgical, and psychosocial history needs to be obtained, along with a detailed physical examination. careful examination of the abdomen for previous operations is important, as is the presence or absence of peripheral arterial pulses. initial laboratory testing includes blood type, hla typing and a panel reactive antibody assay to detect for previous sensitization, complete blood count (cbc), blood urea nitrogen, creatinine, electrolytes, calcium, phosphorous, albumin, liver function tests, prothrombin time, and partial thromboplastin time. serologic studies for cytomegalovirus (cmv), hepatitis b and c viruses (hbv, hcv), human t cell leukemia virus (htlv-1), and human immunodeficiency virus (hiv) are routine. one element of the evaluation process includes baseline age-appropriate screening tests. it is also important and appropriate to maintain a higher index of suspicion for malignancy in patients of this age group. in women, this consists of gynecologic examination and papanicolaou smear, breast examination, and in those over the age of 40 without a family history of breast cancer in the premenopausal years, mammography. in men, testicular examination, prostate examination, and for those over age 50, prostate-specific antigen (psa) assay should be performed. all patients over the age of 50 should undergo screening colonoscopy. a screening purified protein derivative (ppd) test may be used depending on the patient population and patient history. radiologic studies include chest x-ray and electrocardiogram as routine and can include ultrasound or computed tomography (ct) scan of the abdomen to evaluate anatomy if indicated. estimation of urine output preoperatively is important because it determines the significance of postoperative urine output and helps determine the need for any urologic evaluation. a history of claudication warrants a workup for peripheral vascular disease and may also point towards a higher chance of ischemic heart disease. the presence of strong femoral and peripheral pulses indicates that the pelvic vessels will likely be adequate for the transplant vascular anastomosis. assessment of cardiac risk is critical in the evaluation process of elderly patients. cardiovascular disorders, such as hypertension, coronary artery disease, congestive heart failure, and arrhythmias are common in elderly transplant recipients and account for most of the deaths in this population. blood pressure, blood glucose, and cholesterol control is of particular concern because this patient population frequently have or develop these complications. the prevalence of ischemic heart disease is very high in patients with end-stage renal disease, and almost half of the deaths that occur during the first 30 days posttransplant are due to ischemic heart disease [15] . the current guidelines from the american society of transplantation recommend assessing ischemic heart disease risk factors in any patient with a prior history, men over the age of 45 or women over the age of 55 years, cardiac disease in a first-degree relative, current cigarette smoking, diabetes, hypertension, fasting total cholesterol > 200 mg/dl, highdensity lipoprotein cholesterol < 35 mg/dl, and left ventricular hypertrophy. any patient at high risk, including those with renal disease from diabetes, prior history of ischemic heart disease, or more than two of the above risk factors, should undergo an echocardiogram and cardiac stress test. angiography with possible revascularization, if indicated, should be performed prior to any transplantation. asymptomatic patients can also undergo noninvasive tests first that may help determine the risk for posttransplant complications, in the form of chemical stress echocardiography or scintography [15] . based on an initial evaluation, the 2005 canadian society for transplantation guidelines suggested that the following patients with coronary heart disease may be eligible for kidney transplantation: asymptomatic low-risk patients; asymptomatic patients in whom noninvasive testing is negative; patients on appropriate medical therapy with angiographic results showing noncritical disease; and those patients in whom successful interventions have been performed [16] . currently, there is no strong evidence to suggest a benefit to the routine screening of asymptomatic renal transplant candidates for cerebrovascular disease. risk factors for posttransplant cerebrovascular disease include a history of prior disease, age, smoking, diabetes, hypertension, and hyperlipidemia [15] . patients who have already suffered from a cerebrovascular event and have significant deficits may be poor operative candidates due to their poor operative risk and rehabilitative potential. patients with recent transient ischemic attacks need to be adequately evaluated by a neurologist. pulmonary risks associated with surgery for transplantation include infection, fluid overload, and ventilator dependency. pretransplant evaluation of elderly patients with respiratory disease should be consistent with that for the general population who undergo a preoperative pulmonary assessment [17] . the 2005 canadian transplant guidelines suggest that patients should not be considered candidates for kidney transplantation if they require home oxygen therapy, have uncontrolled asthma, severe cor pulmonale, or severe copd, pulmonary fibrosis, or restrictive disease. the latter is defined by fev1 < 25% predictive value, room air po 2 < 60 mmhg with exercise desaturation sao 2 < 90%, or more than four lower respiratory tract infections in the last 12 months [16] . the transplant candidate must be free of all active infections before transplantation could be considered. whenever possible, all treatable infections should be dealt with appropriately. chronic infection precludes transplantation and the subsequent use of immunosuppressive therapy. infectious complications occur frequently in the transplanted patient, with pneumonia being one of the most common infections seen in elderly hospitalized patients. as such, elderly patients must be immunized against influenza and pneumococcus. not too long ago, most centers considered patients who tested positive for hiv inappropriate for transplantation secondary to immunosuppressant-induced opportunistic infection and the suspected short life span. with the advancement in antiretroviral therapy, more centers now are willing to transplant patients who are hiv positive, but the general recommendation is to evaluate on a case-by-case basis. patients with a malignancy prior to receiving an organ may still be a suitable candidate for transplantation depending on the tumor type, stage, and response to therapy. the concern is that malignancies are common after transplantation, possibly due to immunosuppression favoring the growth of malignant cells and/or viral infection. this part is addressed in a later section on postoperative issues. while it has been reported that patients with esrd on dialysis have a higher rate of cancer compared to the general population, this relative risk has been shown to be higher in younger patients [18] . most patients previously treated for cancer benefit from a waiting period prior to renal transplantation to decrease the risk of recurrence. depending on tumor characteristics, recommendations range from no wait time to 5 years. no waiting time is required for basal cell carcinoma of the skin, in situ cancer of the bladder or cervix. a 2-year waiting time is proposed for lymphoma, leukemia, cancers of the prostate, lung, breast (early stage), testicle, thyroid, uterine body, bladder, wilm's tumor, renal cell carcinoma (<5 cm), or kaposi's or other sarcoma. patients with localized, successfully treated carcinoma of the uterine cervix may benefit from waiting 2 years, and in some cases 5 years, prior to transplantation. a 5-year waiting time is recommended for colorectal, invasive breast, and renal cell carcinoma (>5 cm), and malignant melanoma [15, 16, 19] . while some contraindications to kidney transplantation are absolute, many are relative and determined by individual centers. absolute contraindications to receiving a renal transplant include: recent or metastatic malignancy; active substance abuse; severe extrarenal disease with life expectancy of less than 1 year; untreated current infection; psychiatric or other illness impairing adherence to regimen. relative contraindications include: morbid obesity; active heavy tobacco use; acute coronary or cerebrovascular event; hiv infection if untreated or poorly monitored [13, 15] . the actual surgery for transplanting a kidney is the same for the elderly patients as for any adult, with the caveat that careful attention must be paid to fluid maintenance and monitoring in the elderly, depending on the cardiac and pulmonary history. the standard incision for adult kidney transplantation is an oblique incision from the symphysis in the midline, curving in a lateral and superior direction to the iliac crest. the donor renal artery and vein are anastomosed to the recipient external iliac artery and vein, respectively, and the donor ureter anastomosed to the recipient bladder. the kidney is placed in the iliac fossa where it is easily accessible if an ultrasound, biopsy, or other intervention is required. while the benefit of renal transplantation in the elderly has already been established, there is a paucity of data evaluating the safety and efficacy of immunosuppression regimens. most centers use traditional principles and their transplant protocols with modifications when considering the factors unique to the elderly. analysis of registry data suggests that while the risk of acute rejection decreases with age, the impact of rejection on long-term graft function in this elderly population is greater when compared to younger groups. it is of no surprise that posttransplant mortality is greater in the elderly; however, censoring graft survival data for patient death demonstrates no significant difference between outcome in older and younger patients [5, 6, 20, 21] . the goal of an immunosuppression protocol should be to maintain a level necessary for a reduced risk of infection without increasing the risk for rejection. the elderly have less immunocompetence, and the therapy has to be adjusted in the elderly transplant recipient. this may result in a decreased likelihood of immunologic rejection but increased risk of infection. immunosuppressive therapy also has to be adjusted to account for the different pharmacokinetics and altered effects of drugs in the elderly. the aging process results in physiological changes that affect drug absorption, distribution, and metabolism. in addition, due to the many comorbid conditions in the elderly, they often take many medications which may have drug-drug interactions with immunosuppressive medications [22] . there are currently no prospective multicenter trials that specifically evaluate immunosuppressive medication protocols in the elderly in a randomized fashion. most of the time, the elderly are excluded from trials. as such, most of the data is from single-center, observational studies or retrospective database analyses [23] . any approach should be based on the risks of acute rejection, infections, malignancy, and comorbid conditions. there is no set immunosuppression protocol that has been universally accepted in the elderly or any patient population. although acute rejection decreases with recipient age, chronic allograft nephropathy seems to increase with age, and this phenomenon is further confounded by increased death from infectious disease and drug-related causes. this has led to some protocols that support less-intensive immunosuppressive drug therapy in elderly recipients [24] . current treatments consist of triple therapy with corticosteroids, a calcineurin inhibitor (cyclosporine or tacrolimus), and an antimetabolite, but these regimens may be replaced by substitution or addition of newer antiproliferative agents. treatment with mycophenolate mofetil (mmf), which inhibits purine synthesis, has been found to result in a longer time to the first episode of acute rejection but had significantly greater rates of opportunistic infection and graft loss and mortality [25] . one study comparing mmf to azathioprine evaluated over 5,000 patients over the age of 65 and showed improved patient and graft survival with lower rates of late acute rejection with mmf. the most prescribed immunosuppressive protocol is a combination of mmf with calcineurin inhibitor, and there appears to be no contraindication to use this protocol in the elderly [26, 27] . an alternative or supplement to standard triple therapy is the use of augmented immunosuppression with antilymphocyte antibodies, commonly termed "induction immunotherapy." these cytolytic agents have been found to reduce the risk of early rejection but tend to increase the risk of infection. induction therapy in the form of atgam® (equine antithymocyte globulin) or okt3® (muromonab-cd3) was the mainstay but now has been largely replaced by the use of thymoglobulin® (rabbit anti-lymphocyte globulin) or monoclonal antibody therapy directed against the il-2 receptor -zenapax® (daclizumab) or simulect® (basiliximab) [1] . in addition to the immunosuppression and steroids making the elderly more susceptible to infection, fractures, weight gain, and other side effects, they are at a 30% higher risk of developing new-onset diabetes posttransplant per decade of life [28] . this has led to a movement in recent years for the avoidance or early withdrawal of calcineurin inhibitors and/or corticosteroids. multiple studies demonstrated appropriate patient and graft survival, as well as excellent graft function, after using induction agents and minimizing the use of calcineurin inhibitor [29] [30] [31] . considering the elderly's increased risk for adverse affects and infection, and the limited prospective data available, any protocol must consider that decreasing the risk of acute rejection may augment the morbid consequences of rejection. as such, protocols are currently tailored based on donor type and immunologic status of the elderly recipient. the lowrisk recipient of a kidney from a young donor may be a candidate for rapid steroid withdrawal or steroid minimization strategies due to the lower risk of rejection and increased risk of steroid-induced adverse effects. the low-risk recipient of a kidney from an older donor may have an enhanced risk of chronic allograft nephropathy and nephrotoxicity from the calcineurin inhibitors, so it may be appropriate to use a calcineurin inhibitor minimization strategy. as already mentioned, interleukin-2 receptor antibodies or antilymphocyte antibodies may be used as induction agents with a calcineurin inhibitor, with the interleukin-2 receptor antibody showing a superior safety profile. minimizing immunosuppression is not appropriate in an elderly patient with high immunologic risk, so a regimen consisting of antibody induction, corticosteroids, calcineurin inhibitors, and/or mmf is more reasonable [23] . since there is potential for severe consequences with acute graft rejection in the elderly, a biopsy should be performed in all unexplained cases of allograft dysfunction. treatment should be based on histologic findings, whenever possible, with empiric steroid use for treatment of presumed acute rejection used sparingly due to the increased risk of adverse events in the elderly. renal allograft and patient survival in the elderly transplant recipient are currently excellent, when looked at as a group and compared to younger recipients. patient survival at 1, 5, and 10 years ranges from 80 to 90, 70, and 50%, respectively [1, 5, 6, 32] . this is based in part on the type of allograft. based on the 2008 srtr analyzing transplants from 1998 to 2007, 3-month, 1-, and 5-year patient survival rates for those 65 years of age and older receiving a renal transplant are: 98, 96, and 78% for recipients of living-donor kidney transplants, respectively; 96, 92, and 66% for recipients of deceased-donor nonextended criteria donor kidneys, respectively; and 95, 87, and 58% for recipients of deceased-donor extended criteria donor kidneys, respectively [1]. graft survival has increased in parallel, averaging 85% at 1 year and 70% at 5 years [5, 6] . allograft survival at 3 months, 1, and 5 years for those 65 years of age or older are: 97, 94, and 74% for recipients of living-donor kidney transplants, respectively ( fig. 98.1) ; 94, 88, and 59% for recipients of deceased-donor nonextended criteria donor kidneys, respectively; and 90, 81, and 48% for recipients of deceased-donor extended criteria donor kidneys, respectively ( fig. 98.2) [1]. patient death with a functioning graft accounts for the majority of reported "graft loss" in the elderly patients. nearly 50% of graft loss is due to death in the elderly recipient compared to 15% in the younger recipient. acute rejection is reported to occur less often in elderly recipients, but there is an increased risk of chronic allograft nephropathy, especially if the allograft is from the older donor [33] . the predominant causes of death in elderly transplant recipients are cardiovascular disease and infection. most infectious episodes occur in the first 6 months posttransplant, likely due to the degree of immunosuppression. the risks of overimmunosuppression and cardiovascular disease are related to the natural effects of aging and factors having to do with end-stage renal disease. overimmunosuppression will increase infectious complications in all patients, regardless of age. however, the elderly are less immunocompetent, leading them to be more susceptible to infection at lower lev-els of immunosuppressive therapy. most likely to contribute to this are high-dose corticosteroids and antilymphocyte antibodies at induction. other causes of death in the elderly recipient include malignancy and gastrointestinal hemorrhage. death due to malignancy has been reported to increase disproportionately with time after transplantation in the elderly recipient [22] . despite the mortality risks, there is still a better life expectancy and quality of life afforded by kidney transplantation compared to dialysis. with careful selection and responsible follow-up, advanced age alone is not a contraindication to successful transplantation. age should not be the primary determinant of donor allocation; rather, the focus should be on baseline comorbidity or functional status [10] . end-stage liver disease (esld) results from many etiologies and eventually leads to complications including bleeding, ascites, infection, renal failure, fluid and electrolyte disturbances, hepatic encephalopathy, hepatocellular carcinoma, and eventually, liver failure. currently, the only defin the most common diagnoses in elderly patients waiting for liver transplantation are cirrhosis, alcoholic liver disease, hepatitis, primary biliary cirrhosis, and hepatocellular carcinoma. elderly patients should only be considered for transplantation if they are thought to be capable of surviving the perioperative period and complying with the intense chronic medical regimen and follow-up [34] . older patients are frequently seen as higher risk recipients due to their comorbidities and increased mortality to both hepatic and nonhepatic causes [35] . liver transplantation in patients over the age of 55 was discouraged as recently as 20 years ago. however, since that time, there have been many studies demonstrating success in patients over the age of 60, encouraging more centers to list and operate on older patients [36] [37] [38] [39] [40] [41] . more recent data suggest that patients over the age of 70 may successfully undergo liver transplantation; however, it has to be at a less-severe level of disease to have a good outcome [42] . most contraindications for liver transplantation relate to comorbid conditions. relative contraindications include alcohol or illicit drug use in past 6 months in a patient with a history of abuse, severe extrahepatic disease, adverse psychosocial factors, anatomic difficulties resulting from previous abdominal trauma or surgery, and age. absolute contraindications generally include uncontrolled infection or sepsis, extrahepatic malignancy, advanced hepatic malignancy, and irreversible brain injury [39, 43] . hiv infection had previously been considered to be an absolute contraindication for liver transplantation. however, with the significant improvements with antiretroviral therapy and improved monitoring methods, it is no longer a sufficient reason to refuse surgery. while some centers may still list it as a relative contraindication, many will no longer restrict recipients as long as attention is paid to the comorbid conditions. for more than 30 years, the child-pugh classification system was used to predict morbidity and mortality in patients with liver disease. while useful in stratifying patients for transplantation, it does not provide an adequate method of prioritizing patients on the liver transplant waiting list [44] . as a result, organ allocation in adults is now based on the model for end-stage liver disease (meld), which is a logarithmic transformation of the recipient's bilirubin level, creatinine level, and international normalized ratio (inr) into a mathematical model. it allows for an objective assessment of need for transplantation and short-term prognosis while waiting for a transplant. it does not, however, necessarily correlate with posttransplant survival [45] . preoperative assessment of all liver transplant candidates includes abdominal ultrasound, thoracic and abdominal computed tomography, and upper gastrointestinal endoscopy in addition to routine blood studies. patients older than 50 years must undergo screening colonoscopy, and in male patients older than 55 years, the serum prostate-specific antigen concentration must be studied with digital rectal examination. in female patients, cervical and breast cancer screening must be done as indicated before listing. age-related morbidity is one of the main causes of mortality after liver transplantation. older patients have to be evaluated by specialists in the field of cardiology and pulmonary disease [46] . the cardiovascular workup for patients over the age of 60 years includes a routine history and physical examination, ekg, and twodimensional echocardiography. a history of coronary artery disease (cad) or symptoms of exceptional angina are clear indications for performing cardiac catheterization prior to transplantation. a negative stress test is not sufficient to exclude cardiac disease in patients with clinical history strongly suggestive of cad. in this situation, the clinician may elect to proceed directly to cardiac catheterization [47] . doppler studies of the carotid, vertebral, and peripheral limb arteries are performed on these patients if clinically warranted. revascularization strategy must be performed prior to listing for liver transplantation if there is extensive coronary heart disease [38] . diabetes mellitus may be the most important risk factor for the presence of cad in patients with liver disease and must be assessed and managed appropriately in the perioperative setting [44, 48] . older patients with end-stage liver disease, particularly those with cholestatic liver disease, are also at risk for osteopenia or osteoporosis. postoperative corticosteroid therapy will also contribute to bone loss, increasing the risk of sustaining compression fractures. for all elderly patients, determination of vitamin d serum levels and baseline bone densitometry is encouraged [44] . any patient over the age of 60 with a history of encephalopathy, seizures, or ischemic event should have an mri of the brain prior to being listed. older patients also have to be routinely screened for malignancy. patients waiting for liver transplants need to be evaluated for hepatocellular carcinoma (hcc) in particular, as well as for colon, skin, prostate, and breast neoplasms. for liver transplant recipients, the pretransplant status has been found to be associated with survival, and this is seen more in elderly patients. in a retrospective review of 1,446 liver transplant recipients, of which 241 were over the age of 60, the elderly patients were found to be especially at risk for lower survival if they had a bilirubin level of 10 mg/dl or greater, an albumin level of less than 3 g/dl, a markedly prolonged (>20 s) prothrombin time, or generalized poor nutrition. the authors recommended forgoing transplantation in a patient over the age of 60 who is an inpatient in the hospital or in the intensive care unit with any of the above values [49] . the immunosuppression protocol and dose of immunosuppressive drugs do not drastically differ between older and younger liver transplant patients [43] . immunosuppressive strategies vary from center to center in the selection of specific agents, the number of agents, and the duration of use of each agent. the combinations used have evolved to predominantly tacrolimus, mycophenolate mofetil/mycophenolic acid, and steroids. triple drug therapy remains the predominant drug regimen; however, many centers are attempting to minimize or eliminate long-term steroid use. the key is to tailor the regimen to the patient to best prevent cellular rejection, have no associated morbidity with respect to opportunistic infections, have no nephrotoxicity, and preclude the development of infection, which continues to be a leading cause of death in the year after transplantation. although there are some studies reporting that the long-term survival of patients older than 60 years was lower than younger recipients [50] [51] [52] [53] , most studies report similar [38, 54, 55] or even better [43, 56] survival in recipients older than 60 years old. one study evaluating the survival rates of elderly liver transplant recipients found that the short-term survival of the elderly is comparable to those younger adults, but the longer survival was not encouraging. the long-term survival was significantly lower in elderly recipients, with a 5-year patient survival of 52% in the elderly group and 75% in the younger patients ( p < 0.05). the study period was divided into two eras; 1984-1991 and 1992-1997. in both eras, recipient survival in those older than 60 years was significantly lower than younger recipients, lending support to the idea that older recipients are not good candidates for liver transplantation [50] . a different study showing better survival rates in elderly patients looked at 240 liver transplant recipients, of which 23 were over the age of 60. they reported 87.5 and 83.3% 1-and 3-year patient survival in the elderly, respectively, compared to 77.8 and 73.5% in the younger group. graft survival rates at 1 and 3 years were found to be 79.2 and 75% in the older group and 76.5 and 71% in the younger group, respectively. neither set of data showed any statistical significance [52] . some studies divided older recipients into two groups to show the effect of age more clearly: recipients between 60 and 65 years of age and those older than 65 years. one study reported that the patient survival in the older than 65 years of age group was 99%, 82 and 73% in 3 days, 1, and 5 years, respectively [38] . a different study found a lower survival rate in patients older than 65 years than in patients between 60 and 65 years, although there was no statistical significance. overall, patients older than 60 years had lower survival rates than younger patients, which could possibly be explained since that group had a higher rate of hcc as the reason for transplantation [47] . similar results can be found in smaller studies for recipients over the age of 70. one study found a 58% 3-year survival in 33 patients, while another has 1-and 3-year survival rates of 78.8 and 71.4%, respectively [39, 53] . data is limited in this age group, but transplantation in septuagenarians is definitely feasible if the patient is otherwise healthy. there are few studies looking at the survival in older patients after a living-donor liver transplant (ldlt), and the results have been mixed. some investigators reported that recipient age had an influence on allograft failure [48] , while others found that older recipient age and prolonged cold ischemia time increased the risk of graft failure [49] . one of the larger studies investigated the impact of age in living-donor liver transplantation by following recipients over 60 years of age over a 10-year period. they found the following parameters as risk factors influencing survival rate in patients after ldlt: meld score equal to or greater than 25; child's classification c; preoperative status of the recipient being in an intensive care unit; and blood type incompatibility. recipient age of 60 years of age or older had no influence on the survival. 1-, 3-, and 5-year survival of the recipients older than 60 years were 81.9, 78.7, and 78.7%, respectively. interestingly, their results in older patients were better than in younger patients (1-, 3-, and 5-year survivals in patients younger than 60 years is 75, 70.8, and 69.3%, respectively). a possible explanation for this better survival is that the selection criteria of older recipients were more stringent. the meld score for older group recipients was significantly lower, and high-risk older patients were not considered for ldlt as a treatment option for their advanced liver disease in that study [43] . it is evident that after 5 years, survival of patients aged 65 years and older begins to diminish [38] . the 10-year survival of recipients older than 60 years was found to be 48%, which is significantly lower than the 72% survival rate of recipients younger than 60 [47, 57] . one study evaluated 91 transplant recipients over the age of 60 over a 13-year span and reported a 10-year patient survival of 35% in the elderly group and 60% in the younger patients ( p < 0.05). the most common cause of late mortality in elderly liver recipients was malignancy (35%), whereas most of the young adult deaths were the result of infectious complications (24%) [50] . based on the 2008 srtr analyzing transplants from 1998 to 2007, 3-month, 1-, 5-, and 10-year patient survival rates for those 65 years of age and older receiving a liver transplant are 91, 81, 64, and 42% for recipients of deceaseddonor liver transplants, respectively and 93, 85, 71, and 54% for recipients of living-donor livers, respectively. allograft survival at 3 months, 1-, 5-, and 10-years for those 65 years of age or older are 94, 84, 68, and 53% for recipients of living-donor livers, respectively (fig. 98. 3) and 89, 78, 61, and 40% for recipients of deceased-donor liver transplants, respectively ( fig. 98.4) . the results at all intervals were comparable to those of younger age groups [1]. when evaluating a patient's risk for rejection after liver transplant, younger age has been found to be an independent risk factor [58] . older patients usually have a lower incidence of episodes and severity of graft rejection, possibly a result of immune senescence [46, 51, 59] . one study noted that liver recipients over the age of 65 tended to have lower rates of rejection, although there was no statistical significance [38] . some centers have reported no difference in episodes of acute rejection among older or younger recipients [56, 60] . most studies report no statistical differences in the incidence of complications in terms of hospitalization, infection (surgical or opportunistic), repeat operation, readmission, or repeat transplant between the patients older or younger than 60 years [56] . older patients are more prone to having higher incidence of osteoporosis, nontraumatic bone fractures, coronary artery disease, and malignancy after liver transplantation, with skin cancer being the most common [43, 47] . the most prevalent cause of death in recipients older than 60 years is malignancy (both recurrent and de novo) and sepsis [38, 43, 47] . in one study, investigators reported that seven of ten recipients died secondary to sepsis in the early phase after ldlt within 3 months. in patients younger than 65 years of age, most causes of death are related to cardiovascular (myocardial infarction, congestive heart failure, cerebrovascular accident, intracranial hemorrhage) and sepsis. a possible explanation for not having the cardiac problems as a leading cause of death in older patients may be that the older recipients are more rigorously assessed for comorbidities that could be detrimental to outcome. well-selected patients over the age 60 or 65 have a comparable survival after liver transplantation to younger recipients at 1-, 3-, and 5-years posttransplant. advances in surgical technique, improved intensive care, and standardized immunosuppressive therapy all contribute to the good survival results. unfortunately, long-term results have not been as promising, possibly explained by older patients having fewer years of life remaining. nonetheless, this should not preclude liver transplantation in elderly patients deemed strong and otherwise healthy enough to undergo the procedure [38] . chronic heart failure remains one of the most common diseases affecting the population. with increases in life expectancy and improvements in medical care, more elderly patients are being seen by cardiologists and cardiac surgeons for end-stage heart failure. cardiac transplantation is the treatment of choice for many patients with end-stage heart failure who remain symptomatic despite optimal medical therapy. the 2007 report from the registry of the international society for heart and lung transplantation (ishlt) estimated that slightly more than 5,000 heart transplants are performed annually worldwide [61] . the srtr estimates that anywhere from 2,000 to 2,400 heart transplants were performed in the older patients have been excluded from consideration for heart transplantation in the past, typically due to the supposed adverse effect of increased age on long-term survival and the shortage of donor organs. however, advances in posttransplant care have improved outcomes in older patients, and several centers have demonstrated results comparable to younger patients. the criteria regarding the recipient's older age limit continue to be expanded, and older patients are increasingly being considered as potential heart transplant candidates [62] [63] [64] [65] . over the past decade, there has been a significant decrease in mortality in patients with advanced heart failure treated aggressively with medical and device therapy, leading to a reassessment of the role of cardiac transplantation [66, 67] . the ideal heart transplant candidate is a person with endstage heart disease for whom conventional therapy is not likely to provide acceptable symptomatic benefit or satisfactorily improve life expectancy. the clinical practice committee of the american society of transplantation published recommendations in 2001 for considering heart transplantation in patients with cardiac conditions that have not responded to maximal medical management [13] . although severe heart failure refractory to medical therapy is the most common indication for transplantation, other circumstances warranting transplant include severely limiting ischemia not amenable to interventional or surgical revascularization, recurrent symptomatic ventricular tachyarrhythmia refractory to medical therapy, an implantable cardioverter-defibrillator (icd), or surgery and rarely, for the management of cardiac tumors. nonischemic cardiomyopathy accounts for approximately 45% of cases, and coronary artery disease accounts for about 38% of cases. nonischemic conditions include systolic heart failure, defined by left ventricular ejection fraction < 35% (ischemic and dilated cardiomyopathy, valvular heart disease, and hypertensive heart disease); intractable arrhythmia uncontrolled with implantable cardioverter-defibrillator; and hypertrophic cardiomyopathy with persistent heart failure despite valve replacement, pacemaker, or medical therapy. there are a few absolute contraindications to cardiac transplantation. fixed pulmonary hypertension or any systemic illness that will limit survival despite heart transplant, such as high-grade neoplasm, aids, multisystem or active systemic lupus erythematosus or sarcoid preclude transplantation. hiv infection has been considered to be an absolute contraindication to transplant, primarily due to concerns about the increased frequency of infectious and malignant complications and the previously poor survival of such patients. the prognosis of hiv has changed since the advent of highly active antiretroviral therapy (haart), and guidelines are being amended so that hiv infection itself is not a sufficient reason to refuse heart transplantation [68] . age greater than 70 years was an absolute contraindication in previous guidelines, but the ishlt has recently modified their recommendations in 2006 to state that "carefully selected patients > 70 years of age may be considered for cardiac transplantation. for centers considering these patients, the use of an alternate-type program (i.e., use of older donors) may be pursued." [63] the guidelines regarding neoplasm were also modified, with new consideration being given to tumors with low recurrence rate, response to therapy, and negative metastatic workup. in general, the most objective assessment of functional capacity in patients with heart failure, and what may be the best predictor of when to list a patient for transplantation, is measurement of peak oxygen consumption (vo 2 max). this can be measured using exercise testing with ventilatory gas analysis. several studies have demonstrated that peak vo 2 independently predicted mortality, which is highest for patients with values <10 ml/kg/min, and significantly improved if between 10 and 15 ml/kg/min [69] [70] [71] . although peak vo 2 is an important factor used to guide the selection of heart transplant candidates, it does not provide an optimal risk profile. one model that has been validated prospectively is the heart failure survival score (hfss), derived from a multivariable analysis of 268 patients referred for consideration of cardiac transplantation form 1986-1993 at one institution and validated in 199 similar patients from 1993 to 1995 at another institution. it incorporated noninvasive parameters, including the following seven variables and their pathophysiological constructs: presence or absence of coronary artery disease (myocardial ischemia), resting heart rate (activation of sympathetic nervous system), left ventricular ejection fraction (the degree of systolic dysfunction), mean arterial blood pressure, presence or absence of intraventricular conduction defect on baseline ecg (the extent of myocardial fibrosis), serum sodium (the degree of activation of the renin-angiotensin system), and peak vo 2 [72] . the seattle heart failure model is another model that, in contrast to the hfss, incorporated the impact of newer heart failure therapies on survival, including icds (implantable cardioverter-defibrillators) and crt (cardiac resynchronization therapy) [73] . as with other organs, there is no general consensus regarding a preferred immunosuppressive protocol in this age group. treatment with mycophenolate mofetil/mycophenolic acid, a purine analog, has been shown to reduce the rate of rejection and improve survival, but it did have a higher incidence of nonfatal, opportunistic infections as compared with azathioprine therapy [74] . the two most common regimens in 1997, which was used for 75% of transplant recipients, consisted of cyclosporine with mycophenolate mofetil/mycophenolic acid or another antimetabolite and steroids. over the years, these combinations have evolved to be predominantly tacrolimus, mycophenolate mofetil/mycophenolic acid, and steroids (49% of transplant recipients), and to a lesser extent cyclosporine, mycophenolate mofetil/mycophenolic acid, and steroids (29% of transplant recipients). at 1-year posttransplantation, triple drug therapy remains the predominant drug regimen [1]. the ideal immunosuppressive regimen will prevent cellular rejection, have no associated morbidity with respect to opportunistic infections, have no nephrotoxicity, and preclude the development of coronary allograft vasculopathy, which affects 50% of patients at 5 years. this immunosuppressive therapy used to prevent rejection predisposes patients to infection, which continues to be the leading cause of death in the year after cardiac transplantation [58] . a notable trend over the past 10 years has been the declining number of recipients who needed treatment for rejection episodes in the first year after heart transplantation, decreasing from 36% in 1996 to 25% in 2005. this could reflect the improved efficacy of newer immunosuppression medication and regimens, as well as earlier recognition and prompt treatment [1] . multiple studies have demonstrated comparable survival rates in elderly cardiac transplant recipients compared to younger recipients [59] [60] [61] [62] [75] [76] [77] [78] . included in this is a multi-institutional study of the unos database where it was found that there was a satisfactory but lower 5-year survival between elderly (>60 years) and young (18-59 years) recipients (69% vs. 75%, respectively). the elderly group, however, had more infections, renal failure, and longer postoperative length of stay and were at increased risk of malignancy [62] . one retrospective study showed no statistically significant difference in 1-and 4-year survival (1-year survival: 93.3% vs. 88.3%; 4-year survival: 73.5% vs. 69.1%), length of intensive-care unit stay, incidence of rejection, and incidence of cytomegalovirus infection between patients over the age of 70 and younger patients [59] . a 10-year follow-up of cardiac transplant recipients >65 years of age (n = 66) demonstrated survival rates comparable to those of younger patients (<60 years: n = 679; 60-64 years: n = 137) [60] . the adjusted graft survival for recipients over the age of 65 at 3 months (90%), 1 year (85%), 5 years (66%), and 10 years (44%) were all found to be comparable within a few percentage points to various younger age groups (fig. 98.5) [1]. the increased risk of renal failure has been consistent in various studies over the years and may be attributed to the already known preexisting renal disease in elderly, as suggested by elevated preoperative creatinine. another consideration is the nephrotoxic effects of immunosuppression. tailoring therapy for the elderly may be beneficial, and some data support minimizing the use of calcineurin inhibitors and azathioprine in exchange for using mycophenolate mofetil and mammalian target of rapamycin inhibitors (mtor inhibitors, sirolimus) [79] . transplant patients have been the subject of extensive investigation into the increased risk of malignancy, especially in the elderly. increased age has been independently associated with increased risk of malignancy in nontransplanted controls, and heart transplant recipients have been shown to have a 7.1-fold increase in incidence of malignancy [80] . among all solid-organ transplant recipients, skin cancer is the most common malignancy. heart and/or lung transplant recipients have a 26.2-, 21-, and 9.3-fold increased risk of developing lymphoproliferative disorders, head and neck cancer, and lung cancer, respectively. malignancy does not necessarily shorten survival in older recipients, but one may surmise that it does affect quality of life [75] . the demand for heart transplantations is unlikely to ever be fully met, and more resources are needed to slow down the progression of heart failure and prevent the need for transplant surgery in the first place. as ventricular assist device technology improves, it may be used to complement heart transplantation to avoid immunosuppression and its side effect of malignancy in older patients with advanced heart failure. lung transplantation should be considered for patients with advanced lung disease whose clinical status has progressively worsened despite optimal medical or surgical therapy. one thousand four hundred sixty-five lung transplants from deceased donors were performed in the united states in 2007, increased from 840 in 1998 and 941 in 2000. of these, 223 were for recipients over the age of 65, representing 15% of all lung transplant recipients and dramatically increased from 30 (3.6%) in 1998 and 30 (3.2%) in 2000. the percentage of patients 50-64 years of age receiving lung transplants has not changed substantially over the past few years, with 54% of deceased-donor lungs going to these patients in 2007, up slightly from 48% in 1997. the most recent data list 1,005 active patients on the waiting list, with 91 (9%) being over the age of 65. the median time to transplant in this elderly group is 57 days. donor lung shortage has been the major limiting factor to the number of lung transplants performed. the procurement rate of lung from deceased donors has consistently been lower than those for kidney, liver, and heart. while kidneys and livers are harvested from more than 85% of all cadaveric donors, and hearts from 30% of deceased donors, lungs are harvested from only 15% of all cadaveric donors [1]. this discrepancy may be attributed to the lung's vulnerability to potential complications that arise before and after donor death such as aspiration, pneumonia, ventilator-associated lung injury, and neurogenic pulmonary edema. over the past several years, the number of single lung transplants performed annually in the united states has remained stable, while the number of bilateral transplants has consistently increased and even surpassed the number of single lung procedures [81] . the most common indications for lung transplantation, accounting for 85% of procedures worldwide, are advanced chronic obstructive pulmonary disease (copd), idiopathic pulmonary fibrosis, cystic fibrosis, emphysema due to alpha-1 antitrypsin deficiency, and idiopathic pulmonary arterial hypertension. survival benefit has been demonstrated for both single and double lung transplants in patients with cystic fibrosis, pulmonary fibrosis, and primary pulmonary hypertension. there have been less convincing and reproducible results regarding the benefit of transplantation in patients with emphysema or eisenmenger's syndrome [82, 83] . absolute contraindications for lung transplantation include malignancy within the last 2 years (excluding cutaneous squamous and basal cell tumors); significant chest wall deformity; noncurable chronic extrapulmonary infection (active hepatitis b,c, hiv); untreatable advanced dysfunction of another major organ (e.g., heart, liver, kidney); known noncompliance or inability to follow medical regimen, especially if related to an untreatable psychiatric or psychological condition; absence of a consistent or reliable social support system; and substance addiction within the last 6 months [84] . coronary artery disease not amenable to percutaneous intervention or bypass grafting, or associated with significant impairment of left ventricular function, is an absolute contraindication to lung transplantation, but heart-lung transplantation could be considered in highly selected cases. relative contraindications to lung transplantation include: age older than 65 years; critical or unstable clinical condition; severely limited functional status with poor rehabilitation potential; colonization with highly resistant or virulent bacteria, fungi, or mycobacteria; severe obesity (body mass index exceeding 30 kg/m 2 ); severe or symptomatic osteoporosis; and poorly controlled or managed medical conditions (diabetes mellitus, systemic hypertension) [81] . as with other organ transplantation, induction therapy has become a major part of the immunosuppression regimen with lung transplantation. induction therapy was used in the first 5-7 days after transplantation for 57% of all lung transplants performed in 2006, up from only 22% of lung transplants in 1997. among the most common were antilymphocyte antibodies (antithymocite globulin or okt3) or monoclonal il-2 receptor antagonists (basiliximab or daclizumab). baseline therapy prior to discharge at most centers included corticosteroids, calcineurin inhibitor (tacrolimus 83%, cyclosporine), and an antimetabolite (azathioprine 39% or mycophenolate mofetil 52%). maintenance immunosuppression administered for the first year following transplantation was essentially the same. steroids are typically tapered to a low dosage or even discontinued in some protocols. acute rejection within the first year was treated most commonly with corticosteroids, used in 95% of acute rejection cases [85, 86] . despite the multitude of medications available, no drug has been found to be consistently superior in delaying rejection or bronchiolitis obliterans or in prolonging long-term survival. protocols vary widely between lung transplant centers the adjusted graft survival for recipients over the age of 65 at 3 months (92%), 1 year (79%), 5 years (42%), and 10 years (13%) are all comparable within a few percentage points to various younger age groups (fig. 98.6) [1]. the average death rate in the first year after transplantation decreased steadily from 290 per 1,000 patient-years at risk in 1997 to 169 deaths per 1,000 patient-years at risk in 2004, a 10-year low. according to the 2007 ishlt registry report, the median survival for all adult recipients is 5 years, but bilateral lung recipients have a better median survival than single lung recipients (5.9 vs. 4.4 years, respectively) [78] . it is not delineated if this survival advantage is related to the underlying patient characteristics or choice of operation. the impact of underlying diagnosis on survival after lung transplantation has often been linked to age, with older recipients having a significantly shorter survival than younger ones. recipients with copd have the best 1-year survival, but a lower 10-year survival when compared to those with cystic fibrosis and alpha-1 antitrypsin deficiency. in contrast, patients with idiopathic pulmonary arterial hypertension have the lowest 1-year survival, but their 10-year survival approaches those with cystic fibrosis and alpha-1 antitrypsin deficiency [87] . this data is significantly different when evaluating patients over the age of 70. an analysis of unos data of lung transplants from 1999 to 2006 showed that patients 70 years and older had substantially increased risks of 30-, 90-day, and 1-year mortality when compared to younger groups. the authors' recommendation was that lung transplantation may be used with caution in older patients over the age of 60, but should not be performed in patients older than age 70 [88] . management strategies have been more effective at reducing early complications than later ones, which may be due to refinements in surgical technique and postoperative care. however, beyond the first year of transplantation, survival is mostly affected by infections and chronic rejection, and the incidence of these complications has not changed substantially since 1988 [84] . the leading cause of death in the first 30 days after lung transplantation is graft failure, a form of acute respiratory distress syndrome (ards), accounting for almost 30% of deaths [78] . the leading cause of mortality after the first year, typically accounting for 40% of deaths, is chronic allograft rejection (e.g., chronic graft dysfunction), which usually manifests as bronchiolitis obliterans syndrome (bos) [89] . survival 3 years after the onset of bos is only 50% and drops to 30-40% at 5 years [90] . infectious complications remain a leading cause of rejection and death at any point after lung transplantation, in any age group. it has been attributable to up to 35% of deaths in the first year and 20% of deaths thereafter. bacterial bronchitis and pneumonia are most common, but cytomegalovirus, mycobacteria, fungi, and community-acquired respiratory viruses all contribute to morbidity and mortality [84, 87] . malignancy accounts for 7-10% of deaths beyond the first year after lung transplantation. nonmelanoma skin cancer is most common overall, but posttransplant lymphoproliferative disease (ptld) is the most common malignancy in the first year after transplant [78] . other malignancies include colon, breast, kaposi's sarcoma, and transitional cell carcinoma of the bladder [91] . often times, there are patients with multiple organ failure that may benefit from dual organ transplantation. examples include kidney-pancreas and heart-lung. while there has been success with these combined organ transplantations over the years, its use has been limited in the elderly population. from 1998 to 2007, there were a total of 14 kidneypancreas transplants in patients over the age of 65, while none were reported for heart-lung for a patient over the age of 65 [1] . as with individual organs, the overall risk-benefit of the surgery needs to be weighed, considering the overall health of the patient and potential survival benefits of transplantation. while age is often considered a significant factor in determining candidacy, it should not be the limiting factor. the elderly population is on the rise in this country, and older patients comprise the fastest growing segment of the population. this trend is mirrored in the transplantation population. the discipline of organ transplantation has grown remarkably over the last half-century and has evolved from infrequent, highly dangerous procedures with very high mortality to complex operations performed regularly across the country and world. data from centers across the country clearly indicate that patients over the age of 65 can undergo kidney, liver, heart, or lung transplantation with excellent results (fig. 98.7) . the limiting factor, however, is the shortage of organs and excess of patients on the waiting list; which raises many ethical and social concerns regarding transplanting healthy organs into older patients who may not have as much of a survival benefit as a younger patient. although the allocation of organs according to age may be a simple approach to satisfying the goal of social justice, the inclusion of patient comorbidity and potential for survival benefit in the elderly must also be considered. kidney and liver transplantation has been successfully performed and results substantiated in patients over the age of 70. the results depend on the selectivity used to identify those elderly candidates on the waiting list for transplant. cardiac and lung transplants have shown some promising results in patients over the age of 65, but not over the age of 70. it is important to note that with cardiac and lung transplantation, there is a slight discrepancy with the proportion of elderly patients on the waiting list and with overall survival rates. this is likely due to patient selection more than the overall results. this patient population is a highly selective group of elderly patients with cardiac and lung disease, who are often not placed on the waiting list until they worsen clinically. all things being equal, discrimination against older candidates for organ transplantation on age-related grounds alone is not warranted. despite potential utilitarian gains to be made limiting transplantation in the elderly recipients, the sense of fairness in the system will be harmed. elderly patients who are healthy will be the ones who suffer. older patients already face huge hurdles to get on the waiting list for transplantation, and they are already such a small number. there already is enough discrimination against the elderly, and we ought not to add to that injustice by further limiting their access. organ procurement and transplantation network and the scientific registry of transplant recipients: transplant data differences in quality of life across renal replacement therapies: a meta-analytic comparison comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant how old is old for transplantation? patient and graft survival in older kidney transplant recipients: does age matter? kidney transplantation in patients older than 70 years of age renal transplantation in elderly patients older than 70 years of age: results from the scientific registry of transplant recipients acute rejection in the elderly recipient: influence of age in the outcome of kidney transplantation kidney transplantation in elderly people: the influence of recipient comorbidity and living kidney donors donor characteristics associated with reduced graft survival: an approach to expanding the pool of kidney donors dual kidney transplantation: a case-control comparison with single kidney transplantation from standard and expanded criteria donors guidelines for the referral and management of patients eligible for solid organ transplantation evaluation of adult kidney transplant candidates the evaluation of renal transplantation candidates: clinical practice guidelines canadian society of transplantation: consensus guidelines on eligibility for kidney transplantation preoperative pulmonary evaluation cancer in patients on dialysis for end-stage renal disease: an international collaborative study the effect of immunosuppression on pre-existing cancers challenges in the counseling and management of older kidney transplant candidates how great is the survival advantage of transplantation over dialysis in elderly patients? age and immune response in organ transplantation immunosuppression of the elderly kidney transplant recipient rejection and recipient age use of mycophenolate mofetil in immunosuppressive protocols in elderly renal transplant recipients mycophenolate mofetil vs. azathioprine in a large population of elderly renal transplant patients immunosuppression: evolution in practice and trends risk factors for development of new-onset diabetes mellitus after kidney transplantation a calcineurin antagonist-free induction/maintenance strategy for immunosuppression in elderly recipients of renal allografts from elderly cadaver donors: long-term results from a prospective single centre trial long-term results of calcineurin-free protocols with basiliximab induction in "old-toold" programs preferential allocation of marginal kidney allografts to elderly recipients combined with modified immunosuppression gives good results early mortality rates in older kidney recipients with comorbid risk factors renal transplantation in the elderly: surgical complications and outcome with special emphasis on the eurotransplant senior programme liver transplantation trends for older recipients: regional and ethnic variations chronic liver disease in the extremely elderly of 80 years or more: clinical characteristics, prognosis and patient survival analysis liver transplantation in patients over sixty years of age orthotopic liver transplantation in patients 60 years of age and older orthotopic liver transplantation in patients over 60 years old liver transplantation in patients over 60 years of age liver transplantation in patients over sixty years of age liver transplantation in patients over 60 and 65 years: an evaluation of long-term outcomes and survival liver transplant for the septuagenarians: importance of patient selection minimal criteria for placement of adults on the liver transplant waiting list: a report of a national conference organized by the american society of transplant physicians and the american association for the study of liver diseases meld and peld: application of survival models to liver allocation predicting outcome after liver transplantation: utility of the model for endstage liver disease and a newly derived discrimination function impact of age older than 60 years in living donor liver transplantation older age and liver transplantation: a review the prevalence of coronary artery disease in liver transplant candidates over age 50 the elderly liver transplant recipient: a call for caution liver transplant recipients older than 60 years have lower survival and higher incidence of malignancy allograft survival following adult-to-adult living donor liver transplantation outcomes of 385 adult-to-adult living donor liver transplant recipients: a report from the a2all consortium long-term results of liver transplantation in older patients 60 years of age and older liver transplantation in patients beyond age 60 liver transplantation in recipients over 60 similar outcomes, morbidity, and mortality for orthotopic liver transplantation between the very elderly and the young evolution of liver transplantation in europe: report of the european liver transplant registry prognostic model for early acute rejection after liver transplantation age and liver transplantation: a report of the liver transplantation database transplantation in the elderly patient the registry of the international society for heart and lung transplantation: twentieth official adult heart transplant report -2003 heart transplantation in patients seventy years of age and older: a comparative analysis of outcome long-term survival (>10 years) of patients >60, years with induction therapy after cardiac transplantation long-term results of heart transplantation in patients older than 60 years outcomes in patients older than 60 years of age undergoing orthotopic heart transplantation: an analysis of the unos database listing criteria for heart transplantation: international society for heart and lung transplantation guidelines for the care of cardiac transplant candidates -2006 selection and treatment of candidates for heart transplantation. a statement for health professionals from the committee on heart failure and cardiac transplantation of the council on clinical cardiology solid-organ transplantation in hiv-infected patients correlates and prognostic implication of exercise capacity in chronic congestive heart failure clinical determinants of mortality in chronic congestive heart failure secondary to idiopathic dilated or to ischemic cardiomyopathy ejection fraction, peak exercise oxygen consumption, cardiothoracic ratio, ventricular arrhythmias, and plasma norepinephrine as determinants of prognosis in heart failure. the v-heft va cooperative studies group development and prospective validation of a clinical index to predict survival in ambulatory patients referred for cardiac transplant evaluation the seattle heart failure model: prediction of survival in heart failure immunosuppression for cardiac transplantation -the past, present and future should heart transplantation be considered as a treatment option for patients aged 70 years and older? heart transplantation in older candidates a comparative analysis of outcome after heart transplantation in patients aged 60 years and older: the university of alberta experience long-term outcomes of heart transplantation in older recipients poor prognosis of heart transplant patients with end-stage renal failure incidence of malignancies in heart and/or lung transplant recipients: a single-institution experience registry of the international society for heart and lung transplantation: twentyfifth official adult lung and heart/lung transplantation report -2008 assessment of survival benefit after lung transplantation by patient diagnosis listing for lung transplantation: life expectancy and transplant effect, stratified by type of end-stage lung disease, the eurotransplant experience international guidelines for the selection of lung transplant candidates: 2006 update -a consensus report from the pulmonary scientific council of the international society for heart and lung transplantation induction immunosuppression for lung transplantation with okt3 induction therapy in lung transplantation: a prospective, controlled clinical trial comparing okt3, anti-thymocyte globulin, and daclizumab registry of the international society for heart and lung transplantation: twentyfourth official adult lung and heart-lung transplantation report -2007 impact of advanced age in lung transplantation: an analysis of united network for organ sharing data primary graft dysfunction and other selected complications of lung transplantation: a single-center experience of 983 patients post-transplant bronchiolitis obliterans development of malignancy following lung transplantation key: cord-258093-6fn8ei9f authors: hanania, nicola a.; king, monroe j.; braman, sidney s.; saltoun, carol; wise, robert a.; enright, paul; falsey, ann r.; mathur, sameer k.; ramsdell, joe w.; rogers, linda; stempel, david a.; lima, john j.; fish, james e.; wilson, sandra r.; boyd, cynthia; patel, kushang v.; irvin, charles g.; yawn, barbara p.; halm, ethan a.; wasserman, stephen i.; sands, mark f.; ershler, william b.; ledford, dennis k. title: asthma in the elderly: current understanding and future research needs—a report of a national institute on aging (nia) workshop date: 2011-08-25 journal: j allergy clin immunol doi: 10.1016/j.jaci.2011.06.048 sha: doc_id: 258093 cord_uid: 6fn8ei9f asthma in the elderly is underdiagnosed and undertreated, and there is a paucity of knowledge on the subject. the national institute on aging convened this workshop to identify what is known and what gaps in knowledge remain and suggest research directions needed to improve the understanding and care of asthma in the elderly. asthma presenting at an advanced age often has similar clinical and physiologic consequences as seen with younger patients, but comorbid illnesses and the psychosocial effects of aging might affect the diagnosis, clinical presentation, and care of asthma in this population. at least 2 phenotypes exist among elderly patients with asthma; those with longstanding asthma have more severe airflow limitation and less complete reversibility than those with late-onset asthma. many challenges exist in the recognition and treatment of asthma in the elderly. furthermore, the pathophysiologic mechanisms of asthma in the elderly are likely to be different from those seen in young asthmatic patients, and these differences might influence the clinical course and outcomes of asthma in this population. states is currently about 13% but is projected to grow from about 40 million in 2005 to more than 86 million by 2050, accounting for 25% of the population. the age group with the largest growth will be those older than 85 years, which is estimated to be more than 1 million by 2050. 1, 2 in 2004, the us prevalence of asthma for those 65 years or older was 7%, with 1,088,000 reporting an asthma attack in the previous 12 months. 3 older asthmatic patients are more likely to be underdiagnosed, undertreated, 4,5 and hospitalized than younger asthmatic patients. 3 they also have the highest death rate (51.3 per million persons) of any other age group. 6 older women are hospitalized more than twice as often as older men. asthma in older adults is superimposed on a background of aging-related changes in respiratory and immune physiology and often on multiple diseases and conditions common in older age. recognizing the paucity of research, the many challenges that exist in the recognition and treatment of asthma in older adults, and the opportunity to bridge geriatrics and the clinical specialties that focus on asthma, the national institute on aging (nia) sponsored a workshop on asthma in the elderly in herndon, virginia, on september 8 and 9, 2008. the workshop was planned by a committee of 6 physician-scientists from us academic institutions or from the division of geriatrics and clinical gerontology in the nia. the planning committee selected speakers and participants for their expertise in asthma, pulmonology, allergy/immunology, primary care, emergency medicine, geriatrics, and/or gerontologic science (see the list of participants in appendix 1). the immediate goals of this workshop were to summarize the current understanding of the mechanisms of asthma in older persons and to identify knowledge gaps and research opportunities leading to improved medical care and health outcomes for older persons with asthma. these research opportunities are discussed in the body of this report and summarized in table i . [7] [8] [9] in addition, the nia, in collaboration with the national heart, lung, and blood institute and the national institute of allergy and infectious diseases, recently issued a set of program announcements inviting research proposals on asthma in older adults (http:// grants.nih.gov/grants/guide/pa-files/pa-10-263.html, http://grants. nih.gov/grants/guide/pa-files/pa-10-264.html, and http://grants. nih.gov/grants/guide/pa-files/pa-10-265.html). it is a central principle of gerontology that aging itself is not a disease. 10 yet there are physiological changes within organs, tissues, and cells that result in diminished functional reserve and thereby increased susceptibility to stressors, disease, or both. a second principle is that these aging changes are highly variable and account for the great constitutional heterogeneity among older persons from very ''fit'' to very ''frail.'' in fact, the concept of frailty, both its causes and consequences, has become a focus of concentrated gerontologic investigation. at the root of age-associated physiological changes are a number of genetic, epigenetic, and environmental factors. 11 molecular damage accumulates over time, and the capacity for dna repair decreases. 12 cellular senescence, which is believed to be the consequence of accumulated dna and protein damage and reduced proliferative capacity, is becoming increasingly understood at the molecular level. 13 however, just how this correlates with the phenotypic changes of advanced age remains incompletely understood. 14 there has been much written about cellular senescence and the events that lead to cell death. [15] [16] [17] after a finite number of divisions, normal somatic cells invariably enter a state of irreversibly arrested growth, a process termed replicative senescence. 18 in fact, it has been proposed that escape from the regulators of senescence is the antecedent of malignant transformation. however, the role of replicative senescence as an explanation of organismal aging remains the subject of vigorous debate. the controversy relates, in part, to the fact that certain organisms (eg, drosophila species and caenorhabditis elegans) undergo an aging process, yet all of their adult cells are postreplicative. what is clear is that the loss of the proliferative capacity of human cells in culture is intrinsic to the cells and not dependent on environmental factors or even culture conditions. 18 unless transformation occurs, cells age with each successive division. the number of divisions turns out to be more important than the actual amount of time passed. thus cells held in a quiescent state for months, when allowed back into a proliferative environment, will continue approximately the same number of divisions as those that were allowed to proliferate without a quiescent period. 19 the question remains whether this in vitro phenomenon is relevant to animal aging. one suggestive observation is that fibroblasts cultured from samples of old skin undergo fewer cycles of replication than those from young skin. 20 furthermore, when various species are compared, replicative potential is directly and significantly related to lifespan. 21 an unusual b-galactosidase with activity peaks at ph 6 has proved to be a useful biomarker of in vitro senescence because it is expressed by senescent but not presenescent or quiescent fibroblasts. 22 this particular b-galactosidase isoform was found to have the predicted pattern of expression in skin from young and old donors, with measurably increased levels in dermal fibroblasts and epidermal keratinocytes with advancing age. 22 the nature of the expression of this in vivo biomarker of aging in other tissues will be important to discern. for clinical investigators, frailty has proved hard to define primarily because of the seemingly insurmountable heterogeneity inherent in geriatric populations on the basis of these variable rates of organ system decrease and the presence or absence of 1 or more diseases. 9 yet, regardless of the pathway taken to frailty, the clinical picture has common features, including a reduction in lean body mass (sarcopenia), loss of bone mass (osteopenia), cognitive impairment, functional decline, and anemia. on the basis of data derived from large cohorts of elderly patients, fried et al 23 have offered an operational definition of frailty incorporating an assessment of 5 specific characteristics to ascribe a frailty index. on this 5-point scale, a score of 3 or more has been shown to be independently predictive of a range of adverse clinical outcomes, including acute illness, falls, hospitalization, nursing home placement, and early mortality. [23] [24] [25] furthermore, simple performance measures, such as the assessment of walking speed, are predictive of important outcomes, including survival. 26 with the phenotype better defined, attention has shifted to pathophysiology. although frailty can occur in the absence of a diagnosable illness, the fact that some become frail and others do not suggests an inherent or acquired variability in homeostatic pathways. recent evidence from observational studies has raised suspicion that dysregulated inflammatory processes are involved in, if not central to, the variable patterns of aging. increased serum levels of certain proinflammatory cytokines, most notably il-6, are increasingly present with advancing age and to a greater extent with frailty. 27, 28 furthermore, the appearance of this and other inflammatory markers has been associated with a number of adverse clinical outcomes, including decreased strength and mobility, falls, dementia, and mortality. 27 life expectancy, lifespan, and maximum survival from the perspective of those who study aging, there is an important distinction made between median (life expectancy) and maximum lifespan. over the past several decades, with the advent of modern sanitation, refrigeration, and other public health measures, including vaccination and antibiotics, there has been a dramatic increase in median survival. 29 early deaths have been diminished, and more patients are reaching old age. in the united states today, life expectancy now approaches 80 years. 30 median survival is what concerns public health officials and health care providers, but for those studying the biology of aging, it is maximum survival that is the focus of greatest attention. it is worthwhile to note that it has been estimated that if atherosclerosis and cancer were eliminated from the population as a cause of death, about 10 years would be added to the average lifespan, yet there would be no change in maximum lifespan. 31 although several theories have been proposed, none suffice to account for the complexities of aging. lifespan is finite and varies generally from species to species and much less so within species. mice live, on average, 2½ years, monkeys 30 years, and human subjects about 90 years. among species, larger animals generally live longer than smaller animals, but within species, smaller animals are likely to live longer. it is clear that aging is not entirely explained by dna sequence. for example, mice and bats have only 0.25% difference in their primary dna sequence, but bats live for 25 years, 10 times longer than mice. a commonly held notion is that regulation of gene expression accounts for a longevity difference between species. the aging lung large, longitudinal, and more complete studies to determine the effects of aging on the function of the respiratory system improved knowledge about lung structure-function relationships in older age using techniques of imaging and measures of lung function not requiring effort (eg, high-resolution computed tomographic scanning and forced oscillation) improved assessment of lung processes underlying airflow limitation attributable to aging versus copd or asthma, especially in asthmatic patients who smoke studies to examine the effects of aging in ethnic groups and the role of gender epidemiology, effect, diagnosis, and management determine the true prevalence and cost of asthma in the older population develop a uniform definition of asthma to be applied to health care records that will distinguish asthma from copd and mixed asthma/copd evaluate evidence-based treatment algorithms for older asthmatic patients, such as those developed by the national heart, lung, and blood institute and global initiative for asthma guidelines 7 assess the effect of asthma treatment, including direct medical costs of care, indirect costs of care, and value of treatment in improving quality of life 8, 9 assess the effect of comorbid conditions, especially copd and congestive heart failure, on asthma 9 characterize phenotypes of elderly asthma with regard to responses to therapy and long-term outcomes based on age of onset, duration of disease, and environmental triggers develop algorithms for electronic medical record systems that are asthma-specific evaluate effects of current asthma medications in older patients compared with younger patients identify pharmacogenetic determinants of response to asthma medications in older adults identify simpler and safer drug delivery systems and schedules for older adults develop simple methods to differentiate copd from asthma exacerbations in older adults understand how environmental or aging-related factors affect epigenetic changes in asthma in older adults identify differences between older and younger asthmatic patients or between lsa and loa with regard to inflammation, remodeling, intracellular mechanisms, responses to environmental pollutants, and allergy sensitization and their effects on the metabolism and action of asthma drugs identify naturally occurring age-related changes in airway cellular patterns develop animal models of age-related airway inflammation understand the significance of allergy sensitization associated with asthma in older adults (eg, through larger prospective studies) identify the utility of allergy tests, either skin tests or serum specific ige measurement, in reflecting allergy sensitization in older adults identify the role of the microbiome in patients with loa understand the role of non-ige mechanisms in older adults' inflammatory responses to inhalant allergens or pollutants (eg, t h 17 lymphocytes producing il-17 or protease receptor responses to molds and dust mites) determine the roles of adaptive versus innate immune mechanisms on asthma development, progression, and response to treatment in older adults determine whether there are environmental pollutants peculiar to institutional settings identify viruses and other microbiological agents responsible for, and the mechanisms by which they cause, asthma exacerbations in older adults, which might lead to the development of vaccine-or antiviral drug-based interventions determine effects of asthma medications, viral or bacterial load, or allergy status on susceptibility to exacerbations in older patients define rates of infection and specific pathogens in older asthmatic patients distinguish roles of innate immunity in eosinophilic versus neutrophilic asthma it is now clearly established that certain specific genes can alter lifespan, at least in lower animals, but whether these same genes regulate ''aging'' is still in question. for example, transgenic drosophila species expressing increased copies of the free radical scavenging enzymes superoxide dismutase and catalase live on average a third longer than the appropriate controls. 32 in even lower species (eg, yeast and nematodes) the identification of specific genes that influence lifespan 33, 34 has led to the optimistic impression that analogous genes in higher organisms will lead greater insights into the aging process. yet the identification and functional analysis of analogous genes in human subjects remains elusive. the oldest human being alive today is approximately 120 years old. what is intriguing is that the record has remained stable and unchanged by the public health initiatives mentioned above. in fact, there has been some recent data presented that the maximum survival is actually decreasing in the united states. 35, 36 what is interesting is that, unlike the public health initiatives in human subjects in which median but not maximum survival has been enhanced, experimental interventions in lower species have resulted in prolongation of maximum survival. as mentioned above, transgenic drosophila species producing extra copies of superoxide dismutase and catalase survived about 33% longer than controls, 32 and similarly, the maximum survival in c57bl/6 mice fed a calorically restricted diet enhanced by 50% or more. 37, 38 the true mechanisms of aging might well be uncovered with a better understanding of how these interventions affect longer survival. future research in aging should attempt to improve our understanding of the basic biology of aging and interventions that retard the aging process. there is a need for the development and application of a standardized definition of frailty for future clinical investigation. investigations directed at the role of comorbidities in accelerating the aging process are important. furthermore, future research should focus on the development of cellular and animal models of typical, delayed, and accelerated aging and of large collaborative networks in which populations and resources can be shared to study aging and frailty. leveraging on well-characterized existing cohorts, when possible, is recommended. the lungs, like other organs, age and exhibit continued loss of function as a person grows old. lung function is traditionally assessed by means of a number of standardized methods. the most common measurement used is spirometry with the determination of fev 1 and forced vital capacity (fvc). fev 1 and fvc both show continuous decreases of between 25 and 30 ml with each year of life after about age 20 years. 39 the cause of this decrease is usually attributed to the loss of the driving forces for airflow as a result of reduced respiratory muscle performance, loss of static elastic recoil, or both. 39, 40 the decrease in fev 1 in asthmatic patients is largely a function of the decrease in fvc because of the increase in residual volume. 41 stiffening of the chest wall and reduced respiratory muscle performance result in a decrease in total lung capacity and an increase in residual volume because of ever-increasing closing volume. 42 accordingly, these aging processes lead to airflow limitation that might be hard to distinguish from an active disease process. not all older persons are able to perform spirometry, especially those with decreased cognition, coordination, and frailty. in addition, spirometry is effort dependent, and the very old can tire quickly. techniques of imaging and measures of lung function not requiring effort (ie, forced oscillation) should be used in future studies to extend our knowledge about lung structure-function relationships at the very end of life. bronchodilator responses are known to be less marked in the elderly, perhaps as a consequence of the aging effects attributed to the emphysema-like state of the senile lung 43 ; however, this would not explain the slow temporal response to bronchodilators. other studies do not find such age-related bronchodilator differences. furthermore, although methacholine responsiveness has been reported to increase with aging, the exact mechanism for this is not apparent. increased incidence and prevalence of many lung diseases occur with age. alterations in immune function increase the risk of many of these diseases. studies of systemic immunity suggest that sustained antigenic stress over a lifetime leads to a decrease in naive t-cell numbers, an accumulation of memory t cells, and a decrease in t-cell repertoire and b-cell functions but a lesser decrease in innate immunity. 43, 44 little is known about what happens to the immune/inflammatory pathways in older asthmatic patients. the immune system changes seen with aging will be discussed in more detail in the section on pathophysiology. in the united states the national health interview survey asks questions regarding lifetime history of asthma, current asthma prevalence, and asthma attacks in the last 12 months. 3 for all age groups, asthma prevalence has been steadily increasing since 1980. for the 65 years and older age group, asthma is consistently more prevalent in female than male subjects. 3 the national center for health statistics tracks data on physician encounters for asthma. the national ambulatory medical care survey reported that those 65 years or older have the second-highest rate of outpatient office visits after those aged 0 to 4 years. those 65 years and older did not have significantly different emergency department visits than the other adult groups. the 65 years and older age group accounts for a greater proportion of hospitalizations (23%) than the size of its population (13%) would indicate. not surprisingly, the elderly population is a high user of medical resources for the treatment of asthma. hospitalizations and emergency department visits are more common for these patients than for other adult cohorts. some of the increased costs are related to comorbid disease. for example, the presence of comorbid chronic obstructive pulmonary disease (copd) increases the risk of an asthma-related hospitalization in medicare patients 3.6-fold, respiratory medical costs almost 6-fold, and total medical costs 2-fold. elderly female subjects appear at greater risk than elderly male subjects. [45] [46] [47] [48] asthma mortality increased steadily from 1980 until it peaked in 1998. the highest mortality rates for asthma occur in the 65 years and older group. in fact, the increase in asthma mortality between 1979 and 1989 was primarily driven by the 65 years and older group. in addition, the decrease in asthma mortality between 1999 and 2005 was most evident in this age group. elderly women with asthma tend to have higher mortality rates than elderly men with asthma. one reason for the increasing prevalence of asthma in the elderly might be the improved longevity of the population. also, increased office visits for asthma in the elderly might be responsible for fewer attacks. increasing hospital admissions might account for decreased mortality. by continuing to gather surveillance data on asthma, reasons for these trends could become clearer. in addition, surveillance data help to focus intervention efforts in areas of greatest need. in the cardiovascular health study, a large community-based cohort of subjects older than 65 years, questions were asked that were relevant to asthma and provided more insight into the prevalence and effect of asthma in this population. 5, 49, 50 definite asthma was defined as a positive response to the questions indicating that the patient had current asthma and that a physician confirmed the diagnosis. probable asthma was defined as a history of wheezing in the past year associated with chest tightness or breathlessness. excluding smokers and those with a diagnosis of congestive heart failure, 4% of subjects had definite asthma, and 4% had probable asthma. among those who smoked, 11% had definite asthma, and 14% had probable asthma. among nonsmokers, 185 subjects were identified who had definite or probable asthma; 76% were women, and 20% were older than 80 years. the age of asthma onset was spread approximately evenly among decades. twenty-seven percent had late onset of disease after age 60 years, and 25% had onset of disease before age 20 years. as expected, respiratory symptoms in the older asthmatic subjects were more prevalent, with a 2-to 5-fold increase in cough, phlegm, wheezing, and dyspnea. dyspnea on exertion was 1.6-fold more likely to be present in asthmatic patients than in those without the diagnosis. lung function was reduced in those with a diagnosis of asthma. mean fev 1 was 77% of predicted value in those with definite asthma and 89% of predicted value in those with probable asthma compared with 96% in those who did not have asthma. forty-one percent of those with a diagnosis of asthma had airflow obstruction below the fifth percentile for the age group, and peak flow lability was increased. elderly asthmatic patients reported the most common trigger was a viral infection in 58% compared with animal allergies in 30%. two thirds reported seasonal worsening. asthma had a significant effect on quality of life, with 35% of patients with definite or probable asthma reporting a fair or poor health status compared with 17% of elderly patients without asthma. sixty percent of patients with definite asthma reported seasonal allergic rhinitis compared with only 30% in the nonasthma group. despite the high prevalence and morbidity of asthma in this population, inadequate treatment was common. only 40% of those with definite asthma had a rescue albuterol inhaler, and only 30% had inhaled corticosteroid use. 5, 49, 51, 52 the pathophysiology of asthma in the older adult is poorly understood and understudied. many questions about this issue remain: is asthma the same disease in older adults as it is in children and younger adults? is late-onset asthma (loa; asthma that starts in middle age or older) different from longstanding asthma (lsa; asthma of early onset that has persisted into older adulthood)? if loa and lsa are the same disease, then the diagnosis and treatment should be similar. however, if loa and lsa are different phenotypes or at least have a different cause and pathophysiology, then the diagnosis and treatment might differ (table ii) . the traditional view of disease susceptibility has been expanded to include epigenetics to account for the influence of environmental factors and aging on the genomic blueprint. epigenetics is defined as heritable changes in gene expression that occur without alterations in dna sequence. it is the process by which genotype interacts with environment to produce a phenotype and explains differences between cells, tissues, and organs despite identical genetic information. genes function in a milieu determined by the developmental and environmental history of the cell, which constitutes the epigenotype. 53, 54 epigenetic changes or marks can play a major role in human disease. 55, 56 the most common examples of epigenetic marks are dna methylation of cpg islands by dna methyltransferases and chromatin modification of histone proteins, particularly acetylation by histone acetyltransferases and histone deacetylases. 57, 58 the function of epigenetic changes is to regulate gene expression. epigenetic changes are known to contribute to cancer and autoimmune disease and are thought to contribute to common diseases, including cardiovascular disease, diabetes, and the loss of response to stress caused by aging. 59 asthma is a markedly heterogeneous disease, and recent evidence suggests that environmentally induced epigenetic changes contribute to asthma phenotypes and that airway inflammation in patients with asthma and copd might involve epigenetic regulation. 57, 58, 60 methylation patterns and chromatin structure change with age and are thought to contribute to the increase in the incidence of common diseases that begin in middle age. 55, 61 the incidence of asthma in the elderly resembles the incidence of common diseases. moreover, characteristics and asthma drug response in the elderly asthmatic patient differ from those seen in childhood asthma. compared with younger cohorts, elderly asthmatic patients have a higher prevalence, higher rates of bronchial hyperreactivity, more severe asthma, and a lower prevalence of atopy. the symptoms of elderly asthmatic patients are more difficult to control with drug therapy, and these patients have steroid resistance and might respond better to leukotriene receptor antagonists compared with inhaled corticosteroids. [62] [63] [64] [65] [66] [67] [68] [69] [70] [71] the contribution of epigenetics to differences observed between elderly asthmatic patients and younger cohorts is unknown. unlike genetic variants that contribute to disease, epigenetic changes can be reversed and therefore represent potential drug targets. 72 older asthmatic patients are less responsive to albuterol treatments given in the emergency department and are more frequently admitted for hospitalization. 73 thus it appears that the responsiveness to treatment is diminished and the severity of asthma exacerbations is greater. the exact reason for these disparities is not known. immune cell function decreases with aging, a property often termed immunosenescence. 74 one often-confusing aspect of immunosenescence is the observation that aging might be associated with opposing immunologic effects. for example, t-cell secretion of il-2, il-4, or ifn-g has been shown to be both decreased with aging and also increased with aging. 75 it is likely that both phenomena are correct but are dependent on the context of the immune function. thus the effect of aging on t-cell function in the context of allergen stimulation might be different than the effects of aging on t-cell function in the context of viral infection. given that asthma is an inflammatory disorder of the airway, it is of interest to determine whether asthmatic airway inflammation of the elderly might differ from that of younger asthmatic patients and thus represent a distinct phenotype of asthma. these changes might have implications for susceptibility to exacerbations because of viruses or other pathogens, as well as response to treatment. the aging process has been shown to exhibit changes in airway inflammation. an examination of the cellular composition of bronchoalveolar lavage fluid from 19-to 83-year-old subjects without a history of allergies, pulmonary disease, or gastroesophageal reflux showed increased airway neutrophilia, as well as increased numbers of cd4 1 t cells. 76, 77 the t cells also appeared to be more activated in the elderly, with increased expression of hla-dr and cd69. the increase in airway neutrophils with aging has also been observed in asthmatic patients. 78 because there is a phenotype of severe asthma characterized by a predominantly neutrophilic airway inflammation, 79 the question arises as to whether the increased presence of neutrophils contributes to greater asthma severity in the elderly. some of the prominent inflammatory cells recruited into the airway in asthmatic patients are eosinophils, neutrophils, and t cells, which are capable of secreting numerous inflammatory mediators, including leukotrienes and cytokines. it is not known whether immunosenescence affects the production of these mediators in elderly asthmatic patients, either at baseline or during an exacerbation of symptoms. furthermore, it is not known whether age-related changes in their production would have any implication for the clinical presentation or management of asthma in the elderly. peripheral blood eosinophils were isolated from younger (20-40 years old) and older (55-80 years old) subjects for in vitro functional assays. the eosinophil effector functions of degranulation and superoxide production were diminished in the older compared with the younger asthmatic patients. 78 in another study examining the expression of neutrophil mediators in younger and older asthmatic patients, there was decreased baseline expression of leukotriene b 4 in the sputum of older asthmatic patients despite greater numbers of neutrophils. 80 whether these findings have implications during an asthma exacerbation has yet to be determined. nevertheless, the results demonstrate agerelated changes in the function of an inflammatory cell considered pathognomonic for allergic asthma and raise the question of whether additional effects of immunosenescence are relevant to airway inflammation in asthmatic patients. there have been several studies of animal models to address age-related changes in the airway inflammation induced by allergen challenge of sensitized aged animals (see experimental approaches section below). these studies yielded conflicting results, and there is concern that the animal models do not accurately represent the chronic features of human asthma with seasonal allergen exposure and intermittent exacerbations. the aged animals were both sensitized and challenged at old age, which is in contrast to the typical elderly human asthmatic patient who might be exposed to allergens for several decades. typically, nasal and ocular symptoms on exposure to allergens diminish with age. allergen-triggered asthma symptoms also diminish with age. the epidemiology and natural history of asthma (tenor) study examined the natural history of asthma in older (>65 years old) compared with younger patients and found that older asthmatic patients had lower total ige levels, fewer positive skin prick test responses, and less concomitant allergic rhinitis or atopic dermatitis. 81 several studies have demonstrated age-related decreases in total ige and allergen-specific ige levels, [82] [83] [84] [85] [86] [87] suggesting that this might be the explanation for the decrease in allergy symptoms. there is also evidence for an age-related decrease in skin prick test responses to allergens. 88 however, the relationship between total ige levels and allergic disease persists in the elderly, such that subjects with greater ige levels remain more likely to have allergic rhinitis or asthma. 89, 90 given the changes in allergic inflammation with aging, one might conclude that asthma in the elderly should be milder. however, there are several other common triggers for exacerbations of asthma, including irritants (eg, cold air) and respiratory tract infections. estimates suggest that up to 80% of asthma exacerbations in adults are caused by viral upper respiratory tract infections. 91 the role of environmental exposures and allergy in older asthmatic patients is largely unknown. in the general population, evidence regarding the effect of indoor pollution on asthma is summarized in ''clearing the air: asthma and indoor air exposure'' by the institute of medicine for the environmental protection agency published in 2000. 92 evidence was reported for asthma development related to house dust mites and for asthma development associated with environmental tobacco smoke in preschool children. the report also showed evidence for causation of asthma exacerbations for house dust mite, environmental tobacco smoke (in preschool children), cat, and cockroach; an association with exacerbations was found for dogs, fungi, formaldehyde, and rhinovirus. in addition, evidence associating exacerbation of asthma-related symptoms with self-reported damp air was reported in a review of damp indoor spaces and health. 93, 94 there are only a few studies that have evaluated the role of atopy in elderly patients with asthma. one large national study of allergy skin tests that included older adults 95 and several small studies of allergy skin tests in older adults with asthma 81,96-103 j allergy clin immunol volume 128, number 3 were reviewed. allergy skin test results were positive in 8% to 12% of all older adults. the prevalence of positive skin test results or specific ige levels to at least 1 allergen in older adults with asthma ranged from 0% to 75%. those whose asthma had an unknown age of onset ranged from 27% to 60%, those with onset before age 41 years ranged from 56% to 62%, and those with onset greater than age 41 years ranged from 0% to 24% (table iii) . 97, 101, 102 although there were no studies of allergen room exposure or bronchial challenge in older adults, neither prick-puncture skin test results nor specific ige levels predicted the nasal challenge response to dust mites. 104 safety concerns for allergen challenges in older adults are unresolved. technical limitations of allergens, environmental measurements, and age-specific norms and cutoff levels for laboratory and physiologic tests are needed. a few epidemiologic studies suggest an association between outdoor environmental exposures and emergency department or hospital admissions in older adults. 105, 106 in summary, studies of the general population suggest a causation or association between indoor air pollutants and allergy exposure and asthma. there are several small studies suggesting higher levels of positive allergy test results in older adults with asthma than in the general population of older adults. when age of onset is considered, asthma with an early onset (<41 years of age) has a much higher association with positive allergy test results than late-onset asthma. viral respiratory tract infections are common precipitants of asthma exacerbations during childhood. in approximately 80% of children with acute asthma exacerbations, a respiratory tract virus can be detected, with rhinovirus being the most frequent pathogen identified. 107 although it is likely that viruses also lead to exacerbations of asthma in older adults, comprehensive studies regarding the rates and specific pathogens are lacking. several issues have made defining the role of viruses in adult asthmatic patients problematic and include difficulty distinguishing copd from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infection. a number of investigators have explored the incidence of viral infection in adult asthmatic patients. 91, 108, 109 older studies using viral culture and serology for diagnosis demonstrated infection rates of 10% to 29%. 109 in contrast, more recent studies, which include rt-pcr, have shown significantly higher infection rates of 44% to 55%. 91, 108 similar to results found in children, rhinoviruses are the most frequently detected pathogen. few older persons were included in these studies, in which the mean ages of subjects were 30 to 39 years. the incidence of acute respiratory tract infections decreases steadily with advancing age, and rates of viral infection in older adults are influenced by place of residence. 110 among community-dwelling older adults, rates of acute respiratory tract infections are roughly 1% to 2% per year, whereas rates in senior day care centers and long-term care facilities are substantially higher at 6% to 11%. 111 in addition, the epidemiology of respiratory tract infections can be quite complex in these semiclosed populations, with multiple pathogens circulating simultaneously. 112 influenza a, respiratory syncytial virus (rsv), and human metapneumovirus (hmpv) are the most commonly identified viruses among older persons hospitalized with acute cardiopulmonary conditions. 113, 114 most patients who require hospitalization during a viral respiratory tract infection have underlying heart and lung conditions. although studies to date have largely focused on the role of viruses in copd exacerbations, it is reasonable to extrapolate infection rates and specific pathogens from these studies to older adults with asthma. johnston, 115 in ontario, canada, found a seasonal peak in emergency department visits for all acute respiratory tract infections, as well as exacerbations of both copd and asthma, for persons younger and older than 50 years. all the common respiratory tract viruses have been associated with copd exacerbations, and depending on the methodology and season of study, the specific rates of influenza, rsv, parainfluenza viruses, coronaviruses, hmpv, and rhinoviruses vary. 116, 117 wheezing appears to be a common symptom in older adults infected with any of the respiratory tract viruses, particularly rsv and hmpv, and 7% of adults hospitalized with rsv will have a discharge diagnosis of asthma. 114, 118 because most adult infections represent reinfection, the viral load in respiratory secretions tends to be low, making detection with conventional techniques difficult. viral culture and rapid antigen testing, which can be used successfully in children, have poor sensitivity in older adults. the use of molecular diagnostics has vastly improved the ability to detect a number of viruses, such as rsv, parainfluenza, and rhinoviruses, and allows the detection of hitherto uncultivable agents, such as hmpv and coronaviruses. viral infections appear to aggravate reactive airway disease through a number of different mechanisms. it has been postulated that viral infection disrupts the negative feedback loop of acetylcholine on the m2 receptor, leading to increased levels of acetylcholine and increased constriction of bronchiolar smooth muscle. 119 infection of the respiratory epithelium also induces chemokines, cytokines, and immune and growth factors, which result in a proinflammatory state. 120, 121 immunosenescence might affect the ability of older adults to clear viruses efficiently, and thus greater and more prolonged inflammation can result. in summary, respiratory viral tract infections are common among older adults and are likely precipitants of acute asthma exacerbations. furthermore, viral respiratory tract infections might likely precipitate the onset of loa, although this needs to be further examined. 122 comprehensive studies regarding the rates and specific pathogens are lacking in older adults. distinguishing copd from asthma, lack of sensitive diagnostic tests, and issues with asymptomatic infections make it difficult to define the role of infections in older adults. classic symptoms of asthma in the elderly are mostly similar to those seen in younger asthmatic patients. 4, 96 data on the clinical features of asthma in the elderly have been derived from both longitudinal community surveys and case studies. 5, 64, 97, 98, [122] [123] [124] most patients complain of episodic wheezing, shortness of breath, and chest tightness. these symptoms are often worse at night and with exertion and, like those in younger asthmatic patients, are often precipitated by an upper respiratory tract infection. in fact, the majority of elderly patients who have asthma after age 65 years have their first asthmatic symptom preceded immediately by or concomitant with an upper respiratory tract infection. 122 asthma can often be triggered by environmental exposures, such as aeroallergens, irritants (cigarette smoke, household aerosols, and paints), strong odors (perfumes), and inhalation of metabisulfites (found in beer, wine, and food preservatives). asthmatic symptoms can also be triggered by medications, such as aspirin, nonsteroidal anti-inflammatory agents, angiotensin-converting enzyme inhibitors, or b-blockers, which are commonly used by this patient population. this emphasizes the need for the physician to perform a comprehensive review of medications taken by the older asthmatic patient. studies have consistently shown that elderly patients and their physicians frequently overlook symptoms caused by asthma. 5, 73, 125 several factors contribute to the underdiagnosis and misdiagnosis of asthma. one reason, as shown in large community studies, is that most patients first have asthma in childhood or adolescence, and many physicians have had the misconception that asthma is a childhood disease. another important reason is that the symptoms of asthma are more commonly associated with other diseases seen in this age group. the symptoms of asthma in the elderly are therefore nonspecific and might be caused by conditions that mimic asthma. the differential diagnosis of asthma in the elderly is greater than seen in younger asthmatic patients and includes congestive heart failure, emphysema and chronic bronchitis (copd), chronic aspiration, gastroesophageal reflux disease (gerd), and tracheobronchial tumors. comorbid illnesses and the psychosocial effects of aging might also profoundly affect the diagnosis, clinical presentation, and care of asthma in the elderly. one particular diagnosis that is often difficult to detect and frequently overlooked by the patient and physician until the condition is advanced is upper airway obstruction, including the extrathoracic and intrathoracic central airways. common causes of upper airway obstruction include malignancy, infection, inflammatory disorders, trauma, and extrinsic compression related to enlargement of adjacent structures (eg, an enlarged thyroid gland). it appears that malignancy and benign strictures related to airway instrumentation (eg, endotracheal intubation and tracheostomy) are becoming increasingly more prevalent in the older age group. distinguishing chronic asthma from copd can be very challenging, and in some patients asthma cannot be distinguished from copd with widely available diagnostic tests. the management of these patients might have similarities to that of asthma. the distinction between loa and copd can be difficult to define precisely. the lung health study showed that methacholine-induced airways reactivity is present in many patients with mild-to-moderate copd (ie, 63% of men and 87% of women). approximately 85% of patients with tobacco-related copd demonstrate bronchodilator reversibility at least once on repeated testing sessions. the distinction between copd and asthma can be confounded by either the coexistence of the 2 common disease entities, the progression of common pathobiologic mechanisms induced by different environmental agents, or different disease mechanisms leading to an overlapping clinical syndrome. it has been known for more than a century that early-morning wheezing is a prominent symptom of congestive heart failure. it has been called cardiac asthma because it can mimic the clinical picture of typical asthma. the usual symptoms of gastroesophageal reflux in the elderly, such as vomiting and heartburn, might be absent. in a study of elderly patients with esophageal reflux proved by means of intraesophageal ph monitoring, chronic cough, hoarseness, and wheezing were present in 57% of patients. 126 in addition to causing asthma-like symptoms, there is also evidence that gerd might be a cause of worsening asthma. shortness of breath is a common symptom in the elderly and is most commonly caused by heart or lung diseases. it is usually experienced during exertion. shortness of breath at rest is not typical of heart disease or lung diseases, such as copd or interstitial lung disease, except in advanced stages. when present, it should prompt an investigation for asthma because sudden bronchospasm can cause respiratory distress at rest or exercise. paroxysmal nocturnal dyspnea, which is typical of congestive heart failure, is found in a smaller number of elderly patients with asthma. many elderly patients limit their activity to avoid experiencing dyspnea, and others assume that their dyspnea results from their aging process and thus avoid seeking medical attention early in their disease process. however, aging per se does not cause dyspnea, and a cause needs to be always pursued in assessing an elderly patient who complains of breathlessness. there are several other reasons why the diagnosis of asthma in the elderly might be delayed or not made at all. elderly patients have been shown to have a reduced perception of bronchoconstriction, 127 and this might delay medical intervention. many elderly patients are fearful of having an illness and dying and are reluctant to admit they are having symptoms. underreporting of symptoms in the elderly might have many causes, including depression, cognitive impairment, social isolation, denial, and confusing symptoms with those of other comorbid illnesses. cough is a very prominent symptom and might occasionally be the only presenting symptom. wheezing, on the other hand, might not be as prominent, and its presence is not very specific and does not correlate with severity of obstruction. physical examination in elderly patients with asthma is usually nonspecific and might misguide the diagnosis: a negative examination result does not rule out asthma, and wheezing can be found in a number of conditions, such as copd, recurrent aspiration, and ''cardiac asthma'' (congestive heart failure). two distinct clinical presentations have been described for asthma in the elderly. these are based on the onset and duration of the disease state. 97, 124, 128 patients with loa start having asthma symptoms for the first time when they are 65 years of age or older (some studies have suggested middle age or older). some studies of elderly asthmatic patients have shown that, as a group, as many as 40% will have their first attack after the age of 40 years. 97 patients belonging to this group tend to have fewer atopic manifestations, higher baseline fev 1 , and a more pronounced bronchodilator response than those with lsa. patients with lsa start having asthma symptoms early in life. patients belonging to this group tend to have a higher incidence of atopic diseases, more severe and irreversible or partially reversible airway obstruction, and more hyperinflation. the duration of the disease in this group is an important determinant of severity and of the development of irreversible airflow obstruction. 128 longitudinal studies of asthmatic populations, whether new onset or long standing, have shown that remission from asthma is uncommon in older groups, occurring in less than 20% of patients. 130 this contrasts with asthma in children and adolescents, in whom remission of asthma symptoms is common, especially in the second decade of life, and might be seen in as many as 60% to 70% of patients. objective measures to confirm the diagnosis of asthma are uncommonly performed in primary care settings. inhalers are prescribed for patients who are evaluated for asthma-like symptoms, and during a follow-up visit, the patient is asked whether the controller inhaler reduced the frequency of asthma symptoms or whether the albuterol inhaler quickly relieved the symptoms. such an empiric approach might work most of the time for young patients with mild asthma but is more likely to result in an incorrect diagnosis, poorly efficacious treatment, or unnecessary medication side effects in older patients. the onset of wheezing, shortness of breath, and cough in an elderly patient is likely to cause concern. although the adage ''all that wheezes is not asthma'' is true at any age, it is especially true in the elderly. diagnosis based on objective measures is essential. moreover, lung function testing, even in the presence of minimal symptoms, is especially important in this age group because there is thought to be an age-related reduction in the perception of exertional dyspnea in the elderly. 125 an older patient with chronic, untreated, severe airway obstruction caused by asthma might reduce activity to avoid dyspnea and stoically deny impairment of activity. this might reflect either neurocognitive function or changes in lifestyle that favor sedentary activities. there exist some barriers to lung function testing in the elderly. spirometry might be difficult to perform in some situations because of physical or cognitive impairments. however, 80% to 90% of elderly persons are able to perform goodquality spirometry when tested by skilled technologists. [129] [130] [131] [132] [133] the global initiative for obstructive lung disease guidelines for diagnosing the airway obstruction of copd by using a fixed fev 1 /fvc ratio of less than 0.70 caused a high misclassification rate in older persons. 134 however, almost all computerized spirometers automatically calculate the appropriate lower limit of the normal range for fev 1 /fvc ratio and for fev 1 by using race-specific national health and nutrition examination survey iii reference equations. in addition, it is hard to define the lower limits of predicted normal values in this age group. although complete reversibility of airflow obstruction is frequently seen with young asthmatic patients, most elderly asthmatic patients show incomplete reversibility despite continuous intense therapy, and many show fixed airflow obstruction as if they have copd. however, objective measures of lung function, such as spirometric and peak flow measurements, are generally underused in elderly patients, and this also contributes to the delay or absence of diagnosis. 134, 135 lung function testing is especially important in this age group because of the age-related reduction in the perception of dyspnea seen in the elderly. 127 spirometry is easily performed to determine that fev 1 and fev 1 /fvc ratio are demonstrated with the timed vital capacity maneuver. the flow-volume loop, which also measures inspiratory flow, is especially useful when the cause of respiratory tract symptoms is not known and an upper airway obstruction is in the differential diagnosis. although it might be difficult to perform spirometry in the elderly in some situations because of physical and poor cognitive impairment, studies have demonstrated that between 82% and 93% of elderly patients are able to perform the test properly. [131] [132] [133] [134] [135] on the other hand, it might be more difficult to define the lower limits of predicted normal values in this age group. traditionally, an fev 1 /fvc ratio of less than 70% increases the probability of asthma in an elderly patient with asthma symptoms, but this ratio normally decreases with age because of a decrease in elastic recoil, and a ratio lower that 70% might be a normal finding. 136 a brisk response to a short-acting bronchodilator might demonstrate the second cardinal feature of asthma: reversible airflow obstruction (ie, ''a responder''). when airflow obstruction is found in an elderly patient, attempts should be made to demonstrate reversibility after the inhalation of a short-acting b-adrenergic agent, such as albuterol. evidence of reversibility (postbronchodilator fev 1 or fvc increases of >12% and 200 ml) increases the probability of a diagnosis of asthma. elderly asthmatic patients, however, might have an impaired b-agonist bronchodilator response because the number of b-adrenergic receptors on smooth airway muscles is decreased with aging. 137 although the bronchodilator response to inhaled b-agonists decreases with age, 138 this is not the case with anticholinergic agents. 139 airway obstruction might be absent at the time of testing, and further testing might be needed to facilitate the diagnosis. bronchoprovocation testing with a methacholine challenge can be useful, and it is a safe and effective method to uncover asthma in older adults. 140, 141 a negative test result will rule out asthma; a positive test result must be interpreted and include an assessment of pretest probability. 142 in addition, some studies have shown that bronchial responsiveness is heightened in older adults, and therefore aging might be an independent factor that influences airway responsiveness. 143 there is a relationship between the degree of bronchial hyperresponsiveness and prechallenge pulmonary function; a low fev 1 predicts heightened responsiveness. 144 other factors that might contribute to heightened airway responsiveness in the older population are atopy and current or previous smoking history. peak expiratory flow variability might be helpful in the diagnosis and follow-up of younger patients with asthma, but poor coordination and muscle weakness in some elderly patients might lead to an inaccurate reading. 52, 145 a prospective study did not demonstrate any advantage of peak flow monitoring over symptom monitoring as an asthma management strategy for older adults with moderate-to-severe asthma when used in a comprehensive asthma management program. 146 other tests, such as measuring the carbon monoxide diffusing capacity of the lung, have been advocated to distinguish between asthma and copd because the diffusing capacity of the lung is reduced by parenchymal destruction found with emphysema. however, studies have shown that differences in lung function tests, although statistically significant, cannot be used clinically to separate the 2 groups of subjects because of a large overlap. 147 there is growing evidence that the airway function of young and middle-aged asthmatic patients decreases at a greater rate than that of healthy subjects. [148] [149] [150] the rate of decrease increases with increasing age and in those who smoke cigarettes. 149, 151 in patients with loa, there is evidence that lung function is reduced even before a diagnosis is made and decreases rapidly shortly after diagnosis. 98, 152 thereafter, it remains fairly stable. although the effect on older asthmatic patients with lsa is variable, in a random survey of 1200 elderly asthmatic patients older than 65 years, only 1 in 5 patients had normal pulmonary function (fev 1 >80% of predicted value), whereas a similar number showed moderate-to-severe airflow obstruction (fev 1 <50% of predicted value) after an inhaled short-acting bronchodilator. 153 because structural changes of emphysema are minimal in elderly asthmatic patients, except if they are previous smokers, airway remodeling is thought to be the main cause of fixed airflow obstruction. nitric oxide (no) is a gas generated by the action of no synthase from the substrates molecular oxygen and arginine. it was originally identified as a biologically important signaling molecule with the properties of an activity previously described as endothelial-derived relaxing factor. this molecule is important in regulating vascular integrity and blood flow and is thought to be a regulator of vascular smooth muscle relaxation. more recently, it has been found that no can be generated by a variety of inflammatory cells, including polymorphonuclear leukocytes, mononuclear cells, and, importantly, eosinophils. this finding led to the identification of no as a molecule present in exhaled breath. studies of no exhalation have found that it is increased in infection and inflammation of the airway. although high levels of no are found in nasally expired air, studies in pulmonary inflammation have avoided this by redirecting airflow through the oral airway. it has been found that exhaled no reflects airways inflammation and particularly eosinophilic inflammation. exhaled no levels are increased during the allergy season in atopic subjects. inhaled glucocorticoids promptly suppress exhaled no and do so in conjunction with suppression of eosinophilic inflammatory infiltrates. studies have demonstrated that monitoring exhaled no might permit better regulation of asthmatic symptoms, exacerbations, and total steroid use than treatments based on guidelines or symptoms. furthermore, increases in exhaled no levels might predict asthma exacerbations. 154 it is of interest that no levels in expired air decrease after bronchoconstrictive stimulation of asthmatic airways. little is known of the effects of age on no levels in the expired air. it appears that no production and vascular responses to no might be diminished in the elderly, but that effect might be overcome by exercise to increase fitness. an unanswered question in airways biology is whether no is causative of airways dysfunction, a marker for this dysfunction, or an ineffective homeostatic response to airways constriction. [155] [156] [157] [158] [159] challenges in defining asthma in the elderly there is agreement that asthma is both a common and underrecognized health problem for the elderly that leads to impairments of lung function and quality of health and life. the first question that needs to be addressed is why we need to make such a diagnosis rather than just treat the symptoms. there are reasons that physicians must strive to assign a diagnosis to a patient with a symptom complex. the patient is given relief by letting him or her know what is wrong by giving the illness a name, which implies a cause, establishes a prognosis, and initiates a treatment plan. moreover, advancement of the understanding of epidemiology, natural history, pathobiology, and treatment require a definable disease entity. whether the threshold for diagnostic criteria is set at a high level of sensitivity, a high level of specificity, or a high level of accuracy depends entirely on the costs and benefits of an incorrect diagnosis versus a missed diagnosis. for example, enumeration of a disease might require a high level of accuracy, whereas diagnosis of an uncommon and difficult-to-treat disease (eg, metastatic cancer) ought to be highly specific. the diagnosis of a common and easily treatable disease (eg, vitamin deficiency) ought to be highly sensitive, even if there is a risk of overdiagnosis. asthma tends to be one of those disorders that is relatively easy (although not inexpensive) to treat and has morbid consequences if left untreated, suggesting that the diagnostic criteria ought to be highly sensitive. although medical students are taught the rigorous discipline of data collection, differential diagnosis, and test confirmation, most physicians do not practice this way. in practice, physicians typically rely on a constellation of signs and symptoms along with demographic characteristics and recent experiences to establish diagnoses through the process of pattern recognition. there are no shortages of official definitions of asthma, and modifications seem to be added every year. most of these definitions involve the definition of a clinical syndrome (episodic cough, wheezing, and dyspnea), an underlying pathophysiology (airway hyperresponsiveness, variable, and reversible airflow obstruction), an underlying biological process (chronic eosinophilic or neutrophilic inflammation of the airways), and an associated morbid anatomy (basement membrane thickening, smooth muscle hypertrophy, and mucus cell metaplasia). given this, why is it so challenging to diagnose asthma in the elderly? first, the syndrome of asthma is often confused with other common diseases in the elderly, such as copd, congestive heart failure, paroxysmal arrhythmias, pulmonary emboli, recurrent aspiration, and gerd. second, asthma can often coexist with these other conditions, and it can be impossible to determine which of the 2 conditions is responsible for the patient's ill health. this diagnostic confusion can be amplified by the different manifestations of asthma in the elderly. elderly asthmatic patients can be insensitive to exertional dyspnea because of a sedentary lifestyle. they tend to be less atopic and have an incomplete response to bronchodilators. the elderly without asthma tend to show some signs suggestive of asthma: slower emptying of the lung during forced expiration, decreased lung elastic recoil, and a higher prevalence of nonspecific airways reactivity. the hope that formal testing of airways reactivity would prove useful in diagnosing asthma has led to disappointment. in young adults a history of asthma, wheeze, or treatment for asthma plus a positive methacholine challenge test result is highly specific for asthma (99%) but misses about half of the asthmatic population. 160 in epidemiologic studies that have examined various criteria for diagnosing asthma, it turns out that the solution is relatively j allergy clin immunol volume 128, number 3 simple. patients who answer yes to the question ''have you ever had asthma?'' have nearly 100% specificity and 48% to 100% sensitivity when compared with those receiving an independent expert's diagnosis. 161, 162 the problem of diagnosing asthma in the elderly is more complicated because of the overlap with copd. asthma is typically considered a disease of onset in youth driven by atopy and eosinophilic inflammation causing reversible airflow limitation. copd, in contrast, is considered to be a disease of onset in middle age driven by cigarette smoking and neutrophilic inflammation and leading to irreversible airflow limitation. as evidence presented in this workshop has shown, asthma in the elderly displays many of the features of copd. the disease can have its symptomatic onset late in life, often is only partially reversible, and is associated with neutrophilic inflammation. moreover, the current cohort of elderly patients has a high prevalence of past smoking, reflecting the health habits in the united states in the 1940s and 1950s. the failure to deal with the population of elderly patients who have overlapping signs of asthma and copd is not just a matter of classification of disease. it has significant health consequences in that such patients are systematically eliminated from clinical trials and are not covered by treatment guidelines. little is known about how best to treat the elderly patient with asthma who smokes or the elderly patient with copd who has reversible airflow limitation. this confusion is manifest by diagnostic coding in older medicaid patients. of those who were hospitalized with an initial diagnosis of copd, 43% had an asthma diagnosis within 3 years. of those who had an initial hospital diagnosis of asthma, 46% had a diagnosis of copd within 3 years. price et al 161 attempted to develop a discriminant function using clinical and demographic information that would separate patients with copd from those with asthma by using strict physiologic criteria. although several discriminating characteristics were found, the best diagnostic criteria were only 78% sensitive and only 75% specific. we need to ask whether it really is important to make the distinction between asthma and copd in the elderly in terms of prognosis or treatment. one study by hansen et al 136 suggests that regardless of whether a person is given a diagnosis of asthma or copd, the prognosis is mostly determined by the impairment in fev 1 . there are a number of ways to measure the effect of asthma in both young and elderly patients. assessments of symptoms, functional limitations, quality-of-life measures, and risk of adverse events are several that have been suggested by current asthma guidelines. 163 in addition, measuring a patient's satisfaction with his or her asthma symptom control and overall asthma care has been advocated. the use of objective measures of asthma control and satisfaction can be especially important in the elderly because the perception of symptoms might be impaired with advancing age. in addition, many elderly patients unconsciously accommodate to their symptoms or assume that the symptoms are a function of the aging process itself. because the number of unscheduled ambulatory visits, emergency department visits, and hospitalizations are high in elderly asthmatic patients, 164 ,165 and quality-of-life scores are low in elderly patients with persistent asthma when compared with those with mild asthma or no asthma at all, 5 careful assessment of asthma control is essential in this age group. despite severe symptoms and physiologic impairment, most elderly patients with asthma can lead active productive lives if their asthma is appropriately managed. in fact, when elderly patients with severe or difficult-to-treat asthma have been identified by a physician's assessment, they appear to do better than younger patients. in the tenor study, despite lower lung function, older asthmatic patients (mean age, 72 years) had lower rates of unscheduled office visits, emergency department visits, and corticosteroid bursts. 81 patients reported in the tenor study received more aggressive care than younger adults, including higher use of inhaled and oral corticosteroids, and this undoubtedly had an effect on outcomes. the tools to measure asthma outcomes include questionnaires and other self-report tools, such as diaries and standardized medical history forms. standardized questionnaires that assess asthma impairment include the asthma control test, 166, 167 the asthma control questionnaire, 168,169 the asthma therapy assessment questionnaire, 170, 171 and others. [172] [173] [174] [175] there are many tools available to clinicians to assess the quality of life of asthmatic patients. [176] [177] [178] [179] [180] [181] [182] [183] unfortunately, these psychometric instruments that claim to measure the same outcomes might produce disparate results, and none have been targeted for the elderly. in general, results that measure several domains are more accurate when a composite score is derived rather than when subscores of specific domains are compared. medical, administrative, and pharmacy records have also been used, especially to study larger asthmatic populations; these have proved useful for the assessment of a patient's change over time and to measure group differences. clinical trials of asthma therapy and educational, selfmanagement, and health services interventions have used psychometric instruments to assess elderly patients with asthma. in most of these studies, however, the majority of subjects are younger. there are no studies that have specifically determined the reliability and validity of these instruments in elderly persons. this is true of patient-satisfaction measures that have been used to assess asthma care. [184] [185] [186] this is much needed because using lung function testing to measure outcomes has potential limitations in this age group. there are difficulties in defining normal predicted values at a very advanced age, and many patients with physical or cognitive impairment cannot reliably perform these tests. it is hopeful that newer biomarkers of lung inflammation have a particular role to play in the assessment of asthma control in the elderly. tools assessing physical function: self-reported and objective a major goal of geriatric and gerontologic research is to reduce the decrease in cognitive and physical function and prevent disability among older adults. accordingly, many functional status measures have been developed and used to understand the disabling process, as well as to evaluate interventions to prevent functional decline. it is useful to identify instruments that measure functional limitations and disability to investigate the functional consequences of asthma in older adults and to understand the pathway from asthma to disability. functional limitations are restrictions in performing basic physical and mental actions at the whole-person level (eg, walking or climbing stairs), whereas disability refers to limitations or difficulty in performing socially defined roles or tasks of everyday living in a given environmental context (eg, grocery shopping or bathing). 187, 188 both self-reported and objective measures can be used to measure these different stages of disablement. 189 self-reported measures can provide an indication of how well a patient is functioning in daily life and provide an assessment of care needs. these measures incorporate self-perception of function and can assess adaptations made to compensate for decrements in function. 190 for disability assessment, self-reported difficulty or inability to perform basic activities of daily living (adl) is commonly used. for example, a composite score of 8 adl items has been used as an outcome to evaluate the efficacy of a program to prevent functional decline in frail older adults. 191 other composite scores assessing difficulty in ambulation, stair climbing, transferring, upper extremity function, and basic and instrumental adls have been developed. 192 these comprehensive instruments of function and disability are amenable to computer adaptive testing. 193 several objective measures of physical performance are used in studies of older adults and in disease-specific patient populations. tests of physical performance eliminate subjective attitudinal differences in the patient's reporting of physical function limitations. they have the advantage of providing an objective measure for comparisons across populations. 194 these tests are sensitive to change over time and can detect decrements in function that might not be observed with self-reported instruments. many studies in older adults have used physical performance tests as predictors of adverse health events, as well as outcomes. for example, the short physical performance battery, which consists of timed balance, walking, and chair-rise tasks, is a powerful predictor of disability, nursing home admission, and mortality. 195, 196 the short physical performance battery was also used as a screening instrument to identify functionally limited older adults and as an outcome in a randomized controlled trial of exercise. 197 increasingly, objective measures of physical function are used to summarize the effect of total disease burden, including subclinical conditions and impairments, and to identify physiologic reserve that might help some older adults cope with disease burden. clinically meaningful differences have been established for commonly used performance measures. 198 the goals of asthma therapy in elderly patients are not different from those for younger asthmatic patients. 96 they are to treat acute symptoms, prevent chronic symptoms, decrease emergency department visits and hospitalizations, preserve normal activity level, and optimize pulmonary function with a minimal adverse effect from medications. 163, 199, 200 optimal management should also focus on improving health status (quality of life) in these patients, which is often complicated by depressive symptoms and side effects from the drugs commonly used for asthma. 201 unlike many younger adults who might require no medication or just asneeded b-agonist therapy for occasional symptoms, most older asthmatic patients need continuous treatment programs to control their disease. at a time when memory loss is common and financial resources are often limited, many older patients require complicated and frequent dosing with multiple expensive drugs. unfortunately, this has led to a significant rate of noncompliance among the elderly population in general. 45 sex, socioeconomic factors, educational level, marital status, and severity of disease do not seem to be good predictors of compliance in elderly asthmatic patients. in summary, there are many challenges in the treatment of asthma in the elderly, which include a greater propensity to experience adverse events from medication use, as well as potential drug interactions with medications used for the treatment of comorbidities, 4,96 and thus it is particularly important to treat any disease in the elderly, including asthma, with a minimum of therapy while attaining maximum efficacy. a thorough understanding is required regarding which medications will be most effective in the treatment of asthma in the elderly to achieve this balance. because many current therapeutic options and those in development for asthma focus on specific inflammatory cells and mediators, any age-related changes in the airway inflammatory milieu will likely affect their therapeutic efficacy. therefore a rigorous characterization of age-related changes in airway inflammation will facilitate the management of asthma in the elderly. the therapeutic approach to asthma in elderly patients does not differ from what is recommended for young patients. statements on the standard of care for treating asthma have been published by the national institutes of health and are widely used as guidelines. 163, 199 treatment protocols use step-care pharmacologic therapy based on the intensity of asthma symptoms and the clinical response to these interventions. as symptoms and lung function worsen, step-up or add-on therapy is given. as symptoms improve, therapy can be stepped down. in this age group special attention should also be given to the potential adverse effects of commonly used medications. corticosteroids are capable of reducing airway inflammation, thereby improving lung function, decreasing bronchial hyperreactivity, reducing symptoms, and improving overall quality of life. oral corticosteroids should be avoided if possible because they place the patient at risk for bone fracture and increased likelihood of cataracts, muscle weakness, back pain, bruising, and oral candidiasis. 202 many studies have shown that inhaled corticosteroids are safe and effective treatment for persistent asthma, but none have specifically targeted the elderly population. long-term use of inhaled corticosteroids has been associated with a good safety profile, but higher doses of inhaled steroids (eg, >1000 mg/d) are capable of causing hypothalamicpituitary-adrenal axis suppression. local adverse effects, such as hoarseness, dysphonia, cough, and oral candidiasis, do occur but can usually be avoided by the use of a spacer or holding chamber with the metered-dose inhaler and by rinsing the mouth after each use. despite the pivotal role of inhaled corticosteroids in asthma, many elderly patients are undertreated with this group of medications. 5, 203 leukotriene-modifying agents (ltms) are also asthma controllers. these agents have been shown to be effective in preventing allergen-induced asthma, exercise-induced asthma, and aspirin-induced bronchospasm. studies on their use in the elderly are limited. when compared with ltms, low-dose inhaled corticosteroids have favored the latter. the ltms might also reduce asthma exacerbation rates and the need for steroid bursts. the ltms are generally very safe. 66, 204 b-adrenergic agents are important medications in the acute and chronic management of asthma. elderly patients with asthma j allergy clin immunol volume 128, number 3 might be less responsive to certain bronchodilators compared with younger patients. 73, 138 inhaled short-acting b 2 -adrenergic agonists are the treatment of choice for the acute exacerbation of asthma symptoms. despite the minimal systemic absorption seen with these agents, slight tachycardia might be observed. this is presumably because of vasodilatation, which results from the stimulation of b 2 -receptors in vascular smooth muscle. tremor can also occur and is especially troublesome in the geriatric patient. tremor is thought to be caused by stimulation of b 2 -receptors in skeletal muscle. in general, they have been proven to be safe and effective in all age groups. 205 however, b-agonists can cause (1) a dose-dependent decrease in serum potassium levels and (2) a dose-dependent increase in the qt interval on electrocardiography. because sudden death from ventricular arrhythmia can be caused by both of these mechanisms, as well as being a complication of ischemic heart disease, the use of b-agonists in the elderly should be closely monitored. short-acting b 2 -agonists should be used for rescue of symptoms, whereas long-acting agents should be used as maintenance medications only as an add-on to inhaled corticosteroids and never as stand-alone therapy. anticholinergics, such as inhaled ipratropium, a short-acting bronchodilator, and tiotropium, a bronchodilator with 24-hour action, have an excellent safety profile in the elderly. they should be considered when additional bronchodilator therapy is necessary; however, their role in long-term maintenance of asthma in the elderly has not been established. theophylline is an effective bronchodilator and has some antiinflammatory properties. however, its use has been greatly reduced over the past decade because of safety concerns, especially in the elderly. the narrow therapeutic range of theophylline, the frequency of concomitant illnesses that alter theophylline kinetics, and many drug interactions that affect the clearance of theophylline make it essential to closely monitor blood theophylline levels in older asthmatic patients. theophylline toxicity can cause seizures and cardiac arrhythmias, such as atrial fibrillation, supraventricular tachycardia, ventricular ectopy, and ventricular tachycardia. the most common cause for theophylline toxicity is a self-administered increase in medication. controlling triggers. measures should be taken to avoid triggers that can cause worsening of symptoms. as with asthma at any age, education concerning avoidance of aggravating factors that can lead to severe bronchospasm is very useful. although aeroallergens are less important in provoking symptoms in the elderly than in young patients, a program implementing environmental control measures, such as avoiding or minimizing aeroallergen exposure, should be instituted in patients with documented sensitivity to specific allergens. however, such programs might not be successful in all cases, especially because lifestyle changes in the elderly population might be difficult. the most important provocative factors include viral respiratory tract infections and irritants, such as cigarette smoke, paints, varnish, and household aerosols. pharmacologic agents that are often prescribed for concomitant illnesses (ischemic heart disease and hypertension), such as b-adrenoreceptor antagonists (b-blockers), can also provoke bronchospasm. 206 this includes both noncardioselective agents (propranolol, pindolol, and timolol) and, to a lesser extent, cardioselective agents (metoprolol and acebutolol). topical b-blockers are also widely used in the elderly to reduce intraocular pressure in wide-angle glaucoma. with such treatment, sufficient systemic absorption might cause fatal status asthmaticus. 207 the severity of b-blocker-induced bronchoconstriction correlates with the severity of underlying airflow obstruction and the degree of bronchial reactivity and might be reduced by the use of a cardioselective topical b-blocking agent, such as betaxolol. 208 aspirin and nonsteroidal anti-inflammatory agents might precipitate acute bronchospasm in certain asthmatic patients, and angiotensin-converting enzyme inhibitors might cause dry cough in some, worsening the symptoms of asthma. gerd should also be considered a cause of worsening asthma symptoms. asthma education. the complexity of the prescription regimen (number and frequency of medications), coupled with the memory loss and cognitive dysfunction that might be present in this group of patients, contribute partially to poor compliance with therapy. 4, 96 patient education is an effective tool and should be an integral part in the management of asthma. 209 active participation by a patient and family members in monitoring lung function, avoidance of provocative agents, and decisions regarding medications provide asthma management skills that give that patient the confidence to control his or her own disease. mastering the technique of an inhaled medication delivery device is a challenging problem in elderly patients, and the great majority of elderly patients are unable to properly use the metered-dose inhaler, even after proper instruction. [210] [211] [212] [213] use of dry powder devices, although simpler, requires the generation of an adequate inspiratory flow that might be suboptimal in frail patients and those with severe airway obstruction. in such situations the use of spacer devices or nebulizers might be beneficial. patients should recognize the rationale behind using the different medications, the correct way to use them, and their side effects, and polypharmacy should also be avoided. asthma in the elderly can be effectively managed, and despite severe symptoms and physiologic impairment, most patients can lead active and productive lives. a demographic study of 380 low-income elderly persons in chicago found that 26 (10%) without a previous diagnosis of asthma or emphysema had symptoms compatible with those of obstructive lung disease. 214 of patients with a previous diagnosis, only 18% were compliant with medications, and this was largely due to the cost of medications. in addition, health care use was high in this population. telephone intervention offers a simple option in the management of elderly patients with asthma. it has been shown that asthma care by means of telephone triage of adult asthmatic patients can lead to a higher percentage of asthmatic patients being reviewed at less cost per patient and without loss of asthma control when compared with usual routine care in the outpatient clinic. 215 however, it has not been determined whether such an intervention could improve asthma care specifically in persons aged 65 years or older. the following study was designed to evaluate this question. fifty-two elderly asthmatic patients who used their rescue inhalers more than twice a week and had at least 1 emergency department or urgent care visit in the previous year were randomized to an intervention or control group. 216 all patients received 2 telephone calls over a 12-month period. the intervention group received an asthma-specific questionnaire, and the control group received a general health questionnaire. medication use and health care use were evaluated at the beginning and end of a 12-month period. the study was completed by 23 control and 25 intervention subjects. baseline data were similar in both groups. after 12 months, 72% (n 5 18) of the intervention group was taking an inhaled corticosteroid compared with 40% (n 5 10) of the control group. the intervention group had fewer emergency department visits when compared with the control group. sixtyfour percent (n 5 16) of the intervention group had an asthma action plan compared with 26% (n 5 6) of the control group. this study provides evidence that using a simple telephone questionnaire can successfully improve asthma care in the elderly. by empowering the elderly with the appropriate knowledge regarding their asthma, an appropriate discussion about their asthma care can be initiated with their primary care physicians. pulmonary rehabilitation. although pulmonary rehabilitation is recommended as the standard of care for patients with copd, there are only a few studies that evaluate the benefit of rehabilitation for asthmatic patients, and none of these consider elderly asthmatic patients. one study looked at the effects of a 10-week outpatient rehabilitation program for 58 asthmatic patients after 3 years. [217] [218] [219] they found that 39 of 58 subjects continued to exercise regularly all 3 years; there was a decreased number of emergency department visits and a decrease in asthma symptoms. further studies are needed to assess empowerment strategies for elderly patients with asthma, as well as the potential benefits of pulmonary rehabilitation on morbidity and mortality. asthma pathogenesis is complex and incompletely understood. research into the pathophysiologic mechanisms is made more difficult by multiple factors, including the heterogeneity of the disease itself, variable presentations in different stages of life, and the lack of highly relevant animal models. [220] [221] [222] [223] [224] in the last decade, increasing interest in asthma in the elderly has triggered more intensive investigation in both human and animal systems by using ever more sophisticated immunologic methodologies. early investigation with rats revealed a lack of total and allergenspecific ige in response to ovalbumin. 225 this was born out by several later in vivo studies. [226] [227] [228] igg subset analysis (igg 1 vs igg 2 ) provided further support for this phenomenon. igg 1 , correlating in the mouse to a t h 2 response (vs igg 2 [t h 1]) was shown to follow a similar pattern. 227, 228 recent studies [226] [227] [228] of cytokine profiles in aged rodents compared with young control animals enhanced the paradigm that age resulted in less robust t h 2 cytokines, particularly il-4, il-5, and il-13, in favor of t h 1 gene and protein expression. 227, 228 this pattern was not fully supported in a recent chronic murine asthma model 229 wherein il-5 was greater in aged sensitized mice, making the picture more complex. ifn-g, a key t h 1 cytokine, has been consistently overexpressed in aged versus young rodents. [226] [227] [228] [229] eosinophilia, which is considered a key component of (allergic) asthma, was more pronounced in younger versus older animals (bronchoalveolar lavage fluid, lung tissue, or both) after most, [226] [227] [228] 230 although not all, 229 sensitization paradigms. molecular genetics and t-cell subset analysis has allowed further insight into possible mechanisms underlying the waning t h 2 response observed in most models. [227] [228] [229] specifically, elderly mice appear to have more memory t cells, less activated cd4 1 t h 2 cells, and less activated monocytes. 227, 228 resident goblet cells also appear to express upregulation of mucin and mucin gene expression. 229 a key to the impaired t h 2 response was recently found in the gata3 pathway. 228 elderly mice do not phosphorylate components of the extracellular signal-regulated protein kinase/mitogen-activated protein kinase pathway, resulting in lack of downstream signaling with gata3, with subsequent impairment of promoter regions for key t h 2 cytokines, including il-4. this could be an overarching explanation for many findings in the elderly asthmatic patient, including less ige (il-4 and il-13 are needed for opening switch regions for ige production); il-4 and il-13 are highly associated with airway hyperreactivity, and il-5 is associated with eosinophil activation, survival, and, to a lesser extent, trafficking. finally, airway hyperreactivity has been universally found to be greater in young versus aged animals. [226] [227] [228] [229] 231 the mechanisms might be complex, including both an altered key cytokine milieu and alterations in muscle function at the muscarinic receptor level. [231] [232] [233] clinical and translational research research into the pathogenesis of asthma in recent years has led to the discovery of a number of novel, potentially important targets for the development of new treatment options. much of this research has focused on t h 2 lymphocyte-driven processes underlying allergic asthma and its characteristic eosinophilic airway inflammation. abundant information supporting this research has been derived from bronchial biopsy and bronchoalveolar lavage studies largely carried out in a young adult population. it is recognized, however, that the role of allergy and allergic triggers in asthma diminishes with age. 69, 234 in addition, loa is often less reversible, more severe, and frequently occurs in response to a viral respiratory tract infection. 153 a distinct asthma phenotype characterized by normal airway eosinophil numbers has been described. 235 moreover, normal airway eosinophilia might also be associated with abnormal sputum neutrophilia. 236, 237 recent studies have shown that neutrophilic asthma might be associated with activation of innate immune pathways in contrast to the adaptive immune response associated with t h 2-mediated allergic asthma. 238 thus alternative immune pathways involving natural killer t or t h 17 lymphocyte subtypes have been hypothesized as being potentially important in the pathogenesis of asthma, particularly in adult-onset asthma. 239, 240 just as the discovery of t h 2-related pathways has led to important leads in drug discovery for allergic asthma, further clinical research into these alternative pathways should be carried out with the goal of identifying new and exciting targets for future drug discovery. this research should focus not only on the discovery of new molecular targets but also on the identification of noninvasive biomarkers that will help predict the success of any new therapy in an individual patient. asthma is an important disease in the older adult, affecting 7% of the population older than 65 years, which is understudied and frequently underdiagnosed. there are data to suggest that asthma in older adults is phenotypically different from that in young patients, with a potential effect on the diagnosis, assessment, and management in this population. this workshop brought together many disciplines to further our current understanding, resolve gaps in knowledge, and explore future areas of research and education. table i lists specific areas in need of research and study. the coming acceleration of global population ageing the census bureau on prospects for us population growth in the twenty-first century. population and development review national surveillance for asthma-united states asthma in the elderly: current knowledge and future directions underdiagnosis and undertreatment of asthma in the elderly. cardiovascular health study research group increasing u.s. asthma mortality rates: who is really dying? quality of care for older adults with chronic obstructive pulmonary disease and asthma based on comparisons to practice guidelines and smoking status economic burden in direct costs of concomitant chronic obstructive pulmonary disease and asthma in a medicare advantage population report of the national institute on aging task force on comorbidity a painful interface between normal aging and disease epidemiology of aging correlation between deoxyribonucleic acid excision-repair and life-span in a number of mammalian species executing cell senescence a systematic look at an old problem overview of biological mechanism of aging molecular biology of aging replicative senescence: a critical review the limited in vitro lifetime of human diploid cell strains cell culture aging: insights for cell aging in vivo? the relationship between in vitro cellular aging and in vivo human age evidence for a relationship between longevity of mammalian species and life spans of normal fibroblasts in vitro and erythrocytes in vivo a biomarker that identifies senescent human cells in culture and in aging skin in vivo frailty in older adults: evidence for a phenotype phenotype of frailty: characterization in the women's health and aging studies from bedside to bench: research agenda for frailty gait speed and survival in older adults age-associated increased interleukin-6 gene expression, late-life diseases, and frailty decreased cell proliferation and altered cytokine production in frail older adults determinants of longevity: genetic, environmental and medical factors united states life tables gains in life expectancy after elimination of major causes of death: revised estimates taking into account the effect of competing causes extension of life-span by overexpression of superoxide dismutase and catalase in drosophila melanogaster a genetic pathway conferring life extension and resistance to uv stress in caenorhabditis elegans divergent roles of ras1 and ras2 in yeast longevity can an improved environment cause maximum lifespan to decrease? comments on lifespan criteria and longitudinal gompertzian analysis longitudinal gompertzian analysis of stroke mortality in the u.s., 1951-1986: declining stroke mortality is the natural consequence of competitive deterministic mortality dynamics nutritional interventions in aging and ageassociated diseases caloric restriction and aging physiological changes in respiratory function associated with ageing sex and age differences in pulmonary mechanics in normal nonsmoking subjects elasticity of human lungs in relation to age flow and age dependence of airway closure and dynamic compliance human immunosenescence: the prevailing of innate immunity, the failing of clonotypic immunity, and the filling of immunological space inflamm-aging. an evolutionary perspective on immunosenescence patient factors and medication guideline adherence among older women with asthma refill adherence by the elderly for asthma/chronic obstructive pulmonary disease drugs dispensed over a 10-year period deaths: final data for asthma costs and utilization in a managed care organization asthma and its association with cardiovascular disease in the elderly. the cardiovascular health study research group the cardiovascular health study: design and rationale prevalence and correlates of respiratory symptoms and disease in the elderly. cardiovascular health study correlates of peak expiratory flow lability in elderly persons intra-individual change over time in dna methylation with familial clustering epigenetic reprogramming and imprinting in origins of disease aging by epigenetics-a consequence of chromatin damage? epigenetics at the epicenter of modern medicine the role of histone deacetylases in asthma and allergic diseases environmental epigenetics and asthma: current concepts and call for studies epigenetics, disease, and therapeutic interventions epigenetic regulation of airway inflammation epigenetic differences arise during the lifetime of monozygotic twins predictors of loss of lung function in the elderly: the cardiovascular health study overcoming gaps in the management of asthma in older patients: new insights allergic respiratory disease in the elderly the diagnosis and management of asthma is much tougher in older patients effect of age on response to zafirlukast in patients with asthma in the accolate clinical experience and pharmacoepidemiology trial (accept) is asthma in the elderly really different? diagnosis and severity of asthma in the elderly: results of a large survey in 1,485 asthmatics recruited by lung specialists asthma in the elderly asthma medications and their potential adverse effects in the elderly: recommendations for prescribing interleukin 1 genetics, inflammatory mechanisms, and nutrigenetic opportunities to modulate diseases of aging trichostatin a attenuates airway inflammation in mouse asthma model prospective multicenter study of acute asthma in younger versus older adults presenting to the emergency department immunosenescence: emerging challenges for an ageing population pathways to a robust immune response in the elderly variation of bronchoalveolar lymphocyte phenotypes with age in the physiologically normal human lung neutrophils and low-grade inflammation in the seemingly normal aging human lung age-related changes in eosinophil function in human subjects asthma: defining of the persistent adult phenotypes characterization of leukotrienes in a pilot study of older asthma subjects asthma in older adults: observations from the epidemiology and natural history of asthma: outcomes and treatment regimens (tenor) study ige mediated hypersensitivity in ageing influence of ageing on ige-mediated reactions in allergic patients the association of age, gender and smoking with total ige and specific ige total and specific serum ige levels in adults: relationship to sex, age and environmental factors aging and serum immunoglobulin e levels, immediate skin tests, rast age-related serum immunoglobulin e levels in healthy subjects and in patients with allergic disease longitudinal changes in allergen skin test reactivity in a community population sample chronic respiratory symptoms and airway responsiveness to methacholine are associated with eosinophilia in older men: the normative aging study serum total ige and specific ige to dermatophagoides pteronyssinus, but not eosinophil cationic protein, are more likely to be elevated in elderly asthmatic patients respiratory viruses and exacerbations of asthma in adults clearing the air: asthma and indoor air exposures meta-analyses of the associations of respiratory health effects with dampness and mold in homes damp indoor spaces /media/files/report%20files/2004/damp-indoor-spaces-and-health/dampin door2pagerforpdf.pdf. accessed is allergen skin test reactivity a predictor of mortality? findings from a national cohort asthma in older adults asthma in the elderly. a comparison between patients with recently acquired and long-standing disease characteristics of asthma among elderly adults in a sample of the general population asthma severity, atopic status, allergen exposure, and quality of life in elderly persons asthma in the elderly sensitization to cat allergen is associated with asthma in older men and predicts newonset airway hyperresponsiveness. the normative aging study the role of allergy and airway inflammation asthma in the elderly: cockroach sensitization and severity of airway obstruction in elderly nonsmokers prick puncture skin tests and serum specific ige as predictors of nasal challenge response to dermatophagoides pteronyssinus in older adults particulate air pollution and hospital admissions for cardiorespiratory diseases: are the elderly at greater risk? traffic and outdoor air pollution levels near residences and poorly controlled asthma in adults community study of role of viral infections in exacerbations of asthma in 9-11 year old children respiratory tract viral infections in inner-city asthmatic adults the incidence of respiratory tract infection in adults requiring hospitalization for asthma acute respiratory illness in an american community. the tecumseh study acute respiratory tract infection in daycare centers for older persons long-term care facilities: a cornucopia of viral pathogens respiratory syncytial virus infection in elderly and high-risk adults human metapneumovirus infections in adults: another piece of the puzzle the similarities and differences of epidemic cycles of chronic obstructive pulmonary disease and asthma exacerbations a community-based, time-matched, case-control study of respiratory viruses and exacerbations of copd viral infections in patients with chronic obstructive pulmonary disease respiratory syncytial virus infection in elderly adults virus-induced asthma attacks how viral infections cause exacerbation of airway diseases role of viral infections in asthma and chronic obstructive pulmonary disease incidence and outcomes of asthma in the elderly. a population-based study in rochester, minnesota the clinical outcome of asthma in the elderly: a 7-year follow-up study characteristics of asthma in the elderly asthma in the elderly: underperceived, underdiagnosed and undertreated; a community survey determinants of symptoms suggestive of gastroesophageal reflux disease in the elderly reduced subjective awareness of bronchoconstriction provoked by methacholine in elderly asthmatic and normal subjects as measured on a simple awareness scale duration of asthma and physiologic outcomes in elderly nonsmokers asthma in the elderly features of asthma in the elderly factors determining performance of bronchodilator reversibility tests in middle-aged and elderly quality of spirometric performance in older people study of respiratory function in the elderly with different nutritional and cognitive status and functional ability assessed by plethysmographic and spirometric parameters quality control of spirometry in the elderly. the sa.r.a. study. salute respiration nell'anziano 5 respiratory health in the elderly aging on quality of spirometry reversible and irreversible airflow obstruction as predictor of overall mortality in asthma and chronic obstructive pulmonary disease differential changes of autonomic nervous system function with age in man impaired bronchodilator response to albuterol in healthy elderly men and women influence of age on response to ipratropium and salbutamol in asthma bronchoprovocation testing an assessment of methacholine inhalation tests in elderly asthmatics guidelines for methacholine and exercise challenge testing-1999. this official statement of the american thoracic society was adopted by the ats board of directors airway hyperresponsiveness in the elderly: prevalence and clinical implications normal range of methacholine responsiveness in relation to prechallenge pulmonary function. the normative aging study peak flow lability: association with asthma and spirometry in an older cohort a randomized clinical trial of peak flow versus symptom monitoring in older adults with asthma differences in airway inflammation in patients with fixed airflow obstruction due to asthma or chronic obstructive pulmonary disease are chronic wheezing and asthma-like attacks related to fev1 decline? the cracow study rate of decline of lung function in subjects with asthma decline of lung function in adults with bronchial asthma effects of domestic gas cooking and passive smoking on chronic respiratory symptoms and asthma in elderly women findings before diagnoses of asthma among the elderly in a longitudinal study of a general population sample the natural history of asthma in adults: the problem of irreversibility physical activity prevents age-related impairment in nitric oxide availability in elderly athletes effect of natural grass pollen exposure on exhaled nitric oxide in asthmatic children exhaled nitric oxide (no) is reduced shortly after bronchoconstriction to direct and indirect stimuli in asthma height, age, and atopy are associated with fraction of exhaled nitric oxide in a large adult general population sample use of exhaled nitric oxide measurements to guide treatment in chronic asthma exhaled nitric oxide: the effects of age, gender and body size defining asthma in epidemiological studies symptom-based questionnaire for identifying copd in smokers asthma and asthma-like symptoms in adults assessed by questionnaires. a literature review national heart, lung and blood institute national institute of health. national asthma education and prevention program: expert panel report 2-guidelines for the diagnosis and management of asthma. bethesda: national heart, lung, and blood institute asthma in older patients: factors associated with hospitalization asthma exacerbations in north american adults: who are the ''frequent fliers'' in the emergency department? development of the asthma control test: a survey for assessing asthma control validity of the asthma control test completed at home development and validation of a questionnaire to measure asthma control identifying 'well-controlled' and 'not well-controlled' asthma using the asthma control questionnaire association of asthma control with health care utilization and quality of life association of asthma control with health care utilization: a prospective evaluation a new tool for monitoring asthma outcomes: the itg asthma short form perceived control of asthma: development and validation of a questionnaire a 6-item brief measure for assessing perceived control of asthma in culturally diverse patients how should we quantify asthma control? a proposal reliability and validity of the asthma quality of life questionnaire-marks in a sample of adult asthmatic patients in the united states the marks asthma quality of life questionnaire: further validation and examination of responsiveness to change an evaluation of an asthma quality of life questionnaire as a measure of change in adults with asthma a scale for the measurement of quality of life in adults with asthma validation of a standardized version of the asthma quality of life questionnaire development and validation of the mini asthma quality of life questionnaire american translation, modification, and validation of the st. george's respiratory questionnaire a self-complete measure of health status for chronic airflow limitation. the st. george's respiratory questionnaire patient characteristics relevant to effective self-management: scales for assessing attitudes of adults toward asthma applicability of the asthma opinion survey in the spanish population: distribution and relationship with sociodemographic and clinical variables a new treatment satisfaction measure for asthmatics: a validation study an epidemiology of disability among adults in the united states. milbank mem fund q the disablement process assessing the building blocks of function: utilizing measures of functional limitation preclinical mobility disability predicts incident mobility disability in older women a program to prevent functional decline in physically frail, elderly persons who live at home a randomized trial comparing aerobic exercise and resistance exercise with a health education program in older adults with knee osteoarthritis. the fitness arthritis and seniors trial (fast) creating a computer adaptive test version of the late-life function and disability instrument variation in thresholds for reporting mobility disability between national population subgroups and studies a short physical performance battery assessing lower extremity function: association with self-reported disability and prediction of mortality and nursing home admission lower-extremity function in persons over the age of 70 years as a predictor of subsequent disability effects of a physical activity intervention on measures of physical performance: results of the lifestyle interventions and independence for elders pilot (life-p) study meaningful change and responsiveness in common physical performance measures in older adults naepp working group: consideration for diagnosing and managing asthma in the elderly. bethesda: national institutes of health asthma: a six-part strategy for managing older patients drug treatment of asthma in the elderly adverse effects of oral corticosteroids in relation to dose in patients with lung disease underuse of inhaled steroid therapy in elderly patients with asthma loss of response to treatment with leukotriene receptor antagonists but not inhaled corticosteroids in patients over 50 years of age are there any detrimental effects of the use of inhaled long-acting beta 2-agonists in the treatment of asthma? beta-adrenergic-blocking agents in bronchospastic diseases: a therapeutic dilemma respiratory arrest following first dose of timolol ophthalmic solution the effect of topical ophthalmic instillation of timolol and betaxolol on lung function in asthmatic subjects asthma in the elderly: the importance of patient education a comparison of breath-actuated and conventional metered-dose inhaler inhalation techniques in elderly subjects acquisition and short-term retention of inhaler techniques require intact executive function in elderly subjects what determines whether an elderly patient can use a metered dose inhaler correctly? asthma in the elderly. a diagnostic and management challenge prevalence of obstructive airways disease in the disadvantaged elderly of chicago targeted routine asthma care in general practice using telephone triage improving asthma care for the elderly: a randomized controlled trial using a simple telephone intervention asthmatic patients' views of a comprehensive asthma rehabilitation programme: a three-year follow-up a 3-year follow-up of asthmatic patients participating in a 10-week rehabilitation program with emphasis on physical training high-intensity physical training in adults with asthma. a 10-week rehabilitation program animal models of asthma usefulness and optimization of mouse models of allergic airway disease murine models of asthma modeling allergic asthma in mice: pitfalls and opportunities promise and pitfalls in animal-based asthma research: building a better mousetrap van der straeten m. the effect of age on ige production in rats decreased expression of th2 type cytokine mrna contributes to the lack of allergic bronchial inflammation in aged rats induction and maintenance of airway responsiveness to allergen challenge are determined at the age of initial sensitization impaired gata3-dependent chromatin remodeling and th2 cell differentiation leading to attenuated allergic airway inflammation in aging mice effect of ageing on pulmonary inflammation, airway hyperresponsiveness and t and b cell responses in antigen-sensitized and -challenged mice failure of aged rats to accumulate eosinophils in allergic inflammation of the airway age differences in cholinergic airway responsiveness in relation with muscarinic receptor subtypes effect of ageing on nicotine-induced contraction of guinea-pig bronchial preparation effects of age on muscarinic agonist-induced contraction and ip accumulation in airway smooth muscle total serum ige is associated with asthma independently of specific ige levels. the spanish group of the european study of asthma analysis of induced sputum in adults with asthma: identification of subgroup with isolated sputum neutrophilia and poor response to inhaled corticosteroids evidence that severe asthma can be divided pathologically into two inflammatory subtypes with distinct physiologic and clinical characteristics heterogeneity of airway inflammation in persistent asthma: evidence of neutrophilic inflammation and increased sputum interleukin-8 innate immune activation in neutrophilic asthma and bronchiectasis persistent activation of an innate immune response translates respiratory viral infection into chronic lung disease il-17 is increased in asthmatic airways and induces human bronchial fibroblasts to produce cytokines fla co-chair: nicola a. hanania, md, ms section of pulmonary and critical care medicine asthma clinical research center baylor college of medicine houston, tex members sidney s. braman, md warren alpert medical school, brown university division of pulmonary, critical care, and sleep medicine rhode island hospital providence, ri carol saltoun we thank the nia for recognizing the need for this workshop, especially susan nayfield, md, who convened the workshop and provided tremendous support in moving this research field forward; evan hadley, md, the director of the division of geriatrics and clinical gerontology; and basil eldadah, md, who continued the work of dr nayfield and contributed valuable advice and encouragement to the authors in completing these proceedings. key: cord-259012-rk0sd9i5 authors: mehta, hemal; kim, leah n; mathis, thibaud; zalmay, pardis; ghanchi, faruque; amoaku, winfried m; kodjikian, laurent title: trends in real-world neovascular amd treatment outcomes in the uk date: 2020-10-14 journal: clin ophthalmol doi: 10.2147/opth.s275977 sha: doc_id: 259012 cord_uid: rk0sd9i5 purpose: to report trends in real-world outcomes of anti-vascular endothelial growth factor (anti-vegf) therapy for neovascular age-related macular degeneration (namd) in the united kingdom (uk) over the last decade. design: systematic review. methods: medline, pubmed, and embase databases were searched from 9 april 2010 to 8 april 2020 for publications that met the inclusion criteria: treatment-naïve eyes, uk-only data and ≥1 year of follow-up. ichom (international consortium for health outcome measures) outcomes and study quality were assessed. visual acuity (va) trends were assessed in studies with ≥100 eyes at baseline. results: twenty-six studies (n=25,761 eyes) were included, meeting 14–17 out of 20 institute of health economics quality appraisal of case series checklist domains. only ranibizumab and aflibercept outcome data were available. the mean injection number in the first year of treatment was 5.9 in publications from 2010 to 2015 and 7.1 from 2015 to 2020. average baseline va and mean one-year, two-year and three-year va gains gradually improved over the last decade. longer-term studies reported that the visual gains achieved in the first year of treatment were rarely maintained, with under-treatment a likely contributing factor. conclusion: uk real-world outcomes have improved over the last decade with improved service delivery and the adoption of more proactive treatment regimens but are still not always as impressive as registration clinical trial results. access to longer-acting anti-vegf therapies would reduce the treatment burden for patients, carers, and the healthcare system, potentially making replication of clinical trial results possible in the nhs. age-related macular degeneration (amd) is a leading cause of blindness, accounting for approximately 7% of all cases worldwide, 1,2 and in 2017, the european society of retina specialists (euretina) estimated that around 4 million people were living with amd in the united kingdom (uk). 3 its prevalence is set to rise as the world's population ages: it is estimated that 288 million people globally would have either an early or late manifestation of amd by the year 2040. 4 late disease is characterized by a significant loss of central vision gradually due to geographic atrophy, or more rapidly from development of neovascular amd (namd; also termed "exudative" or "wet" amd). 5 it is estimated that 40,000 new cases of namd develop each year in the uk. unlike geographic atrophy, treatments are currently available for namd. 6 the last 10-15 years have seen a transformation in how namd is managed. the introduction of intravitreally administered anti-vegf drugs has transformed the treatment of namd, moving away from an era where laser photocoagulation and verteporfin photodynamic therapy were administered in an attempt to reduce the rate at which vision was lost, to a world where improved visual and morphologic outcomes are regularly achieved, with a corresponding fall in the rate of namd-related blindness. [7] [8] [9] [10] [11] [12] [13] [14] there is seldom a drug that performs better in clinical practice than in clinical trials. there are multiple reasons for this phenomenon. patients tend to be carefully selected for inclusion in clinical trials and dosing regimens are strictly adhered to. real-world clinical practice involves the treatment of many patients who would never have been included in these trials and the same treatment protocols are often not applied. 15 patients miss appointments for many reasons and therefore lose the opportunity to be treated with an effective drug on time, with the outcome that their vision suffers. additionally, restrictions on public funding limit clinic capacity and availability of licensed drugs to patients often until visual acuity (va) has deteriorated to less than the driving standard. 16 these phenomena help explain the global gap in performance between clinical trials and real-world clinical practice for anti-vegf drugs used for the treatment of namd. 17, 18 to better understand the real-world situation in the uk, we performed a systematic review to assess trends in outcomes over the last decade and identify whether registration clinical trial outcomes of intravitreal anti-vegf therapy for neovascular amd have been replicated in uk nhs practice. a systematic literature search was conducted on studies published from 9 april 2010 to 8 april 2020, using medline, pubmed, and embase library databases. the following multipurpose (.mp) search terms and medical subject headings (mesh) terms where available were used: macular degeneration, age related macula degeneration, amd, namd, neovascular, wet, vegf, anti-vegf, ranibizumab, lucentis, aflibercept, eylea, bevacizumab, avastin, visual acuity, visual outcomes, vision, ocular, blindness, registry, database, long term study/studies, observational study/studies, phase iv study/studies, real world, real-world, united kingdom, uk, scotland, wales, northern ireland, england. further references were identified by manually searching included articles and consulting experts in the field. real-world studies of intravitreal ranibizumab, aflibercept and bevacizumab therapy for namd published before the search date were included. included studies were required to have at least 1 year of follow-up data, and eyes were required to be treatment naïve; switching studies were, therefore, excluded. randomized clinical trial results and meeting abstracts were excluded. only studies with uk data were included and, therefore, were all english language articles. the supplementary figure 1 summarises the selection of included studies. it was pre-specified that analysis of va trends would be restricted to studies that contained ≥100 eyes at baseline. the year of publication of the study was recorded to enable comparison of outcomes published in the first half of the decade (9 april 2010 to 8 april 2015) and the second half of the decade (9 april 2015 to 8 april 2020). data extraction and quality assessment of the original studies were performed independently by two authors (lk, pz). outcome measures were cross-referenced against the ichom (international consortium for health outcome measures) checklist, and the quality of each study was assessed using the quality appraisal checklist for case series developed by the institute of health economics (ihe) 19 as this is preferred tool of the national institute for health and care excellence (nice). 20 we identified 26 real-world published studies with 25,761 eyes meeting the inclusion criteria (supplementary table 1 ). there were 13 studies with ≥100 eyes at baseline and reporting relevant va outcomes representing 23,464 eyes. only ranibizumab and aflibercept outcome data was available. the mean baseline va ranged from 48 to 57 letters in included studies. the mean baseline va in general improved over the course of the decade (figure 1 ). there does appear to be variation in baseline va between centres even when data was collected and published at similar times. the mean visual gains from baseline levels to 1 year, where recorded, ranged from −1.3 to +8.0 logmar letters, with more significant visual gains being observed in studies that reported outcomes in the latter half of the submit your manuscript | www.dovepress.com clinical ophthalmology 2020:14 3332 decade than the former (figure 1) . a similar trend was seen in the subset of studies that reported 2-year va data ( figure 2) . a number of included real-world studies stratified visual outcomes according to baseline va. the uk amd emr study, with over 8000 eyes at baseline was the largest study to report on the impact of baseline va on final va. the included studies consistently reported that those eyes with worse baseline va achieved greater gains in relative vision, but the final va outcome was worse than those eyes that commenced treatment with good va. 46 the ichom recommended minimum dataset was only published in 2016. 48 as well as baseline va and mean va gain, it is recommended 15-letter gain and loss from baseline and maintenance of driving-level vision (6/12 or better) are recorded. these parameters were not consistently reported even in studies published after 2016 (supplementary table 1 ). the percentage of treated eyes with >15-letter loss at 1 year ranged from between 5.6% to 10% in included uk real-world studies and by 2 years this ranged from 9.2% to 18% ( table 1 ). the percentage of treated eyes with va >70 letters at baseline ranged from 3.3% to 32.2% in included studies with a clear trend for improvement over the decade. similarly, the percentage of eyes with >70 letter at 1 and 2 years increased with improving baseline vision ( table 2 ). table 1 ). another aspect of treatment burden relates to the average number of clinic visits, with prn regimens requiring between 12-14 visits in year 1, whereas fixed interval regimens required 9 visits in year 1. chandra et al 41 reported a t&e approach after the initial year of fixed dosing with aflibercept. they reported better maintenance of drivinglevel vision in those eyes receiving 5 or more injections (and therefore, by implication, clinic visits) from years 2-5. in terms of time spent in the clinic, the terra study reported that one-stop clinics used less staff resources and were likely to be shorter in duration than the cumulative time spent for two-stop clinics. 40 there were two real-world studies reporting drying of intraretinal and subretinal fluid at the macula as recorded by the treating clinician. both studies investigated aflibercept treatment for namd. almuhtesab et al 21 reported that by the eleventh month of treatment, 53% of eyes were dry and 47% of eyes remained wet. eleftheriadou et al 26 reported 67% of eyes were dry by the end of the first year of treatment with a similar proportion at the end of years 2 and 3. there was not comparative data available on the anatomical outcomes of ranibizumab versus aflibercept treated eyes in the included uk studies. few studies reported adverse event rates (supplementary table 1 ). gupta et al 49 reported that one patient developed acute anterior uveitis (and that they observed no episodes notes: it should be noted that baseline characteristics will be different between real-world studies and compared with registration clinical trials. the percentage of eyes losing >15 letters at 2 years was approximately 9% in the marina registration trial for ranibizumab. in the integrated analysis of 2-year view 1 and 2 data, 7.6% of eyes lost >15 letters from baseline. abbreviations: n/r, not reported; n/a, not applicable. notes: it should be noted that baseline characteristics will be different between real-world studies and compared with registration clinical trials. there is significant loss to follow-up over time in included real-world studies. *study recorded greater than 75 logmar letters and may have included some pre-treated eyes. **study recorded greater than 75 logmar letters. ***study recorded greater than 73 letters that is equated to 6/12 snellen in some clinical trials. mean va gain at 1 year correlated with mean number of intravitreal anti-vegf injections received. only real-world studies with ≥100 eyes at baseline were included. it should be noted that a limitation is that there will be variation in baseline characteristics of included studies. pearson correlation coefficient, r = 0.66 (p = 0.0095) indicating moderate positive correlation that is statistically significant. where it was clear that data from the same eyes had been published more than once, then the largest dataset was included, and the smaller dataset excluded. this applied to the 2 and 3 year data published by eleftheriadou et al. 26 they stated in their 2017 publication, "eyes receiving their first aflibercept treatment between october 1, 2013 and december 31, 2013 were included in this analysis" and in their 2018 publication, ". . . eyes, receiving intravitreal aflibercept injections from 1 september 2013 to 31 february 2014, were included and analysed in this study". therefore, the 2018 publication data only was included. the first 36 and subsequently second-year 43 data of the aflibercept users group was published. so as not to double count eyes, only the larger sample size from the 2017 publication was included when calculating the total number of eyes in this systematic review. williams and blyth 39 published an interesting article primarily focused on eyes with better than 6/12 vision at presentation. although an important topic, and a patient group likely to benefit from early treatment, that particular subset of the population with namd was not the focus of this review. although buckle et al 24 had well over 100 eyes, mean va changes of individual eyes were not presented and so could not be included in the summary graphs. where it was reported that eyes were not treatment naïve, this subset of eyes were excluded from the overall analysis. 40, 44 quality of life quality of life indices such as patient-reported outcome measures were not reported in the included real-world studies. the quality of the included studies varied, with 14-17 out of 20 domains of the ihe quality appraisal of case series checklist satisfied (supplementary table 2 ). many uk nhs services have developed a culture of auditing their real-world outcomes of intravitreal anti-vegf therapy for namd over the last decade, a practice that should be commended. over 25,000 eyes were included in this systematic review and visual outcome trends were assessed in over 23,000 eyes. although representing a lower level on the evidence hierarchy, these realworld studies dwarf the size of randomized clinical trials in this field. baseline va in published studies has gradually improved over the last decade. worse baseline va might be a reflection of the delay in a patient receiving initial anti-vegf therapy, and therefore a surrogate marker of the effectiveness of local referral pathways and capacity of local macular services, rather than as a measure of the intrinsic efficacy of the drug being used. it can be implied that referral pathways have become more streamlined and capacity of local macular services has improved over the last decade. further measures involving home monitoring, strong community links, human or artificial intelligence referral refinement pathways, and adequate resources will support this trend in the future. baseline va is a strong predictor of long-term visual outcomes and restricting treatment until va declines below the driving standard is likely to be counterproductive. similar to the marina 50 and anchor 51 ranibizumab and view 1 and 2 aflibercept registration clinical trials, 52 better baseline va is associated with lower va gains but a greater likelihood of achieving driving-level vision. 53, 54 older age and larger lesion size at baseline were also associated with worse visual outcomes in these registration clinical trials. the mean age of patients enrolled in real-world studies ranged from 76. reported, respectively, in the marina 50 and anchor 51 clinical trials and 78 years reported in the view 1 cohort; the view 2 cohort was on average younger with a mean age of 74 years. 52 characterizing namd lesions on fundus fluorescein angiography has become less common in routine uk nhs practice in recent years (supplementary table 1 ). encouragingly, mean va gains in uk real-world studies have improved over the last decade. of note, the number of intravitreal injections received in the first year of treatment significantly and positively correlated with vision gain, despite differing baseline characteristics in the included studies. mean va gains in included studies ranged from −1.3 to +8.0 logmar letters. the view 1 and 2 registration clinical trials for aflibercept enrolled 2457 study eyes. 52, 55 in the first year, patients received either aflibercept 0.5 mg every 4 weeks (0.5q4), aflibercept 2 mg every 4 weeks (2q4), aflibercept every 8 weeks after three monthly loading injections (2q8), or 0.5 mg intravitreal ranibizumab every 4 weeks (rq4). the three fixed interval aflibercept groups had similar va gains compared with fixed interval ranibizumab at 52 weeks, with mean bestcorrected visual acuity (bcva) gains ranging from 8.3 to 9.3 letters. in the second year of the trial, a prn approach was followed in all treatment arms with the maximum treatment interval capped at 12 weeks. the va gains at 52 weeks in all treatment arms were not fully maintained at week 96 with the mean bcva gain ranging from 6.6 to 7.9 letters, with the most likely cause being the reduced frequency of intravitreal injections in year 2. the 2q8 aflibercept group had similar mean va outcomes to the q4 aflibercept and q4 ranibizumab groups over 96 weeks, but with an average of 5 fewer injections. there was no 2q8 ranibizumab arm in this trial. the proportion of treated eyes with 15-letter loss at 1 year was reported to range from 5.6% to 10% when reported in included uk real-world studies. these numbers almost doubled by 2 years, ranging from 9.2% to 18%. table 1 highlights that over the last decade, the proportion of eyes with 15-letter loss at 1 and 2 years has reduced. the marina trial randomized patients to ranibizumab 0.3 mg, 0.5 mg and sham injections for a period of 24 months. 50 after one year, approximately 5% of the groups treated with ranibizumab lost greater than 15 letters from baseline compared with 38% receiving sham injections. at 2 years, approximately 9% of eyes of the groups treated with ranibizumab lost >15 letters from baseline compared with 47% receiving sham injections. the anchor trial randomized patients into treatment groups with intravitreal ranibizumab (0.3 mg or 0.5 mg) and photodynamic therapy with verteporfin. 51 at one year, groups treated with ranibizumab lost greater than 15 letters from baseline in 6% and 4% of cases, respectively, compared with 36% receiving verteporfin. in the integrated analysis of 2-year view 1 and 2 data, 7.6% of eyes lost greater than 15 letters from baseline. some of the more recent uk real-world studies reported comparable mean va gains to the registration clinical trials at 1 and 2 years; the extent of 15-letter loss is not so favourable, especially in the second year of treatment (ranging from 9.2% to 13.3% in publications in the last 5 years versus 7.6% in the integrated view 1 and only six uk real-world included studies with ≥100 eyes at baseline reported mean va outcomes beyond 2 years, 25, 26, 32, 41, 44, 46 five of these out to 3 years, and chandra et al 41 reporting outcomes data out to 5 years. chandra et al 41 reported the best long-term visual outcomes in the uk with long-term proactive treatment. horner et al 42 had just less than 100 eyes but is worthy of mention as outcomes were reported out to 8 yearsthey reported using a prn approach that mean va could be maintained into the third year of treatment, but by year 7 there was a mean 6.4 letter loss. the third year of treatment represents the last year where mean vision gains from baseline were still reported in the included uk studies. this is in contrast with other healthcare systems, where the fight retinal blindness! registry reported 56 they were able to maintain the va gains for 5 years, but beyond that there was a mean loss of 2.6 letter loss by year 7 -a phenomenon that is likely related to the use of a more proactive t&e treatment approach throughout the disease course. most clinical trials do not provide outcomes data beyond 3 years. the seven-up extension study 56 subsequently treated in routine clinical practice with mainly a prn regimen and with chronic under-treatment from the third year of treatment had a mean loss of 8.6 letters over 7 years. 56, 57 sadda et al reported that it is important to recognize that adequately treating namd remains the best option to optimize visual outcomes in patients, particularly given the risk of vision loss with under-treatment observed in the real-world. 59 mones et al 60 suggest that better long-term visual outcomes could be achieved by changing the community mindset that contributes to under-treatment of this chronic disease. other reasons initial gains may wane over time include loss of patient enthusiasm for frequent treatment and also the progressive onset of atrophic amd. there was considerable variation in baseline va and visual outcomes between centres even when looking at published data from similar time-points in the included real-world studies. the uk amd emr users group published an analysis of anonymized inter-centre variation in va outcomes in 2016. 61 a total of 5811 treatment-naïve eyes of 5205 patients from 13 uk centres were assessed. there was considerable variation in mean baseline va between centres ranging from 48.9 to 59.9 logmar letters. mean inter-centre va change from baseline to 12 months varied from +6.9 letters to −0.6 letters (mean of +2.5 letters). the authors reported these differences are influenced, but not completely explained, by factors such as patient age, starting va, number of injections, and visits. additional factors include socioeconomic status and resource allocation with deprivation being related to worse ocular health outcomes. 62, 63 choosing the right parameters to judge the quality of a good service is an important consideration. looking just at mean va gain could penalize services that have good referral mechanisms in place and start with better baseline va. therefore, the proportion of eyes achieving 6/12 vision might be a better comparator. maintenance of vision after 3 loading injections is another way to assess an intravitreal service. the retinal outcomes group and other expert panels have suggested parameters to record to enable both patient outcomes and service delivery to be audited and compared. 64, 65 three recent publications from the same institution had slightly different visual outcomes. 26, 27, 41 some of this relates to the time-point when eyes were included, consistent with a national trend for better outcomes over time. inclusion and exclusion criteria varied and the way in which missing data was treated was different between the analyses. this highlights the importance of trying to standardize the methodological approach as well as outcomes measured in real-world studies of namd. the mean number of injections in the first year of treatment was 5.9 in publications from the first half of the decade and 7.1 from the latter half. the increase in average first-year injection numbers corresponded with the transition from prn to t&e ranibizumab treatment regimens and the introduction of aflibercept with a fixed treatment interval for the initial 12 months in uk clinical practice. the advantage of fixed interval and t&e dosing over a prn regimen is that each clinic visit is likely to also be a treatment visit. in the analysis by lee et al, 31 the mean number of visits in year 1 for prn treatment was 10.8 versus 8.9 for fixed dose-treatment, with an average of 5.8 injections versus 7.0 respectively. a global meta-analysis of ranibizumab namd real-world outcomes identified that the mean change in va for patients on a t&e regimen was better than prn regimens out to 3 years. 18 t&e patients received on average more injections (6.9 vs. 4.7) but had fewer visits (7.6 vs. 9.2) in the first year of treatment. lee et al 31 compared prn ranibizumab and continuous aflibercept uk real-world treatment outcomes of treatment-naïve namd. after 1 year, the vision gains in the aflibercept arm were greater than those achieved in the ranibizumab arm with similar baseline vision in both treatment groups. however, the authors noted that "the observed va differences are small and likely to be related to more frequent treatment with aflibercept". ozturk et al 33 identified that view 1 and 2 visual gains could be achieved in year 1 in uk nhs practice when patients received 7-8 injections. however, va outcomes were less good when patients received 6 or fewer injections in year 1. a french observational study also highlighted the importance of regular and frequent aflibercept therapy to achieving better visual outcomes out to 2 years. 66 fixed interval regimens for year 1 transitioning into t&e longerterm or t&e regimens after loading injections are now preferred to prn treatment approaches in the uk. 64, 67, 68 anatomical outcomes two included studies reported that between a third and a half of aflibercept treated eyes continued to have intraretinal or subretinal fluid at the end of the first year of clinical ophthalmology 2020:14 submit your manuscript | www.dovepress.com dovepress treatment. in the view 2 clinical trial, 28% of eyes in the 2q8 arm were not dry at the end of 12 months. 52 the longterm visual implications of persistent intraretinal or subretinal fluid are not fully understood. three cases of endophthalmitis were reported in each of the q4 ranibizumab and q4 aflibercept arms of the view 1 clinical trial, giving a rate of endophthalmitis of 1% of patients in those treatment arms but no cases of endophthalmitis were reported in the view 2 clinical trial. 52, 55 the endophthalmitis rates in marina and anchor were 1% and 1.1%, respectively. 50, 51 in real-world studies, it is more common to report rates of endophthalmitis per injection rather than per patient, although both provide useful information. the reported rate of endophthalmitis in a global metaanalysis of real-world outcomes of namd was 17 of 66,176 intravitreal injections (0.026%), 18 with possible underreporting. the number of reported endophthalmitis cases in the uk real-world studies was considerably lower than would have been expected based on reported rates in the literature. 69, 70 buckle et al 24 reported 8 cases in total, with an endophthalmitis rate of 1 in 2124 injections (0.047%). ross et al 45 which also recorded data from gloucestershire, reported 2 cases of endophthalmitis, a rate of 1 in 1828 injections (0.055%). it is likely other uk real-world studies under-reported ocular safety outcomes. it will be important to accurately record ocular safety as new longer-acting drugs become available. prospective studies, which made up only 6 of 26 included studies, have greater potential to accurately capture ocular safety data. systemic adverse event rates were not recorded in many of these real-world studies. systemic anti-vegf drug use is associated with thromboembolic events like stroke and heart attack. although the systemic exposure to intravitreally injected anti-vegf agents is very small, it is not clear from reports in the literature if there is an increased risk of these adverse events when these drugs are used to treat namd, especially in high-risk groups that would have been excluded from clinical trials. 13 the incidence of antiplatelet trialists' collaboration-defined arterial thromboembolic events from baseline to week 96 in the view 1 and 2 clinical trials were similar amongst the aflibercept and ranibizumab groups (2.4-3.8%). capturing systemic safety data can be challenging in an ophthalmology clinic setting. it may be that history of systemic adverse events is not sought most of the time. in the future, cross-referencing a comprehensive prospective uk namd registry with a comprehensive uk stroke registry in a well-defined region might help generate a more definitive answer. a similar approach has been used in singapore. 71 it is clear that maintaining patients' vision for longer, or improving their va has quality of life benefits. however, quality of life assessments and patient-reported outcomes were not available in the included uk real-world studies. this study had a number of limitations. as the ihe study quality assessment identified, the study design, methodology, baseline patient characteristics and outcomes assessments were heterogeneous, making it challenging to compare studies. a meta-analysis was not carried out here, but if that is considered in a future analysis, the real-world studies would need to be weighted by number of study eyes and baseline characteristics adjusted for. some studies were prospective, but most were retrospective where there is a greater chance of selection bias, especially as loss to follow-up rates tend to be high in real-world studies. 15 it is possible uk real-world studies that did not meet the search criteria were not included in this analysis; however, if that is the case, they are likely to represent small studies that would not change the overall conclusions of this study. the real-world studies were not randomized or controlled. va measurements are usually not performed with full refraction in routine clinical practice in contrast to that in clinical trial protocols. there are potential causes for visual decline other than macular degeneration. there may be a publication bias, with the uk centres that reported real-world outcomes potentially having outcomes that were better than the national average. there is a likelihood that some data is duplicated as some study centres may have contributed eyes to more than one publication. nevertheless, the size of the study dataset was large enough to help minimize the impact of some of these limitations. this was the reason that va trends were only assessed in studies with ≥100 eyes at baseline. it is also worth addressing the fact that there is a time lag between what is recorded in clinical practice and when the study is published. the included studies typically reflect what was prevailing clinical practice in the preceding 1-3 years of publication, rather than what was the clinical practice on the publication date. a better approach would be to have prospectively designed registries, which have the benefit of being able to identify and report contemporary realworld practice patterns in a far timelier manner. 72 a minimum set of standardized patient-centred outcomes have been specified by ichom to allow easy comparison between different units nationally and internationally. 48 when future real-world studies are planned, it would be helpful to record the ichom visual outcomes including baseline va, va gain, 15-letter gain and loss from baseline, and maintenance of driving-level vision (snellen va of 6/12 or better). such practice would allow future realworld studies to be more easily compared. maintenance of driving-level of vision is a useful bigpicture statistic to identify if patients are being referred in a timely manner to namd services, and whether they are receiving adequate long-term treatment. maintaining patients' independence clearly has profound economic benefits for the individual, carers and wider society. it is important that the nice health economic modelling reflects this. additional parameters that are recommended by ichom include: patient-reported outcome measures such as the brief impact of vision impairment (ivi) questionnaire, ocular safety, and treatment burden including clinic visit numbers as well as injection numbers. 74 there was a significant reduction in referrals of namd to nhs eye services at the outset of the covid-19 pandemic. in the first month of the lockdown, there was an approximately 72% reduction in referrals in 4 large nhs trusts. 75 if these figures are extrapolated to the whole of the uk, a conservative estimate is that a treatment delay of 3 months could lead to a >50% relative increase in the number of eyes with vision ≤6/60 and 25% relative decrease in the number of eyes with driving vision at one year. 75 the covid-19 pandemic has also meant that many patients are either unable or unwilling to attend routine hospital appointments during periods of quarantine. the namd treatment population largely includes elderly patients with multiple co-morbidities who are at higher risk of death from covid-19 than the general population, explaining the reluctance of patients to visit eye clinics. a short to medium term solution may be establishing fully equipped and staffed community namd treatment facilities where practical. longer treatment intervals and infrequent clinical visits can facilitate better uptake by patients and maintenance of vision for the majority. the observed difference in uk real-world visual outcomes in studies pre and post 2015 supports the role of proactive treatment regimens (e.g. t&e and fixed interval dosing). this emphasizes the need for longer-acting agents that do not require regular treatment visits for patients to maintain their vision. this would not only reduce the burden on patients and their families under normal circumstances but would be of value in reducing visual impact on patients during periods of quarantine. another challenge is to continue to optimize real-world uk nhs treatment outcomes as the population ages and demand for services increases. this will require long-term use of proactive treatment regimens and avoidance of undertreatment, patient education, staff training and governance, greater use of virtual clinics, telemedicine and information technology infrastructure, key performance indicators and adequate resources. 76, 77 conclusion uk real-world outcomes have improved over the last decade with the adoption of more proactive treatment regimens and service improvements but are still not consistently as impressive as those from registration clinical trials or some international observational cohorts with long-term data. the adoption of prospective registries can inform key stakeholders of important changes in clinical practice outcomes in a more timely manner. 72 access to longer-acting intravitreal anti-vegf therapies can reduce the treatment burden for patients and carers and potentially make replication of clinical trial results possible in the nhs. editorial assistance was provided to the authors by dr mark hillen, bsc, phd, through unrestricted grant funding by allergan international plc, dublin, ireland. open access publication costs were also provided through an unrestricted education grant from allergan international at the request of the first author. allergan plc had no role in the design or conduct of this research. all authors met the icmje authorship criteria. neither honoraria nor payments were made for authorship and authors retained full control over the manuscript. hm has received research grants, educational travel grants and honoraria from allergan/abbvie, bayer, novartis and roche outside the submitted work. tm is a consultant for allergan, bayer and novartis; and reports grants, personal fees, nonfinancialsupport from novartis and non-financial support from bayer outside the submitted work. fg has received honoraria for consultancy-advisory boards from alimera, allergan, causes of vision loss worldwide, 1990-2010: a systematic analysis age-related macular degeneration is the leading cause of blindness retinal diseases in europe: prevalence. incidence and healthcare needs global prevalence of age-related macular degeneration and disease burden projection for 2020 and 2040: a systematic review and meta-analysis focal inner retinal hemorrhages in patients with drusen: an early sign of occult choroidal neovascularization and chorioretinal anastomosis the estimated prevalence and incidence of late stage age related macular degeneration in the uk laser photocoagulation of subfoveal recurrent neovascular lesions in age-related macular degeneration. results of a randomized clinical trial a randomized clinical trial of a single dose of intravitreal triamcinolone acetonide for neovascular age-related macular degeneration: one-year results optical coherence tomography findings after an intravitreal injection of bevacizumab (avastin) for neovascular age-related macular degeneration intravitreal bevacizumab treatment of choroidal neovascularization secondary to age-related macular degeneration intravitreal bevacizumab (avastin) for neovascular age-related macular degeneration argon laser photocoagulation for senile macular degeneration. results of a randomized clinical trial anti-vascular endothelial growth factor for neovascular age-related macular degeneration recent trends in vision impairment certifications in england and wales real-world outcomes in patients with neovascular age-related macular degeneration treated with intravitreal vascular endothelial growth factor inhibitors uk amd emr users group report v: benefits of initiating ranibizumab therapy for neovascular amd in eyes with vision better than 6/12 multi-country real-life experience of anti-vascular endothelial growth factor therapy for wet age-related macular degeneration metaanalysis of real-world outcomes of intravitreal ranibizumab for the treatment of neovascular age-related macular degeneration a principal component analysis is conducted for a case series quality appraisal checklist national institute for health and care excellence one-year real-world outcomes in patients receiving fixed-dosing aflibercept for neovascular age-related macular degeneration. eye (lond) visual outcomes of age-related macular degeneration patients undergoing intravitreal ranibizumab monotherapy in an urban population long-term visual outcomes of intravitreal ranibizumab treatment for wet age-related macular degeneration and effect on blindness rates in south-east scotland long-term outcomes of intravitreal ranibizumab for neovascular age-related macular degeneration in a well defined region of the uk bilateral visual outcomes and service utilization of patients treated for 3 years with ranibizumab for neovascular age-related macular degeneration long-term outcomes of aflibercept treatment for neovascular age-related macular degeneration in a clinical setting one-and two-year visual outcomes from the moorfields age-related macular degeneration database: a retrospective cohort study and an open science resource predicting visual outcomes in patients treated with aflibercept for neovascular age-related macular degeneration: data from a real-world clinical setting comparison of two intravitreal ranibizumab treatment schedules for neovascular age-related macular degeneration effectiveness of ranibizumab for neovascular age-related macular degeneration using clinician-determined retreatment strategy uk amd/dr emr report ix: comparative effectiveness of predominantly as needed (prn) ranibizumab versus continuous aflibercept in uk clinical practice three-year visual outcome and injection frequency of intravitreal ranibizumab therapy for neovascular age-related macular degeneration real-world visual outcomes in patients with neovascular age-related macular degeneration receiving aflibercept at fixed intervals as per uk licence three-year follow-up of ranibizumab treatment of wet age-related macular degeneration: influence of baseline visual acuity and injection frequency on visual outcomes visual acuity outcomes in ranibizumab-treated neovascular age-related macular degeneration; stratified by baseline vision first-year visual acuity outcomes of providing aflibercept according to the view study protocol for age-related macular degeneration bevacizumab for neovascular age related macular degeneration (abc trial): multicentre randomised double masked study 24-month clinical outcomes of a treat-and-extend regimen with ranibizumab for wet age-related macular degeneration in a real life setting factors affecting visual acuity after one year of follow up after repeated intravitreal ranibizumab for macular degeneration resource use and real-world outcomes for ranibizumab treat and extend for neovascular age-related macular degeneration in the uk: interim results from terra impact of injection frequency on 5-year real-world visual acuity outcomes of aflibercept therapy for neovascular age-related macular degeneration realworld visual and clinical outcomes for patients with neovascular age-related macular degeneration treated with intravitreal ranibizumab: an 8-year observational cohort (amd8) second-year visual acuity outcomes of namd patients treated with aflibercept: data analysis from the uk aflibercept users group. eye (lond) measuring the benefit of 4 years of intravitreal ranibizumab treatment for neovascular age-related macular degeneration which visual acuity measurements define high-quality care for patients with neovascular age-related macular degeneration treated with ranibizumab? eye (lond) the neovascular age-related macular degeneration database: multicenter study of 92 976 ranibizumab injections: report 1: visual acuity decisional answer tree analysis of exudative age-related macular degeneration treatment outcomes defining a minimum set of standardized patient-centered outcome measures for macular degeneration a treat and extend regimen using ranibizumab for neovascular age-related macular degeneration clinical and economic impact ranibizumab for neovascular age-related macular degeneration ranibizumab versus verteporfin for neovascular age-related macular degeneration intravitreal aflibercept (vegf trap-eye) in wet age-related macular degeneration visual benefit versus visual gain: what is the effect of baseline covariants in the treatment arm relative to the control arm? a pooled analysis of anchor and marina impact of baseline characteristics on treatment response to intravitreal aflibercept injection for wet age-related macular degeneration intravitreal aflibercept injection for neovascular age-related macular degeneration: ninety-six-week results of the view studies seven-year outcomes in ranibizumab-treated patients in anchor, marina, and horizon: a multicenter cohort study (seven-up) long-term outcomes of treatment of neovascular age-related macular degeneration: data from an observational study horizon: an open-label extension trial of ranibizumab for choroidal neovascularization secondary to age-related macular degeneration anti-vascular endothelial growth factor use and atrophy in neovascular age-related macular degeneration: systematic literature review and expert opinion undertreatment of neovascular age-related macular degeneration after 10 years of anti-vascular endothelial growth factor therapy in the real world: the need for a change of mindset the uk neovascular amd database report 3: inter-centre variation in visual acuity outcomes and establishing real-world measures of care clinical and social characteristics associated with reduced visual acuity at presentation in australian patients with neovascular age-related macular degeneration: a prospective study from a long-term observational data set. the fight retinal blindness! project united kingdom diabetic retinopathy electronic medical record (uk dr emr) users group: report 4, real-world data on the impact of deprivation on the presentation of diabetic eye disease at hospital services initiation and maintenance of a treat-and-extend regimen for ranibizumab therapy in wet age-related macular degeneration: recommendations from the uk retinal outcomes group action on neovascular age-related macular degeneration (namd): recommendations for management and service provision in the uk hospital eye service impact of intravitreal aflibercept dosing regimens in treatment-naive patients with neovascular age-related macular degeneration: 2-year results of rainbow aflibercept treatment for neovascular amd beyond the first year: consensus recommendations by a uk expert roundtable panel, 2017 update recommendations by a uk expert panel on an aflibercept treat-and-extend pathway for the treatment of neovascular age-related macular degeneration meta-analysis of infectious endophthalmitis after intravitreal injection of anti-vascular endothelial growth factor agents incidence and outcomes of infectious and noninfectious endophthalmitis after intravitreal injections for age-related macular degeneration incidence of myocardial infarction, stroke, and death in patients with age-related macular degeneration treated with intravitreal anti-vascular endothelial growth factor therapy efficient capture of high-quality data on outcomes of treatment for macular diseases: the fight retinal blindness! project incidence and baseline clinical characteristics of treated neovascular age-related macular degeneration in a well-defined region of the uk a measure of handicap for low vision rehabilitation: the impact of vision impairment profile estimating excess visual loss in people with neovascular age-related macular degeneration during the covid-19 pandemic. medrxiv providing a safe and effective intravitreal treatment service: strategies for service delivery the way forward. options to help meet demand for the current and future care of patients with eye disease -age-related macular degeneration and diabetic retinopathy key topics include: optometry; visual science; pharmacology and drug therapy in eye diseases; basic sciences; primary and secondary eye care; patient safety and quality of care improvements. this journal is indexed on pubmed central and cas, and is the official journal of the society of clinical ophthalmology (sco). the manuscript management system is completely online and includes a very quick and fair peer-review system key: cord-253182-s60vzf3q authors: fang, evandro f.; xie, chenglong; schenkel, joseph a.; wu, chenkai; long, qian; cui, honghua; aman, yahyah; frank, johannes; liao, jing; zou, huachun; wang, ninie y.; wu, jing; liu, xiaoting; li, tao; fang, yuan; niu, zhangming; yang, guang; hong, jiangshui; wang, qian; chen, guobing; li, jun; chen, hou-zao; kang, lin; su, huanxing; gilmour, brian c.; zhu, xinqiang; jiang, hong; he, na; tao, jun; leng, sean xiao; tong, tanjun; woo, jean title: a research agenda for ageing in china in the 21st century (2nd edition): focusing on basic and translational research, long-term care, policy and social networks date: 2020-09-21 journal: ageing res rev doi: 10.1016/j.arr.2020.101174 sha: doc_id: 253182 cord_uid: s60vzf3q one of the key issues facing public healthcare is the global trend of an increasingly ageing society which continues to present policy makers and caregivers with formidable healthcare and socio-economic challenges. ageing is the primary contributor to a broad spectrum of chronic disorders all associated with a lower quality of life in the elderly. in 2019, the chinese population constituted 18 % of the world population, with 164.5 million chinese citizens aged 65 and above (65+), and 26 million aged 80 or above (80+). china has become an ageing society, and as it continues to age it will continue to exacerbate the burden borne by current family and public healthcare systems. major healthcare challenges involved with caring for the elderly in china include the management of chronic non-communicable diseases (cncds), physical frailty, neurodegenerative diseases, cardiovascular diseases, with emerging challenges such as providing sufficient dental care, combating the rising prevalence of sexually transmitted diseases among nursing home communities, providing support for increased incidences of immune diseases, and the growing necessity to provide palliative care for the elderly. at the governmental level, it is necessary to make long-term strategic plans to respond to the pressures of an ageing society, especially to establish a nationwide, affordable, annual health check system to facilitate early diagnosis and provide access to affordable treatments. china has begun work on several activities to address these issues including the recent completion of the of the ten-year health-care reform project, the implementation of the healthy china 2030 action plan, and the opening of the national clinical research center for geriatric disorders. there are also societal challenges, namely the shift from an extended family system in which the younger provide home care for their elderly family members, to the current trend in which young people are increasingly migrating towards major cities for work, increasing reliance on nursing homes to compensate, especially following the outcomes of the ‘one child policy’ and the ‘empty-nest elderly’ phenomenon. at the individual level, it is important to provide avenues for people to seek and improve their own knowledge of health and disease, to encourage them to seek medical check-ups to prevent/manage illness, and to find ways to promote modifiable health-related behaviors (social activity, exercise, healthy diets, reasonable diet supplements) to enable healthier, happier, longer, and more productive lives in the elderly. finally, at the technological or treatment level, there is a focus on modern technologies to counteract the negative effects of ageing. researchers are striving to produce drugs that can mimic the effects of ‘exercising more, eating less’, while other anti-ageing molecules from molecular gerontologists could help to improve ‘healthspan’ in the elderly. machine learning, ‘big data’, and other novel technologies can also be used to monitor disease patterns at the population level and may be used to inform policy design in the future. collectively, synergies across disciplines on policies, geriatric care, drug development, personal awareness, the use of big data, machine learning and personalized medicine will transform china into a country that enables the most for its elderly, maximizing and celebrating their longevity in the coming decades. this is the 2nd edition of the review paper (fang ef et al., ageing re. rev. 2015). the research agenda in response to rapid population ageing in china has been broad, covering areas including the study of the ageing process itself in laboratory and animal studies, to clinical-level studies of drugs or other treatments for common chronic diseases, and finally policy-level research for the care of the elderly in hospital, community and residential care settings, and its influence on health and social care policies . chinese population statistics taken between 1950-2050 show a reduction in crude death rate (cdr) and total fertility rate (tfr), accompanied by an increase in life expectancy at birth and an expansion of the population aged 65 and above (65+, termed the elderly) (fig. 1a) . as of 2019, the population of mainland china constitutes 18% of global total, with 164.5 million chinese citizens aged 65+, 26 million of whom are 80+. by 2050, it is expected that there will be 1.4 billion chinese, with 365 million aged 65+, a number representing 26.1% of the country's total population (fig. 1b) . furthermore, among this ageing population, 115 million are expected to reach an age of at least 80 and 0.6 million are expected to become centenarians (fig. 1b) . when compared with their counterparts born a decade earlier, the current 80+ generation has reduced annual mortality and disability rates, but has increased cognitive impairment and reduced objective physical performance capacity (zeng et al., 2017b) . to achieve what may be considered a 'healthy ageing society', it is first important to address and prepare for the challenges and issues that are associated with rapidly ageing populations. ageing is the primary driver of most, if not all, chronic diseases, including cancer, cardiovascular diseases, diabetes, and neurodegenerative diseases, particularly alzheimer's disease (ad) and parkinson's disease (pd) (kerr et al., 2017; lautrup et al., 2019; lopez-otin et al., 2013) . the most predominant diseases affecting the elderly in china (65+, data from 2017) include sensory diseases, other non-communicable diseases, digestive diseases, respiratory infections and tuberculosis, skin and subcutaneous diseases, neurological diseases, and musculoskeletal disorders, among others (fig. 1c) . from 1990 to 2017, there were dramatic increases in prevalence of all 21 diseases, excluding a very minor reduction in 'neglected tropical diseases and malaria' (fig. 1c) . the major diseases responsible for death of the elderly in china are cardiovascular diseases, neoplasms, chronic respiratory diseases, and neurological diseases, among others (figs. 1d and 2). compared to their younger counterparts, the elderly population are more fragile, and susceptible to conditions such as cardiovascular diseases, chronic respiratory diseases, diabetes, kidney diseases, unintentional injuries, hiv/aids and sexually transmitted diseases (stds), among others (fig. 2b ). in comparison with data from 1990, new patterns of disease mortality characterize the modern elderly, such as a dramatic reduction in the percentage of death contributed by 'neurological disorders' with an increase in deaths due to hiv/aids and stds (fig. 2b, d) . recognition of the current disease demographics in the elderly in china, and accurate prediction of future trends will enable us to be best prepared for different healthcare needs at different times. in wake of the expanding ageing society in china, and the formidable socio-economic and healthcare challenges, we offer the 2 nd edition of our previously published review . here, we aim to provide an update regarding the situation of the elderly in china using a range of expertise and suggestions from multiple fields which may further propel the exciting and ongoing reforms to china's healthcare system. we hope to explore different ageing care models that can be used to best produce a healthy ageing society (chen, 2009; yip et al., 2019; zhan et al., 2019) . the following sections highlight recent developments in the above areas as well as areas for future research. based on ageing phenotypes and the major disease demographics in the elderly in china (figs. 1 and 2), we chose to focus on frailty (including sarcopenia as an independent subsection), cncds (including cardiovascular disease as an independent subsection), mental health disorders, dental health challenges, elderly infections and immune diseases, as well as hiv, syphilis, and other stds. in view of recent reviews on other grand challenges, including cancer tsoi et al., 2017) , chronic respiratory diseases (zhu et al., 2018) , diabetes and kidney diseases (hu and jia, 2018; wei et al., 2019) , these areas will not explored here. frailty is a biologic syndrome characterized by deteriorating function across a broad spectrum of physiological symptoms (fried et al., 2001) . it can be thought of as a state of vulnerability. some have proposed an index approach to categorize different degrees of frailty; however, these attempts are complicated by the multidimensionality of the underlying causes of frailty, thus creating a dynamic, ever-changing value that is difficult to index (rockwood et al., 2006) . the term physical frailty has been applied to age-related loss of muscle mass and function, that is sarcopenia (detailed in the next section). in recent years, frailty research has increased rapidly in china as a strategy to prevent disability in response to an ageing population (chhetri et al., 2019) . research projects were showcased in the following scientific conferences: the 1 st and 2 nd international china conference on frailty in china, jointly organized by the who collaborating centre on frailty, clinical research and geriatric training at the gerontopole, toulouse, france, the chinese embassy in paris, and the national clinical centre for geriatric diseases, china, and the 4 th asian conference for frailty and sarcopenia in dalian in october 2018, organized by the chinese geriatrics society, beijing institute of geriatrics and gerontology and the chinese health promotion foundation. wide-ranging topics included basic science, epidemiology, definitions and measurements, management, as well as service models. such conferences greatly accelerate basic and clinical research on as well as clinical treatment for frailty. frailty may be used as a population indicator of ageing, and be a useful indicator of a need for treatment. research into prevalence, risk factors, prevention, and incorporation into service delivery models in community, hospital and residential care settings are an important part of the ageing research agenda for china. the importance of recognizing frailty in communitydwelling older people in china has been highlighted in a systematic review and meta-analysis by he et al. (he et al., 2019a) . risk factors for a worsening in frailty among community-living older adults include hospitalizations, older age, previous stroke, lower cognitive function, diabetes and osteoarthritis, while higher socioeconomic status and neighborhood green space were protective factors (lee et al., 2014; yu et al., 2018c) . a comparison of prevalence and incidence of frailty between populations may stimulate further research into prevention strategies and inform government policies. using data from a nationally representative study, wu et al. found that 7% of community-dwelling adults aged 60 years or above were frail in mainland china and the prevalence increased dramatically with age, reaching 32.5% for those aged 85 years or above ). substantial regional disparities exist in the prevalence as well as incidence of frailty in mainland china. for example, the incidence rate of frailty in the northeast was more than double than that in the southeast . furthermore, a comparison of frailty and its contributory factors across three chinese populations (hong kong, urban and rural populations of taiwan) using the ratio of frailty index (fi) to life expectancy (le) as an indicator of compression of morbidity showed higher fi/le in taiwan compared with hong kong. risk factors include low physical activity and living alone . the importance of protein intake to slow the decline in muscle mass and physical function over four years supports the importance of nutrition as an underlying factor for physical frailty .the role of inflammatory cytokines in the pathophysiology of sarcopenia is supported by the finding of slower decline in grip strength for those in the highest quartile of telomere length (woo et al., 2014b) . simple tools for frailty and sarcopenia may be used in a community setting as case finding, without the need for professionally trained personnel (woo et al., 2014a; woo et al., 2015b) . this may represent the first step in the approach to community-based intervention such as group exercises with or without nutritional supplementation for frailty and sarcopenia (yu et al., in press; . how community services may be developed to make frailty as a cornerstone of health and social care systems (woo, 2018) depends on the development of existing community infrastructures. two examples have been described previously: the tai po cadenza hub, and the jockey club e health project, where screening data based on the who integrated care for older people toolkit (who) were collected via ipad, followed by action algorithms for items where action is indicated: e.g., frailty, sarcopenia. this model emphasizes the empowerment of older people and their care-givers, societal-level behavioral changes, and the use of technology in the absence of a low cost primary care system orientated to meeting the needs of older people (woo, 2019) . in the hospital setting, detection of frailty may inform choice of therapies and prognosis, such as mortality and hospitalization in chronic heart failure . closely related to the concept of frailty, sarcopenia is an age-related gradual loss of mass and strength of skeletal muscles resulting in reduced physical performance. major pathological features include a loss of satellite cells and motor neurons, as well as less active neuromuscular junctions (cruz-jentoft et al., 2010) . following the publication of the european consensus group on sarcopenia (cruz-jentoft et al., 2019; cruz-jentoft et al., 2014) , an asian group including chinese researchers formed a panel to arrive at a consensus on the definition of sarcopenia, published in 2014 , and recently updated in 2019. the asian criteria differed from the european consensus definitions. an individual international statistical classification of diseases and related health problems code (m62.84) was assigned to 'sarcopenia' which has stimulated both diagnostic and therapeutic trials worldwide. in china, sarcopenia diagnosis requires some special considerations, including anthropometric and cultural differences. the 2019 guideline of asia working group of sarcopenia (awgs) provides updated guidelines on epidemiology, case-finding, the diagnostic algorithm, measurements of muscle mass, muscle strength and physical performance, and intervention and treatment. the prevalence of sarcopenia is estimated to be between 7.3-12.0% among the general older population and was over 25% in the oldest populations (85+) wang et al., 2018a; woo et al., 2015a; xu et al., 2020, in press; yu et al., 2014) . while old age is the primary risk factor for sarcopenia, other risk factors in the chinese population include household status, lifestyle, physical inactivity, poor nutritional and dental status, and some diseases (osteoporosis, metabolic diseases, etc.). in terms of longer-term clinical outcomes, awgs-defined sarcopenia was significantly associated with increased risks of physical limitations at 4 years, slowness at 7 years, and 10-year mortality, but not of hospitalization wang et al., 2018a; woo et al., 2015a; yu et al., 2014) . interventional strategies for the elderly of china have been the subject of recent research. for instance, an intervention for community-dwelling older adults yielded significant improvements in muscle function based on which when protein was offered as an oral nutritional supplement in combination with resistance exercises (kang et al., 2019) . similar findings were reported in j o u r n a l p r e -p r o o f major behavioral risk factors that are responsible for cncds are prevalent among the elderly in china. nearly 80% of deaths are attributable to unhealthy diet, high blood pressure, smoking, high glucose, air pollution (indoor and outdoor), and physical inactivity (who, 2014) . in china, 56.6% of adults aged 60+ have insufficient dietary balance (daily intake of <400g fruit and vegetables), 22.4% are current smokers, 45% use unclean fuel for cooking, 84% are physically inactive, and 11.4% have harmful alcohol use (who, 2012) . risk factors for major cncds, particularly smoking and alcohol use, are unevenly distributed among older men and women. the prevalence of cigarette smoking is substantially higher among men (41.5%) than women (4.3%). the prevalence of harmful alcohol use among men is more than three times as much as that among women (13.3% vs. 4%). substantial rural-urban disparities in the distribution of risk factors exist among older chinese adults. rural residents have a higher prevalence of smoking (23.7% vs. 19.9%), harmful alcohol use (13.3% vs. 7.5%), insufficient dietary intake (60% vs. 49.5%), and unclean fuel use (89% vs. 7.1%) than those in urban areas, while residents of urban areas have a substantially higher prevalence of physical inactivity than their rural counterparts. 2016, cvd was ranked first in mortality rates, higher than the mortality rates attributed to tumors and other prevalent diseases. studies have shown that in 2013, age-standardized cvd mortality in china was 21% lower than in 1990 (gbd, 2015; zhou et al., 2019) . although the age-standardized cvd mortality rate has declined, the absolute number of cvd deaths is still rising rapidly, and increased by 46% between 1990 and 2013. cvd is a large burden for the chinese healthcare system. with the development of medical technology, and the government's focus on chronic disease management, the problem of cvd in china has improved. however, due to the problems arising from population ageing, cvd still has a great impact on national health. major factors for cvd include hypertension, dyslipidemia, diabetes, air pollution, and excess weight (overweight and obesity). some risk factors are specific to china compared to other countries, however, this is changing as china's economy develops and the population ages. hypertension is an important public health problem in china. the prevalence of hypertension in china among those over the age of 18 is 23.2%, and the number of patients with hypertension in china is estimated to be 245 million . in 2013, 2.5 million deaths were attributed to hypertension in china, accounting for 27.5% of all causes of death (trammell et al., 2016) . with the rapid development of the economy and the ageing population, problems with blood lipid levels in china have gradually increased, and the prevalence of dyslipidemia has increased significantly. the main symptoms of dyslipidemia seen in china are low levels of low-density lipoprotein cholesterol (ldl-c) and hypertriglyceridemia (pan et al., 2016) , while dyslipidemia in the west is characterized by hypercholesterolemia and high levels of ldl-c (toth et al., 2012) . with the change of lifestyle following china's economic development, the number of chinese diabetic patients is growing. overall, 47% of adults in china have diabetes or pre-diabetes, which is slightly lower than the 49-52% in the united states . in recent years, there has been a significant increase in the prevalence of excess weight (bmi: 24.0-27.9kg/m 2 ) and obesity (bmi≥28.0 kg/m 2 ) in chinese residents, as noted over a five-year study period (he et al., 2017b) . the prevalence of combined overweight and obesity among men was 33.8%. air pollution is another important factor leading to cvd. among different particles, pm2.5 (an aerodynamic diameter of 2.5 μm or less ) is most closely related to cvd (brook et al., 2010) . a follow-up study of cohorts of elderly people 65+ in hong kong showed that for every 10 μg /m 3 increase in pm2.5 concentration, the risk of total cvd death increased by 22% (wong et al., 2015) . air pollution is also associated with increased blood pressure. for each 10 μg/m 3 increase in pm2.5 concentration, the per capita systolic blood pressure level increased by 1.30 mmhg, the per capita diastolic blood pressure level increased by 1.04 mmhg, and the risk of hypertension increases by 14% . coronary heart disease, atrial fibrillation (af), heart failure, and atherosclerosis are common forms of cvd. technological developments have allowed for an increase in treatment options and testing methods, including percutaneous coronary intervention (pci), radiofrequency ablation, implantable cardiac defibrillator (icd) and pacemaker implantation. since elderly patients are often associated with more complications, treatment decisions for cvd in elderly patients need to be adjusted individually based on an overall scoring of health. coronary heart disease is a common fatal cvd. for the treatment of coronary heart disease, the number of pci cases has steadily increased in china (zhao et al., 2018b) . the creative study explored antiplatelet treatment options for patients after pci in china, and studies have shown that for patients with low response to antiplatelet drugs after pci, a triple antiplatelet intensive therapy combined with cilostazol is safe and effective (tang et al., 2018) . bleeding events should be paid special attention when administrating dual antiplatelet treatment to acs patients aged 75 and older receiving pci (zhao et al., 2018a) . the risk of all-cause, cardiovascular, and stroke deaths in patients with af is significantly higher than in patients with sinus rhythm . the proportion of chinese patients receiving anticoagulation treatments is low. only 12.7% of patients with af and a chads2 score of 2 or more received anticoagulation treatment . patients with af aged 75+ tend to higher chads2 scores but receive less anticoagulation therapy. the risk of one-year follow-up deaths and adverse events in the elderly is more than doubled compared to other populations yang et al., 2014) . cases of af ablation procedures and icd implantation have steadily increased in china. however, european danish studies suggest that primary prevention through icd implantation has limited benefits in elderly patients with non-ischemic cardiac diseases (kober et al., 2016) . therefore, it is necessary to pay attention to the indications when expanding the population eligible for icd implantation in china. in recent years, the etiology of heart failure in china has changed significantly. the proportion of valvular disease (especially rheumatic valvular disease) has decreased. as china is becoming an ageing society, the number of elderly patients with heart failure has increased. at present, most studies suggest that coronary heart disease is a common cause of heart failure in the elderly, and the proportion of hypertension and pulmonary heart disease in elderly patients with heart failure increases with age. in recent years, the use of diuretics in hospitalized heart failure patients in china has not changed significantly, while the usage rate of digoxin has shown a downward trend. the use of acei, arb, aldosterone receptor antagonists and beta-blockers have shown a significant upward trend . lower extremity atherosclerotic disease (lead) is a common disease in the elderly and an important starting point for systemic atherosclerosis. early detection of lead is of great value in the diagnosis and treatment of systemic atherosclerosis (hiramoto et al., 2018) . to reduce the burden of cvd in china, we recommend interventions directed at altering lifestyles and programs dedicated to the detection and management of risk factors, especially for elderly people. research modeling has shown that if dyslipidemia and hypertension are effectively managed, medical expenses to the tone of $932 billion us from 2016-2030 (stevens et al., 2016) . controlling blood lipids and blood pressure of elderly people over 65 years of age represents the most cost-effective strategy (stevens et al., 2016) . mental health disorders, particularly dementia and depression, are major diseases in the elderly of china. alzheimer's disease international (adi) estimates that over 50 million people worldwide were living with dementia in 2019, and that this figure will rise to 152 million by 2050; the current annual cost of dementia is estimated at 1 trillion us dollars which will be doubled by 2030 (adi, 2019). it is estimated that the number of patients with dementia in china constitutes 25% of the dementia population worldwide, with the prevalence of dementia ranging from 5.14% (95% ci 4.71-5.57, in 2014) to 5.60% (95% ci 3.50-7.60, in 2019) for individuals aged 65+ jia et al., 2014; jia et al., 2020) . the patterns and spread of dementia in china vary geographically and between genders. women are 1.65 times more susceptible than men. western china has a higher prevalence at 7.2%, while central and northern china are lower at 5.2 and 5.5%, respectively, southern china has the lowest prevalence at 4.8%, this variation is possibly due to a variety of reasons including diet, exercise, social networks, healthcare, etc. (chan et al., 2013; jia et al., 2020; wu et al., 2018b) . the incidence of dementia in individuals aged 65+ ranged from 17.7 to 24.0 per 1000 person-years using 10/66 dementia research group criteria, while it was 12.14 per 1000 person-years using dsm-iv criteria (jia et al., 2020; prince et al., 2012; yuan et al., 2016) . while health conditions such as depression, diabetes mellitus, and insomnia correlate with dementia in a global fashion, epidemiological evidence from different regions in china also suggests smoking and heavy alcohol consumption as high risk factors (fan et al., 2019; pei et al., 2014; xue et al., 2019) . depression, a risk factor for dementia, is a common but often neglected disease in the elderly in china . data from a cross-sectional study suggest a prevalence of depression of 39% in the elderly which increases to 45% in the most elderly (yu et al., 2012) . in view of the stigma of mental illness in some areas of china coupled with inadequate health services in rural areas, depression is likely underdiagnosed suggesting the real prevalence may be higher. in addition to its contribution to dementia, depression aggravates the quality of life of the elderly and of their family members, brings the risk of death caused by different reasons, and accordingly is a heavy burden on the society and the healthcare system (zhang and li, 2011) . much effort should be made to address mental health disorders in china, including increasing government investment, the training of more geriatric care professionals with specialties in mental disorders, and raising public awareness, especially in conjunction with more active social activities and exercises. although there have been increased care facilities for citizens 65+ and improved access to health services, the diagnosis and management of dementia and depression are still inadequate, especially in rural areas (jia et al., 2020) . the inclusion of steps to manage dementia in the 13 th five-year plan of the central chinese government marked a major step forwards, and such efforts need to be continued. in view of the insufficiency of medical professionals in regards to mental disorders, especially in rural areas, we recommend increased training to such professionals, and the development of policies to encourage health professionals to work (at least for a short period) in rural areas . in recent years, the public awareness of mental disorders, especially ad, has greatly improved thanks to efforts from social media (e.g., drama shows on ad) and dementia organizations. professional interventions, comprising medicine and combined cognitivepsychological-physical intervention (e.g., family and community support plus playing mahjong and practicing taichi) can mitigate subclinical depression and improve overall mental health (kong et al., 2019; wang et al., 2019c; wong et al., 2014) . although no drug at present is available to cure ad, recent progress on the understanding of ad etiology, such as the involvement of impaired mitophagy and reduced grid-cell-like representations in the human ad brain, along with the development of novel stem cell models, and the use of artificial intelligence (ai), will undoubtedly propel the development of novel drugs (fang, 2019; fang et al., 2019; gilmour et al., 2020; kunz et al., 2015; lin et al., 2018) . the china brain project, covering studies on basic neuroscience, brain diseases, and brain-inspired computing, will greatly benefit the development of novel drugs for different neurological diseases (poo et al., 2016) . while oral health is an important part of the whole body, the prevalence of oral disease is high in the elderly in china, but is largely ignored, while here we focus on dental health. dental caries (tooth decay), periodontal disease and tooth loss in the elderly are issues of global health concern. the burden on healthcare cost and the quality of life of these dental diseases in the elderly remain high . maintaining good dental health is an integral part of healthy ageing. as such, developing effective preventive and therapeutic interventions are needed to protect and enhance dental health and well-being tonetti et al., 2017) . dental caries and periodontal diseases are common oral diseases in the elderly and often lead to tooth loss, edentulism (toothlessness), impaired masticatory function and poor nutrition. according to the 4 th national oral health epidemiological survey (fnohes, 2015 (fnohes, -2016 covering the whole of mainland china, caries and periodontal diseases are highly prevalent in the elderly in china; while the prevalence of caries was above 50% in all age groups (3-5, 12-15, 35-44, 55-64, and 65-74 years) , the rate was 98% in the 65-74 years groups (lu et al., 2018; si et al., 2019) . in adults aged 65-74 years, 90.7% had periodontal diseases, including gingival bleeding (82.6%), dental calculus (90.3%) and a deep periodontal pocket (14.7%) (lu et al., 2018; si et al., 2019) . human oral tissues naturally and gradually degrade with age; a fact also exacerbated by modern lifestyle choices, including the prevalence of sugary diets and a lack of oral hygiene (belibasakis, 2018; lamster et al., 2016) . more specifically, age-dependent changes include a reduction in periodontal support, loss of elastic fibers, and thickening and disorganization of collagen bundles in the connective tissue of the oral mucosa (belibasakis, 2018; lamster et al., 2016; wu et al., 2016b) . severe dental health challenges can cause loss of self-esteem, social difficulties, while also being drivers of common diseases, such as ad, pd, diabetes, and hypertension (belibasakis, 2018; bollero et al., 2017; dominy et al., 2019; lamster et al., 2016) . major risk factors of the high prevalence of dental diseases in the elderly in china include the scarcity of dental health knowledge in the general population, low frequency of daily oral hygiene practices, insufficiency of dental care services, and unhealthy diet habits. daily oral hygiene practices are effective for removing plaque and preventing gingivitis. the average awareness rate of dental health in the chinese elderly was 47.6%, only 30.1% of the elderly brush their teeth twice daily, and a mere 0.8% used dental floss (lu et al., 2018; si et al., 2019; . increased attention to the dental health needs of an ageing population urgently requires combined efforts by relevant stakeholders (lu et al., 2018; si et al., 2019; tonetti et al., 2017; . specifically in the case of older adults, knowledge and competence in oral care, awareness of medical comorbidities and of medications relevant to oral care should all be strengthened. epidemiological surveillance and monitoring of oral diseases and oral healthrelated quality of life in the elderly is needed. oral self-care, access to treatments and preventive services and assuring the affordability of dental care are critical for oral health. looking after teeth and gums by brushing twice a day with fluoride toothpaste and cleaning with dental floss are effective in achieving a good oral health status. likewise, the control of risk factors, such as refraining from the frequent consumption of foods and drink high in sugar, and refraining from smoking, are also important. provisions to expand services to older adults, to meet increasing oral healthcare needs in the ageing population, and to ensure the affordability of dental care should all be emphasized by policymakers. we suggest programmes that promote general oral health education as well as public outreach programmes directed towards the elderly via understandable brochures, and the use of television and other social medias. additionally, it is important to improve the country's dental care infrastructure by training more dentists and oral specialists and ensuring the provision of affordable dental healthcare. it has been well documented that altered immune system components and function are characteristic of ageing and form part of the causes of age-related diseases (nikolich-zugich, 2018) . in ageing, a significant decline in the homeostatic, defensive, and surveillance functions of the immune system is noted. prominent features of the ageing immune system include thymus involution, a decrease in naïve lymphocytes, and an accumulation of memory and senescent lymphocytes; more recently, the concept of 'inflammageing' has been developed (ferrucci and fabbri, 2018) . functionally, impaired immune defense, especially against new antigens for which no memory exists, makes older adults increasingly vulnerable to incident and more severe infections. in addition, a decline in immune surveillance hampers the elimination of premalignant cells, leading to cancer development. older adults also manifest a chronic low-grade inflammatory phenotype (clip), a manifestation of the inflammageing concept, that likely results from uncompensated inhibitory immune regulation and/or an inability to eliminate senescent cells (chen and yung, 2019; chen et al., 2019b) . as such, immune dysregulation is a general feature of ageing. here we provide an update on infectious diseases in the elderly in china. we carried out a comprehensive review on infections in china based on the following public databases: the chinese center for disease control and prevention (ccdc), the data-center of china public health science (ccdc, 2019), and the national bureau of statistics of china (nbsc, 2019). the three most common infectious diseases in 2017 were viral hepatitis, pulmonary tuberculosis (tb) and syphilis (detailed in section 2.8) while the three with the highest mortality rate were aids, tb, and viral hepatitis ( fig. 3a-d) . of note, pulmonary tb was more prevalent than the other two in older adults over 65 years of age (fig. 3c ). generally speaking, infectious diseases are more frequent and deadly in older adults, as seen with the recent 2019-ncov epidemic worldwide huang et al., 2020) ; thus, infectious diseases deserve more attention. viral hepatitis is caused by the hepatitis viruses a, b, c, d, and e (hav, hbv, hcv, hdv, hev) and is prevalent throughout the world, posing a significant threat to human health. china is a highly epidemic area of viral hepatitis with 86.6 million people infected with hbv and 7.6 million infected with hcvas of (who, 2018 . in 2018, there were 1.28 million new cases and 531 deaths among the chinese population (nbsc, 2018) . according to the chinese statutory infectious disease report, viral hepatitis mainly occurred in adults between 20 to 65 years old (83.68%, fig. 3e ). its morbidity in older adults was estimated to be 13.52% in 2016 ( fig. 3e ). however, compared with the morbidity, the mortality of viral hepatitis was higher (28.31%) in the aged population ( fig. 3e ). from the survey, the morbidity and mortality rate of viral hepatitis have ranked in the top five for many years. the morbidity of viral hepatitis was stable in last decade, which is likely due to the wide usage of the hepatitis vaccine ( fig. 3g , h). however, the morbidity of hepatitis in the elderly continues to increase yearly. since most cases of viral hepatitis developed into chronic hepatitis, the lifespan extension seen in china has contributed to a higher number of elderly hepatitis cases. luckily, the mortality of hepatitis has declined in both the aged population and the population at large (fig. 3h ). among the five hepatitis viruses, hdv is rarely detected and is not discussed here. hcv (20.13%) and hev (22.6%) demonstrated high morbidity in the aged population (fig. 3f) . however, the highest mortality is caused by two acute types, hav (60%) and hev (66.7%) (fig. 3f) , indicating a weakened immune responses against acute infection in the elderly. significantly, both the morbidity and mortality of hbv in the aged population were lowest among the four types ( fig. 3f ), further indicating the benefit of the hbv vaccine. however, prophylactic vaccines for hcv and other types of viral hepatitis are still lacking. for patients who have been infected, current treatments are still limited, especially for the elderly patients. one of the reasons for this is the lack of a long-term infection model for use in laboratory conditions (winer et al., 2017) . developing an elderly-representative model would be a useful tool for screening treatment options for those affected by hepatitis diseases. mycobacterium tuberculosis and is typically transmitted through coughs and sneezes. the lack of global tb control is the result of several factors, including hiv coinfection, limited vaccine efficacy, a lack of highly specific and sensitive diagnostic tests, and the rise of multidrug-resistant (mdr) and extensively drug-resistant (xdr) tb strains (venketaraman et al., 2015) . according to the who's 2019 global tuberculosis report, china is ranked third in terms of tb burden when compared with other countries (who, 2019a). pulmonary tuberculosis (p-tb) is the second highest ranked cause of morbidity and mortality among the 28 infectious diseases ranked in 2017 (fig. 3a, b) . however, it is the most frequent infectious disease in the elderly (fig. 3c ). the elderly occupied more than half (54.9%) of all deaths from p-tb (fig. 3e ). in the last decade, the incidence of p-tb has decreased year to year, however, the incidence and mortality rates of p-tb in the elderly remains high in china (fig. 3g , f). there are several reasons for the high incidence and mortality rates of p-tb in the elderly: i) an increasingly ageing population; ii) immune decline; iii) delay of diagnosis and treatment. with the increase of the number of elderly patients, p-tb is rapidly becoming a new public health challenge. several risk factors, such as immune decline, smoking, malnutrition, hiv infection and other chronic diseases, make the elderly susceptible to tb . compared with p-tb in the young, p-tb in the elderly has its own characteristics. elderly patients with p-tb are more contagious than the young, and elderly men are more likely to suffer from tuberculosis than elderly women (lee et al., 2017) . in the elderly, early symptoms of tb are atypical and insidious, and can result in misdiagnosis (rajagopalan, 2001) . furthermore, chronic fibrous cavitation and hematogenous disseminated tb are more common in the elderly population. most elderly patients with p-tb get tb in their youth at which time it is better controlled but, as they age, p-tb can result as immune function declines. moreover, elderly tb patients usually present with several complications, which further complicates diagnosis and treatment (nagu et al., 2017) . all these characteristics have brought special focus on the treatment and diagnosis of tb in the elderly. at present, there are several tb guidelines for high-risk groups (who, 2016b), but few for the elderly. previous studies in the elderly have also focused less on the evaluation of targeted strategies for control and prevention. thus it is necessary to pay more attention in the future to the production of control programs and evaluation of targeted interventions for tb in the elderly. aids is a chronic, potentially life-threatening infectious disease caused by hiv, which was first detected in the united states in 1983 ( barré-sinoussi et al., 1983) . in the last decade, the morbidity and mortality of hiv/aids has increased yearly ( fig. 3g, h) , and it has become the top cause of death by infectious disease in china, including in the elderly (fig. 3b, d) . the morbidity and mortality of hiv/aids in the elderly population is also rising significantly, and notably the mortality in the elderly is much higher than that seen in the young (ccdc, 2016). furthermore, because elderly people have many basic diseases and low awareness of selftesting after hiv infection, the elderly are more likely to already be aids patient at the time of diagnosis of their hiv infection (xing et al., 2014) . a study has shown that 35.5% of newly diagnosed elderly hiv infectors had already developed into the aids stage (liu et al., 2012) . with increasing use and efficacy of antiretroviral therapy for hiv infection, the lifespan of hiv/aids patients has been greatly extended, and more and more hiv/aids patients will enter old age (nizami et al., 2019) . the problem of hiv/aids in the elderly will become increasingly serious in the future. firstly, hiv infection is not commonly checked in the elderly in china upon visit to the hospital, which may lead to uncontrolled disease progression and infection to others. second, the treatment of aged hiv/aids patients may cause more adverse effects, such as cardiovascular disease (hanna et al., 2016; kramer et al., 2009) , ad (brousseau et al., 2009) , and diabetes (guaraldi et al., 2018) . furthermore, cognitive disorders, loneliness, shame and depression may increase the likelihood that they fail to follow their drug regimen, or refuse treatment altogether (greene et al., 2018; vincent et al., 2017) . interestingly, hiv infection is also likely a driver of early ageing, as aids patients age more rapidly than the general healthy population (he et al., 2019b; lin et al., 2019) . to address these problems, the diagnostic process in the aged population should be addressed more cautiously; therapeutic drugs and technologies suitable for the elderly patients should be developed. special attention should also be paid to psychological problems of elderly patients. the hiv epidemic as a sexually transmitted disease will be discussed further below. influenza is an acute viral infection caused by the influenza virus. at present, a total of four types of influenza viruses have been identified, including influenza a, b, c, and d (iav, ibv, icv and idv) (petrova and russell, 2018) . among them, only iav and ibv are able to cause seasonal epidemics and clinical disease. yearly, the extent of the influenza pandemic varies around the world, which causes high morbidity and mortality. because elderly individuals above 65 years of age are immunocompromised and may have preexisting conditions, they are more susceptible to influenza infection and its complications. data accumulated in the last decade showed that the morbidity of influenza has increased in both the general and aged populations (fig. 3g ). like other acute infections, the mortality of influenza in aged patients was higher than in younger population (fig. 3h ). during january 1, 2018 to september 28, 2019, a total of 1626 severe influenza cases were reported in hong kong, among which 1058 patients (65.07%) were over 65 years old (chp, 2019b). in 2018, a total of 5984 influenza cases were reported in macau, among which there were 188 cases were over 65 years (hbgm, 2019a) . however, only a small number of influenza cases acquires laboratory confirmation, as patients usually die of other related illnesses brought on by influenza. thus, the influenza-related mortality rate is greatly underestimated. in 2012, the ccdc estimated that the death rate caused by influenza was 18/100000 in northern china and 11.3/100000 in southern china, and most of the deaths occurred among people aged over 65 years (77.8% in southern cities and 69.6% in the northern) (feng et al., 2012) . the excess mortality of respiratory and circulatory diseases caused by influenza was 12.4/100000 and 8.8/100000, respectively, among which 86% occurred in people aged over 65 years (feng et al., 2012) . pneumonia is an acute respiratory infection that affects the lungs, which is especially deadly in children under 5 years and in the elderly (65+). pneumonia has become one of the major causes of death for the elderly over 65 years. the harm and mortality of pneumonia increases with age. the "2018 china health statistics yearbook" reported that the mortality rate (/100000) of urban residents aged 65-69, 70-74, 75-79, 80-84, and over 85 with pneumonia was 19.63, 34.48, 68.38, 219.07 and 865.53, respectively; and that of rural residents was 11.62, 23. 67, 48.61, 127.90 and 445.93, respectively (nbsc, 2018) . since 2003, pneumonia has been one of the top three causes of death in hong kong (chp, 2019a) . according to statists by the hong kong centre for health protection, the mortality rate of pneumonia was 39/100000 in 2017, with a total of 8032 pneumonia-related deaths. of these cases, 94.68% occurred in people aged over 65 years (chp, 2019c) . in macau, pneumonia also has been cited as one of the top three causes of death for many years (hbgm, 2019b). in summary, old age is known to affect the immune system negatively. immunocompromised elderly adults are more susceptible to common diseases such as influenza and pneumonia, both of which were responsible for many deaths in this age group. in some cases, these infections may lead to complications that then lead to death, and this likely contributes to underreporting, hiding the true effects of influenza and pneumonia. there are multiple methods for improving and maintaining healthy immune function in the elderly: physical activity and exercise are known to enhance the immune system, however effective ranges still need to be established and disseminated (venjatraman and fernandes, 1997) . additionally, the development of vaccines must be prioritized, although challenges exist such as finding suitable mass production methods. perhaps surprisingly, sexually transmitted diseases (stds) are becoming an increasing problem among older age groups. many people aged 50 years or older in china remain sexually active, and the shift towards nursing homes has led to an increase in exposure to possible sexual partners (yang and yan, 2016) . unfortunately, many older adults do not take precautions in their sex life, due to reasons such as a decreased worry about pregnancy (tht_uk, 2018) . high-risk sexual behaviors render them vulnerable to the transmission of hiv and other sexually transmitted diseases (stds), likewise low awareness of the potential risks and low use of sexual health services can result in late diagnosis and treatment of stds among older adults. we here describe the current situation of hiv/aids and other stds in older adults in china, and propose potential preventative measures. as mentioned before the incidence and proportion of older adults in the total number of reported hiv/aids cases is on the rise in china (fig. 3a-d) . the rise in both the number of absolute cases and the proportion of std infections was observed in both genders. the vast majority of cases in older adults resulted from heterosexual copulation, and has brought about an alarming increase in the rate of new infections. for example, in chongqing, the proportion of hiv infections reported in those aged 50 years and older increased dramatically from 27 to 58.4% between 2011 and 2019 (chinanews, 2019)at the same time, the overall number of male cases quadrupled, and the female cases tripled between 2012-2018 (wu, 2019) . among women newly diagnosed with hiv in china between 2010-2016, the proportion of those aged 50 years and older increased from 17.8% in 2010 (2 959/16 603) to 38.1% in 2016 (9 981/26 196) . this proportion is even higher in regions with larger rural populations. in guangxi, 46% of newly reported hiv cases in 2014 were men aged 50+ (hu et al., 2019a) . in addition to the increase in newly reported infection among older adults, people infected with hiv can now survive to an older age, increasing the proportion of advanced-age hiv cases. in addition to hiv other stds are increasing in prevalence among the elderly in china. from 2000 to 2013, the incidence of syphilis in people over 60 years of age increased by over 30%. the proportion of people aged 60 years and older among all syphilis cases was also on the rise, from 8.5% in 2004 to 22.0% in 2013 . between 2008-2016, the incidence of condyloma acuminate in china showed a downward trend, with an average annual decline of 2.2%. however, the incidence rate among people aged 50 and over increased by 4.8% annually (yue et al., 2017) . gonorrhea is not common in the elderly, and china saw an average annual decline of 7.9% in the incidence of gonorrhea. this trend was also seen in older adults (4.5%-10.9%) (gong et al., 2015) . this phenomenon may be related to the short incubation period of gonorrhea, the high self-medication rate of patients, the sensitivity of gonococcal bacteria to antibiotics, and the insignificant clinical symptoms of female patients (wang and ni, 2008) . there are several contributing factors behind hiv/stds transmission in older adults. ageing is associated with various physiological changes in the human body collectively known as frailty. however, physiological changes in sexual function often fail to attract societal attention. male sexual dysfunction and disorders often manifest in the slowing of penile erection, prolonged ejaculation, the dampening of sexual desire, impotence, etc. as women age, their vaginal tissue becomes thinner, drier, and less likely to become fertile. for the above reasons, the use of condoms in the elderly seems to be less important. older women may have less interest in or need for sexual intercourse; however, their male counterparts may continue to be sexually active for a long period of time. cravings for sex combined with loneliness may push men to resort to commercial sex to quench their desire for sex. in rural areas, the hiv prevalence is high among street-based female sex workers and female sex workers working at sex-on-premise venues with low quality of hygiene, such as hairdressing shops. use of condoms and other precautions in these scenarios is likely to be lacking . sexual education in older adults is nearly absent, and it is generally assumed that "age is a condom". embarrassment may discourage older adults from obtaining condoms and other precautions. in a survey in guangxi, although 87.9% of respondents were willing to accept condoms issued free of charge by healthcare services, 64.1% of the respondents were unwilling to take them of their own due to embarrassment (qi and pang, 2012) . despite the growing importance of sexual health among older adults, many of them do not seek health services for sexual problems. in china, data on sexual health in older adults are scarce. existing research focuses mostly on males (jiang, 2016) . few actions have been taken to accommodate older adults' sexual health needs in china. engaging older adults in health program development and policy changes is particularly challenging due to concurrent incidences of disability, frailty, and other comorbidities. conventional top-down strategies are often unappealing and less trusted by the target audience. innovative solutions are needed to develop contextualized sexual health services and ensure that they are inclusive, trusted, and reliable. collectively, hiv/stds are becoming an increasing problem in the elderly in china due to diminished precautions in their sex life, a lack of condom usage, and insufficient sexual education, among other issues. future research focuses should include a) routine sexual healthcare and screening for hiv/stds among older adults, especially those who have highrisk sexual behaviors; b) sexual health education and hiv/stds prevention among older adults; c) late diagnosis of hiv/stds among older adults; and d) healthcare providers' attitude on the sexual health of older adults. modifiable health-related behaviors (hrbs) are key contributors to chronic diseases and early mortality, such that by maintaining a vigorous lifestyle, the processes of frailty, disability, and dementia can be postponed or even prevented (lafortune et al., 2016; rizzuto and fratiglioni, 2014; who, 2019c) . similar public health recommendations for hrbs have been promoted worldwide, namely, refraining from smoking and excessive alcohol consumption, consuming a balanced diet, partaking in regular physical exercise, and maintaining frequent social engagements (who, 2015d ). an international comparison study revealed a large degree of consistency in hrb clustering across six nationally-representative ageing cohorts in the east and west, alongside considerable gender-and country-specific variations (liao et al., 2019b) . particularly, older chinese males were characterized by a much higher probability of being smokers (57%) than their counterparts in japan (28%), korea (38%), usa (17%), uk (15%), and in other european countries (21%~33%) (liao et al., 2019b) . comparable findings have been reported in the who's 2019 report on the global tobacco epidemic, which further indicates that the progress of smoking reduction tends to be noticeably slower in china than the global average (who, 2019d). nevertheless, positive developments of china's concerted tobacco control efforts, such as smoke-free public places, a strengthened ban on tobacco advertising, etc., should be acknowledged (li and galea, 2019) . these smoke-free movements have challenged and hope to gradually change social norms regarding smoking, though they may be less effective among older generations with poor health literacy (hu et al., 2016) . the implementation of the healthy china 2030 action plan provides an opportunity to increase tobacco control (li and galea, 2019) , as well as to address a range of risk factors via a population-based multi-sectoral approach (nhcprc, 2019a) . aiming to enhance the overall health of the chinese population, the plan prioritizes 15 major actions, including the promotion of health literacy, the improvement of nutrition, a new national exercise campaign, more tobacco control measures, the promotion of mental health and environmental health; and specific actions dedicated to four target populations (i.e. women and children, teenagers, older adults, and those undertaking special occupations) and five categories of diseases, i.e. cardiovascular and cerebrovascular diseases, cancer, respiratory diseases (e.g. copd), diabetes, and infectious diseases. besides health-related targets for the health promotion actions for older adults, the importance of building an elderly-friendly and engaging environment is highlighted, which embodies "ageing in place" with humane, equitable and sustainable health and social care resources. social engagement is a key determinant of active ageing (world health organization, 2002) , especially within china's collective cultural background (liao et al., 2019b; liao et al., 2020) . in tandem with physical exercise, social activities may generate health benefits not only for the body but also for the soul. chinese square dancing is a social group-based exercise performed to music in public squares or parks. this low-cost and easy-participation activity is highly popular among middle-aged and retired chinese women, estimated at 100 million participants in 2015 (fang, 2015) . square dancers can meet as often as every day, usually in the early morning or evening after dinner, and sometimes both, upon meeting they organize themselves into rank and file, and exercise for nearly two hours, led by the most proficient dancer (liao et al., 2019a) . as an aerobic exercise accompanied by a dance rhythm, square dancing mobilizes the participants' whole body, improving their balance and cardiopulmonary function (liu and guo, 2013) . it is also cognitively challenging, requiring participants to listen to and process the music, focus on movement and balance, and dance to the rhythm with coordinated body movements (kattenstroth et al., 2010) . moreover, square dancing creates a socially enriched environment for participants to interact with peers, keeping them socially engaged and dispelling loneliness (liao et al., 2019a; liao et al., 2020) . square dancing is a typical example of a grassroots group activity that may serve as inspiration for the design of culturally appropriate health promotion programs for older adults. one possibility is developing similar programs that can be implemented throughout the country, and possibly tailoring them to the local needs and/or cultures. in the past five years, central and local governments in china have made enormous efforts in establishing a multi-dimensional geriatric care system to support healthy ageing in chinese society. more than 30 national policies have been issued to drive the development of this care system, including cross-ministerial policy measures for promoting the growth of elderly services and the integrated development of medical, health and elderly care, through the guiding opinions on advancing the development of age-friendly livable environment (ndrc, 2016) , and the state council opinions on promoting the development of elderly care services (nhcprc, 2019b, c) . following the strategies of the national 5-year plan, provincial and municipal governments have all issued local implementation plans. in places such as shanghai, shandong, jiangsu, zhejiang and guangdong, political will has been accompanied by strong financial support (cnca, 2020). as compared to q3 2014, in q3 2019 there was an additional 2.4 million beds added in public and private nursing homes across china, resulting in a total national supply of 7.55 million beds (mcaprc, 2019a, b) . in 2018, the ministry of civil affairs allocated rmb 2.9 billion (usd 400 million) to support the local expansion of care beds in nursing homes as well as the development of community and home care services. in terms of service utilization, the occupancy rate of nursing home beds is at around 50%, i.e. at any time, there are less than 3.8 million residents in these facilities. 748,000 elderly benefited from nursing care subsidies while 5.22 million benefited from social care subsidies (mcaprc, 2019a, b) . in july 2016, the first national pilot of a long-term care insurance (ltci) program was announced in 15 cities across different regions of china (mhrssprc, 2016) . identification of elderly people with severe care dependency was carried out, and local models of financing care for them in nursing homes, community centers as well as at home were implemented. by june 2019 this pilot program covered a total of 88.54 million people, funding services for 426,000 beneficiaries at rmb 9,200 per year per person (nhsaprc, 2019). while geriatric care system development has attracted strong attention from stakeholders and become a major theme for policy, research and investment, the following challenges need to be understood and addressed before meaningful progress can be made to prepare the country for its rapid entrance into an ageing society. the first challenge is that care needs must be assessed comprehensively and should be subject to regular reassessment in order to develop personalized care plans and identify goals that are aligned among care recipients, providers and payers (who, 2017) . generally, there are currently two types of assessments in use in china: one conducted before admission into nursing homes, the other for entry into the ltci programs. the first type can be quite comprehensive but is often used to decide the charge levels associated with the care service. the second type uses a simple 6-item adl questionnaire and links its results to the funding schemes, e.g. maximum hours of care per month. as the assessment of care needs tends to be one-off and disconnected to care plans or goals (hua, 2019; ma, 2017) , it is difficult to allocate resources dynamically and to analyze care performance or economics. the second challenge involves problems with service capacity. on the one hand, 45% of nursing home beds are left unoccupied and, contrary to international best practice, for the beds that are occupied, only less than 20% are actually utilized by people with severe dependency; on the other hand, according to the national health commission, nearly 188 million seniors have chronic diseases, and 40 million have various levels of disabilities (nhcprc, 2019b, c) . among the over 40 million people with different degrees of care dependency and care needs, under 10% have been served by community and home, and the majority have yet to be cared for (mcaprc, 2019a, b) . some policies have been put in place to attempt to fill the huge gap in caregivers, stating that 10 million more caregivers are needed just to care for the existing group of dependent seniors. however, if the current mainstream model of "replacive care" is not changed, growing care service capacity will only lead to an accelerated rate of care dependency among the high-risk population. additionally, such a model of care is highly unattractive to potential workforce candidates. as a corrective move, the central government has now set a goal to train 2 million more caregivers by 2022 (mcaprc, 2019a, b) . the third challenge is distorted allocation of resources. up until the end of 2018, despite plans to establish a home care-dominant, community-backed and nursing home-supplemented system, investment has remained predominantly in heavy assets, i.e. the development of nursing homes as well as senior-living property projects, resulting in the above-mentioned "oversupply" of care beds (qiao, 2019) . since the 13 th five-year plan, the central government has committed to an annual funding of rmb 1 billion to support innovative pilots of home-or community-based care models (mcaprc, 2017 (mcaprc, -2019 . however, for many local governments, the first and foremost priority when developing local care capacity is to specify land for elderly care use and invest in care facilities construction before or while looking for operators of such facilities. in addition to resistance and reluctance from nursing homes and preexisting policymakers, difficulty in understanding senior population's care needs and evaluating care competency among community and home care providers have prevented financial support schemes from materializing in most parts of china. typical examples of the insufficient support for community and home care service development can be seen in the number of government purchase tenders that fell through without enough qualified bidders. while there is no lack of political will and resources to be invested in further developing the care system, there is an urgent need to pay for access and quality. a value-based resource allocation model focusing on improving population health rather than the current fee-for-service care model would provide china a rare opportunity to benefit from a healthily ageing society (gyurmey and kwiatkowski, 2019; mandal et al., 2017) . to address the above-mentioned challenges and seize the opportunity associated with them, pilots should be designed based on local evidence and should be established in four dimensions. firstly, development of care plans should be focused on individually centered goal based on comprehensive assessments. as highlighted in the latest who icope (integrated care for older persons) package, it is essential for countries and health systems to align the efforts of different stakeholders with a shared care plan that is customized to serve the individuals' priorities and goals. secondly, health and social care resources should be integrated to support the realization of personalized goals of care and, at the population level, to delay and reduce care dependency. rather than further developing passive care capacity to compensate for the increasing need for other fragmented services, devoting resources to the reaching of a consensus among care providers and receivers will serve to empower the population itself, and maximize the pooling of financial and human resources, decreasing the need for an expansion of passive services (who, 2019b). thirdly, the education and training of "integrated care managers" should be developed, whose job would be to work actively in primary care settings to identify care needs and coordinate care resources crucial to achieving societal and individual care goals. mobilizing talents with various backgrounds to understand and operate under the comprehensiveness of geriatric health needs, developing their capability to better communicate and coordinate care efforts across public and private sectors would not only facility the integration of various care services, but make the care work more attractive for those seeking long-term career opportunities (wang and song, 2019) . fourthly, a reform of the payment model used in elderly care services should be carried out, focusing on value rather than volume of care for populations at risk of care dependency. healthcare payments have long been moving from an inefficient, fragmented, fee-for-service model to a value-based capitation or bundled payment model. for geriatric care financing, this reform is likely to develop faster than the reform of payments for healthcare services. setting sustainable goals for care and allocating resources accordingly will be a viable realistic solution to caring for the millions of chinese citizens in need . we recognize the complexity of establishing such a health-oriented care system. for the four dimensions of an integrated care system to be aligned around common goals as discussed above, a pre-requisite should be the interconnectivity of data: linking results across personal health records, assessments of geriatric care needs, and total costs of care, including: social and commercial health insurance payment, out-of-pocket private payment, social welfare payment, as well as other sources of funding for elderly care (threapleton et al., 2017) . palliative care is emerging as a new alternative for hospitalized elderly with life-threatening illness. the who defines palliative care as the prevention and relief of suffering of adult and pediatric patients and their families facing the problems associated with life-threatening illness (including malignant and non-malignant diseases). these problems include physical, psychological, social and spiritual suffering of both patients and their family members the aim of palliative care is to enhance the quality of life, promote dignity and comfort, and may also positively influence the course of illness (who, 2016a). palliative care is the basic skill of medical staff in departments where medical care is provided to end-stage patients (e.g. icus, emergency rooms, geriatric and oncology departments) (ning, 2018) . the 2015 quality of death index survey showed that the death quality of mainland china ranked 71 st out of 80 countries, while taiwan and hong kong ranked 6 th and 22 nd , respectively (eiu, 2015) . while palliative care is widely available in western countries, it is limited in mainland china. according to a report in 2016, only 0.7% (146/22,000) of hospitals offered palliative care services. in china, the proportion of course in palliative medicine at medical schools is relatively low and, often only available as electives for undergraduates or postgraduates (liu and yuan, 2009) . questionnaire data of 5 th year medical students in 2017 and of geriatric nurses in 2016, showed that 58.7% of medical students and 55.7% of nurses had no training or education regarding death or terminal care, and 93% of medical students and 94.3% of nurses had not received any education about hospice and palliative care. thus the need for course education in hospice and palliative care at chinese medical schools is extremely urgent. palliative care is recommended to be introduced early in curative treatments when patients are diagnosed with a life-limiting disease or when the palliative care needs of patients are identified. current palliative care in mainland china is still mainly focused on patients with cancer, with only a few palliative care resources available for other chronic conditions such as copd, hiv and renal failure . therefore, in the future, palliative care should be extended to both patients with cancer, with other life-limiting diseases, and their families. many palliative care guidelines have emphasized that the discussion of advanced decisionmaking among patients and their families should be initiated when patients still possess decision-making capacity (cheng, 2018) . patients in mainland china sometimes fail to grasp or accept the truth of a diagnosis and limited survival time (cheng, 2018) . moreover, according to questionnaire reports from 1,084 patients in 2016, awareness of the concept of advance care planning or advance directives in china is still low (kang et al., 2017) . in mainland china, family members are often held responsible for making decisions for the elderly in their care, despite a lack of knowledge or training, and thus may resort to homeopathic remedies. healthcare professionals generally have to ''respect'' any decision made by the families and try their best to ''save'' patients' lives using many life-sustaining treatments, although they generally hold negative attitudes to useless treatments. such an approach is regarded as an appropriate measure in terms of protecting themselves from medical conflicts. misunderstanding of palliative care as 'giving up on treatment and waiting for the death of the patients' by family members of the patients as well as even by some doctors, should be corrected (hu et al., 2019b; ning, 2018; xiao et al., 2019) . there is an urgent need for the development of hospice and palliative care in china. in recent years, hospice and palliative care have witnessed rapid development. more and more patients, families, and health-care professionals come into contact with the concept and realize the benefit of hospice and palliative care, while more and more educators, organizations, government and other intermediary leaders have paid more attention to the promotion and development of hospice and palliative care. the current trend towards an ageing society poses difficulties due to the additional challenges seen in diseases in the elderly, including longer disease durations, more complications, underwhelming responses to treatment, and poor prognosis, thus in response to this trend, china has established the national clinical research center for geriatric disorders (ncrcgd) (o'meara, 2020; yu et al., 2018a) . funded by the central government, the ncrcgd aims to provide innovative models for the diagnosis, management and further research into geriatric diseases at a national level. the ncrcgd focuses mainly on comprehensive and systematic research into pathogenesis, prevention, diagnosis and treatment of age-related diseases such as ad, pd, and cerebrovascular disease (xwhosp, 2017b, 2019). at the same time, it is committed to building a national elderly medical service network and scientific innovation system by integrating resources of clinical and basic research. for instance, a health data management platform for the elderly could provide a scientific basis for management and decision making. furthermore, through the education and promotion of new theories and technologies of geriatrics to grassroots hospitals, the ncrcgd can build a better medical service system, improving the health of elderly people. the ncrcgd strives to promote the combination of academic and clinical research (xwhosp, 2017b, 2019). research on agerelated diseases has been carried on such various aspects as diagnosis, treatment, and prevention in fields such as immunology and molecular biology (o'meara, 2020). the characterization of the gene pool, a series of research findings and new technologies have been applied at the clinic, which promotes the development of gerontology in the direction of precision medicine for early diagnosis, early prevention, and early treatment. the ncrcgd also serves as an educational harbor to foster the training of geriatricians and promote academic exchange (frailty-china, 2019; xwhosp, 2017b, 2019). the organization also undertakes other social responsibilities, including partnerships with hundreds of institutions across the country, relying on their collaborative research network to successfully carry out a comprehensive assessment of multiple systems for the elderly (xwhosp, 2017a). through a comprehensive assessment of the multiple aspects of the elderly's diseases, fitness, cognition, psychology and society, it may be possible to develop a system for early identification of health imbalances in the elderly that characterize certain diseases, aiding in their early prevention, and helping to reduce the burden of the ageing chinese society, as well as improving the elderly health service system. prospectively, the ncrcgd will also play its essential role in guiding the research and clinical guidelines for elderly people care as well as making more contributions to improve elderly people's quality of life in china. in order to deal with the ongoing boom in the elderly population, the chinese government has put more effort into funding research on ageing and its related diseases in recent decades. during the recent (2019) outbreak of coronavirus in china, older patients with preexisting ageing-related diseases were found to have a much higher casualty rates than younger patients (chen n et al, 2019) , again highlighting the importance of preventing ageing-related diseases. in response to this, along with the growing need for improving the quality of life of the elderly in china, more attention has been placed on the development of pharmacological strategies against ageing, organ degeneration and major ageing-related diseases. in this section, we will discuss recent world-wide progress in pharmacological attempts to improve healthspan, and the significant contributions that chinese researchers have made. calorie restriction (cr) was first demonstrated as an effective way to extend lifespan in rodents (de cabo and mattson, 2019), however the physiological mechanisms behind its anti-ageing effectiveness were not fully understood at the time, and remain uncertain. later studies have suggested that cr might extend lifespan by regulating insulin-like growth factor (igf) and mammalian target of rapamycin (mtor) pathways. metformin is primarily known for treating type 2 diabetes, with its underlying molecular mechanisms leading to the to down-regulation of igf-1 signaling, and the inhibition of cellular proliferation, mitochondrial biogenesis, ros production, dna damage, activity of the mtor pathway, etc. . the anti-ageing effect of metformin is under investigation by the tame (targeting ageing with metformin) trial in the usa. acarbose, an antidiabetic drug, could also disrupt the igf pathway. acarbose has been shown to partially mimic the effects of cr and extend lifespan in mice by controlling blood sugar and slowing carbohydrate digestion (harrison et al., 2019) . a clinical trial on acarbose (clinicaltrials.gov identifier: nct02953093), named study of acarbose in longevity (sail), is in phase 2, and will hopefully shed some light on its pro-longevity effect in humans. mtor is a pivotal nutrition sensor that links cellular metabolism with proliferation, growth and survival by regulating amino acid metabolism, proteostasis, mitochondria dynamics, cellular senescence, etc. (liu and sabatini, 2020) . rapamycin, a well-known inhibitor of mtor, has shown life-extending effects in all model organisms and postpones the onset of age-associated diseases harrison et al., 2009; liu and sabatini, 2020) . despite the promising pro-longevity outcome of using rapamycin in animals, its clinical application in human has been obstructed by growing concern of potential side effects from immunosuppression and hyperglycemia (pallet and legendre, 2013) . whether the dosage can be fine-tuned to avoid these side effects will be the determining factor in whether or not rapamycin becomes a future pro-longevity drug. the application of induced pluripotent stem cells (ipscs) from healthy and pathological ageing individuals (liu et al., 2011) is also propelling further mechanistic studies and translational applications for cr. nicotinamide adenine dinucleotide (nad + ) is a fundamental molecule in human life and health; while there is an age-dependent reduction of nad + , nad + augmentation extends lifespan and improves healthspan in different animal models as well as shows potential to treat different neurodegenerative diseases based on phase i clinical trials (gilmour et al., 2020; lautrup et al., 2019; yoshino et al., 2018) . nad + precursors such as nicotinamide riboside (nr) and nicotinamide mononucleotide (nmn) have emerged as promising approaches for intervention against ageing phenotypes and age-related diseases. supplementation via these precursors can elevate nad + level in vivo and improve glucose metabolism, mitochondria biogenesis, dna repair, neovascularization and neuroprotection . additionally, more than five phase i clinical trials indicate that orally taking nr is well tolerated and able to elevate nad + in the blood (gilmour et al., 2020; lautrup et al., 2019) . several clinical trials are currently operating in parallel, investigating nr's effects on metabolic function in bones (nct03818802), in immunity (nct02812238), and nmn's effect in cardiometabolic function (nct03151239), with others also ongoing. in china, although nad + precursors have become widely available commercially as supplements, clinical trials exploring their disease-treating ability in humans are still lacking. senescent cells accumulate in aged tissues and this accumulation is considered one of the driving forces of ageing. senolytics are a class of molecules specifically designed to induce apoptosis of these senescent cells. clearing senescent cells in mice has been shown to substantially alleviate ageing phenotypes, producing potent therapeutic effects in ageingrelated diseases such as ad (bussian et al., 2018; zhang et al., 2019b) , atherosclerosis (childs et al., 2016) and osteoarthritis (jeon et al., 2017) . in 2016, a joint research team of chinese and american researchers found that the molecule abt263 reduced irradiationinduced senescent bone marrow hematopoietic stem cells (hscs) and muscle stem cells (muscs) in mice . abt263 (a bcl-2 family inhibitor), together with dasatinib (an anticancer drug) and quercetin (an apoptosis inducer) are the most commonly used senolytic drugs. the senolytic cocktail of dasatinib plus quercetin (dq) decreased naturally occurring senescent cells, improved mobility and reduced the risk of mortality . however, a small pilot clinical study using the same dq cocktail in patients with idiopathic pulmonary fibrosis (ipf) reported no change in pulmonary function, frailty index, clinical chemistries and reported health, though the beneficial effects on mobility were still noted (justice et al., 2019) . while clinical trials on senolytic drugs are mainly conducted in the usa, the concept of reducing senescent cells to delay the ageing progress has attracted interest from all over the world. since 2016, the national natural science foundation of china (nsfc) has set up special programs, providing millions of rmb to support research on cellular senescence and organ degeneration. as such, it is recommended that china further expand its investment in senolytics research. targeting the microbiota may also improve age-related diseases, including ad. in 2019, china approved the first domestically invented ad drug, oligomannate (gv-971) (wang et al., 2019d) . considering there has been no new approved anti-ad drugs in the past 17 years, this has been exciting news. despite the potential of these advances, more work is necessary to understand how gv-971 works. additionally, due to the relatively short clinical trial period, further investigation with longer lasting trials is highly recommended. most human trials for potential anti-ageing drug candidates are conducted in patients with certain age-related diseases. despite partial overlap of the pathologies of these diseases, the knowledge from these trials cannot be interpreted as treating ageing itself. therefore, to reach the goal of identifying anti-ageing compounds, a more comprehensive study on disease-free, healthily ageing groups with no obvious health issues is in immediate need. china has the advantage of a large and diverse population, providing an ideal subject pool for this type of study. the knowledge gained from such studies would likely open new avenues to better understand the fundamental aspects of ageing mechanisms, facilitating their treatment. from a public health and policy perspective, it can be seen that continuing research into prevention and management strategies will be important for both non-communicable diseases as well as geriatric syndromes, to ensure that it is not only life expectancy that is increased, but also the quality of life, by promoting independence and reducing reliance on elderly care services. regular monitoring of trends in incidence and case fatalities of common chronic diseases would enable estimates of future disease burdens and guide preventive health policies (chau et al., 2013a; chau et al., 2013b) . in addition, solutions to trends in the occurrence of disability and frailty are also needed (yu et al., 2018b) . such data would inform the design of elder-friendly service delivery models across the whole spectrum, from prevention to primary care, hospital and residential care settings (woo et al., 2013; yu et al., 2019) . currently, hong kong, a special administrative region (sar) of china, has the longest life expectancies in the world for both men and women, such that the need to redesign service models is particularly pressing. by 2064, it is predicted that 33% of the population in hong kong will be aged 65 years and over; 70% will have at least one chronic condition, with an increasing prevalence of disability also predicted (yeoh and lai, 2016) . while the health and social care systems are well developed, there is a mismatch of needs as those with chronic conditions are predominantly managed in the public hospital systems, whereas primary care is predominantly in the private sector. a recent review concluded that better integration of health and social care systems with a primary emphasis on the community could be the best way forward for the ageing population in hong kong (threapleton et al., 2017) , exemplified by the formation of nurse-led district health centers in 2019 (fhb, 2019). other community models with an emphasis on promoting group activities to prevent frailty and aid selfmanagement of chronic diseases have also been developed (cadenza). such developments have the potential to enhance the role of primary healthcare professionals in preventing functional decline (morley et al., 2017) , so that many can retain independence even as life expectancy increases. the who's integrated care for older people (icope), formally launched in october 2019, will form a useful blueprint for policymakers to build on their existing health and social care infrastructure (who, 2015c). experiences of elderly healthcare in the european union (eu) may provide useful tips for the situation in china (table 1 ). in the eu, elderly care is provided in each country based on its own social security system and cultural norms. in most european countries, the family and the state are the main providers of support to older people both in activities of daily living (adl) and in instrumental activities of daily living (iadl) (schmid et al., 2012) . europe is characterized by three types of care provision: 1) 'crowding out', whereby the state largely replaces family care; 2) 'crowding in', whereby the state promotes family care; 3) 'mixed responsibility', whereby both the state and the family take a joint responsibility for care, yet have separate functions (brandt et al., 2009) . in china, family is still the traditional provider for elderly care (wu et al., 2016a) . under current national and social developmental conditions of china, the chinese government encourages a '90/7/3' pattern of eldercare system, namely: 90% of all older people are cared for at home, 7% are cared for in communities, and 3% are cared for in institutions (mayston et al., 2017) . a 'crowd out' system dominates in the nordic countries (denmark, finland, norway, sweden, iceland) , where the government strives to create a comprehensive system of care services in order to reduce the care obligation of the family. in continental european countries such as austria, belgium, france, germany and the netherlands, systems are more mixed in their provision of elderly care, though tend towards a 'crowd out' approach (kasearu and kutsar, 2013) . in the island countries, i.e. the uk and ireland, the system is more mixed, and the private market is the dominant welfare provider, with the government providing two main social care services to older people, one being old age pensions and the other being healthcare . southern european countries (e.g. greece, italy, portugal, spain) have a 'crowd in' system whereby families have more responsibilities for care services to older people (kasearu and kutsar, 2013; wu et al., 2014) . eastern european countries have undergone dramatic political, social and economic changes after the soviet era and experienced a rapid change from 'crowd out' to a 'crowd in' system where family is the main care provider and the government provides basic formal care services (kasearu and kutsar, 2013; wu et al., 2014) . in china, owing to confucian culture and its emphasis on the family, it is taken for granted that the family, most notably adult children, has the responsibility to care for older parents, especially in the rural areas of china, thus older people rely mainly on their children or family for support (chen and silverstein, 2000; wu et al., 2016a) . rapid demographic ageing increases the demand for care in all ageing societies. currently, european countries face the enormous challenge of implementing major reforms to elderly care in order to ensure that the needs of older people can be continuously met in the future (brandt et al., 2009; broese van groenou and de boer, 2016) . to this end, european governments have increasingly relied on informal care in addition to regular and traditional formal care providers from professional home care services, day care units and nursing homes (broese van groenou and de boer, 2016; verbakel et al., 2017) . informal care for older people is generally provided by caregivers from both kin and non-kin groups, including spouses, children, relatives, neighbors, friends, etc. (swinkels et al., 2016) . in europe, around a third of people aged 50 years or older provide informal care to older people. however, shrinking family sizes, the increasing participation of females in the workplace, and rising retirement ages, may pose a drastic challenge to informal care in the future (verbakel et al., 2017) . china is currently facing challenges in its family-based elderly care model due to new family formation, the spread of individualistic values, and frequent internal migration from rural to urban areas encouraged by rapid economic development (wu et al., 2018a) . moreover, china's one-child policy has sped up the process of population ageing by accelerating the change of the fertility rate and, in turn, has weakened the family-based elderly care model in china . in europe, new elderly care arrangements have been gradually developing based on a new combination of family obligations, market provision and public support. in nordic countries, the state, family and market have been changing with regards to their roles in the provision of elderly care, specifically by increasing the provision of publicly funded care services in a forprofit capacity (marketization of elderly care) and increasing the importance of family care (szebehely and meagher, 2018) . in estonia, the idea of community-based support for older people has been increasingly set forth in order to postpone the need for institutional eldercare (tulva et al., 2016) (tulva et al., 2017) . when it comes to the current trend of eldercare in china, marketization has also been discussed to a large extent both at academic and policy levels. the 'public-private-partnership' (ppp) model may improve the efficiency of familybased eldercare. in the 13 th five-year plan for national economic and social development (2016-2020) , the opening-up of the market for elderly care services (e.g. purchase of services by the government) was clearly stated (du and wang, 2016) . elderly care reforms might create new challenges for both europe and china, an important challenge being an increase in inequality in eldercare service utilization among different social groups of older people. older people with higher socioeconomic status will be able purchase private care services whereas those with less social capital will have to rely on more family-based care. in addition, for the chinese government, there is a need to take into account larger inequalities derived from immense resource variations across regions during the development and reform of elderly care services. while mainland china can learn many successful experiences from hong kong, the eu, etc., there remains many unique features that demand the creation of an elderly care system tailored to mainland china. in addition to responding to changes and preparing to adapt to an ageing society at the societal and individual levels, understanding of the mystery of ageing at a molecular level will aid the development of novel strategies to slow ageing and to promote healthy longevity. in the below sub-sections, we will focus on how to use centenarians, the china national genebank database (cngbdb), and ai to further propel ageing research. in china, the numbers of the oldest-old individuals (those aged 80+), near-centenarians (95+), and centenarians are increasing at roughly 10% yearly (fig. 4a-b) , providing unique resources for both basic research and clinical studies. there were 3,384 centenarians in 1953, with the number rising to 35,934 by 2010 (abida and gu, 2008) . based on the un's medium variant projection, by 2050 over a quarter of the global oldest-old population will live in china. as the numbers of the most elderly have expanded, the gender structure of centenarians, the proportion from urban and rural areas, and differences in geographical distribution have formed "three-high" trends in china (data from china's 2010 population census, excluding hong kong, macau and taiwan) . first, there is a gender difference, with 75% of centenarians being female (peng, 2011) (fig. 4a) . data from the 6 th population census of china (2010) reported 27,082 (75.37%) female and 8,852 (24.63%) male centenarians. this could be due to both physiological (e.g., female hormone estrogen) and cultural differences (women often do more housework, pay more attention to healthcare) (austad and fischer, 2016; peng, 2011) . second, urban and rural disparities were clear, wherein more centenarians (56%) live in rural areas, possibly due to a healthier living environment, diet and lifestyle in these regions (cai, 2013; peng, 2011; zeng et al., 2017a) (fig. 4c ). and third, there was geographical difference in the distribution of centenarians. the distribution of longevity areas in china presents several significant characteristics, including province-specific: being majorly in hainan, guangxi, sichuan, yunnan, guangdong and xinjiang, and mostly distributed along river basins, with more centenarians along the pearl and yangtze rivers and the lancang river basins. these characteristics of the area distribution of centenarian suggest that areas beneficial to longevity can be divided into two types: 'natural' and 'economically developed' longevity areas (he et al., 2017; zeng et al., 2017a) (fig. 4d) . studies of centenarians can provide valuable information for early prevention of major diseases, premature ageing, and early death, thus providing the scientific support necessary to cope with the quickly approaching arrival of an ageing society in china. centenarians may represent a prototype of successful ageing. a longitudinal study of a danish 1905 cohort suggests exceptional longevity does not result in excessive levels of disability (christensen et al., 2008) . in fact, some centenarians experience a delayed onset of age-related illnesses (delayers), whereas others did not succumb to any age-related illnesses (escapers) (christensen et al., 2008; hitt et al., 1999) . in addition, one case-control study showed that older individuals had a delayed age of onset of cancer, cardiovascular disease, diabetes mellitus, hypertension and osteoporosis than their respective younger reference groups (ismail et al., 2016) . the china hainan centenarian cohort study (chccs) on 1,002 centenarians is now in progress, focusing primarily on examining biological indicators and medical aspects, and extensively examining psychological and sociological factors (he et al., 2017) . all in all, the study of centenarians is a topic of immense importance for population and health policymakers, as well as for the larger aim to achieve long, healthy lives. state-of-the-art technologies enable the 'big data'-based investigation of the molecular mechanisms of human ageing and its associated diseases, providing unique information for therapies and interventions. the cngbdb is a centralized 'big data' hub of biological data, providing data sharing, knowledge search, computational analysis, management authorization, and visualization services to the global research community. built and maintained by the china national genebank (cngb), cngbdb draws from 3 "banks": the living biobank, the biorepository, and the bioinformatics center, and from 2 "platforms": the digitization platform and the synthesis and editing platform. the research data system of cngbdb integrates molecular data from internal and external sources into nine sub-databases including literature, gene, variation, protein, sequence, project, sample, experiment, and assembly (https://db.cngb.org/news/2/). comparative analyses of species and tissues can identify the molecular causes of ageing phenotypes, corroborate or disprove theories on ageing, and help to understand differences in j o u r n a l p r e -p r o o f the mechanisms of ageing across species. genotype comparisons within a species at the level of individuals and populations can help identify genetic reason for differences in lifespan. this approach may be used to compare populations from different regions of china, or chinese and foreign populations, such as ashkenazi jews and okinawan centenarians in japan, two populations well-known for their longevity, facilitating the discovery of chinese-specific agemodifying genes. the identification of potential life-extending genes eases the design of therapeutics that can mimic the effect of these genes in people without those genes. likewise, treatments can be designed for age-related diseases that result from mutated or nonfunctional genes in specific populations. it is also possible to comparatively analyze gene expression at the tissue level, as tissues age at different speeds. since many age-related diseases, such as ad, occur within a specific tissue, understanding the speed at which tissues age can help chinese gerontologists assess the risk of and help to prevent tissue-specific age-related diseases (wieser et al., 2011) . the advent of 'big data' and machine learning have eased the collection and identification of biomarkers associated with biological age and may allow for the development of personalized clinical diagnostic tools for physicians in the near future (aman et al., 2019) . in the field of medicine, biomarkers refer to measurable indices capable of identifying a condition, state of being, disease, or environmental marker whose presence may reflect a pathophysiological state (naylor, 2003) . the use of biomarkers has been applied to the field of anti-ageing technologies, including the prevention and treatment of age-related disease, and has been used to explore methods to delay or offset the ageing process altogether, and will likely serve as key components to advances in the field (campisi et al., 2019) . in some cases biomarkers may more accurately represent a patient's 'biological age', as opposed to a patient's simple 'chronological age', the former of which is thought to be more clinically relevant (lopez-otin et al., 2013) . the following sections will review three applications of biomarkers at the molecular, individual and societal levels, including current findings as well as potential research directions. as stated above, there are multiple tests that can be used to obtain molecular biomarkers, and several have been validated to some degree by current research. molecular biomarker studies can be roughly separated into 2 classes: smaller scale studies attempting to determine the utility of a given biomarker, and machine learning studies involving thousands of samples with the intention of developing clinical assessment tools. as an example of this, a recent study involving elderly hypertensive patients was used to investigate a wide library of potentially useful biomarkers . here, 416 elderly chinese participants were matched with subjects from a pool of 9,000 normal volunteers. after adjusting for confounding covariate factors, the researchers found that only elevated triglyceride levels were strongly linked to high blood pressure (hong et al., 2017) . while these cross-sectional studies are certainly important for determining which biomarkers should be considered for clinical evaluation, one of the limitations, at least in comparison to machine learning studies, is that they have a low number of samples. in the above examples, most participant groups contained less than 500 people. while this is a surplus number in other medical contexts, one of the advantages of machine learning is its ability to process thousands of samples granting increased accuracy. fittingly, one of its primary uses is to draw meaningful conclusions from mass, simple, cheap, and non-invasive tests. another key limitation is that biomarker assessment studies using these 'smaller' cohorts tend to lack any external validation. perhaps one of the most easily accessible tests that comes to mind is a standard blood test, here the usefulness of machine learning has been demonstrated by putin and colleagues, who designed a modular ensemble of 21 deep neural networks (dnns) of varying depth, structure and optimization for the prediction of human chronological age using a basic blood test (putin et al., 2016) . the team trained the dnns using a collection of over 60,0000 samples from routine blood biochemistry and cell counting assays. the researchers reported that the accuracy of their results provided evidence to suggest that machine learning algorithms could be used to design minimally invasive biomarker tracking methods for ageing that would only improve with greater access to training samples (putin et al., 2016) . another study examined 19 serum biomarkers, and its results were externally validated using a separate data set from the framingham heart study (sebastiani et al., 2017) . such studies highlight the ability of machine learning techniques to infer conclusions from basic samples, and to externally validate such conclusions. still, this was one of the very few studies with this type of external validation and more are needed for clinical application. big data can also be used to assist geriatricians for personalized medicine, defined as a medical approach in which treatment is customized on an individual basis based upon disease subtype, genetics, risk, prognosis, or treatment response using specialized diagnostic tests (frohlich et al., 2018) . for instance, predictive biomarkers for the early detection of certain diseases, may help both patients and doctors to decide on appropriate treatment pathways. in addition, the 'internet of things' refers to the ability of technology to send and receive data via the internet. as wearable/compact technologies become more prevalent (i.e., phone pedometers, pacemakers, insulin trackers) and their data becomes easier to store and share, so too does it become easier to use life-logging data to track individual's wellbeing. unfortunately, while there is great potential for this type of technical approach, there are currently very few cases of applications within clinical practice (frohlich et al., 2018) , with many studies still in an exploratory phase, requiring further research. for example, one study shows that machine learning techniques have significant potential in developing personalized decision support for chronic disease tele-monitoring systems; however, it was noted that the system would be improved with a larger library of comprehensive predictive markers (finkelstein and jeong, 2017) . the use of radiomics, the high-throughput mining of quantitative image features from standard-of-care medical imaging that enables data to be extracted and applied within clinical-decision support systems, has also been proposed, especially within the realm of dementia prevention and detection . these studies have benefited from large sample sizes (>1,000 images) using machine learning. this brings us to the issue of noise reduction, which is crucial for effective use of big data and will enable a more robust extraction of features. given the immense amount of data expected to be handled in future projects, finding ways to store, process, and analyze this data also presents a challenge for future research. at the societal level biomarkers have numerous applications. monitoring population-level biomarkers will likely provide an accurate, real-time view of the health state of a given area. this will allow for targeted interventions catered to suit the specific needs of a population. as stated earlier in this piece, modern medicine has provided for major increases in both quality of life at old age, and life expectancy, however, this can also be considered a potential societal burden. earlier the use of federated systems with respect to online medical records and data sharing was discussed as a potential hurdle to some countries and medical systems in the world. china has recently embraced a centralized health informatics scheme, with over 80% of medical organizations above the county/district level, 27% of town level hospitals and all cdc above the county/district level capable of transmitting real-time reporting on the status of epidemics via the public health information system (zhang et al., 2007) . in the future, the data provided by a centralized medical record system has the capacity to train numerous machine learning algorithms for use with biomarkers. another challenge for population-level biomarker implementation is to select low-cost, minimally invasive testing that can be used at a large scale. with respect to china, great advances have been made in the use of medical informatics within the past 30 years. however one of the hurdles going forward for the country is that much of this investment has been driven by industry and the private sector, and a major priority for the country's future should be to divert resources to academic research (liang et al., 2017) . this is especially true for the poorer members of society, or those without ready access to healthcare, as biomarker are an asset in devising appropriate healthcare plans for populations in need . addressing rural areas may be a challenge both in terms of healthcare delivery and biomarker testing, as these regions may lack sufficient infrastructure for both, posing a challenge for the future . we recommend the use of mobile-equipped information technology services to reach more remote regions. in summary, biomarkers have a great deal of potential for how doctors can prevent, diagnose, and treat illness associated with ageing. while there are many hurdles going forward, the application of machine learning and big data to biomarker research will provide new opportunities to understand ageing at the molecular level, deliver personalized treatment at the individual level, and design influential and effective policy at the societal and population level. since the beginning of the 21 st century, china started to enter a period where it may be classified as an ageing society. at the same time, the compulsory healthcare insurance systems in china has undergone a comprehensive and rapid development, while still emphasizing the ideologies of health equity and social justice . three major health insurance schemes have been launched, achieving near-universal coverage in a short time, which gained early appraisal by emulating the goal of the provision of affordable and equitable basic healthcare for all by 2020 (yip et al., 2012) . after the establishment of the urban employee basic medical insurance (uebmi) in 1998, the chinese government implemented the new rural cooperative medical scheme (ncms) for rural residents in 2003, and the urban residents basic medical insurance (urbmi) for urban residents without employment in 2007. as a result, social health insurance coverage increased from 29.7 to 87.9% between 2003 and 2008, and further to 95.7% by 2011, and has been stable since (meng et al., 2012) . in order to further reform the fragmented health insurance system, the latter two of these schemes were combined into the basic medical insurance for rural and urban residents in early 2016, with a target of making the system less complicated, but more equitable for various social groups. in the past 10 years of the new round of healthcare reform beginning in 2009, the chinese government dramatically increased financial investment, with half of all investment in the form of funded premium subsidies for residents to be covered by the social health insurance system (yip et al., 2019) . universal coverage has since led to improved access to and utilization of healthcare (meng et al., 2019) , decreased the prevalence of catastrophic health expenditure (yip et al., 2019) , and reduced out-of-pocket expenditure as a proportion of total health expenditure, especially for vulnerable groups, including older adults (xu and mills, 2019) . however, the social health insurance system in china still faces the dual challenge of population ageing (demand) and inefficient delivery on the side of the healthcare system (supply), raising both health expenditures and individual disease burden. out-of-pocket expenditure as a proportion of disposable personal income increased from 4.98% in urban regions and 5.17% in rural areas in 2008 to 5.59% in 2017 (xu and mills, 2019) . concretely speaking, population ageing addressed the increasing health and social care needs of older people. according to the report on the fifth national health services survey, the prevalence of non-communicable disease had increased more than 20% between 2003-2012, from 50.1 to 71.8%, while the inpatient rate rose from 7.6 to 17.9% in between 2003-2013. the outpatient rate also increased to 49.7% in 2013 (nhfpc, 2015) . the reimbursement of social health insurance improved rapidly and accounted for 42% of total health expenditure in 2017, though while out-of-pocket payments dropped from 60% in 2000 to 28% to 2017, financial protection and services packages were insufficient for the elderly (meng et al., 2019) , especially for those in rural regions. reported a three times-higher risk of catastrophic health expenditure among the old population in rural regions . in 2013, expenditures on hospitalization for older people in urban areas were reimbursed 64% by social health insurance and 53% were covered for their rural counterparts (who, 2015b). regional disparity in health benefits for the elderly with insurance aside, a problem of inequity among different health insurance schemes on health outcomes for older adults is still a great challenge. uebmi recipients were found to have better physical and psychological health outcomes compared to those with urbmi or ncms insurance. this demonstrates a transformation in health insurance reform from an emphasis on the opportunity-oriented health equity measured by coverage and healthcare accessibility to stressing outcome-based equity composed of health outcomes for the elderly, namely "outcome-based health equity", giving priority to disadvantaged groups . in terms of supply-side deficiency and unsatisfied progress in the past 10 years, gaps in the public hospital and pharmaceutical reform have tremendously limited the effectiveness of social health insurance reform, even though the public hospital has removed mark-ups for drug sales, adjusted pricing mechanism, reformed provider payment systems and changed governance structures at the county level (yip et al., 2019) . the hospital-centered health delivery system has induced the growth of both health expenditure and health insurance expenses, which worsened the control of non-communicable diseases and health outcome improvement in ageing society. unexpectedly, the usage of outpatient and inpatient services in primary health facilities declined from 62% and 29% in 2009 to 54% and 18% in 2017 . due to the lack of qualified long-term care facilities, the length of hospitalization was longer for the old population aged 60 and over (who, 2015b), demanding higher expenditure input to cope while wasting health resources. we advocate the immediate application of an integrated health and social care-oriented, particularly in community settings, with the objective of increasing affordability and improving the quality of care for older people. population ageing, family structure shift, and migration, were three major challenges limiting the efficacy of traditional informal care provided by families and their networks. a large proportion of older people with functional disability or dementia will continue to create enormous challenges for an immature long-term care system in china . it was estimated about 40 million (19.5% of the elderly) older people had some sort of functional disability by 2015, among which 12.4 million (6.05% of old population) had a serious status of disability (nhfpc, 2015) . at the same time, china has become the largest country in the world to have over 9.5 million people with dementia (jia et al., 2020) . in response to the increasing need for social care of older people with disability, the central government of china has implemented a pilot practice of ltci policies in 15 cities, while some local governments were also encouraged by the central government to initiate county-level pilot experiments on ltci since 2016, in hopes of stimulating the growth of long-term care providers (luo and zhan, 2018) . most ltci schemes were based on the social health insurance system, though these pilots had distinct and diverse eligibility conditions, premium contributions, need assessment instruments, and benefit packages. the reason for carrying out a pilot practice rather than fully implementing a uniform nation-wide scheme reflected the complexity of ltci, and a worry about cost escalation noted ltci introduction in the more mature ageing societies of japan and germany. after two years of practice, a few evaluations were conducted to estimate the outcome of these pilot practices, identifying a host of problems. there are several characteristics and unique features present in the chinese ltci scheme. at first, coverage was narrow and limited only to older people with the most serious degrees of disability, and excluded older adults with dementia due to security issues and lower quality of care skills. by the end of 2017, less than 2% of the older population in the pilot cities were covered by ltci plans in qingdao (zhu and osterle, 2019) , which was the first city to launch the ltci scheme in china, a higher proportion of those 65 years and older was achieved in the ltci practice of the mature ageing populations in germany (11.7%) and japan (12.8%) (oecd, 2013) . secondly, the need assessment tools used by each pilot city were fragmented and biased. some pilot cities or counties only employed the barthel index to measure physically functional disability, but did not measure cognitive function with any scales, thus leading to the exclusion of older people with dementia from ltci coverage. more seriously, the results of need assessment were not applied to long-term care service provision, but only used as a "gate keeper" for receiving the fixed benefit package. assessment tools should be transformed from simple to comprehensive, from a physically oriented test to a multi-dimension health status one, even from health assessment to service assessment. thirdly, in most pilot plans, long-term care was provided by designated institutions through a contract, and a homeand-community-based caregiver was paid by the insurance scheme, however reimbursements were limited such that a large proportion of costs was still paid out-of-pocket by service users themselves, and unmet needs were still high among the disabled elderly . in addition, the inequality in access to long-term care services between advantaged and vulnerable elderly was enlarged. in most pilot schemes, higher numbers of benefit packages were allocated to insured groups living in nursing homes or receiving formal care than to those living at home receiving informal care. retired people with uebmi had higher affordability and preferred to live in the institutions and received higher reimbursements from insurance. rural residents could not access good quality long-term care facilities, and received fewer benefits. the inequality that remains in ltci practices highlights how policy reform ought to reevaluate and reconstruct the currently fragmented schemes and direct more attention to the disabled elderly with lower socio-economic status and without financial or family support. although china attempted the ltci scheme, its most urgent priority was to establish a unified meanstest public budget system to cover the most vulnerable social groups regardless of their living locations. through lu et al. (2017) 's projection, an investment as small as 0.25% of gdp (equivalent to about 1.25% of fiscal revenue) would greatly benefit the frail elderly and those with serious problems of functional disability and/or poor financial status . in 2016, the central committee of the communist party of china and the state council issued the healthy china 2030 plan. corresponding with the health-related sustainable development goal (sdg), this is a national mid-term and long-term strategic plan for moving towards universal health coverage and improving health equity, with emphases on health coverage for the whole life circle, including healthy ageing (prc, 2019). in 2018, china made a major restructuring of national healthcare governance. the national health commission (originally called the ministry of health) administers and regulates the healthcare delivery system and include two new areas of responsibility: elderly care and tobacco control (yip et al., 2019) . in addition, the national healthcare security administration was established. it is in charge of administering essential health insurances (urban employee basic health insurance, urban-rural resident basic health insurance, which integrated the original urban resident basic health insurance and new cooperative medical scheme) and medical assistance for the poor and vulnerable groups as well as deciding on pricing and drug procurement. rapid ageing and an alarming increase in non-communicable diseases (ncds) have arisen as major health concerns in china marten et al., 2014) . in 2009, the national basic public health service program was established, which included health management for elderly people, patients with major ncds (hypertension and diabetes), among others (nhfpc, 2017) . the program is financed by government funds, and the government's per capita allocation increased from 15 to 55 rmb between 2009 (nhfpc, 2017 . china's ongoing healthcare system reform prioritizes transforming hospital-centered treatment care to integrated and continued care through a tiered healthcare delivery system (meng et al., 2019) . a tiered healthcare delivery model defines the functions at each health facility level, and coordinates care across levels. a common model is that hospitals lead medical alliances to deliver integrated care, and provide support and training to strengthen primary health services wang et al., 2018b; wbwho, 2019) . in addition, residents are able to register with a family doctor team who provide preventive and basic healthcare as well as referral services. the government target is universal registration by 2020 (nhc, 2016) . china has made good progress in improving equal access to healthcare and financial risk protection for socially vulnerable people over the past decade (fu et al., 2018; meng et al., 2019; yip et al., 2019) , but challenges remain. there is a lack of qualified primary healthcare providers who are able to serve as gatekeepers, and the quality of primary healthcare is poorly characterized meng et al., 2019) . previous studies reported very low proportions of blood pressure and blood glucose control among patients with hypertension and diabetes seeking care from primary health facilities, and common over-prescription of antibiotics su et al., 2017; wang et al., 2014) . patients persistently bypass primary health facilities and seek perceived good quality of care in high level hospitals, despite many patients complaining of high medical costs and long wait times . on the other hand, most hospitals still largely rely on fee-for-service payment and tie doctors' salary to the hospital revenue generation, which gives hospitals an incentive to attract and retain patients rather than shifting them primary healthcare. overuse and overprovision of health services are common in china (meng et al., 2019; yip et al., 2019) . consequently, health expenditure has continued to escalate, a trend which threatens the long-term financial sustainability of basic health insurance schemes. the efficiency in using health resources is low (meng et al., 2019; yip et al., 2019) . as china continues to progress as an ageing society, strengthening primary healthcare system to provide integrated care will be fundamental to meet growing health needs and obtain the best value from existent health resources. it is difficult to shift from treatment-based intensive care to population-based preventive care and health management while perverse financial incentive for hospitals are not controlled or eliminated. this requires effective collaboration across related sectors led by a strong coordinating authority and needs to bridge policy dialogue to ensure health in all policies workable and achievable. china's prolonged demographic shift has led to decreased fertility, elevated sex ratios, rapid ageing, fast urbanization and major geographic redistributions (peng, 2011) , an interdisciplinary collaborative approach is necessary to prepare and face the challenges as society continues to age. we present a summary on ways to achieve a healthy ageing society in china at societal, individual, and molecular levels (fig. 5) . breaking knowledge gaps and eliminating boundaries among different sectors to further integrate and synergize different healthcarerelated parties at societal, individual, and molecular levels will optimize the outputs of the chinese healthcare system. the chinese government has adopted a positive stance to investment across the whole spectrum of ageing policies, medical education and training, basic ageing and geriatric research, prevention, primary care, and hospital and residential care. it is necessary to establish updated ageing policies on retirement age, to incentivize employment of the elderly, to encourage lifelong learning, and to invest in senior volunteer programmes (yeoh and lai, 2016) . the education and practice of geriatric medicine has been and will continue to be enhanced, including to further increase the teaching of geriatrics-related subjects in medical school, to design high-quality residency and fellowship programs, and to further integrate geriatric principles into general clinical practice (yu et al., 2018a) . the establishment of the national alliance of ncrcgd has been highly appreciated and welcomed and it will continue to serve as a national platform to educate and train geriatricians. while the achievement of healthy ageing and longevity is emerging as an important task for china as in many other countries, this may also be accompanied by socio-economic challenges. one of the major concern is that creating a society where healthy and active ageing and longevity are taken for granted may lead to a swelling of the elderly in the workforce, leading to limitations in job availability for the young, and proving to be a potent economic issue. countries like china and south korea are entering a society of population ageing, showing low birth rates and increased life expectancy, which changes the whole economy korea, 2017) . population ageing will likely have several macro-economic effects, touching various domains such as overall industrial structure, current account and inflation, output growth, household finance, labor markets, consumption, and even fiscal and monetary policy (korea, 2017) . it is therefore imperative to give a comprehensive assessment of population ageing in view of its effects on society and the economy in the long-term, to provide evidence to inform future policies. while a challenging task, some suggested responses to the early-emerging changes that could be taken to offset the effects of the ageing society include promoting the production of larger families in the young, finding ways to ensure jobs remain for the young should the elderly be able to continue longer in their positions, along with more general preparations on transform to an elderly-friendly society. it is delightful to witness the progress of basic and translational ageing research in china, as supported by increases in the number of grants and funding opportunities, as well as by rising numbers of high profile publications and discoveries (he et al., 2019c) . joint efforts from the government and stakeholders of each and every sector should be encouraged to nurture an elderly-friendly society, of most import are reforming the social support system to support china's ageing society, and the introduction of health service/investment interventions aimed at reducing inequalities in health among older people in china. we suggest current research focus on basic and translational gerontology to improve healthy longevity in the elderly, and on developing an integrated and affordable health and social care delivery system to meet the complex needs of a growing elderly population, and to finally transform china into an ageenabling country where well-being and healthy longevity can be celebrated for decades to come. in response to the ageing society and in order to improve the quality of life of the elderly in china, strategies at societal, individual, and cellular levels are presented, detailed in the text. the art of traditional chinese paper cutting '松鶴延年' (may you enjoy longevity like the pines and the cranes, whereby both considered long living in chinese culture) was from shutterstock with paid standard license. p53-dependent and p53-independent activation of autophagy by arf the nad(+)-mitophagy axis in healthy longevity and in artificial intelligence-based clinical applications sex differences in lifespan isolation of a t-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (aids) metformin as a tool to target aging microbiological changes of the ageing oral cavity oral health and implant therapy in parkinson's patients: review intergenerational help and care in europe providing informal care in a changing society particulate matter air pollution and cardiovascular disease: an update to the scientific statement from the dementia with features of alzheimer's disease and hiv-associated dementia in an elderly man with aids clearance of senescent glial cells prevents tau-dependent pathology and cognitive decline cadenza china's new demographic reality: learning from the 2010 census from discoveries in ageing research to therapeutics for healthy ageing aids database infectious diseases epidemiology of alzheimer's disease and other forms of dementia in china associations of dietary protein intake on subsequent decline in muscle mass and physical functions over four years in ambulant older chinese people trends in hip fracture incidence and mortality in chinese population from hong kong 2001-09 trends in ischaemic heart disease hospitalisation and case fatality in the hong kong chinese population 2000-2009: a secondary analysis temporal and spatial distribution characteristics of hiv-infected and aids patients aged 15 years and over in china from meta-inflammageing at the crossroad of geroscience disparities in hiv and syphilis prevalence and risk factors between older male clients with and without steady sex partners in southwestern rural china sarcopenia in asia: consensus report of the asian working group for sarcopenia epidemiological and clinical characteristics of 99 cases of 2019 novel coronavirus pneumonia in wuhan, china: a descriptive study current situation and progress toward the 2030 health-related sustainable development goals in china: a systematic analysis cancer statistics in china intergenerational social support and the psychological well-being of older parents in china chronic low-grade inflammatory phenotype (clip) and senescent immune dysregulation launch of the health-care reform plan in china advance care planning in chinese seniors: cultural perspectives prevention of disability in the frail chinese older population senescent intimal foam cells are deleterious at all stages of atherosclerosis proportion of people aged 50 years and older in hiv-infected cases doubled in 9 years age-standardised death rates by leading causes of death flu express number of deaths by leading causes of death by sex by exceptional longevity does not result in excessive levels of disability national and local government policies at sarcopenia: european consensus on definition and diagnosis: report of the european working group on sarcopenia in older people sarcopenia: revised european consensus on definition and diagnosis prevalence of and interventions for sarcopenia in ageing adults: a systematic review effects of intermittent fasting on health, aging, and disease porphyromonas gingivalis in alzheimer's disease brains: evidence for disease causation and treatment with small-molecule inhibitors population ageing and the development of social care service systems for older persons in china the 2015 quality of death indexranking palliative care across the worldan economist intelligence unit study, commissioned by the lien foundationkey findings infographic (the economist intelligence unit sleep duration and the risk of dementia: a systematic review and meta-analysis of prospective cohort studies mitophagy and nad(+) inhibit alzheimer disease mitophagy inhibits amyloid-beta and tau pathology and reverses cognitive deficits in models of alzheimer's disease nuclear dna damage signalling to mitochondria in ageing a research agenda for aging in china in the 21st century report on square-dancing in china influenza-associated mortality in temperate and subtropical chinese cities inflammageing: chronic inflammation in ageing, cardiovascular disease, and frailty district health centres machine learning approaches to personalize early prediction of asthma exacerbations frailty asia-china conference from hype to reality: data science enabling personalized medicine research in health policy making in china: out-of-pocket payments in healthy china 2030 global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 1990-2013: a systematic analysis for the global burden of disease study targeting nad(+) in translational research to relieve diseases and conditions of metabolic stress and ageing epidemiological characteristics and trends of chinese syphilis from loneliness in older adults living with hiv the increasing burden and complexity of multi-morbidity and polypharmacy in geriatric hiv patients: a cross sectional study of people aged 65 -74 years and more than 75 years program of all-inclusive care for the elderly (pace): integrating health and social care since 1973 trends in cardiovascular disease mortality among persons with hiv in acarbose improves health and lifespan in aging het3 mice rapamycin fed late in life extends lifespan in genetically heterogeneous mice annual report of notifiable diseases statistical yearbook prevalence and risk factors for frailty among community-dwelling older people in china: a systematic review and meta-analysis hiv and aging in mainland china: implications for control and prevention research basic and translational aging research in china: present and future interventions for lower extremity peripheral artery disease centenarians: the older you get, the healthier you have been association of demographic, lifestyle factors and serum biomarkers with hypertension in elderly chinese people diabetes in china: epidemiology and genetic risk factors and their clinical utility in personalized medication who framework convention on tobacco control in china: barriers, challenges and recommendations vitamin d3 activates the autolysosomal degradation function against helicobacter pylori through the pdia3 receptor in gastric epithelial cells association between sleep duration and sarcopenia among community-dwelling older adults: a cross-sectional study psychometric properties of the chinese mainland version of the palliative care spiritual care competency scale (pcsccs-m) in nursing: a cross-sectional study analysis on the problems and countermeasures of the needs assessment of long-term care insurance in china clinical features of patients infected with 2019 novel coronavirus in wuhan, china. lancet prevalence of mental disorders in china: a cross-sectional epidemiological study compression of morbidity is observed across cohorts with exceptional longevity local clearance of senescent cells attenuates the development of post-traumatic osteoarthritis and creates a pro-regenerative environment the prevalence of dementia in urban and rural areas of china dementia in china: epidemiology, clinical management, and research advances analysis of risk factors for male sexual dysfunction senolytics in idiopathic pulmonary fibrosis: results from a first-in-human, open-label effects of whey protein nutritional supplement on muscle function among community-dwelling frail older people: a multicenter study in china attitudes toward advance directives among patients and their family members in china intergenerational solidarity in families: interplay between the family and the state superior sensory, motor, and cognitive performance in elderly individuals with multi-year dancing activities alzheimer's disease: cellular and molecular mechanisms defibrillator implantation in patients with nonischemic systolic heart failure treating depression with tai chi: state of the art and future perspectives population aging: impacts and policy imperatives metabolic abnormalities, antiretroviral therapy and cardiovascular disease in elderly patients with hiv reduced grid-cell-like representations in adults at genetic risk for alzheimer's disease behavioural risk factors in mid-life associated with successful ageing, disability, dementia and frailty in later life: a rapid systematic review the aging mouth: differentiating normal aging from disease nad+ in brain ageing and neurodegenerative disorders treatment delay and fatal outcomes of pulmonary tuberculosis in advanced age: a retrospective nationwide cohort study transitions in frailty states among community-living older adults and their associated factors effect of an integrated payment system on the direct economic burden and readmission of rural cerebral infarction inpatients: evidence from anhui, china the prevalence, incidence, management and risks of atrial fibrillation in an elderly chinese population: a prospective study healthy china 2030: an opportunity for tobacco control the primary health-care system in china catastrophic health expenditure and rural household impoverishment in china: what role does the new cooperative health insurance scheme play? development of medical informatics in china over the past 30 years from a conference perspective and a sino-american comparison personal and social environmental correlates of square dancing habits in chinese middle-aged and older adults living in communities similarities and differences in health-related behavior clustering among older adults in eastern and western countries: a latent class analysis of global aging cohorts multiyear square dancing is associated with superior mental processing capacity but not memory in middle-aged and older chinese women: a cross-sectional propensity score matching analysis age-specific associations between hiv infection and carotid artery intima-media thickness in china: a cross-sectional evaluation of baseline data from the chart cohort long-term effects of ambient pm2.5 on hypertension and blood pressure and attributable risk among older chinese adults apoe4 causes widespread molecular and cellular alterations associated with alzheimer's disease phenotypes in human ipsc-derived brain cell types recapitulation of premature ageing with ipscs from hutchinson-gilford progeria syndrome mtor at the nexus of nutrition, growth, ageing and disease emerging hiv epidemic among older adults in nanning, china construction of palliative care training contents in china: a delphi study comparative research of middel-aged women fitness effects of taiji quan and sqaure dance intergenerational transfers and informal care for disabled elderly persons in china: evidence from charls the reform of the medical welfare system and health equity for the elderly in china: a study in zhejiang outcome-based health equity across different social health insurance schemes for the elderly in china prevalence of multiple chronic conditions among medicare beneficiaries, united states the hallmarks of aging ageing, dental caries and periodontal diseases a budget proposal for china's public long-term care policy the 4th national oral health survey in the mainland of china: background and methodology crossing the river by feeling for the stones: contesting models of marketization and the development of china's long-term care services a comparative study on the needs assessment and rating assessment of long-term care insurance at home and abroad: taking qingdao and japan as examples (in chinese) realigning the incentive system for china's primary healthcare providers value-based contracting innovated medicare advantage healthcare delivery and improved survival an assessment of progress towards universal health coverage in brazil a journey without maps-understanding the costs of caring for dependent suggestions on further expanding the supply and promoting the consumption of elderly care services the 1st, 2nd 3rd, 4th circular of the central government on supporting the pilot areas of home-based and community-based elderly care service reform what can we learn from china's health system reform? trends in access to health services and financial protection in china between 2003 and 2011: a cross-sectional study ministry of human resources and social security of the people's republic of china integrated care: enhancing the role of the primary healthcare professional in preventing functional decline: a systematic review tuberculosis among the elderly in tanzania: disease presentation and initial response to treatment china statistical yearbook the guiding opinions on advancing the development of age-friendly livable environment by the state council healthcare reform office, national health and family planning commission, national development reform commission healthy china action plan (2019-2030) by the national health commission of the people's republic of china national health commission of the people's republic of china the state council opinions on promoting the development of elderly care services center for health statistics and information, nhfpc. an analysis report of national health services survey in china national health and family planning commission. national basic public health services guideline official paper: implementation of national basic public health services in 2018, by the national health and family planning commission of the people's republic of china the twilight of immunity: emerging concepts in aging of the immune system hospice and palliative care in mainland china: history, current status and challenges trends in mortality from human immunodeficiency virus infection, 1984-2016: an autopsy-based study how health research will support china's ageing population health at a glance: oecd indicators adverse events associated with mtor inhibitors the prevalence, awareness, treatment and control of dyslipidemia among adults in china dementia studies in chinese populations china's demographic history and future challenges the evolution of seasonal influenza viruses china brain project: basic neuroscience, brain diseases, and brain-inspired computing the chinese government: healthy china dementia incidence and mortality in middle-income countries, and associations with indicators of cognitive reserve: a 10/66 dementia research group populationbased cohort study deep biomarkers of human aging: application of deep neural networks to biomarker development a survey of aids cognitive attitudes among middle-aged and elderly men in high-risk areas why is old-care industry unable to be prosperous? (in chinese) tuberculosis and aging_ a global health problem lifestyle factors related to mortality and survival: a mini-review development of pharmacotherapies for the treatment of sarcopenia gendered support to older parents: do welfare states matter? biomarker signatures of aging comparison of the clinical features and outcomes in two age-groups of elderly patients with atrial fibrillation oral health status of chinese residents and suggestions for prevention and treatment strategies estimating the future burden of cardiovascular disease and the value of lipid and blood pressure control therapies in china availability, cost, and prescription patterns of antihypertensive medications in primary healthcare in china: a nationwide cross-sectional survey trends in the informal and formal home-care use of older adults in the netherlands between nordic eldercare: weak universalism becoming weaker randomized comparisons of double-dose clopidogrel or adjunctive cilostazol versus standard dual antiplatelet in patients with high posttreatment platelet reactivity: results of the creative trial integrated care for older populations and its implementation facilitators and barriers: a rapid scoping review designing healthcare for the most common chronic condition--multimorbidity dental caries and periodontal diseases in the ageing population: call to action to protect and enhance oral health and well-being as an essential component of healthy ageing -consensus report of group 4 of the joint efp/orca workshop on the boundaries between caries and periodontal diseases prevalence of lipid abnormalities in the united states: the national health and nutrition examination survey nicotinamide riboside is a major nad+ precursor vitamin in cow milk cancer burden with ageing population in urban regions in china: projection on cancer registry data from world health organization promising community-based practices to postpone the need for institutional elderly care: a descriptive study of community developers in estonia. east-west studies exercise, immunity and aging mycobacterium tuberculosis informal care in europe: findings from the european social survey (2014) special module on the social determinants of health hivrelated shame and health-related quality of life among older, hiv-positive adults association between depressive symptoms and sarcopenia in older chinese community-dwelling individuals gray matter age prediction as a biomarker for risk of dementia use and prescription of antibiotics in primary healthcare settings in china prevalence and ethnic pattern of diabetes and prediabetes in china in 2013 melancholy or mahjong? diversity, frequency, type, and rural-urban divide of social participation and depression in middle-and old-aged chinese: a fixed-effects analysis sodium oligomannate therapeutically remodels gut microbiota and suppresses gut bacterial amino acids-shaped neuroinflammation to inhibit alzheimer's disease progression people-centred integrated care in urban china epidemiological characteristics of legally reported sexually transmitted diseases in china from international development of integrated care systems status of hypertension in china: results from the china hypertension survey world bank and world health organization. healthy china: deepening health reform in china: building high-quality and value-based service delivery prevalence of kidney damage in chinese elderly: a large-scale population-based study control smcfd, prevention. study on global ageing and adult health (sage) wave 1: china national report china country assessment report on ageing and health. geneva: world health organization world report on ageing and health world report on ageing and health (geneva: world health organization) who guidelines on tuberculosis epidemiological estimates for viral hepatitis in the western pacific global tuberculosis report 2019 the icope package of tools risk reduction of cognitive decline and dementia: who guidelines (geneva: world health organization who report on the global tobacco epidemic, 2019: offer help to quit tobacco use (geneva: world health organization) computational biology for ageing long-term hepatitis b infection in a scalable hepatic co-culture system satellite-based estimates of long-term exposure to fine particles and association with mortality in elderly hong kong residents the well-being of community-dwelling near-centenarians and centenarians in hong kong: a qualitative study challenges of population ageing: putting frailty as a cornerstone of health and social care systems combating frailty and sarcopenia in aging populations: switching to a more positive paradigm elder-friendly service delivery models validating the sarc-f: a suitable community screening tool for sarcopenia? defining sarcopenia in terms of incident adverse outcomes telomere length is associated with decline in grip strength in older persons aged 65 years and over active ageing: a policy framework prevalence and correlates of frailty among community-dwelling chinese older adults: the china health and retirement longitudinal study progress of intervention work for high-risk groups in 2018 and work requirements for 2019 associations between quality of relationships and life satisfaction of older mothers in estonia suicide prevention in old age in china 2002-2017: the linkage to the mipaa suicide among older people in relation to their subjective and objective well-being in different european regions effect of aging on periodontal inflammation, microbial colonization, and disease susceptibility prevalence of dementia in mainland china, hong kong and taiwan: an updated systematic review and meta-analysis qualitative study on perceived dignity of cancer patients undergoing chemotherapy in china hiv/aids epidemic among older adults in china during 2005-2012: results from trend and spatial analysis 10 years of china's comprehensive health reform: a systems perspective factors associated with oral health service utilization among adults and older adults in china senolytics improve physical function and increase lifespan in old age sarcopenia in community-dwelling oldest old is associated with disability and poor physical function. the journal of nutrition, health & aging incidence of frailty among community-dwelling older adults: a nationally representative profile in china diabetes mellitus and risks of cognitive impairment and dementia: a systematic review and meta-analysis of 144 prospective studies china national geriatrics clinical medical research center-clinical and scientific research collaboration alliance established in beijing opening of the national clinical research center for geriatric disorders (xuanwu hospital site introduciton of the national clinical research center for geriatric demographic and psychosocial correlates of sexual activity in older chinese people financing institutional long-term care for the elderly in china: a policy evaluation of new models impact of frailty on mortality and hospitalization in chronic heart failure: a systematic review and meta-analysis risk factors and incidence of stroke and mace in chinese atrial fibrillation patients presenting to emergency departments: a national wide database analysis prevalence and patterns of multimorbidity in a nationally representative sample of older chinese: results from charls an investment for the celebration of aging 10 years of health-care reform in china: progress and gaps in universal health coverage early appraisal of china's huge and complex health-care reforms nad(+) intermediates: the biology and therapeutic potential of nmn and nr prevalence and correlates of depressive symptoms in chinese older adults: a population-based study geriatric medicine in china: the past, present, and future a comparison of health expectancies over 10 years: implications for elderly service needs in hong kong incremental predictive value of sarcopenia for incident fracture in an elderly chinese cohort: results from the osteoporotic fractures in men (mros) study effects of a multi-component frailty prevention program in pre-frail community-dwelling older persons: a randomized controlled trial trajectories of frailty among chinese older people in hong kong between 2001 and 2012: an age-period-cohort analysis frailty and its contributory factors in older adults: a comparison of two asian regions (hong kong and taiwan) is neighborhood green space associated with less frailty? evidence from the mr. and ms. os (hong kong) study incidence of dementia and subtypes: a cohort study in four regions in china epidemiological characteristics of condyloma acuminata in china's std surveillance sites from demographics, phenotypic health characteristics and genetic analysis of centenarians in china survival, disabilities in activities of daily living, and physical and cognitive functioning among the oldest-old in china: a cohort study bridging the gp gap: nurse practitioners in china gender and marital status differences in depressive symptoms among elderly adults: the roles of family support and friend support prevalence and risk factors of active pulmonary tuberculosis among elderly people in china: a population based cross-sectional study baseline characteristics and management of patients with atrial fibrillation/flutter in the emergency department: results of a prospective, multicentre registry in china senolytic therapy alleviates abeta-associated oligodendrocyte progenitor cell senescence and cognitive deficits in an alzheimer's disease model an investigation into health informatics and related standards in china management, and outcomes of patients hospitalized for heart failure in china: results from the china heart failure (china-hf) registry epidemiology of cardiovascular disease in china: current features and implications in-hospital outcomes of dual loading antiplatelet therapy in patients 75 years and older with acute coronary syndrome undergoing percutaneous coronary intervention: findings from the ccc-acs (improving care for cardiovascular disease in china-acute coronary syndrome) project percutaneous coronary intervention in patients with acute coronary syndrome in chinese military hospitals, 2011-2014: a retrospective observational study of a national registry mortality, morbidity, and risk factors in china and its provinces, 1990-2017: a systematic analysis for the global burden of disease study disease burden of copd in china: a systematic review effects of exercise and nutrition supplementation in community-dwelling older chinese people with sarcopenia: a randomized controlled trial china's policy experimentation on long-term care insurance: implications for access for more details). c-d. demographics showing the major diseases affected to (c), and death in (d) the elderly in china between 1990 (yellow) and 2017 (green). data source: global burden of disease study figure 2. morbidity and mortality of selected diseases by age in (e) disability-adjusted life years (dalys) (millions) in the elderly (65+) in china in 2017. (per 10000 people) of viral hepatitis, pulmonary tuberculosis (p.tb), influenza, hiv infection and aids from 2004 to 2016 were extracted and presented as general (open) or aged (65 years or older, closed) population ), the 6 th population census of china (2010) and projection (2020-2050) of china's national bureau of statistics. c. women account for 75% of the total number of centenarians in china and the proportion of rural centenarians is far higher than that of urban area. data source: china's 2010 population census, excluding hong kong, macau and taiwan area. the map was made by r. d. geographical distribution of the relative number of centenarians. the proportion of centenarians in china's total population (centenarian ratio) has a significant regional imbalance the authors acknowledge the valuable work of the many investigators whose published articles they were unable to cite owing to space limitations. the authors thank dr. vilhelm bohr at the nia and university of copenhagen for reading of the manuscript. e.f. key: cord-018449-4vdqq961 authors: norrie, philip title: how disease affected the end of the bronze age date: 2016-06-26 journal: a history of disease in ancient times doi: 10.1007/978-3-319-28937-3_5 sha: doc_id: 18449 cord_uid: 4vdqq961 dr. norrie provides a summary of the fifteen currently accepted causes for the end of the bronze age in the near east and then goes on to discuss the sixteenth reason—infectious disease epidemics. these are the real reason that the end of the bronze age in the near east was called either the “catastrophe” or the “collapse” due to its short time frame of 50 years, the mass migration of the general population and the “sea peoples” plus the abandonment of cities such as hattusa, the capital of the hittite empire c.1200 bce. the diseases most likely to cause this collapse are smallpox, bubonic plague and tularemia. in 1700 bce the ancient near east was dominated by egypt in the nile valley and into the levant, the kingdom of babylon in mesopotamia and the minoan civilization in crete. anatolia was made up of small city-states including arzawa. egypt and babylon's military tactics were based on foot soldiers and were no match for the hordes of invaders who came from the central asian plains and swept through the near east. they came in fast twowheeled horse-drawn chariots with a driver and an archer on board. this system of weaponry was developed and refi ned earlier, during years of warfare on the plains of central asia. this type of weapon or style of warfare was unknown among the classical oriental civilizations. the foot soldiers of egypt and babylonia were unable to defend against these invaders. in 1630 bce , the hyksos swept into the nile delta region, and in 1595 bce the hittites swept into mesopotamia. the middle bronze age civilizations c.1700 bce displayed all their characteristic social traits: a low level of urbanization due to an agricultural based society; small cities centered around royal palaces; numerous temples; a strict separation of classes between an illiterate mass of peasants and craftsmen and a powerful military elite. knowledge of writing and education was reserved to a small minority of scribes and the aristocrats. developments in the ancient near east after 1700 bce include the hittite empire beginning c.1700 bce , in c.1600 bce the minoan civilization reached its peak and mycenae in greece was occupied with the mycenaean civilization fl ourishing until c.1200 bce . in c.1450-1500 bce the mitanni kingdom in northern mesopotamia began, minoan culture ended on crete and the kassites ruled babylonia. later the mitanni kingdom was divided in two with the western half taken over by the hittite empire and the eastern half taken over by the assyrians. at the end of the bronze age between 1200 and 1150 bce only the egyptian empire remained with all other empires, kingdoms and citystates having been destroyed in the "catastrophe". human cultural development can be measured by means of the types of materials used to make tools, utensils and weapons. first there was the stone age where hard fl int stone was sharpened by chipping away and honing the cutting edge on another fl int stone. this resulted in a sharp cutting edge, which could be used as a knife, axe or spear tip. the next stage was the copper age, the fi rst of the metal ages. copper by itself is a relatively soft metal; so copper-only metal implements were weak. so the metal workers looked for ways to make the copper stronger. through trial and error they arrived at the idea of mixing or alloying small quantities of tin with the copper to form bronze. the dates for the bronze age varied from region to region depending on the region's copper and tin ore supplies or that region's ability to trade for bronze ingots. for example, the bronze age in the near east (the region of interest in this book) went from c.3300-1200 bce , while in south asia it was from 3000-1200 bce , in europe 2300-600 bce , in china 2000-700 bce and in korea 800-400 bce . by contrast the sub-saharan african region bypassed the bronze age altogether going from the stone age directly to the iron age with the use of imported iron, because the region had no copper or tin mines and no ability to trade for bronze. some cultures went straight from the stone age to the iron age, bypassing the copper and bronze ages, when their culture was infi ltrated by immigrants who brought iron age tools with them; such as when the british colonized australia, new zealand and fiji. focusing on ancient near east, the near east had the earliest bronze age because "metallurgy developed fi rst in anatolia, modern turkey. the mountains in the anatolian highland possessed rich deposits of copper and tin". 1 copper was also found in cyprus, the negev desert and iran. tin was found in more distant places such as far off cornwall (uk) and the north west indian subcontinent, so trade in tin became a vital trade route commodity. the near eastern bronze age has been divided into the early bronze age (c. 3300-2000 bce ), middle bronze age (c. 2000-1600 bce ) and the late bronze age (c. 1600-1200 bce ) by scholars. a more detailed dating system is shown in table 5 .2 . the next stage in human cultural development was the iron age; this is the third and fi nal stage in the usual three-stage sequence of stone age, bronze age and iron age or the fourth in the more detailed fi ve-stage sequence of stone age, copper age, bronze age, iron age and steel age. the iron age ended in each region with the beginning of what is known as the historical period, that is, the local production of suffi cient detailed written sources and records. again the dates for the iron age vary from region to region depending on that region's access to iron ore mines. again anatolia was blessed with abundant iron ore in its mountains. consequently the ancient near east had the earliest iron age from 1300 to 600 bce followed by india 1200-200 bce and europe 1200-400 bce , china 600-200 bce , korea 400-50 bce and japan 100 bce -500 ce . 2 other historians give earlier dates for the iron age in anatolia saying the earliest iron ware dates from about 2000 bce 3 and forged weapons at the latest by 1500 bce . 4 according to the late eminent oxford historian john morris roberts when discussing the hittite empire, he stated it "enjoyed a virtual monopoly of iron in asia, this not only had great agricultural importance but, together with their mastery of fortifi cation and the chariot, gave the hittites a military superiority which was the scourge of egypt and mesopotamia". 5 also "the use of iron weapons by the hittites was believed to have been a major factor in the rapid rise of the hittite empire". 6 by 1200 bce , iron was in common use around the middle east but it would take a few more centuries before it supplanted bronze as the dominant metal even though it was lighter and stronger. one theory for the collapse of the bronze age was a lack of tin either due to it having been mined out or because its trade routes had been disrupted due to raiders, 7 thus forcing metalworkers to look for an alternative metal. hence iron became the next preferred metal. another explanation for the end of the bronze age is simply that iron, once discovered, was found to be a better metal because it was much stronger. a hittite tomb in anatolia housed a dagger that had a smelted iron blade dating from 2500 bce , making it one of the earliest ever examples of smeltered iron. 8 the late bronze age saw the slow continuous transition from bronze to iron throughout the near east region as price and availability of iron, not just the iron-making technology above, determined the rate of expansion of iron usage. thus it was a gradual transition from late bronze age to early iron age over several centuries in the near east around 1200 bce . the end of the hittite empire occurred c.1200 bce 9 and was part of a much larger event-the end of the bronze age. the end of the bronze age was known as the "catastrophe" 10 because it signaled the end of all the known empires in the eastern mediterranean and near east including the hittite empire, the mycenaean kingdoms and the egyptian empire in syria and canaan, but not the central nile based egyptian empire. it was followed by the "ancient dark age" when all that was glorious about these lost empires including, not only their palaces and cities but also their history, religions, writings, art, music, administration and organization, temples, libraries, political systems and trade routes were lost. this loss lasted many centuries until the emergence of the classical greek, assyrian and persian empires and the hebrews later. the catastrophe lasted from c.1200-c.1150 bce and was characterized by its short time frame of about 50 years, mass migrations of populations and mass destruction where whole cities were destroyed and burnt, but also curiously many whole cities were just abandoned intact. it was also characterized by another mass population migration involving raiders called the "sea peoples" who invaded the near east from the mediterranean region. it was "violent, sudden and culturally disruptive". 11 the dartmouth university archaeology department has an online lesson about the collapse of the mycenaean palatial civilization in greece around 1200 bce . it summarizes the causes of this collapse as: economic factors, climate change, internal social upheaval, invasion from outside the aegean world and changes in the nature of warfare. 12 historian robert drews in his book the end of the bronze age has on his list of possible causes of the collapse the following: earthquakes, mass migrations, ironworking, drought, systems collapse, raiders and changes in warfare. 13 the internet website, www.enotes.com , lists the possible causes for the bronze age collapse, which includes the following: volcanoes, earthquakes, migrations, raids, ironworking, drought, changes in warfare and general systems collapse. 14 note that there is no mention of disease as a possible cause of the end of the bronze age in any of these three lists. by contrast this book proposes the more comprehensive list of sixteen causes for the end of the bronze age, including diseases. but the fi nal answer for the causes of the end of the bronze age will be multifactorial as some things will apply to one area, such as earthquakes in greece that do not apply to other areas. a possible major cause though, one that knows no boundaries or political borders when it spreads are infectious disease epidemics. so what is the evidence? mt. hekla is a volcano located on the southern side of iceland. according to volcanologists and egyptologists, it erupted in 1159 bce throwing an estimated "7.3 cubic km of volcanic rock into the atmosphere, placing its volcanic explosivity index (vei) at 5. this would have blocked out the sun leading to cooler temperatures in the northern parts of the globe for a few years afterwards. thus plants would not grow causing famine and eventual disease in the weakened population. traces of this eruption have been identifi ed in scottish peat bogs, and in ireland a study of tree rings dating from this period has shown negligible tree ring growth for a decade". 15 the volcanic explosivity index is a relative measure of the explosiveness of a volcanic eruption on a scale of 1-8, with 8 being a mega-colossal eruption where the cloud column of ejected material would climb to a height of over 50 km. such a large volcanic eruption could have caused famine in the near east contributing to the demise of the region. the scale is logarithmic where each interval on the scale represents a ten-fold increase in the material ejected. by comparison the largest volcanic eruption in recent history was mt. krakatoa in 1883 which had a volcanic explosivity index of 6, and mt. vesuvius which destroyed pompeii in 79 had a volcanic exposivity index of 5. mike baillie is the emeritus professor of paleoecology at the queen's university in belfast, northern ireland and is an expert of dendrochronology, which is the science of dating by means of tree rings. he has built a year by year chronology of tree ring growth reaching back "the last 5,000 years". 16 his work has confi rmed "that the events such as those at 1628 bc, 1159 bc and ad 540, represented abrupt environmental downturns with profound effects on human populations". 17 these dates correspond with dynastic changes in china, the end of the bronze age in the near east and the plague of justinian, respectively. these events were most likely volcanic in cause but he also argues that it could also be due to the impact of debris from comets blocking out the sun and causing temperatures to fall for years, hence poor growth in trees, as shown in their tree rings, and all other plants leading to famine which makes the general population more prone to disease. this has been formalized in his paper "hints that cometary debris played some role in several tree ring dated environmental downturns in the bronze age". 18 earthquakes amos nur is the emeritus professor of geophysics at stanford university, california, usa and he: postulates that earthquakes tend to occur in "sequences" or "storms" where a major earthquake above 6.5 on the richter magnitude scale can in later months or years set off second or subsequent earthquakes along the weakened fault line. he shows that when a map of earthquake occurrence is superimposed on a map of the sites destroyed in the late bronze age, there is a very close correspondence. 19 in his paper "the end of the bronze age by large earthquakes?" 20 nur proposes that a large earthquake storm lasting 50 years from c.1225 to c.1175 bce could have contributed to the end of the bronze age. twentieth-century geophysical data about the geography of active tectonic faults especially at geological plate boundaries, the location of earthquakes, the geography of ground motion intensity, and earthquake frequency-magnitude statistics in the eastern mediterranean show that most of the sites that collapsed at the end of the bronze age must have experienced destructive earthquakes repeatedly in their past. recent and historical evidence shows also that these massive earthquakes reoccur every few hundred years in bursts, or "storms" of large events that sweep across broad portions (500-2000 km in length) of the eastern mediterranean and over short periods of time (50 years) . this suggests that a large earthquake could have contributed to (and probably did contribute to) both the physical and political collapse of the great centers of civilization at the end of the bronze age. this probably began by an earthquake storm that unzipped the plate boundaries in the eastern mediterranean between 1225 and 1175 bce . the earthquakes in this 50-year long storm could have rendered many of the urban centers militarily vulnerable, thus inviting attacks, not by powerful distant sea people but by opportunistic indigenous or neighboring populations. these attacks may have led in turn to the political and social collapse of the centres, followed by a dark age of recovery and rebuilding often lasting a few hundred years. 21 figure 8 of nur's paper shows "superposition of the sites destroyed at the end of the bronze age in 1200 bc and the earthquake intensity vii in our century . the coincidence suggests that the end of the end of the bronze age could be related to earthquakes". 22 (see the table of bronze age earthquake destruction in nur's paper.) 23 drews in his book end of the bronze age dismisses the idea of earthquakes totally. he says that archaeologists only look at their own site and an earthquake may be relevant only to this site and not the whole of the eastern mediterranean. nur, on the other hand, has shown that earthquakes occurred all over the eastern mediterranean and near east. elizabeth b. french is an authority in mycenaean pottery and a former warden of ashbourne hall, manchester university and the former director of the british school of athens, from 1989 to 1994, which is a facility established in 1886 to promote british-based greek archaeological research and study. in 1996 french wrote: archaeologists of my generation, who attended university in the immediate aftermath of schaeffer's great work in 1948, were brought up to view earthquakes, like religion as an explanation of archaeological phenomena to be avoided if at all possible. thus, it is only recently that an earthquake at mycenae has begun to be a serious hypothesis. 24 claude frederic-armand schaeffer (1898-1982) was the fi rst to conduct the excavations at the ancient city port of ugarit at ras shamra in syria from 1929 that showed that the city was destroyed c.1190 bce by the invading sea people as told by ammurapi, the king of ugarit, in a letter to the king of alasiya. in 1948, schaeffer fi rst suggested that an earthquake may have destroyed late bronze age sites. his idea was rejected by archaeologists because the catastrophe was spread over a 50-year period and could not have been the result of a single earthquake. schaeffer did not know then about 50-year long "earthquake storms" as proposed by nur, which have put earthquakes back on the agenda. schaeffer was a french scholar and archaeologist who was the curator of the prehistoric and gallo-roman seum in strasbourg (1924) (1925) (1926) (1927) (1928) (1929) (1930) (1931) (1932) (1933) and the museum of national antiquities in saint-germain-en-laye . fritz schachermeyr (1895 schachermeyr ( -1987 was an advocate for earthquakes playing a role in the end of the bronze age, which he proposed in his book griechische fruhgeschichte . 25 he has a similar view to nur in advocating that catastrophic earthquakes destroyed troy in western turkey, mycenae in greece and knossos in crete about 1200 bce . fritz was a professor specializing in ancient history and more specifi cally in ancient tsunamis usually accompany an underwater earthquake or volcanic eruption. so in line with the above evidence about earthquakes and volcanoes then a destructive tsunami may also have occurred, such as when the volcano on the island of thera erupted sending a massive tsunami to crete destroying many minoan coastal settlements. during the catastrophe many new ethnic groups started to appear in the near east region. indo-european tribes such as the phrygians, thralians, proto-armenians, macedonians and dorian greeks seem to have arrived at this time-possibly from the north. there also seems to have been widespread migration of the aramaeans, possibly from the south east. 26 the people involved in the mass migrations could have been "pushed" by drought and subsequent famine, earthquake destruction, raiders, and "sea people" invasions. they could also have been "pulled" by the prospect of better lands and food, plus safety being far away from raiders. another one of the possible "push" scenarios could be fl eeing disease, and this should be factored in by historians. the "sea peoples" is the name given to a confederacy of seafaring raiders who invaded the eastern mediterranean at the time of the catastrophe. they invaded cyprus, the hittite empire and the levant. they also tried to invade egypt but were repelled. the pharaoh merneptah (reigned c.1213-c. 1203 bce ) referred to them as "the foreign countries or peoples of the sea" in his great karnak inscription. 27 he fought and defeated them at perire, in the western nile delta during the fi fth and sixth years of his reign. later the great pharaoh ramesses iii (reigned c.1182-c. 1151 bce ) had to deal with a later wave of invasions by the sea peoples. the following inscription from his medinet habu mortuary temple describes what happened, who they conquered and who made up their confederation force: the foreign countries (i.e. sea peoples) made a conspiracy in their islands. all at once the lands were removed and scattered in the fray. no land could stand before their arms: from hatti, qode, carchemish, arzawa and alashiya on, being cut off (i.e. destroyed) at one time. a camp was set up in amurru. they desolated its people, and its land was like that which has never come into being. they were coming forward toward egypt, while the fl ame was prepared before them. their confederation was the peleset, tjeker, shekelesh, denyen and weshesh, lands united. they laid their hands upon the land as far as the circuit of the earth, their hearts confi dent and trusting: 'our plans will succeed! 28 ammurapi was the last bronze age king of ugarit. he wrote a letter to the king of alasiya telling how the sea peoples had invaded and destroyed his country: the sea people, like the other mass migrations, may have been "pushed" out of their lands by earthquakes, drought, and famine; and "pulled" to new lands looking for food and minerals such as iron, tin and copper. they too may have been "pushed" out of their lands by infectious disease. there are many hypotheses about who were the "sea peoples". 1. philistine hypothesis : the hebrews called the southern coastal plain of ancient palestine "philistia" and the people who lived there in the fi ve towns called the "philistine pentapolis" of askelan, ashdod, ekron, gath and gaza were called "philistines". there are two schools of thought as to their origin. one school says they were mycenaean because they made distinctive mycenaean iiic pottery, whereas the other school says they were an indigenous canaanite culture. either way they became a force that helped attack egypt as part of the "sea peoples". 2. minoan hypothesis : after the eruption of the volcano at thera (today's santorini), sometime between 1660-1613 bce , crete would have been devastated by fi res and ash causing a cooling climate resulting in crop failures and famine, plus the tsunamis destroying the coastline. the people of the minoan culture would have been forced to leave crete, some scholars say initially to anatolia and from there later to the levant as "sea peoples". 3. greek migration hypothesis : greece not only possibly supplied people for the philistines but also supplied people who migrated to sicily and sardinia as well as fought in troy and later occupied cyprus. so they would have been bands of raiders/invaders like the sea peoples. 4. trojan hypothesis : historian eberhard zangger proposes that the "sea peoples" may have come from troy and its allies, and that the greek literary tradition of the trojan war, as told by the poet homer, may well refl ect the greek efforts to counter those raids. 30 zangger (1958) is a swiss german who has a phd in natural sciences from stanford university and was a senior research associate in the department of earth sciences at the university of cambridge from 1988-1991. he is a writer on geoarchaeology especially in the prehistoric aegean area. mycenaean city states fought each other over decades. refugees from this fi ghting then turned to piracy for survival and that this in turn led to becoming "sea peoples" raiders. 6. italian peoples hypothesis : italy may have supplied some of the sea peoples from the etruscans. 7. anatolian famine hypothesis : in this hypothesis extensive drought in anatolia, which led to famine, in turn forced people from places in anatolia such as lydia to go to sea and become sea-going migrants. these displaced people could later become sea peoples. a famous passage from herodotus portrays the wandering and migration of lydians from anatolia because of famine: in the days of atys, the son of manes, there was a great scarcity through the whole land of lydia … so the king determined to divide the nation in half … the one to stay, the other to leave the land ... the emigrants should have his son tyrrhenus for their leader ... they went down to smyrna, and built themselves ships … after sailing past many countries they came to umbria ... and called themselves … tyrrhenians. 31 8. invader hypothesis : historian michael grant proposed that there may have been another origin for the "sea peoples" besides the aegean. he proposed that "there was a gigantic series of migratory waves, extending all the way from the danube valley to the plains of china." 32 grant (1914 grant ( -2004 ) received a doctor of literature from the university of cambridge and was an english classicist, numismatist and author of more than seventy books on ancient history and ancient coins. fellow historian sir moses i. finley has suggested that the carpatho-danubian region of europe was the original centre of this disturbance. sir michael grant and sir moses i. finley suggest that these people were invaders who destroyed sophisticated cities and built simpler and less complex settlements with plain pottery and simple tools, on top of the ruins. this demonstrates a cultural discontinuity 33 from a more advanced culture to a less advanced culture after the invaders or raiders took over. sir moses i. finley was born in the usa as moses israel finkelstein but changed his surname to finley in 1936. he studied at syracuse university and columbia university and taught ancient history at columbia university and rutgers university in the usa, specializing in the social and economic aspects of the ancient world. after being attacked for his left wing opinions by senator joseph mccarthy in 1954 he immigrated to britain where he taught classics at the university of cambridge from 1955, eventually becoming professor of ancient history from 1970 to 1979 when he was also knighted. the collapse of the bronze age should also be seen as part of the bigger technological picture and changes taking place at the time, that is, the slow change from bronze making to iron working. even though the hittites in anatolia were the fi rst great power to have iron at the time of the collapse, the general regional shift from bronze to iron occurred after the collapse of the bronze age c.1200 bce . 34 the sea peoples' weapons for example were made of bronze, not iron. so iron confi rmed the collapse and end of the bronze age but did not cause it. bronze is made from a combination of 85-95% copper and 5-15% tin. in the ancient world tin was an element in short supply. without tin the only metal available for implements and weapons was the much softer plain copper of the copper age. the near east had few tin mines with anatolia being the main source of tin. the majority of the tin was imported from outside the near east, with cornwall in britain and other sources to the distant east of the near east, such as afghanistan, being the main suppliers. hence the tin trade and its trade routes were very important, like oil trade today. if the tin trade collapsed for whatever reason, such as war or disease, then the bronze age would fi nish, as people would have to look for alternative metals such as iron, also the bronze age could have ended because iron is a stronger hence better metal and would have replaced bronze as a metal of choice. herodotus (c484-c425 bce ) was a greek historian who is regarded as the "father of history". he wrote a detailed history of the greco-persian wars called the "histories" and he "was the fi rst historian known to collect his materials systematically, test their accuracy to a certain extent a nd arrange them in a well-constructed and vivid narrative". 35 he proposed that the bronze age ended because of a long drought that caused famine and social disruption. examples of grain shortages in the hittite empire and demands for urgent resupply of hatti in the late bronze age, just before the end, were mentioned in the last chapter. dendrochronological (tree ring) studies have shown drought years leading up to 1200 bce . "starting from 1209 bce, we see indices smaller than 100 per cent, except for two years, 1205 and 1204 bce. in addition there is a continuous decrease in indices in the last fi ve years of the empire. examining the tree rings shows the existence of dry years which contributed to drought on the lands". 36 peter ian kuniholm founded the aegean dendrochronology project in 1973 and has been its director ever since. this project examines tree rings all over the aegean and near east to make up a chronology of the area from neolithic time to the present. he has shown that in 1190 bce trees grew at only 53.5% of their normal rate, in 1189 bce at 61.1% and in 1188 bce at 62% indicating three consecutive years of drought, which would lead to famine. examination of the data presented in this paper shows that the occurrence of three such poor growth years in a row was rare. 37 kuniholm is the professor of archaeology and dendrochronology at cornell university. he gained his ba at brown university in 1958, his ma at vanderbilt university in 1963 and his phd from the university of pennsylvania in 1977. other researchers also support the arid climate change theory at the end of the bronze age. anthropologist brandon drake from the university of new mexico studied various parameters including mediterranean sea temperatures to show the change in the climate to much drier times at the end of the bronze age and early iron age. 38 by contrast, archaeologist jennifer moody studied the change in building structure over the late bronze age period to show that buildings had verandas, and were airy with good ventilation to keep them cool because the climate became " signifi cantly drier than previously". 39 famine naturally what follows drought is famine. as discussed above, there was correspondence between the hittite king and the egyptian pharaoh about urgent grain shipments for hattusa. famine can drive people from their lands and could be one of the causes for the mass migrations seen at this time, and could also have pushed the sea peoples from their land in search of new territories with food. famine can also weaken people and make them more prone to disease. for example prior to the black death, which started in europe in 1347, there was the great famine which lasted from 1315-1317 which greatly weakened the population of europe. the great famine was not caused by drought, as in the end of the bronze age though, but by several years of excessive rain fall. during this time crops were fl ooded or could not be planted. disease could also cause famine because the farmers or slaves necessary to work the fi elds would have died, hence crops would not have been planted or maintained, let alone harvested, which required considerable man power. robert drews "suggests that these collapses occurred as the result of a fundamental change in the nature of warfare in this period". 40 the horse drawn chariot with an archer behind the driver was introduced in the seventeenth and eighteenth centuries bce and subsequently dominated the near eastern battlefi elds. they did not dominate in the aegean as the topography was different being more rugged terrain with fewer large fl at areas suited to chariot warfare. these chariots were manned by a socially and economically privileged warrior elite (e.g. the hittite empire, the mycenaean kingdoms, city states of coastal syria and the levant (such as ugarit), the hurrian kingdom of mitanni, the kassite kingdom of babylon etc). 41 drews argues that these large massed chariot formations involving sometimes thousands of chariots became vulnerable when they were harassed and killed by highly mobile, lightly armed infantry who used new and better weapons with great success. these new weapons included (a) the aspis-a highly maneuverable small round shield 2-3 feet in diameter as opposed to the sakos or large immobile shield; (b) the javelin which had elliptical heads instead of a barb which allowed easy retraction hence reuse. massed javelins thrown on the run using massed swarming formations were very effective against massed chariots; (c) the new nave type ii sword which was about 70 cm long which "optimized both for slashing as well as stabbing or thrusting" 42 and fi nally (d) "the infantryman's corslet, which protected the trunk, arose, along with greaves for protecting below the knees". 43 this new warfare meant that an entire elite social order of charioteers became redundant and were replaced by infantry and cavalry. this meant signifi cant disruptions of the aristocracy and consequently the royal families. unfortunately drews only provides a single answer solution to a very complex multicausal problem, hence is guilty of oversimplifi cation. also his approach does not apply to the aegean where chariots were less dominant due to the hilly topography. after the end of the bronze age mycenaean pottery continued to depict war chariots as part of the decoration thus confi rming that they had not died out. this assumes that the potters were portraying only contemporary and not historical scenes. the late bronze age palatial kingdoms all had fatal centralized, complex and top-heavy political structures, which made them vulnerable. this bureaucratic domination and top-heavy administration involved the use of a whole scribal class of record keepers and was highly specialized. it also involved the exploitation of the peasantry who funded the whole expensive top-heavy system with their taxes. so when the system was stressed by famine, war or disease for example, it was unable to cope due to lack of funding to prop up "the system". once the administration was affected then other things such as trade became affected. once trade in all important commodities such as tin, grain, olive oil, wine and timber was stopped, the end was inevitable. a weakened administration could also not handle other crises such as peasant revolts, defection of mercenaries, overpopulation and invasion by sea peoples. the general systems collapse theory was fi rst proposed by joseph tainter vast sums of money were needed to run an empire especially one with an expensive and large bureaucracy. besides their administrative expense, there was the cost of the royal family and the large armies necessary not only to defend the empire but also to help expand it. once the revenue from taxes dried up the system, lacking funding, collapsed. so this is a consequence of the the reduced income caused by peasants migrating and dying due to famine, war or disease, but not a cause of the end of the bronze age. this theory put forward variously by vermeule (1960), 45 lakovides (1974) 46 and betancourt (1976) 47 suggests that the piratical activity of the "sea peoples" would cripple trade routes, hence disrupt commerce so much as to bring down the late bronze age empires. the theory refers to a consequence of the "sea peoples" activity and not to why the "sea peoples" were active in the fi rst place. so once again there is a theory which turns out to be a "consequence of" and not a "cause of" the end of the bronze age. the hittite royal families provide many examples of internal fi ghting within a royal family. murder, even of the incumbent king as a means to gaining control of the throne, was accepted practice. fighting between different branches of the royal families leading to civil war would have badly destabilized any empire. oliver dickinson from durham university had a similar view when he stated in chapter 36 "the collapse at the end of the bronze age" in his contribution to the oxford handbook of the bronze age aegean (c3000-1000 bc) that "it is a waste of effort to try to isolate a single cause or prime mover for the collapse." 50 this is because it was most probably the result of several causes. this is what this book is arguing that the end of the bronze age in the near east, referred to as either "the catastrophe" or "the collapse" [ dickinson preferred the term collapse], was the result of a cascade of events beginning with volcanic eruptions and comets. these caused drought which in turn caused famine, which weakened the population so they (rich and poor alike, because disease does not discriminate) were prone to whatever infectious disease happened to be prevalent at the time. this is in agreement with dickinson's "natural disasters like earthquakes, localized droughts leading to famines, or epidemic diseases could have acted as catalysts for trouble or have exacerbated an already deteriorating situation". 51 dickinson also showed that many sites were abandoned at the end of the bronze age not reoccupied for many centuries. this would be expected when an infectious disease epidemic is active. his abandoned city list included places such as gla, messenia and krisa in the aegean, besides the well documented abandonment of hattusa, the hittite capital in anatolia. guy middleton's phd, "theories of mycenaean collapse", favored the idea of infectious disease as a cause of the collapse, so it included a section on "plagues and epidemics" but stated "the main problem with the plague hypothesis is the lack of positive evidence". 52 it also stated "much about the plague hypothesis seems attractive in the way it can explain the changes in settlement pattern, material and social cultural and long-term decline in population levels". 53 the plague hypothesis was also good for "explaining the variability of collapse 54 because "palatial areas may have been more densely settled and thus more seriously affected, while possibly less populous peripheral areas may have been less affected". 55 once the central palace was adversely affected: "this lack of strong central power and instability seems to fi t with the kind of unstable and more mobile society suggested for palatial greece." 56 emeritus robert arnott from oxford university wrote chapter 1 "disease and the prehistory of the aegean" in health in antiquity edited by helen king, in which he listed some of the possible diseases from that time which included: thalassemia, malaria, tuberculosis, brucellosis, malnutrition, scurvy, anemia, measles, chickenpox, oral infection, pneumonia, hemolytic disease, enteropathies, cholera, typhoid, dysentery, tetanus, hookworm, mumps, whooping cough and amoebiosis. note that most diseases listed are infectious diseases. he also gave a possible reason why disease has not been considered as a cause for the end of the bronze age because "many such scholars are completely unaware of the social effects of disease and the major consequences that ensued whenever contacts across disease boundaries allowed a new infection to invade a population that lacked any acquired immunity." 57 arnott referred to the research of j. lawrence angel (also known as the archaeological "bone man") and robert sallares who have found the lethal falciparum malaria dna in ancient skeletons, making malaria a strong infectious disease that possibly contributed to the end of the bronze age. he also supported the drought leading onto disease hypothesis stating "if widespread climatic change and drought were mainly responsible for the decline and collapse of the mycenaean world in the twelfth century bc, as has been suggested … then a natural consequence would have been widespread epidemic disease (e.g. cholera and typhoid) brought on by the shortage of clean drinking water". 58 in conclusion, arnott paints a very bleak picture of life for the ordinary man in ancient times "the harsh reality of a society where life was hard, death and disease were everyday occurrences and the day-to-day ambition of those who lived outside the palaces was simply survival". 59 eric watson-williams wrote an article about the end of the bronze age called "the end of an epoch" in which he championed bubonic plague as the sole cause for the catastrophe. "what seems so puzzling is the reason why these apparently strong and prosperous kingdoms should disintegrate" 60 he questioned. he cites abandonment of cities, the adoption of the practice of cremation of the dead instead of the usual burial because so many people died, and it was necessary to destroy the decomposing bodies quickly, and the fact that bubonic plague is very deadly killing animals and birds as well as humans, affects large areas, spreads rapidly and lingers for many years as reasons for his choice of bubonic plague. unlike panagiotakopulu, he provides no physical evidence, but uses history to compare how things were during later bubonic plague epidemics such as the plague of justinian and the black death to how things were around 1200 bce . watson-williams argues that there were four epidemics of the bubonic plague that we know of in ancient times, namely the hittite epidemic of 1322 bce , the exodus from egypt in the reign of merneptah c.1230 bce , the plague of the philistines c.1130 bce and fi nally the plague "that which destroyed the army of sennacherib (701 b.c.)". 61 he also quotes a pestilence that killed 70,000 men in three days during the reign of king david c.1017 bce that may have been bubonic plague. lars walloe from the university of oslo had a similar view to that of watson-williams when he wrote his article "was the disruption of the mycenaean world caused by repeated epidemics of bubonic plague?" he noted the "large movements of population"; 62 "the population decreased in successive steps during the fi rst two or three epidemics of plague down to perhaps half or one-third of its pre-plague level", 63 and that there was "a substantial reduction in agricultural production". 64 this led to famine and the abandoning of settlements. he thus concluded that bubonic plague accounted for all of these observations rather than other infectious diseases such as anthrax. any historian trying to fi nd the cause of the end of the bronze age and the hittite empire must explain: the short time frame of approximately 50 years, when it occurred between 1200-1150 bce ; the mass migrations not only of normal people but also of the "sea peoples"; and the fact that so many large cities, such as the hittite capital hattusa, were simply abandoned and not destroyed or occupied by raiders or invaders. disease in the form of infection epidemics provides one plausible explanation; there is nothing like a severe widespread plague to deliver the fi nal fatal blow to an empire or an era. the bubonic plague is caused by the yersinia pestis and is transmitted to man by fl eas from small rodents such as rats. it is a very lethal disease killing two out of every three people infected within four days. the usually accepted fi rst outbreak of bubonic plague was the plague of justinian in 541. "the fi rst recorded outbreak of bubonic plague was the world's fi rst great pandemic. called the mortalitas magna (great death) or the plague of justinian, it began in arabia … the pestilence reached constantinople by the spring of a.d. 542 and lurked around the eastern mediterranean until the 760s." 65 new research however by mark achtman has suggested that the bubonic plague began near china c. 600bce and spread to europe via central asia's "silk road". mark achtman's research was published in nature genetics in an article titled " yersinia pestis genome sequencing identifi es patterns of global phylogenetic diversity". 66 his team compared seventeen whole genomes of yersinia pestis isolates from various global sources and "conducted phylogenetic analyses on this sequence variation dataset, assigned isolates to populations based on maximum parsimony and, from these results, made inferences regarding historical transmission routes. the phylogenetic analysis suggests that yersinia pestis evolved in or near china and spread through multiple radiations to europe, south america, africa and southeast asia, leading to country-specifi c lineages". 67 mark achtman bsc, msc, phd from the university of california, berkeley, usa is a canadian microbiology researcher at the university college, cork, ireland where he specializes in the population genetics of bacterial pathogens and microbial phylogeography. prior to this he was a researcher at the max-planck institute in berlin, germany specializing in molecular genetics and infections biology. but, as shown earlier in this book, kozloff and panagiotakopulu argue that bubonic plague, coming from india [? indus valley civilization] could have occurred during the reign of amenhotep iii early in the fourteenth century bce , that is, predating achtman's chinese suggestion by over 750 years. thus, if achtman continued his research he may fi nd that china may have contracted the plague from india, and that india was the primary source of the bubonic plague. this all leads to the plague of the philistines, also known as the plague of ashdod, which occurred c.1190 bce and may have been caused by the bubonic plague. if egypt had bubonic plague during the reigns of amenhotep iii and his son, akhenaten (c1370-1350 bce ) then it could have recurred to the north east in southern canaan fi fty years later. the philistines lived in south canaan at the end of the bronze age and ruled their fi ve city-states (pentapolis of gaza, ashkelon, ashdod, ekron and gath). they were the kingdom of israel's worst enemy and they fought each other many times. their origin is obscure though. some historians, such as carl ehrlich, 68 believe they were "sea peoples" from either the aegean or mycenae in greece who settled in southern canaan after being defeated by pharaoh ramesses iii in c.1190 bce , while others such as riemschneider 69 believe they came from anatolia as refugees from the crumbling hittite empire. as stated earlier the plague of the philistines occurred c.1190 bce 70 while others think it may have occurred later, either 1141 bce or in the second half of the eleventh century bce . 71 but peter kuniholm's aegean dendrochronology project has shown that our current dating scheme for ancient times maybe anywhere up to 150 years out when compared to his tree ring dating scheme. "long standing assumptions and conventions in other egyptian and old world chronology and history will need to be re-examined" 72 he has stated, hence the 1141 bce stated above could in fact have been about 50 years out making it c.1190 bce . according to author lee allyn davis in his book natural disasters , the philistine plague was caused by bubonic plague and began in 1200 bce after the philistines captured the ark of the covenant (a box that contained ancient hebrew records such as the ten commandments and the first torah scroll) from the israelites. the fi rst recorded plague is the one which beset the philistines in 1200 bce , and which is recorded in the bible in the book of samuel. the philistines in this year defeated an army of nomadic hebrews at ebenezer, captured the sacred ark of the covenant and carried it in triumph to ashdod, a city near the mediterranean sea. but their triumph was immediately tainted, according to 1 samuel 5:9: "the hand of the lord was against the city with a very great destruction; and he smote the men of the city, both small and great, and they had emerods (swellings) in their secret parts". the description makes it clear that bubonic plague had invaded the army of philistines, probably from a stricken ship. if it had originated in the ark of the covenant as the bible notes, it would have been mentioned in the old testament. wherever they took the ark (of the covenant), the philistines took plague too. they moved from ashdod inland to gath, then to ekron. the plague followed them. terrifi ed, they trundled the ark of the covenant into a cart pulled by two milk cows. if the cows took the ark to the hebrew border town of beth-shemesh, they reasoned that the lord of israel was responsible for the plague, and had indeed smitten them. the cows took the ark into the fi eld of beth-shemite, joshua stopping alongside a huge stone. israel rejoiced, but not for long. in 1 samuel 6:19, the bible chronicles the inexorable progress of the plague; "and he smote the men of beth-shemesh, because they had looked at the ark of the lord, even he smote the people fi fty thousand and three score and ten men; and the people lamented because the lord had smitten many of the people with a great slaughter". 73 davis gets his idea of the plague coming from a stricken ship and not the ark of the covenant from a book about plague called plague an ancient disease in the twentieth century by charles t. gregg. 74 in it gregg states that the plague of the philistines occurred in the twelfth century bce and that: the plague of the philistines probably invaded the town of ashdod from a stricken ship rather than with the ark of the covenant and then infected the crowds that conveyed the ark to the other affl icted cities. had the plague begun in israel there should have been accounts of it in the old testament, but samuel mentions the disease no more. 75 others who also think the plague of the philistines was bubonic plague include w.j. simpson and w.w.c. topley and g.s. wilson. simpson (1905) 76 affi rms that the pestilence was bubonic plague, and that the "emerods" were plague buboes, and his assertion has been repeated by later writers. topley and wilson (1946) , 77 for example, assert that "in the fi fth and sixth chapters of the first book of samuel there is an unmistakable account of bubonic plague." 78 in his book on the plague of the philistines 81 shrewsbury goes against the conclusions of his fellow british bacteriologists simpson, and topley and wilson and instead endorses the belief of the fi rst century romano-jewish historian titus flavius josephus (37-c.100 ce ) who stated "categorically that it was dysentery, and he also discriminates the epidemic from the simultaneous plague of mice". 82 it is possible that josephus had access to authentic material that has since been lost; it is certain that he was many centuries nearer the ancient jewish tradition than we are, and, though it appears to be fashionable in some quarters to decry the value of tradition as an adjunct to history, it is not wise to ignore it. with the support of josephus, i submit, therefore that the plague of the philistines was one of the forms of bacillary dysentery, either shiga or a virulent flexner dysentery, and that the "emerods" were "piles." 84 note his point that "it is not wise to ignore it". in other words he is warning us that it is not wise to ignore the ideas of josephus. the basis for his fi ndings were the facts that he thought fi rstly the "secret part" of the body as the only part not visible when naked, that is, the anal area and that "hemerods" were in fact hemorrhoids or piles, which would be made worse with dysentery. this is in contrast to the others who thought the "secret part" was the genital area in general hence the "hemerods" were buboes or the swollen lymph nodes in the groin; because buboes are infl amed lymph nodes and there are no lymph nodes in the anal area. the communicable diseases that have scourged armies throughout historical times are typhus fever, typhoid fever, and dysentery, and there can be no doubt that the pestilence that affl icted the philistines fi rst erupted in their army, and was then disseminated by their victorious troops among the civilian population of their cities. typhus fever and typhoid fever can be dismissed, because neither disease is accompanied by the development of swellings around the anus; but bacillary dysentery is frequently associated, because of the invariable concomitant tenesmus, with the formation of external piles, those rounded protuberances from the anal margins that are at fi rst hot, red and painful, but which later often itch considerably as they resolve. it is commonly stated in medical textbooks that bacillary dysentery in hot climates is more prone to give rise to piles than is the disease in temperate ones. the usual explanation given is that the anal sphincter is generally more lax in individuals living in hot lands than in those living in temperate regions. 85 but shrewsbury gives another reason for his conclusion that the plague of the philistines was in fact dysentery and not bubonic plague. there is still the third clue to be considered; to wit, the fact that the gethrites, after deliberate consultation, made "seats of skins" for themselves. to those who still opine that the pestilence of the philistines was bubonic plague, the question may be put: why should any sane individual make themselves seats of skins as a palliative for bubonic plague? of what conceivable use would a skin seat be to a person who is collapsed, delirious, and bed-ridden almost from the onset of that disease? if the "emerods" were plague buboes, the action of the gethrites was utterly nonsensical; but if, as i have argued, they were hemorrhoids, then anyone who has suffered from external piles will agree that the gethrites showed good sense. the difference in comfort to the sufferer from piles between reclining upon a skin seat and sitting cross-legged upon the ground must be experienced to be appreciated, but i can assure the reader that it is profound. 86 the signifi cance of the plague cannot be underestimated. because of this plague the philistines returned the ark of the covenant back to the israelites to get rid of it, which consequently allowed them to fl ourish. whatever opinion is held about the nature of the pestilence that ravaged the philistines, the fact that it caused them to return the ark of the covenant to the defeated and demoralized israelites is indisputable. that restoration deprived the philistines of the inestimable moral advantage that the possession of the ark gave to them, and at the same time restored to the israelites the focus upon which all their national activities and aspirations converged. i therefore affi rm that this act, because it saved the israelite society from almost certain extinction, must be ranked as one of the decisive acts in human history, and i draw support for that affi rmation from the authoritative pronouncement of osterley and robinson (1932) : "yet small and insignifi cant among the nations of the world as israel was, without political infl uence or extended power, it may safely be said that no other people of antiquity holds a place of such profound importance in the history of human thought. it was israel who gave to the world a religion which has directed the spiritual life of nearly half mankind, and, not only among the jews themselves, but in the two daughter faiths of christianity and islam, has molded the beliefs of men in every continent save central and eastern asia". 87 william oscar emil osterley and t.h. robinson were historians who wrote the book a history of israel published by oxford university press in 1932. the other aspect of this plague is the fact that it occurred in palestine, which shrewsbury referred to as the "cock pit" 88 ) of the ancient world. according to osterley and robinson "palestine was the commercial, military and political center of the ancient world, and on it focused all the greatest movements of the peoples" 89 because any conqueror had to control it if they wanted free movement from europe or asia into africa or in the reverse. so controlling palestine was vital because of this movement factor between europe, asia and africa, the same factor that would also have easily spread the plague via the fl eeing masses into adjoining regions thus spreading it throughout the near east during the end of the bronze age. the following hypothesis about tularemia is included for the sake of completeness, so that no option is left out or eliminated from the list of potential infectious diseases that caused the end of the near eastern bronze age. tularemia, also known as rabbit fever, is a bacterial infection caused by francisella tularensis . it is easily spread and is highly virulent making it the perfect infective agent for an epidemic. for these reasons it, along with dysentery (already discussed), the bubonic plague (already discussed), smallpox (to be discussed as the next infective disease), and anthrax (to be discussed later), have been used as infective disease agents for biological warfare. francisella tularensis infects small mammals such as rabbits, hares and other rodents who can in turn infect humans directly or via their ticks or mosquito or fl ies. "humans can get the disease through a bite from an infected tick, horsefl y, or mosquito; breathing in infected dirt or plant material (causing pneumonia); direct contact through a break in the skin with an infected animal or its dead body (most often a rabbit, muskrat, beaver, or squirrel) or eating infected rare meat". 90 so the disease is easily contracted either by direct contact with host rodents, ticks, mosquitoes, fl ies, ingestion of contaminated food and water or as aerosol particles being inhaled. siro trevisanato, an italian-canadian molecular biologist proposed that tularemia was used by the hittites as a germ warfare agent, caused the hittite plague of 1322 bce and later still caused the plague of the philistines. trevisanato (1960-) graduated in 1983 with a ba in biology from suny purchase, usa; in 1986 with an msc in biochemistry from new york medical college, valhalla, usa and a phd in 1994 in molecular biology from the university copenhagen, denmark. avaris was a port city in the northeastern region of the nile delta. it was the major administrative hub for the nile delta during the hyksos era (fifteenth dynasty) and later became the capital of egypt under the hyksos. it was occupied from c.1783 to 1550 bce and according to trevisanato was the port through which tularemia entered egypt c.1715 bce . paragraph 170, column 11, lines 12 to 15 of the hearst papyrus tells of an infectious disease attributed to "the asiatics", that is, people from the syria-canaan-transjordan area also known as the "canaanite illness". 91 it has also been attributed to bubonic plague or typhus. austrian archaeologist manfred bietak uncovered the ruins of avaris at tell el-dab'a in the eastern nile delta. there he also found unequivocal signs of an epidemic. more precisely, the layer dividing the so-called stratum g from stratum f of avaris contains a large number of tombs, which are characterized by a hasty job. this fact is the signature of emergency situations such as those existing during a plague. artefacts in the tombs revealed that they and, thus the epidemic, could be dated to c.1715 bce . 92 during the epidemic of 1715 bce the hebrew population in avaris fared a lot better than the local egyptians because the egyptians living in the city had no immunity to tularemia while the hebrews, who were exposed to sheep and other animals, had a natural immunity to tularemia and survived. if the disease had been bubonic plague or typhus then the hebrews would have died at the same rate as the egyptians. trevisanato also thinks that the hittite epidemic of 1322 bce was due to tularemia rather than bubonic plague. a deadly epidemic, also dubbed the hittite plague, affected most of the middle east towards the end of the fourteenth century bce . the present study determined that its onset was described in the egyptian royal archives, enabling to date it to the last reigning years of akhenaten, that is, just before 1335 bce , and locate the focus to an area northeast of byblos (present-day lebanon). letter ea 96 states that "there is a pestilence in simyra". anyone from simyra was barred from entering nearby byblos, and donkeys were not to be used in caravans because of the pestilence. the measure did not work, as evidenced by letter ea 362 stating the pestilence did reach byblos, and by letter ea 137 stating the byblos ruler became chronically ill. the plague spread further south as attested by the ruler of amurru in present-day southern lebanon, who referred to his relationship with byblos, and mentioned he was now sick, and was going to die (ea 95). still further south, along the coastal trade route from byblos, coeval letter ea 224 reports megiddo "is consumed by pestilence". the east-west trade road going through simyra linked the mediterranean coast to the euphrates. reports from 1335 bce show that east of simyra in babylon, an aristocratic woman died from plague (ea 7), and the local ruler was ill (ea 11), consistent with the spread along the trade route. west of simyra, coeval letter ea 35 from cyprus stated "the hand of nergal is in my country", killing many, in particular individuals linked to copper mining. the attribution of the plague to the mesopotamian god of pestilence nergal points to an origin from the east, that is, via canaanite harbors and indicates that the etiological agent also travelled by ship. 93 note that the letters referred to in the above quote are amarna letters and are quoted from william moran's book the amarna letters published in 1992 by the john hopkins university press, usa. trevisonato argues that initially the epidemic was confi ned to the central area of the near east from cyprus to iraq and from israel to syria, sparing egypt and the neshite or hittite empire. later, after fi ghting between egypt and the hittites at amka on the litani river to east of byblos and simyra in c.1325 bce , the tularemia infection spread into anatolia via the egyptian prisoners of war to cause the 20-year hittite plague. it would have also spread via the various trade routes that went through the levant. in c.1320 bce , arzawa in western anatolia attacked the hittites. eventually, after a hittite counterattack, the hittites laid siege to the capital of arzawa. during this siege the hittites left sheep carrying tularemia outside the city walls. the starving inhabitants of the city brought the sheep into their city where they, unbeknown to the city inhabitants, spread the disease among the population. thus this is the fi rst documented example of biological warfare. trevisonato argues why he thinks the epidemic was caused by tularemia: the reconstruction of the dynamics of the epidemic helps identifying the etiological agent. a disease lasting 35-40 years, infecting humans and animals, causing fever, disabilities, and death, spreading via rodents aboard ships as well as donkeys, points to francisella tularensis , the etiological agent of tularemia. this disease can linger for a long time, and its longevity is incompatible with shorter-lived epidemics such as from bubonic plague, which for instance hit europe around 1347-1349, and in 1629-1634. furthermore, the description in neshite records, e.g. knees, debilitation, and sensation of internal burning, is also coherent with tularemia. moreover, tularemia also fi ts the onset of the infection, as it infects caravans stopping for rest, turning them into carriers for the etiological agent. the aforementioned trading route between the mediterranean sea and the euphrates would have had such contact points allowing for the spread of the pathogen. 94 trevisonato further believes that the plague of the philistines was also due to tularemia, which has canaan, the setting for the plague of the philistines, as a natural reservoir as shown above. he does not believe it was due to bubonic plague or dysentery and puts forward a strong argument: an etiological agent for the philistine plague. the biblical data appear to center around the box as a vehicle for the disease, as well as the rodents that appear shortly thereafter, and are depicted in the "settlement" paid in gold. the hebrew word akhbar for the rodents fails to distinguish between mice and rats. rats would have carried y. pestis but bubonic plague fails to adequately explain the epidemic. mice are a better option; they can carry diseases, and fi t the other data relative to the historical text, i.e. box, idol, and settlement payment. the gold-plated wooden box measured 2.5 × 1.5 × 1.5 cubits (ex. 25.10-22; ex. 37,5-10), that is, 1.1 × 0.7 × 0.7m, giving a volume of roughly 500 l, offering a nest to mice but not rats. the former animals average 20g and are small enough to enter the box through a small aperture possibly hidden by the gold covering. the latter animals average 300g requiring a wider aperture and more internal space. mice nesting in the box would have explored their new habitat upon each transfer of the box, thus offering an explanation for the box transmitting the disease. mice also explain the otherwise odd detail of a small philistine idol falling on the fl oor. once the box was hosted in the philistine temple, the animals exiting the box from the same aperture, would have tipped over the statuette, eventually breaking the extremities after repeated falls (1sa.5.2-5). the fi ve replicas in gold of rodents and tumors to settle the dispute with the hebrews (1sa.6.3-5) also favor mice over rats. given the specifi c gravity of gold, just over 19 kg/l, a gold mouse would be shy of 400 g, while a rat would be shy of 6 kg. considering 10-20 g tumors, the philistines were paying roughly 3-4 kg of gold in total. rat-like tumors would have resulted in 31-32 kg of gold, where the tumors would have only contributed marginally (additional 3-6%) to the gold already provided by the rats, raising the question of their raison d'être. linking mice to the box and to the disease singles out tularemia as the disease portrayed by the biblical text; mice are known to carry francisella tularensis , the etiological agent for tularemia. moreover, the text calls for a disease that originated from animals, can be communicated, can form tumors, and is deadly. 95 so now there are arguments for the three virulent infections namely bubonic plague, dysentery and now tularemia, being present in the near east at the end of the bronze age. smallpox or variole is a virulent infection caused by a virus. it was fi rst called smallpox in europe in the late fi fteenth century to distinguish it from the "great pox" or syphilis. thought to have originated in north eastern africa 10,000 bce , smallpox then spread to egypt and from there onto india. 96 ramesses v is the fourth pharaoh of the twentieth dynasty of egypt and he died c.1157 bce 97 most likely from smallpox. the well-preserved mummy of ramesses v shows classical smallpox lesions on the face, neck and shoulders as verifi ed by donald r. hopkins in 1979. 98 this period was a time of expansion of the egyptian empire, so cases of smallpox could have been imported into egypt because of this expansion into new territories and war. if the pharaoh, who would have been protected from all harm, fi nally succumbed to smallpox; how long had it been ravaging the general population of egypt and how far had it spread in the near east? sir marc armand ruffer in 1910 described a smallpox like rash on a mummy from the same period (twentieth dynasty) as ramesses v, 99 thus giving further primary physical evidence of the existence of smallpox in the near east at the time of its ending between 1200 and 1150 bce . sir marc armand ruffer (1859 ruffer ( -1917 was an anglo-french pathologist who pioneered paleopathology. in 1882 he graduated from oxford with a ba, then in 1887 gained his mbchb from university college in london followed by his md in 1889. in 1916 he was knighted for his services to bacteriology and hygiene and for his services to the red cross organization. normally a pharaoh is mummifi ed and buried precisely 70 days into the reign of his successor 100 but ramesses v was buried two years after his death-why? hopkins suggests three possible reasons for this. first the body may have deteriorated due to the infection hence it needed prolonged mummifi cation. second the embalmers feared being infected by the smallpox. finally there may have been a shortage of embalmers because they too had been killed by the smallpox epidemic. there may have also been a shortage of stone masons and stone cutters as well, because ramesses vi was also buried in the tomb of ramesses v, that is, two pharaohs in the one tomb, which is not the usual practice. tom slattery has degrees in east asian studies from the university of california, berkeley and in english from central washington university. in his book the tragic end of the bronze age. a virus makes history 101 slattery argues that smallpox may have killed ramesses v and started the end of the bronze age. he also argues that as people died with smallpox there were not enough men to mine tin that was vital in bronze production, hence the bronze age ended because less bronze was able to be made. slattery also thinks that the hittite plague of 1322 bce was due to smallpox. the evidence for the existence of tuberculosis during the bronze age comes again from sir marc ruffer and his examination of egyptian mummies. in his book studies in the paleo pathology of egypt he identifi es the typical spinal lesions of pott's disease as shown in plate ix, fi gures 14 and 15. 102 modern science has also identifi ed the dna of mycobacterium tuberculosis in the spine of egyptian mummies, 103 thus providing primary physical evidence for the existence of tuberculosis in the near east in the late bronze age. in the crowded living conditions in cities with malnutrition and poverty, tuberculosis would have had the perfect breeding conditions in which to fl ourish and devastate the local population in the late bronze age with its high mortality rate. infl uenza in an unprotected population had the potential to be catastrophic but there is no good evidence to support this theory. we only have its potential as a cause of an epidemic. poliomyelitis had the potential to be devastating and egyptian paintings confi rm its existence in the late bronze age, so it is a defi nite possible cause of an epidemic. anthrax is a bacterial infection caused by the bacillus anthracis and is usually fatal in both humans and animals. because it is so lethal it is used as one of the agents in biological or germ warfare today. in the late bronze age with no vaccine or antibiotics an epidemic would be catastrophic. the endospores of the bacterium anthracis can survive for decades or even centuries and when they are inhaled, ingested or come in contact with the skin they can cause the disease in animals or humans. herbivorous animals usually ingest the spores whilst grazing and carnivores usually ingest the spores when eating an infected animal. humans usually contract the disease by inhalation of spores, direct contact of spores with the skin or consumption of the fl esh of an infected animal. one of the ten plagues suffered by egypt, as described in the bible, could have been anthrax with the description of the typical anthrax sores on the animals, which confi rms that anthrax existed in the near east in the bronze age; hence this is another possible cause of an epidemic. measles in a vulnerable population has the potential to cause a lethal epidemic, but unfortunately there is no good evidence or records to show it occurred. we only have its potential as a cause of an epidemic. malaria has been infecting humans "for the entire history of the species" 104 and existed in the near east from anatolia through the levant and into the nile in egypt in the late bronze age, as it still does today. so it had the constant potential to cause death in humans, especially the virulent falciparum strain during the end of the bronze age era. typhus is a zoonosis that is transferred to humans via lice. it was common among groups of people who lived very closely together such as soldiers in barracks, sailors in ships, prisoners in gaols and refugees in camps; hence it was known variously as "barrack fever", "ship fever", "gaol fever" or "camp fever". was the epidemic that the egyptian prisoners of war took into the hittite empire, that caused the hittite epidemic of 1322 bce , really typhus "camp fever" and not smallpox or bubonic plague ? also, as discussed earlier-typhus may have caused the plague of the philistines. in summary, what was needed was an epidemic or several epidemics that had the ability to be lethal, widespread and able to continue for long periods of time or recur frequently; this would be able to change the course of history by destroying empires such as the mycenaean and hittite empires and ending the bronze age. because the end of the bronze age is approximately 3,200 years ago, then the virgin population factor has to be taken into consideration as some of the epidemics, such as infl uenza and measles, may have been the fi rst appearance of these infections in history, hence they would be a lot more lethal than they are today in the same area, the near east. of the diseases discussed above, there is evidence that bubonic plague, smallpox and tularemia fi t these criteria and there is evidence of their existence in the near east at the time. dysentery and typhus would be more localized and shorter lived, but still very lethal in its time and place. poliomyelitis and tuberculosis would be too slow to kill and spread over a wide area but potentially lethal locally. anthrax and malaria are also possibilities. there is no good evidence or records to support the existence of infl uenza and measles. they may well have occurred and been lethal, but if they did occur they would have been seasonal and relatively shortlived epidemics. this is in agreement with itamar singer's understanding who said "plagues are already attested in anatolia in the old assyrian colony period (cecen 1995), and are often mentioned in late bronze age syrian documents (klengel 1999b)". 105 so it is possible that diseases could have contributed to the end of the hittite empire and the end of the bronze age in a major way. because of the timeframe of about 50 years from c.1200-1150 bce there was plenty of time to have several major lethal epidemics such as bubonic plague, smallpox and tularemia occur on a widespread scale, supported by more local epidemics such as dysentery, poliomyelitis, tuberculosis, measles, infl uenza, anthrax and malaria. in a time of poor hygiene, no antibiotics and no vaccines these infections (fi ve of which are so virulent that they are still used as germ warfare agents today, namely bubonic plague, smallpox, tuberculosis, anthrax and dysentery) had the potential to devastate the near east and should be factored in as potential cofactors in the future by historians. any future discussions about the end of the hittite empire and end of the bronze age should be considered as incomplete if disease is not considered and included. early bronze age metallurgy in northeast aegean the age of iron ironware piece unearthed from turkey found to be the earliest steel the babylonians ancient history from the first civilization to the renaissance from bronze to iron arms and armour of the greeks the age of iron the catastrophe " part 2 : what the end of the bronze-age civilization means for modern times the catastrophe the collapse of mycenaean palatial civilization the end of the bronze age end of the late bronze age and other crisis periods : a volcanic cause hints that cometary debris played some role in several tree-ring dated environmental downturns in the bronze age poseidon ' s horses : plate tectonics and earthquake storms in the late bronze age aegean and eastern mediterranean the end of the bronze age by large earthquakes evidence for an earthquake at mycenae in archaeoseismology verlag, der osterreichischen akademie der wissenschaften, 1984. wien. (vienna: greek prehistory, the austrian academy of sciences t he great karnak inscription of merneptah : grand strategy in the thirteenth century bc medinet halu inscriptions of ramesses iii's eighth year lines 16-17 as translated by the ancient mediterranean the bronze and archaic ages the bronze age -iron age transition in europe contribution of drought to the collapse of the hittite empire dendrochronological dating in anatolia : the second millenium bc ", (der anschnitt, anatolian/metal iii the infl uence of climatic change on the late bronze age collapse and the greek dark ages changes in vernacular architecture and climate at the end of the aegean bronze age the collapse of complex societies vermule 1960. 46. lokovides a cultural chronology of disease from prehistory to the era of sars y ersinia pestis genome sequencing identifi es patterns of global phylogenic diversity the philistine in transition ; a history from ca die herkunft der philister the plague of the philistines , and other medical -historical essays by encyclopedia of plague and pestilence from ancient times to the present anatolian tree rings and the absolute chronology of the eastern mediterranean 2220 -718 bc natural disasters , (facts on file science library plague an ancient disease in the twentieth century the plague of the philistines the works of flavius josephus translated by w. whiston tularemia did an epidemic of tularemia in ancient egypt affect the course of world history hittite plague ", or epidemic of tularemia and the fi rst record of biological warfare the biblical plague of the philistines now has a name , tularemia 000-years-terro. epidemics of the past smallpox: 1200 years of terror whqlibdoc. who.int/smallpox/wh_5_1980_p22.pdf. ramesses v. earliest known victim note on an egyptian resembling that of variola in the skin of a mummy of the twentieth dynasty 1200 -1100 bc chronology of the pharaohs the tragic end of the bronze age a virus makes history studies in the paleopathology of egypt characterization of mycobacterium tuberculosis complex dnas from egyptian mummies by spoligotyping early origin and recent expansion of plasmodium falciparum mutanuinden kultepe-texten " in (atti del 11 congresso internazionale di hittitologia epidermien im spatbronzezeitlichen syrien -palastina " in michael. (historical, epigraphical and biblical studies in honor of michael heltzer key: cord-017916-wh708hes authors: mocchegiani, eugenio; malavolta, marco title: role of zinc and selenium in oxidative stress and immunosenescence: implications for healthy ageing and longevity date: 2008-08-04 journal: handbook on immunosenescence doi: 10.1007/978-1-4020-9063-9_66 sha: doc_id: 17916 cord_uid: wh708hes ageing is an inevitable biological process with gradual and spontaneous biochemical and physiological changes and increased susceptibility to diseases. some nutritional factors (zinc and selenium) may remodel these changes leading to a possible escaping of diseases with subsequent healthy ageing, because they are especially involved in improving immune functions as well as antioxidant defense. experiments performed “in vitro” (human lymphocytes exposed to endotoxins) and “in vivo” (old mice or young mice fed with low zinc dietary intake) show that zinc is important for immune response both innate and adoptive. selenium provokes zinc release by metallothioneins (mt), via reduction of glutathione peroxidase. this fact is crucial in ageing because high mt may be unable to release zinc with subsequent low intracellular free zinc ion availability for immune response. taking into account the existence of zinc transporters (znt and zip family) for cellular zinc efflux and influx, respectively, the association between znt and mt is important in maintaining satisfactory intracellular zinc homeostasis in ageing. improved immune performance occur in elderly after physiological zinc supplementation, which also induces prolonged survival in old, nude and neonatal thymectomized mice. the association “zinc plus selenium” improves humoral immunity in old subjects after influenza vaccination. therefore, zinc and selenium are relevant for immunosenescence in order to achieve healthy ageing and longevity. ageing is an inevitable biological process that is accompanied with gradual and spontaneous biochemical and physiological changes including increased susceptibility to diseases, adverse environmental conditions and loss of mobility and agility. alterations in the immune functions play a fundamental role in ageing. the inability of an organism in remodeling these immune changes may lead to the appearance of some degenerative age-related diseases. as a result, the "remodeling theory of ageing" has been proposed (paolisso et al . 2000) . various nutritional factors are directly linked with these phenomena as for instance in restoring the immune functions as well as in the capacity to respond to oxidative stress (meydani 2001) , which is in turn the main cause of the immune derangement in elderly (pawelec 2000) . approximately, 40 micronutrients (vitamins, essential minerals and other compounds required in small amount for normal metabolism) have been reported as essential components in the diet (shenkin 2006) . the dietary intake of essential macro and micronutrients is usually inadequate in the elderly (ames 2006) . several causes contribute to this gap. first of all, the poor socio-economic condition present in a large part of old people may lead to a consumption of inexpensive foods deficient in micronutrients, such as carbohydrates (kant 2000) . the gap is worsened by loss of appetite, lack of teeth, intestinal malabsorption and decreased requirement of energy that lead to the final result of frailty, disability and mortality (semba et al. 2006) . some authors have reported that the deficiency of macro and micronutrients in ageing is strictly related to global impairments of the immune functions with subsequent limited defense against external noxae and appearance of age-related diseases (lesourd 2006) . by contrast, recent longitudinal studies in dietary daily intake in human nonagenarian/centenarians (successful ageing) have shown that an adequate consumption of micro and macronutrients as well as a satisfactory content of some trace elements in the cells lead to good performances in several immune functions, especially in innate immune performances (chernoff 2001; mocchegiani et al. 2003) . therefore, nutritional factors may play a pivotal role for immunosenescence in order to reach healthy ageing and longevity. we herein review the role of zinc and selenium, taking into account the pivotal role played by these two micronutrients in the efficiency of the immune functions (buttriss 2000) . recent epidemiological and clinical evidence have shown that in most developing countries deficiencies of these micronutrients are partly responsible for the severity of infectious disease, morbidity and mortality in malnourished children (bhaskaram 2002) as well as in ageing (meydani 2001) . indeed, these two trace elements form an important pillar in the nutrition of young and elderly persons because also involved in tissue integrity (enwonwu and sanders 2001) . thus, it is evident that a deficiency of these elements could lead to a crucial impairment of the organ and tissue function with subsequent influence on many body homeostatic mechanisms, including the immune functions. zinc is one of the most important trace elements in the body, although its presence in nature does not exceed 0.02% (mills 1989) . the major characteristics of zinc include a highly concentrated charge, a small radius (0.65a), no variable valence [low risk of free radical production], ready passage from one symmetry in its surroundings to another without exchange, rapid exchange of ligands (on and off reactions), and binding mostly to s-and n-donors in biological systems. these properties enable zinc to play a major biological role as a catalyst. removal of the catalytic zinc results in an active apoenzyme that usually retains the native tertiary structure (vallee and falchuk 1993) . thus, it is not surprising that zinc is essential for the activity of more than 300 enzymes influencing the activity of zinc dependent antioxidant enzymes, such as superoxide dismutase (sod) and various organ functions having a secondary effect on the immune system (rink and gabriel 2000) . zinc also regulates the balance between the gene expression of metalloproteinases (mmps) and the tissue inhibitors of matrix metalloproteinases (timps; nagase and woessner 1999) . the main function of mmps is the removal of extracellular matrix (ecm) during tissue resorption and progression of many diseases. however, it is notable that mmps also alter biological function of ecm macromolecules by specific proteolysis (shapiro 1998) . therefore, since mmps are induced especially by proinflammatory cytokines (il-1 and tnf-alpha), an overexpression of mmps may lead to excessive proteolysis of ecm, as it occurs in chronic inflammation (gueders et al. 2006) . as a consequence, degradation of ecm and limited cell-cell adhesion may occur, so "trapping" bioactive mediators (moot and werb 2004) . thus, the expression of mmps genes are under the control of some inhibitors of mmps, such as timps gene products, α-2 macroglobulin (α-2m) and 13-amyloid precursor protein (nagase and woessner 1999) . as a result, a balance in the expression of the metalloproteinases [either as activators (mmps) or as inhibitors (timps)] is necessary for an optimal function of many biological systems. examples of altering the balance between mmps and timps or α-2m have been recorded in certain types of cancer, infections and ageing (nagase and woessner 1999) that are conditions characterized by zinc deficiency (fabris and mocchegiani 1995) . zinc also regulates g0/g1 phase of cell cycle through cyclins/cdk complexes in a dose dependent manner. specifically, high doses of zinc (900 μm) result in cell cycle arrest (paramanantham et al. 1996) , whereas low doses of zinc (150 μm) inhibit apoptosis (fraker 2005) . zinc is present in "zinc finger domains" of many proteins, peptides, enzymes, hormones, transcriptional factors and cytokines, which act in maintaining body homeostasis (coleman 1992; berg and shi 1996) . zinc also regulates mrna stability (taylor and blackshear 1995) and extracellular matrix (vallee and falchuk 1993) . moreover, zinc binds enzymes, proteins and peptides with different binding affinity (kd) ranging from 10 -2 to 10 -14 mol/l ( see review mocchegiani et al. 1998 ). these compounds display low biological activity when the zinc-binding doesn't occur, as for instance for thymic hormone named thymulin, which loses its activity in absence of zinc (fabris et al. 1984) . finally, zinc plays a critical role in structure, function, stabilization and fluidity of biomembrane due to its binding to sulphydryl groups forming mercaptides (vallee and falchuk 1993) . zinc also maintains the enzymatic activity of inducible nitric-oxide synthase (inos; bodgan et al. 2000) , with a binding between zinc and two cysteine residues, which are part of the structures of the heme domain of inos (li et al. 1999) . as: (i) nitric oxide (no), via no synthases, affects the gene expression of metallothioneins (mt) in order to protect the host from oxidative stress (arizono et al. 1995) and (ii) no is involved in zinc release from mt, via s-nitrosylation (zangger et al. 2001) , the structural task of zinc in no production is crucial. in this context, the release of zinc by mt, via s-nytrosilation, contributing to raise the intracellular free zinc ions concentration, plays a crucial role in modulating the production of proinflammatory cytokines and in the activation of immune cells (rink and haase 2007) . therefore, the interrelationships between zinc and mt is crucial in maintaining the immune response especially in ageing where the production of proinflammatory cytokines is chronic leading to a constant presence of inflammatory status coupled with low intracellular zinc ion bioavailability (mocchegiani et al. 2004 ). the interrelationship between zinc and mt is also regulated by the special proteins named zinc transporters (znt), which in turn appear to be also specifically involved through regulation of cellular zinc homeostasis via influx, efflux, or vesicular sequestration (cousins and mcmahon 2000; eide 2006 ). the znt, some of which are tissue specific, maintain intracellular zinc concentration in a narrow physiological range in order to avoid cellular zinc toxicity or deficiency when dietary zinc intakes fluctuate. two families of znt have been identified. the znt family decreases cytoplasmic zinc concentrations by secretion, sequestration, or efflux, whereas the zip family increases cytoplasmic zinc influx or release of stored zinc (eide 2006) . therefore, the balance of znt is fundamental to maintain an optimal intracellular zinc homeostasis in ageing, because reduced zinc intake by the diet or intestinal zinc malabsorption or loss of zinc through urine by high levels of proinflammatory cytokines are usual events in elderly (prasad et al. 1993b ). mt, are a group of low-molecular-weight metal-binding proteins who have high affinity for zinc (kd = 1.4×10 -13 m; kagi and schaffer 1998) . mt exist in different isoforms characterized by the length of aminoacid chain: isoform i, ii, iii e iv mapped on chro-mosome 16 in man and on chromosome 8 in mice with complex polymorphisms (west et al. 1990 ). the more common isoforms are i and ii; the isoform iii, also called growth inhibitory factor (gif), is a brain-specific member of the mt family and the isoform iv is restricted in squamous epithelia. mt contain 20 cysteines, all in reduced form, and bind seven zinc atoms through mercaptide bonds that have the spectroscopy characteristics of metal thiolate clusters (maret and vallee 1998) . the zinc/cysteine clusters are of two different types. in the beta-domain cluster, three bridging and six terminal cysteine thiolates provide a coordination environment that is identical for each of the three zinc atoms. in the alpha-domain clusters, there are two different zinc sites; two of them have one terminal ligand and three bridging ligands respectively, while the other two have two terminal and two bridging ligands (maret and vallee 1998) . following these biochemical characteristics, mt distribute intracellular zinc as zinc undergoes rapid inter-and intracluster exchange (kagi and schaffer 1998) . moreover, mt act as antioxidant since zinc-sulfur cluster is sensitive to changes of cellular redox state and oxidizing sites in mt (reduced thiol groups) induce the transfer of zinc from its mt binding sites to those of lower affinity in other proteins (kagi and schaffer 1998) . this transfer confers biological activity to antioxidant metalloenzymes. therefore, the redox properties of mt and their effect on zinc in the clusters are crucial for the protective role of mt in presence of ionizing and uv radiations (cai et al. 1999) , heavy metals (mercury, cadmium), lipid peroxidation, reactive oxygen species, oxidative stress caused by anticancer drugs, and conditions of hyperoxia (sato and kondoh 2002) . this protective role of mt has been studied especially in young-adult mt knockout mice (null mice) for short periods of exposure to toxic metals, such as cadmium for 10 weeks (habeebu et al. 2000) or mercury (one single injection and the effect of mercury analyzed 3 days after the injection; satoh et al . 1997) , or to anticancer agents for 48-72 hrs. (kondo et al. 1997) or in presence of an excess of zinc or zinc deficiency for 3 weeks (kelly et al. 1996) . therefore, the protective role of mt is evident in transient stress condition, as it may occur in young adult-age, in which the chronic status (by stress or inflammation) is a rare event (mocchegiani et al. 2006) . in contrast, this role may be questionable in ageing because the stress-like condition and inflammation by high levels of il-6 are chronic (ashok and ali 1999) , with also a different response to stress with respect to young (degroot et al. 2006 ). since il-6 affects the gene expression of mt (hernandez et al.2000) , these proteins may turn off from protective to harmful agents in ageing following the "antagonistic pleiotropy theory of ageing" (williams and day 2003) . in fact, despite mt increase in ageing, a limited release of zinc by mt leading to an impaired immune and antioxidant response has been proposed (mocchegiani et al. 2000a, b) . in contrast, in presence of lower stress and inflammation, as it occurs in centenarians, mt production is low coupled with satisfactory zinc ion bioavailability (mocchegiani et al. 2002a) . indeed, since il-6 acts on the cells through its subunit receptor gp130 (bravo and heath 2000) , the relative lower gene expression of gp130 with respect to elderly found in centenarians (moroni et al. 2005 ) may imply that a quota of il-6 is inactive in centenarians leading to low gene expression of mt, satisfactory free zinc ion availability and low degree of inflammation (mocchegiani et al. 2002a) . as a result, the satisfactory immune performances and antioxidant activi-ties lead to a good healthy status in these exceptional individuals (mecocci et al. 2000; mocchegiani et al. 2002a) . therefore, the interrelationships among inflammatory status, mt and zinc are pivotal in order to achieve successful ageing, furtherly suggesting a different role of mt in ageing that is crucial for immune response (mocchegiani et al. 2000a ). whether mt might play an antagonistic pleiotropic role remains however to be clearly demonstrated also taking into account that they may play different role in different organs. on this aspect, recent findings in cardiac-specific metallothionein transgenic mice suggest that the expression of these proteins in cardiocytes may alleviate aging-induced cardiac contractile defects and oxidative stress prolonging life span (yang et al. 2006 ). in addition, daf-2 mutant nematodes other than a longevity phenotype, display an altered expression of mt which, in turn, seems to interact with the insulin signaling pathway (barsyte et al. 2001) . therefore, even if the specific function of mt in ageing is still a matter of discussion, all these reports associated to recent findings on the possible role played by mt in modulating cellular respiration and energy metabolism (feng et al. 2005; ye et al. 2001 ) strongly suggest that these proteins are involved in the maintenance of health status and in successful aging. on the other hand, recent findings show a novel polymorphisms of mt1a (a/c at position +647 leading to an asparagine/threonine aminoacid substitution) involved in successful ageing, lower inflammation and satisfactory intracellular zinc ion bioavailability (cipriano et al. 2006 ). with regard to the role played by the znt in ageing and immunosenescence, a paucity of data exists in literature. after an increase from the birth up to adult age in some tissues, pancreas (clifford and macdonald 2000) or brain (nitzan et al . 2002) , significant decrements of both znt and zip families in peripheral leukocytes from elderly women occur, in particular the subtypes znt1 and zip1 (andree et al. 2004) . taking into account that zip family increases cytoplasmic zinc influx (eide 2006) , an intriguing point is that zip14 expression is up-regulated through il-6, and that this zinc transporter most likely plays a major role in the mechanism responsible for an excess of intracellular zinc and, at the same time, for hypozincemia that accompanies the acute-phase response to inflammation and infection (liuzzi et al. 2005 ). since chronic inflammation by high il-6, hypozincemia and risk of infections are usual events in old age (mocchegiani et al. 2003) , the possible alterations of the znt in ageing coupled with the inability of high zinc-bound mt in zinc release, may thus allow still more synergistic deleterious effects on immune response that it may be due or to low or excess of zinc within the cells. this last assumption is supported by the discovery that both low and high levels of intracellular zinc lead to cell death (fraker 2005) . therefore, the intracellular zinc ion availability should be maintained within a strict range in order to exert beneficial effect, otherwise it may trigger pathological pathway cascades possibly contributing to the onset and progression of degenerative diseases (mocchegiani et al. 2006 ). for a prompt immune response against stressor agents and inflammation, macrophages produce some cytokines, such as il-1, il-6, ifn-α, tnf-α, which, in turn, provoke a new synthesis of mt in the liver but, at the same time, an alteration in the zinc status (bui et al. 1994 ). these findings clearly suggest the existence of interplay between mt and the immune system. il-1 affects mt mrna in thymic epithelial cells (tecs) by means of pkc, which is, in turn, zinc-dependent (coto et al. 1992) and participates in metal-induced mtmrna (yu et al. 1997) . moreover, mt are donors of zinc for thymulin reactivation in tecs (coto et al. 1992 ). mt act both as a reservoir of zinc during zinc deficiency and as a zinc buffering protein in presence of excessive amount of zinc in order to prevent zinc toxicity (kelly et al. 1996) . following these findings, mt are, out of doubt, protective agents with also the task in preventing zinc deficiency during an inflammatory status. it has been recently reported that, under inflammatory conditions, mt in the extracellular environment may support the beneficial movement of leukocytes to the site of inflammation representing a "danger signal" for the immune cells and modifying the character of the immune response when cells sense cellular stress. however, high mt produced in chronic inflammation, may alter the normal chemotactic responses that regulate leukocyte trafficking (yin et al . 2005) . taking into account that zinc ions attract leukocytes by inducing and promoting the chemotactic response (hujanen et al. 1995) , high mt production might be dangerous for immune response in presence of chronic inflammation. moreover, (i) the existence of high mt and low zinc ion bioavailability in the atrophic thymus from old mice (mocchegiani et al. 2004 ); (ii) the presence of high mt in lymphocytes from old people and down's syndrome subjects (syndrome of accelerated ageing) coupled with impaired innate immunity (mocchegiani et al. 2002a ) and (iii) the occurrence of atrophic thymus in young stressed mice overexpressing mt (mocchegiani et al. 2002b) , furtherly suggest this dangerous role played by mt in immune function during ageing. additionally, elevated levels of extracellular mt, as it can be found especially in chronic inflammatory sites, can cause a dramatic decreases in cytotoxic t lymphocyte (ctl) activity against allogeneic target cells, reduces the proliferative response of ctll-2 cells to cytokines, and decreases the level of major histocompatibility complex (mhc) class i and cd8 molecules detectable on the surface of lymphocytes (youn and lynes 1999) . therefore, high mt may also have an immunosuppressive effect worsened by the fact they are not donors of zinc in ageing but rather sequester zinc. on the other hand, high mt induce down-regulation of many other biological functions related to zinc, such as metabolism, gene expression and signal transduction (kagi and schaffer 1998 ). an unbalance between mt isoforms leads to impairments of zinc-dependent body homeostatic mechanisms within the brain, as reported in samp10 mice (model of accelerated ageing; wen et al. 2006) . moreover, high mt are an index of unfavorable prognosis in cancer (ebadi and swanson 1988) . however, the limited capability of mt in zinc release is still unresolved problem in ageing, especially regarding to the precise mechanism involved. the zinc release from mt under oxidative stress conditions is accompanied by more mt disulfide bond formation (feng et al. 2006) . but, an intriguing point is that also no provokes the zinc release by mt, via s-nitrosylation (zangger et al. 2001) . despite inos increases in ageing, the release of zinc by mt is very limited. one hypothesis might be an unbalance between no synthases (inos and cnos; mocchegiani et al. 2000a ). however, no donors and zinc fluorescent probes are useful tools in order to study the zinc release from mt and to evaluate the intracellular labile zinc in ageing. using a methodology for testing intracellular free zinc ion availability in pbmc recently developed in our laboratory , it has been shown that the no-induced release of zinc can be preserved at least in nonagenarians carrying mt1a polymorphism favorable for successful ageing (cipriano et al. 2006 ). moreover, a flow cytometric assay for the measurement of intracellular labile zinc was recently developed by haase et al. (2006) the zinc-sensitive fluorescent probe named fluozin-3 was used to quantify the amount of labile zinc in peripheral blood mononuclear cells isolated from human blood. with this method, the intracellular concentrations of labile zinc in resting cells were estimated to be 0.17 nm in monocytes and 0.35 nm in lymphocytes (cd4+; haase et al. 2006) . therefore, the combination of these two novel methodological procedures will permit to study in depth the cause of limited zinc release from mt in ageing and, at the same time, to evaluate the intracellular labile zinc. anyway, a limited zinc release from mt exists in ageing provoking a low free zinc ion availability for immune response and antioxidant activity. the recent discovery of another novel polymorphism of mt (-209a/g mt2a) may indirectly support this assumption. indeed, old subjects carrying aa genotype display high mt, low zinc ion availability, enhanced il-6 and impaired innate immune response with subsequent possible risk for atherosclerosis and diabetes type ii (giacconi et al. 2005) . therefore, mt may have a different role in immunosenescence, following the concept that several genes/proteins that increase fitness early in life may also have negative effects later in life: named "antagonistic pleiotropy theory of ageing" (williams and day 2003) . since the crude zinc balance is negative in old mice and in old human (turnlund et al. 1986 ), zinc supplementations in old mice and in elderly have been carried out in order to improve the immune response. the scientific rationale for the immune supporting role of zinc supplementation "in vivo" finds consistent support by data obtained "in vitro" in immune cells. at this regard, many effects of zinc on immune cells have been shown by assessing the cytokine concentration in the samples after zinc stimulation. when pbmcs are stimulated with zinc, il-1, il-6, tnf-α, soluble (s)il-2 receptor and ifn-γ are released (ibs and rink 2003) . the secretion of il-1, il-6 and tnf-α is induced directly by zinc in monocytes and is independent by the presence of lymphocytes (driessen et al. 1994) . however, the effect of zinc on monocytes may depend upon external stimulation. in fact, zinc inhibits lps-induced tnfα and il-1β release from primary human monocytes and monocytic cell lines through the inhibition of cyclic nucleotide phosphodiesterase activity (von bulow et al. 2005) , suggesting that zinc may display also some anti-inflammatory properties. the dose of zinc used is also a critical variable. in serum-free culture medium, concentrations >100 μm of zinc/l stimulate monocytes but prevent t-cells from activating, perhaps due to the lower intracellular content in t-cells than in monocytes (ibs and rink 2003) . treatment with zinc "in vitro" generally displays also beneficial effects on cell survival but, the effect largely depends upon the cell type and the dose of zinc used. it seems that both apoptosis prevention and induction are mediated by pathways involving zinc and/or zinc-dependent enzymes (clegg et al . 2005; wiseman et al. 2006) . therefore, the modulation of the zinc homeostasis plays a key role not only in preventing apoptosis, when oxidative stress is low, but also in inducing apoptosis, when oxidative stress and cellular damage is high, in order to down regulate immune responses and to eliminate virally infected or malignant cells (fraker and lill-elghanian 2004) . taking into account the strict correlation existing between oxidative stress and immune function especially in response to specific stimuli through the production of proinflammatory cytokines for a prompt immune response (franceschi et al. 2005) , this role of zinc in inducing apoptosis of only damaged cells in presence of high oxidative stress is evident in young-adult age and with a great surprising in very old age (ostan et al. 2006) , perhaps due to the presence of satisfactory zinc ion availability (mocchegiani et al. 2002a ) that regulates p53 activity for health lifespan (bauer and helfand 2006) , being p53 a zinc binding protein (hainaut and mann 2001) . experiments in thymocytes also support this point of view, since media supplemented with zinc from 50 up to 150 μm prevents old thymocyte apoptosis induced by dexamethasone or serum deprivation (provinciali etal. 1998) , whereas the direct introduction of free zinc as zinc-pyrithone inside thymocytes induces apoptosis (mann and fraker 2005) . in this last case, the continuous presence of intracellular free zinc ions can advice the cell that permanent oxidative stress and irreversible damage are present, thus activating proapoptotic pathways. old literature reports that a physiological zinc supplementation in the diet throughout the life span in adult rodents prevents some age-related cell-mediated immune modifications, such as the decreased circulating thymic hormone levels (iwata et al. 1979) . more recently, a physiological zinc supplementation (18 μg/ml zn ++ in the drinking water for 1-month) in old mice induces thymus re-growth and functionality (dardenne et al. 1993; mocchegiani et al. 1995) and restoration of nk cell cytotoxicity . that the benefit of zinc supplementation upon the immune functions in old mice is not to consider an epiphenomenon comes by the analysis of the rate of survival in old zinc treated mice. old mice (inbreed balb/c mice) treated with daily zinc at the dose reported above in drinking water from the pre-senescent age (12-14 months of age) display a significant increment of the rate of survival up to 33th month of age when this strain of mice usually lives up to 28-29th month of age. the increment of old survivor zinc treated mice is particularly significant in the middle age (24-25th month of age; mocchegiani et al. 2000b ). the increased rate of survival is largely due to significant decrements of deaths due to cancer and infection in the middle age (mocchegiani et al. 2000b) . of interest, the crude zinc balance is negative, other than in old mice, also in nude and neonatal thymectomized mice (mocchegiani et al. 2000b (mocchegiani et al. 2007 . a zinc supplementation increases the rate of survival also in nude and neonatal thymectomized mice (mocchegiani et al. 2007 ), which display a very short survival due to thymus absence (piantanelli and fabris 1978) . taking into account that the liver extrathymic t-cell pathway is prominent in nude, thymectomized and old mice in order to compensate the thymic failure (abo 2000) , it is evident the zinc also affects the liver extrathymic t-cell pathway with good performances of the immune functions against external noxae (mocchegiani et al. 1998 ) coupled with increased rate of survival. with regard to elderly, undefined data exist on the beneficial effect of zinc supplementation upon the immune efficiency due to different doses of zinc used and to the length of the treatment (bodgen et al. 1990; boukaiba et al. 1993; cakman et al. 1997; duchateau et al. 1981; fortes et al. 1998; prasad et al. 1993b; sandstead et al. 1982) . although zinc was used at the dose recommended by rda (from 15 to 25 mg/day) in the majority of the studies, prasad et al. (1993b) and boukaniba et al. (1993) have found an increment of thymulin activity and improvements in response to skin-test antigens and taste acuity (zinc dose = 15 mg /day for 4 months); bodgen et al . (1990) have reported no benefit exclusively for increased lymphocyte mitogen proliferative response (zinc dose = 15 mg/day for 1-year); cakman et al. (1997) have found enhanced ifn-γ production by leukocytes (zinc dose = 15 mg/day for 45 days); fortes et al. (1998) report an increased number of ctls (zinc dose = 25 mg/ day for 40 days); duchateau et al. (1981) and sandstaed et al. (1982) have observed an improvement in response to skin-test antigens and taste acuity (zinc dose = 220 mg/day for 1-month). thus, it seems evident from these studies that physiological dose of zinc for a long period or high doses of zinc for short periods might induce limited effects on immune response perhaps due to a zinc accumulation in various organs and tissues with subsequent toxic effect of zinc upon the immune functions (fosmire 1990; sandstead 1995) . in this context, it is useful to remind that high doses of zinc trigger apoptosis of the immune cells in presence of high oxidative stress, as reported above. therefore, zinc supplementation has to be used with caution for short periods and on alternate cycles. following that, in our experience, zinc treatment at the dose of 15 mg zn ++ /day for 1-month in down's syndrome subjects, in elderly and in old infected patients restores thymic endocrine activity, lymphocyte mitogen proliferative response, cd4+ cell number, peripheral immune efficiency (nk cell cytotoxicity), th1/th2 paradigm (franceschi et al. 1988; kahmann et al. 2006; mocchegiani et al. 2003 ) and dna-repair (chiricolo et al.1993) . at clinical level, significant reductions of infection relapses occur in down's syndrome (licastro et al. 1994) in elderly and in old infected patients with a faster outcome from the pathology (mocchegiani et al. 2003) . physiological zinc supplementation was reported to lead to a decrement in plasma lipid peroxide concentrations in elderly people living in a public home (fortes et al. 1997) . the positive effect of zinc on lipid peroxide could derive from its protective effects on sulphydryl groups against oxidation and the fact that zinc is a component of superoxide dismutase (sod; mills 1989) . zinc supplementation is also useful in reducing the oxidative stress in old patients with diabetes type ii (roussel et al . 2003) because it inhibits nf-kb activation and decreases inducible no synthase. as such, the generation of ros decreases, thus zinc provides a protective effect on β cells against death (ho et al. 2001 ). an intriguing point of the zinc supplementation is the increment of znt. elderly women treated for 27 days with 22mg of zinc gluconate /day display significant increments of znt1 gene expression in peripheral leukocytes (andree, et al. 2004) , even if the gene expression of the znt is sensitive in relation to the immune cells considered (whitney et al. 2003) . such increments of znt1 have been also observed in human lymphoblastoid cells adding in vitro 50 or 100 μmol/l of zinc (andree et al. 2004) , furtherly suggesting the relevance of zinc supplementation also in affecting the gene expression of znt and, consequently, the correct maintenance of intracellular zinc homeostasis. that the beneficial effects of zinc supplementation are not to be considered as epiphenomena, it comes by the increased survival also in nude and neonatal thymectomized (ntx) mice treated with physiological zinc (18 μg zn++/day for 1-month) in the drinking water, taking into account that they display a very short survival due to thymic absence and negative crude zinc balance (mocchegiani et al. , 2002b (mocchegiani et al. , 2007 . the prolonged survival is largely due to mortality reduction (about 50%) by infections because zinc also affects the extrathymic t-cell pathway that is prominent in old, nude and ntx mice for t-cell maturation and host defense (abo et al . 2000) . indeed, in vivo and in vitro studies have shown that zinc is a key trace element for liver t-cell maturation and function, particularly for liver nkt cells bearing tcr γδ with high production of ifn-γ (mocchegiani et al. 2004) . of interest, the increment and function of nkt cells (miyaji et al. 2000) and tγδ cells (colonna-romano et al. 2002) also occur in human centenarians, who in turn display satisfactory zinc ion bioavailability and good immune response (mocchegiani et al. 2002a ). all these "in vitro" and "in vivo" studies in ageing, some age-related diseases, and syndrome of accelerated ageing (nude mice, ntx mice, down's syndrome) demonstrate the pivotal role played by zinc supplementation in maintaining or improving global immune response and in fighting the oxidative stress, strengthen by findings observed in human centenarians. however, since zinc also affects mt gene expression (maret 2003) , the question arises whether zinc supplementation in old age may furtherly increase mt causing possible major harmful effects. old zinc treated mice exhibit no further significant increments of liver mt mrna, suggesting that mt in ageing may be already over-expressed before supplementation (mocchegiani et al. 2002b ). moreover, the effects observed during zinc supplementation on the immune system, such as reduced inflammation and restored th1/th2 paradigm (prasad 2000) , suggest that intracellular zinc may return available despite over-expressed mt (mocchegiani et al. 2002b) with a maintenance of their original protective role. therefore, the possible harmful effect of mt in ageing seems to not constitute a problem during physiological zinc supplementation. the beneficial effect of physiological zinc supplementation must be, however, related to the levels of other cations such as cadmium, lead, calcium, iron, manganese and copper. the beneficial effects of zinc on ameliorating toxicity of cadmium and lead, accentuation of zinc deficiency by administration of calcium and phytate, and production of hypocupremia by excessive zinc intake in humans and animals, are some examples of competition phenomena between these cations (hill 1976) . such a competition occurs because these ions have similar valence shell electronic structure and, therefore could be antagonist to each other. for instance, the competition between zinc and iron (fe++) occurs at the level of cysteine-histidine ligands for the formation of iron or zinc "fingers" proteins (prasad 1993a ). if iron is excess, a preferential binding of iron than zinc to the metal free-protein occurs. excess of zinc or zinc deficiency impairs dna-protein interactions of zinc-fingers domains with their cognate dna target sites. in these conditions the production of some transcriptional factors like sp1 or tfiiia is impaired (thiesen and bach 1991) . the same impairment of zinc fingers dna domains occurs in excess or deficiency of copper (prasad 1993a ). this reinforces the notion of the relevance of interactions between zinc and copper as well as with other metals in the immune efficiency (sandstead 1995) . thus a limited range of bioavailability exists for each metal. as such, immune responses are optimum. indeed, the beneficial effect of zinc is strictly dependent by the dose and the length of treatment. zinc accumulation or imbalance zinc-to-copper ratio may occur despite low doses of zinc (fosmire 1990 ). as such, harmful side effects in the cardiovascular system and in the brain may appear with increased low-density lipoprotein and cholesterol (fosmire 1990 ) and neural cell-death (kim et al. 1999) , respectively. therefore, caution in zinc supplementation is necessary for avoiding undesirable and harmful unexpected side effects. zinc supplementation must not exceed 2-3 times the rda/day, for short periods (1-2 months) and on alternate cycles. this treatment doesn't interfere in copper absorption (faillet-coudray et al. 2006; licastro et al. 1994) . zinc picolinate form may be the best supplement (wapnir et al. 1983 ). selenium (se) is an essential dietary element for the prevention of some diseases, including cancer and infections (schwarz 1976) . such an assumption has been subsequently confirmed in animals with a selenium deficiency in the diet and concomitant treatment with various carcinogens, such as 1,2-dimethylhydrazine (dmh) or dimethylbenz(a)anthracene (dmba), compared with animals fed with higher content of selenium in the diet. in this context, although se deficiency appears to affect dmh toxicity with however no inhibition of tumor development by nutritional se (0.1 ppm se; pence and buddingh 1985) , three relevant papers report a greater development of carcinoma by dhm or dmba in various organs (colon and mammary gland) in rats fed with selenium deficiency in the diet in comparison with rats treated with 5 ppm of se (jacobs 1983; liu and milner 1992; mcgarrity and peiffer 1993) . these findings further suggest the ability of dietary selenium to inhibit the in vivo metabolism of carcinogens dmba or dmh with subsequent less development of the tumor. with regard to infection, decreased dietary selenium can change a normally avirulent b3 coxsackievirus (cbv3/0) into a virulent virus (cbv3/20) by inducing changes in viral genoma, especially in viral rna polymerase mutations (duarte et al. 1994 ) that infect heart muscle and cause myocarditis with subsequent possible development of dilated cardiomyopathy and death (beck and levander 2000) . in food, selenium derives from vegetables and animal products and in particular from the consumption of seafood, liver, and cereals. however, in vegetables and cereals the amount of selenium varies in soil in different countries and geographical regions (wasowicz et al. 2003) . indeed, selenium deficiency and related diseases have been well documented in geographic regions where the soil content is low, such as the chinese province of keshan (li et al. 1985) . from this region of china, in fact, keshan disease is named the pathology characterized by selenium deficiency and presence of substantial number of virulent viruses, including coxsackieviruses . mammals can use both inorganic and organic selenium as a nutrient. most of the biological functions of selenium are attributed to selenoproteins, which contain selenocysteine residues responsible for their specific activity. selenoproteins are present in every cell type. the human selenoproteome consists of 25 selenoproteins, mostly involved in antioxidant defence systems (kryukov et al. 2003) . glutathione peroxidases (gpxs), a family of the selenoproteins, protect cells against oxidative damage by catalysing the reduction of hydrogen peroxide and other hydroperoxides (brigelius-flohe 1999; hall et al. 1998) . five selenium dependent gpx isoforms exist in humans and four isoforms in mice. gpx1 is found in the cytosol of almost all cells and catalyses the reduction of free hydroperoxides. gpx2 is expressed in the gastro-intestinal tract and has a substrate specificity similar to gpx1; gpx3 is an extracellular enzyme found in plasma and reduces membranebound phospholipid hydroperoxides (brigelius-flohe 1999) . gpx4 is expressed in various tissues, and reduces phospholipid hydroperoxide and hydrogen peroxide using also thiols, such as 2-mercaptoethanol, cysteine and homocysteine, other than gsh as reductant agents (roveri et al. 1994 ). the isoform gpx6 seems to be specifically expressed in embryonic tissues and olfactory epithelium (kryukov et al. 2003) . it also exist a selenium independent isoform, gpx5, which is an epididymis isoenzyme present in mice and humans (hall et al. 1998 ), but its mrna was found to be not translated into functional protein in human epididymis (ghyselinck et al. 1993) . selenium is also involved in the thioredoxin system, a major enzymatic system that plays an important role in maintaining the redox state of the cell (holmgren 1985) . this system is highly complementary to the gsh system in protecting against oxidative stress (watson et al. 2004) . it comprises basically of thioredoxin (trx) and the selenoprotein thioredoxin reductase (tr) and uses the reducing power of nadph to act as a potent antioxidant system as well as a general disulfide redox system (rundolf et al. 2004) . mammalian tr maintains trx in a reduced state (holmgren 1985) and reduces a variety of other substrates including nondisulphides. the thioredoxin system protects the cell against oxidative stress through a variety of mechanisms. trx can directly quench singlet oxygen and scavange hydroxyl radicals (das and das 2000) , or reduced trx can indirectly serves as an electron donor for trx peroxidase. in addition, human tr is directly capable to efficiently reduce lipid hydroperoxides, hydrogen peroxide and organic hydroperoxides using nadph, especially in the presence of catalytic amount of selenocysteine, thus serving as an important alternative to the gpx pathway for the elimination of harmful hydroperoxides (bjornstedt et al. 1995) . trx system is also critical for signal transduction (arner and holmgren 2000) and in the restoration of the reduced form of several antioxidant compounds, including ascorbic acid, lipoic acid, and ubiquinone (nordberg and arner 2001) . in this context, selenomethionine, a potent catalytic antioxidant in biological system and an aminoacid occurring in proteins in place of methionine (walter and roy 1971) , reacts more efficiently than methionine (padmaja et al. 1996) with oxidants forming methionine selenoxide which, in turn, is effectively and rapidly reduced to seleniomethionine by glutathione (assmann et al. 1998) . in contrast, methionine sulphoxide that it is produced by the oxidation of methionine in presence of oxidants, is not simply reduced by gsh, but it requires a specific enzymatic reaction catalyzed by methionine sulphoxide reductase (levine et al. 1996) . since selenomethionine can occur in proteins such as haemoglobin (beilstein and whanger 1986) , these residues may play a defensive role against peroxinitite. another selenoprotein, which reduces phospholipid hydroperoxides in the presence of thiols, is the selenoprotein p (sep; burk et al. 2003) . sep is expressed in many tissues and represents the major plasma selenoprotein, which contains 50% of the total plasma selenium in the form of selenocysteine. sep protects endothelial cells against damage from peroxynitrite and transports selenium from the liver to peripheral tissues (burk et al. 2003) . last, but not the least in order of importance, is a class of selenoproteins (iodothyronine deiodinase enzymes), which catalyse the peripheral deiodination of thyroxin (t4) to 3,3'5-triiodothyronine (t3). these enzymes play crucial roles in determining the circulating and intracellular levels of t3 and, consequently, the control of growth, development, differentiation, metabolism and finally also the immune response (kohrle 2000; beckett and arthur 2005) . immunologically, the ability of selenoproteins to protect the host from oxidative stress is vitally important, since many host defence systems rely on the microbiocidal effects of macrophage-or neutrophil-generated free-radical species. oxidative species are generated through general metabolism, during the metabolism of xenobiotics and during exposure to ultraviolet radiation (uv) in sunlight. inflammation as a process to clear infection and damaged tissue also generates great oxidative stress. if antioxidant systems are not functioning correctly, host cells will be damaged (mckenzie et al. 1998) . taking into account that the inflammation is chronic in ageing as well as oxidative stress (franceschi et al. 2000) , the role played by selenium through the selenopreoteins in immune response is therefore vital in elderly. the influence of selenium on the immune function can be, in part, attributed to the same selenoproteins involved in the protection against oxidative damage and, in part, to still undefined biochemical pathways. the antioxidant gpxs have probably a role in protecting neutrophils from ros that are produced during inflammation (arthur et al. 2003a, b) . selenium supplementation, in mice, increases the expression of subunits alpha (p55) and/or beta (p70/75) of il-2 receptor (il-2r) from activated lymphocytes and nk cells, thereby enhancing proliferation and clone expansion of cytotoxic precursor cells. in vitro, selenium enhances the release of tumor necrosis factor (tnf), il-1 and il-6 from lps stimulated macrophages ( see review beckett et al. 2003) . however one of the most widely investigated associations between selenium and the immune system is the effect of the micronutrient on neutrophil function. neutrophils produce superoxide-derived radicals to take part in killing of microbes. this type of process is a balance between the production of sufficient radicals to kill invading organisms and the systems that protect the neutrophils themselves from the radicals. thus, although selenium deficiency does not affect neutrophil numbers in a range of species, certain aspects of their function are defective (turner and finch 1991) . neutrophils from selenium-deficient mice, rats and cattle are able to ingest pathogens in vitro but are less able to kill them than are neutrophils from selenium-sufficient animals. this defective function has been associated with decreased cytosolic gpx (gpx1) activity in the neutrophils, which allows the free radicals that are produced in the respiratory burst to kill the neutrophils themselves (arthur et al. 2003b ). therefore, taking into account all these mechanisms, selenium deficiency has been mainly studied in relation to ageing/mortality and in some age-related diseases, whose pathogenesis is related to preservation of membrane integrity and to oxidative damage of biomolecules, such as lipids, lipoproteins and dna. selenium deficiency is a condition, mainly attributed to low selenium content in the soil or to long-term parenteral nutrition. selenium is essential for several biochemical mechanisms and selenium blood decline concentrations relate to chronic age-related disease such as cancer, cardiovascular disease and immune dysfunctions (seiler 2001) . during ageing, selenium deficiency may occur in relation to intestinal malabsorption. however, few data report a marked selenium deficiency in old subjects (seiler 2001) . more recently, a paper has explored the relationships between plasma selenium and mortality in an elderly population for a long period of observation (9 years): the eva (etude du vieillissement artériel) study (akbaraly et al. 2005) . the authors have observed during this long period that the mortality rates were significantly higher in individuals with low selenium [1.01 μmol/l: a value below the cutoff considered as optimal (1.25-1.50 μmol/l; thomson 2004; combs 2001) ]. when the underlying causes of death were considered, an association with low selenium and cancer-related mortality was found. the same authors suggest that plasma selenium could be an indicator of longevity in a preaging, independently living population not specifically at risk for cancer and cardiovascular diseases. survival curves illustrate that the relationship between plasma selenium and mortality remained pertinent during the entire 9-year period (akbaraly et al. 2005) . however, the mechanism of this potential relationship is still under debate and further research needed especially on the role played by selenoproteins on this phenomenon. other authors demonstrate selenium deficiency in elderly people in relation to hypothyroidism (oliveri et al. 1996) . interestingly, human healthy centenarians display selenium values quite similar to normal elderly (savarino et al. 2001 ). as few trials have been carried out up to date in elderly, it is difficult to report a specific beneficial effect of selenium in immunosenescence, even if beneficial effects of selenium supplementation on lymphocyte mitogen responsiveness have been reported in institutionalized elderly individuals (peretz et al . 1991) and in old animals (roy et al. 1995) . moreover, a finnish study adding selenium to fertilizer has shown only an increased selenium status in the general population (young, adult, old; aro et al. 1995 ), but not on its possible beneficial effects. the major evidence of the beneficial effects of selenium relate to age-associated diseases. many studies have investigated the effects of selenium in carcinogen-exposed animals showing a reduction in tumor incidence and/or preneoplastic endpoints (reid et al. 2002) . a supplementation with 200 μg/day of organic selenium in randomized subjects showed preventive effects in the incidence and the mortality from various types of cancer (prostate, colorectal and lung cancer; clark et al. 1998; reid et al . 2002) . another large supplementation trial in which a physiological amount of selenium (50 μg) was recently performed in lixian (north china) in order to test its possible beneficial effect in preventing cancer. a small but significant reduction in total and cancer mortality was observed in subjects receiving selenium supplement. the reduction were shown to be greater in women than men and interestingly more pronounced in persons under the age of 55 years compared to individuals older than 55 years (blot et al. 1995) . considering these results, it can be assumed that younger persons might be more amenable to a protective effect of selenium supplementation with thus a role of selenium in preventing age-related diseases or in enhancing the innate immune defenses in the course of the pathology, as observed in selenium supplemented cancer patients (200 mg/d of sodium selenite; kiremidjian-schumacher et al. 2000) . the relevance of selenium in the etiology of cardiovascular diseases has been also studied. selenium metabolism is potentially involved in several protective biochemical pathways related to cardiovascular disease, such as reduction of ldl levels and lipoprotein oxidation, inhibition of foam-cell formation and shift in prostaglandin production from prostacyclin to tromboxane (alissa et al. 2003) . however, wei et al. (2004) found no association between death for cardiovascular diseases and baseline selenium status in a cohort with a mean serum concentration of 0.93 μmol/l in younger individuals (mean age, 57 years). the major studies on the incidence of cardiovascular diseases in these last 5 years have been performed in adult people using a combinations of multivitamins and some trace elements, including selenium, as possible prevention of cardiovascular diseases (atherosclerosis, myocardial infarction, thrombosis). all these studies have shown a less incidence of cardiovascular diseases after supplementation with these combinations in comparison to placebo groups (czernichow et al. 2005; shenoy et al. 2006) . therefore, the existence of a clear link between selenium deficiency "in se" and cardiovascular disease remains to be clearly defined. finally, an intriguing point is the association between selenium deficiency, immune response and increased incidence of infections in adults and elderly. patients with systemic inflammatory response syndrome display a strong impairment in immune efficiency, a decrease of 40% in plasma selenium concentrations coupled with increased morbidity and mortality rates (forceville et al. 1998) . the interrelationships between selenium deficiency, impaired immune response and infections have been clearly shown in experimental animals. an inoculated avirulent virus in selenium deficient animals turns into a virulent one due to genomic changes within the virus, provoking an impaired humoral immune defence (beck 1999) . in humans, a relevant clinical trial with multivitamins and selenium has shown an increment of cd4+ counts over the baseline levels (coodley 1995) and enhanced gpx and gsh activity (delmas-beauvieux et al. 2006) in hiv infected patients this finding suggests that cysteine/gsh are effective natural inhibitors/combaters of (aids) viruses and thereby capable in preventing the development of chronic virus diseases that can lead to aids (rayman 2000) . moreover, supplementation with multivitamins and trace elements, including se, during treatment of pulmonary tuberculosis may reduce mortality in subjects co-infected with hiv (range et al. 2006 ). therefore, an enhanced oxidative stress, caused by selenium deficiency, is the reason of possible viral genetic changes (beck et al. 2003) and increased progression of viral infections with subsequent impaired immune defense (daniels 2004) . additionally, it is also of interest for the role played by selenium deficiency in viral infections the following points: (i) the emergence during these last 4 years (from 2003) of a newly recognized human disease agent (coronavirus) that causes sars from guangdong province of china (lashley 2006) as well as from northern vietnam (reynolds et al. 2006) , where significant areas of overt selenium deficiency exist (xia et al. 2005) ; ii) the increased risk of enhanced virulence of influenza virus in elderly (ellis et al. 2003 ) associated with a possible selenium deficiency (seiler 2001) . therefore, the selenium deficiency may be considered as a relevant risk factor for the appearance of age-related diseases (cancer, cardiovascular diseases and infections by viruses, which may become more virulent or mutated). such a risk is of relevance in elderly because accumulating data suggest that persistent infection with varicella-zoster virus (vzv; arvin 1996) , epstein-barr virus (ebv; stowe et al. 2007 ) and particularly cmv (mcvoy and adler 1989) impacts upon the immune system in aging and may contribute to the immune risk phenotype (irp), which predicts remaining longevity in the very elderly (pawelec et al. 2005) . specific study on these aspects should be encouraged taking into account the possible relevant implications for public health. dietary zinc and selenium are important nutritional factors for the immune response in protecting against the appearance of age-related diseases. the regulation of zinc ion bioavailability by selenium and selenoproteins has been recently investigated (maret 2003) . zinc/thiolate coordination occurs in mt affecting the binding and release of zinc from mt. zinc/thiolate cluster of mt can be oxidized by glutathion disulfide (gssg) or other disulphides in order to release zinc. however, the efficiency of this chemical reaction seems very low even at high concentrations of gssg in the absence of selenium. in contrast, the release of zinc from mt occur very rapidly following the addition of selenium compounds that has the capacity to form a catalytic selenol(ate), releases zinc (maret 2003) . the mechanism of the reaction was suggested to proceed through an activated selenenyl sulphide r-se-s-g intermediate which, in turn, oxidizes the zinc-thiolate cluster of mt to form r-se-s-mt with the concomitant release of zinc during the oxidation (chen and maret 2001) . the selenol group is subsequently released by the attack of a nearby thiol group of mt that convert r-se-s-mt into thionein generating a catalytic cycle of oxidative zinc release from mt. other oxidized selenium compound, such as selenoxide and selenic acid may be directly reduced by mt through the formation of a r-se-s-mt intermediates and the concomitant release of zinc, followed by the formation of an inter-or intramolecular disulfide bond (chen and maret 2001; jacob et al. 1999; klotz et al. 2003) . selenium compounds also catalyze the release of zinc from mt in peroxidation and thiol/disulfide-interchange reactions. in presence of t-butylhydroperoxide, gpx catalyses the mt oxidation with subsequent zinc release, suggesting that mt may serve as reducing agents for gpx (or at least some gpx isoforms) in alternative to gsh (jacob et al. 1999) .therefore, the assessment of zinc ion bioavailability, mt and selenium concentrations could represent useful tools for studying the physiology of successful ageing. indeed, a recent study shows that 84.4% of the 'healthy' nonagenarian/centenarians display both zinc and selenium levels equal or greater than the lowest values in the elderly (savarino et al. 2001) . moreover, healthy nonagenarians display low mt, good zinc ion bioavailability (mocchegiani et al. 2002a) and satisfactory gpx activity (mecocci et al. 2000) . these findings suggest that an adequate zinc and selenium content in cells and tissues are crucial to achieve health ageing and longevity. in this context, girodon et al. (1999) determined the effects of a long-term (for 2 years) daily supplementation with zinc (20 mg) plus selenium (100 μg) on immunity and the incidence of infections in a large number (n.725) institutionalized elderly people (> 65 years). the main results of the study were: (1) selenium deficient patients decreased from about 80% to 5-10% in the selenium supplemented group after 6 months of supplementation with respect to placebo group; (2) antibody titres after influenza vaccine were higher in groups that receive trace elements; (3) trace element supplemented patients were those who remained most free of respiratory tract infections than placebo group. these findings suggest that low dose supplementation of zinc and selenium provides significant improvement in elderly patients by increasing the humoral response after vaccination and decreased influenza compliances (respiratory tract infections) with thus possible achievement of health longevity. beneficial effects obtained by zinc and selenium supplementation alone or associated on immune response and at clinical level are summarized in table 1 . therefore, even if some controversial finding exists on the "real" necessity of micronutrient supplementation (dangouret al.2004) , the huge amount of data reported associated to observational data, clearly suggests that zinc and selenium play a pivotal role for immunosenescence in order to achieve healthy ageing and longevity. however, zinc seems to plays the major role because some biochemical mechanisms involved in the action of selenium are under the control of zinc ion bioavailability, which in turn is affected by mt and znt expression. one of the most relevant biochemical pathways is the release of zinc by mt through interactions with gpx and intracellular disulphides. however, some points require further investigations. first of all, the reason of a possible limited zinc release in ageing and the biochemical mechanism involved, in particular addressing no-related intracellular pathways. such an investigation is relevant taking into account the double face of no action: or as antioxidant or as inducer of cell death (colasanti and suzuki 2000) . although useful tools are now available, such as no donors and zinc fluorescent probes (zinpyr-1 and fluozin-3), in order to test the capacity of the cells in the zinc release by mt, the quantity of labile intracellular zinc in old age remains to be furtherly explored. this last point is also crucial because a fine modulation of intracellular labile zinc is fundamental in order to avoid an excessive zinc release by mt that can result toxic for the cell with subsequent cell-death. moreover, the association of these studies with the role played by znt in ageing may give a more exhaustive picture of the role played by zinc in ageing. the results may form a rationale to select old individuals who effectively need zinc supplementation because zinc, in a some extent, may be also toxic for the immune system leading to a further worsening of the already dysfunctional immune functions in ageing. in fact, many clinical trials of zinc supplementation in elderly report contradictory data on the benefit of zinc supplementation upon the immune functions. thus, it is necessary to have many useful tools to screen real zinc-deficient old subjects. among these tools, the genetic screening for some polymorphisms of mt, such as mt1a, might constitute a useful additional value in screening old subjects healthy ageing and longevity. indeed, old subjects noncarriers of the c allele for mt1a +647 polymorphism display a better preservation of intracellular zinc homeostasis at advanced age, less inflammation, and are predisposed to the longevity with respect to old subjects carrying the c allele for the same mt polymorphism. this finding further suggests that only a certain number of old subjects are prone to zinc supplementation, and not all old population. in the case herein reported, a simple genotype screening might be useful to check the old subjects who should more frequently assess their zinc status for a possible zinc supplementation. in this context, genetic studies and the effect of zinc supplementation exclusively in old subjects with determinate polymorphisms for mt and il-6 are studied in zincage project (www.zincage.org) funded by european commission (ec) in fp6. another project funded by ec in fp5 (zenith) confirms the presence of defects in zinc status and immune response in elderly. however, the biology of zinc is very complex and further studies are necessary in ageing especially addressed to the zinc-binding proteins strictly related to the inflammation and oxidative stress because both these conditions are the basis for the onset of a possible zinc dyshomeostasis in elderly (mocchegiani et al. 2006) . with regard to selenium, the mechanisms of action of se through selenoproteins against oxidative damage have been clear established, even if some aspects at genetic level especially regarding to the glutatione peroxidases require further studies. indeed, while on one hand the genomic sequence of all gpxs isoforms has been established, the evolutionary reasons of an incorrect splicing of the selenium-independent gpx5 in humans is still to investigate. anyway, selenium through selenoproteins has a wide range of action affecting the antioxidant system, the thyroid hormones turnover and the immune functions with a special focus on innate immune response. on the other hand, a correct thyroid hormone turnover affects the immune performances (mocchegiani et al. 2006 ). as such, selenium treatment has been performed in various pathologies characterized by selenium deficiency, high oxidative stress and impaired immune function, such as cancer, infections, cardiovascular diseases as well as ageing. in this context, the more intriguing finding is the discovery that selenium deficiency in the diet or in soil is implicated in the mutation of a normally avirulent b3 coxsackievirus (cbv3/0) into a virulent virus (cbv3/20) by inducing changes in viral genoma. moreover, a marginal selenium deficiency (1.10 μmol/l) causes a higher rate of mortality (by cancer) in old people with respect to old individuals with baseline selenium values (1.25 μmol/l). therefore from the review data herein reported, zinc and selenium in the daily diet during ageing may be relevant in order to preserve immune and antioxidant functions, which can lead to healthy ageing and longevity. alternatively, a combined oral supplementation of these micronutrients can be recommended taking into account the beneficial effects of zinc and selenium in improving the humoral immune response in old vaccinated individuals (duchateau et al. 2004; girodon et al. 1999) . however, the gap between the estimated average requirement of zinc and the upper limit of safe intake is relatively narrow, because excessive zinc may be toxic (fosmire 1990 ). concerning to selenium, even if few reported cases have been associated with an excessive intake of selenium, it has to be taken into account that the institute of medicine of the national academy of sciences has set a tolerable upper intake level for selenium at 400 micrograms per day for adults to prevent the risk of developing selenosis (johnson et al. 2003) . therefore, supplementation with zinc and selenium can be recommended in old people who effectively need zinc and/or selenium supplementation after a careful evaluation of the "zinc/selenium status" through plasma measurement, clinical features and possibly evaluating the intracellular content of zinc and selenium. the usefulness of mt polymorphisms in identifying subjects at risk for zinc deficiency might be an additional tool. as such, the impaired immune functions in elderly, through these two trace elements, may be restored with subsequent healthy ageing and longevity. physiological responses of extrathymic t cells in the liver selenium and mortality in the elderly: results from the eva study the controversy surrounding selenium and cardiovascular disease: a review of the evidence low micronutrient intake may accelerate the degenerative diseases of aging through allocation of scarce micronutrients by triage kirschke cp et al investigation of lymphocyte gene expression for use as biomarkers for zinc status in humans nitric oxide mediated metallothionein induction by lipopolysaccharide physiological functions of thioredoxin and thioredoxin reductase effect of supplementation of fertilizers on human selenium status in finland selenium supplementation: does soil supplementation help and why? selenium in the immune system varicella-zoster virus the aging paradox: free radical theory of aging reduction of methionine selenoxide to selenomethionine by glutathione longevity and heavy metal resistance in daf-2 and age-1 long-lived mutants of caenorhabditis elegans new tricks of an old molecule: lifespan regulation by p53 selenium and host defence towards viruses host nutritional status and its effect on a viral pathogen selenium deficiency and viral infection selenium and endocrine systems selenium immunity and disease deposition of dietary organic and inorganic selenium in rat erythrocyte proteins the galvanization of biology: a growing appreciation for the roles of zinc micronutrient malnutrition, infection, and immunity: an overview human thioredoxin reductase directly reduces lipid hydroperoxides by nadph and selenocystine strongly stimulates the reaction via catalytically generated selenols the linxian trials: mortality rates by vitamin-mineral intervention group the role of nitric oxide in innate immunity effects of one year of supplementation with zinc and other micronutrients on cellular immunity in the elderly a physiological amount of zinc supplementation: effects on nutritional, lipid, and thymic status in an elderly population receptor recognition by gp130 cytokines tissue-specific functions of individual glutathione peroxidases zinc status and interleukin-1 beta-induced alterations in mineral metabolism in rats selenoprotein metabolism and function: evidence for more than one function for selenoprotein p nutrient requirements and optimisation of intakes metallothionein in radiation exposure: its induction and protective role zinc supplementation reconstitutes the production of interferon-alpha by leukocytes from elderly persons catalytic oxidation of zinc/sulfur coordination sites in proteins by selenium compounds nutrition and health promotion in older adults enhanced dna repair in lymphocytes of down syndrome patients: the influence of zinc nutritional supplementation polymorphisms in mt1a gene coding region are associated with longevity in italian central female population zinc deficiency-induced cell death decreased incidence of prostate cancer with selenium supplementation: results of a double-blind cancer prevention trial survey of mrnas encoding zinc transporters and other metal complexing proteins in pancreatic islets of rats from birth to adulthood: similar patterns in the sprague-dawley and wistar bb strains update on vitamins, minerals, and the carotenoids the dual personality of no zinc proteins: enzymes, storage proteins, transcription factors, and replication proteins gamma/delta t lymphocytes are affected in the elderly impact of selenium and cancer-prevention findings on the nutrition-health paradigm interleukin 1 regulates secretion of zinc-thymulin by human thymic epithelial cells and its action on t-lymphocyte proliferation and nuclear protein kinase c integrative aspects of zinc transporters effect of supplementation with antioxidants upon long-term risk of hypertension in the su.vi.max study: association with plasma antioxidant levels micronutrient supplementation in later life: limited evidence for benefit selenium: does selenium status have health outcomes beyond overt deficiency? restoration of the thymus in aging mice by in vivo zinc supplementation thioredoxin, a singlet oxygen quencher and hydroxyl radical scavenger: redox independent functions responses to mild cold stress are predicted by different individual characteristics in young and older subjects the enzymatic antioxidant system in blood and glutathione status in human immunodeficiency virus (hiv)-infected patients: effects of supplementation with selenium or beta-carotene induction of cytokines by zinc ions in human peripheral blood mononuclear cells and separated monocytes rna virus quasispecies: significance for viral disease and epidemiology immunosenescence and the lung beneficial effects of oral zinc supplementation on the immune response of old people the status of zinc, copper, and metallothionein in cancer patients zinc transporters and the cellular trafficking of zinc influenza-and respiratory syncytial virus-associated morbidity and mortality in the nursing home population nutrition: impact on oral and systemic health zinc, human diseases and aging thymic hormone deficiency in normal ageing and down's syndrome: is there a primary failure of the thymus? effect of zinc supplementation on in vitro copper-induced oxidation of low-density lipoproteins in healthy french subjects aged 55-70 years: the zenith study metallothionein disulfides are present in metallothioneinoverexpressing transgenic mouse heart and increase under conditions of oxidative stress metallothionein transfers zinc to mitochondrial aconitase through a direct interaction in mouse hearts selenium, systemic immune response syndrome, sepsis, and outcome in critically ill patients zinc supplementation and plasma lipid peroxides in an elderly population the effect of zinc and vitamin a supplementation on immune response in an older population zinc toxicity roles for cell death in zinc deficiency the many roles of apoptosis in immunity as modified by aging and nutritional status inflamm-aging. an evolutionary perspective on immunosenescence oral zinc supplementation in down's syndrome: restoration of thymic endocrine activity and of some immune defects genes involved in immune response/inflammation, igf1/insulin pathway and response to oxidative stress play a major role in the genetics of human longevity: the lesson of centenarians structural organization and regulation of the gene for the androgen-dependent glutathione peroxidase-like protein specific to the mouse epididymis novel -209a/g mt2a polymorphism in old patients with type 2 diabetes and atherosclerosis: relationship with inflammation (il-6) and zinc impact of trace elements and vitamin supplementation on immunity and infections in institutionalized elderly patients: a randomized controlled trial. min. vit. aox. geriatric network matrix metalloproteinases (mmps) and tissue inhibitors of mmps in the respiratory tract: potential implications in asthma and other lung diseases flow cytometric measurement of labile zinc in peripheral blood mononuclear cells metallothionein-null mice are more susceptible than wildtype mice to chronic cdcl(2)-induced bone injury zinc binding and redox control of p53 structure and function the majority of human glutathione peroxidase type 5 (gpx5) transcripts are incorrectly spliced: implications for the role of gpx5 in the male reproductive tract metallothionein induction by restraint stress: role of glucocorticoids and il-6 mineral interrelationships. in: prasad as (ed) trace elements, human health and disease dietary zinc supplementation inhibits nf-kappab activation and protects against chemically induced diabetes in cd1 mice polymorphonuclear leukocyte chemotaxis induced by zinc, copper and nickel in vitro zinc-altered immune function circulating thymic hormone levels in zinc deficiency selenium redox biochemistry of zinc-sulfur coordination sites in proteins and enzymes selenium inhibition of 1,2-dimethylhydrazine-induced colon carcinogenesis the antioxidants-vitamin c, vitamin e, selenium, and carotenoids biochemistry of metallothionein effect of improved zinc status on t helper cell activation and th1/th2 ratio in healthy elderly individuals consumption of energy-dense, nutrient-poor foods by adult americans: nutritional and health implications. the third national health and nutrition examination survey, 1988-1994 metallothionein i and ii protect against zinc deficiency and zinc toxicity in mice zinc-induced cortical neuronal death with features of apoptosis and necrosis: mediation by free radicals selenium and immunocompetence in patients with head and neck cancer role of copper, zinc, selenium and tellurium in the cellular defense against oxidative and nitrosative stress the deiodinase family: selenoenzymes regulating thyroid hormone availability and action enhanced apoptosis in metallothionein null cells characterization of mammalian selenoproteomes emerging infectious diseases at the beginning of the 21st century nutritional factors and immunological ageing methionine residues as endogenous antioxidants in proteins keshan disease: an endemic cardiomyopathy in china crystal structures of zinc-free and -bound heme domain of human inducible nitric-oxide synthase. implications for dimer stability and comparison with endothelial nitric-oxide synthase detection of enteroviral rna in paraffin-embedded myocardial tissue from patients with keshan by nested pcr oral zinc supplementation in down's syndrome subjects decreased infections and normalized some humoral and cellular immune parameters age, dietary selenium and quantity of 7,12-dimethylbenz(a)anthracene influence the in vivo occurrence of rat mammary dna adducts interleukin-6 regulates the zinc transporter zip14 in liver and contributes to the hypozincemia of the acute-phase response single and three-color flow cytometry assay for intracellular zinc ion availability in human lymphocytes with zinpyr-1 and double immunofluorescence: relationship with metallothioneins zinc pyrithione induces apoptosis and increases expression of bim thiolate ligands in metallothionein confer redox activity on zinc clusters cellular zinc and redox states converge in the metallothionein/thionein pair selenium: an essential element for immune function selenium and difluoromethylornithine additively inhibit dmh-induced distal colon tumor formation in rats fed a fiber-free diet immunologic evidence for frequent age-related cytomegalovirus reactivation in seropositive immunocompetent individuals plasma antioxidants and longevity: a study on healthy centenarians nutrition interventions in aging and age-associated disease zinc in human biology functional alteration of granulocytes, nk cells, and natural killer t cells in centenarians nutrient-gene interaction in ageing and successful ageing. a single nutrient (zinc) and some target genes related to inflammatory/immune response mtmrna gene expression, via il-6 and glucocorticoids, as potential genetic marker of immunosenescence: lessons from very old mice and humans metallothioneins (i+ii) and thyroid-thymus axis efficiency in old mice: role of corticosterone and zinc supply the variation during the circadian cycle of liver cd1d-unrestricted nk1.1+tcrγδ +cells lead to successful ageing. role of metallothionein/il-6/gp130/parp-1 interplay in very old mice zinc, metallothioneins and longevity. effect of zinc supplementation: zincage study zinc, t-cell pathways, aging: role of metallothioneins metallothioneins/parp-1/il-6 interplay on natural killer cell activity in elderly: parallelism with nonagenarians and old infected humans. effect of zinc supply zinc and immunoresistance to infection in aging: new biological tools zinc, metallothioneins, immune responses, survival and ageing reversibility of the thymic involution and of age-related peripheral immune dysfunctions by zinc supplementation in old mice interrelationship among neutrophil efficiency, inflammation, antioxidant activity and zinc pool in very old age regulation of matrix biology by matrix metalloproteinases matrix metalloproteinases postnatal regulation of znt-1 expression in the mouse brain reactive oxygen species, antioxidants, and the mammalian thioredoxin system selenium, zinc, and thyroid hormones in healthy subjects: low t3/t4 ratio in the elderly is related to impaired selenium status effect of zinc ions on apoptosis in pbmcs from healthy aged subjects rapid oxidation of dl-selenomethionine by peroxynitrite metabolic age modelling: the lesson from centenarians flow cytometric evaluation of the dna profile and cell cycle of zinc supplemented human chang liver cells human immunosenescence: is it infectious? effect of dietary selenium deficiency on incidence and size of 1,2-dimethylhydrazine-induced colon tumours in rats lymphocyte response is enhanced by supplementation of elderly subjects with selenium-enriched yeast hypopituitary dwarf and athymic nude mice and the study of the relationships among thymus, hormones, and aging effects of zinc deficiency on th1 and th2 cytokine shifts zinc deficiency in elderly patients flow cytometric analysis of cd3/tcr complex, zinc, and glucocorticoid-mediated regulation of apoptosis and cell cycle distribution in thymocytes from old mice the importance of selenium to human health the effect of multi-vitamin/mineral supplementation on mortality during treatment of pulmonary tuberculosis: a randomised two-by-two factorial trial in mwanza, tanzania selenium supplementation and lung cancer incidence: an update of the nutritional prevention of cancer trial factors associated with nosocomial sars-cov transmission among healthcare workers in hanoi zinc and the immune system zinc homeostasis and immunity antioxidant effects of zinc supplementation in tunisians with type 2 diabetes mellitus supplementation with selenium restores age-related decline in immune cell function regulation of the mammalian selenoprotein thioredoxin reductase 1 in relation to cellular phenotype, growth, and signaling events requirements and toxicity of essential trace elements, illustrated by zinc and copper zinc nutriture in the elderly in relation to taste acuity, immune response, and wound healing recent studies on metallothionein: protection against toxicity of heavy metals and oxygen free radicals enhanced renal toxicity by inorganic mercury in metallothionein-null mice serum concentrations of zinc and selenium in elderly people: results in healthy nonagenarians/centenarians essentiality and metabolic functions of selenium clinical pictures of malnutrition in ill elderly subjects low serum micronutrient concentrations predict frailty among older women living in the community matrix metalloproteinase degradation of extracellular matrix: biological consequences micronutrients in health and disease rationale and design for the cardiovit study (cardiovit, atherosclerotic vascular disease and hyperhomocysteinemia: an epidemiological study in indians, additionally evaluating the effect of oral vitamin supplementation) chronic herpesvirus reactivation occurs in aging zinc inhibits turnover of labile mrnas in intact cells transition metals modulate dna-protein interactions of sp1 zinc finger domains with its cognate target site assessment of requirements for selenium and adequacy of selenium status: a review selenium and the immune response stable isotope studies of zinc absorption and retention in young and elderly men the biochemical basis of zinc physiology zinc-mediated inhibition of cyclic nucleotide phosphodiesterase activity and expression suppresses tnf-alpha and il-1 beta production in monocytes by elevation of guanosine 3',5'-cyclic monophosphate selenomethionine, a potential catalytic antioxidant in biological systems absorption of zinc by the rat ileum: effects of histidine and other low-molecular-weight ligands selenium status of low-selenium area residents: polish experience thioredoxin and its role in toxicology prospective study of serum selenium concentrations and esophageal and gastric cardia cancer, heart disease, stroke, and total death changes of metallothionein 1 and 3 mrna levels with age in brain of senescence-accelerated mice and the effects of acupuncture human metallothionein genes: structure of the functional locus at 16q13 individuality and variation in gene expression patterns in human blood antagonistic pleiotropy, mortality source interactions, and the evolutionary theory of senescence endothelial response to stress from exogenous zinc (zn2+) resembles that of no-mediated nitrosative stress, and is protected by mt-1 overexpression effectiveness of selenium supplements in a low-selenium area of china metallothionein prolongs survival and antagonizes senescence-associated cardiomyocyte diastolic dysfunction: role of oxidative stress zinc metallothionein imported into liver mitochondria modulates respiration metallothionein mediates leukocyte chemotaxis metallothionein-induced suppression of cytotoxic t lymphocyte function: an important immunoregulatory control metal-induced metallothionein gene expression can be inactivated by protein kinase c inhibitor nitric oxide selectively releases metals from the amino-terminal domain of metallothioneins: potential role at inflammatory sites zincage project key: cord-009713-sxd4t2tz authors: nan title: poster presentations date: 2020-01-10 journal: dev med child neurol doi: 10.1111/dmcn.14411 sha: doc_id: 9713 cord_uid: sxd4t2tz nan what are the perspectives and understanding of healthcare professionals including occupational therapists on treatment and care of babies with infantile spasms and early-onset epilepsy? a qualitative design dm middleton university of roehampton-online, birmingham, uk objective: to explore the perspectives and understanding of allied healthcare professionals (occupational therapists, physiotherapists, speech & language therapists) that work with children and epilepsy in order to guide and advocate for this population group. methods: a qualitative study design using interpretive thematic analysis with the data from participants in 10 semi-structured interviews. results: the professionals had worked across acute and community settings and had previous experiences of working with children with epilepsy with some awareness of these needs. there were 5 themes that emerged: (1) housing and social needs, (2) epilepsy, psycho-social and mental health needs, (3) therapy approaches, (4) training for allied healthcare professionals, and (5) adolescents, young girls, women and epilepsy. conclusions: there are gaps in service provision for certain areas and will be shared within the presentation. epilepsy requires additional considerations for safety that other conditions may not require. it is crucial in the interests of public health for children and families with epilepsy to be able to advocate for resources and their specific needs. poster no. 004 time to onset of cannabidiol (cbd) treatment effect and resolution of adverse events in patients with dravet syndrome: pooled analysis of two randomised controlled trials solution) at 10mg/kg/day (cbd10; gwpcare2) or 20mg/ kg/day (cbd20; both trials) or placebo for 14 weeks. cbd treatment started at 2.5mg/kg/day and reached 10mg/kg/day on day 7 and 20mg/kg/day on day 11. percent reduction in cumulative convulsive seizure frequency for each treatment day (including previous treatment days) and timing of adverse events (aes) were assessed. results: overall, 194 patients were randomised to cbd and 124 to placebo. cbd led to significantly greater percent reductions in convulsive seizure frequency than placebo in gwpcare1 (cbd20 39% vs placebo 13%, p=0.0123) and gwpcare2 (cbd10 49%, cbd20 46% vs placebo 27%, p=0.0095 and p=0.0299). in the pooled data, treatment differences in seizure reduction emerged during titration and were maintained throughout the study, with nominal significance (p<0.05) achieved by day 13 for cbd10 and day 12 for cbd20. onset of the first reported ae occurred during titration in 60% of patients with aes. aes resolved within 4 weeks of onset in 40% of patients and by the end of the study in 60%. increases in alt/ast (>39 upper limit of normal) occurred in 3 (5%) patients for cbd10, 25 (19%) for cbd20, and 1 (1%) for placebo; all were on concomitant valproate. all elevations resolved, either spontaneously while continuing cbd, after discontinuing cbd, or after reducing cbd, valproate, and/or clobazam dose. conclusions: cbd treatment effect (seizure reductions and aes) may occur early, during titration. the majority of aes resolved during the study. poster no. 005 low dose fenfluramine hydrochloride oral solution provides long-term, clinically meaningful (≥50%) reduction in seizure frequency in dravet syndrome: interim analysis of a long-term openlabel extension study objective: to characterize long-term safety and durability of effect for adjunctive fenfluramine (ffa) in treating dravet syndrome (ds). methods: patients (2-18y) with ds entered a long-term openlabel extension (ole) (1503) after completing one of two phase 3 studies: study 1 (14wks; placebo or ffa 0.2 or 0.8mg/kg/d [max, 30mg/d] or study 1504 (15wks; placebo or ffa 0.5mg/kg/d [max, 20mg/d]) . stiripentol was excluded in study 1 but mandatory in study 1504. in 1503, patients received ffa 0.2mg/kg/d for month 1; dosing was titrated to effect thereafter. effectiveness and tolerability were assessed at months 1, 2, and 3, then at 3-month intervals. results: at interim analysis (13-mar-2018) , 158/187 patients continued into ole; 89% completed 12 months of ffa (mean dose, 15.2mg/d; median duration, 400d [range, 71-703d] ). during the entire ole, median percentage change in monthly convulsive seizure frequency (mcsf) for ffa vs pretreatment phase 3 study baseline was -63.6% (p<0.001); clinically meaningful (≥50%) and profound (≥75%) mcsf reduction from baseline were 63% and 41%. at month 12, median and mean longest interval between convulsive seizures were 26 and 60 days (range, 2-589d); 71% of caregivers and 83% of investigators rated patients 'much improved/very much improved'. the most common adverse events included appetite decrease, pyrexia, nasopharyngitis, and diarrhea. no valvular heart disease or pulmonary hypertension was observed in any patient. conclusions: treatment with ffa resulted in robust, sustained reductions in mcsf and was generally well tolerated. no valvular heart disease or pulmonary arterial hypertension was observed in any patient at any time. ffa may be an important, novel antiepileptic drug for long-term ds treatment. poster no. 006 zx008 (low dose fenfluramine hydrochloride oral solution) provides long-term, clinically meaningful reduction of convulsive seizure frequency in young (<6 years old) dravet syndrome participants: analysis from a long-term open-label study results: a total of 42 of 158 (26.6%) participants who enrolled in the ole were <6 years old upon entry into the phase 3 studies. the median baseline monthly convulsive seizure frequency (mcsf) before double-blind treatment was 10.7 seizures/month (range, 4.0-147.3 ) in this patient subgroup (<6y). at the time of the ole interim analysis, the median decrease in mcsf in the <6 years subgroup over the entire observation period compared to baseline was -75% (p<0.001) compared with -64% in the overall study population (2-18y). the most frequently reported adverse events included pyrexia, upper respiratory tract infections, decreased appetite, and diarrhea. no valvular heart disease or pulmonary arterial hypertension was observed. conclusions: treatment with zx008 provided sustained, clinically meaningful reduction in mcsf in ds participants <6 years old. importantly, effective control of seizures in this young age group might be expected to mitigate the negative neurodevelopmental outcomes reported to be associated with treatment-refractory seizures. the improving provision of epilepsy care for children in england and wales methods: all relevant health boards and trusts (hb/t) were invited to register to participate and identify a hb/t lead. a snapshot survey was completed via a bespoke online platform by the hb/t lead describing local provision as of april 2018. data was analysed by the rcpch including regional and national aggregates and longitudinal comparison to previous 2012, 2014 reports. results: 148 hb/t with a paediatric epilepsy service across england and wales registered to participate and submitted data. 94.6% (140/148) of hb/t employed a consultant paediatrician with expertise in epilepsy; 77.7% (115/148) had some epilepsy specialist nurse (esn) provision; 85.8% (127/148) had a defined epilepsy clinic seeing patients at secondary level. 92.6% (137/148) of hb/t had agreed referral pathways to tertiary paediatric neurology services. satellite paediatric neurology clinics were hosted in 77.0% (114/148) of hb/t. conclusions: there are improvements in the overall numbers of epilepsy nurse specialists, paediatricians with expertise and specific clinics for children and young people with epilepsies. the findings led to comprehensive recommendations to hb/ t and commissioners, informed updates to the epilepsy best practice tariff and themes within the nhs long term plan. poster no. 008 diagnosing and managing seizures on picu: an explanatory sequential mixed methods approach tonic clonic seizures. awake and sleep eeg showed temporal focal slowing. she was labelled as non lesional focal epilepsy after a normal mri scan and was discharged on keppra. she had multiple admissions with cluster of brief seizures at the age of 12, 16, 25, 26, 34, 38 and 46 months associated sometimes with febrile illness with poor response to intravenous aed's. she was diagnosed with autism at 42 months. 2nd child: 38 months old younger sibling had seizure onset at 9 months. seizures were tonic in nature, brief, multiple and in clusters over a period of 2 to 3 days. eeg's showed non-specific slowing during seizures. array cgh revealed chromosome 3p26.1 microdeletion. keppra was commenced and increased but recurrent cluster of seizures at the age of 15, 19 and 24 months required admission with poor response to iv aed's. family history revealed that half-sister (biological father's daughter who had epilepsy and global developmental delay) was diagnosed with pcdh 19 epilepsy. gene tests were requested on both siblings and both were heterozygous for pcdh 19 mutation. she had delayed social and communication skills from 2 years with a diagnosis of autism at 30 months. 3rd child: 1 year old half sibling (father's 4th child from 3rd relationship) has tested positive for pcdh 19. her development is normal and so far there have been no seizures. conclusions: pcdh 19 epilepsy is increasingly recognised as one of the early onset infantile encephalopathies. gene testing is likely to yield a diagnosis with a family history or with a typical phenotype. poster no. 010 seizure, developmental and cognitive outcomes in children post hemispherotomy tt tay 1 , dr reed 2 , vj josan 3 , sr rust 4 , jt tan 5 1 university of manchester, manchester, uk; 2 neuropsychology team, paediatric psychosocial service, royal manchester children's hospital, manchester, uk; 3 neurosurgery, salford royal nhs foundation, manchester, uk; 4 paediatric neuropsychology, royal manchester children's hospital, manchester, uk; 5 paediatric neurology, royal manchester children's hospital, manchester, uk introduction: patients with focal refractory epilepsy secondary to structural hemispheric changes have been shown in retrospective studies to have significantly improved seizure outcomes following hemispheric disconnection. the aim of this study was to report the seizure and cognitive outcomes in our cohort and investigate prognostic factors for seizure outcomes. methods: this was a single-centre retrospective study on children and adolescents who had hemispherotomy for refractory epilepsy in the royal manchester children's hospital between 2008 and 2017. results: twenty-two patients were included with median (range) age of seizure onset and of surgery of 4 (0-168) and 72 (13-217) months respectively. median (range) time from seizure onset to surgery was 38.5 (12-172) months. the most common aetiologies were antenatal/perinatal middle cerebral artery infarct (n=6) and malformations of cortical development (n=6). at 1 year after surgery and at last follow-up (median [range] 38 [2-107] months), 50% (10/20) and 32% (7/22) achieved complete seizure freedom. the number of anti-epileptic medications decreased for 10 (45%) at last follow-up. lateralisation of ictal and interictal eeg (p=1.00, p=0.11), aetiology (p=0.75), age of first seizure (p=0.45) were not associated with seizure recurrence. five who had formal neuropsychological testing using the wechsler intelligence scale for children (wisc) showed improvement in cognitive abilities across all subsets post-surgery. ten children showed reduction in median vineland adaptive behaviour score, from 58 to 49.5, indicating a failure to progress rather than regression of skills. nine (45%) had newly reported behavioural or psychiatric issues including sleeping problems, challenging behaviours, autistic spectrum disorder. sixteen (84%) were reported by parents/carers to show improved verbal abilities postoperatively while the rest had unchanged verbal abilities. conclusions: we present a cohort of children with early onset seizures who had hemispherotomy at a relatively early age. our cohort showed good seizure outcomes and cognitive improvements. there were no prognostic factors for seizure outcome identified in this small group. the mri phenotype of atp1a3-related disease contrast, all ahc patients with mri abnormalities (83%) had a hypoplastic corpus callosum. the only patient with normal mri was the patient carrying mutation p.g497r, associated with a mild clinical phenotype. of the patients with clinical ataxia (n=7), 5 (71%) had cerebellar atrophy on mri; 2 patients with cerebellar atrophy were not ataxic. two (67%) of the 3 patients with severe intellectual disability had cerebral atrophy. conclusions: atp1a3 mutations have subtle radiological findings, clustering around callosal dysmorphisms, as well as pontine and cerebellar abnormalities that seem to form distinctive mri phenotypes for ahc and capos. study of larger cohorts is required to more accurately define mutation-specific phenotypes and allow for quantitative analysis. poster no. 012 long-term safety and efficacy of adjunctive perampanel in paediatric patients (aged 4 to <12y) with partial-onset seizures (pos) or primary generalised tonic-clonic seizures (pgtcs) in study 311 r flamini 1 , a patten 2 , ly ngo 3 1 pediatric and adolescent neurodevelopmental associates, atlanta, ga, usa; 2 eisai ltd., hatfield, hertfordshire, uk; 3 eisai inc., woodcliff lake, nj, usa objective: study 311 (nct02849626) was a multicentre, openlabel, single-arm study of perampanel oral suspension (0.5mg/ ml) in paediatric patients (aged 4 to <12y) with pos (with/ without secondarily generalised seizures [sgs] ) or pgtcs. here, we report long-term (1y) safety and efficacy data of adjunctive perampanel in paediatric patients from study 311. methods: this analysis included cumulative data from all enrolled patients in the core study (23wks of treatment) and extension phase a (52wks of treatment). assessments included monitoring of treatment-emergent adverse events (teaes), median percent change in seizure frequency per 28 days from baseline, and 50% responder and seizure-freedom rates. results: of 180 patients enrolled in the core study (pos, n=149; sgs, n=54; pgtcs, n=31), 136 patients entered extension a. of these, 14 patients discontinued extension a; most common primary reasons for discontinuation were adverse events (3.7%) and inadequate therapeutic effect (2.9%). for all patients, mean (standard deviation [sd] ) time since diagnosis was 5.7 (2.9) years and mean (sd) duration of exposure was 41.5 (17.3) weeks. during baseline, 55.6% of patients received two concomitant anti-seizure medications. teaes were reported in 162 (90.0%) patients; somnolence was the most commonly reported (27.2%). median percent reductions in pos, sgs and pgtcs frequencies at weeks 1-13 were 43.0%, 57.9% and 79.3%, respectively; these were maintained at weeks 40-52 and were 69.4%, 73.8% and 100.0%, respectively. seizure-freedom rates for pos, sgs and pgtcs at weeks 40-52 were 13.0%, 24.4% and 38.5%, respectively. conclusions: long-term (1y) adjunctive perampanel is generally safe, well tolerated and efficacious in paediatric patients aged 4 to <12 with pos (with/without sgs) or pgtcs. poster no. 013 long-term adjunctive perampanel and healthrelated quality of life (hrqol) in paediatric patients (aged 4 to <12y) with partial-onset seizures (pos) or primary generalised tonicclonic seizures (pgtcs): study 311 ea portillo 1 , a patten 2 , g meier 3 , m malhotra 3 , ly ngo 3 1 paediatric neurology unit, department of paediatrics, hospital universitario virgen del roc ıo, sevilla, spain; 2 eisai ltd., hatfield, hertfordshire, uk; 3 eisai inc., woodcliff lake, nj, usa objective: study 311 (nct02849626) was a multicentre, openlabel study of adjunctive perampanel oral suspension in paediatric patients (aged 4 to <12y) with pos (with/without secondarily generalised seizures [sgs] ) or pgtcs. we report long-term (1y) hrqol data using the euroqol 5 dimensions-youth (eq-5d-y) scale from study 311. methods: this analysis included cumulative data from all enrolled patients in the core study and extension phase a (23 and 52wks of treatment, respectively). eq-5d-y was assessed at baseline, week 23 and week 52, and included five domains (mobility, self-care, doing usual activities, pain/discomfort, feeling worried/sad/unhappy). the eq-5d-y visual analogue scale (vas) was also assessed; increases in vas correspond with improvements. data are for observed cases. results: all 180 enrolled patients were included in the eq-5d-y analyses. the proportion of patients reporting 'a lot of problems' was similar during baseline vs week 52: mobility, 20/112 (17.9%) vs 13/68 (19.1); self-care, 44/112 (39.3%) vs 23/68 (33.8%); doing usual activities, 27/112 (24.1%) vs 18/68 (26.5%); pain/discomfort, 4/115 (3.5%) vs 2/70 (2.9%); feeling worried/sad/unhappy, 4/113 (3.5%) vs 1/70 (1.4%). outcomes were also similar for 'no problems' during baseline vs week 52: mobility, 64/112 (57.1%) vs 43/68 (63.2%); self-care, 42/112 (37.5%) vs 27/68 (39.7%); doing usual activities, 53/112 (47.3%) vs 34/68 (50.0%); pain/discomfort, 78/115 (67.8%) vs 50/70 (71.4%); feeling worried/sad/unhappy, 80/113 (70.8%) vs 52/70 (74.3%). mean (standard deviation) change in eq-5d-y vas from baseline at week 52 was 5.1 (16.6). conclusions: long-term adjunctive perampanel treatment (up to 1y) does not negatively affect hrqol (based on all eq-5d-y domains) in patients aged 4 to <12 years with pos (with/without sgs) or pgtcs. poster no. 014 efficacy and safety of adjunctive perampanel for partial-onset seizures (pos) in adult, adolescent and paediatric populations (studies 304, 305, 306, 311) . in study 311, 149 patients received perampanel ≤12mg/day (without enzyme-inducing anti-seizure medications [eiasms] ) or ≤16mg/day (with eiasms) (23-week treatment period). efficacy assessments included median percent change in seizure frequency/28 days from baseline, 50% responder rate and seizure-free rate. safety assessments included the incidence of treatment-emergent adverse events (teaes). results: the median percent reduction in seizure frequency/ 28 days was greater with perampanel at 4 (23.3%), 8 (28.8%) and 12mg/day (27.2%) vs placebo (12.8%; p<0.01) in adolescent/adult patients and was 40.1% in paediatric patients. the 50% responder rate during the maintenance period was greater with perampanel at 4 (28.5%), 8 (35.3%) and 12mg/ day (35.0%) vs placebo (19.3%; p<0.05) in adolescent/adult patients and was 46.6% in paediatric patients. seizure-freedom rates were greater with perampanel at 4 (4.4%), 8 (3.5%) and 12mg/day (4.1%) vs placebo (1.0%; p<0.05) in adolescent/ adult patients and was 11.5% in paediatric patients. teaes occurred in 61.7%-89.0% of adolescent/adult patients with perampanel 2-12mg/day (vs 66.5% in placebo patients), and in 89.9% of paediatric patients. teaes observed in pediatric patients were similar to those reported in adolescents and adults. conclusions: these studies suggest perampanel is efficacious and generally safe in paediatric, adolescent and adult patients with pos (with/without sgs). methods: patients who completed either of the rcts could enter this ole trial (gwpcare5/nct02224573). patients received gw pharmaceuticals' plant-derived highly purified cbd medicine (100mg/ml oral solution). the primary endpoint was safety. the secondary efficacy endpoints were median percentage change from baseline in drop and total seizure frequency. results: overall, 99% (366/368) of eligible patients with lgs entered the ole. median follow-up was 150 weeks (3d to 179wks); 119 patients (33%) withdrew. mean age: 16 years; 33% ≥18 years; 54% male. baseline median seizure frequency/28 days: 80 drop seizures; 168 total seizures. during the extended follow-up, the incidence of adverse events (ae) was 96%; serious aes 42%; aes leading to discontinuation 12%. most common aes (≥20%): diarrhoea, convulsion, pyrexia, somnolence, vomiting, upper respiratory tract infection, and decreased appetite. aes of alanine aminotransferase increased occurred in 8% of patients. there were 11 deaths; none deemed treatment-related by the investigator(s). median percentage reductions in seizure frequency (12-wk windows over 156wks) was 48-71% for drop seizures and 48-68% for total seizures. conclusions: long-term treatment with add-on cbd in patients with lgs produced sustained seizure reductions, with no new safety concerns. poster no. 016 management of status epilepticus in children with dravet syndrome jaa holland, u rajalingam paediatrics, hinchingbrooke hospital, huntingdon, uk objective: status epilepticus is reported to be the second greatest cause of mortality in children with dravet syndrome. we aimed to review the evidence on convulsive status management in children with dravet syndrome to guide local practice. methods: literature review. results: pubmed search using search terms 'dravet' or 'scn1a' and 'status epilepticus' returned 149 results, of which 8 were relevant. only one of these articles presented specific data on reported effectiveness of medications used in acute seizure management; this was based upon retrospective questionnaire data and defined status epilepticus as seizures lasting 30 minutes or longer. here, the most efficacious agents reported to terminate such seizures within 10 minutes were intravenous barbiturates (16 of 19 patients) and benzodiazepines (60 of 102 patients). rectal benzodiazepines, chloral hydrate and intravenous phenytoin or lidocaine were reported as less effective. the remaining articles presented expert and consensus opinion, all advising early administration (some at seizure onset) of buccal or intravenous benzodiazepines. provision of rescue medication for home use, with individualised plans, is recommended. one author advocated giving three doses of benzodiazepines sequentially. an article summarising a consensus panel described sodium valproate as a preferred second line option where benzodiazepines are ineffective, but there was no overall agreement on other possible medications. several articles advised caution in using phenytoin in acute seizure management. one source discusses possible harm from high dose barbiturates. conclusions: status epilepticus management for children with dravet syndrome should feature early, rapidly acting benzodiazepine administration. for second line treatment, phenytoin and barbiturates are commonly used in 'standard' status epilepticus management protocols, but there are potentially concerns around their use in this patient group. these concerns, however, appear largely theoretical. in the absence of evidence favouring a specific management protocol, individualised care plans should be designed with involvement of patients and their carers. poster no. 017 zx008 (low dose fenfluramine hydrochloride oral solution) significantly reduces frequency of generalized tonic-clonic seizures in dravet syndrome: pooled analysis from two phase 3 clinical trials jh cross 1 , a gil-nagel 2 , b gunning 3 , d battaglia 4 , k riney 5 , g farfel 6,7 , a mistry 6,7 , b galer 6,7 , g morrison 6,7 , a gammaitoni 6,7 , k pagano 6,7 1 great ormond street hospital, london, uk; 2 servicio de neurologia, hospital ruber internacional, madrid, spain; 3 stichting epilepsie instellingen, zwolle, the netherlands; 4 gemelli hospital, rome, italy; 5 mater children's hospital, brisbane, qld, australia; 6 zogenix, inc and int, emeryville, ca, usa; 7 zogenix, inc and int, maidenhead, uk objective: zx008 (low dose fenfluramine hcl oral solution) significantly reduced the frequency of convulsive seizures in patients with dravet syndrome (ds) in two phase 3 clinical trials. we conducted a pooled analysis of these trials to analyze the effect of zx008 on the frequency of tonic-clonic seizures (tcs), recently identified as a major risk factor for sudden unexpected death in epilepsy. methods: the frequency of generalized tcs and focal-to-bilateral tcs in patients with ds enrolled in one of two phase 3 clinical trials of zx008 added to current antiepileptic drug regimens were analyzed. results: 206 patients (55% male, mean age 9y) were enrolled and randomized to placebo (n=84), or zx008 0.8 (n=40), 0.5 (n=43), or 0.2 (n=39) mg/kg/day. the median baseline monthly frequency of generalized tcs ranged from 8.0 to 12.3/month in the four dose groups, and decreased during treatment by 80%, 64%, and 48% in the zx008 0.8, 0.5, and 0.2mg/kg/day groups, respectively, and by 10% in the placebo group. focal-to-bilateral tcs were experienced by fewer patients and had a median baseline frequency of 2.0 to 4.7/ month. during treatment, median percentage reductions in focal-to-bilateral tc frequency were 97%, 33%, and 69% in the zx008 0.8, 0.5, and 0.2mg/kg/day groups, respectively, and 39% in the placebo group. most common adverse events included decreased appetite, diarrhea, and fatigue. no valvular heart disease or pulmonary arterial hypertension was seen in any participant at any time. conclusions: zx008 substantially reduced the frequency of tcs. zx008 may be an important, effective new treatment option for ds patients. objective: mutations affecting tbc1d24 have been associated with an expanding spectrum of phenotypes including developmental delay, hearing impairment, doors syndrome and a range of epilepsies. a number of different movement disorders, including ataxia, spasticity and episodic paroxysmal dystonia have also been described. here we report two unrelated patients with biallelic tbc1d24 variants, in whom exerciseinduced dystonia was a major disease feature. methods: both patients were diagnosed through whole-exome sequencing. clinical information was obtained by a review of the medical notes, clinical correspondence and available video footage. results: both patients were found to have compound heterozygous mutations in tbc1d24, associated with an episodic dystonic/dyskinetic movement disorder reliably triggered by exertion. in the case of patient 1, exertion of specific body parts induced specific localised symptoms: for example, singing would precipitate orolingual dyskinesia. both girls experienced truncal dystoniaspecifically, lateral flexion of the trunkbrought on by prolonged walking. both girls also had epilepsy; of note, the exercise-induced movements and postures were captured on eeg and had no ictal correlate. conclusions: although tbc1d24 mutations are an established genetic cause of epilepsy, our study further confirms that not all paroxysmal events in people with tbc1d24 mutations are epileptic in nature. tbc1d24 should be included in the genetic differential diagnosis of patients with complex neurological syndromes associated with paroxysmal exercise-induced dyskinesia. objectives: heterozygous de novo rhobtb2 mutations have recently been reported in developmental and epileptic encephalopathy, but the associated movement phenotypes are not fully delineated. in order to better define the expanding phenotype and movement disorder in rhobtb2-related disease, we report a series of 9 unrelated patients presenting with complex movement disorders as well as epilepsy and developmental impairment. methods: cases were identified both in the uk (through the neurogenetic services at great ormond street hospital and the national hospital for neurology and neurosurgery, london), and from international collaborating centres. data were collected retrospectively by the patients' clinicians, using a standardised proforma. results: nine individuals were identified, aged from 2 to 55 years. 8/9 had epilepsy. of these, 4/8 had achieved seizure freedom at their last review. the commonest seizure types were focal onset with impaired awareness and/or focal to bilateral tonic-clonic seizures. 7/9 also had a paroxysmal movement disorder, which included hemiplegic or asymmetrical episodic weakness in 5/7, generalised dyskinesia in 4/7, episodic focal dystonia in 3/7 and episodic ataxia in 3/7. all individuals affected by a movement disorder had at least two different types of episodes. movement disorders improved significantly after treatment with carbamazepine in three children. cognitive ability varied from average to severe intellectual disability and in all but one case, developmental delay predated the onset of epilepsy. conclusions: rhobtb2 mutations cause a complex neurological phenotype associated with both epileptic and non-epileptic paroxysms. paroxysmal events occurring in people with known rhobtb2 mutation should therefore not be assumed always to be epileptic in nature. our study confirms that a wide variety of movement disorders are reported, including some which fall within the spectrum of alternating hemiplegia of childhood (ahc). rhobtb2 should thus be considered as a potential gene for ahc, other complex movement disorder phenotypes and epilepsy-dyskinesia syndromes. poster no. 020 evaluating seizure recognition and the use of electroencephalography in the paediatric intensive care unit objective: in the paediatric intensive care unit (picu), seizures are challenging to detect given patient complexity, comorbidity and sedation. this has led to both over-and under-treatment of seizures. there is growing literature on the use of continuous electroencephalography in picu, considered gold standard but not universally available, but little on standard electroencephalography (eeg). this study aims to investigate the indications for eeg requests, their efficacy and the use of antiepileptic drugs (aed) in picu, hypothesising a difficulty in clinically differentiating between epileptic and non-epileptic events and suboptimal use of aeds. methods: this retrospective study examined eeg reports over 2 years at a tertiary picu. data was collected on participant characteristics, eeg indications and findings and aed use. results: 185 eeg reports from 142 participants were included. median age was 6 months (iqr 1mo-3y 6mo). indications for eeg (often multiple per eeg) included suspected clinical seizures (64%), suspected subclinical seizures (21%), prognostication (28%) and suspected encephalopathy (8%). 63% of participants with suspected seizures were sedated and 43% of all participants were encephalopathic. clinical episodes suspected to be seizures were captured in 41/141 eegs. only 22% of these were eeg-confirmed seizures. captured movements shown not to be seizures are qualitatively described. 6% of patients with suspected seizures had electrographic seizures with no clinical correlate. most confirmed seizures were in participants without pre-existing epilepsy. antiepileptic(s) were changed prior to 25/35 captured events. seizures were present in 28% of these cases, while 60% had neither clinical nor electrographic seizure activity. 7/8 participants with confirmed clinical seizures had aeds changed. conclusion: it is challenging for clinicians to differentiate between seizure and non-seizure movements in picu. moreover, there are issues of over-medication and low event-capture rate with eeg. we propose a multidisciplinary education strategy and investment in ceeg to address these issues. introduction: glucose transporter 1 deficiency syndrome (glut1-ds) is a rare neurometabolic disorder causing impaired glucose transport into the brain. in the majority of patients, it is caused by an autosomal dominant heterozygous mutation in the scl2a1 gene. ketone bodies generated by a ketogenic diet (kd) provide the brain with an alternative energy source and is gold standard therapy. we report our experience for our cohort of patients at royal manchester children's hospital. methods: retrospective case note review of 14 patients with glut1-ds at royal manchester children's hospital from 2004 to 2019. results: 14 patients -8 male, 6 female. age range 3 to 19 years. average age at diagnosis was 6 years 3 months (range 4mo-9y). there was a history of seizures in 11 of 14 patients with average seizure onset of 2 years 6 months. seizures types were absences (5/11), generalised tonic-clonic (3/ 11), myoclonic (2/11), myoclonic astatic (1/11), tonic (1/11) and focal to bilateral tonic-clonic (1/11). ketogenic diet was used in all patients for a range of 4 months to 10 years 7 months. no significant adverse effects occurred that required discontinuation. six patients complying with kd are seizure free and not taking antiepileptic drugs (aeds). one of these patients had occasional tonic-clonic seizures with illness and loss of ketosis but has been seizure free for >18 months. five patients are non-compliant with kdtwo have good seizure control with aeds, potentially limiting motivation, and two (siblings) have a parent with glut1-ds and learning difficulties. learning difficulties were reported in 10 patients. other symptoms included ataxia (8/14), dysarthria (5/14), tremor (4/14) and dystonia (4/14). one patient presented with episodic hemiplegia. conclusions: patients with glut1-ds are a heterogeneous group leading to challenges in diagnosis, management and prognosis. ketogenic diet has been effective in managing this cohort but compliance was a limiting factor. objective: to conduct a survey regarding the management of relapse in children epilepsy in following weaning off aeds. methods: we conducted an online survey in the east of england (eoe) via the eastern paediatric epilepsy network (epen) regarding the management of relapse in children epilepsy after weaning aeds. epen is a network of paediatricians and nurse specialist with eoe who manage lead in management children with epilepsy within all the dgh's in the region. the questions in the survey asked about various aspects of management of patients after relapse, including the choice of anti-epileptic medication restarted, if started, any further investigations undertaken, and finally, the length of aed treatment before a second attempt at weaning might be considered. results: we received 17 responses from paediatricians in 16 dgh's across eoe. there was a large degree of variation in the responses to all of the questions in the survey. the frequency and semiology of seizures on relapse seemed to play a key role in decision making, as did the thoughts and views of the family and patient themselves. it was interesting to note there was a variation in response to whether any further investigations would be undertaken and if these were deemed necessary. most clinicians responded that they would continue aeds for another 2 years before attempting weaning again. conclusions: there is variability in the management of epilepsy relapse in the eoe and we suspect that this may also be the case nationally. to investigate this further, we would envisage extending the survey nationally, via open ukwhich is an organisation that links the various regional paediatric epilepsy networks across uk. this would enable establishing a standardized guideline for management of epilepsy relapse in the future. objective: de novo dominant mutations in dhdds were recently identified as a cause of developmental and epileptic encephalopathy. dhdds encodes dehydrodolichyl diphosphate synthase, which is essential for dolichol monophosphate synthesis and protein glycosylation. we report two half-siblings with a new pathogenic, maternally inherited dhdds missense variant, c.614g>a(p.arg205gln), identified through whole-exome sequencing. method: case note and literature review. results: sibling 1, aged 11 years, presented at 11 months with global developmental delay, hypotonia and frequent absences with eyelid myoclonia. from age 3, she developed atonic drop attacks, myoclonic seizures, tremor, ataxia and facial dyskinesia. dyskinesia and mobility deteriorated from age 7 and she is now largely non-ambulant. severe learning disability with possible cognitive deterioration and insatiable appetite are also features. sibling 2, aged 9 years, developed blank spells associated with eyelid flickering at 12 months and atonic drop attacks aged 5. development delay is present, but progress is greater than her sibling. dyskinesia, tremor, ataxia and deterioration in mobility are features. neither is dysmorphic. eegs on both showed bursts of irregular generalised spike wave associated with head nods and eyelid flutter. photosensitivity was not shown but both were treated with anti-epileptic medication. mri scans are normal. clobazam and zonisamide improved seizure control in both. mother has mild learning difficulties, tremor and dyspraxia. she had generalised tonic clonic seizures, from age 14 to 18 years, well controlled with lamotrigine. compared to the six known cases in the literature, our report confirms atonic seizures and dyskinesia as important features of this disorder, in addition to common characteristics of myoclonic component to seizures, hypotonia and tremor. learning disability is of variable severity. conclusions: this is the first report of familial inheritance of dhdds related developmental and epileptic encephalopathy and describes variable severity of the phenotype within family members. the features described are consistent with those previously observed. objectives: to evaluate whether the duration of treatment has an effect on the relapse rate in children with cae attending a paediatric neurology centre in cyprus, and whether the eeg can be used as a prognostic tool. methods: electronic patient database review of patients with cae, who have discontinued treatment attending the paediatric neurology clinic between years 2008-2017. results: fourteen patients with cae, off treatment were identified (7 male). age at presentation ranged from 3 to 9 years (median 6.5y). all patients underwent an eeg to confirm diagnosis and those who presented with seizures other than absences were excluded. twelve patients were treated with valproic acid (depakine) and 2 with ethosuximide (zarontin). in 10, absences resolved on first line monotherapy, whilst 4 were refractory requiring combination therapy. positive family history was present in 2 (non-identical twins), attention deficit in 2, and learning difficulties in 1 patient. all initial eegs were consistent with cae, patients also underwent an eeg post seizure control to confirm resolution. mean time to seizure cessation was 3.9 months, mean duration of treatment 2.2 years; 4 patients discontinued treatment after 1 year of seizure freedom. prior to withdrawing treatment all patients had an eeg (normal 6, mildly abnormal with brief generalised discharges 6, photosensitivity 1, brief electrographic absence 1). relapse occurred in 3 patients who required re-instigation of treatment. mild abnormalities on eeg prior to coming off treatment did not correlate with a higher relapse rate. there was no difference in relapse rate in patients on treatment for 1, 2 or more years. patients were followed up for a mean of 7.8 years. conclusions: treating patients with cae for less than 2 years does not affect relapse rate provided patients are seizure free, also confirmed by eeg normalisation, which may be used as an additional predictor. background: mutations in unc80, encoding part of the unc79-unc80-nalcn channel complex, causes autosomal-recessive severe infantile encephalopathy, this is a rare case of profound global developmental delay with psychomotor retardation. only 19 individuals have been reported to date. unc80 deficiency is characterized by hypotonia, strabismus, oral motor dysfunction, postnatal growth deficiency, and developmental delay. the majority of individuals do not learn to walk. all individuals lack expressive language. additional features can include nystagmus, extremity hypertonia, a highpitched cry, repetitive and self-stimulatory behaviours, constipation, clubfeet, joint contractures, and scoliosis. there is no loss of skills suggestive of neurodegeneration. case presentation: 11-year-old, with a recent confirmed diagnosis of unc80 gene mutation and microcephaly. she had profound global developmental delay, learning disability, bilateral squint with cortical blindness, seizure disorder, sleep apnoea, head drops, movement disorders, feeding difficulty, scoliosis and constipation. term baby with normal anti-natal history. induction of labour for iugr. good apgar, at birth but developed respiratory distress with cardiac problems. birth weight 2050 g. neurologically: floppy with reduced muscle tone and microcephaly. had a short neonatal admission and discharged with cardiac, endocrine, neonatal and neurodevelopmental delay follow-up. she had no spoken words and communicated by crying. she was only able to sit transiently and never walked. she was wheelchair bound with gmfcs, macs, cfcs and edacs level 5 each, needing full 24-hour support from patents and carers. ddd study confirmed unc80 gene mutation, her cousin was also noted to have same gene mutation via exome sequencing and with similar clinical picture. conclusion: early diagnosis is key for genetic counselling for further children and ensuring global support as reported individuals span ages from birth to 15 year. the diagnosis is established in a pro-band with developmental delay and hypotonia by identification of bi-allelic pathogenic variants in unc80 on molecular genetic testing. poster no. 026 cognition and disease burden in scn1a positive dravet syndromea 10-year follow-up study development, disease burden and sleep profile of patients with dravet syndrome. methods: this is a follow-up to a 2009 study previously involving 141 ds patients with detailed developmental and clinical information available. participants completed a structured postal questionnaire on epilepsy severity and disease burden, the adaptive behavioural assessment system (abas-3), the sleep disturbances scale for children, pediatric quality of life inventory (pedsql) and the strength and difficulties questionnaire. results: 123/141 from the original cohort were contactable and 70 (57%) of carers completed the outcome measures. the developmental quotient at follow-up was significantly lower compared to the earlier study (p=0.001), and 89% of affected individuals had a severe or profound learning disability. we observed the steepest decline in cognitive functioning in those that were youngest (age 0-5y) at original study onset (p=0.001). poorer developmental quotients correlated with early onset of initial developmental concerns (rs=0.31; p=0.037), later mobility problems (rs=0.30; p=0.015), higher levels of behaviour problems (rs=0.26; p=0.043) and worse pedsql scores (rs=0.31; p=0.015). carers health and wellbeing was negatively affected in 98% of cases and in 90%, at least one of the two carers quit their job due to their child's illness. sleep problems as measured by total sleep scale score were reported in 40% of patients, whilst 71% had at least one abnormal sleep scale category. only 49% of individuals with abnormal sleep scores received treatment. rs=spearman rho correlation coefficient. conclusions: this study highlights the ongoing cognitive decline in ds, particularly affecting younger patients, alongside often untreated sleep problems and a significant disease burden on primary carers. with new therapeutic opportunities on the horizon, early interventions appear crucial to avert the observed severe cognitive decline. poster no. 027 forced normalisation as a factor in behaviour deterioration on the ketogenic diet e hassan 1 , vj whiteley 2,3 , hj tan 1 1 department of neurology, royal manchester children's hospital, manchester, uk; 2 therapy and dietetics, royal manchester children's hospital, manchester, uk; 3 school of health and society, university of salford, salford, uk introduction: there have been a number of reports that demonstrate a correlation between improved seizure management and deterioration of behaviour with psychosis in adults and children. forced normalisation is a concept where there is deterioration in behaviour when better seizure control is achieved with antiepileptic drugs (aeds) or epilepsy surgery. the ketogenic diet (kd) is a treatment option for children with refractory epilepsy with approximately 50 to 60% showing at least 50% reduction of seizures and 15% of those patients reaching seizure freedom 6 months after treatment. although forced normalisation has been discussed in literature following aeds and neurosurgical interventions, it has not been reported following the use of kd. cases: of the 195 children that have commenced on kd over the last 7 years at royal manchester children's hospital, 59.5% responded to the diet (at least 50% improvement in seizures) and 10.8% were non-compliant. we present 6 patients under the care of the kd service, whose behaviour deteriorated on kd when seizure reduction was >50%. the behaviour changes described by parents included poor sleep, unsettled, agitation, head-banging and shouting. five out of the six patients stopped kd treatment, with subsequent improvement in behaviour. conclusions: there are reports that patients on the ketogenic diet with seizure freedom show improvement in their behaviour, unlike our small cohort whose behaviour deteriorated. forced normalisation has been explored in paediatric patients as a cause for behaviour deterioration following surgical and medical management for intractable seizures. the associated factors of deteriorating behaviour have not yet been explored in depth with the ketogenic diet. objective: we wanted to determine how lacosamide was being used in children locally, and what their outcomes were at a year. methods: we undertook a registered, retrospective, clinical audit using hospital electronic records. we ascertained every patient aged <18 years who had been dispensed lacosamide january 2016-january 2018. the electronic health records were reviewed, and data collected using a standard proforma, including: patient demographics, age of seizure onset, seizure type, ecg and mri findings, baseline seizure frequency, seizure frequency 2, 6, and 12 months on lacosamide, maximum dose prescribed (mg/kg/day), and adverse effects at 2, 6, and 12 months. results: 20/42 (48%) patients were male, the median age was 9 years (range 2mo to 17y), with a mean age of onset of 3 years (range 2mo to 11y). 35/42 (83%) had epileptiform activity on eeg and 24/42 (57%) had an abnormal mri. 24/ 42 (57%) had focal seizures. 27/42 (64%) had a minimum of one seizure a week. 28/42 (66%) had previously tried 3 or more antiepileptic drugs (aeds), and 38/42 (90%) had drug resistant epilepsy prior to starting lacosamide (already failed 2 previous aeds). all patients had lacosamide alongside another aed. the mean daily dose of lacosamide was 7.3mg/kg/day (range 1.3-20.6). at 12 months, 15/42 (36%) of patients reported a >50% reduction in seizure frequency. 36/42 (86%) remained on lacosamide 1 year after starting, and 9/42 (21%) experienced an adverse side effect. conclusions: in this local audit, lacosamide was mostly prescribed for drug resistant epilepsies and was used in polytherapy. a third of patients saw a significant reduction in seizure frequency on lacosamide, although some were also started on other treatments during this period. most patients remained on lacosamide after 12 months, and about 1 in 5 experienced one or more adverse side effect. cacna1a is a large gene which encodes for the alpha subunit of a neuronal ion channel and it is expressed widely throughout the central nervous system (cns). pathogenic variants in this gene have been associated with many phenotypes. most commonly episodic ataxia type 2 (ea2) and spinocerebellar ataxia type 6 (sca6). rarer phenotypes include, familial hemiplegic migraine, paroxysmal tonic upgaze, epilepsy, and intellectual disability with autism. here we present the case of an 8 month old girl who presented with new onset paroxysmal abnormal eye movements during an intercurrent illness. the referring clinicians felt these episodes may be epileptic. however, an electroencephalogram (eeg) captured these movements which were non-epileptic downbeat nystagmus. all other initial investigations including cerebrospinal fluid glucose and neurotransmitters were normal as was her neuroimaging. over the next year her nystagmus became constant. she had otherwise normal development. at 16 months her gait was noted to be abnormally unsteady and broad based (even accounting for age). the nystagmus and ataxia changed in severity from day to day, she could have 4 to 5 more severe days followed by 4 to 5 better days, they never completely resolved. she had no family history of abnormal eye movements or ataxia. subsequent genetic testing revealed a cacna1a c.3787g>a p(glu1263lys) missense variant described only twice previously in ea2, both with very different phenotypes to our patient. neither of her parents carried the same genetic variant. this case is the first reported case of this cacna1a variant presenting as downbeat nystagmus followed by ataxia. both her age of presentation and her initial presenting features are very different to the typical phenotypes associated with this gene. it broadens the phenotype of cacna1a, and also broadens the differential diagnoses associated with abnormal eye movements in infancy. the importance of following up as yet undiagnosed patients who may go on to develop new and revealing symptoms is highlighted. objective: to undertake a questionnaire-based survey retrospectively exploring parents'/carers' recall of, and views on, the safety and risk advice given at the time of their child's epilepsy diagnosis. methods: questionnaires were distributed throughout scotland via scottish paediatric epilepsy network (spen). parents'/ carers' of 5 to 12-year-old children were asked to complete the questionnaire prior to their seizure clinic appointment. results: 178 questionnaires were suitable for inclusion. seizure burden was evenly distributed: 37% <1 seizure/month, 23% >1 seizure/month, 22% >1 seizure/week and 18% had absences only. respondents could recall post-diagnosis information being provided on: water safety (50%), taking medication regularly (91%), sports/activities (57%), seizures in sleep (62%), first aid (78%), prolonged seizures (53%) and/or sudep (45%). there was no statistically significant difference in the duration of epilepsy diagnosis between those who could recall information being given (m=3.77y, sd 2.747) and those who could not (m=4.138y, sd 2.84; t test p=0.42). the majority of information was given via clinic discussions (75%). 46% received written information, 28% directed to websites and/or independent search (12%). most information was 'just right' (71% water safety, 94% on taking aed regularly, 68% on sports/activities, 68% on seizures in sleep, 83% on first-aid for seizures). approximately 30% of respondents want more information on seizures in sleep, water safety and sports/activities. 46% of respondents felt worried following information about seizures in sleep, 57% about prolonged seizures and 67% regarding sudep. conclusions: a substantial proportion of parents'/carers' do not recall receiving safety information on epilepsy despite this being standard practice through spen. this appears to be unrelated to the duration of their child's epilepsy. repeated timely reinforcement may be of benefit. a high proportion of parents'/carers' felt concerned following information provided on nocturnal seizures, prolonged seizures and sudep. this should be recognised with support in place for further discussions. poster no. 031 seizure outcome in responsive vagus nerve stimulation therapy in children and young people v rasiah, n barnes, s carter, k das, r robinson, z tahir, s varadkar great ormond street hospital for children nhs foundation trust and ucl gosh institute of child health, london, uk aim: vagus nerve stimulation (vns) therapy is an established treatment for pharmacoresistant epilepsy. newer responsive-vns (rvns) systems use ictal-tachycardia detection as a biomarker of seizure onset and automatically deliver additional stimulation on detection to abort the seizure. we reviewed the seizure outcomes in children and young people (cyp) implanted with rvns at great ormond street between 2012 to 2018. methods: data were collected prospectively on 41 patients who had an aspiresr â rvns inserted during time period of 2012 to 2018. reduction in seizure frequency and severity, wean of medications and treatment complications or side-effects were assessed at time-points of 1 year, 18 months, 2 years and 3 years post-implantation. results: 41 cyp (mean age 11.9y) had rvns inserted. at 1 year, 34% (14/41) had a positive response graded as >50% reduction in seizure frequency or severity (i.e., duration), 32% (13) had benefit though <50% benefit, and 32% (13) of cyp were non-responders. this increased at 18 months to 41% (14/29) of children showing response >50%, a further 41% showed response 50% and only 17% (12/29) non-responders. response was over-all sustained, with response lessening in only 2 children between 18 months and 2 years. reduction of medication burden was achieved in 22% (9/41) (not attempted in all cyp). no patients achieved seizure freedom. replacement of vns from an older model to rvns showed further benefit. complications were infrequent: 12% (5/41). device removal for infection was required in one child of small body size; successful replacement was possible within the year. conclusions: vns is a useful treatment option for cyp with pharmacoresistant epilepsy. seizure outcomes with rvns in cyp are better than with standard vns. response is sustained. benefit may not be seen by 1 year; therapy should be continued until at least 18 months. in our patients who responded later than 1-year, further optimisations of duty cycle and current were made. replacement of older vns. devices with rvns led to additional benefit. these findings are consistent with reported outcomes from adult series, though seizure freedom is not seen in cyp. in our centre, cyp who seemed to benefit most were those whose epilepsy was of structural aetiology and those with focal seizures, although our numbers were not large enough to assess the significance of this. poster no. 032 atp1a3 mutation in twins presenting with apnoeic episodes, suspected seizures and possible dystonic events objective: we report the case of monochorionic diamniotic twins presenting at the age of 5 months with infantile seizures and apnoeic episodes. the eiee gene panel revealed a mutation in the gene atp1a3, supporting the clinical diagnosis of alternating hemiplegia of childhood (ahc). methods: case report. results: twin r presented with staring episodes, eye deviation and tonic posturing of limbs. episodes occurring mainly in clusters, affecting either side and requiring rescue medications for termination. profound apnoeic episodes needing resuscitation were also noted. twin s presented few weeks later with a very similar presentation. developmentally making satisfactory progress with twin r showing only very mild delay. the array cgh from twin r was normal. several investigations were performed including two normal standard eegs, a normal sleep eeg, a normal ecg, an echo showing a small pfo and an mri scan demonstrating a left sided mesial temporal lobe sclerosis. similar mri findings were reported in twin s. investigations such as urine organic acids and amino acids, plasma amino acids, carnitine, acylcarnitine, transferrin glycoforms, mucopolysaccharidosis screen, ammonia and lactate were all normal. pyridoxine was tried with no improvement, levetiracetam was added and afterwards changed to carbamazepine. sodium valproate was commenced eventually after an episode of prolonged clinical seizure. the eiee gene panel revealed a de novo atp1a3 mutation in both twins. flunarizine was commenced following this result. a video telemetry managed to capture both epileptic and non-epileptic episodes in twin r. the epileptic episode was characterised solely as apnoeic episode due to a left temporal seizure activity spreading onto the opposite hemisphere which is concordant with the imaging finding of left mesial temporal sclerosis. conclusions: knowledge of the atp1a3 mutation allowed clinical correlation of a diagnosis of ahc, matching the wide clinical spectrum of ahc including paroxysmal dystonia and epilepsy. poster no. 033 epilepsy in a child development centre population pc kenyon, njv cordeiro, gl duffy rainbow house child development centre, irvine, ayrshire, uk objective: to assess all the cases in a child development centre (cdc) population with epilepsy, to enable characterisation of the caseload. methods: all case notes of children with an epilepsy diagnosis coded on the cdc database were retrospectively reviewed for demographic, investigation and treatment data. results: 67 children were identified. 27% were diagnosed before a year of age, and over half before their third birthday. 84% of patients had an eeg, and of these, 70% had an abnormal eeg. 55% had genetic testing performed, and of these, 86% had a genetic cause of their epilepsy identified. 78% had an mri scan, and of these, 69% had a structural cause for their epilepsy identified. 90% had global developmental delay, and 90% had a diagnosis of learning disability. one third have a diagnosis of cerebral palsy, 16% have autism spectrum disorder, and 13% have a hemiplegia. 66% are seizure free, the majority of whom have their epilepsy controlled with one medication. 12% had adherence concerns identified. conclusions: compared to a general paediatric epilepsy clinic, this group of children were diagnosed earlier in life, had higher rates of genetic or structural causes identified, and were less likely to be seizure free. results: case 1. a 4-year-old with autism spectrum disorder (asd) developed hand waving in front of her face in bright light from 3 years. multiple myoclonic seizures occurred with screen use and her family live in complete darkness. eeg demonstrated photosensitivity, generalised spike-slow wave after hand waving and 3-3.5hz spike-wave with myoclonia. clonazepam has been commenced. case 2. a 10-year-old with learning difficulties and a family history of generalised seizures presented aged 6 years with forehead rubbing leading to loss of part of her eyebrow. eeg showed photosensitivity and the generalised spike-wave of absences and eyelid myoclonia (em). sodium valproate was used but replaced with lamotrigine due to weight gain. case 3. a 4-year-old with a family history of generalised seizures presented aged 2 years with hand waving in front of her face, requiring her nursery to provide a dimly-lit setting. eeg demonstrated generalised polyspikewave, 3-hz spike-wave and myoclonia with photic stimulation. lamotrigine was ineffective and replaced with sodium valproate. case 4. an 11-year-old with likely asd developed hand waving in front of her face in bright light aged 4 years, triggering generalised tonic convulsions (gtc). she had a non-induced gtc in dappled sunlight. there was on-going anxiety and thoughts of self-harm. eeg showed photosensitivity and bursts of spikes-polyspikes. lamotrigine was ineffective; seizures stopped with sodium valproate. conclusions: the self-induced seizures of sunflower syndrome are difficult to treat and are associated with physical, psychological and social impairments. sodium valproate is the most effective medication which may be problematic in this predominantly female patient group. what are the information needs of parents whose child is diagnosed with glutaric aciduria type 1 to help preserve neuro-developmental outcome? objectives: to assess the information needs and support of parents at the time of diagnosis of ga1 in their child, and how to support them in preventing metabolic decompensation and preserving neuro-developmental function. methods: a focus group with five parents was conducted using a topic guide to direct the discussion, which was recorded and fully transcribed. data were analysed using thematic analysis. two researchers were involved in initial coding of data and key analytic decisions. results: two main themes were identified. 'understanding the condition' explored parent's needs to understand the scientific complexity of ga1 and to be aware of the 'worst case scenario' associated with loss of metabolic control, and brain injury. parents reported clinicians did not give then enough information on the ga1, and were forced to use other information sources, sometimes seeking out scientific papers. information on managing crises was insufficient, with parents not understanding what the doctor meant about commencing the emergency regime when their child was 'sick'. parents reported living in terror of their child experiencing metabolic decompensation and permanent brain injury. 'managing the condition' explained how parents coordinated and controlled the involvement of other carers and outlined parents' need to be active partners in medical management to feel in control. parents wanted to know the results of regular biochemical tests for reassurance, but found they were not easily accessible. parents could not leave their child in the care of another adult because they did not have sufficient knowledgeable about ga1 or were known to 'cheat' by offering the child food they should not have. the transition into school was a particular challenge. conclusions: the study highlights the importance of addressing parents' initial and ongoing informational needs so they can fulfil their role and protect their child from metabolic decompensation and permanent brain injury. poster no. 036 normal transferrin isoelectric focusing in a child with cog4 related congenital disorder of glycosylation objectives: congenital disorders of glycosylation (cdg) are a large group of rare multisystem diseases caused by defective linkage of oligosaccharides to newly synthesised proteins or lipids. several cdg subtypes are the result of mutations in subunits of the conserved oligomeric golgi (cog) complex. this includes cog4-cdg, an autosomal recessive disorder caused by pathogenic variants in the cog4 gene. in the two cases previously reported transferrin isoforms were abnormal, consistent with defective n-glycosylation. methods: we describe a 3-year-old female born to non-consanguineous parents. she presented with severe global developmental delay, dysmorphic features, postnatal progressive microcephaly, complex epilepsy, rhizomelia, spastic quadriplegia, and feeding problems from early infancy. results: mri brain showed global cerebral atrophy, predominantly supratentorial, with relative cerebellar sparing. trio exome sequencing and analysis identified compound heterozygous cog4 variants in the proband, a maternally inherited pathogenic splice site variant c.1061+1g>a and a paternally inherited likely pathogenic splice site variant c.1647+5g>a. messenger rna analysis showed that the c.1647+5g>a variant caused aberrant splicing, with skipping of exon 12 and the introduction of a premature stop codon in exon 13, likely to result in nonsense mediated decay. analysis of transferrin isoforms was normal (by both isoelectric focussing and mass spectrometry). since cog4-cdg also affects o-glycosylation apolipoprotein ciii (apociii) isoelectric focussing was undertaken, however this too was normal. conclusions: transferrin and apociii isoelectric focusing are screening tests for n-and o-glycosylation defects. however, both have their limitations and some cases of cdg have normal transferrin or apociii glycoforms escaping those screening tests. this is the first case of a patient with cog4-cdg with normal biochemical markers to be described. this case also demonstrates the diagnostic power of next generation sequencing for rare metabolic disorders, where the biochemical screening may be inconclusive. poster no. 037 developmental delay in a young infant with nonclassical combined malonic and methyl malonic aciduria (cmamma) caused by homozygous missense mutation in acsf3 gene kd dayasiri 1 , eg goh 1 , sk kodagali 1 , jb baruteau 2 , ga anand 1 1 oxford university hospitals nhs foundation trust, oxford, uk; 2 great ormond street hospital, london, uk introduction: acylcoa synthetase family member 3 (acsf3) activates malonylcoa and methymalonylcoa into their respective thioesters. acsf3 deficiency causes non-classical cmamma, a rare inborn error of metabolism characterised by presence of methyl malonic acid in higher concentrations than malonic acid in urine. the reversal is seen with classic cmamma caused by malonylcoa decarboxylase deficiency (mcd). case report: 5-and-a-half-month old male infant second born to consanguineous south asian parents presented with severe failure to thrive and recurrent vomiting. his older sibling who had failure to thrive and neuro-developmental delay died at 7 months without a genetic diagnosis. initial blood tests revealed metabolic acidosis, pancytopenia and coagulopathy. neuroimaging was unremarkable. subsequent evaluation revealed normal levels of methionine, homocysteine and red cell folate. significant methylmalonic aciduria with mild malonic aciduria without evidence of other abnormal metabolites (propionyl-coa metabolites: hydroxypropionate, and methylcitrate or tiglylglycine) in urine suggested the diagnosis of non-classic cmamma, confirmed by homozygous missense variants in acsf3 gene revealed by trio-exome sequencing. neurodevelopmental assessment at 8 months revealed global developmental delay with general hypotonia; gross motor (4-6mo); fine motor (4-6mo); speech (5-6mo) and social (under 6mo), and without any regression. carnitine was supplemented to avoid secondary depletion caused by the excretion of mma. parents were advised to avoid prolonged fasting and to provide emergency regimen (powdered carbohydrate drink mix) in the event of acute deterioration. conclusions: this report describes an unusual paediatric presentation of non-classic cmamma. urine organic acids allows identification of increased ma and mma excretion and highly suggestive of the diagnosis, thus avoiding additional investigations determination of urinary mma/ma ratio can help differentiating between classical and non-classical forms. methods: we conducted retrospective case note analysis of the five paediatric cases with confirmed diagnosis of the late onset pompe disease, referred to the highly specialised metabolic service. results: three of five patients (current age 14-22y) presented with delayed motor milestones in early childhood (mean age: 3.3y). one patient initially presented with episodes of thigh pain and high ck. in addition, when 10 years he re-presented with recurrent abdominal pain with high ck. the remaining one presented with muscle pain upon exercise with high ck. all apart from one had muscle weakness affecting limb girdle muscles and axial muscles. the remaining one presented with proximal muscle weakness by the age of 19 years. all patients remained ambulant, one developed scoliosis and two were on non-invasive ventilation. cardiac involvement as ventricular dysfunction requiring targeted treatment was observed in one. pathology showed vacuolated deposits in three patients and non-specific myopathic changes in one. four are on enzyme replacement therapy (ert) and tolerated well. conclusions: late onset pompe disease is a multisystem disease and should be considered in cases of isolated respiratory problems, lower back pain, rigid spine, and myopathy or exercise intolerance with elevated serum ck if these symptoms cannot be attributed to another disorder. poster no. 039 delay in diagnosis and misdiagnosis of ataxiatelangiectasia: a systematic review pubmed, scopus). the cochrane library was also searched. the search protocol is available. the inclusion criteria were: all dates, all languages, all ages, human participants and clinical relevance. the exclusion criteria were: no reference to ataxia-telangiectasia within the article, not an original article, animal studies, article not clinically relevant. results: search returned 184 541 articles; 13 868 titles and abstracts were reviewed after removing 170 673 duplicates. full text review includes 1106 articles of which 343 case series and 459 case reports were identified (12 518, exclusions; 244, articles not found or not accessible). mean age of first sign or symptom of a-t in 563 cases reviewed to date was 31.4 months (range -11d to 312mo). the mean age of diagnosis in 209 cases in which it has been reported was 81.4 months (range -22d to 624mo). there was a mean time of 34.9 months from presentation to clinician, to diagnosis of a-t (range -0 to 306mo, median 11mo) in the 71 cases in which this was reported. 20/563 (3.6%) cases had a documented alternative diagnosis prior to the diagnosis of a-t. 10/20 (50%) of these children were incorrectly diagnosed with cerebral palsy and 3/20 (15%) with hyper-igm syndrome. the mean delay from incorrect diagnosis to a diagnosis of a-t was 87 months with the longest delay 306 months. conclusions: this study is the first comprehensive systematic review of scientific literature on ataxia-telangiectasia. we aim to describe the natural history of the condition and, along with results from the natural history of a-t (n-hat) study, systematically define, where possible, the conditions presentation, course, and prognosis. (80%) people with a-t presented with gait ataxia or disturbance, and 13/751 (1.7%) with truncal ataxia. the most common presenting feature in cases without ataxia were developmental delay, or regression, and choreoathetoid movements. the second most common neurological presenting sign was dysarthria in 118/751 (15.7%) cases, and at least 2 of these had no associated ataxia. dystonia was a presenting sign in 37/751 (4.9%) cases, including 3/37 (8.1%) with no associated ataxia. 64/751 (8.5%) initially presented with no neurological signs or symptoms. conclusions: this study is the first comprehensive systematic review of scientific literature on ataxia-telangiectasia. these results show that 91.5% of people with a diagnosis of a-t presented initially with at least one neurological sign or symptoms. this completed review will lead into the natural history of a-t (n-hat) study, a longitudinal, retrospective and cross-sectional study. the role of serum oxysterol in the diagnosis of niemann pick c m alcheikh, g connolly, n cluskey, s osullivan royal hospitals belfast health and social care trust, belfast, uk introduction: neimann pick c is a neurovisceral disease that is caused by cellular cholesterol trafficking disruption. historically, the diagnosis of niemann pick c was made using filipin staining and skin fibroblast cultures. recently genetic testing of npc1 an npc2 genes are available. mutations of either gene also affect cellular trafficking of cholesterol and detecting oxidative cholesterol metabolities can also be diagnostic of nieman pick c. serum oxysterol can be used as a first line test with subsequent genetic confirmation and has a positive predictive value of >97%. methods: we present a case of an 11-year-old boy who was referred to genetics initially with absence of up gaze, severe restricted downward gaze, developmental delay, regression of skills and frequent falls. in the last 1 year his parents and school observed progressive deterioration of his symptoms with gelastic cataplexy, markedly decreased tone, increasing difficulty with memory loss and slurred speech. these symptoms are strongly suggestive of niemann pick c disease and oxysterols were requested which showed elevated oxysterol level of 128.7ng/ml (normal range 9.6-37). he was started on miglustat. genetics confirmed the diagnosis. results: overall the child's parents report that since commencing the miglustat he is more confident and they have recently seen him hop and skip which they haven't seen in quite a while. conclusions: oxysterol is suitable biomarker for neimann pick c disease and can be used as first line with the genetic confirmation of gene npc1 and npc2 at later stage. as modifying treatment with miglustat is available it is important to attempt diagnosing the condition as early as possible and oxysterol level can be used as screening test for neimann pick c when clinically suspected. introduction: biotinidase deficiency is a rare autosomal recessive inborn error of biotin metabolism. biotinidase catalyses biocytin to biotin, a deficiency of which can present with neurological symptoms including hypotonia, seizures, feeding difficulties, lethargy, optic atrophy, and sensorineural deafness. case: a 9-week-old female presented with a 4-week history of seizures and developmental delay. examination revealed generalised and axial hypotonia and delayed smile. she continued to have seizures despite initial treatments including levetiracetam and carbamazepine. mri brain was normal and initial interictal eeg on day 1 post admission revealed no significant abnormalities. ambulatory eeg on day 10 showed a focal onset epileptic seizure with sharp and slow wave activity originating predominantly from the left occipito-parietal region. normal investigations included paired plasma and csf glucose, lactate and culture, csf neurotransmitters, microarray and epilepsy gene panel. on day 11 post admission her biotinidase result was reported showing no activity. biotin was commenced at 10mg once daily and her seizures abruptly stopped. she was discharged home on day 14 and weaned off levetiracetam and carbamazepine. her development was normal at 12-month follow-up. genetic testing was declined by the family. discussion: biotinidase deficiency can present from the neonatal period up to 10 years of age with a mean age of 3.5 months. in recent years our understanding of pathogenic changes in the biotinidase gene has increased through sequencing for novel mutation. this has important implications for families and consideration should be given to offering affected families genetic counselling. treatment is available with oral biotin that rapidly improves symptoms, with seizures usually resolving within days and other symptoms showing improvement within weeks. objective: we present a previously well 16-year-old boy with a known m.3271t>c mutation experiencing 2 weeks of vomiting, lethargy and exercise intolerance. method: he was mildly dehydrated, fully consciousness but tachycardic and hypotensive. his ph was 7.28 with be -17.3, hco3 9.4 and lactate of 16.4. electrolytes, fbc and inflammatory markers were normal. he was admitted to picu for fluid management and sodium bicarbonate. tachycardia persisted during the first 24 hours though he remained stable. he had a good urine output, was on non-invasive monitoring and an echocardiogram was normal. his gas lactate ranged from 14.1 to 16.8. the following day he deteriorated with kussmaul respirations, tachypnoea, increased tachycardia and hypotension. venous blood revealed a ph 7.14, pco2 1.6 hco3 11.3 be -19 and lactate 18.5. he became unresponsive with refractory hypotension and multiorgan failure. arterial blood showed a ph 6.8, pco2 5.3 and a lactate >20 with indeterminable be or hco3. for over 24 hours he had a blood lactate level of >20. rhabdomyolysis and acute kidney injury occurred with a ck of >200 000 requiring haemofiltration. encephalopathy, with multiple white matter microhaemorrhages on mri brain, and acute liver failure, with thrombocytopenia and coagulopathy, ensued. multiple inotropes were required. the prognosis was very guarded. off sedation he was unresponsive, apnoeic and areflexic however an eeg showed an alpha rhythm which prompted on-going heroic efforts. he required prolonged haemofiltration, ventilation and inotropes with 26 days intensive care. results: the patient made an astounding recovery. he required 1 month of neurorehabilitation and returned to his cognitive baseline, achieving a grades at gcse 5 months later. liver and renal dysfunction resolved. conclusions: this case demonstrates that mitochondrial metabolic crises in melas can be severe and result in profound acid-base derangements. our patient was expected to not survive but uniquely did so without significant neurodisability. neuronal ceroid lipofuscinosis in children from central africa gl fisher, n shah, p watts, ja te water naude noah's ark children's hospital, university hospital wales, cardiff, uk objective: the effective and rapid diagnosis of neuronal ceroid lipofuscinoses (ncls) has become more relevant with the advent of disease-modifying treatments. some ncls have a more stereotyped clinical presentation: we describe two cases in a non-consanguinous family, originally from the democratic republic of the congo, with variant ncl. methods: retrospective case series. results: the index case was initially diagnosed with a focal epilepsy: on review this child had myoclonic seizures in the context of a slow developmental decline, with mild spasticity. ophthalmology was not diagnostically helpful, and a putative diagnosis of ncl was suggested by lymphocyte inclusions. neither enzyme nor dna analysis was available at that stage, although dna was retained. a brother presented with nystagmus and visual inattention in 2017: examination showed myoclonic jerks with a bull's eye maculopathy and an abnormal peripheral retinal vascular leak. mri imaging showed some element of cerebellar atrophy, which on review was also the case with his brother's scans. some lymphocytes (20%) contained fingerprint bodies, suggestive of variant ncl. this was confirmed by dna sequencing which was consistent with a diagnosis of mfsd8/cln7-related ncl. the identical dna alteration was also found in the index case. conclusions: ncl is not described in children from central africa: the presentation, investigations and laboratory findings and evolution are consistent with that for other children with variant ncl. obesity screening of patients affected by duchenne muscular dystrophy (dmd) in a tertiary paediatric neuromuscular centre and the effectiveness of metformin use in weight control in those with confirmed insulin resistance m neocleous 1 , s spinty 1 , r madhu 1 , p dharmaraj 1 , c degoede 2 , k cooke 1 , c greaves 1 1 alder hey hospital, liverpool, uk; 2 royal preston hospital, preston, uk objective: to assess whether patients affected by duchenne muscular dystrophy (dmd) who are currently followed up in alder hey hospital, uk are receiving obesity screening when clinically appropriate. to assess whether metformin use in those who are insulin-resistant, has been effective in controlling weight. methods: using the neurology department records, a list of patients with dmd currently under our services and those transitioned to adult services in the last 5 years, was generated. the patient record system, meditech, was used to collect patients' demographics, latest weight/height value and bmi. for patients classified as overweight/obese, completion of obesity screening was assessed as well as initiation of appropriate treatment (metformin). for patients on metformin, the following parameters were collected: weight pre and post-steroids, age of start of excessive weight gain, confounding variables and medications, weight/height/bmi at initiation of metformin and at 6-monthly intervals, side-effects, cessation of medication and reasoning. results: sixteen out of 90 patients were found to be above the 98th weight centile. in 38 patients, weight was at 3 or more centiles above height. using the non-dmd standardised bmi classification, 47 patients were identified as being overweight/ obese. 16 patients received obesity screening; 7 were found to be insulin resistant. 4 of those were started on metformin. 7 patients overall were started on metformin. 2 of those exhibited overall weight loss. 3 patients were found to have gained weight and 1 patient showed weight increase up to 18 months post-metformin initiation with subsequent weight loss. conclusions: there is a need for a validated and agreed bmi classification in dmd. screening for insulin resistance in this patient group should be considered for implementation as standard practice, especially if patient is classified as overweight/obese. a larger-scale study would be required to assess the effectiveness of metformin in this patient population. objective: niemann-pick disease (npd) is an autosomal recessive metabolic disorder with a prevalence of 0.4 to 0.6/100 000 worldwide, marked by varying degrees of lipid storage and foam cell infiltration in tissues, associated with hepatosplenomegaly, pulmonary insufficiency or central nervous system involvement. npd type a and b are allelic disorders caused by mutations in the sphingomyelin phosphodiesterase-1 gene, smpd1 (11p15.1-15.4), characterized by a primary deficiency of acid sphingomyelinase activity, resulting in an accumulation of sphingomyelin. in contrast to npd-a, npd-b is the milder, lateronset form, with no neurological involvement. in this paper, we report on three paediatric cases with npd-b who present an atypical phenotype marked by neurological involvement. methods: the three patients were diagnosed at the age of 1 with hepatosplenomegaly. the first is a girl who presented psychomotor regression at the age of 3 and epileptic seizures at the age of 10. she died at the age of 15. the second is an 8 years old girl who presented growth retardation, kyphosis and neurodevelopment regression since the age of 6. the third is a 15 years old boy with a mild phenotype marked by developmental delay and an aggressive behaviour. splenectomy was performed at the age of 8. results: genetic testing was performed, and all patients presented mutations of the smpd1 gene, confirming the diagnosis of niemann-pick type b. the c.1177t>g(p.trp393gly) mutation was common in all cases. in addition, heterozygous mutations c.573delt(p.ser192alafs*65) and del c.560_606del were found in the first and second case, respectively. conclusions: all cases present a complex phenotype, marked by psychomotor regression which is atypical for npd type b. the severity of the disease seems to be correlated to the genetic mutation-the most severe phenotype was associated with c.573delt. further work is necessary to more clearly delineate genotype-phenotype relationship in npd. objective: acute encephalitis syndrome (aes) is a group of symptoms and signs, which help diagnose encephalitis. since there is no definite treatment for most, role of fluids seems crucial. therefore, the objective of our study was to describe the association of low admission weight and weight loss in the hospital (as clinical marker of dehydration) with outcome of patients of acute encephalitis syndrome. to describe the association between changes in weight and blood lactate levels (at admission and discharge as indicators of hydration and acid base status) and outcome in children with acute encephalitis syndrome. methods: all children aged 1 month to 14 years with fever and altered sensorium and/or new onset seizures from september 2011 to september 2012 attending kanti children's hospital, kathmandu, nepal were recruited. weight-for-age (wfa) using z score and serum lactate were assessed at admission and discharge. total fluid input and output was monitored daily. results: of the 92 patients, 62% had low admission wfa or lost weight-after-admission (lwaa) (group a) and 38% no low wfa or didn't lwaa (group b). there was 19 times risk of death and 7 times risk of bad outcome (death or sequelae) in group a compared to b. bad outcome was significantly associated with less admission wfa, more fluid deficit, and trend for higher admission serum lactate. death was significantly more in those with low wfa, more lwaa, longer illness, more 5% dextrose and 0.5 normal saline, higher sodium and higher urea at admission. methods: we conducted a prospective cross-sectional study recruiting children aged between 1 month to 14 years attending kanti children's hospital, kathmandu, nepal with altered sensorium and two of the following: fever, seizure, focal neurological deficit, csf pleocytosis, electroencephalogram and computer tomography suggestive of encephalitis, over 1 year. in these patients, ve was if csf cell count was <1000cells/ mm 3 (lymphocyte predominance) and absence of non-viral pathogens in the csf or blood. bm was csf cell count >1000cells/mm 3 (polymorph predominance) and csf protein >0.45g/l and csf/plasma glucose <40%, and/or positive gram stain and/or bacterial culture. je was ve with ≥40units of anti je-igm in the csf and/or serum. all cns infections were defined as, suspected cases by treating clinician with or without fever with lp showing csf cells >4/mm3. results: out of 38, bm was found in 47%, je 21% and other causes in 32%. although who definition of aes was not significantly associated with all cns infections (p=0.069), it was significantly associated with ve (p<0.001, sensitivity 74%, specificity 93%, ppv 94%, npv 70%) and bm (p<0.001, sensitivity 30%, specificity 7%, ppv 33%, npv 6%). conclusion: we validate who aes definition of bm and ve as a significantly useful screening tool for children with these diseases specially in resource poor settings, endemic areas and where confirmatory tests were not easily available. objective: the aim of this case series is to raise awareness of this autosomal recessive encephalopathic syndrome that presents after birth in the multi-ethnic population in england. although aicardi goutieres syndrome (ags) is rare, its importance lies in the fact that that its presentation may be mistaken for other neurological conditions associated with congenital infections. results: all 6 of the patients were seen in our paediatric outpatient neurology clinic. the age of presentation ranged from the neonatal period to the first 20 weeks of life. all 6 patients were of pakistani origin and 5 were from consanguineous marriages. they all had an uneventful antenatal period with normal birth weight and head circumference. the initial presentation seems to be of poor feeding and irritability. further observations include truncal hypotonia, limb spasticity intermittent dystonic posturing coinciding with the onset of poor head growth and chilblains. 3 of our patients had abnormal movements with diffuse slow wave electroencephalogram activity. nystagmus with visual inattention and poor visual acuity were a typical finding in all of them by the age of 3 months. the ct scans showed cerebral calcification in all of them and mri suggested brain atrophy. the most striking abnormality was a raised level of csf interferon-alpha (infa) in an absence of other infection or metabolic disorder. csf inf a is a reliable diagnostic marker and can thus be used to differentiate patients with ags from other conditions. three of our patients had the same gene mutation, rnaseh2c. conclusions: ags is a rare disorder, however in patients from consanguineous marriages that depicts microcephaly, poor tone and global developmental delay, diagnosis of ags should be considered. as ags is a progressive neurological condition, early support and prognosis can be provided for affected families. t thomas 1 , ht yeo 1 , sv barron 1,2 1 paediatric neurology, kk hospital, kampong java, singapore; 2 university of newcastle, newcastle, uk objective: we report the association of mild encephalopathy with a reversible splenial lesion (mers) with a primary dengue virus infection. this case implies the existence of a wider spectrum of neurological involvement in dengue virus infections. case description: a 12-year-old girl presented with acute confusion, dysarthria and bilateral limb weakness following a 4-day history of fever. symptoms resolved after 2 hours; neurological examination was completely normal. she later experienced a second episode of slurred speech, dysphasia and right arm weakness which lasted an hour. a contiguous lesion involving the genu, body and splenium of the corpus callosum and bilateral posterior periventricular white matter was evident on the mri brain scan, with restricted diffusion and t2-hyperintensity. cerebrospinal fluid analysis showed no inflammation and polymerase chain reaction assay for respiratory viruses was negative. her clinical and radiological features were consistent with mild encephalopathy with a reversible splenial lesion (mers). on day 2 of admission, she developed a generalised maculopapular rash with leukopenia (white blood cell count 1.819109/l) and thrombocytopenia (platelets 1359109/l). serology (igm/igg) for dengue virus was negative and a positive dengue ns1 antigen was thus indicative of a primary dengue virus infection. she was given fluid rehydration and advised bedrest. at discharge (day 6 admission) she was well with no sequelae. conclusions: mers is a mild form of virus associated encephalopathy (vae), which are a spectrum of clinico-radiological syndromes associated with common childhood viral infections. the clinical and neurological symptoms in our patient occurred early in the course of illness (typical to vae) as opposed to after or late in the illness as is typical for postinfectious encephalopathy syndromes associated with dengue virus infections (e.g., acute disseminated encephalomyelitis). shouldering the burden of sepsis norfolk and norwich university hospital nhs trust, norwich, uk; 2 sheffield children's hospital, sheffield, uk aim: we report a case of a 15-year-old boy who presented with right brachial plexus neuritis secondary to meningococcal group b sepsis. brachial plexus neuritis or neuralgic amyotrophy (also known as parsonage -turner syndrome) is a rare disorder affecting the brachial plexus. it can be caused by various infectious agents and is characterized by acute onset of intense pain in the shoulder and arm followed by weakness, sensory loss and atrophy. methods: a 15-year-old boy, previously fit and well presented to the emergency department with an acute onset of excruciating pain in his right shoulder, radiating down his arm and hand with associated paresthesia. few hours later, he developed an evolving non-blanching purpuric rash to the chest, back, shoulder and right arm. he gradually developed weakness in the right arm and sensory loss over the ulnar aspect of the right hand. he then began to complain of headache, photophobia with subsequent vomiting. he was treated for meningococcal sepsis with intravenous ceftriaxone and received three fluid boluses for hypotensive shock with vitamin k correction for his associated coagulopathy. he received analgesia for right shoulder pain. results: blood cultures and blood pcr confirmed neisseria meningitidis group b type, nt subtype. mri of the shoulder showed inflammation consistent with brachial plexus neuritis with motor impairment affecting the right side c4 to t1 myotomes and sensory impairment involving the right c6 dermatome. the patient was treated with oral prednisone and gabapentin whilst receiving neurorehabilitation from physiotherapy and occupational therapy. he made a very pleasing recovery after few months and currently has no motor or sensory deficit of his right shoulder and arm. conclusion: brachial plexus neuritis should be considered in the differential when a child presents with sudden onset pain and weakness of the shoulder and arm. in review of literature, brachial plexus neuritis associated with meningococcal infection has not been described previously. to the best of our knowledge, this is the first reported case of its kind. introduction: previous cohort studies on paediatric multiple sclerosis (ms) have reported very low frequencies for a primary progressive ms course (ppms) ranging from 0 to 7%. an age-dependent increase in the rate of primary-progressive courses has been well described in the adult ms population. objectives and methods: we describe five patients presenting prior to the age of 18 years and fulfilling the 2017 mcdonald criteria for ppms. patients were identified from the national hospital for neurology and neurosurgery (nhnn) and the uk childhood inflammatory demyelination (uk-cid) network. results: patients presented at a median age of 15 years (range: 11-17y), with at least 1-year history of progressive deterioration of their balance (n=2) or progressive worsening of lower limb function (n=3). over time, all patients developed lower limb spasticity, three patients developed cognitive difficulties, three had visual problems, three had bladder involvement. median edss at 2 years was 5 (range: 4 to 7). cerebrospinal fluid (csf) oligoclonal bands were detected in all 4 patients tested. dissemination in space on first mri was seen in all patients with peri-ventricular (n=4), cortical juxtacoritcal (n=2), infratentorial and spinal cord (n=4) lesions. all patients showed new lesions on repeat mri imaging. contrast enhancement was present in 3 out of 4 (75%) during the disease course. three patients had genetic investigations to exclude other mimics. a trial of iv methylprednisolone was unsuccessful in 3 patients. all patients were on symptomatic treatment for spasticity and pain, including oral/intra-thecal baclofen, gabapentin and sativex. conclusions: given the rarity of primary progressive course in paediatric ms, presentation with progressive neurological symptoms and signs in young people should prompt evaluation for genetic causes. nevertheless, our five patients presented with clinical, mri and immunological features consistent with a diagnosis of primary progressive multiple sclerosis. objective: clinical course in nmdar-antibody encephalitis is variable and difficult to predict. we aimed to identify clinical features in the presenting disease episode associated with worse functional outcome and/or relapsing disease course. methods: systematic review of the literature was conducted to identify published cases with individually reported data. clinical and treatment characteristics at first episode, outcome at ≥12 months, and monophasic vs. relapsing disease course were recorded. results: 1651 cases were identified from 693 articles (73% female; 48% ≤18 years old at onset). 91% received immunotherapy at first episode: corticosteroids in 81%, ivig in 66% and therapeutic apheresis in 33%. second-line immunotherapies were used in 32% at first episode, most frequently rituximab (17%), cyclophosphamide (5.1%), or both (7.2%); emerging second-line treatments (intravenous/intrathecal methotrexate, subcutaneous/intravenous bortezomib, intravenous tocilizumab) were used in 1.8%. life-threatening adverse events or death related to immunotherapy occurred in 1.9%. in a univariate analysis of 682 cases with ≥12 months follow-up data, poor final outcome (defined as modified rankin scale [mrs] score 3-6) occurred in 30% and was associated with very young or elderly age at onset, movement disorder, decreased consciousness, autonomic dysfunction, mechanical ventilation, higher mrs score in the acute phase, longer hospital stay, extreme delta brush on eeg, abnormal mri, csf pleocytosis and elevated csf protein (all p<0.05). a subset of 198 cases followed up for ≥36 months were analysed to identify associations with relapsing course, which occurred in 29%. in univariate analysis, factors protective against relapse were <30 days delay in first-line immune therapy, therapeutic apheresis, ivig, rituximab and other second-line treatments at first episode (all p<0.05). conclusions: worse functional outcome of nmdar-antibody encephalitis is associated with very young or elderly age at onset and worse disease severity in the acute phase. relapsing disease course is associated with delayed or insufficient early immunotherapy. objective: we describe three children with familial hemophagocytic lymphohistiocytosis (fhlh), who presented with an atypical chronic demyelinating illness. an initial working diagnosis of 'clippers' (chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids) was made in two cases. methods: retrospective case series. results: case 1: an 11-year-old girl presented with diplopia and squint with evolving ataxia. mri showed multiple enhancing white matter lesions in the pons, medulla and cerebellum raising the possibility of 'clippers'. her symptoms and neuroimaging responded only partially to treatment with ivig and steroids. genetic testing revealed a compound heterozygote mutation in the rab27a gene consistent with griscelli syndrome type 2 with fhlh. case 2: a 5-year-old boy had nocturnal headaches with a squint evolving over time. mri showed demyelination and swelling predominantly in the cerebellum. significant radiological resolution with steroids was followed by recurrence of demyelination on weaning steroids. a brain biopsy lesion was consistent with 'clippers'. genetic testing revealed a heterozygote variant in the stxbp2 consistent with fhlh v. case 3: a 9-year-old girl had a 7-month of intermittent fevers, deranged lfts and recurrent bilateral optic neuritis responsive to steroids/ivig. mri brain showed multiple areas of demyelination largely in the subcortical white matter. oligoclonal bands were positive in the csf. she developed a pleural effusion, high ferritin, deranged coagulation, lymphadenopathy and a rash found to be a cutaneous t-cell lymphoma. genetic testing revealed a homozygous mutation in the unc13 gene consistent with fhlh 3. all three children are awaiting stem cell transplantation. conclusions: fhlh can present with an isolated atypical demyelinating illness or with neuroimaging suggestive of 'clippers'. there may be no signs of systemic inflammation. we propose that all children with atypical recurrent cns inflammation and presentations consistent with 'clip-pers' undergo genetic panel testing for fhlh and natural killer cell functional testing. objective: the most common paediatric presentation of mog-ab disease is with acute disseminated encephalomyelitis (adem), or optic neuritis (on). with increasing recognition of the association of mog-abs with seizures in children, we present a case series of affected children. methods: retrospective anonymised case note review of affected children presenting between 2005-2019, from 5 uk paediatric neurology centres. patients were followed up for median of 6 years (range 0.5-16). results: 15 cases (7 female) of mog-ab-positive epilepsy patients were identified; median age at first presentation was 6 (range 2-14y). the most common preceding mog-ab disease was multiphasic adem (mdem 6; adem 3; adem-on 2; adem and transverse myelitis 1; nmosd 2; on 1). median time to recurrent seizure onset was 3 months (range 0-60). focal epilepsy/seizures were most common (12/15). eeg abnormalities were found in 14/15 patients, all demonstrated slowing/encephalopathy which was generalised or focal; epileptiform discharges were reported in 3 patients. brain mri was abnormal in all patients (8 with multifocal hazy/ poorly marginated lesions involving grey and white matter; 4 leukodystrophy-like pattern, 2 cortical encephalitis and 1 reported with subtle changes in brainstem). 8 patients received immunotherapy, all required at least 1 anti-epileptic drug (aed) and 8 children continue to have on-going breakthrough seizures. median mrs (modified rankin scale) at last follow-up was 1 (range 0-3), indicating no significant disabilities despite symptoms in clinical examination, age appropriate behaviour and development. conclusions: focal epilepsy is more common and more likely to follow an mdem presentation in children with mog-abs. with the relapsing nature of mog-ab disease there is a high risk of long-term cognitive impairment. further preclinical studies are urgently required to determine whether this epilepsy is due to ongoing inflammation or as a result of the mri changes commonly seen. this will help inform future management decisions regarding immunotherapy. poster no. 056 maternal mid-gestation cytokine dysregulation in mothers of children with autism spectrum disorder autism spectrum disorder (asd) is a developmental disorder characterised by a spectrum of deficits in social interactions/ communication combined with stereotypical, repetitive behaviours. recent evidence suggests maternal immune activation (mia) during pregnancy may predispose offspring to asd. the aim of this study was to examine the mid-gestation cytokine profile in mothers of children with a subsequent asd diagnosis. maternal-child dyads were recruited to a prospective population-based pregnancy study; the scope study, new zealand. children with confirmed diagnosis of asd at 6 years were enrolled in the nested cohort, along with matched neurotypical controls. cytokine concentrations (pg/ ml; mean [sem]) were examined in maternal serum samples taken at 15 and 20 weeks gestation using mesoscale discovery proinflammatory, cytokine and chemokine assays. of 2032 mothers recruited to the scope-nz study, 16 children completed follow-up and had reported asd at 6 years. these were analysed alongside 16 neurotypical matched controls. downregulation of il-17a occurred at 20 weeks gestation in cases when compared to controls (mean [sem]). 2-way anova revealed a relationship between il-17a concentration and weeks' gestation f(1,49)=4.183; p=0.0462, and also il-17a concentration and asd status f91,49)=7.801; p=0.0074. posthoc uncorrected fisher's lsd revealed a significant difference between cases (-0.3846 [0.1426] ) and controls (-0.1207 [0. 05068]) at 20 weeks gestation p=0.0160. ifnc is also downregulated at 20 weeks gestation in cases when compared to controls. 2-way anova revealed a relationship between ifny concentration and weeks gestation f(1,53) =5.692; p=0.0206. posthoc uncorrected fisher's lsd revealed a significant difference between cases (0.347 [0.0215] ) and controls (0.4345 [0. 1685]) at 20 weeks gestation p=0.0476. we have shown altered cytokine expression at 20 weeks gestation in mothers of children who progress to develop asd. this adds to the growing body of evidence that maternal immune regulation may play a role in foetal neurodevelopment. objective: acute disseminated encephalomyelitis (adem) is an immune mediated inflammatory cns disorder, predominantly affecting white matter, with a wide differential (1). here we describe a rare mimic of adem that is essential to consider in order to avoid a catastrophic outcome. case history: a 12-year old girl presented with a 2 day history of confusion, dysarthria, ataxia and left-sided squint, preceded by 2 weeks of general malaise and headache. examination confirmed encephalopathy and a left third cranial nerve palsy. mri brain was suggestive of adem and mri spine was normal. a recommended work up for adem was performed. rapid resolution of her symptoms occurred following intravenous methylprednisolone for 3 days. 2 years later she presented with acute left lower limb ischaemia and underwent emergency embolectomy of a popliteal arterial obstruction, with myxomatous material identified. preoperative echocardiogram confirmed a large atrial mass which was surgically removed. pathology confirmed an atrial myxoma (am). retrospective review of her initial mri images concluded that embolic phenomena from the am was the most likely explanation of her first presentation. conclusions: am is a very rare primary cardiac tumour and left sided am can embolise to the cerebrovascular system. early identification of am is important as, untreated, it can cause multiple embolic events and sudden cardiac death. 12% of adults with am present with neurological symptoms and this can mimic multiple sclerosis. am presenting with acute neurological symptoms masquerading as adem in paediatrics has not been previously reported. careful follow up is essential as late neurological complications (including cerebral arterial aneurysms) are recognised. this case highlights that adem is a diagnosis of exclusion and that mimics for acute focal neurology with encephalopathy and t2 hyperintensities on mri require careful consideration, including embolic phenomena. clinical examination alone does not exclude am and consideration of echocardiography is recommended. we describe an 8 year old boy with a rare demyelinating disorder: balo's concentric sclerosis. a routine optician review raised concerns about papilloedema in an asymptomatic child. a ct brain identified a well-demarcated high-density lesion in the left posterior frontal lobe with surrounding oedema. mri brain with contrast identified the lesion had central rim enhancement and slight diffusion restriction. alternating layers of high and low signal intensity gave it an 'onion bulb' appearance. the differential included balo's concentric sclerosis, a single demyelinating lesion, or a tumour. routine blood tests were unremarkable. csf oligoclonal bands were normal as were other csf indices. markers of immunology, including ana, anca, anti-mog, anticardiolipin, and aquaporin 4 antibodies were all negative, with normal complement levels. esr was mildly elevated when taken during an episode of acute tonsillitis. imaging 3 months later demonstrated an increase in the size of the lesion. a biopsy revealed inflammatory demyelinating pathology mediated by a perivascular and parenchymal t-and b-lymphocyte infiltrate and macrophage activity with associated demyelination lacking a perivenular distribution. there was no evidence of neoplasia, vasculitis, granulomas, or viral infection (including negative pcr testing). no treatment with corticosteroids was given, and the child remained asymptomatic. imaging, at 9 months from presentation, revealed the lesion had substantially reduced in size. there was still a rim of enhancement. as with all single demyelinating lesions, it is difficult to predict the clinical course. we opted to adopt a 'wait and see policy' and offer surveillance imaging and clinical review. balo's concentric sclerosis is a rare demyelinating disease, characterized by concentric lamella of alternating demyelinated and partially myelinated tissues. mri shows one or more concentrically mulitlayered ring-like lesions, usually in the cerebral white matter. most case reports describe cases predominantly in young adults, with few reports of cases in children. objective: cognitive and acquired neurodevelopmental deficits have been reported in children with opsoclonus-myoclonus syndrome (oms) and are associated with more severe and relapsing disease course. however, there is a paucity of data regarding cognitive dysfunction in children with stable neurological disease. we report on serial cognitive assessments of 4 children with oms demonstrating evolving cognitive dysfunction with milder disease course. methods: retrospective analysis of clinical features at presentation, investigations, treatments, clinical course including relapses and neuropsychological testing. results: four children (m:f 1:1) diagnosed with oms between 17 and 35 months were followed up for 4 to 10 years. neuroblastoma was identified in one child. oms severity scores ranged between 8 to 12/15 at presentation. patients underwent immunotherapy in accordance with european oms protocol. all patients were in remission by 7 months (range 4-13mo), with treatment maintained for 1 year. one child remained relapse free whilst 3 other children had one clinical relapse which was immunotherapy responsive again. in all cases, progressive cognitive dysfunction was reported despite being in remission and stable off treatment for 20 months (range of 12-31mo; 3 oms score 0/15 and one 2/15). sequential neuropsychological testing scores showed mean declines in fsiq of 16 (13-19) , viq of 24 (20-27) and piq of 17 (-2 to 30) between time of oms remission/stable disease and longer term follow-up time point (4-10y). conclusions: our cases demonstrate progressive cognitive dysfunction occurring in children with oms who have a milder disease and long after completion of treatment. children continued to develop but with a widening gap in comparison with peers. damage to cerebellar-cortical circuits at onset of the disease that becomes more apparent with time or indeed persistent ongoing low grade inflammation may explain this deterioration. the past decade has seen increasing cases of acute flaccid paralysis (afp) associated with enterovirus d68 (evd68) infection. it presents in clusters approximately every 2 years. we report three cases of afp due to evd68 that presented in november-december 2018. cases: two patients developed afp following a viral upper respiratory tract infection and one developed lower limb hypotonia and weakness during an inpatient admission with refractory epilepsy. two required admission to the paediatric intensive care unit for respiratory compromise and required tracheostomy ventilation. mri showed acute flaccid myelitis (afm) consistent with evd68 in 2/3 cases, consisting of central cord t2 hyperintensity in the cervical region over multiple segments with subsequent enhancement of the thalamus and cauda equina on follow-up imaging in one patient; and ventral surface enhancement of the conus and cauda equina in another. mri in the third patient was normal. electromyography and nerve conduction studies were normal in two patients but revealed a severe generalised motor axonal poly-neuronopathy in the third. two patients received intravenous immunoglobulin, corticosteroids or plasma exchange therapy and showed slow motor improvement in a distal to proximal pattern. the one patient without mri changes had received long-term oral corticosteroids but received no additional treatment and returned to baseline neurological function within 4 weeks. discussion: our cases demonstrate the range and clinical course of peripheral neurological presentations secondary to evd68 infection. we highlight the importance of sending repeat samples from multiple sites when the diagnosis is suspected, given that initial samples tested negative, and of sending samples to a national surveillance laboratory for confirmatory testing. ongoing national and multinational surveillance studies will hopefully continue to advance our understanding and treatment of this disease. poster no. 061 nmda receptor encephalitis a potential complication of biologic therapy for juvenile idiopathic arthritis? n abbassi 1 , t rossor 1 , r close 2 , a skippen 1 , k armon 2 , p bale 2 , g ambegaonkar 1 1 paediatric neurology, addenbrookes hospital, cambridge, uk; 2 paediatric rheumatology, addenbrookes hospital, cambridge, uk a 12-year-old girl presented with headaches, confusion and agitation, followed by seizures. she had presented at 20 months with polyarticular arthritis and was managed over subsequent years on methotrexate alone (2y) with added etanercept (anti-tnf alpha, 5y), tocilizumab (anti il-6, 2y) and abatacept (cd 80/86 t-cell modifier, 3y prior to presentation). flares of disease following a period of control necessitated the changes in monoclonal antibody therapy. at this presentation she was managed on methotrexate, abatacept and 5mg prednisolone for polyarticular rheumatoid factor negative juvenile idiopathic arthritis (jia). at presentation the patient was agitated, non-verbal and had one generalised seizure. examination demonstrated acute confusion, with increased tone, brisk reflexes and bilateral clonus in her lower limbs. iv ceftriaxone, acyclovir and clarithromycin were commenced. full blood count, liver function tests and inflammatory markers were unremarkable. infective serology was non-contributory. csf was unreactive with normal protein and jc virus pcr negative. mri brain 5 days after presentation showed increased t2 and flair signal intensity in the white matter of the right parietal lobe, in-keeping with an inflammatory process. eeg showed diffuse slowing with delta brush. she commenced iv methylprednisolone, followed by prednisolone. she continued to deteriorate and underwent plasmapheresis for treatment of presumed nmda receptor encephalitis, subsequently confirmed by anti-nmda receptor antibodies in serum and csf. she was commenced on rituximab (b-cell depletion, anti-cd 20), and continued to undergo plasmapheresis over the course of 4 weeks. she gradually improved and was discharged home after a 10-week inpatient stay. several adult and two paediatric cases of nmda receptor encephalitis are reported in patients on biologic therapy for autoimmune disease. autoimmune diseases are more common in those already affected by one autoimmune condition. it is unclear what contribution an autoimmune history or immunomodulation made on the development of this condition. introduction: the incidence of acute flaccid myelitis (afm) associated with enterovirus infection occurring in biennial clusters since 2012 has been reported in the us (bmj 2018, 18; 363:k5246) and recently in europe. previously, cases with transverse myelitis (tm) with anterior-horn cell or peripheral nerve involvement have been collectively termed tm-plus (neurology 2016; 87;s46-s52). we aimed to identify cases of tm-plus from a retrospective cohort of children to identify potential cases of 'undiagnosed' afm, and to evaluate the clinical and radiological features alongside long-term outcome. methods: consecutive cases of children (<16y of age) who presented to a large paediatric neurosciences centre from 2009 to 2016 fulfilling the transverse myelitis consortium working group criteria modified for the paediatric population (neurology 2015; 84:341-349) were retrospectively evaluated for additional features of anterior horn-cell involvement (fulfilling criteria for afm (current treat options neurol (2017) 19: 48)) or peripheral nervous involvement; and were collectively evaluated with the contemporary tm-plus cohort (2016) (2017) (2018) . results: 25 cases of tm were identified, 7 of which were excluded from further analysis; ms (n=6), adem (n=1). 8 cases of tm-plus were identified, 4 before 2016 and 4 after, all associated with a viral prodrome. flaccidity (n=8) and asymmetry (n=6) was noted at presentation, with corresponding nerve conduction studies revealing a motor axonopathy with sensory sparing (n=6) and anterior horn cell involvement confirmed in 3 cases. all cases with anterior horn cell involvement had poor outcomes while both cases with good outcomes had peripheral involvement and normal mri brains. conclusions: tm-plus was detected in our cohort from 2009 to 2016 with biennial clusters noted in 2016 and 2018. the clinical presentation, investigations and long-term outcomes appear consistent in both groups. acute necrotising encephalopathy is more severe when associated with influenza background and objective: acute necrotising encephalopathy (ane) is a rare but potentially life-threatening condition associated with viral infections. a familial and recurrent form (ane1) has been identified by mutations in the nuclear pore ran binding protein (ranbp2). we report the morbidity and mortality when associated with influenza infection. methods: we performed a review of paediatric ane cases from 1999 to 2019 evaluating the clinical, biochemical, microbiological and neuroimaging appearances as well as outcomes. results: the cohort comprised 6 children (2 boys), age ranging from 8 months to 3 years 9 months (<2y n=5), of which 4 had a confirmed genetic diagnosis and 2 were ranbp2 negative. there were 13 episodes of encephalopathy, with recurrences in 3 cases (2 ane1). 10 of these episodes had infectious aetiology identified: coronavirus n=2, parainfluenza n=1, adenovirus n=2, h influenzae n=1, influenza (h1n1 n=3, h3n2 n=1). clinical features of fever and encephalopathy were consistent (100%), and seizures and sixth nerve palsies prominent (50% each). csf revealed absent pleocytosis, normal-elevated protein and negative virology. symmetric involvement of the thalami bilaterally was present in all cases, and all ane1 cases were associated with haemorrhage and external capsule/claustrum involvement (100% specific and sensitive). the outcome following influenza infection was striking, death n=1, vegetative n=2, 4 limb motor and movement disorder n=1. 2 of these cases had previous episodes of encephalopathy with noninfluenza infection and did have recovery, albeit with moderate to severe disability. all 3 cases were never immunised against influenza infection and suffered grave outcomes. conclusions: influenza infection in ane has the poorest outcome therefore vaccination should be a mandatory consideration for the known cases of ane. introduction: acute flaccid paralysis (afp) is characterized by a rapid onset of limb weakness. we describe six cases of afp in children aged 9 months to 3 years of age who presented to a tertiary paediatric neurology service in the east of england over a 5-year period from november 2013-november 2018. retrospective analysis of the six cases was performed, reviewing their clinical course and management, as well as their radiological, electrophysiology and laboratory results. results: case 1, a 9-month-old boy, presented in november 2013 with a viral urti requiring escalation of care to picu due to a significant respiratory compromise. only on subsequent recovery was the child found to have a unilateral upper limb flaccid paralysis. this child was positive for enterovirus serotype d68. cases 2 and 3 in our series presented in 2016 with acute weakness of the lower limbs with an mri brain and spine showing enhancement of the lumbar spinal roots. both have made a good recovery. enterovirus was not detected in either case. the final three children in our series presented in autumn 2018 with weakness of a unilateral upper limb following a viral urti, with all three being positive for enterovirus. unfortunately, they have shown minimal recovery of motor function of the affected upper limb. one child, a 3year-old girl, showed a more severe clinical course involving a prolonged period of intensive care and a tracheostomy for long-term ventilation. she has undergone neurorehabilitation and an upper right arm nerve transfer. conclusions: in our case series, four patients presented with an acute viral urti associated with an upper extremity weakness, and subsequently all four were positive for enterovirus. clusters of acute limb weakness in paediatric patients have been linked to outbreaks of non-polio enteroviruses, termed acute flaccid myelitis (afm). objective: to present an interesting case of recurrent anti-mog demyelinating disease and provoke discussion regarding possible immunomodulatory therapy. methods: a 14 year old girl presented, initially at 5 years of age, with headache and vomiting. she was initially treated as atypical tuberculosis meningitis based on csf cell counts, but later developed a 6th nerve palsy and was diagnosed with optic neuritis. anti-mog antibodies were positive and they were commenced on iv methylprednisolone. she clinically improved and was discharged on weaning oral prednisolone, antibodies were negative following treatment. results: a few months later she had her first relapse, with an acute decline in visual acuity. an mri showed new lesions in her optic chiasm and both optic nerves with associated bilaterally reduced visual evoked potentials. she was again treated with iv methylprednisolone, with rapid improvement, followed by a switch to weaning oral prednisolone. anti-mog antibodies were negative following treatment. she was symptom free for 7 years until her second relapse, when she presented with facial palsy, swallowing difficulties and slurred speech. mri showed brainstem and periventricular white matter demyelination, with positive anti-mog antibodies. she was again treated with iv methylprednisolone, followed by oral prednisolone, but was maintained on low dose prednisolone as her anti-mog antibodies remained weakly positive despite being symptom free. these were stopped at patient request due to low mood and abdominal pain in february 2019, with no recurrence of symptoms as yet. repeat mog antibodies have been sent and are awaited. conclusions: this case shows an interesting relapsing/remitting pattern of anti-mog demyelinating disease, which appears to be very steroid responsive, however on her second relapse her anti-mog antibodies remained weakly positive despite steroid therapy. discussion is welcomed on whether prophylactic immune modulation therapy should be considered with this child, such as azathioprine, mycophenolate mofetil or rituximab. objective: to highlight the utility of early mr imaging in children presenting with acute severe encephalopathy and to consider whether there might be a subgroup of children with myelin oligodendrocyte glycoprotein antibody (mog-ab)associated demyelination who might be candidates for early intense immunomodulation. methods: we report two cases with mog-ab-associated acute demyelination who relapsed with new neurological symptoms after initial steroid therapy had been discontinued. results: two toddlers were initially admitted to intensive care with acute encephalopathy and acute symptomatic seizures. both had an initial ct head during picu admission; one was reported normal; the other was suggestive of diffuse cerebral oedema. both children improved with supportive care only and were discharged home within a week. both children presented again over the following 2 to 4 weeks with new neurological symptoms but without encephalopathy. mr imaging demonstrated demyelination and they were treated with steroids. both children relapsed as steroids were being weaned and/or stopped. repeat mr imaging at this stage demonstrated new enhancing lesions. it was subsequently found that both children were mog-ab positive. conclusions: reliance on cranial ct imaging in the context of a young child with acute encephalopathy and seizures can be misleading. prediction of the severity of mog-ab-associated demyelinating syndrome at onset is challenging. mr imaging in the acute phase with early follow up imaging may identify this subgroup. case: hb is a 7 year old boy who presented with sudden onset diplopia and painful ophthalmoplegia, following a 12 day history of frontal headache. on examination, he had a left vith nerve palsy, partial left iiird nerve palsy and normal right eye movements. the remainder of his neurological and general systems examination was normal. his initial ct head scan and pre-contrast mri of the brain were normal. he was discharged from the local hospital following normal blood tests and imaging. clinical course: nine days later, his symptoms worsened including severe vomiting, worsening frontal headache and photophobia. he was treated for a possible underlying infective cause with ceftriaxone and acyclovir. given the broad underlying differential diagnoses, hb had extensive infectious and immunological blood workup which was unremarkable. a repeat mri brain scan with contrast revealed a lesion in the left cavernous sinus, possibly of vascular origin. differentials included cerebrovascular venous sinus thrombosis, tumour and inflammatory causes such as tb, sarcoid and zoonoses. hb continued to be conservatively managed and completed his course of ceftriaxone and acyclovir. repeat mri imaging 2 months later showed some resolution of the lesion and a diagnosis of tolosa-hunt syndrome was provisionally made. hb's symptoms continued to improve and further repeat mri scan 6 months later showed ongoing resolution of the lesion. discussion: according to the ichd-3 beta classification of tolosa-hunt syndrome, hb fulfilled the diagnostic criteria given his presentation of unilateral headache, granulomatous inflammation of the cavernous sinus on mri, palsies of ipsilateral iiird, ivth and vith cranial nerves. steroid use has been reported to be beneficial although more evidence is required in the paediatric population, refractory cases may respond to azathioprine and methotrexate. objective: we present a case of internuclear ophthalmoplegia unresponsive to steroid treatment which clinically improved with folinic acid supplementation. method: a retrospective chart review. results: our patient presented with acute internuclear ophthalmoplegia, ataxia and bilateral ptosis. she had a background of hypoplasia of the corpus callosum and optic atrophy with visual impairment, learning difficulties and asd. mri brain demonstrated symmetrical high signal intensity in the region of the medial longitudinal fasciculus and periaqueductal grey matter. she was investigated to exclude an inflammatory cause and was treated with high dose steroids. follow up mri did not show any improvement post steroids and there was no clinical improvement. subsequent csf investigations showed a low level of 5-methyltetrahydrofolate of 35nmol/l (normal range 72-172nmol/l). she was commenced on folinic acid 15mg once daily and her symptoms improved. on follow up her eye movements had significantly improved as had her ptosis. follow up mri brain showed partial resolution of the areas of abnormal signal in the periaqueductal grey matter. conclusion: internuclear ophthalmoplegia is a sign usually associated with an inflammatory or demyelinating cause. our case did not respond to steroid treatment but has associated low levels of 5-methyl tetrahydrofolate and has responded to treatment with folinic acid. this is sometimes associated with underlying mitochondrial disorders but muscle biopsy in this case did not show any evidence of mitochondrial disease. mri brain has shown partial resolution of the abnormal signal in the periaqueductal grey matter. introduction: paediatric intracranial aneurysms are rare. the pattern of disease is different to that in adults and there is far less literature available. i provide a case as an example of the presentation and progress of a child with a dissecting vertebrobasilar artery aneurysm. presentation: 11-year-old boy presented to his local hospital with sudden-onset headache, photophobia and vomiting. bloods and observations were normaldischarged. symptoms recurred more severely the following day. managed as meningitis. 4 lumbar punctures were 'bloody' and considered failed. mri brain 2 days post-admission demonstrated a vertebrobasilar aneurysm. transferred to the regional neurosurgical centre. transfer to neurosurgical/neurovascular centre: cerebral angiography revealed dissecting vertebrobasilar aneurysm (1298910mm). fusiform component extending beyond aici/ pica origins. wide-necked saccular component. procedure and progress: loaded with aspirin and clopidogrel. underwent endovascular procedure the following daycoil embolization, flow-diverting stent to the aneurysm. ongoing low dose dual anti-platelet therapy. made an excellent recovery with no neurological deficits. further imaging -x-ray cervical spine for possible arcuate foramen or atlantoaxial instability, normal. ultrasound liver/spleen, normal. discharged home 10 days post-transfer. patient background: past medical historyunder the gp for 18 months of headaches. traumasignificant fall from bicycle 2 years before with forced lateral flexion of the neck. posited that this may have been a contributing factor in aneurysm development. no significant family history. lifestylean active boy, enjoys weightlifting and motocross. weightlifting also posited as a contributing factor. conclusions: i provide a case which i hope will raise awareness of paediatric intracranial aneurysms and stimulate discussion concerning their management and aetiology. poster no. 070 cavernoma in children: cddft experience of two cases d jayachandran, s chandraiah darlington memorial hospital, cddft, darlington, uk aim: to report two cases of congenital cavernoma diagnosed in children presenting with neurological symptoms. cases: case 1: 10-year-old female presented with multiple left facial focal seizures in the form of twitches with full awareness. there was no family history of epilepsy. a typical event was captured lasting 70 seconds during the awake eeg and was reported as focal seizure arising from right hemisphere. an mri brain scan showed 2 popcorn balls lesions within the frontal/fronto parietal lobes, one on each side (right>left) with evidence of bleeding. she remains seizure free on carbamazepine. ccm gene results are awaited and neurosurgeon opinion was not for intervention and for local follow up. case 2: 12-year-old male had presented with confusion at 7 years of age. he also had transient loss of vision, vomiting, headaches with a few minutes unresponsive episode during admission. with a diagnosis of migraine, he had an mri brain scan as op that showed multiple cavernous haemangiomas in the cerebrum and cerebellum with the largest demonstrating a fluid level in the left parieto-occipital region. family history revealed that father had seizures secondary to brain cavernomas. he was positive for krit1 (ccm1) mutation. neurosurgeons advised active monitoring and he presented again at 12 years with focal onset seizures with impaired awareness. eeg was normal but mri showed a new cavernoma in the left temporal horn with bleeding. he remains well on carbamazepine with a plan for yearly mri scans. conclusions: congenital cavernomas of brain can be sporadic or familial, can be multiple and in any location including brain stem and can result in physical disability secondary to bleeding. in the majority of cases bleeding is spontaneous and diagnosed on mri scans after a neurological event. objective: foxp1-related intellectual disability syndrome is characterised by developmental delay, variable physical features and autism. diagnosis has increased with better access to broad genetic testing. we present a case report of a child with foxp1 mutation whose presentation was notable for significant cerebral venous ectasia. case: child s presented aged 1 year with gross motor delay (not sitting or weightbearing) along with relative macrocephaly (91st-99th centile), strabismus and prominent superficial forehead veins. intracranial imaging was arranged in which ct angiogram raised a possibility of an arteriovenous fistula. subsequent catheter angiography excluded this but demonstrated extensive tortuous cerebral venous ectasia. the venous ectasia was not felt to explain her developmental difficulties. initial genetic testing including microarray and pik3ca and pten analysis was normal. s made some developmental progress but remained globally delayed compared with her peers. reanalysis of her dna against a panel of genes associated with intellectual disability identified a de novo heterozygous pathogenic variant in the foxp1 gene, c.1507c>t, p.(arg503ter) (east anglian medical genetics service). discussion: foxp1 acts as a transcription factor and is likely to be involved in the development of many different tissue types. a wide range of genetic aberrations affecting foxp1, including point mutations and large structural anomalies, lead to overlapping clinical phenotypes. this patient demonstrates many relevant clinical features including developmental delay with autistic traits, relative macrocephaly with a prominent forehead, strabismus and early gross motor developmental delay. however, descriptions of associated neurovascular anomalies in foxp1 syndrome are scarce, with a single case report recording a venous angioma and none of cerebral venous ectasia to our knowledge. foxp1 follow up studies and whole exome or genome sequencing may help determine whether there is an additional genetic cause for this child's cerebral venous ectasia or whether it is foxp1 related. objective: a 2017 rcpch guideline was published to increase awareness of stroke in children and standardize best practice. the need for urgent (within 1h) ct angiography in children presenting with suspected stroke and criteria for thrombolysis were set out. we aimed to review the acute management and investigation of pais in children (1mo to 16y) since the introduction of the guideline with an emphasis on identifying candidates for thrombolysis. methods: retrospective notes review in a single regional neurology centre over a 20-month timeframe. results: eighteen cases were identified (8f:10m) with two mortalities. age range 2 months-13 years (mean 4.8y). 10/ 18 presented in peripheral hospitals and 8/18 in the regional centre. no cases had pednihss score documented on presentation. 9/18 had dedicated vascular imaging (cta/ mra) on initial imaging. 12/18 presented with a hemiparesis, 2/18 with seizures, 2/7 dysphasia, 1/7 headache, 1/7 ataxia. 5/18 cases had a stroke post cardiac surgery, 5/18 idiopathic stroke, 3/18 post varicella angiitis, 2/18 arterial dissection, 2/18 cardiomyopathy and 1/18 embolic stroke as a complication of central line insertion. 5/18 presented with an acute hemiparesis with a clear time of onset. no cases received thrombolysis. 1/5 was imaged within 1 hour of presentation. 1/5 had vascular imaging (mra or cta) on presentation. 1/5 cases was discussed acutely with paediatric neurology; this case was not suitable for thrombolysis due to cardiomyopathy. in retrospect the other 4/5 cases were suitable candidates for thrombolysis. conclusions: the results highlight the continued need for enhanced awareness of paediatric stroke as a medical emergency. most acute strokes will present to peripheral hospitals. therefore, there is a need for regional multidisciplinary integrated pathways amongst emergency department physicians, paediatricians and radiologists to ensure prompt vascular neuroimaging and discussion with a paediatric neurologist about the possibility of thrombolysis in suspected pais. poster no. 073 'a nudge, a fall and a weakness'a common but missed cause of paediatric stroke r shyam 1 , r bahri 1,2 , a kumar 1 , v jain 1 1 department of paediatric neurology, santokba durlabhji hospital and medical research institute, jaipur, india; 2 norwich medical school, university of east anglia, norwich, uk objective: this study retrospectively analysed paediatric strokes with further evaluations and outcomes of strokes related to minor injury, to isolate characteristic features and outcomes in these patients. methods: paediatric patients (6mo to 15y age), presenting with acute stroke between january 2015 to january 2019 were retrospectively recruited from a tertiary care hospital in north india. from this cohort, strokes following minor injury were analysed for clinical profile, investigations and outcomes (measured by international paediatric stroke study scoring system, ipss). results: of the total 114 cases, 50 (43.8%) were post-minor injury (m: f 2.5:1; mean age 14.2ae3.4mo). of the remaining (n=64; mean age 5ae4.5y) most common aetiologies were moya-moya disease (n=10, 15%) and transient unilateral arteriopathy (n=8, 12%). the post-minor injury group revealed a median time of 60 minutes from trauma to stroke onset. more than 1/3rd (36%; n=18) had transient episodic hemi-dystonia on the hemi-paretic side after a median of 4 days of symptoms onset. 90% (18/20) of children where results were available had anaemia. ct head in all (n=50) showed calcification of the lenticulo-striate vessels. subsequent brain mri (n=20) confirmed ct findings of basal ganglia ischaemia. mr angiogram and thrombophilia screen (n=6) done in the first few patients were normal and hence not pursued subsequently. follow ups of 44/50 (6-48mo; median=12mo) showed good recovery in the majority (66%; n=29/44). the median ipss score for these children was 0.5. conclusions: trivial injury leading to basal ganglia stroke was the most common cause of paediatric stroke, occurring exclusively in less than 2 year-olds. ct head was diagnostic (calcification in lenticulo-striate blood vessels and ischemia) with no further information revealed from vascular imaging or thrombophilia work-up. children were commonly anaemic, a potential causative association. often transient episodic hemidystonia of the hemiparetic side after a few days was witnessed. neurological outcomes in most children with this entity is good. introduction: rcpch launched guidance on paediatric stroke in march 2017. we present a series of paediatric patients who presented with stroke following this publication. we audited this group of patients against the key standards of the rcpch guidance. methods: we retrospectively analysed cases between april 2017 and april 2019. we identified cases from a neurology database and audited acute management using rcpch guidance 2017 as standard. results: we identified 11 children with stroke in the last 2 years. ages ranged from 21 months to 16 years with a mean age of 8 years at presentation. 7 children had haemorrhagic stroke and 4 had ischaemic stroke. the majority involved the anterior cerebral circulation (10/11). underlying aetiology was identified in 6 patients, 5 of whom had haemorrhagic stroke. 2 of the patients died. only 2 out of 11 patients had brain imaging within an hour of presentation. only one patient was eligible for thrombolysis, however due to contraindication she underwent thrombectomy. discussion: stroke pathways are well developed in adult services. due to the rarity of stroke in childhood and challenges with recognising symptoms, treatment is often delayed. symptoms in children need a high index of suspicion. the findings of this audit support the development of an all wales paediatric stroke pathway. we aim to facilitate activation of the stroke pathway when children present with the fast symptoms. we also hope to increase awareness of stroke in childhood. withdrawn. objective: stroke is a common childhood neurological disorder, affecting at least 400 children in the uk each year. the majority of children have residual sequelae across a wide domain of functions, with significant personal and societal consequences. recent rcpch guidelines have proposed criteria for hyperacute treatments; this would require rapid recognition of the potential diagnosis by clinicians. here we describe the acute care pathway of a group of children with confirmed arterial ischaemic stroke (ais). methods: parents of children aged >28 days and <18 years referred to gosh (ais) (2015-2019) were approached and sent a questionnaire exploring their experience of navigating through the healthcare system on initial presentation. responses were tabulated where possible and reported as frequencies; qualitive results were thematically coded and categorised for analysis. results: 41/90 eligible parents responded. 999 and the gp were the first port of call for the majority (n=12 for each). ten parents stated they had 'no idea' what initial symptoms might represent. when directly asked if they had suspected a stroke, nearly 2/3 stated 'no'. f.a.s.t features (f: face a: arm s: speech t: time) were noted in a third of patients and only 10 patients were given a diagnosis of stroke at first presentation. on initial discharge, a correct diagnosis of stroke was provided to 21 patients. notably, the need for improved education of paediatric stroke, for healthcare providers was raised by nearly 50% of parents surveyed. conclusions: the study demonstrates the need for further education to be delivered in pre-hospital, primary and secondary healthcare settings for recognising acute stroke in children. this will be an essential step in the delivery of hyperacute treatments. background: hereditary spastic paraparesis refers to a heterogeneous group of inherited neurodegenerative disorders characterized by progressive lower limb spasticity and weakness. there is marked genetic heterogeneity in hsp with all modes of inheritance described for the different loci and causative genes implicated up to now. we present a case of a child with a complex diagnosis of hsp with a homozygous missense mutation in nt5c2 underlying hereditary spastic paraplegia spg45. case presentation: this child had initially been diagnosed as having bilateral cerebral palsy with diplegic pattern and gmfcs ii. he had gross motor and speech and language delay. there was a family history of consanguinity. mri scans had initially been described as showing evidence of periventricular leukomalacia and he had been referred for consideration of sdr. following tertiary assessment there were clinical concerns that the overall diagnosis may need to be reexplored. review of his mri scans demonstrated similarities to a case series of hsp with a rarer form of hsp (spg45). he subsequently tested positive for spg45 nt5c2. a second case with similar clinical findings has now been identified in our region. mri scan findings will be presented. summary: spg45 is a rare but important cause of a cerebral palsy phenotype and testing for nt5c2 should be considered in the differential diagnosis and investigation of patients presenting with cp. recommendations on patient suitability for sdr has focused on children functioning at gmfcs level ii or iii. sdr has been considered for gmfcs levels iv and v however the decision to progress can be challenging. the goals in these children are significantly different with the focus being around comfort and pain relief rather than mobility. we describe the case of a boy with a mixed pattern movement disorder involving 4 limbs which had initially been managed with oral medications baclofen, trihexiphenidyl and intramuscular botulinum toxin. due to the child having a vp shunt the family didn't wish to consider itb pump. despite optimisation of oral medications and intramuscular botulinum toxin spasticity was a significant issue adversely impacting on quality of life. escalation of baclofen was unsuccessful due to loss of head control and duration of action of botulinum toxin injections appeared to be limited to 4 to 6 weeks before tone increased again. this resulted in significant difficulties with moving and handling. in view of this the option of selective dorsal rhizotomy was explored. the goal was to improve ease of personal care and sleep. post-operative outcomes greatly exceeded the family expectations. along with a reduction in tone in the lower limbs they were delighted to report several unexpected improvements. these included: improved functional ability with the left upper limb which facilitated switch access; improved truncal control making moving and handling easier; a reduction in extension posturing which had been particularly problematic pre-operatively; significant improvement in sleep; improved mood. this resulted in the local team exploring eye gaze technology with him. these functional benefits have significantly improved the quality of life for not only the patient but his family. further research into the benefit of sdr in this group of patients should encompass care and comfort outcomes, sleep assessment and measurement of pain. introduction: clonidine has become increasingly repurposed for the management of childhood dystonia. one potential advantage of clonidine is the availability of patches for transdermal delivery. we aimed to review the use of transdermal clonidine patches in our institution. methods: a retrospective notes review of children and young people (cayp) with dystonia issued transdermal clonidine patches as identified from pharmacy records. results: a total of 45 cayp were identified, median age at initiation of clonidine of 7 years 5 months (range 10mo to 14y and 5mo). prior to initiation of patches 43/45 cayp were already receiving clonidine, including 5 acutely receiving iv clonidine infusions. one child with difficult iv access experiencing an acute deterioration of dystonia was lost to follow up following transfer to local services. the commonest indications for transdermal clonidine were concerns about 'on/off' effect of enteral doses (n=23) and concerns about enteral absorption (n=17). transdermal clonidine was discontinued by 5/44 cayp (3 as patches wouldn't adhere, 1 receiving patches as a temporary bridge from iv to enteral clonidine and 1 due to severe local cutaneous reaction). one additional clonidine naive child experienced significant hypotension with a 0.75µg/kg/hour transdermal dose but tolerated a reduced dose of 0.25µg/kg/hour. follow up for the remaining 39/44 children ranged from 2 months to 6.5 years (median 1y). the median transdermal dose was 1.67µg/kg/hour (range 0.25-8.05µg/kg/h). additional enteral clonidine was used by 25/44 cayp. efficacy of transdermal clonidine was difficult to determine, but 18/44 cayp retrospectively scored 2 on the clinical global improvement-scale, suggesting significant improvement. conclusions: in cayp receiving enteral clonidine switching to transdermal clonidine patches appears to be well tolerated, with 88.6% of cayp continuing with longer term use. further prospective work is required to determine the efficacy and safety profile of transdermal clonidine. objective: to review the indications for and outcomes following itb for children and young people (cayp) at our centre. methods: 42 patients were identified undergoing itb pump insertion from 2006 to 2015. 35 had reports available. a retrospective note review was performed, with data extracted using a standardised data collection proforma. results: median age at itb pump insertion was 9 (range 4 to 18). hypertonia was described as dystonia, spasticity and/or dyskinesia. median length of follow up was 3 years (range: 1mo to 9y). choice of outcome measure was dependent upon the goals identified for surgery. care provider child health index living with disability (cpchild) data was available for 23 cayp at baseline and 18 cayp at 1 year. cpchild improved from a median score of 45.5 to 58.2 at 1 year (p=0.03, wilcoxon signed rank test). burke-fahn-marsden dystonia rating scale (bfmdrs) data was available for 12 cayp at baseline (median: 92.5 for motor, 30 for disability), 10 cayp at 1 year (median 98.25 for motor, median 28 for disability), all with a clinical picture of dystonia. gross motor function measure (gmfm) was available for 9 cayp at baseline (median=40), 8 cayp at 1 year (median 47) and 7 cayp beyond 1 year (median=43.1). gmfm and bfmdrs were not statistically significant. pain was measured with paediatric pain profile, available for 14 cayp at baseline, 6 cayp in 1 year and 3 cayp beyond 1 year. median of most troublesome pain improved from 29 at baseline to 17 in 1 year. conclusions: for a heterogeneous cohort of cayp with motor disorders, itb appeared to improve ease of care and comfort, indicated by change in cpchild. multiple measures are required to fully capture benefits seen in this cohort, which should be focused on their individual needs for intervention. objective: to evaluate neurosurgical interventions and outcomes in the management of hemidystonia. methods: the pubmed database was searched including terms 'hemidystonia', hemi-dystonia', 'unilateral dystonia', 'dystonia and (pallidotomy or thalamotomy)', 'dystonia and (dbs or 'deep brain stimulation')' and 'dystonia and (itb or 'intrathecal baclofen')', up to may 2019. papers were included if written in english and presenting outcome data for human participants undergoing a neurosurgical intervention for management of hemidystonia. reference lists of included papers were also reviewed. individualised patient data was extracted. to facilitate comparison across patients with and without validated dystonia scale scores individual patient outcomes were categorised on a 6-point scale ranging from 'worsened compared to baseline' to 'very marked improvement'. results: we identified 53 reports meeting inclusion criteria, describing 144 unique patients (20 <18y of age). ablative methods (85/144 cases) most commonly targeted the thalamus, and dbs (59/144 cases) the gpi. in recent years dbs is reported far more commonly then ablative surgery. reported follow up ranged from 6 months to 10 years. one patient underwent itb but no further individual data was available. out of the 144 cases 82 had individual outcome data. objective measures were available in 38 dbs and 7 ablation cases, most commonly the bfmdrs. reported outcomes in dbs patients were 2/47 worsening compared to baseline, 4/47 no change, 13/47 slight improvement, 10/47 moderate improvement, 9/47 marked improvement and 9/47 very marked improvement. for the ablative cases 0/35 worsened, 12/35 no change, 6/35 slight improvement, 10/35 moderate improvement, 3/35 marked improvement and very marked improvement. complications were reported in 2 dbs cases (1 shielded battery syndrome, one infection) and 7 ablative cases (2 depression and 5 transient hemiplegia). conclusions: available evidence for the neurosurgical treatment of hemidystonia is of low quality, but suggests generally positive results, with few complications reported. introduction: acute flaccid myelitis (afm) is a recently characterised condition causing multiple muscle paralysis and life-changing disability in children. no medical treatment is effective. however, recovery of denervated muscle function is possible via nerve transfer surgery. such treatment is complex, specific to the individual and should be carried out by specialist teams. objective: to describe the clinical features, management and outcomes of nerve transfer surgery following the 2018 afm outbreak. methods: retrospective analysis of patients with afm treated with nerve transfer surgery in 2019. surgical criteria: persistent motor deficits (paralysis) 6 months post onset with neurophysiologic signs of denervation and donor nerve availability. results: eight patients (m=f, aged 26-75 months; mean 40) were referred between march and july 2019. at initial onset/ infection: 6/8 had involvement of all four limbs and trunk and 4/8 had involvement of the phrenic nerve. mean date of initial assessment within specialist centre was 10.5 months post onset (range 4-38). at this time 7 had upper limb paralysis (4 right, 3 left) and 1 had bilateral lower limb paralysis. following consultation, 1 declined surgical intervention and 2 are awaiting surgery. 5/8 patients have proceeded to surgery: 4/5 cases presented with three-or-more nerve root involvement. 10 nerve-transfers have been performed (median 2 per patient). no surgical complications were encountered. early clinical functional outcomes from this cohort following surgery are currently being collated and evaluated and will be presented in full at conference. conclusion: this study supports international experience that nerve transfer surgery can improve functional outcomes in afm. the delivery of care in the nhs requires coordination and referral to specialist centres. experiences with this cohort will inform decision making and improve patient outcomes and family expectations during the next outbreak of afm. poster no. 083 a catastrophic case of acute flaccid myelitis t chakrabarty 1 , c lundy 1 , g doherty 1 , d bhattacharya 2 , p moriarty 1 , d peake 1 1 royal belfast hospital for sick children, belfast, uk; 2 royal victoria hospital, belfast, uk objective: acute flaccid myelitis (afm) is a rare but serious neurological condition characterised by acute onset of flaccid weakness in one or more limbs with distinct abnormalities of the spinal cord grey matter on magnetic resonance imaging (mri) and without any features suggesting an upper motor neuron disorder. in recent years, there has been a global increase in the incidence of afm associated in some cases with a non-polio enterovirus, ev-d68. the long-term prognosis in most cases remain poor. we present a severe case of afm in a 3-year-old boy with catastrophic consequences. method: retrospective review of clinical course, neuroimaging, treatment and neurorehabilitation. results: a 3-year-old boy presented with clinical encephalitis. he deteriorated over 24 hours and developed an encephalopathy, multiple cranial nerve deficits, and complete flaccid paresis requiring picu support. csf 2 weeks apart showed a resolving lymphocytic pleocytosis with increased protein (0.5 to 0.92 g/dl). serial mri brain and spinal cord showed extensive signal abnormality involving thalamus, dorsal pons, medulla, cervical cord, conus along with cauda equina. nerve conduction studies were consistent with a severe acute motor axonal neuropathy. eeg showed a posterior dominant encephalopathy. infective (including edv-68), metabolic, immunological (aqp4 and mog abs) and genetic (ranbp2) tests were negative. immunomodulation therapies (methylprednisolone, ivig, and plasma exchange) resulted in no clinical improvement. resolution of signal changes in the thalami, brainstem and spinal cord along with mild generalised cerebral atrophy was noted in repeat mri after 3 months. 10 months following presentation he remains fully ventilated with no significant motor improvement despite intensive rehabilitation including use of passive range of movement devices and functional electrical stimulation. conclusion: this is one of the most severe cases of afm, representing the wider spectrum of afm involving encephalopathy, dominant bulbar signs and quadriparesis. mirror movement disorder (mmd) is a rare movement disorder with a prevalence of less than 1 in a million in which involuntary symmetrical movement is observed in the limb contralateral to the voluntary limb movement. we report 2 children with an mmd. case 1: a 15-year-old girl following an uneventful pregnancy and normal delivery, born to nonconsanguineous parents presented with difficulties with fine motor activities like writing. parents noticed from age of eight that her left hand would make similar movements to her right hand in activities like writing, combing etc. maternal grandfather has mmd. case 2: a 9-year-old girl following an eventful pregnancy and normal delivery to non-consanguineous parents presented with an mmd at age of 5 years first noticed whilst writing and this continues affect her activities of daily living. there is no family history of mmd. both children are neurodevelopmentally normal and have normal mri brain and spine. mmd have been described congenitally due to prenatal insult before 28 weeks gestation, kallman syndrome and klippel-feil syndrome or as an acquired due to hemiplegic stroke and parkinson's disease in adults. pathogenesis is thought to be due to lesions in supplementary motor area, corpus callosum or cervical lesions. mutations in dcc and rad51 gene are present in 35% of the cases. the multimodal mri and neurophysiological studies have revealed that the motor system is completely disorganised with abnormal crossing at brain stem level and abnormal communication between both brain hemispheres in these children. there is a positive family history in some cases. the upper limbs are commonly involved. diagnosis is usually clinical and treatment is symptomatic with support at school and limiting repeated complex and sustained movements involving both hands. poster no. 085 acute spinal cord infarction in children: a review of the presentation, aetiological investigations and outcomes in 6 children m shehata, ar hart, cd rittey, e davies department of paediatric neurology, sheffield children's hospital nhs foundation trust, sheffield, uk aims: acute spinal cord infarction is poorly understood in the paediatric population. we reviewed cases presenting to a single paediatric neurology centre in uk between 2010 and 2019 to explore common themes of presentation, aetiology and outcome. material and methods: cases of spinal cord infarction presenting to a single centre were identified from our spinal database and medical records were reviewed to determine clinical presentation, aetiological investigations, management and outcomes. results: six children/young people were identified, 2 male, 4 female, age range 3 to 14 years. 4 participants presented with symptoms after seemingly trivial movements or trauma, including: being kicked in the back whilst playing football, bending forwards to tie hair up, getting up to walk in the garden, and performing a crab gymnastic movement. 2 had no obvious precipitants. initial presentation was neck or back pain in all patients, progressing to bilateral lower limbs weakness, sensory deficit, lost reflexes, and urinary/bowel involvement. mri imaging failed to reveal the diagnosis when performed early in 1 participant. the level of lesions for each participant were: t2-3; t2-6; t2-t12; c2-t6; c1-t8; and isolated to the conus. aetiological investigations, including thrombophilia screens, failed to reveal a cause in any participant. 2 initially received steroids because the differential diagnosis included an inflammatory disorder. 2 patients received aspirin, 5/6 gained motor improvement but none returned to normal. all had residual bladder problems, 5 had bowel sequelae. conclusions: spinal cord infarction may be related to minor trauma or movements. the association with a chiari 1 malformation is previously described in adults. outcome is poor. although motor improvement can be seen, children do not return to normal functionally. aetiological investigations and treatments vary within a single centre. national recommendations are required to standardise practice. cost of care for long-term ventilation patients r belderbos, v kumar, l alkhalidi east lancashire nhs trust, lancashire, uk background: advances in neonatal and paediatric intensive care have increased the survival of children with life threatening or life limiting conditions. there has been a significant rise in children on long-term home invasive ventilation. high profile cases have been in the media recently with debate on whether such interventions should be implemented focussing on ethics but without evidence of cost benefit analysis. children on long-term invasive ventilation are a high cost group with complex and varying underlying medical conditions requiring input from multiple teams, including 24 hour carers, medical and multidisciplinary team input as well as recurrent hospital and picu admissions. in addition, the cost of equipment and drugs makes this a costly intervention. in any limited healthcare system rationing decisions have to be made: drug and other therapies are subject to health economic analyses. this study aims to assess cost per annum for ltv and a cost benefit analysis. objective: identify patients on ltv including comorbidities. assess cost of ltv to quantify cost-benefit analysis. measure outcomes: death/admissions/recovery. methods: review of patients requiring home long-term invasive ventilation july 2009-july 2019. analysis of costs: clinic visits, hospital admissions, costs of equipment; cost of medication. outcomes and quality of life: mortality, admissions and length of stay; decannulation, ability to communicate and mobility analysis; ability of parents to work. results: 9 patients: 3 died (aged 1, 7 and 15y), 4 decannulated, 3 ongoing ltv (aged 15mo, 19 and 22y), 5 night package £140 000 pa, accessories £12 000 pa, replaceables/service £92 000, average cost home ltv around £350 000 pa. conclusions: ltv ventilation is an expensive treatment: its use should be analysed on a cost benefit analysis in a similar way to other available treatments. objective: to assess the feasibility of recruiting to a study, performing and interpreting aeeg in preterm infants, and to assess family and staff members' views. methods: a prospective feasibility study. 7 preterm neonates between 26 and 30 weeks postmenstrual age were recruited for continuous aeeg monitoring using adhesive electrodes whilst receiving nicu care. we studied optimal methods of attaching leads, impedance data, number of electrode changes, and preliminary aeeg findings. staff and parents were asked for feedback on the process and their involvement. results: we recruited 36.8% of eligible babies. nuprep and sorbaderm were the most effective combination for skin preparation. the aeeg recording was good quality if staff were engaged and knew when electrodes needed to be changed. four of the seven (57.1%) babies showed seizure activity on aeeg, none of which were diagnosed clinically. babies with seizures were born earlier, had lower birthweights, and had more complications than babies without seizures. feedback showed parents and staff were positive, although staff reported caring for the baby was harder. 75.0% of parents and 87.5% of staff would 'definitely' recommend the study to parents with a premature baby. conclusions: the use of continuous aeeg in preterm neonates in feasible, with similar recruitment rates to other studies in the department, and a positive experience for parents and staff. a high rate of electrical seizures was detected. background: the 'magnetic resonance imaging (mri) to enhance the diagnosis of fetal developmental brain abnormalities in utero' (meridian) study showed improved diagnostic accuracy and confidence for detecting fetal neurological abnormalities compared to ultrasound. the additional information provided by in utero mri altered prognosis in 44% of women. the meridian study did not report whether the neuro-developmental prognoses given to women varied between clinicians or were accurate. objectives: to assess the variation in prognosis given to pregnant women by clinicians in feto-maternal units for 5 different fetal brain abnormalities. methods: we contacted one clinician at each of the meridian feto-maternal units and asked what percentage chance of normal neuro-developmental outcome they would give pregnant women for 5 fetal neurological abnormalities: isolated ventriculomegaly 10 to 12 mm; unilateral hypoplasia of the cerebellar hemisphere, isolated hypoplasia of the cerebellar vermis, isolated cisterna magna, and isolated blake's pouch cyst. respondents were asked to give a percentage chance of normal outcome, although some used free text to answer. results: responses were received from 14 senior obstetricians in 14 feto-maternal units. there was general agreement for isolated mild ventriculomegaly with respondents replying that 90 to 95% would have normal developmental outcome. wider variation was seen for posterior fossa abnormalities, with the suggested chance of normal outcome for one condition ranging from 10 to 90%. conclusion: estimating long-term neuro-developmental outcome based on antenatally detected neurological abnormalities is challenging due to limited high-quality data. our data highlights there is high variation in outcomes offered by different clinicians for the same abnormality. further work is needed to determine what advice is given by obstetricians on the potential developmental outcomes of a wide range of fetal brain abnormalities in current practice, how well these agree with published evidence, and whether the involvement of paediatricians with experience in neuro-developmental disorders improves prognostication. background: in-utero mri (iumri) detects fetal brain abnormalities more accurately than ultrasonography (uss) and provides additional clinical information in around half of pregnancies. there is little published data on whether postnatal neuroimaging beyond 6 months of age changes the diagnostic accuracy of iumri nor its ability to predict developmental outcome. methods: families enrolled in the meridian study whose child survived to 3 years of age were invited to have a case note review and assessment of developmental outcome with either the bayley scales of infant and toddler development, the ages and stages questionnaire or both. a paediatric neuroradiologist, blinded to the iumri results, reviewed the postnatal neuroimaging if the clinical report differed from iumri findings. diagnostic accuracy was recalculated. a paediatric neurologist and neonatologist categorised participants' development as normal, at risk, or abnormal, and the ability of iumri and uss to predict developmental outcome were assessed. results: 210 participants had case note review, of whom 81 (38.6%) had mri after 6 months of age. the diagnostic accuracy of iumri remained higher than uss (absolute differ-ence=25%, 95% ci 21% to 29%, p<0.0001). developmental outcome data was analysed in 156 participants: 111 (71%) were normal, of whom 56 (51%) had a normal or favourable prognosis on uss and 76 (69%) on iumr (difference in speci-ficity=18%, 95% ci 7% to 29%, p=0.0008). no statistically significant difference was seen in infants with abnormal outcome (difference in sensitivity=4%, 95% ci -10% to 19%, p=0.727). conclusions: iumri remains the optimal tool to identify fetal brain abnormalities. it is less accurate at predicting developmental outcome, although iumri is better at identifying children with normal outcome than uss. further work is needed to determine how the prognostic abilities of iumri can be improved. poster no. 090 introducing hypothermia or not decision algorithm (honda) guideline in the assessment of neonates following hypoxic insult at birth in a district general hospital a sproule, j courtney, m mcgowan ulster hospital, belfast, uk introduction: hypoxic-ischaemic encephalopathy (hie) accounts for up to 30% of cases of cerebral palsy. hie can be caused by multiple events and occurs in 2/1000 births. hypoxic insult at the time of birth can result in an encephalopathic state characterised by: need for resuscitation at birth, neurological depression, seizures and electroencephalographic abnormalities. the toby study demonstrated that induction of moderate hypothermia within 6 hours of birth for 72 hours duration in infants who had perinatal asphyxia resulted in improved neurologic outcomes in survivors. therapeutic hypothermia is the only proven neuroprotective treatment for hie. an assessment tool was required as there was no standard proforma for neurological assessment for babies with a low cord ph (<7.1) in our district general hospital (dgh). this was to ensure that all infants who met the toby criteria received the appropriate treatment within the recommended timeframe. methods: the honda assessment tool was developed for use in the tertiary neonatal intensive care unit. this assessment tool was adapted to use in a dgh as a guideline. the honda included the criteria from the toby study with a user-friendly flow chart. a comprehensive neurological examination is outlined with text and images to ensure reliable and repeatable findings by different clinicians over time. results: the honda tool ensured a standard algorithm was used to assess those infants who had a hypoxic insult at birth. it has standardised record keeping and repeated neurological examination of at-risk infants. conclusions: the honda is a comprehensive and userfriendly algorithm to ensure those infants who meet requirement for therapeutic hypothermia are being appropriately identified and treated. poster no. 091 foetal exposure to misoprostol and mobius syndrome s tilib-shamoun, a siddiqui, v ramesh king's college hospital, london, uk background: mobius syndrome is a rare condition comprising a collection of specific congenital anomalies, usually congenital lower motor neuron 6th and 7th cranial nerve palsies. hydrocephalus, cerebellar hypoplasia, orofacial and limbs deformities have been reported in some. the literature links mobius syndrome to early foetal exposure to misoprostol, a synthetic prostaglandin e analogue widely used for medical termination of pregnancy. for abortions it is used by itself or with the anti-progestogen mifepristone; the combination is 97% effective during the first trimester of pregnancy. the mechanism by which misoprostol disrupts brainstem development resulting in hypoplasia or absence of central brain nuclei is not elucidated as yet. suggested mechanisms include selective vulnerability to hypo-perfusion and ischaemic injury of the foetal brain stem due to direct disruption of the foetal vasculature or to global foetal hypoxia because of uterine contractions and placental ischaemia. clinical case: we report a case of an infant with known exposure to misoprostol from failed medical termination of pregnancy (top) at 12 weeks gestation, who presented with an abnormally increased head circumference, multiple lower motor neuron cranial nerve palsies (7, 11 and 12th cranial nerves). his mri scan showed hydrocephalus due to cerebral aqueduct stenosis, inferior vermian hypoplasia and loss of bulk of the right facial collculus of the pons. conclusions: it is vitally important to counsel expectant mothers following exposure to misoprostol and failed top of possible congenital anomalies if the woman elects to continue with the pregnancy. poster no. 092 neurological examination in unwell neonates: health care professionals' perspectives a fadilah, ar hart department of paediatric neurology, sheffield children's hospital, sheffield, uk objective: to explore health care professionals' opinions of neurological examination in unwell neonates. methods: a questionnaire designed to assess views on examining unwell neonates neurologically was distributed to all uk neonatal and paediatric neurology units. questions included likert scales, with scores ranging from 0 to 6. scores of 4 to 6 were taken to be positive, 1 to 3 negative or equivocal. answers were compared between consultants and other staff members using chi-squared testing, with p<0.05 assumed statistically significant. results: 192 responses were received, although not every question was answered. 106/192 (55.2%) responders were based in general paediatrics, 60/192 (31.3%) in tertiary neonatal units, and 18/192 (9.4%) in paediatric neurology. 92/192 (47.9%) were consultants. 59/192 (30.7%) performed a neurological examination in all unwell neonates, 114/191 (59.7%) in most. 84.8% of consultants felt confident performing a neurological examination, compared to 57.0% of other health care professionals (p<0.05). consultants were also more confident at interpreting the results and using them to formulate management and prognosis (all p<0.05). 140/192 (72.9%) did not find a high-quality neurological examination documented routinely in medical notes of half or more unwell neonates. 86/167 (51.5%) reported using the classical neurology examination adapted for neonates, 22 (13.3%) used the hammersmith neonatal neurological examination or an adapted version. the most difficult aspects were fundus and cranial nerve examination. the most frequently cited challenges were: effect of medication; difficulties in interpretation; equipment and lines; experience; time limitations; and risks of handling unwell neonates. 124/171 (72.1%) wanted a new standardised neurological examination for unwell neonates; 9 (5.2%) did not. conclusions: non-consultant grade health care professionals feel less confident performing a neurological examination in unwell neonates. all responders highlighted a number of challenges to performing and interpreting the results. around three-quarters of responders want a new, standardised neurological examination for unwell neonates, which could address these challenges. use of re-standardised griffiths scales of child development (3rd edition) in a healthy cohort at 4 to 5 months of age objective: the griffiths scales of child development (gscd) is an established tool for the developmental assessment of children from birth to 6 years. in 2016, the gscd underwent significant revisions, and was re-standardised using contemporary cohorts. to date, no studies have reported on its use in healthy children post-marketing. our aim is to examine the use of the gscd-iii in a healthy population of infants aged 4 to 5 months and to provide the first published data on the use of the revised griffiths-iii. methods: in a prospective observational study of healthy, fullterm infants, participants were recruited into a randomized controlled trial of infant massage. griffiths iii assessments were performed by aricd-trained practitioners across 5 subscales and a general development quotient (gd) at 4 to 5 months. results: 178 children were considered in the analysis, male: female ratio 101/77. mean (sd) birth weight was 3.53 (0.46) kg and mean birth gestational age was 39.8 weeks (sd 1.22). mean (sd) age at assessment was 4.5 (0.3) months, with 98 (55.1%) children being assessed according to 4/12 rounded norms, and 80 (44.9%) to 5/12 norms. no difference was found in either arm of the study in any subscale. scores were considerably greater than average (dq 90-109) in all subscales but particularly subscales b, d and gd. mean (sd) developmental quotients (dq) in a=121.0 (15.9); b=130.7 (11.6); c=119.0 (9.7); d=127.0 (8.4); e=123.3 (11.1) and in gd=128.3 (10.1). using the published cutoffs, we found that 97.2% (n=173) of our cohort scored 'above average' or greater in gd. conclusions: we have provided the first data on the use of griffiths-iii in a healthy cohort. scores were higher than expected across all sub-scales. this may be due to the characteristics of our cohort but raises concern that griffiths-iii may overestimate ability in young infants. objective: metabolic investigations are important in the investigation of children with disordered development. the aim of this audit was to determine if paediatric metabolic investigations were ordered as per current best practice evidence at tallaght university hospital, dublin, republic of ireland. methods: we used recommendations from seven publications to guide this audit and identified indications for performing metabolic investigations. we reviewed metabolic investigations sent on paediatric patients at tallaght university hospital from 1 january 2018 to 31 december 2018. we identified the clinical indication for investigating patients by reviewing dictated clinic letters available on the hospital intranet and confirmed investigation results by reviewing scanned copies available on the hospital intranet. we compared the indications for metabolic investigations with published expert guidelines. results: metabolic investigations were performed on 254 patients from 1 january 2019 to 31 december 2018. six patients had inconclusive results and were referred to the metabolic team at temple street children's university hospital dublin for further assessment. there have been no metabolic diagnoses made to date as per tallaght university hospital dictated letters. of the 254 patients, 104 had a diagnosis of autism spectrum disorder (asd). of those with asd, 33 had a confirmed or suspected intellectual disability. 158 patients (62%) met best practice recommendations for metabolic investigations. of the 96 patients who did not fulfil recommendations, 71 (74%) were for children with asd. conclusions: we identified two areas that could improve patient care by optimising diagnostic yield and improving resource utilisation at the hospital. first, we recommend clinicians send targeted investigations and avoid blanket investigations for children with disordered development, including asd. second, we recommend clinicians include relevant clinical details on request forms to improve diagnostic yield. finally, we question the value of metabolic investigations for intellectual disability in the absence of other clinical risk factors or comorbidities and suggest this requires further study. the early developmental course of babies with sturge-weber syndrome n thapa 1 , t fosi 2,3 , v siyani 3 , j sloneem 3 , h richardson 3 , s aylett 2,3 1 university college london medical school, london, uk; 2 ucl great ormond street institute of child health, london, uk; 3 neurodisability, great ormond street hospital, london, uk background: sturge-weber syndrome (sws) is a rare neurocutaneous condition which arises from a mutation in g protein subunit alpha q. the hallmark is leptomeningeal angiomas often associated with a facial port-wine birthmark. seizures, stroke-like episodes and hemiplegia are common clinical presentations. objective: to describe clinical features of infants with sws under 3 years and their developmental trajectory in relation to seizure onset. methods: a retrospective case note review was conducted on 90 children aged below 3 years with sws under clinical review at our centre. the medical history and standardised developmental test results (language, cognition, motor and visuospatial skills) contained in patients' assessment reports were analysed. results: common clinical features of children with sws aged under 3 years were: seizures in 81 patients (90%), hemiplegia in 52 patients (57.8%) and glaucoma in 42 patients (46.7%). their developmental trajectory was a decrease in the mean percentiles (for language, cognition and motor skills) and mean developmental quotients (for visuospatial skills) over the first 36 months. infants with unilateral brain involvement had significantly higher cognitive percentiles than those with bilateral brain involvement (p<0.01), but both groups showed the aforementioned pattern. children with epilepsy had worse language (p=0.039) and cognitive outcomes (p=0.004) than children without seizure onset. there was seizure onset in the first year in 62 infants (78.5%). in these patients, earlier seizure onset was associated with a higher language percentile (p=0.041) at age 36 months or at the time of seizure onset. conclusions: following treatment of early seizures in sws language recovery appears to occur over time relative to cognition. the functional plasticity of language might account for these observations. it is proposed that seizure prevention and optimal seizure control in the crucial first year of life will benefit cognitive and language development in patients with sws. objective: rett syndrome (rtt) is a rare neurodevelopmental disorder primarily affecting females, characterized by loss of speech, stereotypies, abnormal hand movements, motor and cognitive impairment. diagnosing rtt before regression occurs remains a challenge and there is an increasing interest in early diagnosis, due to the ongoing gene therapy clinical trial in rtt. methods: retrospective case notes review. the patient was born at term after induction of labour for reduced movements, with meconium-stained liquor, but was well. poor crying and suck noted at birth with gradual deterioration of feeding, with frequent chest infections, necessitating peg-feeding at 6 months. peripheral/axial muscle weakness and hypotonia were noted at this time. mri brain showed mild underopercularisation of sylvian-fissures; thin corpus-callosum. mrs, mri spine, echocardiogram, and eeg were normal. vitamin b12 deficiency was found, treated with hydroxycobalamin. sleep study showed hypoventilation with frequent apnoeas and low respiratory rate, leading nocturne bipap. emg was myopathic. muscle biopsy showed marginal loss of complex-i activity in the respiratory-chain-enzymes analysis. results: videofluoroscopy showed delayed swallow and disorganised pharyngeal stage leading to peg feeding. over the following months, no regression noted but only minimal motor progression seen; she was interactive and smiled. at 12 months, regression in her motor abilities was notedshe stopped fixing, following and smiling with progressive microcephaly and hand writhing movements. eeg showed epileptic encephalopathy with tonic/myoclonic jerks. whole-exomesequencing showed a de-novo pathogenic mutation in the mecp2 gene (nm_004992.3:c.1157_1200del,p.[leu386fs] ) and the diagnosis of rtt was confirmed. after 3 months, she restarted smiling and fixing/following and making motor progress but continues to have seizures. conclusions: this case illustrates early-onset features in atypical rtt with central breathing abnormalities, bulbar insufficiency, generalized hypotonia before regression. evidence of mitochondrial dysfunction is in keeping with recent reports suggesting neuronal redox imbalance in rtt as one of the disease pathogenic contributors. objective: neurodegeneration with brain iron accumulation (nbia) comprises a group of rare genetic disorders characterized by progressive extrapyramidal and other neurological symptoms due to focal iron accumulation in the basal ganglia.1 b-propeller protein-associated neurodegeneration (bpan) is the most recently identified subtype of nbia caused by heterozygous variants in wdr45 at xp11.23. we report a new subtype of bpan caused by a de novo wdr45 variant in a 6-year-old girl. methods: case report on a new subtype of b-propeller proteinassociated neurodegeneration (bpan) caused by a de novo wdr45 deletion in a 6-year-old girl and review of the literature. results: we report a 6 year old girl with bpan due to a large (5824 bp) de novo chrx:g.48,930,034_48,935,858del (hg19) deletion in wdr45, presenting with early-onset global developmental delay, hypotonia, seizures, and speech apraxia. the patient presented at the age of 10 months with hypotonia and motor developmental delay, following a normal birth history, and at 14 months developed complex partial seizures and later on steroid-responsive electrical status epilepticus of slow-wave sleep (eses). she has made minimal developmental progress and has remained profoundly globally developmentally delayed and cognitively impaired, and has still not achieved independent ambulation. conclusion: we have described the clinical, neurophysiological and neuro-imaging findings in a 6-year-old girl, the unique combination of which may assist in the diagnosis of further similar cases. bpan is an exceedingly rare, severe and debilitating disorder with a broad spectrum of clinical heterogeneity and variable age at presentation with early-onset symptoms. early detection and diagnosis are very important in order to offer proper genetic counselling to affected families and provide symptomatic treatment to patients. next-generation broad-spectrum genetic analyses will enable early detection of bpan in the paediatric age group in order for patients to be diagnosed prior to reaching adulthood. introduction: how to measure the effectiveness of an early intervention program in low resource setting. can assessments lead to interventions? and with improvements leads to new interventions, can new assessment lead to new interventions? can this system be measured for its effectiveness and improved based on feedbacks and results? an attempt to set up child development centres in low resource countries using software, apps and e-learning. method: 5 years of data in early interventions was analysed in lucknow, india. in phase 1, 527 children with non-progressive neurological problems were given best available local interventions. only 8% compliances and improvement were seen. based on the feedback algorithms were written to create individual profile of children based on their skills (uk curriculum of excellence), disability score, information processing preference, educational and behaviour problems. based on the score each child generates an individualised profile and an intervention plan delivered by app for parents (p-bac-drv) and app (t-bac-drv) at child development centres. the assessment is repeated every 2 months and new individualised profile is generated with new set of intervention. in total more than 2000 interventions are developed, and the algorithm helps in deciding which main areas to target at one time. result: the current system in low resource settings have either no service or results are close to 10% prevent disability in non-progressive neurological problems. our system has shown to prevent disability in about 60% of children. supported by government start up initiative the program has won in top 40 data innovations in india. conclusion: use of technology to provide training, exams and support professionals in the low resources areas is the solution to provide effective services. pattern recognition is the key delivered by software and auto audits has been placed to measure and improve the system. introduction: medical advances in the treatment of cns tumours has enhanced survival but also impacted on levels of residual morbidity and participation. service provision has not increased alongside the improvement in survival, with many patients not being able to return to their previous level of activity and participation following their oncology treatment. nice cancer services for children and young people 2014 state: 'children and young people who have had a central nervous system malignancy should receive a specialist neuro-rehabilitation care package'. robbie's rehab, a charity funded physiotherapy service embedded within the southampton children's hospital therapy service, launched june 2017, provides supplementary physiotherapy for children diagnosed with brain and spinal tumours under the care of southampton children's hospital. objective: to accurately identify and quantify the need for this service. method: prospective data was collated and reviewed june 2017-may 2019. results: year 1: 30 patients; year 2: 32 patients. 94 new episodes of physiotherapy (average 3.9 per month), 303 direct clinical contacts. reasons for accessing the service: need for enhanced intensity of rehabilitation on discharge (n=23), enhanced inpatient rehabilitation (n=18), bridge the gap whilst awaiting community services (n=11), change in symptoms (n=12), pre-op assessment (n=5), support for palliative care planning (n=7), support for complex social and emotional needs (n=8), disease progression (n=7), higher level rehabilitation not fulfilling community criteria (n=12), facilitate access to local exercise facilities (n=13), within oncology clinic for assessment/one-off treatment (n=8), post-op assessment (n=11), individualised goal orientated participation (n=4). 8 patients had an estimated 2 weeks reduction in acute bed days. conclusions: robbie's rehab referrals are for a variety of multifactorial reasons with rereferral often needed within their pathway. it has enabled earlier discharge, improved transition to community services and opportunities for therapy access previously not available. results: our proband presented at 5 weeks with marked stridor and bulbar weakness after a normal pregnancy. he subsequently developed respiratory failure requiring nocturnal bipap and was found to have a type i laryngeal cleft. initially he met developmental milestones but at 5months developed features of axial weakness with further regression at 9months with limb weakness and loss of deep tendon reflexes. emg confirmed denervation in genioglossus, as well as proximal and distal limb muscles without evidence of neuropathy. genetics for smn1 gene and smard were negative. inherited peripheral neuropathy 56 gene panel testing identified a heterozygous missense variant c. 631t>c, p.(cys211arg) in exon 5. the variant is predicted to alter a highly conserved amino acid, has not been reported before and has not been identified in control databases. in silico prediction tools supports the pathogenicity of the variant. mutagenesis of the equivalent amino acid in mice produces impaired motor control and denervation. conclusions: the gars gene encodes an ubiquitously expressed glycyl trna synthetase which has an integral role in protein synthesis in all eukaryotic cells. missense gars mutations can lead to distal hereditary motor neuropathy as well as a sensorimotor neuropathy phenotype (cmt2d) typically with adolescent or early adulthood onset. objective: to discuss sma, which is one of the differentials in a hypotonic child and bring to light the diagnosis is not always cerebral palsy (cp). method: descriptive case report. results: case 1: 4-month-old girl admitted to icu with severe pneumonia. case 2: 9-month-old boy, both admitted to the intensive care unit with severe pneumonia. case 3: 15-month-old girl, presented to outpatient with progressive 'floppy' limb weakness and swallowing and breathing difficulties. case 4: attended opd with worsening respiratory distress, difficulty feeding, difficulty managing secretions. all 4 had perinatal histories of uncomplicated deliveries but subsequent early respiratory distress and oxygen requirement for the first few days of life. all had been 'floppy' since birth, with severe gross motor delay, feeding difficulties, poor weight gain and recurrent chest infections. cases 2, 3 and 4 had been diagnosed with cp despite having normal neuroimaging. examination of all 3 children was similar and consistent with clinical diagnosis of sma. findings included an alert, interactive child; frog-legged posture; 4-limb hypotonia and weakness with legs more affected than arms; absent deep tendon reflexes; bell-shaped chest; and tongue fasciculation. genetic testing for all confirmed homozygous deletion of exon 7 of the smn1 gene. in all the cases creatinine kinase levels were normal, ruling out myopathy. conclusions: the incidence of sma is 1/10 000 livebirths. it can be diagnosed clinically from pathognomic features when genetic testing is unavailable and should be considered in any hypotonic child, irrespective of perinatal history. a wide clinical spectrum that ranges from early death to near-normal adult life exists. families must be counselled regarding implications of this genetic diagnosis. correct early diagnosis and multidisciplinary intervention can vastly improve outcomes. poster no. 102 syros studylong-term reduction in rate of respiratory function decline in patients with duchenne muscular dystrophy (dmd) treated with idebenone l servais 1 , c lawrence 2 , oh mayer 3 , cm mcdonald 4 , u schara 5 , t voit 6 , e mercuri 7 , gm buyse 8 respiratory function decline in dmd is caused by the underlying weakness and degeneration of the respiratory muscles leading to impaired inspiratory and expiratory effort and associated complications. idebenone reduced the rate of respiratory function decline over 52 weeks in the phase iii delos trial. syros is a long-term study in former delos patients who transitioned to idebenone under expanded access programs following a variable untreated period. here, we aimed to characterize the long-term effects of idebenone on respiratory function. patients were managed according to routine clinical practice. respiratory function was assessed by calculating the annualized decline in forced vital capacity (fvc) and peak expiratory flow (pef), expressed as percent predicted (%p). comparisons were made between treated and untreated periods and to matched external controls. data on bronchopulmonary adverse events (baes) and hospitalizations were collected. data from 18/64 former delos patients were available. at delos baseline, mean (sd) age and fvc%p were 13.3 (2.7) years and 58.7% (17.6%); all patients were glucocorticoid non-users and 83.3% were non-ambulatory. patients were treated for an average (min-max) of 4.2 (2.4-6.1) years compared to an average untreated period of 2.1 (1.1-5.5) years. the annual rate of fvc%p decline was almost halved (3.8% vs 7.4%) when comparing these periods. for the external comparisons, declines remained lower across all treatment years (up to 6y) compared to the matched group of untreated patients. comparable results were seen for pef%p. the risk of baes was reduced by 68% during longterm idebenone treatment versus untreated periods, leading to fewer hospitalizations due to respiratory causes (0.06 vs 0.15 events per year). long-term treatment with idebenone results in a consistent and sustained reduction in the rate of respiratory function decline for up to 6 years. two placebo-controlled trials of 52-week duration (phase ii delphi, phase iii delos) showed that idebenone consistently reduced respiratory function decline rate in patients with advanced dmd. long-term data from the delphi-extension (delphi-e) study and syros (delos patients who transitioned to idebenone under an expanded access program) are now presented. the aim was to assess the consistency of the long-term effect of idebenone on respiratory function across both placebo-controlled trials and their respective long-term data collections. 11 delphi-e and 18 syros patients with abnormal (<80%) forced vital capacity (as percent predicted, fvc%p) were treated with idebenone for an average of 2.0 and 4.2 years respectively. annualized fvc%p decline rates were compared to untreated patients from syros or matched external controls (matched for baseline fvc%p) from the cinrg duchenne natural history study (cinrg-dnhs). mean (sd) baseline age was 13.6 (2.3) and 13.3 (2.7) years in delphi (n=11) and delos (n=18), respectively, and fvc%p was 47.2% (19.7%) and 58.7% (17.6%). for the first 2-year period, where data were available for both studies, the average annual decline rate was comparable in treated patients (4.5% and 5.4% in delphi-e and syros) and lower than in untreated syros patients and external controls (7.9% untreated and 8.1% in cinrg-dnhs). during years 3 to 6, the annual decline rate was consistently lower than for matched controls. treatment with idebenone resulted in a sustained reduction in the rate of decline in respiratory function across both placebo-controlled 52week studies and across both long-term data collections, with follow-up time of up to 6 years. the consistency observed across 2 independent datasets adds to the robustness of the treatment effect of idebenone and its potential to modify the course of respiratory function decline in dmd. poster no. 104 a rare mutation in dync1h1 causing a mixed clinical phenotype of spinal muscular atrophy with lower extremity predominance and hereditary spastic paraplegia: a case series in a family el goh 1,2 , s jayawant 3 , g anand 1 objective: to describe the identification of a rare mutation in the dync1h1 gene as a cause of a mixed clinical phenotype of spinal muscular atrophy with lower extremity predominance (sma-led) and hereditary spastic paraplegia (hsp). methods: case series of three family members (father and two sons) across two generations. results: there was a history of early childhood-onset, progressive lower limb muscle weakness and atrophy. no relevant family history of neuromuscular disorders was reported on both the paternal and maternal sides of the family. examination revealed markedly diminished tone and power in the lower limbs, with wasting and a positive crossed adductor reflex. there were no abnormalities detected in the upper limbs and sensation was preserved throughout. neurophysiological testing showed moderate to severe chronic denervation of the lower limb muscles with sparing of the peripheral sensory nerves. hsp panel was negative but charcot-marie-tooth (cmt) panel demonstrated a heterozygous sequence change in the dync1h1 gene: c.1808a>t p.(glu603val), which was present in all affected family members. discussion and conclusions: mutations in the dynein gene are typically associated with sma-led or cmt. a mixed sma-led and hsp phenotype has previously been shown to be caused by mutations in bicd2. bicd2 encodes a golgin, which is a component of dynein-based transport, and plays a key role in mrna transport during oogenesis and embryogenesis. we present the first case series of a mixed clinical phenotype of sma-led and hsp occurring due to a mutation in dync1h1. this was the first observation of the c.1808a>t p.(glu603val) variant at our laboratory and was not listed in the genome aggregation database, suggesting an extremely rare variant. opening the lid on unilateral ptosis in paediatric nf1 e hassan 1 , e witter 1 , z mughal 2 , l robinson 3 , d weisburg 3 , sa roberts 4 , e hupton 3 , j eelloo 3 , e burkitt wright 3,5 , s garg 3 , l lewis 3 , dg evans 3,5 , sm stivaros 3,6,7 , g vassallo 1,3,5 introduction: neurofibromatosis type 1 (nf1) is a genetic disorder with a birth incidence of 1 in 2-2700 individuals and prevalence of around 1 in 4000 worldwide. ptosis is a welldocumented feature in this condition and is known to be associated with plexiform neurofibromas or in the noonan phenotype, with bilateral ptosis. unilateral ptosis in the absence of a plexiform neurofibroma is not a common feature in nf1. we describe a number of patients with nf1 who demonstrated unilateral ptosis. methods: a retrospective cohort study was carried out using the patient database within the nf1 service based in st mary's hospital, manchester, uk. children and young adults aged 2 to 18 years with nf1 were identified via the patient database and patients with a presentation of ptosis were identified. results: six children with unilateral ptosis were identified, four females and two males (ages 2-18, mean=9.5y). five had unilateral ptosis affecting the right and one the left, with no differences observed between sporadic or familial disease. five patients had complex disease; however, none had any other associated complication to account for the unilateral ptosis apart from nf1. they did not meet the diagnostic criteria for noonan syndrome, and none had plexiform neurofibromas in the orbital or peri orbital area. discussion: it is unclear why there is an increased incidence of unilateral ptosis in our cohort of nf1 patients, in the absence of plexiform neurofibromas and noonan's syndrome. ptosis in nf1 has been associated with a noonan syndrome phenotype in nf1 patients. the general hypotonia and myopathy observed in these patients could also factor into the causes for ptosis. further research is necessary to investigate the aetiology of increased unilateral ptosis in nf1 patients. objective: sma is a severe neuromuscular disorder characterised by progressive muscle atrophy and weakness. scoliosis is a highly prevalent complication and surgery is almost invariably required in 'sitters'. data on secondary outcomes are limited, and this study investigates post-surgical respiratory (fvc%) and motor function, weight gain, pain and satisfaction. methods: we retrospectively reviewed the notes of 33 patients who never walked or lost ambulation (sma type ii/iii) who successfully underwent scoliosis surgery at great ormond street hospital: spinal fusion (25), magnetic (4) or traditional (4) growth rods. we performed phone interviews and run a focus group for families on pre and post-surgical satisfaction. results: median follow-up before and after surgery was 3.9 (0.9-12.3) and 3.7 (0.4-10.5) years respectively. mean annual rate of fvc% decline improved post-surgery in sma ii: -2.8 versus -7.4 (p<0.001), with similar trajectories in sma iii. mean annual rate of hammersmith functional motor scale's scores decline did not change significantly (-1.2 vs -1.6, p<0.001), while the revised upper limb module's scores showed a less progressive deterioration (-1.3 vs -2.3, p=0.07). a negative deviation from previous weight curve after surgery was observed in 17/33 requiring food supplements (5); one/4 with significant weight loss (>5% of total weight) needed gastrostomy. pain was frequently documented, especially hip pain (13/33) requiring painkillers (8), intra-articular steroids (2) and surgery (1). nine/10 families participating in the phone interview reported major improvements in posture, physical appearance, self-image; all rated the procedure as very successful. however, 7/10 did not report significant improvements in quality of life due to reduced mobility and increased unmet care needs. five families attended the focus group reporting on both positive and negative aspects of their experiences. conclusions: this study provides relevant data and suggestions to improve the current multidisciplinary approach of scoliosis surgery in children with sma. poster no. 107 sunfish part 1: 18-month safety and exploratory outcomes of risdiplam (rg7916) treatment in patients with type 2 or 3 spinal muscular atrophy (sma) objective: spinal muscular atrophy (sma) is a severe, progressive neuromuscular disease caused by reduced levels of survival of motor neuron (smn) protein due to deletions and/or mutations of the smn1 gene. while smn1 produces fulllength smn protein, a second gene, smn2, produces only low levels of functional smn protein. risdiplam (rg7916/ ro7034067) is an investigational, orally administered, centrally and peripherally distributed small molecule that modulates smn2 pre-mrna splicing to increase smn protein levels. sunfish (nct02908685) is an ongoing, multicentre, double-blind, placebo-controlled study (randomised 2:1, risdiplam:placebo) in patients aged 2-25 years, with type 2 or 3 sma. methods: sunfish part 1 (n=51) is a dose-finding study assessing the safety, tolerability and pk/pd of risdiplam; pivotal part 2 (n=180) assesses the safety and efficacy of the risdiplam dose level that was selected based on results from part 1. sunfish part 1 included patients of broad age ranges and clinical characteristics (functional level, scoliosis and contractures). an interim analysis of part 1 (data cut-off, 06 july 2018) showed a sustained, >2-fold increase in median smn protein versus baseline after 1 year of treatment. adverse events were mostly mild, resolved despite ongoing treatment and reflective of the underlying disease. despite not being designed to detect efficacy, risdiplam improved motor function measures over 12 months versus natural history. results: safety, tolerability and pk/pd will be reported from all patients in part 1 who have received treatment with risdiplam for a minimum of 18 months. updated part 1 exploratory efficacy data, including motor outcome measures, will also be presented. the clinical benefit of risdiplam is being assessed in part 2, which is ongoing worldwide. objective: ryr1 encodes the skeletal muscle ryanodine receptor, an intracellular calcium-release channel that is crucial to excitation-contraction coupling in muscle. gene variants can cause heterogeneous myopathies, including dominantly inherited central core disease. both autosomal dominant (ad) and autosomal recessive (ar) pattern of inheritance have been reported. methods: retrospective case notes review. results: sibling 1: female, presented during the first year of life with motor developmental delay. at 4 years of age she is able to sit unsupported and crawl but not stand or walk. she has facial weakness, but no feeding difficulties or ophthlamplegia. she has axial and proximal weakness with antigravity power in neck flexors and hip flexors (mrc 3/5) and sub-gravity power in hip abductors/extensors and knee flexors/extensors (mrc 2/5). there are severe hip, knee and ankle fixed contractures. power and joint range is normal in upper limbs. muscle biopsy showed type-1 fibre predominance and core-like structures. sibling 2: female, presented at birth with feeding difficulties. at 3 months of age she is fully nasogastric fed. there is no facial weakness or ophthlamplegia. she has good head control with active head lift in prone, and antigravity power in hips, knees and ankles. she has mild hip and knee contractures and shoulder girdle weakness. both siblings have been confirmed to be heterozygous for a ryr1 pathogenic frameshift variant (c.12063_12064dupca p.(met4022fs)) inherited from father and a likely pathogenic missense variant (c.14598g>c p.(lys4866asn)) inherited from mother. both parents are asymptomatic. conclusions: the clinical and pathological features of ad ryr1-related myopathy are well recognized but much less is known about ryr1-related disorders secondary to an ar pattern of inheritance. we report two siblings with ar ryr1related myopathy with similar genotypes but different phenotypic features demonstrating intra-familial variability and expanding current knowledge on this disorder. results: our probands were the second and third children of consanguineous irish parents who were fourth cousins. antenatally, reduced fetal movements and amniotic fluid was noted with both probands. at birth, both had arthrogryposis and the second sibling required prolonged intubation at birth. both had significant developmental delay; a more severe phenotype in the younger. on examination, both had myopathic facies, inability to bury eyelashes, full eye movements, high arches palates, drooling, a weak cry, micrognathia but a preserved suck. they both had long thin fingers, with thumbs held adducted and dimpling of elbows and hands. peripheral reflexes were absent but there were good anti-gravity movements of the lower limbs. both were noted to have pectus excavatum and progressive scoliosis. muscle biopsies showed dystrophic features of fibrosis, hypertrophy and atrophy of fibres and variation in fibre size with increased fibrous connective tissue. occasional central cords and multiple mini cords were also seen in the second proband. whole exome sequencing identified the compound heterozygote mutation (ttn c.95076delc in combination with ttn c22226c>tp. (ser7409leu) and ttn c.40405g >a p. (asp13469asn)). conclusions: mutations in the titin gene (ttn) have been implicated in several skeletal and or cardiac phenotypes to date. each individual variant of the compound heterozygote has not been reported as pathogenic mutations and have been detected in the general population at 0.7% frequency. however, the presence of the triple count may certainly account for the severe phenotype of our probands. poster no. 110 gene-replacement therapy (grt) in spinal muscular atrophy type 1 (sma1): long-term follow-up from the onasemnogene abeparvovec phase 1/2a clinical trial objective: sma1 is a rapidly progressing neurologic disease caused by biallelic survival motor neuron 1 gene (smn1) deletion/mutation. the smn grt onasemnogene abeparvovec (formerly avxs-101; approved in us) treats the genetic root cause of sma and is designed for immediate, sustained smn protein expression. in a phase 1/2a trial (start [cl-101]; nct02122952), sma1 patients received a one-time onasemnogene abeparvovec infusion at low dose (cohort 1, n=3) or high dose (cohort 2, n=12), and demonstrated improved outcomes versus natural history. no patients in start received nusinersen during the 24-month follow-up after dosing. sma1 patients in start could rollover into a long-term follow-up study (study lt-001; nct03421977). primary objective: long-term safety. methods: sma1 patients have annual visits (5y), then phone contact (additional 10y). patient record transfers are requested. safety assessments include medical history and record review, physical examination, clinical laboratory evaluation, and pulmonary assessments. efficacy assessments include developmental milestone evaluation to determine maintenance of the highest achieved milestone in the parent study. results: as of 8 march 2019, 13 patients (cohort 1, n=3; cohort 2, n=10) had enrolled in study lt-001 and had a baseline visit. for patients in cohort 2, the mean (range) age and time since dosing were 3.9 (3.4-4.8) years and 3.7 (3.3-4.3) years, respectively. all patients in cohort 2 (10/10) were alive. no developmental milestones achieved in start were lost, and new milestones have been achieved, supporting the durability of onasemnogene abeparvovec. updated data will be presented. conclusions: one-time onasemnogene abeparvovec administration at the high dose continues to provide prolonged and durable efficacy with milestone development in lt-001. poster no. 111 micu1-myopathy: a mitochondrial disorder that mimics a congenital muscular dystrophyreport of 2 siblings with variable phenotypes m fernandez, m sa, v gowda evelina london children's hospital, london, uk objective: micu1 encodes a selective calcium-channel subunit within mitochondrial inner membrane whose function is essential for buffering cytosolic ca2+ transients and activating atp production. mutations in micu1 have been reported in 20 different families with muscle weakness, fatigability and developmental delay, with normal lactate despite being a mitochondrial disorder and persistently elevated creatine kinase (ck) usually in the range of congenital muscular dystrophies (cmd). the phenotypic spectrum is highly variable and keeps expandingother features include progressive extrapyramidal signs, learning disabilities, nystagmus and cataracts. we report the clinical features of 2 siblings from a consanguineous family with the homozygous c.1078-1g>c splicing mutation in micu1. methods: retrospective case notes review. results: sibling 1: boy, older sibling, presented aged 7 years. he had short stature which was investigated when found to have ck of 13 000iu/l. he complained of occasional cramps. muscle biopsy showed mild dystrophic changes with reduced alpha-dystroglycan that indicated a possible congenital disorder of glycosylation. his mri brain was normal. he was diagnosed with autism. sibling 2: girl, diagnosed antenatally with cerebellar hypoplasia, confirmed postnatally as inferior-vermis hypoplasia. presented at 5 years with occasional cramps, mild tightness of tendo-achilles, and ck of 3500iu/ l. her height and weight were on 2nd centile. muscle mri showed a small area of high signal in the left adductor magnus related to a group of normal vascular structures. neurophysiology studies were normal. no other systemic involvement was seen in either of them. next generation sequencing revealed the micu1 mutation described. conclusions: our work expands the phenotypical spectrum of micu1 deficiency and highlights the variability in patients within the same family. targeted analysis of the micu1 gene in patients with high ck levels resembling a cmd picture may be warranted, even in the absence of prominent muscle features. the role of dystrophin brain isoforms on early motor development and motor outcomes in young children with duchenne muscular dystrophy half of patients have central nervous system (cns) manifestations. two dystrophin isoforms, dp140 and dp71, play an important role in cns function. those lacking dp140 have a more severe cns phenotype, most marked in those lacking dp140 and dp71. our objective is to determine whether lack of dp140 and dp71 also has an adverse impact on early motor development. methods: the northstar ambulatory assessment (nsaa) is a scale of motor function. clinical information for 320 dmd participants was classified by dmd mutation location and effects on isoform expression as follows: dp140+_dp71+ (dp427 absent, dp140/dp71 present), dp140-_dp71+ (dp427/dp140 absent, dp71 present) and dp140-_dp71-(dp427/dp140/dp71 absentall isoforms affected). results: amongst 4 to 6 year olds, median total nsaa scores were lower in the dp140-_dp71+ (p=0.0088) and dp140-_dp71-groups (p=0.0001) than the dp140+_dp71+ group, most markedly in the dp140-_dp71-group. for example, for 6-year olds, median total nsaa scores were 26 (dp140+_dp71+), 23 (dp140-_dp71+) and 17 (dp140-_dp71-). amongst 4 to 6 year olds, a lower percentage of participants achieved a full score of 2 (normal, achieves goal without assistance) for the nsaa sub-items in the dp140-_dp71+ (p<0.0001) and dp140-_dp71-(p<0.0001) groups than in the dp140+_dp71+ group, most markedly in the dp140-_dp71-group. for example, amongst 4-year-olds, percentage of visits for which a full score was recorded for jump were as follows: 56% (dp140+_dp71+), 19% (dp140-_dp71+) and 0% (dp140-_dp71-). conclusions: in addition to the known cns phenotype, young dmd patients lacking dp140 also exhibit lower median total nsaa scores and greater early motor delay, most markedly seen in those lacking both dp140 and dp71 (lacking all dystrophin brain isoforms). this has important implications for patient prognostication and clinical trial design. background: most commonly known as a rare subtype of guillain-barr e, miller fisher syndrome (mfs) has evolved since it was first described in 1956. the syndrome is characterised by a triad of ophthalmoplegia, ataxia and areflexia but clinical variations do occur. it occurs more often in men than woman (ratio 2:1) with the average age of onset 43.6 years. mfs is associated with positive anti gq1b antibodies, which is concentrated in cranial nerves iii, iv and viexplaining the link with ophthalmoplegia. clinical case: we present an unusual case of a 2-year-old boy with background of macrocephaly and pre-existing developmental delay with a previous mri which showed mild signal change in periventricular white matter bilaterally. he was admitted with a subacute history of proximal muscle weakness and fatiguability. he had no obvious focal neurological signs apart from intermittent lid hopping and ptosis. differential diagnosis included myasthenia, demyelinating disorders or an underlying pre-existing luecodystrophy. anti gq1b antibodies were checked along with extensive metabolic investigations, lumbar puncture, muscle biopsy, anti-cholinesterase and antimusk antibodies along with repeat mri. all investigations were negative including mri which showed no significant change from previous. the only findings were strongly positive anti gq1b antibodies. in the interim, the patient was started on trial with pyridostigmine with significant clinical improvement. conclusion: atypical variants of mfs should be a differential in children with subtle eye signs without ophthalmoplegia. lid hopping and fatiguability should raise the suspicion of mfs and anti gq1b antibodies should be tested. pyridostigmine has been reported to be effective in mfs. potential utility of muscle mri in congenital myasthenia syndrome secondary to agrn mutation found on whole exome sequencing (wes) congenital myasthenia syndromes (cms) are caused by genetic defects affecting neuromuscular transmission, resulting in muscle weakness and fatigability. agrin, an extracellular matrix molecule released by the nerve is essential at the neuromuscular junction. the large coding gene agrn, has a number of exons and with increasing variants found on wes, it is time consuming and complex to undertake functional studies to define pathogencitiy. previous reports of agrn mutations have a phenotype with prominent distal leg weakness and changes in the soleus on mri. we describe a differing presentation and striking changes on mri, especially in the posterior compartment of the thigh. a 10-year-old presented with deterioration in his gait and difficulty climbing the stairs. he was born at term, via a normal vaginal delivery. his parents were consanguineous, and he had three well siblings. he was reported to walk by 2 years. on examination he had a waddling gait and was unable to run or hop. he had proximal weakness with a positive gowers sign, together with weak eye closure. muscle biopsy showed non-specific myopathic features, however an mri of the lower leg found widespread fatty muscle atrophy of the thigh and calf with relative preservation of the adductor longus, rectus femoris and semitendonosis. wes revealed an agrn mutation (c.5952_5963del) and a homozygous mutation in the nebulin gene (not felt to be clinically relevant). single fibre emg confirmed electrodecrement on repetitive nerve stimulation. the patient has been commenced on treatment with salbutamol. our patient had very distinctive changes on mri and nonspecific muscle biopsy changes. muscle mri changes prompted further genetic testing when symptoms fitted a clinical diagnosis of a congenital myasthenic syndrome. with increasing variants found of unknown significance in these patients, collation of mri imaging to try and elucidate patterns of changes will be important. mcardle disease (glycogen storage disease type v) is an autosomal recessive condition caused by pathogenic mutations in both copies of the muscle glycogen phosphorylase (pygm) gene encoding the muscle-specific isoform of glycogen phosphorylase, 'myophosphorylase' exclusively affecting skeletal muscle. it is the commonest form of glycogenosis. mcardle disease shows significant clinical variability, with symptoms ranging from mild discomfort during exercise to marked muscle weakness and rhabdomyolysis with myoglobinuria. the second wind phenomenon is unique to mcardle disease and consists of improved exercise tolerance with a decrease in heart rate after a rest. despite the majority of patients recalling symptoms during the first years of life, mcardle is infrequently diagnosed in children, 66% of patients being diagnosed after 20 years of age according to a recent review. here we report two patients diagnosed with mcardle disease at the age of 11 and 6 years respectively. case one presented with fatigue and inability to increase pace of walking from the age of 4. hills lead to earlier fatigue. she was able to participate in gymnastics and dancing. presentation was with fluctuating ck levels (700 to 28 000). she had no second wind phenomenon or myoglobinuria. case two presented at 6 years with a history from 18 months of reduced exercise tolerance and myalgia after low intensity physical activity with no evidence of myoglobinuria or second wind. on formal assessment there was no evidence of muscle weakness or functional impairment. ck was persistently raised ranging from 650 to 4000. in the light of symptoms and ck levels a rhabdomyolysis panel was requested in both cases leading to diagnosis. objectives: to explore characteristics of anxiety experienced by young males with duchenne muscular dystrophy (dmd) using: 1. qualitative analysis of focus group discussions with dmd boys and their parents. 2. parent-report scales of anxiety/emotional problems. methods: eight boys aged 7 to 18 years with dmd and 14 dmd parents participated in separate child and parent focus groups. perspectives on anxiety were elicited using semi-structured discussions, and framework analysis was applied to identify themes. scores on five parent-report scales were determined and scales were compared for content and sensitivity. results: from group discussions, six characteristics of anxiety were recurrently reported: catastrophic conclusions; rigidly held anxieties; extreme distress; unexpected/unfamiliar; social anxieties; physical changes and needs. many features echo the anxiety phenotype in autism spectrum disorder (asd). four further themes described relevant contextual factors: individual, family, social and environmental responses. from parent-report scales, younger dmd boys (7-11y; n=12) had significantly higher total, general and social anxiety scores compared to population means on at least two scales (p<0.01; p<0.01; p<0.05). the older dmd group (12-18y; n=6) trended towards higher scores in total, general and separation anxiety (p=0.10; p=0.06; p=0.051) compared to population norms. different scales varied in their diagnostic sensitivity and item content, which may influence their utility in dmd. conclusions: anxiety can be a pervasive and impactful issue in dmd. it appears to have some shared traits with anxiety in asd and may be influenced by situational factors, such as living with a disabling, life-limiting condition. screening with standard anxiety scales may not accurately capture the full spectrum of the phenotype in dmd, therefore further evaluation to determine optimal screening instruments in dmd is warranted. however, multi-modal assessments tailored to dmd are key to identifying those in need of support to optimise the mental well-being of young people with dmd. objective: as part of the clinical psychology service in paediatric neurology we developed a tic management group to support young people and their parents to develop positive coping in relation to their tics. the group combined psychoeducational, emotional regulation and habit reversal therapy (hrt) components. this evaluation aimed to establish the effectiveness of these groups in reducing tics and associated distress. method: twenty-eight children, aged 9 to 13 years and their parents attended one of seven tic management groups facilitated between february 2015 and november 2018. these children had been referred to the clinical psychology for support with tics. each group consisted of 5 weekly, 1-hour sessions with a review session 4 weeks later. a parent group was held in parallel. both the young persons and parent groups were facilitated by the clinical psychology team. homework tasks were provided to support hrt skill practice and consolidation of learning of the group content between sessions. the following pre and post group measures were completed by the young people and their parents: the paediatric index of emotional distress, the yale global tic severity scale, the parent tic questionnaire and session rating scales. measures were collated and descriptive data reviewed. results: 96% of children found the group was helpful in the management of tics. 57% of children were 'less bothered by their tics'. 70% of children felt more confident in controlling their tics. parents reported a greater understanding of tics and a reduction in the severity of their child's tics. conclusions: results indicate the tic management group is effective in building young peoples' understanding of tics, confidence in tic management whilst providing peer support. the findings also indicate that parents found the groups informative and valued the opportunity to share experiences with others. background: patients with epilepsy often have deficits in cognitive, physical, psychological and social functioning, and treatment should aim to alleviate these deficits. epilepsy surgery is considered for medication refractory epilepsy with aims to improve patient quality of life. a recent study highlighted the importance of a multidisciplinary workup prior to epileptic surgery, including a neuropsychiatric assessment. part of this assessment should identify patient expectations of epilepsy surgery, so that these can be addressed peri-operatively. at king's college hospital (kch), london, these assessments are routinely performed by the paediatric liaison service as part of the children's epilepsy surgery service (cess). aim: to analyse retrospective data of pre-operative patient and carer expectations between october 2018 -september 2019 at kch. methods: a record of patient and carer expectations is routinely recorded as part of kch cess neuropsychiatric assessments. the responses were compiled and analysed using qualitative content analysis. results: a preliminary survey of 12 cases with an average age of 11 (range 5-15) identified 15 responses that were grouped into broader classifications (cognitive, seizure experience, social process, school experience, mental state and general improvements). simple analysis showed carers most often expected surgery to reduce the need for medications (42%), ablate seizures (33%), increase school performance (25%), independence (25%) and overall quality of life (25%). this compared to child responses, where the most common expectations were a reduction in lifestyle restrictions (42%), a cure for epilepsy (33%), decrease in medications (25%) and increased independence (25%). conclusion: consideration of both child and carer expectations during pre-epilepsy surgery neuropsychiatric assessments is important in order for services to manage each individual's expectations. unmanaged unrealistic expectations may lead to a negative psychological outcome for either child or carer. expectations should be weighed up against an individual's clinical profile. poster no. 119 neural correlates of conversion hemianaesthesia in an adolescent: a novel fmri case study m ray, a zaman, t alam leeds teaching hospital nhs trust, leeds, uk aim: to highlight the novel functional magnetic resonance imaging (fmri) findings in an adolescent with rare conversion hemianaesthesia. methods: we hereby report a right-handed 14y old boy who presented with inability to perceive sensations on the right half of body without any motor weakness causing him to have frequent injuries on his right leg as well as burns on his right hand without realizing. when he wore a jacket, he felt warm on one side of the body more than the other. his birth and developmental history were non-contributory. neurological examination was unremarkable except for right hemisensory disturbance. the mri of brain and spine, peripheral nerve conduction studies and somatosensory evoked potentials did not show any evidence of dysfunction were normal. he underwent fmri on a 3t philips achieva. the paradigm consisted of stimulating both the right and left hands and feet with three dissimilar stimuli (cold, brushing, pin-prick-pain) . the order of the stimuli was pseudorandomised and after each stimuli delivery, feedback was obtained. results: both the hand and foot sensory motor cortices were successfully stimulated. irrespective of which hand was being stimulated, there was left hemisphere sensory motor cortex dominance (with the brushing and cold stimuli), however selfreport from the participant confirmed detection of stimuli on the left-side only. there was more sensory-motor activation when the stimuli were delivered to the right hand. pain stimuli successfully activated parts of the 'pain matrix', furthermore enhanced attention effects (frontal pole activations) were observed with right-sided stimulation (supports lack of stimuli detection ability). the pain stimuli were more effective on the hands than foot, reflected by increasing activation and also self-report from the participant. conclusions: the fmri findings are unique and support the evidence of neuroplasticity and the current study paves the way for future studies investigating conversion hemianaesthesia. poster no. 120 chronic paroxysmal hemicrania presenting as facial pain in a child with autism and bipolar disorder: diagnostic challenges case presentation: a boy diagnosed with disintegrative psychosis aged 3, revised to autism with bipolar disorder, had been on carbamazepine with risperidone for poor mood control. withdrawal of risperidone produced tardive oromotor diskinesia responsive to clonidine. aged 11, when mood improved on aripiprazole, carbamazepine was withdrawn. he then presented with episodes of distress preceded by withdrawal, unilateral but not side-locked facial flushing, with additional flushing of neck, back and wrists. behaviours included hitting wrists off walls, chewing of hard objects and requesting pressure to his head. episodes occurred 8-9 times/ day, lasting 2-60 minutes. he showed rhinorrhea and tearing, attributed to crying, during events. the attacks self-terminated. results: mri and electroencephalogram were normal. failed pharmacological trials included paracetamol, amitriptyline, gabapentin and oxcarbazepine. diclofenac provided mild pain relief and morphine reduced the incidence of attacks. reintroduction of carbamazepine resulted in improvement at 30mg/kg/day but did not eliminate pain. sequencing of scn9a was normal. a plan to wean morphine alongside a trial of indometacin, initially at 25mg twice-daily was successful at 50mg twice-daily. episodes ceased, including all autonomic features. exacerbation at 4 weeks occurred in context of an intercurrent illness and was managed with an additional dose of indometacin. conclusions: cph is underreported in the paediatric age group. in our case, the patient's inability to describe events, and an additional psychiatric diagnosis added complexity. the possibility of pain as a cause for early psychotic breakdown in a developmentally vulnerable child cannot be excluded. criteria emphasising side-locked headache and autonomic features, and not recognising associated symptoms elsewhere may also delay recognition in children. objectives: piih can be a challenging condition to diagnose and manage with risks of misdiagnosis, permanent sight loss and frequent comorbidities. we aimed to review our practice to identify areas of uncertainty to help formulate important questions to address within a clinical guideline. methods: a single centre retrospective case notes review of all cases referred to neurology with suspected piih (papilloedema confirmed by a consultant ophthalmologist in all cases) during an 18-month period. results: 14 (12f: 2m) cases were identified. age range 8 to 15 years. mean 13 years. 8/12 had a bmi >98th centile. one case was referred to an obesity service. 6/14 had a comorbid headache disorder and 4/14 had anxiety/depression. all cases had neuroimaging (13 mri, 1 ct) with 4/14 having dedicated venography. in 2/14 cases lumbar punctures (lp) were conducted under general anaesthesia (ga). in 4/14 cases lp was not done; 2 due to presence of a chiari malformation and 2 due to procedural failure related to body habitus. intracranial pressure (icp) monitoring was done in one of these four cases. all children were treated with acetazolamide as first line therapy. frusemide, zonisamide and topiramate were also used in single cases. 5/14 children had repeat lps due to failure of resolution of symptoms. 2/14 cases had sight threatening piih with permanent visual loss in one case. 5/14 cases were discussed with neurosurgery. one child with evolving visual failure had an emergency ventriculo-peritoneal shunt. conclusions: important questions raised were: should all obese children with piih have access to a specialised obesity service? should all children have dedicated venographic imaging? how reliable is measuring csf opening pressure under ga? where lp is not possible should icp monitoring always be done? should repeat lps be done for persistent symptoms? should csf diversion surgery be restricted to cases of sight threatening piih only? objective: to describe a case of revesz syndrome due to a de novo missense variant in tinf2. case report: a male infant was born at 35 weeks gestation by emergency lscs due to maternal hypertension and reduced amniotic fluid. from 32 week's gestation, reduced fetal growth was identified. the proband was born by at 35 weeks. birth weight was 1.7kg (0.4th-2nd centile) and occipitofrontal circumference (ofc) was 31.7cm (2nd-9th centile). he spent 15 days in the scbu. he developed thrombocytopenia (nadir: 679109/l), which resolved pre-discharge. periventricular calcifications on cranial ultrasound prompted torch screen and ophthalmology review. a right pre-retinal haemorrhage with overlying organised vitreous haemorrhage was identified, which remained stable on subsequent reviews. aged 8 weeks, he was smiling, fixing and following with good head control. aged 5 months, he developed new wobbly eye movements and was no longer fixing or following. bilateral retinal detachments were identified. ct and subsequent mri showed diffuse calcification within the thalami, posterior limb of the internal capsule, deep white matter, cerebellar atrophy and thin corpus callosum. findings on examination included ofc of 0.4th centile, rotatory nystagmus and central hypotonia. whole-exome sequencing identified a pathogenic de novo variant in tinf2 (c.845g>a, p.arg282his). he subsequently developed thrombocytopenia and anaemia and is transfusion dependent. discussion: trf1 interacting nuclear factor-2 (tinf2), protein regulates telomerase and prevents telomere shortening. revesz syndrome is a severe form of dyskeratosis congentia, with multi-system involvement and early onset in-utero. revesz syndrome is characterised by intrauterine growth retardation (iugr), microcephaly, cerebellar hypoplasia, bilateral exudative retinopathy, intracranial calcifications and progressive bone marrow failure. revesz syndrome is distinguished from hoyeraal-hreidarsson syndrome by the presence of retinopathy. telomere disorders should be considered in infants with a background of iugr, thrombocytopenia, retinopathy and intra-cranial calcifications with a negative torch screen, as early features mimic congenital infection. objective: currently the most commonly reported neurological complication of sca is overt stroke. reversible cerebral vasoconstriction syndrome may be more frequent in patients with sickle cell anaemia than reported at present. the scarcity of prevalence studies however makes it difficult to improve diagnostic accuracy in these patients. methods: a 16-year-old ghanaian female was rushed to the paediatric emergency room with first episode of sudden severe global headaches initially started 8 hours prior to arrival. the headache was so excruciating that she described it as her heart was beating in her head. there was associated neck pain, back pain, dizziness, and vomiting. there was no fever or dark urine. she was first diagnosed with sickle cell anaemia (genotype ss) at 2 years of age after she was treated for dactilitis. she had since then been in her usual state of health with no history of blood transfusions or surgeries or admissions. she was compliant with her medications (folic acid 5 mg daily). a physical examination and all investigations were also normal. on day six of admission patient had a generalized tonic clonic seizure with some degree of left sided weakness after having her bath. this was aborted with intravenous diazepam and a magnetic resonance imaging (mri) of the brain was requested. the mri of the brain revealed diffuse narrowing of the cerebral arteries with no areas of bleeding or oedema. reversible cerebral vasoconstriction syndrome was therefore suspected. results: the headache rapidly improved after starting nimodipine and repeat angiography at 3 months showed no vasoconstriction, confirming the diagnosis. on follow up she is doing well academically with no neurological deficits. conclusions: the true incidence of rcvs in patients with sickle cell is uncertain, thus sensitizing medical practitioners is important. introduction: status dystonicus (sd) is a life-threatening disorder of generalised, painful dystonic movements and muscular spasm in patients with severe neurodisability. while rare, it may be complicated by rhabdomyolysis, multi-organ dysfunction, and death. infection, pain, gord, and medication failure are common triggers, but in approximately one-third of cases, sd is idiopathic. mordekar et al. (2017) identified a series of 11 patients in whom sd occurred secondary to gi dysfunction. assisted feeding (e.g., via gastrostomy), and aberrant bowel peristalsis may trigger the onset of sd. this was a retrospective analysis which aimed to estimate an incidence rate for feed-induced sd (fisd). methods: patients presenting to sheffield children's hospital over a 5-year period with sd were identified. episodes were studied to assess for the nature of the onset of sd and as to the likelihood that the trigger was feed related. incidence of fisd as a proportion of total sd was calculated and or calculation performed to explore relative risk of sd between individual trigger factors. results: twenty-four individual episodes of sd were identified. 13 (54%) arose from non-feed-related sources (nfisd), and 11 were felt to be fisd (46%). 6 additional patients were entered into a feed-induced dystonia (fid) group, whom showed clinical evidence of dystonia in relation to gi sources, but not sd. with the exception of infection, the relative risk of sd secondary to gi dysfunction was significantly higher than pain/gord and medication failure combined (or 0.11 (95% ci 0.02-0.56) and 0.05 (95% ci 0.01-0.44) respectively). conclusion: gi dysfunction coupled with severe neurodisability could serve as a trigger in a number of previously idiopathic sd cases through disruption of the neuro-enteric axis. however, overlap between triggers for fisd and nfisd, and significant variation between groups is evident, in addition to a lack of statistical study power. large, prospective studies are needed in the future to corroborate with these findings. poster no. 125 dystonia can twist the patient, physician and the scans: hypermanganesemia, a rare cause of dystonia in children r kumar, s ali liaqat national hospital, karachi, pakistan introduction: manganese (mn) is a chemical element with symbol mn and atomic number 25. mn in the environment can cause toxicity with dystonia and other movement disorders. waterborne mn has a greater bioavailability than dietary manganese. according to results from a 2010 study, higher levels of exposure to mn in drinking water are associated with increased intellectual impairment and reduced intelligence quotients in school-age children. we have recently reported a suspected autosomal recessively inherited syndrome of hepatic cirrhosis, dystonia, polycythemia, and hypermanganesemia in cases without environmental mn exposure. the rarity of the disease can become a challenge for the physicians to recognize this as a cause of dystonia in children. it also has a characteristic finding on mri with t1 hyperintensity in basal ganglia rather than on t2. case report: we present a case of a 6-year-old girl with dystonia who was previously healthy. she has been suffering from this for the last 6 months and currently one of her 4 years old sister started showing similar symptoms. physical examination revealed marked dystonia (score of 24 on baryalbright dystonia scale) and polycythemia (haematocrit 65). magnetic resonance imaging (mri) brain showed basal ganglia hyperintensity on t1 weighted images. hypermanganesemia was suspected and samples send for serum level which came out to be high. water samples were tested, which came out to be normal. chelation was done and the dystonia improved. conclusions: dystonia in children should be thoroughly investigated and rare, treatable causes should not be ignored. objectives: sodium valproate is used primarily for the treatment of epilepsy in children. it is a well-established teratogen, with 4 in 10 babies at risk of developmental disorders and 1 in 10 babies at risk of birth defects. this risk has been known since the 1970s and yet it is estimated that since then 20 000 children in the uk have been left with disabilities as a result. in 2016, the medicines and healthcare products regulatory agency released guidance for its use, which included a risk acknowledgement form. patient safety alerts were issued in 2017 asking all organisations to identify females taking this medication. we aimed to identify all girls taking sodium valproate in the south eastern trust under paediatrics requiring annual risk assessment; patients under the additional care of a neurologist; patients receiving an annual review. methods: patients were identified through paediatric epilepsy nurse records and data collected through the electronic care record and medical notes from august 2018 to december 2018. results: 24% (n=30) of girls with epilepsy currently taking sodium valproate, 73% under the age of 10 years, 37% profound learning difficulties/disability and considered to be at low risk of pregnancy, 7% (n=2) potentially currently at risk, 81% were under the additional care of a neurologist, 87% reviewed in the past year. conclusions: sodium valproate must not be considered first line treatment in girls with epilepsy and >75% of girls in our trust are not receiving it. of those receiving it, the majority are felt to be low risk due to young age and/or profound disability. we identified two patients at risk and steps were taken to ameliorate this. we have demonstrated good awareness; however lifelong education of families is crucial to reducing the burden of fetal valproate syndrome. rett syndrome (rtt) is neurodevelopmental disorder affecting approximately 1 in 10 000-15 000 live female births, most commonly associated with mutations in the mecp2 gene. hand stereotypies and gait disturbance, as well as spasticity and dystonia, have been noted in rtt since the first descriptions of the syndrome. objective: this review aimed to explore the prevalence of reported movement disorders in rtt. data sources and extraction: pubmed and embase databases for papers describing features of movement disorders in rett syndrome. papers were selected for inclusion to be reviewed if they included description of case report, cohort or case-series of patients with rtt which included a description of clinical features of their movement disorder. selected papers were divided into 3 epochs: (i) pre-1999, (ii) 2000 to 2009, and (iii) 2010 onwards. results: 32 studies (13 in the first epoch, 10 in the second epoch and 9 in the third epoch) reported on movement disorders including stereotypies in rtt patients. hand stereotypies were almost universal in reported cases, diminishing but not disappearing over time. gait disturbance and ataxia/tremor were also very common (>50% cases). elements of hypertonia were also common, increasing with age. in earlier descriptions spasticity was commonly described, with more frequent reference to dystonia/rigidity in more recent reports. myoclonus and choreoathetosis are uncommonly reported in rtt. conclusions: movement disorders beyond hand stereotypies are common in rtt, most notably tremor. hypertonia is a common feature seen in rtt, increasing in prevalence with age, and with an apparent change in nomenclature over time, (i.e., early epoch spasticity, late epoch dystonia). dystonia was specifically reported in 229/417 cases. further work is required to explore the relative contribution of dystonia and rigidity to hypertonia in rtt, as well as the impact of these impairments when present. introduction: headache is the common complaint in children, and the source of it, a great deal of worry for general practitioners and parents. one of the commonest causes of headache in paediatrics is migraine. methods: a prospective study was conducted to evaluate the demographic data, clinical spectrum and grading the child with migraine by using the paediatrics migraine disability assessment (ped-midas) questionnaire and to start prophylactic treatment for those with the higher grades in the department of paediatrics in tertiary care hospital. all children with migraine from age 5 to 18 years were included while all other types of headache cases were excluded. results: total 112 children with migraine were studied. approximately 80% children complained of bilateral frontotemporal headache in which 69.64% presented with throbbing type. other associated features were photophobia, phonophobia, nausea and vomiting. 75% had skipped meal, followed by altered sleep and exam stress as aggravating factors. 94.6% required medication for headache relief. headache duration and frequency was approx. 17 days and 9 days/month. 57.1% cases were diagnosed migraine without aura and 42.9% cases were diagnosed as migraine with aura. loss of full school days due to headache was approx. 2 days for period of 3 months. based on ped-midas score, 50% of children with migraine had grade i disability while 42.9% and 7.10% cases had grade ii and grade iii disability respectively. correlation of ped-midas score with frequency and severity were significant (p<0.001) while with duration of headache was insignificant (p<0.245). conclusions: all patients with higher ped-midas grade are warranted prophylactic treatment. both ped-midas scores and grading can be successfully used for assessing the migraine disability and its easier, less time consuming, bedside diagnostic tool, can be used widely in routine clinical evaluation and management. objective: to review the cases referred to this uk-wide study of children with possible variant creutzfeldt-jakob disease (vcjd) and report the differential diagnosis in children presenting age 10 years or older. methods: children meeting the case definition for progressive intellectual and neurological deterioration (pind) were identified via the british paediatric surveillance unit. details were obtained by standard questionnaire. results: between april 1997 and august 2019, 4589 children had been notified to the study. 2068 were found not to meet the pind case definition. 2006 had an underlying diagnosis to explain their deterioration, with over 210 different disorders including 6 vcjd cases (the last identified in 2000). there were 104 children who presented to clinicians when aged 10 years or over, including all the 6 vcjd cases. of the other disorders in this age group the commonest were: mitochondrial cytopathy 16, adrenoleukodystrophy 9, lafora body disease 8, huntington's disease 7, neuronal-ceroid lipofuscinoses 6, niemann-pick type c 6, metachromatic leukodystrophy 4, sspe 4, wilson's disease 4. when reviewed in 2017 there was no underlying diagnosis in 225 pind cases; 108 of them had diedonly 14 underwent autopsy. the recent identification of the first patient with vcjd who was mv heterozygous at prnp codon 129 reinforces the need for continued vcjd surveillance, particularly as a study of archived appendix samples from uk hospitals published in 2013 indicated that approximately 1 in 2000 of the uk population is carrying abnormal prion protein in the gastrointestinal tract. in the absence of a validated vcjd screening test the pind study remains the only means of performing systematic surveillance of the neurodegenerative diseases that make up the differential diagnosis of vcjd. objective: transient lesions in the splenium of corpus callosum (scc) are rare findings in mri brain in paediatrics. in literature, it has been described as reversible splenial lesions syndrome (resles) and mild encephalitis/encephalopathy with reversible splenial lesions (mers). the condition has diverse aetiology and widely variable neurological presentation but the prognosis is usually favourable. we present two cases of resles with predominantly expressive dysphasia but varying causal associations. method: retrospective review of resles case series exploring clinical course, investigations, neuroimaging, treatment and recovery. result: case 1: a 15 year-old-girl presented with confusion, fever and low oxygen saturation. she had alagille syndrome and partially corrected tetralogy of fallot. her neurological manifestations were expressive dysphasia, dysarthria and difficulties with spatial awareness. interestingly she was able to use occasional words that were abusive in nature. mri showed prominent focus of abnormal signal and restricted diffusion in scc. her blood culture grew staphylococcus aureus and echo revealed infected shunt. treatment involved shunt replacement and prolonged iv antibiotics. repeat mri showed resolution of splenial lesions. she continued to improve neurologically. case 2: a 9 year-old-girl presented with paroxysmal episodes of head turning, head drop and staring for a few seconds. she refused to feed. she showed emotional lability with expressive dysphasia but preservation of expletives. neurologically she was intact. mri brain showed high signal with restricted diffusion in scc. her blood and csf investigations including mog, aquaporin, nmdar, lyme antibodies were negative except asot was 400. her eeg was normal. she received a course of ivig and azithromycin. her repeat mri showed resolution of the lesion in splenium. she made complete recovery over next few months. conclusion: splenial lesions are rare but clinically significant but not 'non-specific'. expressive dysphasia is a prominent symptom. awareness of resles/mers will avoid unnecessary investigations and assist in the prognostication. background: the evidence-base on managing paediatric-headaches is sparse resulting in wide variation in practice with nice guidelines commencing over 12 years of age. this study aims to evaluate outpatient management of paediatric headaches. objective: to investigate paediatric headache referrals to a tertiary hospital over a 1-year period, exploring patient demographics, headache type, role of neuroimaging, management and outcome. methods: this prospective study reviewed headache referrals for the year 2018-2019. the data was collected following weekly emails to relevant clinicians. the patient demographics, headache classification, imaging, management and outcome were collated on a proforma from the electronic patient-records. results: there were 99 patients. the median age of patients at first outpatient appointment was 12 years (range 3-17y); 63.6% were female. incidence of headaches increased with age. female preponderance of headaches existed in all age groups and was most substantial post-puberty with a 2.4:1 female-to-male ratio in patients aged 13 to 17 years. migraine was the most common diagnosis, affecting 46.5% of patients. 51% of referred patients underwent a brain mri scan, all of whom had a normal neurological examination. no mri scans found pathology contributing to headache presentation. 91% of patients were discharged from neurology clinic after first or second neurology appointment. non-pharmacological management was the most common intervention and consisted of: headache diary, lifestyle advice, education, relaxation techniques. the most common medications prescribed bar simple analgesia were sumatriptan (12%), propranolol (9%) and pizotifen (9%). conclusions: a multidisciplinary and biopsychosocial approach to managing paediatric headaches, consisting of non-pharmacological and pharmacological methods resulted in a positive outcome, with majority discharged from tertiary care after first appointment. prescription of sumatriptan and propranolol first line for acute and prophylactic management respectively, was in accordance with current clinical recommendations. the role of mri scanning for paediatric headaches requires further exploration and perhaps more stringent guidelines. objective: the head-up tilt test (hutt) is the gold standard autonomic function test for identifying disorders of blood pressure (bp) and heart rate (hr) regulation, specifically with excessive falls in bp and or hr, as well as excessive postural tachycardia (pt). the 10 minute active standing test (ast) is quicker and easier to apply, e.g., in an outpatient clinic, and may be more sensitive in demonstrating pt. we aimed to compare the yield of these abnormalities when using ast vs hutt. methods: this was a retrospective, clinical notes review, and registered clinical audit of unselected consecutive children and young people undergoing hutt immediately preceded by an ast. results: data was available on 86 children and young people, 56 (67%) female, aged 3 to 18 years (median 14). 12/84 (14%) with complete data sets for the first 10 minutes of hutt and the ast had abnormally large drops in bp and or hr on hutt. only 1/12 positive on hutt was also positive on ast. however, an additional 6/84 (7%) were positive on ast but not on hutt, giving 18/84 (21%) positive in total. 8/86 (9%) with hr data sets for 10 minute hutt and ast had abnormally large rises in hr on hutt. only 3/8 positive on hutt were also positive on ast. however, an additional 10/86 (12%) were positive on ast but not on hutt, giving 18/86 (21%) positive in total. while hutt yielded more cases with significant falls in bp and or hr than ast (14% vs 8%), combining the tests gave the highest yield (21%). while ast yielded more cases with significant rises in hr than hutt (15% vs 9%), combining the tests gave the highest yield (21%). conclusions: we recommend routinely undertaking a 10 minute ast prior to the 45 minute 60°hutt, in children and young people. objective: the aim of our work is to describe the respiratory function trajectories and their correlation with motor function in a cohort of spinal muscular atrophy type 2 and non-ambulant sma3 paediatric patients. methods: this is a retrospective 9-year study in patients recruited in the ismac natural history study (uk, italy, us). the following respiratory data were collected: lung function data (forced vital capacity absolute (fvc) and fvc% predicted, non-invasive ventilation (niv) requirement. recumbent or ulnar length were used as surrogate for height in fvc%pred. calculation. comorbidities affecting lung function such as aspiration were collected. anthropometrics and motor function scores as hammersmith functional motor scale (hfms), revised performance of upper limb (rulm) were noted. we excluded patients in interventional clinical trials and nusinersen therapy. results: data were available for 437 patients: 348 sma2, 89 sma3. mean age at first visit was 6.9 (ae4.4) and 11.1 (ae4) years for sma2 and 3. 180/215 (84%) sma2 and 39/49 of significant lesions. a review of practice of asking routine or non-urgent mri requests should be considered in view of an unlikely significant result. retrospective review of brain magnetic resonance imaging referrals in children less than 12 years (r[20] ) is an ultrarare disease characterised by drug-refractory epilepsy, cognitive impairment and behavioural problems. non-pharmacological treatments should be considered alongside antiepileptic drugs (aeds) early after diagnosis to benefit prompt seizure control and preserve cognitive function. we aimed to understand the use and experience of ketogenic diet therapy (kdt) in r(20) by patients families carers (pfcs) and healthcare professionals (hcps), assessing its efficacy and safety, and contrasting nhs kdt service provision with patient demand. methods: literature searches were conducted on use of kdt in r(20) and similar complex epilepsies. two surveys were developed to gather demographic, diagnostic and clinical care information. surveys were qualitative and descriptive with patient and expert collaborators assessing content accuracy and readability. responses were discussed at a patient and expert workshop. results: the number of responses (42 pfcs, 23 hcps) was considered significant given the ultra-rare status of r(20). 50% of pfcs had tried kdt. seizure activity, behaviour and cognitive outcomes were ranked equally important by hcps and pfcs. significant improvement in seizure activity, cognition and alertness were reported; side-effects were typically mild but with one report of increased seizure frequency. the high rate of comorbidities, older age at presentation, behavioural problems and cognitive impairment can make implementing kdt in r(20) challenging. pfcs report quality of life would be most improved with reduced aed side-effects; hcps report they would consider reducing or withdrawing aeds where kdt is successful. conclusions: kdt may not be suitable for every r(20) patient, but there is a strong consensus that it should be considered as an early intervention. in the uk, nhs kdt services are predominantly available for paediatric patients, with very limited adult access. a detailed health economic analysis illustrating reduced acute care costs and improved quality of life may encourage more widespread kdt implementation. objectives: whole exome sequencing (wes) with a 2-week result turnaround time has become available on the nhs for children in an intensive care setting. we aimed to determine the diagnostic utility and impact on clinical care of wes in a regional paediatric neurology centre. methods: retrospective case notes review. results: six cases (4m, 2f) were identified. three patients were dependent on long-term respiratory support. a pathogenic mutation was detected on wes in 5/6 cases (83%). one case required 'reverse phenotyping' with an abnormal transferrin glycoform electrophoresis confirming that two heterozygote variants of the rtf1 gene were consistent with a congenital disorder of glycosylation (cdg). no other variants of unknown significance were found. three children presented with neonatal onset epileptic encephalopathy (two cases had scn2a, one case wwox), one child with intractable epilepsy from 2 months of age (rft1 mutation associated with cdg) and one child with hypotonia and ventilator dependence after a respiratory infection at 4 months of age (ighmbp2 mutation associated with spinal muscular atrophy with respiratory distress). wes found no pathogenic mutation in a 3-year-old with intracranial calcification, microcephaly, epileptic encephalopathy and severe developmental regression. in 5/6 cases other single genes/panels had been sent prior to initiation of wes with multiple single genes/panels sent in 3/6 cases. in 3/6 cases wes detected the gene thought most likely based on clinical phenotyping on the request form. conclusions: wes has a high diagnostic yield in this cohort of patients. reaching a prompt diagnosis facilitated withdrawal of care in one case (ighmbp2) and helped to exclude an epilepsy surgery hypothesis in four cases as well as guide prognosis in all cases. wes should be considered as a cost-effective alternative when multiple single genes and/or genetic panels are being sent off in parallel due to clinical urgency. objective: the care provided in the time surrounding the death of a child shapes long-term memories and has potential to impact on the grieving process. there are no specific guidelines for picu staff in relation to what good care looks like at this time. we sought insight into practice across the uk to build an evidence base, improve care provided and share good practice. conclusions: from the survey feedback, we found this was an area that all units believe can be improved. in relation to acps, we hope this will be more widely introduced. we know that 60% of patients admitted to picu are life limited. these difficult conversations with family help guide management, understand wishes, and formal documentation ensures all staff are aware. several units with higher uptake of hospice/home care found early conversations with families beneficial. units with a dedicated palliative nurse stated this allowed more time with families. we believe this should become a standard of care. staff training is limited in most units. for something so difficult and frequently encountered, it is vital we equip staff better. prioritising children with epilepsy in the first seizure clinic cp white, s brown, ka hapgood, s tuohy children's epilepsy service, morriston hospital, swansea, uk objective: rising demand for limited first seizure clinic appointments was leading to increasing waiting times and the feeling that children with epilepsy were waiting too long for their first assessment. concern was also expressed that families were not receiving our first seizure leaflet or given instructions about capturing any further episodes either on video or by making a written record when initially seen. methods: from april 2018 all families were sent a letter acknowledging the referral and asking them to contact the specialist epilepsy nurse if they had any concerns prior to the appointment. later modifications included a seizure information leaflet and a seizure record document. we have analysed the results of the first year of using this system. patients were identified from the clinic database and further information was obtained by reviewing clinic letters. results: our initial concern that the specialist nurse would be inundated with phone calls from worried parents were not realised as only 13% (14/104) of parents contacted the service before their appointment. these were invariably parents whose children had had a second episode (10/14). 8 had had further generalised tonic clonic seizures. 11 children had eegs performed before their first appointment. this included all the children given a diagnosis of epilepsy. 71% of these children (10/14) were given a diagnosis of epilepsy made compared to 19.5% of other referrals (p<0.01). although a higher percentage of families who were reminded about videoing any further episodes did so the difference between the two groups was not statistically significant. unfortunately, overall waiting times were not affected. conclusions: a simple change to the way in which the service is delivered has led to earlier identification of those children with epilepsy. we are looking at other ways of improving the accuracy and timeliness of the appointments. introduction: paediatric idiopathic intracranial hypertension (iih) is an uncommon disorder and presentation is varied with children presenting to paediatricians, paediatric neurologist, and ophthalmologists. there are many areas of diagnosis and management where evidence is limited. a national adult evidence and consensus-based guideline was published in 2018. no national paediatric guideline exists to aid the further investigations and management of the cases. the iih meeting at the bpna conference in 2017 and january 2019 set the scene for collaborative work on this topic. aim: to develop a national paediatric iih guideline based on the available literature such as modified dandy criteria, friedman 2013 classification and icdh-3 classification and consensus amongst various members of bpna chan group, members of rcpch, ophthalmology, neurosurgery and radiology, and patients. methods: a core children's headache iih guideline development group was established and has met at four national special interest group meetings between november 2017 and september 2019. topics discussed include incidence of papillioedmea, csf dynamics in iih, bpnsu iih data, ophthalmology good practice, regional iih pathways in uk and setting up of the delphi process. the paediatric iih study day in september 2019 with invited patient/parent representatives highlighted the impact on families with the disorder with need for better communication about the disorder, clear guidelines and sharing of good practice amongst clinicians. an email list of bpna chan group, rcpch members, ophthalmologists interested in the guideline was created. results: a set of 55 statements were drafted for delphi consensus work. these are currently being reviewed by the core guideline development group prior to being circulated to the wider working group. conclusions: goal setting for the next process with the delphi process to work with the core committee and a wider working group will be presented at the bpna conference 2020. objective: nhs england's marginal rate emergency threshold (mret) and readmission fund funded the chameleon project 2018 (twitter account: @chameleonproje1), to improve children's end of life care. this funded a lead disability paediatrician with expertise in paediatric palliative care (10h/wk), a children's palliative care nurse (3d/wk) a network administrator (2d/wk), and additional hours for paediatricians in the critical care, oncology, and neonatal units, and in each of the local district general hospitals (total 18h/wk). methods: tools were developed to aid identification of children in the last year of life and to support anticipatory care planning. the team attended ward rounds and provided teaching sessions, advice and support. children who died an expected death in the 12 months of the project were ascertained from the child death review teams. non-elective admissions, bed days, and costs were tabulated. we also evaluated the documentation of care plans and post bereavement family feedback questionnaires. results: 29 children died an expected death. the same number died during the previous 12 months. the median number of non-elective admissions reduced from 2 to 1 per child, specialist ward bed days reduced from 504 to 251 (50% reduction). for children admitted to picu in the last 12 months of life, the total picu bed days reduced from 342 to 184 (46% reduction), the median length of stay reduced from 21 days to 11 days, and the maximum length of stay reduced from 141 days to 38 days. the percentage of children who died an expected death who had documented anticipatory care plans rose from 50% to 72%. conclusions: the network of clinicians with expertise in paediatric palliative care working together across a region improved anticipatory care planning and reduced admissions and bed days for children in their last year of life: better care with reduced costs. child a, a boy with speech and language delay, presented at 2 years of age with self-resolving episodes of floppiness, ataxia, and disorientation. there was associated muscle weakness and drooling. these unusual episodes occurred 3 to 4 times per week and were often triggered by excitement, especially physical and emotional overstimulation. they lasted from a few minutes to an hour, with no residual deficit. episodes could also be triggered by having late meals (fasting episodes). investigations including an mri/mra brain, eeg, sleepdeprived eeg and video telemetry did not reveal any significant abnormalities. metabolic and endocrine tests were normal. as his presenting symptoms were consistent with episodic ataxia, possibly a periodic paralysis spectrum, a trial of acetazolamide was given, which showed some improvement in the number and severity of the episodes. at 8 years of age, genetic sequencing results revealed child a has a recessive 23kb deletion within the long arm of chromosome 22, band q11.21. this is a homozygous intragenic deletion within the tango2 gene. tango2 is a 'transport and golgi organization 2' homolog. the function of tango2 is unknown; however, in previous studies, depletion in drosophila s2 tissue culture cells was observed to cause fusion of the golgi with the er. a recent study of 14 individuals with tango2, illustrated that child a has a clinical phenotype which is consistent with those previously reported in the literature. although seizures are present in 75% of individuals with tango2, child a has not had any seizures to date. although no effective treatments for this rare condition are known, early diagnosis is important so that individuals and their families are aware of the potential encephalomyopathic crises and arrhythmias which occur. further research in elucidating the structure and function of the tango2 protein may lead to effective therapies in the future. objective: hie affects around 1.68/1000 live births. prognostication relies on clinical progress, neurophysiology, neurological examination, and magnetic resonance imaging (mri). there is limited information on the relationships between mrs brain results and visual appearances of the brain on mri and clinical features. this work studied the use of mrs in this cohort. methods: mrs is used routinely in all neonates with hie in our unit, so approval for this service evaluation was obtained from our clinical governance department. we identified neonates with hie between jan 2010 and march 2016 who had mri and mrs in the first 7 days of life. medical notes were reviewed, and mri results categorised as normal or abnormal. mrs results and clinical features were compared between mri groups using parametric or non-parametric testing. correlation and regression analyses studied relationships between clinical features and mrs results. p-values of <0.05 were assumed to be significant. results: 82 participants were identified, 19 were excluded because they did not meet our inclusion criteria. data from a total number of 63 neonates were analysed using r studio. babies with abnormal mri scans had significantly lower birth weight (p=0.018), gestational age (p=0.037), and higher scores in the sarnat staging scale (p=0.04). the analysis of the mrs data also revealed that these babies had lower levels of n-acetylaspartate (naa) in their parieto-occipital region (p=0.006), as well as higher levels of lactate and lactate to choline both in the parietooccipital region (p=0.032 and p=0.007 respectively). finally, these significant mrs variables were significantly correlated with time to normalisation of lactate in single linear regression. background: more children and young people are surviving with an acquired central nervous system injury (traumatic or non-traumatic). the first nhs england (nhse) specialist specification for paediatric neurorehabilitation services was written in 2013. evidence for benefits of early neurorehabilitaion after adult stroke are compellingevidence for early neurorehabilitation in cyp is emerging. methods: service information was collected from all england and wales pnr units in 2019. results: 15/17 units contributed. activity is increasing (464 (2012/13); 530 (2013/14); 595 (2014/15). 10/17 (60%) are major trauma units (50%) have dedicated coordinators. several units cannot offer daily therapy. most units discharge cyp home. conclusions: considerable neurorehabilitation in-patient activity is taking place but there remains an absence of secure funding, adequate staff, dedicated beds, key members of the mdt, protected time for pro-active patient specific discharge planning. neurorehabilitation is an integral part of the neuroscience clinical pathway and our children deserve a fully resourced service as described in the service specification. tuberculosis/sarcoidosis (1). out of the sub-categories, the group of refractory seizures/status epilepticus were most likely to have repeated imaging with either ct or mri within 3 years (80%), followed by the group of ventriculo-peritoneal shunt blockage (77%), space occupying lesion (20%) then head injury (14%). out of 5 patients with refractory seizures/ status epilepticus, 4 were already known to have epilepsy. also, most repeated imaging included a subsequent head mri. conclusions: most common indications for ct head were head injury and shunt blockage (as this was a neurosurgical centre). the groups most likely to have repeated imaging were refractory seizures/status epilepticus and shunt blockage. with children presenting with known epileptic seizures in the emergency department, it is important to consider clinical data and seek to devolve decision to image. poster no. 150 isolated radial nerve palsy, a rare presentation of congenital wrist drop c duggan, n mcsweeney cork university hospital, cork, ireland isolated congenital radial nerve palsies are a rare phenomenon and typically spontaneously recover within 6 months. the true incidence is not known, but in a recent study 2.6% of infants presenting to a brachial plexus injury clinic had an isolated congenital radial nerve palsy. patient a is a 10-week-old male who presented at birth with a left sided wrist drop following a non-traumatic elective caesarean section at 38+5/40. his birthweight was 4.23kg (91st centile). movement of the wrist and digits were impaired to absent with preservation of function at the shoulder and elbow. there was a nodule noted in the left upper limb, anatomically superficial to the radial nerve. it was a normal pregnancy with no antenatal or postnatal issues. he attended physiotherapy and occupational therapy who provided a splint. on examination at 10 weeks, there was weakness of the extensors of the left wrist. the 3rd, 4th and 5th digits remained fully flexed at rest and could be extended passively but not actively. extension of the thumb and index finger had recovered at 10-week review. function at the shoulder and elbow joints were preserved with normal flexion of the wrist and digits. a scar was noted superficial to the radial nerve at the same location as the lesion described at birth. the remaining systemic and neurological examinations were normal with typical development and appropriate growth. the working diagnosis at present is an isolated radial nerve palsy likely caused by in-utero compression. the nodule and scar noted above are consistent with lesions described in a previous case series. these were hypothesised to be areas of fat necrosis secondary to compression; resulting in the palsy. patient a's lack of further neurology such as a generalised brachial plexus palsy makes a birth injury less likely. further investigations and follow-up are awaited. background: valproate is an effective antiepileptic medication. if a woman becomes pregnant while taking valproate, her baby is at risk of congenital malformations (1 in 10) and developmental disorders (4 in 10). furthermore, it is associated with an increased risk of autism spectrum disorder and adhd. in 2018, the nhs/hse recommended new restrictions on the use of valproate, including a national pregnancy prevention program (prevent) and avoidance in prescribing to female patients of childbearing potential unless other treatments are ineffective or not tolerated. objective: to review the use of valproate in a well-defined population of at risk females with moderate to profound intellectual disability (id). identify the patients at risk and imbed the guideline into our practice. methods: a retrospective chart review was carried out of all girls aged between 6 and 18 years, attending the daughters of charity disability service (doc) in dublin, ireland. data such as diagnosis, valproate use, degree of id/gross motor function classification system (gmfcs), documentation of menarche and discussion regarding risk of valproate use were recorded. results: in total 9 females aged between 6 and 18 years where identified as currently using valproate out of 73 charts reviewed (12%). of the 9 patients identified, 2/9 had moderate id (gmfcs iii) and 7/9 had severe to profound id (gmfcs iv-v). 3/9 had menarche documented. 2/9 had the risk of valproate discussed. conclusions: in our cohort, a significant number of girls remain on valproate. 22% complied with new guidelines regarding discussions around the risks of valproate; highlighting the 78% of patients in need of counselling. an annual risk acknowledgement form was placed in their charts to prompt discussion next visit. in children with intellectual disability, conversations regarding contraception are difficult but essential. if valproate is used, then the risks must be fully understood by parents and carers. evaluation of the management of children up to age of 10 years with cerebral palsy in southend university hospital large district university general hospital against nice guidelines (nice guidelines ng62). methods: clinic notes of all 42 registered children with cerebral palsy (cp) up to 10 years of age as of june 2019 were included in the study. this was because there was no early data on children above 10 years age. results: 22 patients were age 0 to 5 years and 20 patients age 6 to 10 years. 15 were male and 27 females. 11 had hemiplegic, 3 quadriplegic, 18 diplegic and 10 dystonic cp. only 27 (64%) had gmfcs levels recorded. 11 (26%) were <28 weeks, 18 (42%) were 29 to 36 weeks and 13 (31%) were term. mri head findings: white matter changes including pvlin 29 (69%), 3 (7%) hie changes, 3 (7%) basal ganglia changes, 3 (7%) congenital brain malformation, 2 (4%) infarction. 1 migrated to area with no mri report. all the children received multidisciplinary team (mdt) input including physiotherapy. comorbidities werechildren on medications for gastro-esophageal reflux -9 (with 6 peginsertions). for epilepsy -5, for dystonia/spasticity -5, for constipation -12, for poor salivary control -2. behavioral issues noted in 7 and 1 was on adhd medications. 8 had botulinum toxin injections and 4 had selective dorsal rhizotomy for spasticity. documented discussion of diagnosis with family was in 28 (66%) patients and none in 14 patients (31%). only 50% patients had vitamin d levels checked. conclusions: management was in line with nice guidelines. they all had mdt input. there is a need to improve documentation of -evidence of discussion with parents, gmfcs level by age 2 ½ years plus, hip surveillance from age 2 years for gmfcs level iii to v and annual vitamin d levels especially for gmfcs level iii to v, peg fed and children on multiple anti-epileptic medications. poster no. 153 intracranial hypertension in children: an updated systematic review l di genova 1 , n desai 2 , s esposito 1 , p prabhakar 3 1 pediatric clinic, department of surgical and biomedical sciences, universit a degli studi di perugia, perugia, italy; 2 department of paediatric neurology, great ormond street hospital nhs foundation trust, london, uk; 3 neurosciences, great ormond street hospital nhs foundation trust, london, uk objective: our goal is to provide an overview on paediatric intracranial hypertension. methods: given that the last update of the diagnostic criteria of idiopathic intracranial hypertension was published in 2002, a thorough medline search of all english articles was conducted between 2002 and 2019. results: intracranial hypertension may be primary, with a paediatric annual incidence ranging between 0.63 and 0.71 per 100 000 children or arise from a secondary cause. misdiagnosis or delayed intervention can lead to poor quality of life and morbidity. in 2013, this condition was reconsidered, due to new accepted values for opening pressure and advances in neuroimaging; the importance to develop effective therapeutic strategies in order to prevent blindness was thus highlighted. to date, the main strategies described involved both medical and surgical approaches; nevertheless, there have been no paediatric intervention studies. disease monitoring plays a key role in the definition of the best timing and modality of treatment. recently, a risk stratification has been proposed with the aim to facilitate an adequate evaluation and proper care of children with intracranial hypertension: visual monitoring could represent an objective tool to manage these patients. in recent years, important evidence for the efficacy of acetazolamide emerged in the idiopathic intracranial hypertension treatment trial. surgical treatment is the modality of choice in children with worsening vision impairment, intractable headaches despite maximal medical management or in case of intolerance to medical therapy. conclusions: there are poor evidences about paediatric intracranial hypertension's outcomes. unfortunately, children's quality of life is heavily influenced by pain and permanent vision loss. standardized therapeutic strategies remains uncertain, highlighting the need for longitudinal studies to identify the best treatment in childhood. in order to alleviate symptoms and prevent permanent chronic sequelae, careful clinical evaluation and ophthalmological monitoring could be a useful guide to better manage this medical condition. objective: cerebral sinovenous thrombosis in childhood is a life-threatening neurological entity with uncertain epidemiology, potentially complicated by secondary intracranial hypertension. in the literature, there is a lack of evidence supporting the main strategies to approach both these medical conditions. our objective is to highlight the value of a prompt diagnosis aiming to define a tailored management approach based on children monitoring. methods: we review the main findings regarding cerebral sinovenous thrombosis and intracranial hypertension in children through illustration of a case with otogenic sinus thrombosis and secondary intracranial hypertension. results: a 7-year-old boy developed a local venous sinus thrombosis because of the spreading of a primary infective process from his middle ear into the sigmoid sinus complex, facilitated by anaemia and dehydration. the venous outflow disturbances led to secondary intracranial hypertension. the management aimed to treat cerebral thrombosis with anticoagulants and intracranial hypertension through medical and surgical strategies. the insertion of the lumbar-peritoneal shunt was necessary when medical approached failed and visual function deterioration was evident. careful clinical evaluation and ophthalmological monitoring helped us in the tailoring of the best treatment with the aim to alleviate symptoms and prevent sequelae of increased intracranial pressure. in the literature, no paediatric intervention studies regarding the main strategies to reduce intracranial pressure have been published. moreover, there is a lack of evidence supporting the safety of anticoagulation therapy, reducing the possibilities to safely manage cerebral thrombosis in childhood. conclusions: in children, a multidisciplinary approach is essential to manage both cerebral thrombosis and intracranial hypertension and ensure an optimal follow-up, aiming to prevent visual and therapy-related complications, possible relapses and their early diagnosis. from our perspective, monitoring our patient with clinical manifestations and visual status helped us to plan the best timing and modality of treatment and intervention. yearly rate of progression of fvc% predicted (available in n=260) was 3.6% in sma2 and 3.5% in sma3. in sma2, fvc% predicted declined steeply from 5 to 15 years of age, followed by a levelling. conversely, in sma3 patients fvc% predicted declined slower but steadily from 10 years of age. 136/298 (46%) sma2 and 8/71 (11%) required non-invasive ventilation due to respiratory infections or hypoventilation conclusions: the results of this ongoing collaborative work suggests that in sma2 and 3 lung function declines from age 5 and 10 respectively. lung and motor function correlate well in both sma2 and 3. this data will help the assessment of the long-term efficacy of new treatments for sma this review aims to study the appropriateness of mri brain referrals following implementation of local changes to improve compliance to the nice cg150 standard. methods: following an earlier survey (es; 01/06/16 -30/06/ 17) of mri brain referrals for headaches in children over 12 years, key recommendations included adding pop-ups in the neuroimaging request system (ice) of nice cg150 and headsmart clinical guideline v2 as well as verbal consent obtained from senior paediatrician before request was made. following these implementations, requests for mri brain were analysed during 01/06/2018 -31/12/2018 in the same district general hospital. referral was deemed compliant if the nice guideline cg150 standard were met. results: 50 children were referred for mri brain scan (mean 7/ month vs 10/month in es). 43 (86%) referrals were compliant (vs 67% compliance in es). 13 (26%) referrals were 'urgent' (vs 30% urgent es) and 37 (74%) 'routine' or non-urgent (vs 68% routine es). 12 (92%) of urgent referrals (vs 35% es) and 31 (84%) of routine referrals (vs 65% es) were compliant mri brain guidelines for neuroimaging in less than 12 years exist (headsmart clinical guideline v2 and nice epilepsy qs27) but are limited. this study aimed to assess current practice of mri brain referrals in children under 12 years. methods: retrospective review of mri brain referrals in children under 12 years performed between mri brain scans were done (m:f 1.1:1) 92 (43%) referrals under headsmart and 33 (36%) of these were urgent requests; significant brain abnormality was seen in 26 (79%) in urgent and 1 (0.01%) in nonurgent cases. 45 (21%) referrals under epilepsy qs27 and 12 (27%) were urgent requests; significant brain abnormality in 2 (17%) in urgent and 2 (6%) in non-urgent cases. 78 (36%) were miscellaneous requests and 24 (31%) were urgent; significant brain abnormality in 8 (33%) in urgent and 13 (24%) in non-urgent cases. overall mri brain showed significant abnormality in urgent requests (52%) compared to non-urgent requests (11%) poster no. 147 investigating factors that influence unplanned admissions and a&e attendances in those with pre-existing neurological conditions in childhood s dowsell 1 , k kananaviciute 1 , r parslow 1 , am childs 2 1 university of leeds, leeds, uk; 2 paediatric neurology, leeds general infirmary, leeds, uk objective: previous papers have shown increasing demands and costs to the nhs in relation to the inpatient care of children with neurological conditions. unplanned admissions may reflect a lack of effective care and have been shown to correlate with high outpatient clinic did not attend (dna) rates 2. the aim of this study was to determine factors underlying unplanned admissions and accident & emergency (a&e) attendances in a cohort of patients under the care of the leeds regional paediatric neurology service over a 3-year period. methods: all children <18 years who had paediatric neurology outpatient appointments in 2013 were identified using hospital databases. clinical and demographic data was extracted from electronic case notes. those without a definitive neurological diagnosis or who had moved to adult services during the study period were excluded. the cohort was cross referenced to a&e databases and admission records from 2015 to 2018. poisson regression was used to identify any correlation between specific predetermined factors to assess their influence on a&e attendance and admission rates. results: a cohort of 291 patients was established and 53 had a total of 82 unplanned admissions during the study period. 183 patients had a&e attendances with a total of 570 attendances. higher dna rates, younger age and certain diagnostic categories correlated with increased rates of unplanned admissions. the role of emergency care plans in preventing admission was unclear as only 27/147 patients with epilepsy had care plans in place. conclusions: this study confirms the association between increased rates of a&e attendances and unplanned admissions in children with specific neurological disorders and high dna rates. this is relevant for service planning as it highlights the need to target scarce resources towards 'higher' risk patients with more complex diagnoses where more integrated care and support may prevent or reduce unplanned hospital attendances.poster no. 148 audit comparing great ormond street hospital headache clinic diagnoses and management of patients aged 12 to 17 years to nice clinical guidelines a ward 1,2 , p prabhakar 1 1 neurology, great ormond street hospital, london, uk; 2 university of glasgow, glasgow, uk introduction: between 16/4/18 and 15/4/19 the gosh headache clinic saw 85 new patients aged 12 to 17 years. the nice clinical guideline 150 (cg150) on the diagnosis and management of headaches in over 12s covers tension-type headache, migraine, cluster headache and medication overuse headache. this audit aims to compare gosh diagnosis and management to those of the cg150. methods: using the patient list from the headache clinic data was gathered by accessing outgoing clinic letters via epic. raw data was collected on; age, gender, description of headache (pain location, quality, intensity, duration and frequency) and associated symptoms, triggers, previous imaging, previous and current treatments. the management data collected include: diagnosis and treatments offered, as well as whether gosh offered lifestyle advice, psychology, occipital nerve block or riboflavin. this data was then compared to cg150. results: 37 (62.7%) of diagnoses made by gosh matched the cg150 diagnosis. 22 (37.3%) diagnoses differed, with 14 of these due to discrepancy between chronic/episodic and/or presence of aura and 6 due to the vague diagnoses of migraine-type, new daily persistent, migrainous etc. fitting the cg150 definition of chronic migraine. all but one patient was managed in line with the guidelines. 76.9% of patients had brain imaging prior to attending the clinic, with 21.7% of these reporting positive findings. discussion: despite 22 patients' diagnosis differing between gosh and cg150, all but one patient was managed in line with the guidelines. this is likely due to nice recommended management being the same for any type of migraine. improvements could be made in documentation of frequency and duration of headache and aura, as well as more routinely offered lifestyle advice, psychology and riboflavin recorded in outgoing clinic letters. objective: to review the purpose of ct head requests from emergency department of a busy tertiary hospital as part of quality improvement. due to increasing evidence of ct scan radiation predisposing to leukaemia and brain tumours, it is best to keep ct scans to the minimum if clinically indicated. this project reviewed the indications for ct head and also looked at patients who had repeated ct or mri head scans within 3 years. methods: data was collected retrospectively looking at a snapshot period of 3 months between september-november 2018. patients were <18 years of age and they had a ct head from emergency department at king's college hospital, london. trauma patients were excluded. data was collated with aid of the neuro ct department 'cris' system. results: out of 56 patients, reasons for ct included: head injury (29), ventriculo-peritoneal shunt blockage (13), refractory seizures/status epilepticus (5), space occupying lesion (5), orbital cellulitis (1), intracranial haemorrhage (1) objectives: mutations in kif1a are associated with a wide range of neurological disorders, ranging from hereditary spastic paraparesis (hsp) to sensory neuropathies to a severe infantile neurodegenerative disorder. collectively, they are extremely uncommon but likely to be under-recognised. we aim to report the spectrum of kif1a-related disorders from a single tertiary neurology centre, with a view to improving understanding and awareness of these rare conditions. methods: affected individuals known to great ormond street hospital were identified through liaison with consultants involved in the care of children and young people with movement disorders. clinical information was collected through a retrospective review of case notes. results: twelve individuals in 9 families were identified. all had heterozygous kif1a mutations including three previously unreported variants. severity ranged from a fatal neonatalonset disorder with contractures, absence of visual development, and agenesis of the corpus callosum on mri to hsp with preservation of ambulation into the second or third decade of life and entirely normal mri. upper motor neuron signs were found in 10/12 children and a primarily sensory neuropathy was present in 9/11 children assessed. 3/12 children also had extrapyramidal signs (dystonia). some degree of learning difficulties and/or disorders of mood or behaviour were present in all children. optic atrophy, mr brain white matter changes and epilepsy were also common, especially in those children who were more severely affected overall. conclusions: kif1a related disorders are so diverse that it is arguably misleading to consider them as a single disease entity. features common to the majority of affected patients include upper motor neuron involvement, and neuropathy (even in the absence of an obvious sensory deficit), with high risk of other neurological and neurobehavioural comorbidities. objective: ataxia with oculomotor apraxia type 2 (aoa2) is a slowly progressive, autosomal recessive disease characterised by the triad of ataxia, oculomotor apraxia, and sensorimotor neuropathy that results from mutations in the gene encoding senataxin (setx), a dna/rna repair protein essential for genomic stability. we investigated a 16-year old male with a history of unsteady gate for genetic and molecular changes associated with aoa2. in this report we describe a case of aoa2 with two clear pathogenic setx mutations, one of which is novel, as well as two further setx changes likely to be in cis polymorphisms that have previously been reported as pathogenic. methods: two independent lymphoblastoid cell lines obtained from the patient were used for western blotting of senataxin and protein markers of other autosomal recessive cerebellar ataxias. the setx gene was sequenced to identify possible disease-causing mutations. results: western blotting showed reduced levels of senataxin. serum afp level was elevated at 15lg/l (normal 0.0-7.0lg/l). genetic sequencing revealed two clear pathogenic setx mutations. one of these was a novel mutation, c.2990delg; p.(cys997phefster32), a deletion causing a reading frameshift resulting in truncation and loss of expression of senataxin protein from this allele. the other, c.6638c>t; p.(pro2213leu) was a missense mutation within the helicase domain which has previously only been reported in the homozygous state in a japanese aoa2 patient. two further sequence changes, c.1807a>g; p.(asn603asp) and c.1957c>a; p.(gln653lys), were also identified in our patient. conclusions: the reduced senataxin expression and elevated afp levels support a diagnosis of aoa2 in our patient. genetic analysis found a novel pathogenic mutation and documented the first case of another pathogenic mutation in the helicase domain outside of japan. the case contributes to the growing diversity of setx mutations known to be responsible for aoa2. key: cord-015372-76xvzvdg authors: nan title: national scientific medical meeting 1996 abstracts date: 1996 journal: ir j med sci doi: 10.1007/bf02945204 sha: doc_id: 15372 cord_uid: 76xvzvdg nan zero months months months months group a 5.53 5.09* 5.66** 6.11"* 6.26** 4 zero months group b 6.06 6.4** values are means; *p<0.05 and **p<0.0l~ most other studies show neutral effects on insulin sensitivity, with minimal incidence of glucose intolerance. this may be partly explained by the diversity of age, diagnosis (whether insufficiency or deficiency state), other pituitary deficiencies and replacement therapy, and possibly by dosage ofgh utilised in these studies. clostridium difficile-associated disease (cdad) is primarily a nosocomial condition. community-acquired disease has been described but the incidence is low "). during a recent outbreak, we prospectively reviewed all new cases of cdad to determine what proportion of cytotoxin positive cases were community or hospital acquired. during a 4 month study period, 73 cases were identified. history of diarrhoeal episodes were recorded for each case. selected isolates were typed using pyrolysis mass spectrometry (pms). community-acquired cdad was defined as diarrhoea, on or within 72 hours of admission, in association with a positive stool cytotoxin test for c.difficile and in the absence of hospitalisation within 60 days. sixty-five cases (89%) were hospital acquired. fifteen patients (20.6%) had cdad on admission; 8 (11%) were community acquired, 7 (9.6%) had been recently hospitalised (4 at st. james's hospital, 3 at other hospitals). pms typing of faecal isolates revealed that 2 predominant strains were responsible for the hospital outbreak; one of these strains was also isolated in community-acquired cases. this study suggests that the incidence of communityacquired cdad may be higher than previously reported. we suggest that all newly admitted or transferred patients with diarrhoea should be screened for this organism. several studies have confirmed that activated protein c resistance (apc-r) occurs in 20-60% of thrombosis patients and is therefore more common than congenital deficiencies in the inhibitors of coagulation such as atii1, proteins c and s. homozygosity for the factor v (fv) gene mutation is associated with a 50-100 fold increased risk of venous thrombosis while heterozygosity is associated with a 5-10 fold increased risk. the mutation, however, is highly prevalent in the general population, a prevalence of 5% has been reported in several european countries. its frequency in the population of northern ireland (ni) has not yet been reported. we screened a group of 72 generally healthy elderly individuals (av. age 81.3; range 76-97 yr on several occasions for apc-r using an assay based on the prolongation of activated partial thromboplastin time by the addition of apc. a mean ratio of 2.64 (range 1.72-3.46) was measured. seven individuals (9.8%) had ratios <2.3 (av. 2.11; range 1.72-2.28). these subjects were then analysed for the fv mutation by pcr amplification and restriction analysis. the 4 individuals with the lowest ratios (av. 2.0; range 1.72-2.15) were found to be heterozygous for the mutation. none of these 4 individuals were deficient for protein c, protein s or atiii. the frequency of apc-r (5.8%) within this ni elderly group is similar to that reported by others in the uk whose studies would have included a generally younger population. the successful ageing of these individuals perhaps underlines the low risk associated with heterozygosity. alternatively a higher prevalence of the mutation may exist in the general population of ni, where the incidence of heart disease is one of the highest worldwide. the insulin-like growth factor ii gene (igf2) is imprinted. thus, in contrast to most genes where both maternal and paternal copies (alleles) are transcribed into rna and expressed, 1gf2 is normally only expressed from the paternal copy (monoallelic expression). alterations causing biallelic expression of igf2 may lead to excess growth factor production, and thus, to tumourigenesis. this study evaluated igf2 expression in a series of childhood cancers. to date 41 tumours have been evaluated using pcr based methodology (26 wilm's tumours, 12 rhabdomyosarcomas, 3 miscellaneous). dna was extracted and a polymorphic site apal within the igf2 gene was amplified and digested. this identified 10 samples as heterozygous for igf2, meaning that separate maternal and paternal alleles were distinguishable. rna from these informative samples was extracted, pcr amplified and restriction digested, to identify monoallelic versus biallelic profiles at the expression level. samples with normal imprinting (monoallelic) displayed allele a (236bp) or allele bl/b2 (176/63 doublet). biallelic samples displayed both alleles. using this approach 3/5 informative wilm's tumours and 2/ 4 rhabdomyosarcomas demonstrated biallelic expression. in conclusion, biallelic expression of igf2 was detected in a significant number of wilm's tumours and rhabdomyosarcomas, and should be considered; with other genetic alterations, as a candidate mechanism in tumourigenesis. the proinflammatory cytokines, tnf~, il8 and il-6, may mediate host metabolic and immune responses to cancer possibly leading to paraneoplastic phenomena such as cachexia. the cellular origin of these cytokines in the cancer patient, in many cases, remains unknown. we examined proinflammatory cytokine levels intracellularly, using flow cytometry, in pbmcs from oesophageal cancer patients (n=14) and age and sex matched controls (n=10). tnf~ and il-6 levels were significantly increased (p<0.05) in pma stimulated t cells and monocytes from the cancer patients when compared to the healthy controls. these results were confirmed using standard elisa assays. following cotlagenase digestion, increased levels of tnfa and il-6,were detected in oesophageal tumour infiltrating t cells when compared to cells from normal mucosa. there was also increased production of tnf~ and il-6, but not il-ib, in malignant epithelial cells when compared to normal and halothane and maintained by 50% nitrous oxide-oxygen, 0.75-1.5% halothane, with spontaneous ventilation. tc rose marginally in group 1 and fell in group 2 (not significant, ns). tp in groups 1 and 2 at induction and 20 and 30 minutes were, respectively, (mean + sem, celsius) 31.4+0.33 vs 31.6+0.3, ns; 33.9+0.3 vs 33.4+0.3, ns and 34.5+0.4 vs 33.2+0.3, (p<0.05). overall incidence of shivering-was 14.%, but not significantly different between the groups. the data suggests that preemptive application of the space blanket increases tp in paediatric patients during general anaesthesia and tends to conserve tc. chronic actinic dermatitis (cad) an uncommon, eczematous, photosensitive eruption is diagnosed on history, clinical examination, skin biopsy and abnormal light tests. drug induced photosensitivity may look identical clinically, have a similar history and patients with cad may be treated with potentially photosensitising drugs. we therefore reviewed all patients with cad and compared their monochrumator light tests with patients who had drug induced photosensitivity. phototesting was performed on unaffected skin of the back with an irradiation monochromator; the minimal erythema dose (med) determined for a series of wavelengths between 300 and 400 nm, in 14 patients with drug induced photosensitivity and 7 patients with cad. of ten females, four males with drug induced photosensitivity, age range 40-77 (mean 61 yrs), ten (71%), were photosensitive in the uva range (320-370nm), the implicated drugs including, quinine, sparfloxacin, amiodarone, doxycycline, mefenamic acid, nalidixic acid, fenbrufen, diclofenac, enalpril and prochlorperazine maleate. three patients with rosacea were photosensitive to doxycycline. the re/nainder (29%), were tested after discontinuation of the drug and their light tests were normal. in the cad group, (four males and three females), age range 38-86 (mean 71.5 yrs), three patients (43%), were sensitive to uva, uvb and visible light, four (57%) to uva and uvb. in conclusion, uva dissociated from uvb photosensitivity seems a relative but not absolute sign of drug induced photosensitivity. this pattern of light tests should prompt a detailed drug history to elucidate the causative agent. phototesting should be performed while on the offending drug as testing days or weeks after discontinuation will give normal results. patients at risk of bone fractures by measuring bone mineral density (bmd) and markers of bone turnover and to assess the correlation of these with the severity of cld. twenty three patients with cld had bmd measured by dual-energy x-ray absorptiometry scanning of hip and lumbar spine. bone formation was assessed using serum levels of procollagen type 1 peptide, osteocalcin and bone alkaline phosphatase, and bone resorption was assessed using 2 hour urinary excretion of hydroxyproline, pyridinoline and deoxypyridinoline. 48% and 39% of patients had evidence of osteoporosis at the lumbar spine and femoral neck respectively. biochemical results showed that 74% of patients had an increase in all 3 bone resorption markers and 42% had an increase in markers for bone formation. bmd at the lumbar spine was lower in patients with cholestatic liver disease compared to patients with other types of'liver disease (p=0.004). no correlation was found between bmd and patient age, bilirubin, albumin, inr or duration of liver disease. conclusions: osteopenia occurs in up to 62% of patients with cld due to a high bone turnover state where bone resorption exceeds formation. osteoporosis is most severe in those patients with cholestasis. a detailed profile is presented of all 632 leukaemia and multiple myeloma (icd-o code 169) patients registered by the southern tumour registry during the 8-year period 1983/1990 "). annual age-adjusted rates of 13.9 and 8.7 per 100,000 were seen for males and females respectively. these levels indicate a lifetime (up to 75 yr) risk of 1 in 68 for males and 1 in 116 for females. the main morphological sub-types registered were multiple myeloma (31%), cll (25%), aml (18%) cml (9%) and all (8%). one, two and five-year survival rates were examined; age at diagnosis and lesion type were extremely significant factors in relation to patient outcome. the overall incidence levels indicate that irish rates were relatively high by internatiomil standards r we assessed effects of reducing the volume of hyperbaric bupivacaine by giving half the volume as isobaric bupivacaine. when using 0.5% hyperbaric bupivacaine for spinal blockade, the segmental spread and cardiovascular effects of the block have been shown to be dependent on the volume of local anaesthetic injected. 40 patients undergoing elective surgery were studied in a prospective, randomised, double-blind trial: group 1 (20 patients) received their local anaesthetic as two equal aliquots of 0.5% hyperbaric bupivacaine and 0.5% isobaric bupivacaine respectively; group 2 (20 patients) received their local anaesthetic as two equal aliquots of 0.5% hyperbaric bupivacaine. there was no significant difference found between the two groups with regard to maximal height of block (group 1, mean (range), t7 (t4-ti 1); group 2, t8 (ts-t11)), rate of onset of blockade, or time to maximal blockade (group 1, mean (sem), 23.55 (2.41) rain; group 2:20.89 (2.95) min). there was no difference found between each group in either cardiovascular stability or vasopregsor usage. the administration of a mixture of 0.5% isobaric bupivacaine and 0.5% hyperbaric bupiv/~caine confers no advantages over administration of the same volume of 0.5% hyperbaric bupivacaine alone. propofolis used as a sedative during regional anaesthesia. providing titrateable sedation, it can compromise haemodynamic stability. a propofol ketamine combination provides stable haemodynamics during total intravenous anaesthesia, avoiding emergence phenomena m. we compared two sedative regimes in patients having spinal anaesthesia. following informed consent, 40 patients, asa i-ii, undergoing spinal anaesthesia were randomized to one of two groups (n=20). group i (propofol-ketamine) received loading doses of 0.4mg/kg propofol, 0.1mg/kg ketamine followed by an infusion of 1.2mg/kg/h and 0.3mg/kg/h respectively. group ii (propofol) received bolus 0.5mg/kg and infusion 1.5mg/kg/h. subsequent infusion rates were titrated to effect using a sedation score. heart rate, blood pressure, oxygen saturation, end tidal c02 and oxygen requirements were recorded. observation continued for the recovery period and patients visited the following day. data were analysed using t-test, chi 2 test and anova. groups were demographically comparable. sedative and respiratory indices were similar for both groups. there was no difference in total propofol requirements between the groups; group i -146_+194mg, group ii -137_+1:52mg (mean _+ sd). there was a large difference in mean arterial pressure, being much lower in the propofol only group. both groups had an uneventful recovery without emergence phenomena. our results do not confirm the described additive effect of andketammc . ketamine.with propofol for sedation propofol ' =~2) confers haemodynamic stability during spinal anaesthesia. we designed a controlled study to investigate whether there is a direct relationship between the degree of postoperative pain and the development of negative middle ear pressure in adults following tonsillectomy. middle ear pressure was measured by tympanometry. pressures were classified as type a (o to -99 mmh20), type b (flat) or type c (-100 to -350 mmh20) tympanograms. 30 patients with type a tympanograms, undergoing tonsillectomy were enrolled in the study. patients had daily tympanometry whilst in hospital and then weekly until amrmalisatign. a questionnaire incorporating visual analogue pain scores was filled in at the same time. a control group of 26 patients with type a tympanograms, undergoing appendicectomy and endotracheal intubation was used. follo~v up was available on 26 patients. 13 patients (50%) developed type c tympanograms, 5 patients 09%) type b and 8 (31%) patients remained unchanged. no member of the control group developed any change in middle ear pressure (chi squared = 27.5, p < vol. 165, 1996 irish journal of supplement no. 2 medical science 0.001). there was no relationship between pain scores for throat pain or otalgia and the development of negative middle ear pressure. 8 patients recorded higher pain scores for throat pain at day 7 then day 1, only 3 of this group had negative middle ear pressure. middle ear pressure reverted to normal at day 7 in 15/18 patients and in the remaining 3/18 it was normal at day 14. this study demonstrates the development of transient negative middle ear pressure following tonsillectomy in 69% of patients. this change is unrelated to the degree of postoperative pain nor is it associated with otalgia. postoperative ward analgesia remains suboptimal. this may be partially related to inadequate early use of opioids to attain minimum effective analgesic concentration (meac). we examined the incidence and predictors of severe postoperative pain on admission and discharge from our postoperative recovery room (rr). verbal pain scores were obtained in a pilot study of 202 patients on rr admission and discharge. procedures were classed as open cavitary, laparoscopic, orthopaedic, ent or body surface surgery. intraoperative use and dosage of narcotics and nonsteroidal (nsaid) analgesics, anaesthetists' experience (prefellowship or post-fellowship nchd, consultant) were noted, and rr opioid usage recorded. pain scores and analgesic use were examined using mann-whitney, ~2 analysis and logistic regression. moderate or severe pain was experienced by 25% of patients on either arrival or discharge. median intraoperative morphine dosage was 5 mg. opioid use was slightly (median morphine dosage 8 mg, p < 0.05) higher in patients undergoing cavitary surgery; these patients had the highest pain scores on rr arrival and departure. 21 patients (10%) received > 10 mg morphine intraoperatively. discharge scores of 6/10 or higher occurred in 24 patients (12%). opioid usage and pain scores were unrelated to level of training. nsaid use/nonuse was unassociated with differences in opioid use or rr pain scores. no morbidity attributable to analgesic use (desaturation, slow respiratory rate) occurred. nonattainment of meac is frequent after open cavitary surgery. conservative opioid dosages continue to be employed despite inadequate early postoperative pain relief; this does not change with increasing experience. reporting such findings in departmental audit may help to alter perioperative management; such data may serve as a baseline for future interventional studies. diclofenac is frequently used for analgesia after tonsillectomy. recently concern has been expressed about the effect of diclofenac on prolonging bleeding time. one recent retrospective study found its use in tonsillectomy was associated with an increase in reactionary haemorrhage. we designed a randomised controlled study to compare the effects of rectal diclofenac and im pethidine given at induction with pethidine alone, in children undergoing tonsillectomy. fifty nine patients were entered into the study. there were 26 males and 33 females, mean age 6 years, range (3) (4) (5) (6) (7) (8) (9) (10) (11) (12) (13) . patients were randomised according to chart number. thirty five patients received rectal diclofenac after induction. twenty four patients acted as controls. there were no significant differences in operating time or operative blood loss between the two groups. in the recovery room the diclofenac group was significantly less restless than tl~e control group (p < 0.05, chi squared test), with less crying, movement and agitation. there was no difference in postoperative recovery and no primary or reactionary haemorrhage. one patient in the diclofenac group developed a secondary haemorrhage. this study demonstrates a significant reduction in restlessness in the recovery room in children receiving rectal diclofenac. no increase in reactionary haemorrhage was demonstrated. diclofenac remains a safe and effective analgesic agent in children undergoing tonsillectomy. elderly patients have decreased dose requirements for many drugs compared to the young. few studies have examined dose requirements of opioids in the elderly when administered via patient controlled analgesia (pca) 1. we compared the pca morphine requirements between young and elderly patients. records were retrospectively analysed from 1,000 consecutive patients receiving pca for post-operative pain. inclusion criteria (i) age less than 10 years or greater than 60 years, (ii) upper abdominal surgery, and (iii) morphine pca usage. 238 patients fulfilled the inclusion criteria. 89 patients were young and 149 were elderly. the mean age in the young was 29 years and in the elderly was 69 years. 51% were female in the younger group, 40% were female in the older group. pain scores at rest and on movement were similar in both groups 3.8 and 6.7 respectively in the young, 3.2 and 6.2 in the elderly. (p > 0.05, students t-test). morphine usage over 48 hours was 58 + 32.1mg in the young, and 37 + 20.3 in the elderly. (mean + s.d.) (p.< 0.05, students t-test). elderly patients required significantly less morphine via pca to achieve the same pain scores as the young. these findings are consistent with studies showing decreased requirements of other drugs in elderly. the erythrocyte sodium-lithium countertransport (slc) is abnormal in essential hypertension and some other forms of cardiovascular disease (cvd) but the considerable overlap in its activity in patients with these conditions and in normotensive healthy subjects remains a strong point against its possible utility as a marker for cvd. we sought to address this issue in greater detail. twenty-nine hypertensive patients (19 with family history of cvd) aged 56.4+1.9 years (mean + se) and 32 normotensive subjects (12 with family history of cvd) aged 45.9 + 1.9 years, participated after informed consent. slc were determined in 35, 50, 70, 100 and 140mm sodium chloride; and the vmax and km of the transporter determined. hypertensive and normotensive individuals with family history of cvd (n = 31) had higher slc activity (0.331 + 0.011 vs 0.238 + 0.011, p < 0.0005), greater vmax (0.473 + 0.019 vs 0.397 + 0.018 mmol/lcell.h, p < 0.006) and lower km 56.0mm (median) vs 95.5 (p < 0.001) than hypertensive and normotensive subjects without such a history (n = 30). however, none of these parameters was sufficiently discriminatory as evidenced by the considerable overlap in the scattergrams for the two groups. on the other hand not only was the median quotient vmax/km significantly different 7.89 vs 4.20 (p < 0.001), but also the scattergram separated the two groups. this may reflect an effect of hereditary factors on the identified rate-limiting step in the transport system. capsaicinadministration results in depletion of substance-p sensitive nerves. this study was carried out to observe the impact on the morphology of mitral valve endothelium. the experimental group received capsaicin i.p. on day four of life; control animals received drug vehicle only. animals were anaesthetised by chloral hydrate and hearts were removed following perfusion of 4% glutaraldehyde, and were routinely processed for scanning electron microscopy. normal endothelial morphology showed an ordered and structured pattern, with large raised nuclei covered in discrete microappendages: no zoning was observed over the valve surface. following capsaicin administration, valves were seen to be torn and possessed a denuded endothelium. nuclear bulges changed in both apparent height and area, with the surface partially denuded of microappendages. one month following systemic administration of capsaicin to neonatal rats, a serious alteration of mitral valve endothelium morphology and integrity had occurred. depletion of substance-p may have resulted in mechanical insufficiency of the mitral valve. this study was funded by the health research board. with expanding applications and increasingly aggressive stress protocols, concerns about the safety of dobutamine stress echocardiography (dse) have arisen. the purpose of this study was to analyse prospectively the safety, adverse event profile, and complication rate of dse. prospective data was recorded in a consecutive series of 309 patients undergoing dse for diagnostic evaluation of chest pain, for risk assessment following myocardial infarction or for detection of hibernating myocardium. the maximum dose of dobutamine used was 50 mcg/kg/min in 24.6% of patients and 40 mcg/kg/min in 73.1%. atropine was used in 6. 8% long-term outcome following coronary artery bypass grafting may be related to the prevalence of major risk factors and their treatment following surgery. we aimed to establish the prevalence and current management of coronary risk factors in a group of consecutive patients attending our hospital. this is a report of the first 100 patients. data was collected by a structured patient interview, chart review, physical measurements and blood sampling. there were 74 male and 26 female patients, average age 61.5 years. the mean length of time since surgery was 2.2 years. thirty-nine patients had a recurrence of angina and this occurred on average ll months after surgery. as regards risk factors, 22 were active smokers, 56 were ex-smokers and only 22 had never smoked. two thirds of the patients were taking regular exercise; only 6 took no exercise at all. seventy-two percent of patients had a cholesterol greater than 5.5mmol/l, yet only 10 of the patients were on lipid lowering drug therapy and a further 16 were on a lipid towering diet. twenty-nine patients had a systolic bp > 160 or a diastolic bp > 90 and 15 of these were on antihypertensive therapy. seventy-seven patients were overweight but most of these had received specific advice regarding weight reduction in the preceding year. our results show a high prevalence of treatable risk factors in this high-risk group with inadequate treatment in many cases. new combined primary and hospital care strategies for cardiac rehabilitation and long-term secondary prevention of coronary heart disease are required. if the goal of modern therapy of acute myocardial infarction (ami) is preservation of myocardium, the occurrence of cardiac failure could be regarded as a treatment failure. in recent studies of iv thrombolysis and primary ptca the frequency of left ventricular failure (lvf) following ami has been as low as 3.5%. this very low rate might be explained by selection bias in patients recruited to randomized trials. the purpose of this study was to examine the frequency of lvf in a consecutive alterations in nitric oxide (no) synthesis have been implicated in cardiomyopathy, ischaemic heart disease and septic shock. recent work has suggested a possible role for nitric oxide in cardiac arrhythmogenesis. the effects of inhibiting no synthesis with l-name (n c -nitro -l -arginine methyl ester) on cardiac electrophysiology have not been fully determined. the dominant frequency of electrically induced ventricular fibrillation was determined in l0 anaesthetised pigs (30-42 kg) using a fourier transform. the dominant frequency (7.8 _+ 0.5 hz in lead ii) was not altered by treatment (8.5 _+ 0.5 hz) with l-name in a group of 16 pigs (45-58 kg) the effect of l-name (10 mg/kg) was assessed in relation to energy required to defibrillate. there was no significant difference in the energies required to achieve successful defibrillation on 80% of attempts between the l-name group (104.9 _+ 8.0 j) and the control group (111.1 _ 11.9 j), and on 100% of occasions, l-name (122.5 + 11.5 j) and control (137.5 _+ 13.1j). the results show that inhibition of no synthesis has no significant effect on the dominant frequency of ventricular fibrillation or on the efficacy of defibrillation in the pig heart. received either 100mg (7pts) or 200mg (19 pts) oral flecainide followed by a maintenance dose of 100mg bd. all pts were euthyroid. none had significant hypertensive, valvular or ischaemic heart disease. 23 pts had normal echocardiograms, 3 had mildly dilated atria. of the 26 pts 17 (65%) converted to sinus rhythm, 15 within 72 hrs and 2 at 12 and 21 days respectively. 2 subsequently, he was found to have paralysis of all the muscle groups of his right upper limb apart from some flexor movements in his fingers with areflexia and sensory loss over the c5/c6 dermatomes. the findings were thought to be in keeping with a brachial plexus.lesion. an mri scan showed a "haematoma" or "fibrosis" around the brachial plexus~ emg studies revealed a complete lesion from c5/c7 with evidence of partial function at c8 and a good function at c4. despite physiotherapy, at follow up 2 months later there was no improvement in the emg findings. though brachia~ plexus injury has always been considered a complication of central venous line insertion <l), there have been no cases described, in the literature in the last 10 years. central lines are mandatory irt major surgical cases but one must always be aware of the possible complications caused by them. body weight (bw) in icu patients fluctuates due to alterations in body mass (1) and water (2) and is usually estimated rather than measured. we hypothesised that (i) estimated weights are inaccurate and (ii) changes in true body mass (tbm) are masked by changes in water content. on admission, icu patients whose expected length of stay (los) was > 5 days were placed on a bed incorporating 4 load cells (accuracy of _ 0.1 kg). bw was estimated by icu staff. mbw was then recorded 12 hourly under standard conditions. changes in mbw due to pack insertion/dressing changes were excluded. we calculated tbm as mbw minus cumulative fluid excess, corrected for insensible losses c2~. patients received standardized nutritional support from day 3 and urinary nitrogen on day 6 was calculated we studied 20 patients whose mean (sd) age, mbw, los and apache ii score were 44.3 yr (18.54), 70.5kg (14.39), 10.0 days"(6.78) and 18 (3.8) respectively. mean error in estimated weight on admission was 10.3% (nurses) and 12.2% (doctors). mean protein and calorie intake was 64g and 1670 kilocals/day. mean decrease in mbw during icu stay 0.22 kg/day (range 0.21 kg (gain) to 0.49 kg). mean reduction in tbm was 0.56 kg/day (range 0.28-0.86 kg/ day) and this correlated with urinary nitrogen loss (r=0.7). in icu, (i) estimated weight is significantly inaccurate and should not be used in physiological calculations and (ii) rapid and significant decreases in body mass occur which may be underestimated due to fluid accumulation. dopamine appears to influence pituitary function and is associated with decreased circulating human growth hormone and insulin-like growth factor i m which could exacerbate catabolism, and therefore wasting, during critical illness. at 12 hrly intervals from admission, patients whose expected length of stay exceeded 5 days, were weighed (measured body weight, mbw) under standardized conditions,-using a bed incorporating 4 electronic load cells (accuracy + o.1 kg). standard demographics, apache ii score and use of dot~amine by infusion was recorded. changes in weight due to removal./ insertion of prostheses, packs/dressings were excluded mbw was converted to true body mass (tbm) using measurements of cumulative fluid balance (1000 ml = 1 kg) and insensible lossr patients received nutritional support, starting on day 3, based on their admission mbw. there were no significant differences in mean age, weight, length of icu stay, admission apache ii scores and mean daily protein/calorie intake between 14 patients who had received dopamine by infusion (group d) and 18 who had not (group nd). mean (sd) decreases in mbw during icu stay were 0.42 (0.08) kg/day (group d) and 0.20 (0.05) kg/day (group nd) (p<0.0i). mean decrease in tbm was 0.55 (0.10) kg/day and 0.35 (0.07) kg/day respectively (p<0.05). thus group d were losing an additional 1.4 kg body mass per week relative to group nd. the use of dopamine by infusion is associated with an accelerated loss of lean body mass during critical illness. adhesion of polymorphonuclear leucocytes (pmns) to pulmonary endothelial cells is an initial step in the inflammatory process characterising the adult respiratory distress syndrome. previous studies using human umbilical vein endothelial cells (huvecs) have suggested that lipopolysaccharide (lps) is a potent stimulus for pmn adhesion to endothelial cells. the aim of this study was to investigate the effect of lps on pmn adhesion to human pulmonary artery endothelial cells (hpaecs). human pmns were coincubated with hpaecs _+ lps (0.001-10mg/ml) with 2% serum for 1 hour. the effect of phorbol myristate acetate (pma) (125 ng/ml) was also examined. percentage adhesion stimulated by pma was 66+10sd. lps did not significantly increase adhesion at any of the concentrations used. to confirm the activity of lps pmns were incubated at 37~ with 0.01-10mg/ml lps + 2% serum for 1 hour and labelled with flourescent antibodies to the mac1 adhesion molecule complex (cd 18/cd 1 lb). facs analysis indicated upregulation of both cd18 and cdllb. thus in the system used, lps did stimulate pmn adhesion molecule expression, indicating that the lack of adhesion reflects a difference in hpaec response to lps compared to that reported for huvecs. this work was supported by the health research board ireland. although inhaled corticosteroid therapy is of undoubted benefit in the management of asthma, dysphonia is a recognised sequela. this study was designed to examine longitudinally the effect of inhaled steroids on the voice and vocal cords of newly diagnosed and previously untreated asthmatics. twenty subjects were recruited and underwent voice and vocal cord assessment prior to and 3 months after starting inhaled steroid treatment. the assessment consisted of 1) rating dysphonia using a visual analogue scale, 2) acoustical analysis of the voice and 3) videostroboscopic examination of vocal cord activity. prior to commencing inhaled steroid therapy for their asthma 14 subjects had normal voices, 5 subjects were mildly hoarse and one was moderately hoarse. vocal cord pathology was noted in 12 subjects, 2 patients had vocal cord nodules and the remainder were noted to have mildly oedematous cords together with a glottic chink. at 3 month follow up, improvement in voice was noted in 2 subjects, one patient felt more dysphonic but there was no change in vocal cord appearance. one subject was noted to have developed a mid glottic chink with no associated change in voice. one subject had clearing of mild vocal cord oedema and improvement in voice. this study demonstrates that 60% of subjects commencing inhaled steroid therapy for asthma have mild vocal cord pathology. voice is more likely to be improved following use of inhaled steroids for 3 months then made worse. although the relationship between elastin degradation and emphysema is well known, recent evidence suggests that a more complex process of pulmonary remodelling occurs within the emphysematous lung. the aim of this study was to assess the extent of extracellular matrix remodelling by ultrastructural examination of its two major components, elastin and collagen. emphysema was induced in rats by the intratracheal administration of porcine pancreatic elastase (1.2u/g body weigh0 and human lungs were obtained at surgical resection for lung carcinoma. emphysema was confirmed histologically in both animal and human samples by measurement of the mean. linear intercept. matching sections were immersed in 2.5m naoh and 88% formic acid to digest elastin and collagen respectively. scanning electron microscopy with stereo-pair imaging allowed 3-d visualisation of elastin and collagen frameworks. the distribution of emphysema was primarily panacinar in rat lungs a'nd centriacinar in human lungs. as expected in both types of emphysema, elastic lamellae were disrupted and perforated with multiple fenestrations. accompanying this disintegration was a marked increase in thickness of collagen fibrils which in some cases coalesced irish journal of medical science imparting a sheet-like appearance to the airspace walls. unique to human centriacinar emphysema, collagen formed helices which spiralled around alveolar septae to form bulky walls between adjacent airspaces. in conclusion, these findings lend support to the novel concept of aberrant collagen remodelling in the pathogenesis of emphysema. small cell lung carcinoma (sclc) is the most aggressive of the four common cell types of lung carcinoma. less than 10% of patients with sclc are alive two years after diagnosis. staging procedures, treatment regimens and survival results were reviewed in a small regional centre to make a comparison with larger treatment centres. thirty-one cases of sclc seen by one physician from 1985 to 1993 were reviewed. staging was clinical. treatment was undertaken in conjunction with the local oncology and radiotherapy services. 42% of patients had limited disease where as 58% had extensive disease at diagnosis. in patients with limited disease, 20% were alive at 18 months and there was a 10% long term survival rate i.e. greater than three years. average length of survival in limited disease was 456 days. survival results were comparable with those treated with chemotherapy alone and combination chemotherapy and radiotherapy. in patients with extensive disease the best results were from those treated with a combination of chemotherapy and radiotherapy with art average survival of 353 days. these figures compare favourably with those from larger multidisciplinary centres. the factors contributing to our relative success may relate to continuity of care achieved in a smaller centre. nasal cpap is a very effective therapy for osa, but is cumbersome, and compliance varies. we prospectively evaluated 91 consecutive osa patients treated with ncpap, who were asked to complete questionnaires before, and 2 to 12 months after starting therapy. this stttdy intended to examine both the patient's subjective response to ncpap and their bed-partner's impressions also. replies were received in 84 (92%) patients. patients were divided i~to 4 groups depending on whether they had a bed-partner, and according to their response to an initiat question assessing overall improvement in sleep quality and daytime al'ertness with ncpap, ranging from 0 (minimal/none) to +4 (excellent). patients were called responders if they scored > 2. group a (45 pts, 54%) were responders with bed-partners; group b (10 pts, 12%) non-responders with bed-partners; group c (15 pts, 18%), were responders (12 pts, 14%) and nonresponders (3 pts, 4%) without bed-partners; and group d (14 pts, 17%) had stopped ncpap. nine questions were directed at the bed-partner, and assessed their perception of changes in both the patient's and their own sleep quality, daytime alertness, mood and quality of life, and also to changes in the relationship between patient and bed-partner following institution of ncpap. these questions scored from -1 (worse) to +3 (marked improvement). significant improvement in all parameters for the patient (mean + sd = 2.4 + 0.7) were noted in group a. in addition, group a bed-partners reported ~ubjective improvement in the same parameters (1.7 + 1.1). group b improvements were less, (1.8 + 1.0 in patients, and 0.6 + 1.1 in partners). overall, the data indicate a subjective success of therapy in 68% of patients, but the bed-partner's replies indicate this figure underestimates the true response rate. furthermore, the results show significant improvements in the bed-partner's sleep quality, daytime alertness, mood and quality of life, indicating that successful treatment of osa patients with ncpap also gives significant benefits to their bed-partners. vincent's hospital, dublin. neutrophil collagenase (mmp 8) is a member of the matrixmetalioproteinases (mmps), a family of highly homologous zinc endopeptidases which play a crucial role in many physiological processes. the aim of this project was to develop a purification system for mmp 8 from purulent sputum and raise polyclonal antibodies. after initial extraction, contaminating proteins were removed with a zinc chelate affinity column. mmp 8 was then separated, from another closely related mmp, gelatinase b, on a q sepharose ion exchange column using a nacl gradient. the final purification step was carried out with an orange sepharose affinity column. sds-page analysis indicated the presence of purified protein with bands corresponding to latent neutrophil collagenase (85kd) and products of coll~igenase autodegradation at lower molecular weights (55kd & 57kd). a 10fold increase in specific activity was observed, with a 20% final yield, which provided mg quantities of pure enzyme. this work is funded by forbairt and the. irish american partnership. cd30 is a protein first described as a surface marker on hodgkin's lymphoma cells. recently cd30 has been demonstrated on th2-type t lymphocytes (produce il-4, 5, 6, l0 and 13), which have a pro-inflammatory cytokine profile. but is not found on thl-type t lymphocytes (produce il-2 and ifn-gamma). its ligand, cd30l, has also been described, cd30-cd30l interaction has been shown to aid the development oft lymphocyte clones into a th2 rather than a th 1 phenotype. th2-type cytokines are inextricably linked to the aetiology of inflammatory airway disease. firstly we investigated serum cd30 levels in various patient groups. we have demonstrated significant differences in serum cd30 levels in the following groups, atopic asthmatics (mean = 149 iu/l, n = 62), non-atopic asthmatics (mean = 107 iu/l n = 13) and atopic rhinitis/dermatitis (mean = 90 iu/l n = 36) and normal controls (mean = 14 iu/l, n = 9). secondly we cultured peripheral blood mononuclear cells from allergic individuals and normals. when these cultures were stimulated with house dust mite antigen (der p 1) and il-2 or der p 1 with both il-2 and i1-4, surface expression of cd30 on t lymphocytes could be demonstrated using fluorescent staining and flow cytometric analysis, after 9 days culture in the allergic individuals but not in normals. the presence of i1-4 in the culture increased the degree of surface cd30 expression. these results are important as they show that allergic individuals have an expandable population of memory t lymphocytes which respond to allergen by expressing cd30 and developing th-2 phenotype. most work on cd30 and th-2 cytokines has hitherto been carried out an t cell clones. we have developed a relatively simple in vitro system of looking at t lymphocyte response to allergen which will allow the testing of novel therapeutic interventions with a view to modulating the immune response in allergic disease. our work also suggests that even non-allergic patients with inflammatory airway disease may have increased th2 activity, which has not been shown previously. scimitar syndrome is a rare congenital disorder consisting of a spectrum of abnormalities including hypoplasia of the right pulmonary artery, dextroposition of the heart, anomalous pulmonary venous drainage of the right lung into the inferior vena cava and anomalities of the right diaphragm. bronchiectasis and respiratory tract infections on the right side are the usual clinical presenting features. a 70 year old male patient was referred to the outpatient clinic with a history of recurrent chest infections which were slow to resolve following antibiotic therapy. physical examination revealed decreased air entry, coarse crepitations and a prolonged expiratory wheeze in the right lower lobe. the only abnormalities on routine biochemical and haematological screening were an elevated esr of 69 and a slightly raised white cell count of 15. a chest x-ray revealed hypoplasia of the right lung when compared to the left. in addition to this there was a vascular shadow present in the right lower robe representing an anomalous pulmonary vein which appeared to drain to below the diaphragm on the night side. bronchoscopy showed a normal left bronchial tree. on the right, no apical segment was detected in the right lower lobe. otherwise no endobronchial lesion was seen. a dynamic computerised axial tomographic scan of the thorax was performed. this showed a dilated anomalous right lower pulmonary vein which was clearly seen to enter the inferior vena cava below the diaphragm. in addition the right lung was again noted to be hypoplastic when compared to the left. these findings were pathognomonic of the scimitar syndrome. "the patient was treated symptomatically and is presently stable. conclusion: scimitar syndrome, with its wide spectrum of abnormalities should be considered when reviewing plain chest x-ray in patients with recurrent right lower lobe respiratory tract infection. recent studies indicate that the ability of circulating neutrophils to regulate surface levels of adhesion molecules may be altered in disease situations. the aim of this study was to determine if changes in neutrophil responsiveness accompanies chronic inflammation in cf. neutrophils in blood samples from 17 cf patients and 13 age-matched control subjects were analysed by flow cytometry for expression of l-selectin and mac-1 (cd1 lb) following stimulation by interleukin-8 (il-8) and fmlp. as expected, both il-8 and fmlp provoked a decrease in surface levels of l-selectin and an increase in cdi lb levels. however, the magnitude of these changes was significantly lower in cf patients than in control subjects (table) . these results suggest that chronic exposure to inflammatory stimulii in vivo may alter neutrophil responsiveness in cf. given the emphasis on rational prescribing, we reviewed drug use in a 208 bedded long-stay unit. prescribing patterns were analysed on an appointed day thereby obtaining a "snapshot" of prescribing practices. one hundred and ninety four long-stay residents, with a mean age of 78, were on 1188 drugs, the maximum number of drugs per patient was 12, the minimum 1 and the average 6.1. sixty percent of prescriptions fell within one of the following therapeutic categories:-central nervous system (cns) preparations (321 prescriptions), analgesics (145), gastrointestinal preparations (139) and cardiovascular preparations (i 25). there were 19 ,prescriptions for respiratory drugs and only 36 prescriptions were for antibiotics. the most commonly prescribed cns preparations were anti-psychotics (127), benzodiazepincs (1 t 3), anti-depressants (30). 43% of all analgesics prescribed (63) were nsaids. the most commonly prescribed h2 blocker was cimetidine (33). nuseals aspirin (43), digoxin (35) and captopril (24) were the most commonly prescribed cardiovascular drugs. 25% of drugs were issued on an as required basis, i.e. "prn". the most commonly prescribed prn therapeutic classes were analgesics (100 prescriptions) followed by gastrointestinal (74) and cns preparations (68). these results contrast with prescribing patterns in hospitals and general practice and may provide an insight into the challenges and realities of management in long-stay units. supported by the health research board. evaluation of physician requests to hospital based clinical pharmacist for (1) drug information, (2) possible adverse drug reaction (adr) was undertaken over a two year period from jan '94 to dec '95 (admissions -1,667, opd attendances -5,908). overall 55 requests were made. (1) drug information: advice/information on new drugs, formulation, dosage, safety consideration prior to drug prescribing was given in 23 cases. (2) suspected adr: a total of 32 suspected adverse drug reactions were investigated. in 4 cases, no adr link was established, after extensive literature/data base search. adr's were confirmed in 28 cases of which 11 were reported to n.d.a.b. regular on-going interaction between physicians and clinical pharmacy allowed critical analysis of new drugs and heightened awareness of, potential adverse drug reactions in current clinical practice. we previously demonstrated that commonly prescribed medications are not easily identified by patients, doctors or nurses in the hospital setting o,2~. we then investigated the ability of hospital pharmacists, 33 in all, to identify the same 12 commonly prescribed branded and generic drugs. correct identification as follows:-bendrofluazide k (32/33), cimetidine (33/33), diazepam 5mg (31/33), diazepam 5mg generic (30/33), digoxin (24/33), ferrous sulphate (14/33), frusemide (16/33), mefenamic acid (33/33), paracetamol (27/33), prednisolone (1 l/ 33), temezepam (33/33), theoph3/lline (25/33). pharmacists had 78% correct answers compared with 62% for nurses and 42% correct for doctors. the pharmacists had no difficulty recognising drugs with brand names written on them e.g. cimetidine, but like nurses and doctors had difficulty identifying the plain white tablets e.g. prednisolone. generic drugs were tess well recognised. a number stated that they were unwilling to definitively identify medication with no clear marking. pharmacists were also asked to list the top 5 prescribed drugs, l0 got 1/5 correct and 23 got 0/5 correct. in contrast 36 out of 80 doctors got 1/5 correct, 25 got 2 right and only 4 got 3 right. we conclude that hospital pharmacists are generally better than doctors or nurses at identifying commonly prescribed drugs but their knowledge of the top 5 prescribed drugs is not as good at that of doctors. all professionals need assistant in this important task. suggesting reduced activity or more iranians with inherited variants of cholinesterase. one iranian subject with very low activity (dibucaine number below 20, atypical) had a history of apnea. these data indicate that the frequency of atypical and heterozygote genes for cholinesterase activity leading to prolonged apnea with succinylcholine (suxamethonium) is much higher in iranian than irish populations. this study emphasises the importance of ethnic pharmacology. it is has been advocated that funding for the prescibing of methadone in general practice should be provided separate from the indicative drugs budgeting scheme on the assumption that this may act as a disincentive to g.p.s to take on care of drug addicts. the objective was to analyse the current level and cost of methadone prescribing in 550 general practices in the eastern health board over a six month period. there was a review of methadone prescriptions for gms patients from jan. to jun. 1995. 1,087 persons received prescriptions. 3,945 scripts were issued. the age-specific prescribing rate for the total population was 6/10,000 (males 10/i 0,000, females 3/10,000). males aged 25-34 years had the highest age specific rates (44/100,000). the cost of methadone prescriptions amounted to s for the six months there was a trend towards an increase in the number of g.p.s who prescribed methadone over the period. only four of the 70 g.p.s (5.7%) who prescribed methadone issued in excess of 50 scripts for the period studied. for a small number of g.p.s methadone prescribing is a significant cost item on their budget. in the light of this, government policy should be reviewed with a view to excluding methadone from the indicative drug budgeting scheme. sciences, mashhed, lran. there is increasing evidence that some of the wide variation in the response to medicines has a genetic origin which may be expressed on a racial basis. to further study inter-ethnic differences in pharmacology we compared the activity of an enzyme responsible for the breakdown of endogenous substances and drugs -serum cholinesterase (pseudocholinesterase), dibucaine and fluoride numbers -in 200 irish and 200 iranian healthy subjects. irish subjects had significantly higher serum cholinesterase activity (7.28 + 0.14 vs 5.22 + 0.09 u/ml, mean + sem, p < 0.01 drug prescribing data may reflect changes in therapy and disease pattern. we reviewed current drug use among patients (n = 578) in a dublin teaching hospital in "snapshot" fashion on a designated day, and compared it with that obtained in 1985. in 1985, patients received an average of 7.8 different drugs each, with 41% on 5 or more and 3% on none. by 1995, the average was 6.8 (range i -19), with 62% on 5 or more. the percentage of patients receiving heparin fell from 42% to 13%, due mainly to a reduction in use on the medical side. the proportion of patients prescribed hypnotics fell from 55% to 37%, while ssri's are now the most used anti-depressants. antibiotic choice changed from amp/amoxicillin to coamoxiclav and the cephalosporins. diuretics remained the most frequently used cardiovascular agents, accounting for 4% of all drugs used and prescribed for around one quarter of patients. digoxin use remained constant, and by 1995, 20% of patients were on anti-platelet doses of aspirin. at least four different agents were in use in each of calcium antagonist, beta blocker and ace inhibitor classes. some of these changes in therapy reflect therapeutic advances, changes in disease management, greater choice of therapy and amendment of less than desirable therapeutic practices. on the other hand, some may reflect fashion or pharmaceutical promotion, rather than change as a consequence of evidence-based practice. acknowledgements: pharmacy staff, st. james's hospital and the health research board. studies of in vivo endothelial function in humans have usually involved intraarterial cannulation and the subsequent administration of substances that stimulate the endothelium to produce nitric oxide (no). such techniques are invasive and potentially hazardous. an alternative non-invasive method would be of benefit. animal studies have indicated that reactive dilation of vascular beds may be at least partially endothelium dependent. this study aimed to determine whether reactive hyperaemia in the human forearm was an endothelial dependent process with the potential to be used as a non-invasive method of stimulating the endothelium. ten volunteers underwent brachial artery cannulation and randomly received either placebo or n-monomethyl-l-arginine (l-nmma) (8~mol/min), an no synthase inhibitor, for 10 minutes. following this reactive hyperaemia was induced by the inflation of an arm cuff to 200 mmhg for 5 minutes and the response to this was measured by strain-gauge plethysmography. when flows had returned to baseline the process was repeated with the remaining substance. results were analysed by repeated me~isures anova. l-nmma resulted in significant reduction of basal forearm blood flow (p<0.01). there was no significant difference in reactive hyperaemia with either l-nmma or placebo. in conclusion, no does not contribute to reactive hyperaemia in the human forearm. dublin 8. home-based infusion therapy has been widely recognised as the optimum for treatment of disease states that require daily intravenous therapy from a patient-care aspect. conditions necessitating intravenous therapies in hiv disease include: cmv retinitis, intractable cryptosporidial diarrhoea, azole-resistent candidosis, nutritional support with total parenteral nutrition, chemotherapy for aids-related malignancies and palliative care in the terminal phase of the disease. the need for such therapies is increasing as patient survival improves. in 1993, the home-infusion service was set up in recognition of the need to treat patients, requiring intravenous therapy, in the home environment. this has been brought about by the development of small, light-weight pumps suitable for ambulatory use, the development of a service for aseptic compounding and the availability of permanent in-dwelling venous catheters. we describe the impact of this service on our patient cohort. to date, sixty-five hiv positive patients have received parenteral therapy at home. patients' age, sex, risk group, cdc stage, cd4 count, indication for therapy, complication rate and response to treatment are described. the provision of this service has reduced the number and length of patient admissions with associated improvement of quality of life. in addition, it recognises that patients prefer to be treated in the home environment aided by a co-ordinated multidisciplinary approach. since blood alcohol levels over 80 mg/100 ml are now illegal for vehicle drivers we have investigated if the commonly held "safe" limit of two drinks will bring the young adult over the legal limit and if this amount of alcohol will affect their psychomotor skills. following informed consent 33 healthy volunteers, nonhabitual drinkers on no medication (16 male, 17 female), with a median age of 24 (range 20-27) years participated and refrained from alcohol for at least 2 days. each drank within 15 minutes two standard drinks (35.5 ml each ) of 37.5% vodka (2.7 units of alcohol) plus 60 ml of orange juice at about 90 minutes after a standard mid-day meal. their psychomotor performance was estimated by the number connecting technique at 45 minutes after alcohol consumption and they were also asked to rate their feelings (which included alertness, clear-headedness, competence and attentiveness) using a visual analogue scale of 1 to 10. blood samples at one and two hours later were collected from the antecubital vein and analysed on the same day for alcohol content using enzymatic methods. mean (+ sem) blood concentrations of alcohol at 1 and 2 hours respectively were 25.39 + 6.19 and 21.62 + 4.58 mg/100 ml. in males and 36.43 + 11.89 and 38.66 + 3.43 mg/l-00 ml in females. values were significantly higher in females. blood concentrations in females were also higher (p < 0.01) than in males when expressed per kg body weight. while the blood alcohol in both the genders was considerably lower than the current legal limit in ireland their psychomotor skills as estimated from their task completion time and their answers to questionnaires were indicative of an impaired cns function. thus while 2 drinks may keep many subjects below the legal limit, there is considerable inter-individual variation with females showing higher concentrations and both genders have evidence of impaired performance at these lower levels. a non-linear approach was used to develop an hrv parameter, robust to both data non'-st~itionary and missing data points. unlike the standard chaos approach, using higher dimensional embeddings and time-delays, we employed a onedimensional correlation integral plot. the parameter thus obtained, allows an estimate of the spatial spreading of the attractor (ssa) or spatial variation of rr intervals along a straight line. heart rate data from 18 volunteers (22:00 to 06:00 hr), ~ifter oral placebo or propranolol 80 mg, investigated the ability to detect drug effect. vitamin e (~-tocopherol) is the most important dietary antioxidant in lipid and cell membranes and its intake reversely relates to the incidence of coronary heart disease and certain cancers. estrogen regenerates oxidized tocopherol radical in vitro m but such interaction has not been investigated in postmenopausal women receiving estrogen containing hormone replacement therapy (hrt) although estrogen containing oral contraceptive may reduce plasma vitamin e levep. we studied 21 healthy post-menopausal women (aged 46 -56) ammenorrheic for at least one year. fifteen subjects took a combination of harmogen provera therapy and 6 acted as a control group. blood samples were taken from all subject at baseline and after 4 weeks. in the hrt group, serum fsh levels were greatly reduced (86.46 + 25.27 vs 68.67 + 11.59 iu/1, p < 0.04, mean + sd, after hrt) with an increased serum oestradiol level (< 20 -28.68 vs 603.67 + 343.56 umol/1, p < 0.0001). no change occurred in the control group. vitamin e status, measured either as plasma or red cell ~-tocopherol respectively showed no change in both groups (hrt group 26.48 + 5.42 vs 27.17 + 3.39, 23.79 + 5.19 vs 24.93 + 4.37 gmol/1, p > 0.05). we conclude that in post-menopausal women, 4 weeks estrogen containing hrt did not alter vftamin e concentrations in vivo. we assessed the clinical benefit of the newer markers of bone formation: osteocalcin (oc), procollagen 1 carboxyterminal peptide (picp), bone alkaline phosphatase (balp), and bone resorption: carboxyterminal telopeptide of type 1 collagen (ictp) and urinary deoxypyridinoline crosslinks (dpd) over traditional assays such as total alkaline phosphatase (talp) and urinary hydroxyproline (oh/pr) in 23 patients with primary hyperparathyroidism (phpt). patients were sampled basally, then at 2, 6, 24, 48 and 72 hours post surgery and again at 1.5, 3, 6 and 12 months post op. the mean basal p1cp level was 89+26 ug/l (normal: 38-202) this increased to a peak at 48 h (168+_74 ug/l), then declined to normal at 6 weeks (116+56 ug/l). mean basal urinary dpd levels were raised at 8.6+1.2 nm/mm cr. (normal 2.0-6,0), they had normalised by 6 months to 5.9-+1.4 nm/mm cr. mean balp levels were always normal, although normal the yearly mean oc level was significantly lower than the basal value. mean 1ctp, oh/pr and talp levels were always normal. therefore bone turnover in phpt is best assessed by the newer markers picp and dpd. we have previously described seasonal variation in fibrinogen with higher levels in winter. as fibrinogen is an acute phase reactant, the winter rise may be a response to seasonal infections. the present study investigates this hypothesis by examining seasonality infibrinogen and markers associated with infection: white cell count (wcc), interleukin-6 (1l-6), human herpes virus 6 (hhv6) and herpes simplex virus (hsv) antibodies. monthly blood samples from healthy volunteers age 75 and over were measured for fibrinogen, wcc, il-6, hsv and hhv6 reactivation over a 1 year time period. a rhythmometric method was used to examine the data for seasonality. statistical significance was measured using the fstatistic. a highly significant seasonal variation (sv), peaking in mid-february, was found for fibrinogen (n=24; sv=0.629 g/ 1; f=76.148; p<0.01). no significant seasonal variation was present for measures of wcc (n=24; sv=0.209 e9/l; f= 1.940; p>0.05), hhv6 (n=24; sv=0.065 au; f=0.653; p>0.05), hsv (n=7; sv=6.055 au; f=2.048; p>0.05) or il-6 (n=7; sv=1.235 pg/ml; f=0.558; p>0.05). the present investigation does not support the hypothesis that seasonal variation in fibrinogen is a direct effect of the acute phase response, initiated by a seasonal variation in level of infection. the explanation for the seasonal changes in fibrinogen remains unknown. increased plasma homocysteine and reduced plasma antioxidants are risk factors in the development of vascular disease. design: 131 subjects drawn from elderly people living in the community (median age 85 yr, range 60-102 yr; 81 female). total plasma homocysteine, vitamin c, gamma tocopherol, retinol and beta carotene were measured by high pressure liquid chromatography. homocysteine levels in elderly males [median (range) = 12.35 um (4-18.1), n=241 were significantly higher than in vol. 165, 1996 supplement no. 2 irish journal of medical science elderly females [8.45 um (4.8-24.8), n=30]. these values were also higher than in a younger (30-49 years) male cohort [mean = 7.85 um, n= 610]. no correlations to vitamin concentrations were found, nor was there a correlation to age within the elderly cohort. within the elderly females, a significant negative correlation with age was found in vitamin c, gamma tocopherol and beta carotene (p<0.05). however a significant increase in retinol was noted. a very strong correlation between vitamin c and gamma tocopherol levels was noted in the elderly population sample (p<0.001 after multiple regression). conclusion. homocysteine levels in the elderly are higher than in samples of a younger population. a gender difference is maintained in the elderly. the provision of extended care forms one part of a spectrum of health care for older people. in the eastern health board area all patients over the age of 65 must be assessed by the multidisciplinary geriatric team prior to placement. we report on the experience of the total number of referrals for assessment for extended care to one department of geriatric medicine in a 268 bed teaching hospital. ninety-eight patients listed for extended care in 1994. the mean number of days between listing for long term care and placement was 49 _+ 45 days (range 3 to 206). almost one quarter of patients died while in hospital awaiting long term care: this underlines the frailty of patients who are admitted to hospital and request long term care. two patients were transferred to other institutions and 10 patients were able to get home. of the remaining patients 35 (63%) were placed in statutory or voluntary long term care accommodation and only 37% were eligible (usually financially but in some cases due to significant disability) for nursing home care using the terms of the 1993 nursing home act. patients who are listed for long term care through a general hospital are in general very frail, they tend to have a very extended length of stay and the provisions of the nursing home act only apply to a minority. these findings underline the need for provision of adequate statutory and voluntary extended-care places within the eastern health board area. there are over 40 screening assessments for cognitive function and choosing the most appropriate may be difficult. increasingly the importance of behavioural dysfunction is recognised. can any of the cognitive assessments help to predict behavioural dysfunction.'? we compared and contrasted the folstein mini mental state examination (mmse) and the cognitive assessment schedule (cas) of the clifton assessment procedures for the elderly (cape) and compared them with the behavioural rating scale (brs) of the cape. the study was carried out on a total of 21 referrals to the occupational therapy departments by geriatricians in the meath hospital and st. james's hospital. all subjects were over 65 and medically stable. the time scale involved was may-july 1995. the mmse and the cas were administered within the one sitting and each was timed. brs was rated the same day by either a staff or family, member. the average time to complete the mmse (416 + 124 s) was longer than the cas (342 + 171 s) but this was not statistically significant. the mmse and cas were significantly correlated (r = 8208, p < 0.0001). the cas was significantly correlated with the behaviour scale (r = 0,551, p < 0.01) whereas the mmse was not. these results suggest that equivalent assessments of cognitive function may be made with the mmse or cas, but a low cas score will be a better prediction of behavioural dysfunction. a spectrum of neurological and myopathological changes are associated with patients in intensive care units. we observed several patients post discharge from icu who presented with unexplained dysphagia which we suspected may be associated with the neurological complications of sepsis. the particular complication of dysphagia as a neurological manifestation of sepsis has not been documented. our descriptive study presents a series of three patients with persistent dysphagia which may represent a similar phenomenon. we selected patients for the study ranging from 75-87 years of age and on the basis of medical history including icu stay, sepsis, and intubation. all patients presented with dysphagia as observed on videofluoroscopy. we studied the video findings in-depth in order to ascertain if similar swailow patterns were present in these patients and if this could be correlated with their medical history. each of the three patients presented with similar dysphagia signs. the oral phase of the swallow was moderately atypical but the pharyngeal phase was significantly atypical. it was felt that intubation alone was not the sole causative factor of this dysphagia. the polyneuropathy associated with sepsis in icu may explain the atypical swallow patterns observed in these patients. the severity of the persistent dysphagia can cause serious respiratory and medical consequences. there is a need for further investigation of this phenomenon to identify patients who are at risk. little attention has been paid to the prevaience and phenomenology of behavioural disturbances among medical patients despite awareness of the high prevalence of cognitive vol. 165, 1996 supplement no. 2 impairment in this patient population. we screened 79 consecutive admissions to a department of acute geriatric medicine. patients were evaluated over a 2 week period using a modified version of the brief agitation rating scale. medication use, cognitive function and impact on nursing time were also measured. the prevalence of behavioural disturbance in this population was 19/79 (24%). the most frequent behavioural abnormalities were restlessness (12), complaining (12) and screaming (6). the most common underlying disorders were dementia, stroke disease, personality disorder and paranoid psychosis. the behavioural disturbance was only documented in the medical notes in 7 patients (37%) and in only 5 cases was a psychiatric consultation sought. these findings demonstrate that behavioural disturbances are not only common but also under-documented in elderly medical patients and there is a need for training in the detection and management of behavioural symptoms in this patient group. in lower limb trauma where there is severe compound fracture, the successful treatment of this depends on adequate bone and soft tissue debridement. as a result, subsequent bone defects can lead to instability and often require large amounts of bone grafts, and major soft tissue reconstruction is reaquired to obtain skin cover. large soft defects can by reduced bv primary bone resection and shortening of the limb. this will improve the chance of bone healing if performed in the presence of an external fixator, then lengthening at a site away from the traumatised area can gradually restore limb length. two cases are presented to demonstrate .the effect of compression / distraction techniques on soft tissue and bone injuries in these difficult situations. wegener's granulomatosis -wg (15), churg strauss syndrome -css (4), polyarteritis nodosa -pan (2) and unclassified (5). using the chc definitions, the diagnoses were wg (5), microscopic polyangiitis -mpa (10), pan (1) and undefined (10). there was concordance in only 5 patients (all wg). there is significant discordance between these two criteria sets. since the acr criteria does not recognise mpa, they tend to overdiagnose wg. in addition, the chc criteria cannot be applied without a biopsy and therefore surrogate features which predict the underlying histology are required to allow more practical application of the chc definitions. the objective was to determine the value of examination of dried freshly produced saliva, under light microscopy, in patients with xerostomia related to secondary sjogrens syndrome. ten patients with known connective tissue disease or rheumatoid arthritis attending rheumatology clinic were enrolled into the study, all with symptomatic xerostomia and dry eyes. all had an abnormal schirmer's test. five normal patients were enrolled, all of whom were without clinical evidence of rheumatological disease. control patients were enrolled who had no clinical evidence of rheumatological disease, a salivary sample was collected and examined by light microscopy. serum was also examined for the presence of anti-ro/la, rheumatoid factor, and anti-nuclear factor. all ten patients demonstrated 'reindeer horn' type ferning of saliva, a pattern of shorter thicker clubbed branches of crystallised mucus, in contrast to the normal ferning pattern of the healthy subjects. conclusion: we have shown in this preliminary report that light salivary microscopy is a simple test easily performed in an outpatient setting which could be a useful diagnostic procedure in sjogrens syndrome. recently, two sets of criteria have been proposed for the nomeclature of primary vasculitides, the 1990 american college of rheumatology (acr) classification criteria and the 1992 chapel hill consensus conference (chc) definitions. the aim of this study was to determine the concordance of these two systems in a cohort of patients with primary systemic vasculitis. patients with systemic vasculitis were recruited who had a biopsy proven diagnosis or, who had typical clinical features associated with a postive antineutrophil cytoplasmic antibody (anca). the case notes were reviewed and patients were classified according to both sets of criteria. twenty-six patients were recruited, 21 of whom had a positive biopsy. applying the 1990 acr criteria, the diagnoses were, primary pulmonary hypertension (pph) typically affects young individuals, and has a high morbidity and mortality. secondary pulmonary hypertension complicating connective tissue diseases likewise carries a poor prognosis. we evaluated the acute and chronic effects of ketanserin, a selective serotonin type-2 receptor antagonist in 2 patients with pulmonary hypertension in the acute study ketanserin was administered as a peripheral venous infusion during right heart catheterisation. following encouraging results during catheterisation oral administration of ketanserin 160mg daily in divided doses was instituted. in patient 1, a 30 year old female with probable pph, serial cardiac catheterisations over a 1 year period showed a significant, sustained reduction in both mean pulmonary artery pressure from 49 mmhg at baseline to 24 mmhg at 1 year (normal 10-20 mmhg) and pulmonary vascular resistance 1118 units at baseline to 288 units at 1 year (normal <200 units). in patient 2, a 61 year old female with limited scleroderma (crest) echocardiography after 1 month's oral ketanserin showed a reduction in estimated peak right ventricular systolic pressure from 60 mmhg at baseline to 13 mmhg (normal range 15-30 mmhg). the acute and long term response to ketanserin with improyement in pulmonary haemodynamics in these patients suggests that if a beneficial effect is detected during catheterisation long term oral therapy may be worthwhile. levels were low (< 7.9 iu/1); normal though above average (>-8 -<10 iu/l) and moderate high (>10 -<15 iu/l) respectively. gonadotrophins for ovarian stimulation were commencing initially at 225 iu for group a & b and at 450 iu for group c. ivf performance was poor in most aspects (total follicles, oocytes & embryos transferred) in group b comparing with group a or c; the cumulative ongoing pregnancy rate (pr) over 2 ivf cycles in group b; was 15% comparing with 27.6% in group a (p < 0.05) however there was no significant difference in pr in group c (20%) comparing with other two groups. cycle day 3 fsh screening is predictive of follicular development in ivf. high initial dose of gonadotropins help to improve the pregnancy rate in the presence of moderate high level of fsh. the purpose of this study was to evaluate patient satisfaction with antenatal care provided in the perinatal day centre (pndc). a self administered questionnaire was administered to 61 consecutive patients. the main indications for referral were suspected small-fordates (34%), non-proteinuric hypertension (23%), glucose tolerance testing (15%), reduced fetal movements (10%) and post-term evaluation (7.5%); 51% were nulliparae. thirty-two percent of patients were reviewed in the pndc on the day of referral; the rest within 7 days. twenty eight percent of patients lived more than 10 miles from the hospital and 48% spent more than 30 minutes in travelling there. eighty five percent of patients scored their level of satisfaction with the service provided in the pndc as > 7 out of 10; only 6.5% would have preferred admission; 42% said that they would prefer to visit the pndc 5 times per week to avoid admission. the main area of dissatisfaction related to the waiting time for review prior to discharge, with 69.5% of patients waiting over 3 hours. patients attending the pndc report a high level of satisfaction; changes to reduce the visit duration have been introduced. to examine the change of taking-up the essential preconceptual measurements; rubella immune status, cervical cytology and prophylactic folic acid intake; following specific advice and publicity through 3 general public meetings with new patients prior to in vitro fertilization (ivf) programme. in 1994 we studied 281 new couples for ivf for the presence of some specific pre-conceptual data (group a). in this study we follow-up the same intake in another 229 new women interviewed to commence ivf programme from january 1995 till september 1995 (group b). in group (b) the taking-up measurements were dramatically improved. however, 30% and 18% stilldid not have rubella immunity test and cervical cytology performed; compared to 54% and 36% in group (ai respectively (p<0.001). while folic acid intake was sustained at >90% in both groups. following specific advice the rate of taking-up of preconceptual measurements prior commencing ivf programme was improved. there is a future need for continuous enhancement of the publicity and advice regarding the importance of preconceptual measurements. the aim of this study was to introduce icsi to ireland for treatment of specific cases of male factor infertility. following an introductory proving period using the bovine model, thirtyeight couples with infertility attributed to the male were selected for an icsi attempt. ovulation induction, oocyte retrieval and luteal management were as described for conventional ivf tm. the average age of patients selected for icsi were 34.5 + 3.7 years and 36.4 + 4.6 years for the female and male respectively, with an average duration of infertility of 4.8 + 2.6 years. a 64 year old woman presented with a three day history of parasthesia in her lower limbs and difficulty walking. neurological examination revealed sensory loss in her limbs and truncal ataxia. rombergs sign was positive. pelvic examination revealed a large pelvic mass that was distinct from the uterus. routine blood investigations were normal. csf culture, ct brain and serum electrophoresis were negative. anti-purkinjie cell antibodies were not present. ca-125 levels were elevated at 159 micrograms/litre. laparotomy revealed a 20 cm left ovarian tumour. a total abdominal hysterectomy, bilateral salpingo-oophorectomy and omentectomy was performed. histology revealed a poorly differentiated clear cell adeno-carcinoma of the left ovary. the capsule was intact and peritoneal washings were negative. she made a good postoperative recovery. she received six courses of carboplatin without ill effect. her neurological symptoms resolved. subacute cerebellar degeneration can occur as a paraneoplastic disorder in ovarian carcinoma. the mechanism by which cancer can cause neurological disorders is not fully understood. paraneoplastic cerebellar degeneration occurs with or without the presence of purkinjie cell antibodies. the aim was to review all red cell transfusions in gynaecological surgery in 1994. a retrospective review of blood bank records and individual charts was carried out. 4611 patients underwent gynaecological surgery; 97 (21%) were cross matched and 60 (1.3%) were transfused. 184 units were transfused. there were no single unit transfusions. the mean number of units transfused per patient was 3. this accounted for 33% of all units transfused this year. 92% of patients were undergoing elective surgery. the overall cross match/transfusion ratio was 2. intraoperative difficulty was recorded in 56% of cases. 64% of patients were transfused perioperatively and 36% postoperatively. the percentage of patients requiring blood transfusions in the the main individual operation categories was as follows: radical surgery: 57%; total abdominal hysterectomy and salpingo-oopherectomy, 17%; vaginal hysterectomy and repair, 16%; subtotal abdominal hysterectomy, 30%; vaginal hysterectomy alone 12.5%; and total abdominal hysterectomy alone 5%. adverse reactions to transfusions were seen in 5% of patients. conclusion: the majority of patients transfused were undergoing elective surgery. vaginal hysterectomy was associated with greater blood loss than abdominal hysterectomy. only half of all units cross matched were transfused. dilatation and curettage (d+c) is the most common operation performed in the u.k. the liberal use of d+c has been criticised. the objective of this study was to evaluate the use of outpatient endometrial pipelle biopsy and determine its safety in terms of detecting abnormalities. complications and financial costs were also evaluated. data was reviewed from an active gynaecological unit from february 1993 to january 1995, using theatre and outpatient records. a total of 303 d+cs and 104 endometrial pipelle biopsies were performed in this period. 9 malignancies were detected by d+c and 1 by pipelle biopsy. a total of 24 and 3 benign abnormalities were detected by each method respectively. there was a higher complication rate in the d+c group but the failure rate was higher in the endometrial pipelle biopsy group. the monetary savings over this period is estimated at s there were no missed malignancies to our knowledge over the 8 year period since endometrial pipelle bioposy was introduced to this hospital. our study indicates that outpatient endometrial pipelle biopsy appears to be safe, efficacious and economical. while ultrasound findings may sometimes be in conflict with clinical examination, it is the case that there are instances when ultrasound findings have, following subsequent laparotomy, been found to be wholly incorrect. it is therefore not surprising that there remain some gynaecologists who view ultrasound with scepticism, preferring to rely solely of their clinical findings. there have been few studies that directly compare clinical, ultrasound and surgical findings in the detection of pelvic masses. the objective of the study was firstly to directly compare the reliability of clinical and ultrasound examination findings in the detection of pelvic masses proven by subsequent laparotomy and secondly to determine the accuracy of ultrasound in detecting malignancy. this was as a retrospective review of 86 women who underwent a laparotomy because of a pelvic mass between january 1993 to february 1995. information was obtained from theatre and patient records. real time abdominal ultrasound was used. findings at laparotomy were correlated with clinical and ultrasound findings. the sensitivity and specificity of ultrasound in detecting a uterine mass was 94% and 99% respectively. this contrasts sharply with clinical examination (sensitivity = 74% and specificity = 94%). similar findings were obtained when ultrasound was compared to clinical examination in detecting ovarian masses. ultrasouud is capable of predicting benign disease with reasonable confidence but the prediction of malignancy is less reliable. in conclusion, ultrasound is more sensitive and specific in detecting pelvic masses compared to clinical examination. vincent's hospital, dublin. osteoporosis occurring during pregnancy or lactation is a rare event despite the homeostatic demands of the foetus for calcium. we investigated the case of a 24 year old woman who, immediately following vaginal delivery of her first child, developed severe back pain due to a vertebral compression deformity of the second lumbar vertebrae. bone mineral density (bmd) was measured by dual-energy x-ray absorptiometry. calcium metabolism and bone turnover were studied. there was a severe reduction in bmd in the spine (z-score = -4.8) and f e m o r a l neck ( z -s c o r e = -3.6); but, serial measurements showed no further reduction in bmd. indices of calcium metabolism and bone turnover were normal. pregnancy-induced osteoporosis is a severe but self-limited disorder in calcium homeostasis of unknown aetiology. women with low bmd prior to pregnancy may be at increased risk. in view of increased demand, supplemental calcium and vitamin d should be considered during pregnancy and lactation. crumlin, dublin 12. the aim of this study was to assess the clinical status on admission and the critical care m a n a g e m e n t of children p r e s e n t i n g with m e n i n g o c o c c a l i n f e c t i o n . t h i s was a retrospective study of the charts of 46 consecutive admissions. mean age was 3.43 years (+3.46). the average duration of symptoms prior to admission was 20.4 hours (+11.09). on admission 17.4% were hypotensive, 45.6% had clinical signs of haemodynamic instability and 54.8% of cases that had a wood gas analysis on admission had a metabolic acidosis (bases excess < -5.0). the mortality rate was 10.9%. 80% of deaths were hypotensive on admission and all had a metabolic acidosis. of the 41 survivors 9.7% were hypotensive on admission, 39% had clinical signs of cardiovascular compromise, 78% were admitted to the high dependency unit, 25% required invasive pressure monitoring and 7.3% were ventilated and received inotropic support. in this study children presenting with m e n i n g o c o c c a l infection have a high incidence of cardiovascular instability. successful management is dependent on early presentation and initiation of therapy and on aggressive intensive care monitoring and support of the cardiovascular i11 and vital organ systems. the normal crying curve and incidence of colic for term infants are well known. we studied prospectively the crying pattern and the incidence of colic in preterm'infants to determine if prematurity influenced these behaviours. the subjects were consecutive preterm infants admitted to the cork neonatal units for two and a half months from july 1995. a continuous 24 hour diary was completed on each infant by the neonatal nurses, when the babies were on full oral feeding and no longer required intensive care. the parents completed the diaries 'after discharge. colic was defined according to wessel's rule of threes. two unwell babies were excluded. the duration of follow up was from 2 to 16 weeks. fifty infants were recruited and 45 completed the study (4 lost to follow up and one withdi'awn due to sepsis). their mean (range) gestational age was 31 (26-36) weeks and birthweight was 1.52 (0.64-2.4) kg. the mean (range) age of crying onset was x(y-z) weeks; crying, peak 'was x(y-z) weeks and crying offset was x(y-z) weeks. one baby developed colic in the period of follow up. conclusions: the incidence of wessel's colic was less than expected in these preterm babies. the crying pattern according to chronological age was different from that clescribed in term babies. in general preterm babies had a delayed onset of crying, but the pattern became similar to term babies when allowance was made for gestational age. the findings'suggest that the crying patterns of early infancy have a developmental basis. we re-evaluated 18 children who had had rs (1979-86), with their closest-age siblings using the wechsler scales, coopersmith self esteem inventory and achenback child behaviour checklist (acbc) (duffy j. et al 1991). the rs patients' means were consistently lower than that of their sibs. however, comparison of mean raw data, using "t-tests", yielded significant differences only in the acbc scores, in that rs children exhibited significantly more problem behaviours than their sibs (p=0.033). after categorisation of iq data, further comparisons between the groups (using x2), found rs patients were significantly more likely to score "below average" in tests of verbal iq compared to their sibs (p=0.04). age of onset and clinical stage were also found to be more important predictors of outcome. children less than 1 year of age at onset of rs had significantly lower iq scores on all measures of cognitive ability (p=0.003) and more problem behaviours (p=0.01) than children over 1 year of age. no significant differences were found in comparison with sibs. clinical stage to which rs progressed affected only verbal iq scores. children in whom consciousness had been impaired had significantly lower iq scores than both their sibs and rs children in whom consciousness was less impaired (p=0.02). in conclusion outcome remains cautiously positive, with 13/18 rs children attending mainstream schools or in employment without apparent difficulties. a national breastfeeding policy was introduced by the department of health in 1994. factors identified for promotion of breastfeeding were based on the who/unicef "ten steps for successful breastfeeding". we present clinical cases which suggest that one step may need to be modified. the charts of breastfed babies admitted to the special care baby unit were reviewed for one year following the introduction of the national breastfeeding policy to this hospital. thirteen term breastfed babies were admitted because of fever and dehydration. none of the babies had water or bottle feed supplements. ten of the thirteen mothers were primigravida. eleven babies were admitted in the six months following the introduction of an exclusive breastfeeding policy. the nursing staff were then alerted to the risk of dehydration, but two further babies of mums committed to exclusive breastfeeding were admitted in the subsequent six months. routine biochemistry, haematology and a limited septic screen was performed in all babies. three of the thirteen babies had lumbar punctures. the mean (range) weight loss on admission was 9.5 (4.1-16)%. the mean (range) plasma sodium level was 147.6 (138-156)meq/1 and the mean (range) urea was 6.5(2.1-13.4)meq/t. there was no growth from the cultures of the blood, urine, csf and swabs. all the babies were given intravenous fluids and parenteral antibiotics for 48 hours. the outcome was satisfactory in all babies and breastfeeding was reestablished in eleven of the thirteen babies. conclusions: the common factor to these babies was inadequate fluid intake prior to admission associated with stricl~ adherence to the policy, and avoidance of all supplements including water. we conclude that the who/unicef step 6 "not to give food or drink other than breastmilk unless medically indicated" is too restrictive in the immediate postpartum period. 42.5% of children reported headache in the previous 12 months 44.8% of girls and 40.5% of boys reported headache (p < 0.0001). 0.6% of children reported daily headache 5.9% of children reported weekly headache 9.4% of children reported monthly headache 22.5% of children reported headache less often than monthly the percentage of children with headache at each frequency, other than daily, increased with increasing age. in girls headache showed a marked rise at ages 14, 15 and 16 years. reported prevalence of headache in the past year in 5 to 15 year old aberdeen children was 66% and 48% was recorded for swedish children aged 8, 11, 13 and 17 years old. this study is the first community based prevalence study of headache in irish schoolchildren. our aim was to test the hypothesis that there is no correlation between the type of feeding & swallowing disorder the child has with the neurological diagnosis or the radiological findings. a further purpose was to develop a classification of the feeding & swallowing disorders which would guide us towards a management plan. a retrospective analysis of the data collected between the years 1988-94 from the feeding & swallowing clinic at booth hall children's hospital was done. 73 children were included in our study 9 ages ranged from 4 months to 17 yrs. all the children were assessed by the members of the feeding & swallowing team and had videofluroscopic assessment by the same radiologist. neurological signs, speech therapy assessments & videofluroscopy findings were compared between children with spastic quadriparesis & those without. significant differences were noted. a clinical classification was devised using cluster analysis. we conclude that there is no causal relationship between the neurological diagnosis & the type of dysphagia. there are three distinct groups of children who require different strategies of clinical management. surveillance commenced in january 1995 to continuously monitor the incidence of surgical site infections (ssi). employing modern optical scanning technology (formic for windows version 2.0, formic limited, london) a questionnaire was designed, which required minimal completion time. the questionnaire includes relevant data based on the american national nosocomial infections surveillance system for ssi including the ssi risk index. surveillance commences at the time of surgery and continues until the patient's discharge. optical scanning technology allows rapid reading of surveillance questionnaires thereby bypassing the bottleneck of manual data entry. by october 1995, details of 2,156 procedures had been recorded. the crude ssi rate for these patients was 2.7%. the patient risk index used demonstrated that there were increased chances of developing ssi in certain patient groups. seventy-nine per cent of ssi had presented by the 10th post-operative day. the length of stay increased by an average of 4 days in patients developing ssi. regular feedback to individual surgeons, theatre and ward staff maintains awareness and highlights possible problems. we recommend optical scanning technology to all those engaged in surveillance work. this system would be especially useful were data collected is transported from outlying hospitals to a central receiving centre for collation and analysis. in 1872 francis crumpe published a paper ~ in which he described the therapeutic effect of poisonous mussels (psp) on a case of tetanus. he obtained the mussels from tralee ship canal on the occasion of its infrequent emptying, and entertained the idea of using them in tetanus after treating a young girl with psp who recovered after 24 hours. prior to the use of psp he described it's paralytic effect in two cockrels who both recovered. in concluding his successful use of psp he speculated as to the clinical nature and role of the toxin tralee ship canal was opened in 1846. the water was relatively stagnant and would have contained plenty of nutrients. as such it would have been an ideal habitat for toxic algae which may have been brought across the atlantic as spores in bilge water 2. the emptying of the canal may well have been done at times of algal blooming. this is the first irish report of psp and a most remarkable use of saxitoxin (?) in the treatment of tetanus, antedating the current management by seventy years. this study was carried out to quantify the published research on smoking in irish medical journals; to ascertain the type of research carried out; and to identify the authors of that research. during the 35 years under study, 50 papers explicitly dealing with smoking were published. only 2 papers appeared in forum. there was a decline in published papers in the eighties with a resurgence in the early nineties. of the 50 papers, a majority were observational and ten were editorials. only one paper dealt with smoking cessation, and one with preventive work. general practitioners were poorly represented as authors. one doctor (prof. r. mulcahy) published at least one paper on smoking in each quinquennium since 1960. this study underlines the relative insignificance of smoking as a topic for research in ireland. a major sea change in attitude will be required if the government's targets for smoking cessation are to be realised, particularly if they are to be achieved by relying on the medical profession. radiology represents a major cost centre within a hospital. lack of awareness of cost amongst doctors may result in the inappropriate requesting of radiology services. this study assesses doctors knowledge of the cost to a tertiary referral hospital of commonly performed radioj'ogical procedures and investigations. doctors were asked to estimate the cost of 9 items namely -chest,x-ray, arch aortogram, ultrasound abdo., lumbosacral spine, barium enema, ct brain, ct abdo., ultrasound abdomen, i.v.p. and percutaneous gastrostomy tube insertion under radiological screening. 60 doctors in st. vincent's hospital were surveyed. doctors as a group overestimated the cost of all 9 individual tests, by margins ranging from 10% (i.v.p. & gastrostomy insertion) to 100% (ct brain/ct abdo.) the total cost to the hospital of all 9 items was s consultants'overestimated this total cost by 107%, followed by registrars, interns and s.h.o's who overestimated the total cost by margins of 51%, 43% and 12% respectively . conclusion: doctors tend to overestimate what radiological procedures and investigations cost a public hospital, often by quite wide margins. thus, any excessive requesting of radiology services by docto.rs is not due to a lack of awareness of their true cost to the hospital. (ded) in dublin. secondly, to identify the major cancers contributing to years of potential life lost (ypll) for the ehb, each cca and ded in males and females. in ireland little work has been done to date on disease specific premature mortality. crude death rates weight all deaths equally; in comparison, ypll emphasise deaths among younger persons and provide a measure of the burden of premature mortality. premature mortality for the 322 deds in dublin for the years 19988 and 1989 was estimated using ypll, which was calculated by subtracting the date of death form 65. ypll due to each of the major disease groups were ranked for each ded. seventy-one thousand four hundred and sixty-eight &471468) years of potential life were lost in dublin in the 1988 and 1989. 21.9% of ypll was due to injury and poisoning, 20.64% to cancer, 15.6% to circulatory disease. however, when the major cause of ypll was established for each ded, injury and poisoning was the number one cause of death in 25.5% of the deds; cancers 24%, congenital and perinatal conditions 21.5% and circulatory disease 14%. by emphasising deaths in younger individuals ypll is a valuable tool for planning and monitoring local health promotion initiatives. serum total homocysteine (thcy) levels are inversely associated with dietary intake of folic acid and b vitamins and raised levels have been linked with chd. we have examined the association between thcy concentration and the risk of chd in middle-aged men in 18 british towns. we used a nested case control study design, within an ongoing prospective study, thcy concentration was measured in serum samples, stored at entry to the study, from 110 incident cases of myocardial infarction and 118 controls. cases and controls were frequency matched by town and age group. levels of homocysteine [geometric mean (95%c1) were significantly higher in cases than'controls: homocysteine 13.5 (12.6 -14.3)gmol/l vs 11.9 (11.3 -12.6)lamol/l; p = 0,005. there was a graded increase in the relative risk (odds ratio; or) of chd in the 2nd, 3rd and 4th quartile of thcy (or 1.4, 1.9, 2.2; trend p = 0.006) relative to the first quartile. adjustment for age, town, social class, body mass index, smoking, physical activity, alcohol intake, hypertensive status, serum cholesterol and serum creatinine did not attenuate this association, (or 2.1,2.3, 2.7; trend p = 0.04). the findings suggest that thcy is an independent risk factor for chd with no threshold level. in summer 1995, a diagnosis of cryptosporidiosis was made 25 in a child who had visited a pet farm. this child had participated in a summer project involving 161 children and nine adults. reports of a similar illness among other project members, prompted an outbreak investigation. a cohort study consisting of two phases was initiated. 95% (162/170) of project participants responded to a self-administered questionnaire in the first phase. thirteen children met the case definition, of whom seven had cryptosporidium detected in their stools. illness was significantly associated with having visited a pet farm. (p<0.000005). 75% of those ill sought medical attention, of whom two were hospitalised the second phase of the cohort study was conducted among those who had visited the pet farm. 95% (52155) were interviewed. illness was significantly associated with play in sand, to which animals had access, at a stream's edge beside a picnic area (p<0.005). contact with various animals was not statistically significantly associated with illness. however the small numbers involved may have obscured such an association. this outbreak highlights a potential hazard for children visiting pet farms and also that cryptosporidiosis is a significant but often overlooked cause of morbidity in healthy children. managers of pet farms need to be aware of the potential for transmission of disease to visiting children. strict implementation of hygiene measures is essential to minimise risk. the mrc vitamin trial highlighted the importance of folic acid in the prevention of neural tube defects(l). since 1993, the department of health has recommended periconceptional folic acid supplements. the objective of this study was to document the knowledge and behaviour of women in child bearing years to periconceptional folic acid. a cross sectional community survey was conducted using an interviewer administered questionnaire in dublin. three hundred and thirty five women took part in the study. approximately two thirds 213/335 (63.6%) had heard of folic acid. knowledge was significantly associated with higher social class and higher education (p<0.o5). few 18/335 (5.4%) had been advised to take folic acid before pregnancy. only 9/335 (2.7%) of the women in the study were currently taking folic acid supplements. three quarters of the group (75.9%) would be willing to take periconceptional folic acid supplements if they knew it would reduce the risk of malformations. the majority (77.4%) would prefer to take folic acid in tablet form. this study clearly shows that few women in childbearing years have been advised on folic acid. however, if advised appropriately the majority would be willing to take periconceptional folic acid in tablet form. future publicity campaigns involving all health professionals should address these issues. unstable intra-articular fractures with or without dislocation of the phalangeal joints often lead to joint stiffness ana loss of function. nine patients with comminuted intra-articular phalangeal fractures were treated in our unit by dynamic external fixator using "pins and rubber bands traction system". the mean age was 32.3 years, and the follow-up average was 4.6 months. five patients had full and good range of motion in the involved joints. three patients had poor results, and one patient underwent open reduction one week following the original procedure. the technique and our results are discussed. this dynamic frame is compact, comfortable for the patient, easy to apply and allows early mobilisation. careful selection of patients and close follow-up in the first few weeks are needed. this study examines how gp's store and handle vaccines. all 144 gp's in a health board region were invited to take part. gp's were interviewed in their practice premises about how they dealt with vaccines fridges were examined and temperature recorded post interview. oral polio was taken from 20 randomly selected fridges for potency testing. cold chain monitors and freeze watch indicators were used to monitor batches of vaccine stored. of the 144 gp's, 142(98.6%) agreed to participate, 140 used 111 fridges to store vaccine, 2 store vaccine at room temperature. of the 111 fridges, 6 (5.4%) had the power supply safeguarded, 9 (8.1%) had thermometers, 36 (32.4%) had vaccine only stored therein. during defrosting, vaccine was inadequately protected in 22 (19.8%). of the 138 gp's who use multi-dose vaccine vials, 133 (97.2%) keep them for further use at the end of a day/session, 3 store them at room temperature. 42 (37.8%) fridges had temperatures outside the recommended range. 13 (28.2%) coldchain monitors indicated vaccine exposed to more than 10~ 18 (90%) of the oral polio samples showed a reduction in total titre of live virus, however, none were below the minimum acceptable. this study indicates that vaccine potency could be seriously compromised due to breaks in the cold-chain and suggests the need for guidelines to be drawn up, implemented and monitored to ensure the integrity of immunisation schemes. comparison was made with a study carried out in 1983. in addition the range of antimicrobial agents tested included new oral cephalsporins and quinolones that were not then available. three hundred microorganisms isolated from mid stream urine (msu) samples were examined by standard microbiological techniques. antimicrobial susceptibility testing to 12 antimicrobial agents was performed on significant pathogens (>105 organisms per ml) by disc diffusion test, and minimum inhibitory concentrations of antibiotics was carried out by e test on organisms found resistant by disc testing. by comparison with 1983 resistance amongst e.coli, the most commonly isolated pathogen, had increased for the following: ampicillin by 6% to 61%, co amoxyclav by 4.4% from 0%, trimethoprim by 18% to 28% and nitrofuradantin by 5% from 0%. no increase in resistance occurred to cephradine (4%), or nalidixic acid (5.4%). resistance to cefixime, ofloxacin and ciprofloxacin, was 3%, no resistance was encountered to cefotaxime. for proteus species resistance to ofloxacin, ciprofloxacin and cefotaxime was 4%, and for enterobacter sp 20%. enterococci were sensitive to ampicillin and augmentin but the numbers were small. pathogens isolated from patients domiciled in the inner city were significantly more resistant to nalidixic acid (20%), cefotaxime (6%), cefixime (14%), ofloxacin and ciprofloxacin (12%) than those isolated from patients in rural areas. the purpose of this study is to examine the relative importance of obstetric complications (0c%) in the aetiology of schizophrenia and mania. using the dublin psychiatric case register, birth records of 635 patients with an icd-9 diagnosis of schizophreniaor mania were obtained. these records were evaluated, for obstetric complications using two scales, the lewis, owen and murray scale (lom) it~ and the parnas scale 121. the mothers of those going on to develop schizophrenia did not differ from those going on to mania as regards maternal age, parity, social class, or period of pregnancy. however, males who developed schizophrenia when compared to males developing mania, experienced significantly more oc's when rated by the lom scale (p=0.007) and.more frequent oc's on the parnas scale (p<0.001) of greater severity (p=0.018). no significant differences were found between females with schizophrenia and those with mania. dublin. the aim was to evaluate the diagnosis, symptomatology and level of functioning of patients presenting with a first episode of psychosis to a catchment area service and a private psychiatric hospital. all patients presenting with a first episode of psychosis were assessed using the scid-p,,the positive and negative syndrome scale (panss) and the global assessment of functioning scale (gaf). fifty-eight patients (34 male, 24 female) ranging in age from 15 to 65 years (mean + sd = 28.4 + 10.8) were included in the study. the mean total panss score was 84.8 (sd + 21.6) and was strongly correlated with the gaf score (p < 0.001) but independent of age (p = 0.16). males had a significantly lower gaf score compared to females (p = 0.04) but there was no gender difference in the total panss score (p = 0.20), twenty-five patients (43%) had a lifetime prevalence of drug abuse or dependence but only 12 patients (21%) had signs of drug abuse or dependence in the month prior to presentation. level of functioning was strongly influenced by the severity of psychopathology. substance abuse is common in individuals presenting with a first episode of psychosis. the aim was to evaluate the presence of involuntary movements in patients presenting with first episode psychosis to a catchment area service and a private psychiatric hospital. patients presenting with first episode schizophrenia and schizophreniform psychosis were assessed for involuntary movements using the involuntary movements scale (a.i.m.s.). 28 patients (17m., llf.), age range 15-67 years (mean=30.5 years.) were included in the study. one patient (3.5%) satisfied the strict criteria of schooter and kane for spontaneous dyskinesia. 7 patients (6m., if.), had minimal involuntary movements in at least 2 body areas, predominantly orofacial. the total a.i.m.s. score was positively correlated with the number of days spent in hospital per year of follow up (p=0.01). the group with involuntary movements were found to have spent more days in hospital per year of follow up, 94 v. 55 days (p=0.047). for patients with first episode schizophrenia or schizophreniform disorder spontaneous dyskinesia is not common. however involuntary movements at presentation may be a predictor of poorer outcome. psychiatry has moved from custodialcare towards care in the community. adequate reprovision will have to be made in order to discharge the remaining continuously hospitalized patients. the objectives of this study were to describe a.n entire long-stay hospital population, to examine the differences between the old and new long stay groups within this populatian and to evaluate the needs for community residential and day care facilities in order for hospital closure to take place. the study group consisted of the total long-stay population of st. davnet's hospital, monaghan. the patients were assessed using the community placement questionnaire (cpq) one hundred and twenty four patients were included in the study. fifty-six were female and 89% were single. the mean age of the total group was 68.7 years. the majority suffered from schizophrenia. the assessment revealed a globally disabled group with multiple handicaps. the new long-stay group were disabled as the old long-stay group. the patients were characterised into four groups with regard to placement recommendations. these were a specialist unit for chronically disturbed geriatrics, a geriatric unit, a high support hostel and a medium support hostel. the remaining population of this hospital were highly dependent with multiple handicaps but would live in community with adequate support. there is little difference between the needs of the old long-stay and those of the new long-stay. failure of the immune system to identify self peptides is likely to lead to the development of an autoimmune reaction. susceptibility to autoimmunity is strongly influenced by genes clustered in the hla region (chromosome 6p) particularly class i (a, b and c) and class ii (d, q and p). it has been suggested that there is an autoimmune component in the aetiology of schizophrenia. of many conflicting reports from case/control studies using hla antigens the most consistent finding has been an increased frequency of hla-a9 (now split into a23/a24). additionally, a susceptibility locus for schizophrenia has been reported near the hla locus. to attempt to confirm the hla a9 hypothesis, we have genotyped a preliminary sample of 63 familial schizophrenic probands and 77 unrelated controls at the hla-a region, using a pcr-ssop technique. the frequency of hla-a24 (the major component of a9) in patients and controls respectively was 12.5% vs 15.5%. these findings do not support the hypothesis. some of the discrepancy may be due to unspecific cross-reactions produced by commercial antisera used in the microlymphocytotoxicity method of previous studies. however it is also possible that the hla associatton with schizophrenia may reflect linkage disequilibrium with unidentified gene(s) within the hla region which is less strong in the irish population. schizophrenia is a common mental disorder affecting about 1% of the general population with a devastating disturbance of mind and personality. family, twin and adoption studies have demonstrated that the disease is largely genetic with a polygenic mode of: transmission. dopamine receptors have been implicated in the aetiology of the disease. as yet 5 dopamine genes have been identified (d1-d5). in particular the d3 receptor is expressed in the limbic regions of the brain, implicated in the control of emotions. association studies of a d3 polymorphism (glycine to serine substitution at position 9,) with schizophrenia have produced conflicting findings, many of which, however, have demonstrated a significant excess of homozygosity, or excess of the 1 -l genotype at this polymorphism. in this study, 200 familial schizophrenics and 239 irish unrelated controls were genotyped. the result show a small increase in the frequency of the 1-1 genotype which did not attain statistical significance (patients, 41.5% vs. controls, 38.5%). homozygosity (alleles 1-1 and 2-2) was also slightly increased in the patients (patients, 55.5% vs. controls, 48.9%). the small increase in the frequency of the 1-1 genotype and of homozygosity in the patients is in keeping with earlier findings but suggests that the effect, if any, of d3 sequence variation in the development of the disease is small. lack of information about general practitioners' (gp's) ability to prescribe psychotropic medication may affect patients' compliance. in this study, 73 out of 75 patients attending a psychiatry out-patient clinic completed a questionnaire which documented how many had run out of medication, the steps taken if they had and the role each patient thought their gp played in their treatment. 82% indicated that their gp knew what their current medication was but only 46% thought that their gp could provide them with a prescription if they did not have one from the clinic. this figure was similar in those who had (21%) and had not (79%) run out of medication in the past. on running out of medication, 42% of patients waited until their next appointment, 29% attended their gp and the remainder either contacted the department or went to a chemist. in conclusion, many patients do not appreciate the entitlement of their gp's to prescribe psychotropics for them. literature regarding whether or not the social class distribution of patients with psychiatric illness may differ from the general population remains controversial. we sought to clarify this by examining social class at the time of birth, to see whether patients with serious psychiatric illnesses (schizophrenia and mania) differ from the general population. paternal occupation of 450 schizophrenic patients, and 77 manic patients, from the dublin psychiatric case register, were obtained from birth registration details and categorised according to central statistics office criteria, the same-sex previous live birth was used as a matched control. there was no difference between the social class of patients with schizophrenia or mania (p=0.32). neither patients with schizophrenia (p=b.31) nor mania (p=0.153) differed from controls in social class distribution. paternal social class was found to be related to amount of time spenr in hospital (p<0.001', mean=439.62), and educational age (p<0.001, mean=15.01) and "age at onset of the illness" (p=0.03, mean=31.59). these results suggest that social class of origin may not be related to the development of either schizophrenia or mania. however, social class of origin may be relevant in terms of presentation of schizophrenia for treatment. cognitive function is widely recognised to be impaired in schizophrenia but there is an ongoing debate as to whether this impairment is generalised or localised, progressive or static, similar in both sexes, or related to symptoms. using the positive and negative syndrome scale (panss)'we measured psychopathology in 48 chronic in-patients (27m, 21 f; mean age 68.0+12.7) who satisfied feighner criteria for schizophrenia. subsequent to this, we assessed their global cognitive function using the mini-mental state examination (mmse) and their frontal cognitive function using a new instrument, the executive interview (exit). poor performance on the exit was associated strongly with increasing severity of negative (r=-0.74, p<0.001) but not positive (r=--0.09, ns) symptoms,'in both males (r=--0.73, p<0.001) and females (r=--0.76, p<0.001). overall exit performance declined modestly with increasing age (r=--0.32, p<0.05) but this phenomenon was co'nfined to females (r=--0.64, p<0.01; males: r=--0.13, ns). mmse performance was also associated with negative symptoms (r=--0.67, p<0.001) but decreased mm:e prominently with age (r=--0.59, p<0.001) and showed no gender difference. frontal dysfunction in schizophrenia appears to be intimately related to negative symptoms over the course of severe chronic illness, and may reflect among males a more static' trait deficit than is accessed by the mmse. this study was supported by the stanley foundation. while determinants of the course of schizophrenia are unclear, emerging evidence suggests that the longer psychosis proceeds unchecked before initiation of anti-psychotic therapy, the poorer may be long-term outcome. we have reported that, among older in-patients, increasing duration of initially untreated psychosis in the pre-neuroleptic era was associated with a deterioration to a state of muteness (after controlling for intervening variables). the current survivors of this population have now been examined more extensively using the positive and negative syndrome scale (panss), the mini-mental state examination (mmse) and the executive interview (exit). among these 48 patients (mean age 68.0+12.7), after controlling for age and for the duration and continuity of subsequent antipsychotic treatment, increasing duration of initially untreated psychosis was associated with greater severity of negative symptoms (p<0.005) and with lower scores on the mmse (p<0.05) but not with executive dysfunction on the exit (p=0.3). increasing duration of initially untreated psychosis appears to be associated with the evolution of more prominent negative symptoms and cognitive impairment in a manner consistent with an active, morbid process in schizophrenia that can be ameliorated by anti-psychotic drugs. this study was supported by the stanley foundation and the health research board. patients who are selected and who agree to participate in the royal college examinations play an important role. as psychiatrists and exam organisers, we should be aware of the potentially stressful experience which this might present. the purpose of our study was to elicit attitudes to the exam, and also knowledge of the examination procedure. a questionnaire comprising 10 questions was circulated to 30 patients who had participated in the royal college examinations. responses were received from 28 (93%) of the 30 patients. there were 14 males and 10 females in the responding group. none of the patients had previously participated in the examinations. all of the respondents (n=28) felt that the candidate had been polite towards them during the interview. 38% (n=9) of the patients were nervous prior to the examination, and this group was predominantly female (n=6). 21% of the patients (n=5) did not know that they would receive payment for their participation. 67% (n=l 6) did not know that they might be physically examined as part of the examination procedure. 17% (n=4) of the patients described experiences which had been upsetting for them the results of our study suggest that on the whole patients tolerate the exam procedure quite well. one of the central issues concerning physiotherapists in stroke rehabilitation is the emergence of abnormal tone. rehabilitation involves re-establishing a normal postural control mechanism (ncpm)"~. abnormal tone may develop in the presence of severe sensory and proprioceptive loss. the patients' attempts to move and find a stable base can lead to compensatory movement patterns and asymmetrical postures. positioning is used by physiotherapists to influence the distribution of muscle tone and facilitate symmetrical postures. it is essential that the patient is made aware of his 'position in space' as failure to do so presents no feedback regarding movement resulting in inertia ~2~. standardised positioning charts have been used in hospitals. the physiotherapist liaises with nursing staff regarding correct use on a 24 hour basis. this study looked at the role of a more individualised approach to positioning in the form of a photograph. patients were randomised to two positioning groups group a standard vs group b photograph, and their positioning was scored by a 'blinded' research physiotherapist over an eight week period. the results of a pilot study on a small number of patients revealed that nursing staff preferred a positioning chart individually tailored to the patient's problems. from a physiotherapy perspective, improved postural awareness correlated with better positioning scores in group b. the prevention of compensatory movements, posture is critical in stroke rehabilitation, the use of an individualised positioning chart requires further evaluation. we discuss the case of a fourteen year old boy who presented with bilateral ptosis present since birth, microcephaly and pigmentory retinopathy"!. he was found to have mild facial and proximal limb weakness. creatinine kinase and ldh were raised. muscle biopsy showed ragged red fibres consistent with a mitochondrial myopathy ~2~. electron microscopy showed abnormal mitochondria. the term mitochondrial myopathy describes a diverse range of clinical disease ~3~ and this is discussed. she developed a vasculitic skin rash with pruritis and oedema associated adenopathy, low grade fever and mouth ulcers. lab tests showed leucocytosis, eosinophilia and abnormal liver function. skin biopsy indicated an inflammatory picture without vasculitis. ct thorax confirmed axillary and para-aortic adenopathy. lymph node biopsy confirmed a reactive lymphadenopathy. the aim of. this study was to assess the characteristics of patients referred for pudendal nerve studies over a one year period. 31 consecutive patients were asked a standard questionnaire and nerve studies were performed as described by kiff and swash m and swash and snook~2k of the 31 patients, only 3 were male. the age range was from 21 to 79 (mean 50). 10 presented with constipation and 19 with faecal incontinence. two had both symptoms. bladder incontinence was presented in 10 of 31 patients. of these, faecal incontinence was the cardinal symptom in 8 patients, constipation in 2. 12 patients were nulliparous. of the remaining 17, 14 had a history of complicated births involving forceps (7), caesarean section (4), post partum haemorrhage (1), breech without forceps (2) . 14 patients had pelvic surgery and one had major trauma. 22 of 31 patients had bilaterally delayed pudental nerve terminal motor latency (pntml). 7 of 31 people had unilaterally delayed pntml, 2 were right sided, 5 were left sided. 2 had normal studi~s. the range of measurements was 1.8 -9.2 ms with a mean of 3.65 ms. in conclusionl delayed pntml was seen in 11 of 12 patients with constipation and 19 of 20 with faecal incontinence. pelvic surgery and a complicated obstetric history were significant. urological symptoms were also a common association. the p50 component of the middle latency-auditory evoked potential is attenuated in response to the second of paired clicks in a normal population. in schizophrenia, this attenuation is minimal. in alzheimer's disease (ad), the results have varied between centres depending on the frequency of the stimuli and the interclick interval. we studied 10 ad patients, 10 elderly controls (ec) and 10 young controls (yc) using a paradigm of 32 sets of paired clicks. in contrast to previous studies, our study demonstrates significantly larger absolute p50 generation and recovery amplitudes in ad patients compared to elderly controls and young controls. the purpose of study was to establish a simple screening vol. 165, 1996 irish journal of supplement no. 2 medical science test to identify asymptomatic intracranial aneurysms (icas). an association between atherosclerosis and icas is recognised. elevated serum lipoprotein (a) [lp(a)] is an independent risk factor for atherogenesis. we aimed to assess the degree of correlation between serum lp(a) and the occurrence of sporadic ruptured aneurysms and familial asymptomatic aneurysms. lp(a) levels were measured in (a) 50 patients with icas and 42 normal controls, (b) 25 first degree relatives of patients with familial subarachnoid haemorrhage (sah). icas were detected by cerebral angiography. patients with sporadic icas had significantly elevated lp(a) levels when compared with matched controls. mean level was 20.1 mg/dl in patients and 10.8mg/dl in controls. in the familial studies, 10 out of i1 subjects with asymptomatic icas had elevated lp(a) levels. one young female with elevated lp(a) had a pre-aneurysmal dilatation at operation. six out of 14 subjects without icas had elevated lp(a) levels; four of these were in the second or third decade of life and may yet develop aneurysms. conclusions: lp(a) has potential as a biological marker for icas. follow-up studies are required on angiographically negative subjects. we have begun a genetic case-control study to establish if particular apoprotein (a) gene polymorphisms can be correlated with the occurrence of icas. post mastectomy breast reconstruction has undergone several changes in the recent years. attitudes have changed towards the problem from both the patient and the reconstructive surgeon, as aesthetic outcome receives a greater emphasis than previously. there is a shift towards using autologous tissue as a means of reconstruction; these new technically difficult procedures entail a longer learning. centralization of this type of reconstruction in highly specialized centres only will serve the patient better. we share our experience of post mastectomy breast reconstruction spread out over the past five years. seventy-eight consecutive cases of breast reconstruction are included in the study. different techniques of breast reconstruction were used with a recent switch to transverse rectus abdominis myocutaneous (tram) flap; we feet that tram flap is the gold standard of breast reconstruction as far as the ultimate cosmetic result is concerned. ours is only a moderate sized study compared to some published, yet it is representative of the experience of most of the plastic surgery units in the british isles. clinically significant paraneoplastic neurologicaldisorders are rare, most are associated with small cell lung, female genital tract and breast carcinoma. the malignancy is often silent and the neurological manifestations vary from encephalomyelitis, cerebellar degeneration, sensory neuropathy to neuromuscular block. prognosis is usually poor. pathogenesis is thought to be related to cross reaction with neurons of antibody produced to tumour antigens. detection of these antineuronal antibodies in serum has assisted diagnosis of paraneoplastic encephalomyelitis in which anti-hu antibodies are present and cerebellar degeneration, in which anti-yo are found. in our lab, we used avidin-biotin-complex immunocytochemistry to detect anti-hu (cortical neuron antibodies) and anti-yo (purkinje cell antibodies) in patients' sera. tests were performed on human frontal cortex and cerebellum, at 1 in 500 and 1 in 4,000 dilutions, with positive and negative controls. of 68 sera, 6 were positive. two patients had repeat positives; in one, antibody titre rose in the second sample. subsequent patient review showed 3 positives (2 patients) had identifiable carcinoma with paraneoplastic cns signs, 2 had no identifiable malignancy but had no other cause of their cns disorder and are being followed up; details of one patient were unavailable. these results are similar to other centres. the proliferation of tumour cells despite the presence of tumouricidal mediators could be due induction of a heat shock response, a universal cellular defence mechanism in host cells and possibly tumour cells. protection may be mediated either by increasing intracellular levels or surface expression of heat shock proteins (hsp). the aim was to assess the effect of heat shock induction on tumour cell protection against host effector cells. the heat shock response was induced in sw707 colorectal cells by either sodium arsenite (0-320~tm for 6hr) or by hyperthermia (42~ for 20 rain). monocyte (m0)-mediated cytotoxicity or flow cytometry to evaluate surface expression of hsp60 and hsp70 were assessed. cytotoxicity showed a significant decrease in all treated groups (p<0.002) when compared to the control value. there was also a significant decrease in all groups (p<0.001) when compared to the 42~ value. no significant alteration in surface expression of either hsp60 or hsp70 was seen. conclusion: heat shocking tumour cells significantly protects them from m0-mediated tumour cell lysis. since the flow cytometric data indicate that there is no concomitant increase in surface expression of hsp60 and hsp70 on the tumour cell following heat shock, it can be inferred that induction of intracellular hsp levels are responsible for the protective effect on the tumour cells. a 4 week qol study in 157 consecutive advanced cancer patients was undertaken to compare the subjective 28 question fact-g with simple subjective global tools (visual analog, categorical scales: vas, cas), objective tools (spitzer qli and ecog performance status) and verbatim patient description. we anticipated the high drop out rate enrolling 157 to achieve 87 complete study patients for statistical purposes. the study sample appeared representative of the advanced cancer population in the usa. generally qol was satisfactory despite the severity of illness. there were significant differences in all measures between those who described qol in verbatim responses as positive and negative, particularly cas, vas, and qli (p<0.0001). there were significant intercorrelations between qli and ps (observer rated), vas and cas (subject rated) respectively (p<0.0001). taking patient description as the gold standard, simple, global qol measures e.g. vas or cas are as effective as multidimensional ones (fact-g and qli). irish journal of medical science males had more dysphagia. survival from diagnosis was greater for females </=65 years (female median 18 months, male median 13 months, p<0.0016). anorexia was associated with reduced survival since diagnosis in the total population and in males. anorexia anddysphagia were associated with reduced survival from referral. advanced cancer patients were polysymptomatic. symptom prevalence differed with age, gender and cancer site. the pattern of g1 symptoms was related to gender and severe weight loss. specific symptoms were associated with reduced survival. there was a gender difference in survival favoring females. the administration of recombinant interleukin-2 (rll-2) is limited by the induction of increased microvascular permeability. the in vivo antineoplastic effects of taurine in combination with rll-2 were investigated and its impact on the associated vascular leak was examined. lung metastases were established in mice via tail vein injection. ten days after injection mice were randomized into treatment groups. on day 18 the mice were sacrificed; lungs were removed, weighed and metastases counted. treatment of tumour-bearing mice with rll-2 alone resulted in a significant reduction in tumour nodule incidence compared to a control group, while the~group recei'~ing rll-2 + taurine showed an even fuither reduction in the incidence of lung nodules. animals receiving rll-2 showed a significant increase in mean wet lung weight compared to control lung weight, while mean wet lung weight of the rll-2 + taurine group was significantly less than that of the rll-2 group.and comparable to control values. animals receiving ril-2 + taurine in vivo demonstrated significantly enhanced splenocyte-mediated antimelanoma activity ex vivo compared to animals receiving rll-2 alone. thus taurine may have an important role in modulating both metastatic growth and the associated toxicity of rll-2 immunotherapy. a prospective analysis of symptoms in 1,000 patients on initial referral to the palliative care service of the cleveland clinic was made using the paradox relational database. the median number of symptoms per patient was 11 (range 1-27). the 10 most frequent symptoms were pain 82%, easy fatigue 67%, weakness 64%. anorexia 64%, >10% weight loss 60%, lack of energy 59%, dry mouth 55%,'eonstipation 51%, dyspnea 51% and early satiety 50%. patients 65 years and under had more pain, sleep problems, depression, anxiety, vomiting and headache (all p<0.01 ).'the prevalence of early satiety, nausea, vomiting and anxiety were greater in females; dysphagia 3nd hoarseness in males. patients with >/= 10% weight loss had more gi symptoms; of these females had more nausea, early satiety; the progn.o'stic significance of abnormalities in the p53 tumour suppressor gene and in the expression of its protein in colorectal carcinoma may be influenced by the method of analysis used. we studied p53 abnormalities in 66 patients with colorectal cancer followed for more than 10 years. single-strand conformation polymorphism analysis (sscp) was used to detect alterations in exons 5-8 of the p53 gene. paraffin sections were examined immunohistochemically for p53 overe,xpression with the monoclonal antibody do-7 (dako) both with and without microwave antigen retrieval. abnormalities of the p53 gene were found in 41% of cases by sscp analysis but were unrelated to age, sex, tumour size or differentiation. outcome was unrelated to sscp abnormalities (p=0.19). overexpression of p53 protein was seen in 47% of cases by immunohistochemistry without microwave antigen retrieval and in 52% of cases with microwaving. poor long-term survival was related to immunohistochemical expression of p53 protein either with (p=0.03) or without (p=0.02) microwave antigen retrieval. these results suggest that immunohistochemical detection of the p53 protein product may be more useful than sscp analysis of the encoding p53 gene in identifying those at high risk of colorectal cancer recurrence and death. dublin 9. the anti-tumour activity of tumour infiltrating lymphocytes (tils) is known to be poor and therapeutic manipulation of these cells has met with little success. suppressor macrophages (smo) influence t cell cytotoxicity and proliferation. we hypothesized that smo are a component of the lymphoreticular infiltrate and that these cells may be related to lymphocyte numbers within the tumour. tgf-b may influence macrophage phenotype. colorectal and breast tumours were obtained within an hour of resection. tumours were dissaggregated with collagenase and dnase for three hours. antibodies was used to identify smo (rfd 1 and rfd7) and t cell subsets (cd4 and cd8) by flow cytometry on the resulting cell suspension. pre-op blood was collected from patients and tgf-b levelsdetermined by elisa. conclusions: we have shown for the first time that smo, defined by the antibodies rfd1 and rfd7, are present within breast tumours. we have also shown that the balance of t cell subsets is different in these tumours and may be related to smo content. circulating tgf-b levels are increased in breast cancer and associated with greater smo numbers. this was not found to be the case in colorectal cancers. these results imply the existence of a fundamental difference in the make-up of the lymphoreticular infiltrate between these cancers. swelling of the upper limb is an uncommon but well irish journal of medical science recognised complication of breast cancer treatment. in severe cases, patients have limited arm function and feel disfigured. in a pilot study, the incidence of arm swelling following complete axillary clearance in the immediate post-operative period and at long term follow-up was investigated. arm volume measurements were performed using an opto-electronic volometer (bosl medizintechnick, hamburg). both ipsilateral and contralateral arm volumes were assessed. the expected volume of the ipsilateral arm volume was calculated using the formula vr = v1 = 31 mls for right handed people and v1 = vr = 25 mls for left handed people (vr and v1 = volume of the right and left arms respectively). the difference between the expected and actual volume of the ipsilateral arm was expressed as a percentage of the expected volume. twelve patients undergoing axillary clearance for breast cancer were prospectively evaluated pre-operatively, 48 hours and 5 days post-operatively. a second group of 48 patients who had had axillary clearance at least 3 months previously (range 3 to 116 months) were also evaluated. there was no significant change in arm volume in the immediate post operative period. clinically detectable arm welling was found on 3 patients who had undergone axillary clearance at least 3 months previously but none had any impairment of arm function. we conclude that axillary clearance can be performed safely and that arm swelling is an uncommon complication. a larger study is planned to investigate factors such as the influence of pectoralis minor division, duration of the operation and the number of axillary nodes retrieved on upper limb volume. epidermal growth factor (egf) is a potent mitogen and has been shown to accelerate healing of epithelial damage both in the skin an.d the gut. in the skin egf is not produced locally as the requisite mrna is not present but egf receptors are present on the surface of basal keratinocytes. egf is produced in various sites in the gi tract including the submandibular salivary glands. we have hypothesised that as there is upregulation of salivary egf production in some enteropathies a similar situation may occur in disorders of the skin with an associated enteropathy. using a sensitive radio-immunoassay, egf activity was estimated in stimulated saliva from 87 patients with various skin disorders, 49 patients with gastrointestinal disease, 8 patients with mixed dermatological and gut disease and 41 normal healthy volunteer controls. elevated egf activity was found in the following groups of patients : skin cancers, psoriasis, acne, oesophagitis and ulcerative colitis. the hypothesis of up-regulation of salivary egf production in skin associated enteropathy was rejected but the discovery of elevated egf activity in skin cancers and psoriasis may have aetiological and therapeutic implications. the malignant fibrous histiocytoma (mfh) is considered an uncommon malignancy. its potential for invasion, metastasis and death of patient has been reported in literature. it can be confused with other tumours including fibrosarcoma. salient histologic features include cells of both the fibrocytic and histiocytic series. mfh with its high recurrence rate and lethal potential merits an aggressive evaluation and treatment. we present unusual case of recurrent mfh treated in our unit with an open question as to what qualifies to be adequate primary surgical excision. the recommended management of localised merkel cell carcinoma has been wide surgical excision, combined with adjuvant radiotherapy in selected cases. the risk of recurrent regional disease is reported to be between 30% and 45%. a 70 year old woman with merkel cell tumour on the cheek is presented; this patient was treated exclusively with radiotherapy to a total dose of 50 gy over 18 days. the tumour regressed rapidly during the treatment, and there were no signs of local or regional recurrence. the patient is still alive and free of disease for 45 months. immune in origin with a heightened cutaneous immune response to ultraviolet light. the coexistence of cad and pbc is a new association which has not previously been documented and may not be fortuitous given the similar pathogenesis of both diseases. chronic actinic dermatitis (cad) is a rare photosensitive disorder which primarily affects elderly men resulting in an eczematous reaction to ultraviolet-radiation and sometimes visible light. the pathogenesis has been attributed to an autoimmune process, possibly in response to a photoallergen which has yet not been identified. we report a 71 year old female patient who developed cad four years after being diagnosed with primary biliary cirrhosis (pbc). abnormal monochromator irradiation tests were detected with narrow band ubv, uva and in addition visible light wavelengths. phot0provocation tests induced florid vesicular eczema and multiple patch and photo-patch tests were positive, findings typical of cad. immunoglobulin g was elevated at 2290 mg/dl and liver histology was typical of pbc with an elevated anti-mitochondrial antibody. routine biochemical and immunological tests were ~ormal and porphyrin screen was negative. azathioprine 50 mg/day induced remission of cad. pbc is an auto-immune disorder where cell-mediated immunity is impaired, suggesting that sensitized t lymphocytes may cause damage to bile ducts. the pathogenesis of cad may be autowe present two cases of cutaneous polyarteritis nodosa (pan) associated with seronegative arthritis: the first patient, a 50 year old male presented in 1993 complaining of a7 year history of pain, stiffness and swelling affecting his right ankle. he also noted intermittent tender nodules on the dorsum of his foot and over his ankle over the preceding three years. the second patient, a 51 year old male, presented .in 1994 complaining of a 5 month history of tender nodules on his shins, and pain and swelling of his right ankle. skin biopsies of the nodules in both cases showed medium vessel vasculitis consistent with polyarteritis nodosa. neither patient had any symptoms or signs to suggest systemic involvement. the only abnormality.0n laboratory investigations for vasculitis was elevated esr. x-rays showed periosteal elevation and new bone formation in case 1, and were normal in case.2. bone scan demonstrated increased uptake at the talo-navicular joint in case 1 and at the fight ankle in case 2. synovial biopsy and mri confirmed the presence of an inflammatory arthropathy in patient 1. joint involvement has been a prominent feature throughout the course in both cases requiring aggressive treatment with vol. 165, 1996 irish journal of supplement no. 2 medical science cyclophosphamide and systemic corticosteroids in case 1. cutaneous pan is a localised cutaneous vascular disorder with a benign chronic relapsing course. in one reviewl, 12 of 23 patients had arthralgias but an association with arthritis has not been emphasized in the literature to date. we conclude that this condition may present as a seronegative arthropathy in which the joint symptoms may be the most prominent feature and aggressive immunosuppresive therapy may be required for control. cardiac transplantation patients have an increased risk of skin disease. in our centre, 119 heart transplants were performed with a 5 year survival of 75%. eighty three patients are now alive and 39 have required dermatological assessment. the mean age of patient was 48.3 years, (range 11-64 years); 99 males, 20 females. skin infections were diagnosed in 13 of 39 patients. drug side effects, including sebaceous hyperplasia and steroid acne, were common. in the patients who developed skin cancer, mean time from transplant to development of lesions was 3.1 years. eleven of 36 patients had 32 non melanoma skin cancers (nmsc), 28 squamous cell carcinomas (scc), 4 basal cell carcinomas (bcc), giving scc/bcc ratio of 7:1. three of 11 patients had multiple skin cancers, one had 12 tumours. nine of 39 patients had actinic keratoses, two thirds of whom had sccs. nineteen of 39 patients had viral warts, two of whom had sccs. viral warts, premalignant and malignant lesions were located on sun exposed sites. skin complications of cardiac transplantation though mild were very common. the observed incidence of nmsc in age matched cardiac transplant recipients, appears much higher than the expected incidence of 171.38 per 100,000 population (national tumour registry 1994). regular dermatological assessment of cardiac transplant patients is necessary to detect skin disease and early skin cancer. the increased incidence of warts and skin cancer in renal transplant recipients {rtr} is well known. the oncogenic potential of unusual human papilloma virus {hpv} types has been postulated from warts and in both premalignant and nonmelanoma skin cancer (nmsc). the possible etiological role of sun-exposure in facilitating the development of hpv associated skin disorders is also suggested. a clinical study to assess the risk factors for development of these lesions in 50 rtr attending the dermatology servic& age and sex matched haemodialysis patients were similarly examined as controls. 40 male and 10 female patients with a mean duration of transplant of 10.6 years, range 1 to 25 years. a total of 191 nmsc (range 1 to 57),175 scc and 16 bcc, ratio 10.9:1, were excised from 26 rtr of which over 95% had viral warts, mosle commonly occurring on sun exposed sites and always predated the development of neoplastic lesions. both were associated with mean duration from transplantation, 4 years for warts and 10.8 for skin cancer and not the type of immunosuppressive treatment. none of the control patients had similar findings. conclusions: the close clinical association of viral wart lesions and development of skin cancer in these patients suggests a close relationship to immunosuppression, in addition to exposure to ultraviolet radiation. this study highlights the high rate of nmsc in rtr. these patients justify early and regular skin assessments soon after transplantation with advice on sun protection. sensitivity to ultraviolet (uv) light may be established by exposure to broad band uva and uvb radiation. the minimal erythema dose (med) can be determined at individual wavelengths using a monochromator. uv action spectra of photosensitive disorders may thus be constructed. we examine the value of this process in distinguishing two clinically similar photosensitive disorders. the radiation from a xenon arc is separated into component wavelengths using the monochromator. each wavelength is focused on unaffected skin, on the patient's back. the patient is exposed to a range of doses of w radiation. the med is determined for a series of wavelengths from 300 to 400 nm. chronic actinic dermatitis (cad) and drug induced photosensitivity are photosensitive disorders which may have similar clinical history and presentation. ten cad and 14 drug induced photosensitivity patients were tested. uva photosensitivity was seen in 71% of the latter group. the remaining 29% had normal mlts as the implicated drug had been discontinued prior to testing. cad patients were sensitive to both wa and wb radiation. forty-three percent of these patients were also sensitive to visible light (400 to 800 nm). monochromator light test (mlt) results show that uva photosensitivity dissociated from wb photosensitivity is indicative of a drug induced light sensitive disorder. sensitivity to both wa and wb however indicates a diagnosis of cad. mlts can therefore distinguish between clinically similar photosensitive disorders. bartholomew's hospitals, london. patients with mpd have an increased incidence of both thrombosis and haemorrhage suggesting a pivotal role for; platelets in these conditions. this study aimed to examine platelet activation antigen expression in stable patients with mpd and to examine the predictive value of these antigens prospectively. 52 patients with mpd had p selectin and gp53 measured using a refined minimally manipulative flow cytometric technique. expression of p selectin -median 5.1% (inter quartile range 2.1-10.9), control 2.0% (1.3.-4.0) and gp53 -median 4.0% (1.8-5.7), control-2.1% (1.0-2.9), were significantly elevated p<0.01. patients were followed for a median of 26 months. 15% experienced thrombosis and 6% bleeding during follow up. at entry to the study 48% of patients had previously experienced thrombosis, median disease duration 8 deaths, 3 of which were caused by thrombotic events in which the mpd was a major risk factor. increased expression of p selectin or gp53 expression failed to predict thrombosis or bleeding in this study. nor was any significant retrospective relationship demonstrated. however, previous thrombotic events were strongly associated with future events (p<0.05). this association was independent of disease, duration, age and medication. not surprisingly disease duration was also correlated with thrombotic/bleeding events. taurine levels fall in gut mucosal cells during critical illness. however, taurine transport into human intestinal cells is poorly understood. the aim was to establish the efficiency of taurine uptake by enterocytes, and to examine uptake under stressful conditions. to investigate efficiency of taurine uptake, confluent caco-2 cells were incubated for time points up to 10h. in a second study, cells were incubated for 9h with medium containing dexamethasone and / or cytokines. media for both studies was supplemented with [3h]-taurine. radioactivity was related to mg/ml protein to calculate rate of taurine uptake for each time point. study 1: uptake exhibited a steady linear response which approached saturation at 7h. maximal uptake occurred at 9h after which the rate levelled off. study 2: dexamethasone alone reduced taurine uptake by 75.4% (p<0.001) and in combination with tnf-c~ and ifn ~/ it decreased transport by 66.3%. (p<0.001). lps alone impaired uptake by 56% (p<0.001). conclusion: we have established the time course over which taurine transport reaches its maximum rate in caco-2 cells, and that corticosteroids and cytokines significantly impair uptake of taurine in these cells. elderly individuals have an increased risk of infection suggesting that immune responsiveness is altered with age. changes in the level of proinflammatory cytokine production may be an important indication of any such age related change. using flow cytometry we examined intracellular tnfet, il-lf~ and il-6 in pbmcs from normal healthy volunteers of different ages ranging from 22 up to 85 yr (n=28). tnf and il6 levels from pma stimulated cd3 positive cells (t cells) were shown, using this technique, to increase in an age dependent manner (p<0.05). no il-113 was detected in any t cell sample. no significant differences were observed between the different age groups for tnfa, il-1 g or il-6 in cd 14+ cells (monocytes). the age related changes detected by flow cytometry have been confirmed using conventional elisas. this novel method of proinflammatory cytokine detection has detected increased tnf and il6 levels in t cells from elderly healthy volunteers which may help explain some of the exaggerated inflammatory responses seen in elderly patients. detection of proinflammatory cytokines by conventional elisa or bioassay is problematic due to the presence of naturally occurring biological inhibitors. flow cytometry allows the simultaneous detection of both intra and extracellular antigens thus intracellular cytokine levels can be quantified while cell surface markers allow cell type identification. a range of monoclonal antibodies were examined for tnfcx, il-lg and il-6 using saponin permeabilisation oft cells (cd3), monocytes (cd14) and epithelial cells (ber-ep4). t cells and monocytes were grown in ~culture, t~p :to 72 hr with or without pma activation, and intracellular cytokine levels were shown to increase with time, with the stimulated samples producing more cytol<ine than the spontaneous.samples (p<0.05). elisas performed on these same samples (n--:24) correlated well with the flow cytometric results (r=0.52). tnf~x, il-113 and il-6 are detectable !n monocytes while only tnfa and il-6 have been detected in tcells and epithelial cells using this methodology. this novel technique will allow us to identify the cytokine producing cell while also avoiding the influence of the extracellular millieu, thus being useful for a number of research and diagnostic applications. all the viral hepatitides are said to be common in the middle east. hepatitis a viru s (hav) seroprevalence is said to be 100% in the adult population of gulf countries. hepatitis b, c and d seroprevalence are taken from blood banks data which are biased by selection criteria and the background of blood donors. very little is known about hev in the uae. vol. 165, 1996 supplement no. 2 irish journal of medical science the aim was to investigate the seroprevalence of hav, hbv, hcv, hdv & hev in the uae. we prospectively recruited volunteers drawn from all the uae, socioeconomic classes and from different age groups in both sexes. each donated 10ml. of venous blood and using an indirect enzyme immunoassay were tested for total ig to hav; hbsag using monoclonal antibody t.o hbsag; for hcv antibodies using recombinant antigens hc-34, hc-43, c-100 and ns-5, (3rd generations); for total ig to hdv and for total ig to hev. positive samples were retested in duplicate for confirmation. this large sero-epidemiological study clearly shows that hav is decreasing in the uae. hbv is low but significant, hcv is similar to southern european countries, hev is lower than expected and hdv does not exist in hbsag carriers in the uae. reactive oxygen and nitrogen species produced by inflammatory cells plays a role in tissue injury and inflammation. taurine, a bamino acid present in high concentrations in leukocytes functions as an anti-oxidant by scavenging the mpo derived oxidant, hypochlorous acid, to form taurinechloramine. experimental colitis was induced in male sprague-dawley rats and randomised into two groups. one group received tap water whilst the second group was supplemented with taurine (4%). these groups were sub-divided into those receiving tnbs/ ethanol (n=8) or saline (n=8). an increase in wcc count, particularly neutrophils was found in colitis. tat~rine was found to reduce the severity of the disease (ns) usin.g a colon macroscopic score. in the first group, respiratory burst activity was reduced in animals that had developed colitis (p<0.05) although mpo activity was augmented (p<0.05). nitric oxide production was 2.2 and 1.8 fold respectively higher in inflamed and non-inflamed areas of the colon than that by normal colonic mucosa. animals supplemented with taurine demonstrated attenuated m po activity (p=0.001). administration of taurine did not lead to a reduction in nitric oxide production. thus, taurine appears to have a beneficial role in reducing the severity of disease. a reduction in mpo and respiratory burst may be beneficial in reducing tissue damage. to women subsequently identified by a national screening programme which revealed 438 to be positive for rna of hepatitis c, type lb. 94 were referred to this centre for evaluation. 10 had moderate activity by modified knodell index, mean 8 (_+1.4), bridging fibrosis and a mean alt of 77 (42-176). six months dual therapy was administered. two patients withdrew due to depression (2) and hyperthyroidism (1). one patient di d not respond. seven responded with normalisation of alt and negative pcr. eight patients showed improved histology (kai 4 +_ 1.5), fibrosis was unchanged. adverse reactions in the treated group included marrow suppression (1) and thyrotoxicosis (1) . at six months follow up four remain in remission with normal alt negative pcr, three have relapsed, (pcr positive, mean alt 87(50-150). we conclude that despite adverse prognostic indicators in this homogenous group with chronic hepatitis c, lb and long disease duration, dual therapy with interferon and ribavirin achieved results comparable to prolonged high dose interferon in patients with more favourable initial prognoses. the aim of the study is to evaluate a 5 day course of azithromycin in combination with omeprazole in eradication of h.pylori. twenty-four patients with proved h.pylori infection and peptic ulcer disease were treated with omeprazole 40 mg daily for 2 months plus azithromycin 500 mg daily for 5 days. h.pylori was diagnosed on the basis of clo test and histology. this was done at the beginning and 3 months after the treatment. eradication was defined as negative clo test as well as negative histology. out of 24 patients, 2 patients were lost to follow-up. only 21 patients were analysed. sixteen patients responded to treatment and had successful eradication as well as healing of their ulcers. these included 8 patients with gastric ulcers (79.95%), 4 patients with duodenal ulcers, 2 patients with gastric and duodenal ulcers and 3 patients with non-ulcer dyspepsia. five patients did not respond including 2 with non-ulcerative dyspepsia. 2 duodenal ulcers and 1 gastric ulcer. however their ulcers have healed and symptoms relieved and they were treated with other h.pylori eradication regimes. conclusion. in this small study we have shown that azithromycin 5 mg oncedaily for 5 days is an alternative safe effective and well tolerated monotherapy for eradication of h.pylori. it has been suggested that hepatitis c virus (hcv) infection is associated with a high prevalence of autoimmune disease, but that this risk may be diminished in patients who received a low viral load at initial infection. the aim was to determine the prevalence of symptoms, signs and markers of autoimmune disease in a group of women vol. 165, 1996 irish journal of supplement no, 2 medical science infected with hcv contaminated anti-d immunoglobulin. 50 patients, mean age 44.3 years (range 32 -65 yrs) were examined. 7 patients (14%) were rheumatoid factor positive. ana was positive in 6 patients (12%) but titres were 1/10 in 4/6. thyroid globulin antibodies were found in 3 patients (6%) with 1 also being tm positive. 2 further patients were positive for thyroid microsomal ab. prevalence of apa, ara, sm were 4%, 2% and 2% respectively. one patient had cryoglobulins detected while antibodies against mitochondria and lkm-i were not found only one patient of 50 was symptomatic. these levels of antibodies are no greater than levels in the general population and similar to other groups infected with hcv contaminated anti-d. these results further support the hypothesis that either low viral innoculum or long duration of infection may in some way result in a low level of autoimmunity. a previous study (ilan et al, arch int. med., 1993; 3: 1588-1592) suggested that lga deficiency disposes towards hepatitis c virus (hcv) infection in some patients. it has also been suggested.that iga deficiency may occur as a result of the viral infection as a secondary event. the aim was to determine the prevalence of selective and partial lga deficiency in patients with hcv infection using a radio-immunodiffusion technique. serum lgg and igm levels were also examined. immunoglobulin levels were measured in 67 patients, 59 women and 8 men, mean age 45.3 years (range 29 -72 years) infected with blood between 1977 and 1990. none of the patients were found to have selective or partial iga deficiency. mean iga = 2.59 g/l (range 0.86 g.1 -5.19 g/l). furthermore no patient exhibited deficiency of igg or igm. conclusion : no evidence of iga or other immunoglobulin deficiency exists among this group of patients with hcv infection. while it may be possible that lga levels decrease following infection, no evidence exists that this phenomenon persists in the long term. hereditary non-polyposis colorectal cancer (hnpcc) is the most common form of hereditary colon cancer and accounts for up to 10% of the overall cancer incidence. the disease is inherited in an autosomal dominant manner andis characterised by predominantly right-sided tumours. hnpcc is caused by mutations in one of four mismatch repair genes. these genes are homologues of the bacterial mismatch repair systerfi and their function is to detect and correct defects in dna. the hmsh2 gene is reported to account for up to 60% of cases, hmlhi, hpms1 and hpms2 account for 30%, 5% and 5% of cases respectively. we have collected eighteen irish hnpcc families which satisfy the amsterdam criteria for the disease. we have screened the entire hmsh2 gene in eight of these families. a combination of single strand conformational analysis (sscp) followed by dideoxy sequencing was used to detect defects in the dna. sequence analysis revealed the presence of a novel polymorphismin exon 5 in one family and a possible splice site mutation in the remaining ten families, using a novel mutation detection technique. departments of medicine and immunology, university college hospital, galway. serial iga gliadin antibody (igaga) studies are used as a surrogate for repeated small intestinal biopsy to monitor dietary compliance in treated coeliac patients. we have correlated igaga levels with indices of hyposplenism (platelets and erythrocyte "pits") to determine if either index can be used to monitor adherence to a gluten free diet. the study population of 129 biopsy proven coeliacs was stratified according to dietary status into 114 gluten free diet (groups a) and 15 normal diet (group b). the iga gliadin antibody titres were significantly lower in group a than group b (44.5 : 126 units p = 0.007). in group a gliadin antibody titres showed a statistically significant correlation with both platelet (p = 0.039) and pits count (p --0.04) ; in group b gliadin antibody titres correlated with platelet counts only (p -0.003). those ona gluten free diet were further subdivided according t ~ reported degree of adherence to the diet (strict diet -sgfd, lax'diet -lgfd). significantly higher gliadin antibody titres were found in lgfd than sgfd (103.6; 27.9 p = 0.003), but the ptatelet and.pit counts were similar in the two groups. igaga is superior to platelet or pit coums in monitoring dietary'compliance in coeliac disease. hospital, galway. iga endomysial antibodies (igaea) are said to be more specific and sensitive indicators of coeliac disease than iga gliadin antibodies (igaga). initially the igaea substrate was monkey oesophagus and more recently umbilical cord. a new commercial product has becomeavailable using primate smooth muscle (accu track -diagnostic slides). we have undertaken a preliminary study to compare the performance of this lgaea assay and igaga elisa in treated and untreated coeliacs, coeliac relatives and controls. the study population consisted of 127 biopsy-proven coeliacs who were stratified according to "reported" dietary status into 89 good gluten free diet (group a), 24 poor gluten free diet (group b) 14 normal diet (group c) and 10 unaffected coeliac relatives (group d) and 5 controls (group e). elevated igaga (>25 units) were found in the following groups : a 37%, b46%, c 50%, d 20%. igaea were positive in a 27%, b 33%, c 50%. with respect to igaga positivity, there were 11 false positive igaeaa 18%, b 12.5%, c 14% and 23 false negative -a 8%, b 8%, c 14%, d 20%. in this preliminary study in untreated coeliac patients the performance of the igaea test was on a par with the igaga assay. alt and fibrosis may be associated with a non-alcohol steatohepatitis and these processes may be synergistic. finally, number and type of riba bands is not a predictor of inflammatory activity. ~stepping hill hospital, stockport, uk sk2 7je. 2royal oldham hospital, rochdale rd., oldham ol1 2jh. we investigated upper gut bleeding in patients aged 75 years and over. a proforma addressing demography, drug therapy, clinical status, timing of endoscopy / surgery, and outcome was used. 109 consecutive patients (median age 80 years, range 75-92) were studied over 6 months. 106 (97%) underwent gastroscopy with a 97% diagnostic yield. 32 patients had severe oesophagitis, 2 had oesophageal malignancy, 29 had gastric ulcers -5 of which are malignant and 23 had duodenal ulcers. ulcerogenic drugs were implicated in 52 patients. 38 patients were referred for surgery, 8 operated upon with one postoperative death. 51 had haemoglobins of 10g/dl or less. all malignant lesions were inoperable. the overall mortality was 6% reducing to 2% if neoplasla were excluded. co-morbidity influenced mortality. 92 patients were discharged with a median hospital stay of 15 days. information on cause of bleeding greatly influenced management. the prognosis of gut haemorrhage in the very old need not be so poor. a few require surgery but the majority respond to active medical resuscitation which is a key factor in determining outcome. we advocate low threshold for endoscopy, judicious use of ulcerogens and adherence to guidelines on management of upper gut haemorrhage. haemochromatosis (hh), a common recessively inherited disorder of iron metabolism is closely linked to the hla-a locus on chromosome 6. linkage studies have demonstrated a close association between (hh) and the hla alleles, a3 and b7 ("ancestral haplotype"). heterogeneity at the molecular level may account for the variance in clinical phenotypic expression. the aim was to evaluate phenotypic expression of hh in the presence/absence of the a3-b7 ancestral haplotype. 32 probands (26m:6f) from unrelated irish families were investigated. phenotypic variability was assessed with regard to l) age; 2) % trans.sat.; 3) serum ferritin; 4) liver bx iron grade; 5) body iron stores and 6)symptomatology. three males were homozygous for a3b7, 15 were heterozygous for a3b7 and 2 were non-a3b7. symptomatology, trans, sat., serum ferritin and liver bx grade were not influenced by homozygousity or heterozygousity for a3b7. conclusion: there were no significant differences in phenotypic expression on comparison of the three haplotype groups. no predominant genotype appears to be responsible for phenotypic severity in irish families indicating the possibility of multiple mutagenicity of the hh gene. of 1013 riba positive anti-d associated chronic hepatitis c patients, 438 were pcr positive but had surprisingly mild disease. the disease status of the pcr negative patients was hitherto uncertain and is the subject of this study. 20/72 riba positive patients referred to this centre were biopsied because of elevated alt (4) or florid symptoms which dated from inoculation (16). 1 2 3 4 histological activity index * 5,1,0,1 3,2,5(f), 2(f), 0,4(f), 2,1,2 0,2,1,2 2,2,3 no bile duct damage, lymphoid follicles or aggregates was observed. 3/20 had mild periportal fibrosis (f), 2 of these had steatohepatitis with obesity (1) and impaired glucose tolerance (1) suggesting dual pathology. we conclude that riba positive, pcr negative patients have minimal disease activity. elevated the association between the hla locus and haemochromatosis (hh) has allowed early identification of affected siblings. it is unclear what proportion of subjects who are predicted to be homozygous or heterozygous for the disease by hla typing develop the disease. studies correlating clinical features with hla type in families from ireland -a putative source of this celtic trait have not been described. the aim was to correlate clinical, biochemical and pathologic features of hh with hla typing in 67 first degree relatives of 12 probands. initial analyses identified 12 homozygous (hh), 40 heterozygous (hn) and 15 normal (nn) individuals. however, 11/40 hn individuals had stainable iron on liver biopsy, confirming hh. further hla analysis revealed 7 homozygous x heterozygous matings and identification of all disease haplotypes within each pedigree allowed final classification of 30 hh, 25 hn and 12 nn individuals. vol. 165. 1996 supplement no. 2 conclusion: this study demonstrates the importance of hla typing in the clinical management of families with hh, furthermore, in multiply affected families the incidertce of homozygous x heterozygous matings is high indicating the high degree of "pseudodominance" in the irish population. the degree of acute hepatic failure after severe trauma and sepsis is related to the extent of hepatocyte (hc) damage and cell death resulting from either necrosis or apoptosis. we have previously demonstrated that tnf-ct and lps can directly lead to hc necrosis, but not apoptosis. recent, studies have shown that reactive oxygen intermediates (roi) and nitric oxide (no) are capable of inducing apoptosis in eukariotic cells. however, it is unclear whether roi or no are involved in hc cell death. the aims of this study were to evaluate the role of no and roi in hc cell death (apoptosis vs necrosis). hcs were isolated from sprague-dawley rats, and cultured with the no donor, sodium nitroprusside (snp) or the roi generation system, hypoxanthine-xanthine oxidase (hx-xod) and h202. the effect of lps, tnf-t~, and ifn-y alone or in combitmtion with different antioxidants and the no synthase inhibitor, n-methyl arginine (nma) on hcs was also assessed. snp caused a dose-dependent increase in hc apoptosis. roi generated by hx-xod and h202 did not induce hc apoptosis, but were responsible for hc necrosis. tnf-ct alone failed to induce hc apoptosis, but when ~combined with antioxidants resulted in increased hc no production and apoptosis. this effect was attenuated by nma. snp also induced hc damage and hc necrosis. moreover, tnf-ct-mediated hc damage and necrosis could be further reduced by the combination of antioxidants and nma. these results indicate that roi preferentially induce hc necrosis, but not apoptosis. induction of no resulted in both hc apoptosis as well as hc necrosis, which suggest that overproduction of no may be detrimental during the sirs. irish journal of medical science intervention was not uniform. mean albumin was 34.3g/1. mean weight was 57.8kg. poor cognitive status greatly increased the requirement for dietetic consultation time. lack of dietetic resources results in inadequate monitoring of these patients following discharge. this study highlights the need for a dedicated clinical nutrition service, for medical services for older people. periconceptual consumption of folic acid has been shown to decrease the incidence of neural tube defects. the preventative strategy of universal food fortification with folic acid presents the possible risk of masking the diagnosis of cobalamin deficiency in pernicious anaemia. in addition, the ultimate longterm effect of universal exposure of adult or foetal cells to a synthetic substance, ie. folic acid, is unknown. in this study, the threshold oral dose of folic acid in a number of foods above which metabolically-unaltered vitamin appeared in serum postprandially was determined in a young and elderly population by microbiological assay of serum pre-fractionated by hplc. subjects on a five-day regime of fortified cereal and bread along with their normal unfortified diet. were shown to have a threshold level of 400~g/d, abovewhich unaltered folic acid appeared in the serum. individuals given folic acid in either isotonic saline, milkor white bread exhibited a threshold level of 200~tg per serving. from patterns of food consumption in ireland, even moderate levels of fortification are likely to lead to some population groups being exposedto excessive amounts of un-altered folic acid in serum. many older people are nutritionally compromised. there is clear evidence that: nutrition intervention reduces morbidity m and mortality in older patients. to identify the spectrum of nutritional abnormalities referred for dietetic intervention and the problems associated with nutritional assessment, 50 elderly patients were alphanumerically selected from files of the department. of nutrition and dietetics. the most common dietetj.c interventions were: use of supplements 60%; high protein high calorie diet 46%; nasogastric feeding 26%; reduction fat 8%; iron/thiamine assessment 6%; high fibre diet 6%; diabetic diet 4%; nutrition swall6w programme 2%; lipid lowering diet 2%. some 60% referred required nutritional supplements, but the profile of an increase in oxidative stress in cystic fibrosis patients has been suggested. activated neutrophjls in the presence of chronic lung inflammation in addition to increased activity of the electron transport chain in cfmay. increase free radical generation. antioxidant protection against free radical attack is likely to be compromised as a i'esult of deficiencies in fat soluble antioxidants vitamins. in the present study stimulated thiobarbituric aoid reacting substances (tbars) were measured to determine the ability of plasma to withstand lipid peroxidation. copper was used to in!tiate the breakdown of lipids to lipid hydroperoxides and eventually to aldehydes, mainly malonyldialdehyde (mda). pooled cf plasm a and pooled control plasma were incubated for 0, 30, 60, 90, 140 and 200 min. mda complexes with thiobarbituric acid which absorbs at approximately 535 rim. there is a lag phase where antioxidartts vol. 165, 1996 irish journal of supplement no. 2 medical science in the plasma or tissue protect against lipid peroxidation, then a log phase where the protective effect is overcome and finally the reaction reaches a plateau when lipid peroxidation is complete. absorbance at 532 nm was measured in all samples and zero order and first derivative spectra were obtained. the lag phase appears to be longer in the pooled cf plasma compared with controls. plasma t~-tocopherol levels were within the normal range in both groups, indicatin~ an alternative protective effect in cf. mild hyperhomocysteinaemia is an established risk factor for heart disease. a source of homocysteine in humans is the essential amino acid methionine found in protein of animal origin. in an 8-week study weekly fasting plasma homocysteine levels were examined in a group of healthy male subjects (n=6) under normal dietary conditions (weeks 1 to 4) and in response to graded increased methionine intakes (weeks 5, 6, 7). nutrient intakes, including methionine, were calculated from 4x3-day food records. under normal dietary conditions weekly mean plasma homocysteine levels were not significantly different (anova) from each other ranging from 6.82+1.77 to 9.42+2.73~tm/1. doubling daily methionine intakes (supplementing with 25mg/ kg/d) did not result in a significant increase in plasma homocysteine (8.56+3.68~m/1), however, significant increases were achieved when diets were supplemented with methionine at levels of 50 and 75mg/kg/d resulting in mean plasma homocysteine levels of 13.37+5 9 and 18.051am/1+11.08, respectively. mean plasma homocysteine levels returned to baseline (8.76 + 3.42 ~tm/l) 10 days post supplementation. we conclude that supplementary methionine results in a significant increase in plasma homocysteine only when levels of five times the normal dietary intake are reached. this study is evaluating the use of a synthetic construct which encompasses primer binding sites for lpl and a variety of cytokine and other transcripts, to quantify lpl expression in cultured human monocyte-derived macrophages. following isolation of total rna at various times during cell culture, its reverse transcription (rt) using random hexamer primers generating first strand cdna and specific amplification of lpl cdna targets by polymerase chain reaction (pcr), generates products identifiable on gel electrophoresis. quantitation of message is obtained by incorporating the pawl08 construct in the rt assay in varying quantities as an internal standard with known amounts of monocyte-macrophage rna (l~tg). pcr amplification of this construct yields size distinguishable products from that produced by the monocyte-macrophage lpl cdna transcript. pcr conditions for the assay have been optimised at 29 cycles of denaturation (tmin @94~ annealing (1.5min@55~ and extension (lmin@72~ lpl mrna has been detected in cultured monocytes and macrophages throughout their differentiation. also increased expression of monocyte lpl mrna has been observed following 15 hr incubations with chylomicrons (30t~g/6x 106 mononuclear cells/ ml)-when compared with controls. interestingly, little or no lipase mrna was detectable in circulating monocytes using identical pcr conditions to preparations of mrna from the day 4 and day 8 cultured cells. this methodology will now permit investigation of the factors controlling lpl expression in cultured human monocytic cells. replacement growth hormone (gh) therapy in adult hypopituitarism is attracting increasing interest. in 1992 markussis (l) detected premature atherosclerosis by ultrasonography in the untreated patient 9 we have shown plaque regression with patients on replacement gh (norditropin) in a 4-month trial. 11 females and 9 males were recruited, mean age 49.6 years. at each timepoint plaque characteristics were measured by duplex ultrasound. 6 patients showed a large reduction in plaque size (mean 21%) after four months treatment (p value < 0~00l). similarly, highly significant values in cholesterol, hdl and ldl and apo a1 are achieved. chol hdl ldl apo a 1 pretreatment 6.54 1.23 5.04 119 posttreatment 5.64 w 1.24 w 3.79 w 109 ~ w achieve a high degree of statistical significance (p< 0.001). the significant reductions achieved in plaque characteristics in six patients studied who showed plaque formation correlates with other parameters traditionally accepted as reducing cardiovascular risk. hypertension is found in approximately 70% of patients with cushing's syndrome, but the mechanism is poorly understood. previous studies in our unit have examined levels of exchangeable sodium, plasma renin and angiotensin ii and cardiac sensitivity to phenylephrine. one previous study has demonstrated enhanced pressor responsiveness to noradrenaline in a group of patients with cushing's syndrome due to adrenal adenoma. we have investigated the blood pressure response to noradrenaline in 7 patients with pituitary dependent cushing's syndrome and in 7 controls matched for age, sex and bmi. noradrenaline was infused for 10 minute intervals at five different concentrations between 0.01 and 0.18 mcg.kg.min -~ multiple systolic and diastolic readings were recorded and the infusion was stopped if the systolic pressure became > 200 mmhg, diastolic _> 1 l0 mmhg or the systolic pressure rose > 35 mmhg. basehne blood pressure in the patients with cushing's disease (cd) was 140/88 + 6/3 compared with 122/83 + 6/6 mmhg in the normal controls (nc). in 6 of the 7 patients with cushing's disease, the test had to be stopped before completion of the protocol, whereas this was necessary in only one control subject the change in blood pressure from basehne to the blood pressure value recorded either at the time the test was stopped or at the peak blood pressure reading during equivalent noradrenaline infusions was compared between the matched pairs. the mean change in diastolic pressure was 22 + 5 mmhg in cd compared with 7 + 2 in nc (p<0.05). there was no statistically slgmficant difference in either systolic pressure (28 + 5 vs 26 + 5 mmhg) or mean arterial pressure (23 + 5 vs 14 + 3 mmhg). these results demonstrate an increased diastolic pressor response to noradrenahne tn cushing's disease. increased pressor sensitiwty to uoradrenaline may contribute to the elevated blood pressure seen in cushing's disease. increased plasma homocysteine (thcy) is an independent risk factor for premature vascular disease. patients with insulindependent diabetes have an increased prevalence of cardiovascular disease. accordingly, we measured plasma thcy concentration in 119 such patients (15-59y), randomly selected, and in 51 control subjects. in controls, thcy was higher in males than in females (supine: geometric mean (95% ci): ,8.3 (7.2,9 6) v 5.9 (5.1,7.0) i.tmol/l, p<0.001), as previously described, but there was no gender difference in patients. male patients, without microvascular complications, had lower thcy than controls (supine: 6.5 (5.4, 7.8) v 8.3 (7.2,9 6) ~mol/l, p<0.05), but values in female patients without complications were similar to those of female controls, thcy significantly correlated with age in diabetics but not in controls, thcy increased in patients with increased severity of microvascular complications, partly due to the effect of age. thcy was higher when standing.than when supine in both controls (8 0 (7.0,9.1) v 7 1 (6.4,8.0)lalmol/l, p<0.05) and patients (6.9 (6.5,7.4) v 6.4 (6.0,6.9)l.tmol/l, p<0.02). the absence of gender difference, the association between thcy and age, and higher levels with increasing microvascular complications suggest thcy could be of pathogemc significance in iddm patients, despite unexpectedly low levels in male patients without complications. differences.between supine and erect samples may be due to haemodilution of albumin-hound thcy in the latter a review of the treatment outcome of thyrotoxicosis with standard dose/doses of radio-active iodine (sdrai) in 67 consecutive patients presented to the endocrinology department, uchg, from december 1992-december 1993 was analysed. the mean pre-treatment levels of free thyoxine (ft4) was correlated with the treatment outcome. there was statistically significant difference in the pre-treatment ft4 between responders and nonresponders to the first dose rai (p = 0.001). response with hypothyroidism and/or euthyroidlsm was considered successful treatment 43/67 (64 2%) responded to a single dose rai; 26/ 67 (38.8%) and 17/67 (25 4%) responded with euthyroldism and hypothyroidism respectively 19/67 (28.4%) and 3/67 (4.5%) responded to the second and third doses of rai respectively giving a total response rate of 92.5% and 97% respectively. interestingly, 2/67 (2.99%) patients failed to respond even to the fourth dose rai 4/67 (5.97%) patients with t3 toxicosis (3 females and 1 male). two responded to the first dose (one with hypothyroidism and the other with euthyroidism), the remaining 2 required a second dose, which produced the same results. no statistically significant difference in the response rate between t3 and t4 toxicosis (p = 0.9) was observed. inherent in the st. vincent declaration targets is the need for continuous data collection and audit. we present preliminary information from the mater database, the first prospective audit of patients from a homogenous irish population. 1,051 iddms (527m:524f) were identified with the following characteristics (mean + sd), age 37.3 + 14.4 years, duration of dm 185 + 11.2 years, bmi 24.4 + 3.0 (males) and 24.2 + 4.0 kg/m2 (females), hbalc 8.6 + 1.97% (n<6.2%). no male:females differences existed in the above nor in macrovascular complication rate 10.1% (predominantly peripheral vascular &sease and lschaemic heart disease). however, males were more likely to be current smokers (34% vs 27%, p = 0 01). hypertension rates (17.2m vs 15.4%f), cholesterol > 6.5 mmol/1 (6.2m vs 9.8%f) were similar but more males had cholesterol < 5.2 mmol/l (64.8m vs 53.8%f, p < 0.01). clinical nephropathy was present in 11.4% of males vs 8.7% in females (p<0 05) 11.9% had clinical peripheral neuropathy. retinopathy will be described elsewhere. 10.4% of females and 2.3% of males had a history of hyperthyroidism and 2.5% of females vs 1.4% of males of hypothyroidism. 7.8% had history of psychiatric disease. conclusion although not a population based study, care of iddm in ireland is almost totally hospital clinic based cigarette smoking is identified as the major problem to be addressed patients with diabetes meltitus (dm) are at a higher risk of developing vascular complications, including coronary artery disease (cad). we performed a detailed analysis of predictors of cad and its seventy in patients with dm and chest pain 19 patients in total single vessel cad (svd) in 4, double vessel (dvd) in 5, and triple vessel (tyd) in 5 on cine contrast angiography clinical, biochemical and dobutamme stress echocardiographic findings are tabulated below for patients with angiographically proven coronary artery disease. patients with tvd had a longer duration of dm (19 4 years) and were more likely to have retinopathy (100%) the sensitivity of dse was excellent for severe disease. conclusion' duration of dm, retinoapthy, and a positive dse were the best predictors of severe cad in a diabetic population with chest pain the haemodynamic hypothesis for the pathogenesis of diabetic microangiopathy argues that an initial increase in microvascular flow leads to sclerosis and disturbed microvascular autoregulation. we have recently demonstrated impairment of vasoconstrictor responses to endothelin-1, a potent endothelium-derived constrictor substance, in niddm and have suggested that this could contribute to the initiation of microangiopathy the purpose of this study was to determine whether responsiveness to endothelin-i is also impaired in iddm. non-specific vascular smooth muscle contraction was assessed using high dose serotonin eleven patients with iddm and 11 control subjects underwent forearm blood flow (fbf) measurement by venous occlusion plethysmography in response to local infusions of endothelin-1 (5 pmol/min for 60 minutes) and serotonln (30 la g/min for 2 minutes) control subjects showed slow onset vasoconstriction in response to endothehn-1 reaching maximum at 35 minutes (p<0.01) the diabetic group did not respond to endothelin-i group differences were significant (p=0.02). the two groups showed similar vasoconstriction in response to serotonln. in conclusion, vasoconstriction in response to endothelin-t is impaired m iddm non-specific vascular smooth muscle contraction is preserved. impaired vascular responsiveness to endothehn-i is a possible common mechanism for the pathogenesls of microanglopathy in 1ddm and niddm. we measured total corrected (tca) and standardised ionised calcium (lca) in a population of 76 intensive care (1cu) patients (with a mean age of 57+22 years, 59% male) to determine the prevalence of abnormalities in circulating calcium and its possible determinants severity of illness was measured by the apache ii score (acute physiological and chronic health evaluation). for comparison of ica we examined 20 subjects undergoing arterial gases which proved to be normal and 40 non-critically 111 hypoxlc subjects ica was measured on arterial gas samples and corrected for ph 84% of icu patients had a total ca (unadjusted) of < 2 2mmol/l. after adjustment for serum albumin, 55% of icu patients had an tca <2 2 mmol/1 30% of icu patients had a serum phosphate of <0.8 mmol/1 ica in controls was 1.44 + 0.017 mmol/1 and 1.38 + 0.015 mmol/1 in hypoxlc non icu patments (ns) ica in icu was lower: 1.34 +0.016 (<0.003). tca and lca were not slgmficantly related. tca and ica did not sigmficantly differ between patients who died and who survived in the icu, and they were not related to apache ii score. belfield, dublin 4. from july 1987 to june 1995 there was a 16-fold increase m the annual number of specimens submitted to the virus reference laboratory because of a perceived risk of contracting hiv through a needlestick injury, blood splash, human bite, or through occupational exposure. needlestick-associated specimens also comprise an increasing proportion of 'at-risk' specimens, rising from 0.9% m the year july 1987-june 1988 to 9.4% in the year july 1994-june 1995. between july 1992 and june 1995 a total of 1787 patients had specimens submitted for hiv antibody testing after a perceived'exposure to hiv of these only 209 patients had more than 1 specimen taken. although the time of putative exposure is rarely avadable, the median interval between 1st and 2nd postexposure specimens for these 209 patients is 3 months with 136/ 209 (65%) lying between 1 to 6 months. if the risk of hiv refection from a needlestlck injury is assessed as sufficient to warrant serological investigation, the timing and number of blood samples are important. a negative report from a single early specimen may not indicate an absence of infection a basehne specimen and follow-up specimens at 6 weeks, 3 months and at a minimum of 6 months post-exposure are recommended appropriate serology for other viral mfections (hepatitis b and hepatitis c) should also be considered. since the beginning of 1995 a significant sustained increase in the numbers of hepatitis a cases has occurred. the number of cases m 1995 was 229 against 121 in 1994. this reverses the continuous fall observed over previous years. the reason for this increase remains unidentified at present this increase has occurred following a dramatic increase in the total number of hepatitis a igm tests carried out by the vrl since february/ march 1994 the increase in the number of tests carried out since this time is primarily attributable to increased hepatitis testing following receipt of hepatitis c-contaminated rhesus anti-d immunoglobuhn. analysis of the age profiles of the positive patients and of all the referrals indicates that 95.5% of positive results were found m patients aged 50 yr or less whdst 31% of all hav igm tests were performed on individuals aged 51 yr or greater. this raises the question whether greater selectivity should be employed when requesting hepatitis a tests studies report compliance rates ranging from 30 to 50% in hiv negative patients there has been no comprehensive study of compliance in hiv positive patients. accurate measurements of compliance are not easy; easy measurements of comphance are not accurate "). to determine the compliance rate in hiv posmve patients attending st. james hospital, dublin, one hundred consecutive patients attending the service were interviewed (homosexual 46, ivdu 45, heterosexual 9). the questionnaire was divided into three sections. firstly, a medical review was completed by the clinicmn which included demographic data, cd4 count, cdc staging, karnofsky index and prescribed medication. secondly, the pharmacy detailed the medication dispensed to each patient. the third section comprised a patient interwew to determine adherence to, and understanding of prescribed drug therapy. we report an overall comphance rate of 61%. this was unevenly distrtbuted between the two main patient groups (89% in homosexuals, 24% in ivdu) the following factors were found to mfluence compliance: number of medications, cdc stage, karnofsky index, dysphagia, educational and socio economic factors. we also found that poor patient understanding of the prescribed therapy significantly affected compliance. the aim was to determine the incidence of stds in patients presenting for hiv testing at the department of genito-urinary medicine, saint james's hospital. a retrospective analysis of all patient notes who presented for hiv testing between july '94 and december '94 was undertaken. according to clinic policy all patients had been screened for the following stds; neisseria gonorrhoea, chlamydia trachomatls trlchomonas vagmalis, candida, human papilloma virus, herpes simplex virus syphilis and hepatitis b in addition intravenous drug users (ivdus) were also screened for hepatttls c all patients underwent pre test counselhng. sex, age, risk groups and diagnoses were noted. 504 patients presented for hiv testing, of whom 66% were male, 34% female, wtth an average age of 28.5 years. of the total, 8% were, or had previously been ivdus. of the total 46 ivdus, 37 were heterosexual males 2 were bisexual and 4 were females 10.2% of the male patients were homosexual and 4 4% btsexual there were 15 posmve hiv tests (3% of total); 14 males and 1 female. in this group there were 5 patients with hepatitis c, all of whom were ivdus. no other stds were detected in the hiv negative group hepatitis c was diagnosed in 20, hepatttis b in 4, anogenital warts in 58, herpes gemtalis in 10, syphilis in 3, n. gonorrhoea in 9, t. vagmalis in i, c. trachomatls m 12, g vaginalis in 5 and candldlasis in 47. this study confirms the importance of std screening in all patients requesting a hiv test. of the total testing for hiv, 30% had a concurrent std diagnosis although no stds were identified in the hiv positive group this may be more a reflection on the makeup of the irish hiv positive population, the majority being ivdus, rather than a difference m the mode of sexual toxoplasmosis is the most common opportumstlc infection of the central nervous system in aids patients. in clinical practice the diagnosis depends on clinical, radiographic and serological findings coupled to chnical response to therapy brain biopsy is not routinely performed. in this retrospective review, we describe our experience with diagnosing toxoplasmosis we examined (a) the clinical demographics and presentation, radiographic findings, response to therapy and patient outcome (b) role of polymerase chain reaction (pcr) in detecting toxoplasma gondii from blood and csf samples (c) the usefulness of serology in diagnosing acute infection. all cases diagnosed as toxoplasmosls based on the above criteria were reviewed. pcr to detect toxoplasma gondn dna used primers to the b 1 gene giving a 223bp amphficatton product serological tests used were sabln-feldmen dye test and latex agglutination. there were 25 cases diagnosed (17 m, 8f, cd4 0-300; cdc iv 19). 3 panents unknown to be hiv posmve presented with cerebral toxoplasmosis 22 patients were not receiving continuous systemic prophylaxis against pce diagnostic value oft gondii pcr in blood and csf showed a sensmvlty of 20%, specificity of 100%, ppv was 100% and npv was 40% determination of lg subtype was of limited value 25% (6) of patients were seronegatlve of whom 50% (3) had histologically proven disease 2 of these latter 3 cases were pcr negative the dye test was of poor predictive value this review confirms the need to combine all parameters in making a diagnosis of toxoplasmosis in lmmunocompromlsed hosts. the performance of the newly developed, rapid and fully automated m~croparticle enzyme immunoassay abbott imx hiv-1/hiv-2 3rd generation plus assay for the detection of antibody to hiv-1 and hiv-2 including subtype o m human serum or plasma was assessed the assay was evaluated by testmg specimens from blood donors, diagnostic populations and hospitalized patients, hiv seroconverslon panels confirmed hiv-positive specimens, and potentially interfering specimens. the abbott imx hiv-1/hiv-2 3rd generation plus assay showed an overall apparent specificity of 99.97% (lower limit of 95% ci 99.84%) in the tested blood donor populations (n=347t). this comparable to the specificity found for the abbott imx hiv-i/hiv-2 3rd generation plus eia (99 93%) and the axsym h1v-1/hiv-2 assay (99 90%). the apparent sensitivity of the abbott imx hiv-i/hiv-2 3rd. generation plus assay is at least equivalent to that of the abbott imx hiv-i/hiv-2 3rd generation plus eia and the axsym hiv-i/hiv-2 assay. of 21 hiv-i seroconversion panels tested, the abbott imx hiv-1/hiv-2 3rd generation plus assay detected seroconverslon earlier on up to 6 panels, depending on the comparison assay. among 785 specimens from asymptomatic and symptomatic hiv patients, the abbott imx hiv-1/hiv-2 3rd generation plus assay detected 100 (785) including 7 specimens characterized as hiv-1 subtype o. the abbott imx hiv-1/hiv-2 3rd generation plus assay is an extremely sensltlve and highly specific assay for the early detection of antibody to hiv-1/hiv-2 and shows at least an equivalent performance to the abbott imx hiv-i/hiv-2 3rd generation plus eia and the axsym hiv-1/hiv-2 assay. the fully automated imx instrument system offers ease of use and rapid results on a widely accepted and reliable platform. streptokinase (sk), a 47kd protein produced by group c b hemolytic streptococci, is a widely used thrombolytic agent. anti-sk antibodies arise either as a result of therapeutic administration of sk or following natural mfection with streptococci although the clinical significance of antl-sk antibodies is not clear, there is evidence that some anti-sk antibodies arising from natural infections can interfere with sk activity tn vtvo, resulting in thrombolytlc failure. to facilitate further investigations of these antibodies, we have developed and validated a highly sensitive functional assay, which measures sk neutralisatlon activity of serum independently of other circulating inhibitory factors in the sample, and a rapid and convenient enzymeimmunoassay for the detection of anti-sk antibodies. analysis of over 200 random serum samples from the local blood bank with the enzymeimmunoassay showed the prevalence of antl-sk antibodies to be approximately 13%. all the positive samples and an equal number of the negative samples randomly selected were analysed by the functional assay the agreement between the results of the two assays was excellent indicating that our enzymelmmunoassay was a convement method for detection of anti-sk antibodies which could neutrahse sk activity m vitro irish journal of medical science tuberculosis drug therapy, isolation precautions and prophylaxis. conventional methods of detection such as microscopy and culture either lack sensitivity and specificity or are timeconsuming. in this study we investigated the use of a pcr based diagnostic assay for the detection of m. tuberculosis in sputum samples this assay has been developed by bioresearch ireland (bri) and raggio italgene. sputum samples were lysed and pcr amplified using an m. tuberculosis complex-specific primers. the results obtained using the bri/c-trak tm technology were initially compared to the amplicor system (hoffman la roche). both probe detection methods represent fast and reliable methods for the detection of m. tuberculosts in clinical samples. this test is designed to eliminate the possibility of obtaining false negatives. strongyloldes stercoralis infection in humans ts endemic in the tropics. as travel is becoming more common, it will be seen more frequently. two cases of this infection in irish people are described. case i. a 21 year old women had travelled and worked in poor rural areas of mexico for one month, three years before presentation. two and a half years later she developed abdominal discomfort, anorexia and sore throat. myalgia, arthralgta and a transient skin rash began to appear in the next month. eosinophilia, mild anaemia and raised liver blood tests were noted. elisa test for strongyloides was positive but parasites were not seeri in the faeces. ivermectin was given and the patient feels better. case ii. a 31 year old nurse had arthralgia, fatigue and some weight loss for 18 months'. on two occasions in the last four years, she had been travelling extensively in s.e. asia for a total of four months. she was admitted to hospital because of acute fever and loin pain. a urinary tract infection was diagnosed. absolute eosinophil count was i'aised 0.63x10^9/1. esr was 17mm/hr. strongyloides elisa was positive and treatment administered as above. strongylotdes is the most important nematode in the returned tropical traveller. it can multiply and persist within the body for long periods of time and it can cause hypertnfection syndrome, a protean fulminating infection of bowel, lungs, blood stream and brain, in those who are lmmunocompromised. diagnosis can be difficult by stool microscopy. thlabendazole has side effects but ivermectin is safe and effective. june 1995, there was an outbreak of c.difficde-associated diarrhoea (cdad) at st. james's hospital. the aims of this study were to determine the incidence and outcome of cdad in hiv positive and negative patients we prospectively reviewed all patients with diarrhoea, a positive c.difftcile cytotoxin assay, and in whom no other infectious cause for diarrhoea was identified demographic data, history of diarrhoeal episodes, risk factors and outcome were recorded. the incidence of cdad in hiv negative patients was 1.2 per 100 hospital admissions, compared to 1 per 100 admissions m hiv positive patients. the average number of courses of antibtotlcs received, in hiv negative patients prior to the onset of symptoms was 2.3, and 76% of this group were exposed to third generation cephalosporins. hiv positive patients received an average of 3.4 courses of antibiotics and no patients received third generation cephalosporins. there were no deaths due to cdad in hiv positive patients however 4 hiv negative patients died from severe pseudomembranous colitis in conclusion we documented a unexpectedly low incidence and complication rate of cdad in hiv positive patients this is surprising considering their multiple hospital admissions and exposure to ant~microbial and chemotherapeutic agents. the number of new positive hiv specimens detected at the virus reference laboratory has risen from a cumulative total of 638 m july of 1987 to 1597 in september of 1995. we examined our data to determine the proportional make up of these positives by major risk group. in august 1987 64.7% of positive specimens were from intra venous drug abusers (ivda) by september 1995 ivda made up 49% of the total positive hiv specimens. positive specimens from homosexual individuals rose fro.m l0 9% of total positives in august 1987 to 20.6% in september 1995 there were no recorded positive specimens from heterosexual exposure in august 1987 but in september 1995 8.9% of positive specimens recorded heterosexual exposure. a further category which includes blood donors, haemophiliacs, transplant patients and organ donors made up 25% of total positives in august 1987 and in september 1995 made up 22.4% of total positives. we further examined our data in order to show when these changes occurred by ascertaining how many new positive patients have been discovered per year in each of the main risk groups. see in the united kingdom echovlrus type 22 (echo-22) is regularly isolated, with nearly 200 reports annually to the central public health laboratory. reports increased during 1986-1988 and overall it is the second most commonly reported echovlrus in the u.k. echo-22 epldemiology is different to that of other enteroviruses; over 90% of patients with echo-22 tsolated are less than 2 years of age echo-22 shows distinctive and unique cytopathogenic features in tissue culture, and based on sequence analyses, it seems to belong to a separate subgroup of picornaviruses. echo-22 has been associated with respiratory symptoms in premature infants, myocarditis and severe encephalitis. in 1989 an outbreak of acute flaccid paralysis associated with echo-22 was described in jamaica in six patients, four of whom died. we describe three cases of sudden death in infants associated with echovirus type 22 infection case i: s d. born 20/7/94; birth asphyxia and death at two days of age; echo-22 isolated on 2217194 from spleen. this study assessed the antibiotic sensitivity of organisms causing urinary tract infections (uti) among genito-urinary medicine (gum) clinic attenders in order to determine whether it is worthwhile giving tetracycline for dipstick (nitrite) positivity, even in the absence of clinical features of uti. we looked retrospectively at 100 laboratory confirmed uti's diagnosed among gum clinic attenders over a period of eight months. we assessed antibiotic sensitivities of the organisms involved, and determined how many dipstick positive urines which were left untreated turned out to be real uti's. 86% of uti's were due to coliforms and 66% of these were sensitive to tetracycline. 4% of uti's were due to staphylococcus saprophyticus, 3% due to beta haemolytic streptococcus group b, 2% due to enterococcus, 2% due to proteus species and 2% due to coagulase negative staphylococci. 25% of nephur positive urines were left untreated. 32% of these were nitrite positive. failure to treat a positive urine dipstick which turned out to be a uti necessitated a further clinic visit for adequate treatment. nitrite positive urines should be treated as a uti, even in the absence of clinical features of uti, either with trimethoprim or tetracycline. the number of untreated uti's and unnecessary extra visits to gum clinics would have been reduced with the use of judicious antibiotic therapy for nitrite positive urines. strains of enterococci resistant vancomycin have been reported with increasing frequency. in 1995, we investigated an increase in the frequency of vancomycin-resistant enterococcus faecium (vref) among patients in the haematology/oncology unit using pulse-field gel electrophoresis (pfge) to genotype these isolates and to assist in establishing the source of these vref. eighteen clinical isolates of vref from blood, urine sputum and-faeces and two environmental isolates were collected from separate patients between march and july 1995. minimum inhibitory concentrations (mics) to several antibiotics including teicoplanin and vancomycin were determined by agar dilution. pfge were performed following smal restriction endonuclease digestion. antimicrobial susceptibility testing revealed high level resistance to vancomycin and teicoplanin; mics >128 mg/ l and >32 mg/l respectively. this antibiogram is consistent with the van a phenotype. pfge of all 20 isolates revealed identical patterns indicating clonal spread of vree subsequent implementation or infection control measures reduced the frequency of vref isolation. pfge proved useful in demonstrating clonal spread of vref and.in emphasising the need for infection control measures. a prospective audit of baeteraemia in our 600 bed teaching hospital was carried out from february 1991 to march 1993. clinical and microbiological data were collected on 520 episodes of bacteraemia in 78 patients. of these 230 (62%) were hospital acquired and 200 (38%) community acquired. urinary tract and respiratory tract sources were implicated in 30% and 14% of community acquired episodes, making e. coli and s. pneumoniae the commonest community acquired isolates (41% and 16% respectively). other gram negative bacilli accounted for 13% and s. aureus for 11%. coagulase negative staphylococci were the commonest hospital acquired isolate (24%) followed by s. aureus (22%), e. coli (i5%) and enterococcus spp. (10%). enterobacter spp. were the second commonest gram negative isolate (5%). central venous cannulae were implicated in 43% of hospital acquired cases. urinary tract infections accounted for 20%. 63% of which were catheter related. invasive diagnostic procedures (angiography, prostate and liver biopsies, sinography) were implicated in t0 episodes. gentamicin resistance was found in 9% of hospital acquired aerobic gram negative bacilli and mrsa accounted for 13% of hospital acquired s. aureus. these figures are higher than expected but may be explained by outbreak of mrsa and gentamicin resistant entercobacter spp. which occurred during the study period. the past severalyears have seen a significant increase in the recognition of moraxella (branhamella) catarrhalis as a respiratory pathogen (~). the pathogenic mechanisms employed by the organism are largely unknown, but adherence may play a role ~2~. in our investigation the haemagglutinating ' activity of 40 isolates of m. catarrhalis was determined by a microtitre method. no isolate agglutinated horse, chick or sheep red blood cells (rbc). seventeen isolates agglutinated human rbc, x~hile 7 of these 17 isolates also agglutinated rabbit red. blood cells. haemagglutination of human and rabbit red blood cells was inhibited by porcine mucin. galactose inhibited the haemagglutiriating activity of the 7 isolates which agglutinate both human and rabbit rbc and yet bad no effect on the haemagglutinating activity of the isolates which haemagglutinate human rbc alone. .electron microscopy studies of the bacteria demonstrated a diffuse outer fibrillar layer on the surface of haemagglutinating positive isolates, thislayer was subsequently removed following trypsin treatment, as was the haemagglutinating activity. a 200 kda trypsin sensitive protein appears to be associated wfth haemagglutinating properties. mrsa is an increasingly important cause of morbidity, and is spreading from large hospitals to smaller community-based facilities and nursing homes. the objective of this survey was to obtain an indication of the size of the mrsa problem in ireland prior to introducing national mrsa control guidelines. a survey of all microbiology laboratories in ireland was carried out over two weeks in spring 1995. for patients from whom mrsa was isolated during the study period standard demographic and clinical data were requested and period prevalence/1000 discharges was calculated. all 45 microbiology laboratories surveyed responded. mrsa was isolated from 448 patients during the 2 week period. the period prevalence of mrsa/1,000 discharges was 16.5. males aged 65+ had the highest rate of infection (50/1000 discharges). half of all isolates were from patients in surgical or medical wards, but 4% were from community-based sources e.g. gps, nursing homes, hospices. thirty-two percent of mrsa patients were infected rather than colonised. mrsa is clearly a substantial problem in ireland. while it is largely a hospital problem at present, the increasing trend for day procedures and shorter stays means that infection will increase in the community. a survey in a university hospital in the usa revealed 41% of mrsa cases to be communityacquired. tonsil core specimens were cultured for bacteria including mycoplasma, chlamydia and ureaplasma urealyticum in 70 children undergoing tonsillectomy for recurrent acute tonsillitis. serology for chlamydia and mycoplasma pneumoniae was obtained in 55 of the children. the polymerase chain reaction (pcr) was used to investigate the presence of chlamydia pneumoniae in core tonsil tissue. ureaplasma urealyticum was cultured in three children (4.3%) and mycoplasma salivarium in two children (2.8%). culture was negative for chlamydia pneumoniae and mycoplasma pneumoniae. the complement fixation test for chlamydia species was positive in 16/55 children (29%) indicating previous infection. specific immunofluorescence testing for c. pneumoniae was positive for lgg (titre> 16) in 10/55 (18%). igm antibody to c. pneumoniae and antibodies to c. trachomatis and c. psittaci were not detected. ninechildren (16%) had titres > 32 to m. pneumoniae. pcr failed to demonstrate c. pneumoniae. aerobic and anaerobic bacteria were cultured from all specimens. the culture of ureaplasma urealyticum in 4.3% of our patients indicates a higher rate of colonisation then previously thought. this study 49 irish journal of medical science demonstrates past infection with c. pneumoniae in 18% and with m. pneumoniae in 16% of children with recurrent tonsillitis. however c. pneumoniae and m. hominis do not play a significant role in childhood recurrent tonsillitis. multiply resistant enterococci are increasingly common causes of serious infection in hospitalized patients. high level gentamicin resistance (mic > 1000 mga) in enterococci further compromises the therapy of such infections. we have identified seven clinical isolates of enterococcus hirae demonstrating high-level gentamicin resistance (hlgr: mic > i000 mg/1). to our knowledge this is the first report of hlgr for this enterococcus species. plasmid analysis has demonstrated the presence of a single, large plasmid in all seven isolates, as well as several smaller plasmids in some of the isolates. filter mating experiments have revealed that in all seven cases, hlgr was transferred to a laboratory recipient e. faecalis jh-22 by conjugation. plasmid analysis of transconjugant strains confirmed transfer of the large plasmid in all cases. based on restriction enzyme profiles, two distinct conjugative plasmids were identified for the e. hirae isolates investigated. at present we are using southern blot techniques with oligonucleotide probes designed to hybridise to the hlgr determinant found in other species of enterococcus. the results will confirm whether or not the same resistance determinant is responsible for the dissemination of hlgr in the genus enterococcus. dublin 8. aminoglycosides remain commonly used in the treatment of severe gram negative infection and have conventionally been given on a twice or thrice daily basis. single daily dosing offers advantages with respect to less nephrotoxicity, better bactericidal activity, convenience, nursing time, cost and should avoid subtherapeutic dosing which has a significant impact on outcome. we reviewed serum gentamicin assays from january to december 1995 to assess potential toxicity and subtherapeutic dosing in patients who received once daily gentamicin and those who received multiple daily dosing. 4346 assays were performed in the study period. 520 of those were random assays and not included. there was a trend towards significantly less potentially toxic levels in the once daily group compared to the multiple daily group (p<0.1). once daily dosing produced significantly less subtherapeutic dosing (p<0.001). over 98% of peak assays in the once daily group were in the recommended range. we conclude that current practice of multiple daily dosing of gentamicin leads to significant underdosing and more potentially toxic trough levels. measurement of trough assays only in patients who are treated with once daily aminoglycosides is sufficient and will have considerable cost savings. respiratory, syncytial virus (rs virus) is a major respiratory pathogen of infants less than 1 year old. it occurs in annual epidemics during the winter and early spring in temperate climates. during rs virus epidemics a significant number of infants less than 6 months old are hospitalised with symptoms of bronchiolitis and pneumonia. rs virus exists in two antigenically distinct subgroups, a and b which are known to cocirculate in the same community during the same rs virus season. there is much debate regarding the virulence of one strain over the other. using a panel of monoclonal antibodies specifically directed against the two rs virus strains, 167 rs virus isolates from specimens sent to the virus reference laboratory, university college dublin, over seven consecutive rs virus seasons (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) were typed and the rs virus subgroup predominance monitored. subgroup a was the most predominant of the rs virus isolates accounting for 67.7% of the total and was found to be the predominant rs virus strain in six out of the seven rs virus seasons studied. subgroup b predominated in a season in which the number of rs virus detections peaked much later than normal. treatment of fungal infections in patients in intensive care unit (icu.) is usually empiric. the aim of this study was to identify candida species isolated from i.c.u. patients and to test their susceptibility to antifungal agents to enable more directed therapy. forty candida sp. from 23 patients in i.c.u. were isolated from the following sites, blood culture (5), central venous catheter (7), chest drain fluid (5), wounds (8), catheter urine (8), bronchial lavage (3), sputum (4). strains were identified by standard procedures. minimum inhibitory concentrations of amphotoeracin b, 5-flucytosine and fluconazole were obtained by agar dilution test and e test. the isolates were identified as c.albicans (22), c.glabrata (8), c.krusei (5), c.tropicalis (2), c.parapsilosis (2), c.kefyr (i). all the candida species were sensitive to amphoteracin b (mic = 1-<025mg/l), and 5 flucytosine (mi c= <025mg/l). c.albicans and c.parapsilosis were fluconazole sensitive (mic = 16-15mg/l). four of eight c.glabrata were fluconazole resistant (mic = >256mg/l). c.krusei, c.tropicalis and c.kefyr were also resistant (mic = >256 mg/l). wbilst there were no major discrepancies between the agar dilution test and the e test, the agar dilution test was laborious and required a high degree of skill. the e test was easier to read and more reliable results were obtained provided the inoculum was carefully standardised. this study shows that azole antifungals should not be ganglion is probably the commonest tumour encountered in the hand and the wrist. it often arises from tendon sheath or lining of a joint capsul. the treatment can be surgical or nonsurgical, the latter includes aspiration with or without injection of steroids. surgical treatment of ganglion can pose a difficult situation to deal with. it requires hand surgeon to deal with one such problem, we present a 46 year old man with tender mass in the hypothenar eminence. during surgical exploration it was obvious that the ganglion was infiltrating the wall of the ulnar artery, and the histology proved this later. the clinical features, management arid the outcome of this unusual case are discussed. ischaemic preconditioning (ipc) of the myocardium with repeated brief periods of ischaemia and reperfusion (i-r) prior to prolonged ischaemia significantly reduces subsequent infarction. following ipc two "windows of opportunity" (early and late) exist during which prolonged ischaemia can occur with reduced myocardial infarction, we investigated if ipc of skeletal muscle prior to flap creation improved subsequent flap survival and perfusion in either early or late windows. the latissimus dorsi muscles (ldm) of sprague-dawley rats were used. group 1: (control, n=12). the ldm was elevated as a thoracodorsatly based island flap group 2: (early ipc, n=8). the ldm was preconditioned with two 30 minute episodes of normothermic global ischaemia with intervening 10 minute episodes of reperfusion prior to elevation. group 3: (late ipc, n=8). the ldm was elevated 24 hours after ipc ischaemia was created by occlusion of the thoracodorsal artery and vein and the intercostal perforators having previously isolated the muscle on these vessels. muscle perfusion was assessed by a laser doppler perfusion imager. one week after flap elevation the percentage of muscle necrosis was measured by computer-assisted planimetry ipc significantly reduced muscle flap necrosis (table) in both early and late windows. muscle flap perfusion was similar in all groups. this study compares the biochemical, serological and histopathological findings in 20 women with chronic hepatitis c virus (hcv) infection with 20 age-matched women with established autoimmune hepatitis (aih). there is increasing evidence of autoimmunity in hcv liver pathology. because of different treatment regimens for hcv (d-interferon) and aih (steroids, immunosuppression), clear distinction between the two diseases is desirable. liver enzymes (alt, ast, alkaline phosphatase), antinuclear factor (anf), anti-smooth muscle (asm) and antimitochondrial (ama) antibodies are compared for both groups of patients. liver biopsies from all women were compared using the grading and staging system of ishak et al (1995) . the results show that while some women in both groups show elevated liver enzymes, positive anf and asm autoantibodies, the values are much higher in aih. similarly aih patients show overall more severe disease on liver histology. both groups demonstrate poor correlation between histological features and autoantibody titre. we conclude that distinction between hcv and a!h is usually possible with liver histology and serology. some women with chronic hcv and positive autoantibodies however," demonstrate a histological and serological picture suggesting that chronic hcv may be mediated by an immunopathogenic mechanism. irish journal of medical science terminal changes only, 5 showed lymphocytic meningitis and 4 of these also had perivascular lymphocytic inflammation (cd3 positive) in the subependymal regions, brainstem and choroid plexus. two brains showed purulent meningitis and one case had central pontine myelinolysis probably related to profound metabolic disturbance. basal ganglia mineralization, hiv encephalitis (hive) or hiv leucoencephalopathy (hivl) were not present. these findings differ considerably from those described in us cases, in whom the majority have evidence of hiv within the cns. relatively early death from systemic infection may account for the lack of hive/hivl in these cases. the lymphocytic meningitis and perivascular inflammation may represent an immuno-allergic reaction, previously reported as "early" changes, regarded as important in inducing vascular damage which allows subsequent entry of h1v into the brain. the aim of this study is to assess apoptosis in areas of interface hepatitis and spotty necrosis in hepatitis c virus (hcv) infected liver biopsies, and to correlate the degree of apoptosis with severity of histological activity. 25 liver biopsies were randomly selected from a group of type lb hcv positive women. these patients were diagnosed by recombinant immunoblot assay (riba) test and the presence of hcv rna was confirmed using the polymerase chain reaction (pcr). apoptosis was demonstrated in the biopsies by the oncor apoptag in-situ hybridisation technique. the average number of apoptotic hepatocytes per portal tract, and within the parenchyma per 10x objective, was determined. the modified histological activity index (h.a.i.) was used to score each biopsy. comparison of the results shows that increasing numbers of apoptotic hepatocytes are consistently associated with increasing scores for interface hepatitis and spotty necrosis. it is concluded that apoptosis occurs in hcv infected livers and that it correlates with increasing histological activity .indicating a significant role for apoptosis in the pathogenesis of hcv liver disease. and university of edinburgh, scotland. paediatric aids represents only 5% of cases worldwide, in most published series parental iv drug use was the main risk factor, cns pathology was a late feature of the disease and antiretroviral treatment had been given. we studied eleven brains from romanian children with probable postnatal hiv infection using standard neuropathological stains and immunostains for lymphocyte markers and hiv p24 antigen. death was due to systemic infection, mostly pneumonia or gastroenteritis; antiretroviral treatment had not been given. three cases showed we studied the role of the p53 and bcl-2 genes in the pathogenesis of post-transplant lymphoproliferative disease (ptl). ten cases were examined by immunohistochemical and molecular methods. immunohistochemistry was performed using standard and antigen retrieval methods, with the p53 do-7 and the bcl-2 oncoprotein clone 124 antibodies. dna was extracted from paraffin blocks and subjected to pcr, and single-strand conformation polymorphism (sscp) analysis searching for mutated p53 genes. samples showing any evidence of aberrant migrations were further analysed by direct sequencing. pcr was also used to detect bcl-2 gene rearrangements. we employed a technique called representational difference analysis to search for previously undescribed translocations or deletions which may be involved in breast carcinogenesis. dna was isolated from both invasive ductal carcinoma of the breast and normal tissue from the same patient. following restriction enzyme digestion and tigation of oligonucleotide linkers, pcr was carried out on both tumour and normal dna using oligonucleotide specific primers to obtain a representation of each genome (amplicons). digestion with the same restriction enzyme removed the original linkers, and a second set of oligonucleotides were ligated to normal amplicons only. the tumour derived amplicons were subtractively hybridised to the normal and subsequent pcr was used to isolate fragments unique to the normal dna (difference products). this was possible since oligonucleotides were ligated to normal dna only. following a series of further subtractive hybridisations and subsequent amplifications, purified difference product was obtained. difference products in the size range 500-1500 bp were obtained. following further rounds of subtractive hybridisation and amplification, purified difference product will be sequenced and characterised by comparison with known gene sequences. the chromosomal location of the affected gene will be established by in-situ hybridisation and somatic ceil hybridisation, using the difference product as probe. protein s is secreted by osteoblasts and case reports of reduced bone mineral density in patients with total protein s deficiency have lead to the hypothesis that this inherited disorder is associated with generalised osteoblast dysfunction predisposing to osteoporosis ~. we have assessed bone formation in 8 patients (2 male and 6 female) with total protein s deficiency and 4 controls (2 male and 2 female) using two recently available sensitive markers; serum osteocalcin (oc) and serum procollagen 1 carboxyterminal peptide (p1cp), both secreted by the osteoblast. the mean total protein s level amongst the patients was 40 _+ 12% (ref range 62-135%), mean oc was 14.2 ng/ml (ref ~'ange 5.2-59 ng/ml) and the mean picp was 81.5 + 15 uga (ref range 38-02 ug/1). in the control group, mean oc was 12.6 _+ 5 ng/ml and the picp was 124 + 37 ug/1. there was no statistical difference between both groups using either marker. in conclusion bone formation as assessed by serum osteocalcin and p1cp appears to be normal in patients with total protein s deficiency. hereditary spastic paraparesis (hsp) is a variably expressed neurodegenerative disorder which exhibits clinical and genetic heterogeneity. hsp can be inherited in an autosomal dominant (ad), autosomal recessive (ar) or x-linked manner. ad-hsp has been linked to a number of loci. we have ruled out linkage to these loci in a large irish family affected with ad-hsp. the aim of this study was to determine whether ad-hsp is linked to spinocerebellar ataxia loci (sca), sca-i & sca-ii. ad-hsp can be clinically similar to sca. dna was extracted from blood taken from 45 co-operating family members. microsatellite markers spanning the sca-i and sca-ii loci were amplified by pcr. individuals were genotyped and linkage analysis was carried out using the linkage set of programs. significantly negative lod scores were obtained for both sca-i and sca-ii loci. d6s274 gave maximum exclusion of 18cm on either side of the sca-i locus with a lod of -2.11 at a recombination fraction of 0.18. d12s105 gave maximum exclusion of 13cm on either side of the sca-ii locus with a lod of -2.08 at a recombination fraction of0.13. other markers examined also outruled linkage to these loci. we conclude that the gene for ad-hsp is unlinked to the major sca loci. serum vitamin b12 is frequently measured in the investigation of anaemia, and in screening neurological and other disorders. frequently, patients are found with low serum vitamin b12 level with a normal hb and without clinical abnormalities relevant to vitamin b 12 deficiency. this study was carried out to determine the significance of a low serum vitamin b 12 level. 959 vitamin b12 measurements were carried out over an 8 month period using a chemiluminescence method (abbott imx). clinical data was obtained retrospectively. of the 959 samples 81 (8.4%) representing 65 patients had a low serum vitamin b12 level (>180 pg/ml) with a mean of 152 pg/ml (39-179). data was available on 44 patients. 20 (45%) had a hb below the normal range with median serum vitamin b12 level of 158 pg/ ml (75-184). 19 (45%) had a normal hb, mcv and mchc with a median serum vitamin b12 of 152 pg/ml (52-210), and 5 had a normal hb with an abnormal mcv or mch. lft's, autoantibodies, schillings test and bone marrow examination data will be presented. in conclusion in patients with a low serum vitamin b 12 level, there was no significant difference in the b12 levels in those patients with a normal or a low hb concentration. it would appear that serum vitamin b12 is a poor discriminatory test but that changing the normal range may not help in screening. low serum vitamin b12 on its own may not appear to provide adequate grounds for lifelong replacement therapy. of 1 in 133 for males and 1 in 172 for females. as expected the overall incidence of hodgkin's was lower with one third of male and one quarter of female lymphoma cases affected by the disease. a distinct age specific pattern is evident depending on lesion type. marked variation in incidence levels were noted throughout the study region. an extremely varied pattern is evident in the survival rates for lymphoma patients. the cork and kerry rates for malignant lymphoma are relatively low when compared with international levelstzl obstetric complications and schizophrenia: methodology and mechanisms perinatal complications and clinical outcome within the schizophrenia spectrum 96) negative symptoms, cognitive impairment and duration of initially untreated psychosis in schizophrenia davnet's hospital, monaghan, and royal college of surgeons in ireland retinal pathology in kearns sayre syndrome mitochondrial dna and disease mitochondrial myopathies: clinical features, investigation, treatment and genetic counselling phenytoin induced pseudolymphoma. a report of a case and review of the literature cutaneous reactions in head injured patients receiving phenytoin for seizure prophylazis hydantoin induced pseudopseudolymphoma branhamella catarrhalis: an organism gaining respect as a pathogen correlation between branhamella catarrhalis adherence to oropharyngeal cells and seasonal incidence of lower respiratory tract infections 206) epidem1ology and survival rates for all 324 lymphoma patients registered in cork and kerry over the eight year period an indepth review of all 324 lymphoma (icd -o code 196) patients registered by the sourthern tumour registry during the eight year period 1983/1990~l annual age adjusted rates of 7.6. and 5.4 per 100,000 were seen for males and females respectively. these levels indicate a lifetime (up to 75 yr) risk references 1. cancer, the irish experience cancer incidence in five continents volume v immunohistochemistry for bcl-2 oncoprotein without antigen retrieval gave negative results, but with antigen retrieval, showed positive staining in 6 out of 8 cases. no bcl-2 rearrangements were detected by pcr. the combination of sscp and sequencing confirmed only wild type dna in all cases, p53 immunohistochemistry by standard methods revealed positive staining in only one out of nine samples analysed. when the antigen retrieval method was employed for this antibody, positive staining was seen in > 10% of tumour cells in four further cases.our results suggest that p53 does not play major role in ptld. bcl-2 overexpression but not rearrangement may contribute to the development of ptld. transplant arteriopathy (ta) is the major cause of death in cardiac allograft recipients. the pathogenesis is unclear. we have previously shown a plasma cell predominance in the infiltrate of ta, leading us to hypothesise a role for epstein-barr virus (ebv) infection in its pathogenesis. an association between cytomegalovirus (cmv) and ta has previously been suggested. the aim of the study was to investigate the role of epstein-barr virus (ebv) and cytomegalovirus (cmv) in the pathogenesis of ta.we performed pcr for cmv and ebv dna and protein (lmp) in seven cases of ta, involving cardiac allografts. restriction mapping was used to confirm that pcr products were either cmv or ebv dna respectively.cmv dna was found in four cases. ebv dna was found in six of the seven cases and ebv lmp staining was present in six cases. ebv was detected in all cases by either pcr or ihc.our results suggest that ebv infection may play a pathogenic role in transplant arteriopathy. the evidence for a similar role for cmv ~s less strong. st. vincent's hospital. hereditary spastic paraplegia (hsp) is a neurodegenerative disorder characterised by progressive spasticity, primarily of the lower limbs. it can be inherited in an autosomal dominant (ad), autosomal recessive or x-linked manner~ we have identified a large irish family (family a) affected with ad hsp that cosegregates with dementia. three. loci have previously been identified that are linked to ad hsp in families of different ethnic origin. the locus on chromosome 2 is reported to be the major hsp locus. the aim of the present study was to examine family a for linkage to the chromosome 2 hsp locus.dna has been extracted from blood taken from all 45 co-operating family members for genotyping. polymorphic microsatellite markers from chromosomal region 2p24-21 have been amplified by pcr, electrophoresed on a denaturing polyacrylamide gel and detected by silver staining. linkage analysis was carried out using the linkage series of programs. linkage analysis excluded the hsp gene from the chromosome 2p locusl the most significant marker was d2s367, with a lod score of-2.12 for recombination fraction 0.19, thereby excluding approximately 19cm either side of this marker. negative lod scores were also obtained for the other markers chosen (d2s391, d2s392, d2s352, d2s 174) excluding 20cm, 8cm, 4cm and 8cm respectively.the current study has therefore successfully excluded linkage of ad hsp in family a to the major locus on chromosome 2p. further studies are underway to exclude linkage of hsp in this family from other candidate loci, prior to carrying out a genome wide search. the presence of dementia in this family in association with hsp suggests that a new and as yet unidentified gene is responsible. vincent's hospital. eye and ear hospital, dublin. ched is a corneal endothelial dystrophy characterised by diffuse bilateral corneal opacities resulting in impaired vision. both autosomal dominant and autosomal recessive modes of inheritance have been described. another endothelial dystrophy, posterior polymorphous dystrophy (ppmd) has been linked to 20qll.we have used homozygosity mapping to analyse a pedigree with autosomal recessive ched for linkage to 20ql.1. all affected individuals are offspring of consanguinous matings. homozygosity mapping is based on the principle that these offspring would be homozygous for genetic markers near the disease gene. homozygous regions would be random between different offspring of these matings, except at the di-sease locus shared by affected offspring.dna was extracted from blood taken from 22 family members, 14 of which have ched. allele frequencies were determined in pooled dna from affected individuals. pooled dna from unaffected individuals was used as a control. at the disease locus, a shift in allele frequencies towards a single homozygous allele would be observed in the affected dna pool. pooled dna was genotyped by pcr for 3 polymorphic microsatellite markers in the region of20qll. pcr products were separated on a polyacrylamide gel and visualised by silver staining. similar allele frequencies were observed at these loci in both dna pools demonstrating independent assortment of alleles. in addition, affected and unaffected family members were individually genotyped at these loci and no significant loss of heterogeneity in the affected individuals at these loci was observed. these data indicate exclusion of linkage of the ched gene to 20qll. key: cord-022659-chwk2bs4 authors: nan title: abstracts: poster session date: 2004-10-08 journal: ann neurol doi: 10.1002/ana.410320224 sha: doc_id: 22659 cord_uid: chwk2bs4 nan an immune etiology has been postulated for acute cerebellar ataxia of childhood (acac) since it frequently follows viral infections. we analyzed serum and cerebrospinal fluid (csf) from 6 acac patients for antibody cross-reacting with cerebellar neurons. serum and csf were obtained within 7 days of onset of pancerebellar ataxia from subjects aged 3.5 to 11 years. varicella infection preceded 4 cases. results of enhanced cranial ct scans were normal; csf demonstrated 2-122 cells/mm3 with sterile cultures. serial dilutions from 1 : 20 of serum and undiluted csf were screened for antineuronal antibody by indirect immunofluorescence (iif) using frozen, unfixed normal human cerebellum. serum (1 : 400) was examined further for antineural antibody by western immunoblotting using purified cerebellar neuronal extracts as antigen. serum from age-matched, neurologically normal pediatric inpatients served as the control group for iif and immunoblot experiments. in acac patients, no antineuronal immunoreactivity was observed by iif. immunoblots demonstrated no consistent pattern of immunoreaction when comparing acac to controls, though 1 patient exhibited distinct bands at 200 kd (neurofilament protein) and 54 kd. although antecedent infection suggests an immune etiology for acac, our preliminary results do not support a humoral mechanism for this disorder. ingrid taff; joseph zito, robert gould, and steven pavlakis, great neck and manhasset, ny in a 20-month period we studied 69 patients between the ages of 7 weeks and 2 1 years with magnetic resonance angiography (mra). studies were performed on a 1.5t magnet (siemens magnetom sp) with a circular polarized head coil. a three-dimensional time-of-flight technique was utilized. occasionally, images were obtained after gadopenetate dimeglumine infusion. two-dimensional projection images were calculated using a maximum intensity projection algorithm and recorded on laser film. sixty-seven patients also had routine mri. a sampling of vascular lesions was demonstrated. nineteen patients had clinical and mri evidence of stroke. mra revealed intracranial vascular occlusion in 2 patients, diminished focal cerebral flow in the affected area in 4, and generalized ipsilateral underdeveloped cerebral circulation in 4. a moya-moya vascular pattern was found in 4 and sickle-cell vasculopathy was found in 1 patient. seven mras were normal. seventeen vascular hamartomas were demonstrated including 2 vene of galen malformations, 7 arteriovascular malformations, and 8 venous angiomas. three aneurysms were found. thirty-one mras were normal. we find m u to be a valuable adjunct to routine mr imaging in the evaluation of pediatric patients with potential cerebrovascular disease. it demonstrates a spectrum of pathology, is noninvasive, and allows for serial follow-up examinations. angiography in pediatric cerebrovascular disease p4. thalamic change in acute encephalopathy of adult rats. twelve weeks after grafting, clinical and histological studies were performed. we developed a protocol for evaluating functional deficits that follow spinal cord injury in the rat. the survival, growth, differentiation, and parenchymal integration of the graft were documented histologically on semi-thin section. animals that received the transplants demonstrated qualitative and quantitative improvements in several parameters of locomotion. donor tissue integrated most often with the host spinal cord at interfaces with host gray matter; however, some implants also exhibited sites of fusion with damaged host white matter. we suggest embryonic rat spinal cord transplantation may be a useful treatment of spinal cord injury and a possible therapeutic strategy in human spinal cord injury and amyotrophic lateral sclerosis. the basic neuropathophysiology of hemineglect after unilateral cerebral lesions is still not clear. one theory holds that degraded perceptual processing occurs in the damaged hemisphere due to intrahemispheric deficits. another holds interhemispheric interaction at fault, with the intact hemisphere actively inhibiting spatial cognitive processes in the damaged one. we tested 11 adult macaca fascicuhris with acute neglect on a task in which the whole visual surround was restricted to 15 degrees from central fixation, and a second in which an opaque lens occluded the eye either ipsilateral (ipsi) or contralateral (contra) to the lesion. using paired t tests, in the first task there were no differences in reaction time to the ipsi and contralesional hemifields. in the second, there was no change in extent of the ipsilesional field (obtained with the contralesional eye occluded), as compared to its extent without occlusion. the contralesional field, however, improved significantly ( p < .03) with the ipsilesional eye occluded. since reducing sensory input to both hemispheres leads to no worsening of hemineglect, but reducing sensory input to the intact hemisphere alone leads to improvement of hemineglect, we conclude that adverse interhemispheric interactions play a major role in the pathophysiology of hemineglect. we assessed the sensitivity and applicability of a new, cornbined cognitive and mood screening battery for multiple sclerosis (ms). sixty consecutive, untreated clinically active ms patients, 30 each relapsing-remitting and chronic progressive, underwent the battery and head mri upon entering 2 concurrent treatment trials. the battery combines the faust-fogel brief cognitive screen and visual analogue dysphoria scale, both previously validated in other neurological diseases. cognitive domains tested were immediate and delayed sentence and word-pair recall, verbal fluency, and conflicting response suppression. patients marked ''usual mood" along a "happy-sad" cartoon continuum. relapsing patients were program and abstracts, american neurological association 235 younger (32.8 vs 41.2 yr mean), with shorter ms durations (6.4 vs 11.3 yr), and had lower kurtzke disability scores (1.7 vs 5.8). modified qualitative mri grading (lesion burden, confluence, localization) was compared. half as many relapsing patients (43% vs 83%) scored ''abnormal'' cognitively, despite similar "sadness" rates (20% vs 23%). subjective dys-~ phoria in both groups correlated with denser periventricular lesion burdens. the battery was well tolerated and easily administered within 10 minutes without special equipment. this combined cognitive and mood screening battery is sensitive and convenient for clinically active ms. alternate forms of the battery are needed for repeatability. questionnaires may be reliable and valid supplements to laboratory tests for brain-damaged patients, as they can be applied to situations for which laboratory testing is not possible. we investigated the usefulness of informant-based data in alzheimer's disease (ad) by comparing caregivers' subjective evaluations of 83 probable a d patients' performance on an abbreviated version of the memory self-report questionnaire to objective evaluations derived from an extensive battery of neuropsychological tests and to clinicians' evaluations. similar information was obtained from 39 healthy agematched controls. caregivers' subjective appraisals of patients' memory correlated significantly with objective measures of secondary memory, with all cognitive variables, measures of activities of daily living, and clinicians' evaluations of dementia staging. scores were independent of clinical indicators of depression. the abbreviated memory questionnaire showed good reliability, internal consistency, and external validity. its positive predictive value is 63.5 and its negative predictive value is close to 100%. results suggest that (1) informant-based questionnaires may be useful for obtaining valid information on cognitive ability outside of laboratory settings; (2) the scale reflected more than just memory functions; and (3) the scale may be promising for screening cognitive difficulties in epidemiological or clinical settings. although neglect along the horizontal dimensions of extrapersonal space is well recognized, there are only a limited number of observations documenting neglect along the vertical and radial spatial dimensions. we report an investigation of neglect along the 3 principal dimensions of extrapersonal space in a patient with bilateral mesial temporo-occipital infarctions. neglect was assessed by asking the patient and controls to bisect lines of 4 lengths oriented in 3 directions with respect to the body: horizontal, vertical, and radial. our patient showed significant neglect of upper vertical and far radial space, as well as neglect of left hemispace. his line bisection errors were consistently in a direction opposite the slight directional biases shown by controls for all 3 line orientations ( p < .05). the magnitude of the patient's bisection errors increased by moving the lines toward the neglected sectors of 3-dimensional space. neglect of upper vertical and far radial space was also evident on line cancellation tasks. our results suggest that following focal brain injury, neglect may be observed along all 3 dimensions of extrapersonal space. these findings provide further empirical support for functional specialization within inferior and mesial temporooccipital regions for attending to upper vertical and far visual space (previc, 1990) . p12. posterior cortical atrophy: degenerative disease with primary visuospatial and visuosemantic deficits a. kertesz, m . polk, and a. kirk, london, ontario, and saskatoon, saskatchewan, canada posterior cortical atrophy is a recent, and heidenhahn's disease is an old, label for a miscellaneous group of patients with imaging or pathological and clinical evidence of visuocognitive deficits and cortical atrophy localized to the posterior cortex. the extent of this cortical localization and the nature of the pathological findings are not fully agreed upon, but spongiform degeneration and alzheimer pathology have been described. detailed examination of patients who are representative of the problem and have uniquely specific deficits is presented. one patient had visual associative agnosia, prosopagnosia, and transcortical sensory aphasia. lexicosemantic experiments of categorization, word retrieval, and comprehension of auditory and visual stimuli showed a specific impairment of visuoverbal semantics. a striking preservation of phonological, orthographic and visual structural input, and intercategory dissociations was demonstrated. consistency of errors argued for specific loss of semantic knowledge. another patient with apraxia, primary visuospatial deficit, agraphia, and amnesia at the beginning had predominantly right-sided posterior cortical atrophy, demonstrating further fractionation of the entity and the striking specificity of visuospatial function. the behavioral specification of degenerative disease is clinically and theoretically important. permanent neurological deficits after ischemic stroke are mainly determined by the location and size of the infarct. clinical recovery also depends on the functional state of adjacent brain tissue, where both neuronal loss and deactivation without gross morphological damage may affect flow and metabolism to a varying degree (g. mies et al, stroke 1983; 1422-27) , and where the ability to respond to stimulation by appropriate neuronal recruitment may be impaired. therefore, degree of resting hypometabolism and of responsiveness to functional activation may provide a measure of prognosis. in 26 patients (age 60.7 10.9 yr) with aphasia consequent to ischemic stroke of the dominant hemisphere, regional cerebral metabolic rate of glucose (rcmrgi) was measured at rest and in 17 of them also during spontaneous speech, using positron emission tomography (pet) of 2-(f18)-fluoro-2-deoxy-~-glucose (fdg). the pet study and a standardized neuropsychological test battery to assess the main aspects of language were performed around the fourteenth day after the stroke, and the language functions were assessed again 3 to 5 months later. performances in various dimensions of language 2 weeks and 3 to 5 months after stroke were related to rcmrgl in topographically meaningful areas at rest and during activation using wilcoxon-rank program and abstracts, american neurological association 237 sum test and multiple regression analysis. severity of aphasia was assessed by the token test, which showed a bimodal distribution to slight and severe, and a lower representation of moderate cases. global and all regional cmrgl at rest and during activation were significantly correlated to scores in token test at first and second examination, with the highest correlation coefficients ( -0.7 to -0.61) for broca's, wernicke's, and left temporoparietal regions. for performance after 3 to 5 months, the relationships were still significant with lower coefficients. verbal fluency also was correlated to kmrgi, but with lower coefficients that slightly increased for the recovery state. language performance at different stages in the course after ischemic stroke was significantly related (r = 0.84 for token test, r = 0.93 for verbal fluency). however, there exists a high variability in recovery that may be explained by stepwise regression of metabolic values. significant effects were observed only for cmrgl of the left hemisphere outside the infarct (partial r' = 0.21) at rest and for cmrgl within the infarct (0.27), the contralat-era1 mirror region (0.16), and broca's region (0.17) during activation, with a sum of all partial weight factors of 0.46 at rest and 0.72 during activation. our results furnish 2 indicators for recovery of aphasia: the resting metabolism of the left hemisphere outside the infarct, and the activated metabolism in residual tissue within the infarct and in languagerelated areas. although the hemispheric metabolism at rest might be related to neuronal loss and thereby to the brain's reserve capacity, the extent of metabolic activation indicates neuronal recruitment and the capability of neuronal networks for functional recovery. heparin therapy for acute myocardial infarction: the timi-i1 pilot and randomized trial combined experience m . a. sloan, t . r. price, m . l. tevrin, and s. forman for the timi investigators, baltimore, m d of 3,924 myocardial infarction (mi) patients treated with rt-pa and heparin, 29 (0.7%) developed ischemic cerebral infarcts (ci). all ci patients had detailed neurological evaluations and 27 (939%) had c t scans. age range was 40 to 74 years (mean 60 yr), 25 were male, and 22 were caucasian. electrocardiographic location of mi was anterior in 22 (76%) and nonanterior in 7 (249%). six cis occurred within 6 hours; 1 between 6 and 12 hours; 2 between 12 and 24 hours; 4 between 24 and 48 hours; 13 during the second week; and 3 others distributed over the 4 weeks after study entry. six of 29 cis did not involve cerebral cortex; 9 (319%) had multiple cis. of 24 cis thought to be embolic in origin, 17 had at least 1 cardiac abnormality (mural clot, wall motion abnormality, aneurysm, or transient atrial fibrillation) known to be associated more specifically with embolism than just the diagnosis of myocardial infarction. eight of 27 (30%) with ct scans had hemorrhagic conversion of varying degrees. the time of occurrence and sites of ci after rt-pa and heparin therapy for acute mi are similar to those reported in the prethrombolytic area. nancy futrell andjeanne m. riddle, detroit, m i photochemical irradiation of the carotid artery of rats has been used to induce endothelial damage, producing a nonocc h i v e thrombus (that apparently embolizes spontaneously) thrombi and emboli and multiple cerebral infarcts. evidence for embolism generally has a presumptive component. to document further that cerebral infarcts in this model are indeed due to embolism, we studied the ultrastructure of the carotid thrombi and the presumed cerebral emboli using scanning and transmission electron microscopy (sem, tem). the right carotid artery of 9 wistar rats was irradiated with a laser (632 nm, 200 mw/cm2, 15 min) following the injection of the photosensitizing dye photofrin 11, 12.5 mgikg. rats were sacrificed from 1 to 24 hours later. endothelial damage with formation of a fragmenting thrombus, composed mainly of platelets and erythrocytes (with no fibrin in most areas), was present in the carotid arteries of all rats by sem. sem was done on 36 cerebral vessels, 3 1 containing peripheral blood elements, with single (1) and aggregated (6) platelets (causing occlusion in 3), single (10) and aggregated (10) erythrocytes (without occlusion), and single (1) and aggregated (3) leukocytes (without occlusion). tem demonstrated that the platelet aggregates did not adhere to the cerebral endothelium. the endothelial surface of all cerebral vessels was normal, which provided additional evidence that the mechanism of cerebral infarction in this model is embolism. model of repetitive ischemia: this effect is significantly enhanced when combined with mild hypothermia ashfaq shuaib and elisabeth sechocka, saskatoon, saskatchewan. canada there is considerable evidence that glutamate release resulting in activation of postsynaptic receptors (especially nmethyhaspartate) is a major mechanism of ischemic neuronal injury. in vivo experiments have shown that a more severe release of glutamate may be responsible for the excessive damage seen with repeated ischemic insults. we have shown that in cell cultures the effect of brief repeated insults is more severe than a single insult of similar duration. in the present study, we tested the protective effects of cgs-19755 in a cell culture model of single ischemic and multiple-insult paradigm. in the multiple-insult paradigm, in some cultures cgs-19755 was combined with mild hypothermia to see if this would offer additional protection. cgs-19755 offered a dose-dependent protection in cell cultures exposed to a single ischemic insult. cgs-19755 was protective to cultures exposed to repeated ischemic insults. the protective effects were enhanced significantly when they were combined with hypothermia, resulting in almost complete protection of the cultures. the combination of therapies appears to be a valuable strategy in neuronal protection during cerebral ischemia. toby i. gropen, i . prohovnik, t . k. tatemirhi, z. sharif; and m. hirano, new york, n y although a rare syndrome, mitochondria1 encephalomyopathy, lactic acidosis, and stroke (melas) may offer a unique insight into stroke mechanisms. we report novel observations in a patient with melas studied with serial and quantitative cerebral perfusion after stroke using """tc-ceretec spect and '3ixe rcbf. a 24-year-old man with melas presented with left-sided headache, generalized seizures, fluent aphasia, and right hemianopia. serial ct and mri showed infarction of the posterior left hemisphere in a multiterritorial distribution. spect performed 15 days after stroke showed 20 to 30% greater flow in the infarct than in normal brain, which reversed 109 days after stroke. quantitative rcbf (m2 isi, reflecting mostly gray matter), when corpatients died. we recommend ct evaluation in all patients who have a seizure or lose consciousness during the peripar-tum period. despite intensive management, mortality is high. seizures should not be attributed to eclampsia without careful neurological assessment. when prenatal care is sought, women should be counseled about the dangers of cocaine to themselves as well as to their babies. changes in circulating blood volume following stephan a. mayer, matthew e. fink, laura lenniban, louise m. klebanoff; auis beckford, lsak prohounik, william young, and robert a. solomon, new york, n y reduction of blood volume (bv) has been implicated as a risk factor for delayed cerebral ischemia (dci) due to vasospasm after aneurysmal subarachnoid hemorrhage (sah). volume expansion guided by target filling pressures has gained popularity as a means of preventing or reversing dci; however, the adequacy of central venous pressure (cvp) as a reflection of bv in this setting remains unclear. we measured bv and cvp concurrently in 10 patients (5 males, 5 females; mean age 57 yr) 1 day after craniotomy (mean 3.5 days after sah) and an average of 5.5 days later. the mean bv (mllkg) measured using chromium5'-labeled red blood cells (rbcs) fell from 69.7 to 55.3 (normal range 55-80), a reduction of 21% ( p = .05, paired student's t test). despite this, mean cvp (mm hg) remained unchanged (7.1 vs 7.9). similar reductions of plasma volume (2 1%) and rbc volume (24%) accounted for no change in mean hematocrit (33.2 vs 33.5). bv fell 25.7% among grade iiiliv patients (n = 5 ) compared to 14.7% among grade 1/11 patients (n = 5). a moderate correlation between bv and cvp ( r = .48, p = .16) was found only with the first set of measurements. time-related alterations in venous capacitance, myocardial contractility, or systemic vascular resistance may explain our findings. axel rosengart, louis r. caplan, michael s. pessin, atherostenosis of the extracranial vertebral artery (ec-va) has rarely been studied systematically in series of patients with acute vertebrobasilar strokes or transient ischemic attacks. we identified by conventional angiography and neuroimaging (ct, mri, ultrasound, mr angiography) 45 patients with ec-va disease among 154 patients with posterior circulation ischemia. patients with cardiac sources of emboli were excluded. the probable etiologic mechanisms were: group a: vertebral artery origin (vao) atherostenosis with embolism-19 patients; group b: vao atherostenosis with hemodynamic spells-7 patients; group c: 1 patient with vao atherostenosis and both intra-arterial embolism and hernodynamic spells; group d: ec-va dissection-8 patients (6 unilateral, 2 bilateral); 1 patient had perioperative compromise of the ec-va with presumed intra-arterial embolism; group e: vao disease in addition to other distal vascular lesions-9 patients (2 with intracranial va and 7 with basilar artery [baf occlusive disease). ec-va disease is not always benign. vao atherostenosis and dissection of the ec-va are sources of intra-arterial emboli. hemodynamicrelated ischemia occurs with bilateral and unilateral va disease but is often transient. vao atherostenosis is often accompanied by severe occlusive disease of the intracranial va and ba. program and abstracts, american neurological association 239 sebastian e. ameriso, vicky l. y. wong, andvas gruber, hidemi ishii, and mark fisher, los angeles and la jolla, c a , and kanagawa, japan hemostasis abnormalities are associated with ischemic stroke. these changes typically are demonstrated in antecubital venous blood samples and may not necessarily represent changes within the vasculature of the brain. the purpose of this study was to identify potential differences in hemostatic profile from samples of cranial versus noncranial venous sites in patients with acute ischemic stroke. eight patients were studied within 7 days of acute brain infarction. some patients were studied on 2 separate days. blood was drawn from the external jugular vein and immediately thereafter from an antecubital vein without the use of tourniquet. we measured hematocrit, leukocyte count, platelet count, fibrin d-dimer (cross-linked fibrin fragment), plasminogen activator inhibitor-1 (pai-1, an important antifibrinolytic protein), and anticoagulant proteins thrombomodulin and activated protein c. a jugular-to-antecubital ratio was calculated for each paired blood sampling. thirteen paired samples were obtained from the eight patients. external jugular-to-antecubital ratios (mean to-antecubitat ratio for pal 1 was significantly different from 1 ( p < 0.05), with higher concentrations in jugular samples. in conclusion, levels of hemostatic proteins measured from cranial venous blood may differ from antecubital samples in patients with acute ischemic stroke. in animal models of transient cerebral ischemia, the effects of repetitive insults are more severe than a single ischemic episode of similar duration. we used the cell culture model of ischemia to determine if the effects of repetitive ischemia are similarly more severe in this model of ischemia. for cell culture, we used fetal mice cortical astrocytic and postnatal cerebellar (glutamatergic) granular neurons and cerebral gamma-aminobutyric acid (gaba)ergic cells. lactic dehydrogenase (ldh) (activity per gram protein) release in the medium was used as a measure of cellular damage. compared to a single insult, there was a large increase in ldh release during repetitive ischemia in astrocytes (233 vs 7 5 , p < 0.02) and granular cells (129 vs 41, p < 0.001) (highly significant) and a modest (but significant) increase in the cortical neurons (11.6 vs 7.5 p = 0.05). the demonstration that repetitive ischemia produces more severe damage in cell culture would suggest that the mechanisms are not predominantly vascular. cell culture could prove useful to study the mechanisms of neuronal damage with repetitive ischemia. we studied the spontaneous recovery of neurological function after acute ischemic stroke using a standardized stroke nih stroke scale scale ( n i h stroke scale) to assess the extent of improvement, differences in stroke types, and early predictors of later outcome. we performed serial neurological assessments on admission; 24, 48, and 72 hours after admission; and 7 to 10 days and >30 days after admission. twenty-six patients had presumed embolic occlusion of the middle cerebral artery (mca) and 14 had a clinical diagnosis of lacune. admission score was better in the lacune group compared to the mca group. the mean scores for all patients improved by the 7to 10-day and the >30-day examination, but the degree of improvement was greater in the mca group than in the lacune group at >30 days ( p < 0.004). the degree of change at 7 to 10 days correlated with the change in score at 24 hours ( r = 0.45, p < 0.05) and 48 hours ( r = 0.86, p < 0.05). most patients improve after acute ischemic stroke, but to variable degrees and at different rates. david w. desmond, thomas k. tatemichi, miguel figueroa, dew'itt t . cross, and yaakov stern, new yovk, n y to investigate the effects of lacunar infarction (li) on cognitive function, we examined 57 li patients 3 months after stroke (age = 71.6 ? 9.0 yr; education = 9.2 2 4.7 yr) and 241 stroke-free nondemented control subjects (age = 70.6 k 6.5 yr; education = 12.4 k 4.5 yr) with a battery of neuropsychological tests. li was defined as a presenting infarct of 5 2 cc and a mean volume of any additional subcortical infarctions of 5 2 cc on ct scan. using multiple regression analyses, with significance set at p < .01 to minimize the risk of type i error, we considered the role of li as a correlate of performance in multiple cognitive domains. controlling for the effects of demographic factors, vascular risk factors, alcohol use, and depression within the multivariate models, li was a significant independent correlate of deficits in memory ((3 = -.40, p = .0002), verbal (p = -.28, p = .0025), visuospatial (p = -.51, p < .oool), abstract reasoning (p = -.31, p = .0029), and attentional skills (p = -.50, p < .0001). we further investigated the effects of infarct number, volume, and location, as well as atrophy, on global cognitive function within the li group. the only significant independent correlate of global cognitive performance was a preponderance of left-hemisphere infarctions (p = -.07, p = ,0454). these results suggest that li may produce dysfunction in multiple cognitive domains, particularly when the left hemisphere is differentially involved. p30. increased intracranial atherosclerotic stroke in hispanics and blacks from northern manhattan ralph l. sacco, christina zamanillo, t . shi, andj. p. mobr, new york, ny intracranial atherosclerosis has been found to be more frequent in blacks compared to whites, whereas hispanics have rarely been characterized. among 2 10 consecutive patients from northern manhattan over age 39 hospitalized at the presbyterian hospital from 1990 to 1991, cerebral infarction occurred in 32 whites, 84 blacks, and 74 hispanics. all patients had at least one c t scan, 96% had duplex doppler, 94% transcranial doppler, and 12% angiography. strokes were classified as atherosclerotic (ath), cardioembolism, lacunar, and as infarcts of undetermined cause. ath was further subdivided into extracranial (eath) or intracranial (iath) . overall, the frequency of ath was similar in the three racelethnic groups (white 2096, black 16'96, hispanic 2096) . the distribution of the atherosclerosis, however, was different in whites compared to blacks and hispanics. whites had more eath stroke than blacks and hispanics (white 17%, black 7 % , hispanic lo%), while iath was similar in blacks and hispanics and greater than in whites (white 394, black 895, hispanic 10%). nonwhites have more iath stroke than whites. the similarity in the distribution of atherosclerosis between blacks and hispanics argues for shared environmental risk factors, rather than genetic differences. ethnic differences in stroke risk factors may help explain differences in infarct subtype. we studied 10 mild to moderate alzheimer's disease (ad) patients with a series of "0 water bolus positron emission tomographic (pet) activation studies, and compared them to similar studies in 10 age-matched normal controls. for each group, pet images were mapped onto the subjects' mri scan, and results of a particular activation condition were averaged across the group. naming a series of pictures (line drawings of animals) minus counting abstract designs as a baseline produced strong activation of the anterior cingulate gyrus only in the ad group. silent reading of words minus viewing a baseline series of "xs" similarly showed strong activation of the anterior cingulate gyms in the ad subjects but not the normals. naming 1 block (activation condition) of 80% unnamed pictures, minus a second block (baseline) of easily named pictures, demonstrated much greater cingulate activation in the ad patients, for naming of the more difficult pictures. we conclude that this cingulate activation may reflect the greater involvement of an attentional network (of which the anterior cingulate is a part) in tasks requiring a higher degree of "mental work" on the part of ad patients. dementia in alzheimer's disease j. w. pettegrew, k. panchalingam, w. e. klunk, and r. j alzheimer's disease (ad) predominantly affects the brain, resulting in the loss of multiple cognitive abilities. some studies suggest the membranes of peripheral cells are involved in the disease. to investigate erythrocyte membrane molecular dynamics in ad patients and age-matched controls, we investigated erythrocyte membrane molecular motion at the surface (fluorescamine), aqueous-hydrocarbon interface (dppe-ans), and hydrocarbon core (1219j-as; ppc-dph) by steady-state fluorescence anisotropy measurements of 16 probable ad patients (5 males; 11 females) and 20 (1 1 males; 9 females) age-matched controls. cognitive function was assessed by the mini-mental, mattis, and blessed scales. we found that intergroup comparisons revealed decreased motion at the surface ( p = 0.001) and aqueous-hydrocarbon interface ( p = 0.03) and increased motion in the hydrocarbon core ( p = 0.01) of the moderately to severely impaired ad patients compared to the controls. in the ad patients, there were significant correlations between decreasing membrane surface motion and worsening blessed scores (males p = 0.05; r = 0.7; femalesp = 0.04; r = 0.5). these findings suggest that molecules are being produced in the brain of ad patients that gain access to the circulation. these molecules insert into the erythrocyte membrane and secondarily alter erythrocyte membrane molecular motion. the production of these molecules correlates with the dementia and could contribute to the molecular pathophysiology of the disease. parkinson's disease (pd) and alzheimer's disease (ad) are 2 common disorders of old age and may therefore coexist. the prognosis in demented pd patients is poor and early recognition of such cases is therefore desirable. the objective of this study was to identify characteristics that distinguish pd + ad from pd patients during early stage. all patients were clinically evaluated over a 22-year period . clinical diagnosis of dementia was made only when unequivocal clinical evidence of progressive decline in memory and cognitive function was documented, and pathological diagnosis of ad and pd was made using standard criteria. twentysix patients who had only pd or pd + ad were identified; 20 had no dementia and at autopsy had pd. six patients had clinical evidence of parkinsonism and dementia and at autopsy had 2 distinct pathological findings-pd and ad. these 6 cases could be classified as having simultaneous or sequential evolution of pd + ad. those with sequential onset had pd before age 65 years but were inexplicably functionally disabled early on, whereas those with simultaneous onset manifested pd after age 65 years. pd + ad patients had rapid disease progression, shorter survival, poorer drug response, and more side effects of levodopa than pd patients. to study the prevalence ofwhite matter lesions in the general elderly population, and to investigate whether white matter lesions were relatively frequent in subjects with classic vascular risk factors and with hemostatic risk factors, magnetic resonance scans were obtained of 11 1 participants, aged 65 to 85 years, of the rotterdam elderly study. the subjects for the imaging study were a random sample from the general population, stratified by age and gender. t2-weighted images were obtained in the axial plane. white matter lesions were considered present when moderate or severe periventricular hyperintensities or when more than 5 small focal lesions or focal confluent lesions were found. overall, 27% of subjects had white matter lesions. the prevalence and severity of le-program and abstracts, american neurological association 241 sions increased with age. history of stroke or myocardial infarction, presence of peripheral arterial disease, factor viic activity, and fibrinogen level were each significantly and independently associated with the presence of white matter lesions. significant relations with actual systolic as well as diastolic blood pressure, with a history of hypertension, and with plasma cholesterol were observed only for subjects between 65 and 74 years. this study suggests that white matter lesions in the elderly may be related not only to the classic cardiovascular risk factors. but also to hemostatic factors. joan m. swearer, paula nelligan, hanno muelher, beatrice woodward, and david drachman, worcester, ma although behavioral disturbances occur frequently in alzheimer's disease and other dementing disorders, little is known about the factors that predict their development or predispose to their occurrence. in the present study we examined 2 sets of possible predictive/predisposing factors retrospectively for behavioral disturbances in 35 mildly to severely demented, community-dwelling patients. the factors examined included: individual distinguishing features (age, gender, age of onset, premorbid personality traits, prior psychiatric history) and dementia severity (dependence in activities of daily living [adls) and self-care, duration of dementia, global disease severity). spearman correlations and t tests were used to assess the relative influence of these factors on the occurrence of 3 types of aberrant behaviors: aggressive behaviors, disordered ideation, and motor abnormalities. forty percent of the patients exhibited aggressive behaviors, 77% exhibited disordered ideation, and 63% had motor abnormalities. neither a prior history of psychiatric disorders nor premorbid personality traits were associated with the occurrence of the target behaviors. dependence in adls and self-care and greater global severity were associated ( p < .01) with the frequency and severity of aggressive behaviors, disordered ideation, and motor abnormalities. these results suggest that severity of dementia is a consistent and reliable factor in the development of aberrant behaviors, whereas preexisting personality traits are not. dementia of the alzheimer t y p e w. j. burke, a. ranno, w. h . roccafrte, s. p. wengel. b. l. bayer, and n . k. willcockson, omaha, ne l-deprenyl is an irreversible inhibitor of mao-b that has been reported to cause modest improvements in short-term memory and behavioral symptoms in persons with dementia of the alzheimer type (dat). thirty-eight subjects meeting research criteria for mild d a t were enrolled in a placebo-controlled, double-blind trial of r-deprenyl at a dose of 5 mg twice a day. subjects underwent extensive clinical and neuropsychological assessments at entry, and at 2 and 8 months. after 8 months, subjects taking both l-deprenyl and placebo showed a significant decline in their scores on the mini-mental state examination, the clinical dementia rating (cdr) scale, and the sum-of-boxes score derived from the cdr. when the change in scores on these clinical measures was examined across the 2 groups, there was no significant difference. there were no significant differences within or between groups on several behavioral measures including the brief psychiatric rating scale and the cornell rating scale for depression in dementia. neuropsychological testing demonstrated no significant differences berween groups based on mean score change. l-deprenyl did not affect cognition or behavioral symptoms of dat in this 8-month study. k. marder, m-x. tang, r. ottman, l. cote, y. stern, and r. mayeux, new york, n y the etiology of dementia in parkinson's disease (pd) is probably multifactorial but there may be a shared susceptibility for p d and alzheimer's disease (ad). reliable risk factor interviews were conducted with informants of 15 1 nondemented p d patients (pd-d) and 65 demented p d patients (pd + d) enrolled in a longitudinal community study of pd. p d + d were older (78.9 yr) than pd-d (71.4 yr) and had later age at onset of motor signs (71.1 yr) than pd-d (64.8 yr) ( p < ,001). the frequency of smoking, alcohol use, head injury, and family history (fh) of pd did not differ but fh of ad was significantly more frequent in the pd + d group (or 2.25, ci 1.01-5.01). using stepwise logistic regression, only age of onset of motor signs 2 6 5 (or 2.86), education <8 years (or 2.53), and the interaction of age of onset of motor signs and fh of a d (or 3.49) were independent predictors of dementia in pd. to address variable years at risk for development of dementia, life table analysis revealed the cumulative risk of a d to age 90 in first-degree relatives of p d + d was .312, and .119 in pd-d relatives ( p < .05). cox proportional hazards analysis controlling for the differences in ages of the relatives of both groups yielded a rate ratio of 2.06 (ci 1.2-3.7) for the development of a d among p d + d compared to pd-d relatives. we conclude that a genetic susceptibility to a d may raise the risk for dementia in patients with pd. differentiated from alzheimer's disease? john c. mowis, elizabeth grant, rita canfield, eugene rubin, and daniel mckeel, jr, st louis. mo vascular dementia (vd) is believed to account for 20 to 30% of all us cases of dementia; however, pathologically confirmed cases are quite rare. this discrepancy suggests that current diagnostic criteria lead to the clinical overdiagnosis of vd. twenty v d subjects (mean age 78.5 yr; 9 men, 11 women) were diagnosed solely on the basis of the presence of dementia, a history of stroke(s), and a documented relationship of stroke to onset andlor course of dementia; ischemic scores (is) and neuroradiographic findings were not used for diagnosis. compared with 89 subjects (mean age 75.2 yr; 34 men, 55 women) with dementia of the alzheimer type (dat), there were no significant group differences for comparable clinical dementia rating stages of dementia for measures of language, activities of daily living, or general cognition. the vd group scored significantly higher than the dat group on the modified is (f [91, 64] = 138.2, p < ,0001). all 27 autopsied d a t subjects had verified alzheimer's disease (ad); 8 also had cerebral infarctions. the 3 autopsied v d subjects had 168, 160, and 55 cc of brain tissue affected by stroke; 1 (168 cc) also satisfied histological criteria for ad. we conclude that (1) the clinical features of vd and a d overlap considerably; (2) diagnostic criteria based on the temporal association of stroke with dementia may have predictive value for vd; and (3) the frequent coexistence of a d and strokes indicates that refinement of criteria is needed to distinguish "mixed" and "pure" vd. clinicopathological correlation remains essential for any study of putative vd. left-handedness has been proposed as a marker for decreased survival in the general population, but possible effects of handedness on longevity in alzheimer's disease (ad) have not been examined. we hypothesized that left-handed ad patients would evince more rapid deterioration and therefore die at an earlier age than right-handed patients. subjects were 103 demented patients consecutively confirmed at autopsy to meet nincds-adrda criteria for "definite" ad. handedness was determined from structured interviews with primary caregivers and validated for most subjects with the edinburgh inventory of handedness. age at onset of dementia symptoms retrospectively determined by caregivers was used to calculate the duration of illness at the time of death. because of reported gender differences with regard to longevity, we first partialled out effects of gender before using hierarchical regression procedures to test the hypothesis. four of 46 men and 2 of 57 women with definite ad were left-handed. the mean age at onset did not differ significantly between handedness groups (f [ l,loo] = .82), but the mean duration of symptoms ( alterations in the optical properties of brain can be used to detect pathological changes in patients with alzheimer's disease (ad). using time-resolved spectroscopy (trs) and phase-modulation spectroscopy (pms), we measured the absorption (ua) coefficient, scattering (us) coefficient, and mean photon pathlength (pl) of red light directed through the base of the frontal lobes of 28 patients with ad and 11 age-matched control subjects. the measured values and the asymmetry index (ai) (an indication of the symmetry of the measurements between the left and right side of the brain) were correlated with the severity of disease as determined by mini-mental state score. there were significant differences between the ad and control group for ua, us, pl, and the standard deviation of ai. there was no correlation between the mms score and ua, us, or pl. however, the highest asymmetry index values were seen in moderately impaired patients , which suggests that the asymmetrical nature of the pathological process detected by optical spectroscopy is most marked during this stage of the illness. this noninvasive technique may provide a convenient method to detect and monitor the pathological changes that occur in the brain of patients with ad. disease p41. memory impairment in very mild alzheimer's a memory impairment is often the earliest indication of alzheimer's disease (ad). we investigated 3 components of disease learning and recall to determine which aspect of memory function is impaired the earliest in incipient ad. using the mayo clinic alzheimer's disease patient registry, which is a longitudinal prospective project on ad and normal aging, we identified 34 patients with very mild ad (i.e., with a mini-mental state score of 24 or greater) and 34 age-and sex-matched controls. we assessed performance on 2 memory measures: the rey auditory verbal learning test and the buschke free and cued selective reminding test (fcsrt). the 3 parameters evaluated included a measure of acquisition, total learning over trials (tl), and delayed recall (dr). on the fcsrt, an index of facilitation of performance with semantic cues (sc) was assessed. results indicated that all 3 indices, tl., dr, and sc, were capable of separating the mild ad group from the controls ( p < 0,001). using a linear discriminant analysis with stepwise variable entry, the measure that assessed the patient's ability to use semantic cues (sc) was the most sensitive parameter for separating the 2 groups ( f = 15.38, p < 0.0002), and the acquisition parameter (tl) was also useful at adding some additional predictive power (f = 8.48, p < 0.005). the delayed recall measure, however, did not add anything to the previous 2 measures. it appears that very early ad can be detected using appropriately structured memory tasks, and these procedures can be helpful in identifying at-risk individuals. alzheimer's disease (ad) has an insidious onset that is difficult to date reliably. we developed a standardized interview to provide objective criteria for dating the onset of 7 different symptoms (memory complainr, performance problems, language deficits, disorientation, depression, behavior problems, and psychosis), yielding an estimated disease onset date. inrerrater reliability (icc = 0.99;p < ,001) and interinformant reliability (icc = 3 5 ; p < .001) for the onset of first symptom was high. interrater agreement for the order in which symptoms appeared was high (icc = 0.72-0.98) as was interinformant reliability for all symptoms except memory complaint. the interview was administered to 2 16 patients with ad. mean estimate duration of illness was 4.26 years k 3.47 years and correlated significanrly with problems in instrumental activities of daily living. sixty-six percent had memory complaint and 45% had performance problems as their initial symptom. this technique provides a reliable characterization of disease onset. longitudinal studies will determine if particular onset symptoms differentially predict disease progression. the purpose of this study was to determine whether there is an excess of white matter disease (wmd) in alzheimer's disease (ad). brun and englund (1986) reported an excess of wmd in brains of patients with ad vs age-matched controls. there have been reports both confirming (bowen et al, 1990; fazekas et al, 1990) and refuting (leys, 1990) these findings using ct and mri in patients with clinically diagnosed ad. postmortem t2-weighted mri scans and program and abstracts, american neurological association 243 neuropathology were graded on 9 brains of pathologically confirmed ad subjects and 6 brains of age-matched neuropathologically normal controls. white matter lesions were scored on a 0 to 3 scale (none, mild, moderate, severe) separately for periventricular (pvl) and deep white matter (dwm) areas in mri scans and lux01 fast blue (lfb)-stained brain sections. correlations between mri and neuropathology were good ( r = 0.61 for pvl, r = 0.66 for dwm). pvl scores were higher in ad than in normal subjects on mri (ad: 2.2 l 0.9 vs controls: 0.2 rfr 0.3; p < .005). on pathology the difference in scores did not reach significance (ad: 1.3 2 0.7 vs controls: 0.5 * 0.4; p = 0.2). similarly, dwm scores were higher in ad subjects than normals on mri, but not neuropathology. in conclusion, ad brains have a significant excess of wmd on mri compared to controls. although the pvl and dwm scores for pathological sections are not different in the 2 groups, mri is much more sensitive than lfb-stained sections for wmd. thirteen autopsy cases of progressive supranuclear palsy (psp) were investigated for clinical-neuropathological correlations and heterogeneity. we reviewed clinical records of 11 men and 2 women aged 61 to 89 years (mean age 72 yr) with disease duration ranging from 4 to 12 years. most patients had classic features of psp including ophthalmoplegia, postural instability, and extrapyramidal signs. dementia was eventually observed in 9 of the 13 patients (67%). six of 9 patients (67 %) on whom adequate initial documentation was available presented with memory loss or behavior change. five of the 13 patients (395%), including 4 with an initial presentation of memory loss, were diagnosed clinically as having alzheimer's disease (ad) rather than psp; neuropathological diagnoses in these cases varied: i had combined ad-psp; 1 had ad-psp combined with parkinson's disease (pd) changes; 1 had psp-pd; and 2 had "pure" psp. the 2 patients with concomitant pd changes showed lewy bodies in the substantia nigra, locus coeruleus, nucleus basalis, and neocortex. the remaining 8 patients were clinically diagnosed as having psp; neuropathological diagnoses in these cases included 4 with "pure" psp and 4 with psp that also met neuropathological criteria for ad (psp-ad). these findings emphasize the clinical and neuropathological heterogeneity in psp. the neuropsychological battery developed for the consortium to establish a registry for alzheimer's disease (cerad) is currently used in many research studies to index the cognitive impairments of alzheimer's disease. in spite of its widespread use, normative informarion on the battery, important for interpretation of performance, has not been available. we report norms for the cerad battery based on a large sample of elderly control subjects (n = 398; white men and women; ages 50-89 yr) enrolled in the national study of cerad. performance on the neuropsychological measures was examined separately for subjects with high (2 12 yr) and low (< 12 yr) education. distribution of scores and basic descriptive information (means and sd) for each measure were determined. significant age and sex effects were observed on most cognitive measures in the highly educated group. in contrast, no significant age effects were observed in the low education group. effect of sex was not explored in this group due to the limited sample size (n = 48). further exploration of cerad performance in normal controls from underrepresented groups including minorities, residents of rural communities, and individuals with low education is in progress. intraneuronal inclusions of cytoskeletal proteins appear in several neurological diseases; for example, the neurofibrillary tangles of alzheimer's disease contain a cytoskeletal protein, tau. because the previously described slowing of axonal transport in aged animals might lead to accumulation of cytoskeletal proteins in nerve-cell bodies and axons, we assessed the abundance of 2 major cytoskeletal proteins in brain tracts of rats at age 4 months or 25 months. immunoassay was performed with monoclonal antibodies to alpha and beta tubulin and to nf-l (the core neurofilament protein) by published methods. samples were dissected in a standardized fashion and 2-mrn pieces of the following tracts were assayed: optic nerve, corticospinal tract (medulla), superior cerebellar peduncle, l5 dorsal root, and l5 ventral root. between 4 months and 25 months, the nf-l content approximately doubled in each brain site. tubulin substantially increased at of aged rats all sites except the fimbria-fornix. in contrast, tubulin did not change in the spinal roots. nf-l increased slightly in the ventral but not the dorsal root. this tendency of senescent brain neurons to accumulate cytoskeletal proteins in their axoplasm may predispose them to formation of intraneuronal inclusions in various degenerative diseases. we performed a prospective study of preoperative magnetic resonance imaging (mri) in 13 consecutive patients with intractable partial epilepsy who underwent a stereotactic resection of an extrahippocampal temporal lobe foreign-tissue lesion, "lesionectomy," between june 1986 and january 199 1. interpretation of the mri studies was performed by an investigator blinded to the presurgical evaluation, surgical outcome, and pathology. hippocampal formation (hf) atrophy was assessed using mri-based volumetry (n = 10) and visual grading of the h f (n = 13). mri-detected hf atrophy has been shown to be a reliable marker of moderate to severe mesial temporal sclerosis (mts) (cascino gd, et al, ann neurol 1991; 30:31-36 evidence from experimental animals indicates that endogenously produced platelet-derived growth factor (pdgf) is an important regulator of glial proliferation and differentiation. because of the striking degree of glial proliferation in chronic epilepsy, we sought to determine whether cultured glia from human epilepsy tissue would be responsive to pdgf. the effects of pdgf on dna synthesis, proliferation, and relative distribution of a2b5(+) glia were studied in a cell culture derived from temporal lobe white matter of adult epilepsy lobectomy tissue. by immunocytochemistry, glial fibrillary acidic protein (gfap) was detectable in 90% of cells in untreated or 4-day pdgf-treated (10 ng/ml) cultures, which confirmed their astrocytic nature. in contrast, a2b5( +) cells increased from 10 to 30% in untreated cultures to 75% after pdgf treatment, which suggested that type 2 astrocytes (a2b5[ + 1, gfap[ +]) had been elicited. dna synthesis of cells resembling oligodendrocyte-type 2 astrocyte (0-2a) progenitors occurred within 24 hours after program and abstracts, american neurological association 245 pdgf treatment as evidenced by nuclear incorporation of brdu in bipolar a2b5( +) cells. these studies demonstrate that expansion of adult human gfap( +) astrocyte populations is sensitive to regulation by pdgf. further, these data imply the existence of pdgf-responsive 0-2a progenitor cells in astrocyte-rich cultures derived from human epilepsy tissue. ( we have recorded vagal and esophageal-evoked potentials after electrical (e) and balloon (b) stimulation in 10 epileptic patients who had vagal stimulators for the control of intractable epilepsy and the results were compared with esophagealevoked potentials in 10 healthy controls and 3 diabetic patients. the vagal and esophageal-evoked potentials showed similar configurations with 3 major positive and negative potentials. the amplitudes of the responses habituated rapidly over 30 trials at 2 per second up to 1 per 6 seconds. latencies were shorter from the upper esophagus (20 cm above lower esophageal sphinctereles]) cf. lower esophagus ( 5 cm above les) yielding conduction velocities of 5 to 7 meters per second but conduction was significantly slower in the diabetics. the vagal-evoked potentials have validated the use of esophageal-evoked potentials as a practical method of assessment of the integrity and speed of conduction in vagal afferent pathways in man. ronald e. kramer and neil l. rosenberg, englewood. co seizure disorders were analyzed in patients in whom toluene was the sole or major drug of abuse. toluene abuse is increasing; therefore, physicians should gain experience with its neuropathological and ciinical sequelae. a retrospective chart review found 15 patients meeting criteria. the average patient age was 28 years; abuse onset averaged 16.7 years; abuse averaged 10.7 years; and 11 patients were male. ten were daily, 3 were weekly, and 2 were intermittent users. seizures occurred in 2. one suffered a single generalized tonic-clonic seizure without recurrence and without treatment. his we characterized the clinical dose-response curves for relief of parkinsonism and production of dyskinesias as a function of plasma levodopa and 3-0-methyldopa levels in 6 patients with parkinson's disease (pd) and fluctuating responses to oral levodopa/carbidopa. dose response to graded intravenous levodopa was measured after overnight drug withdrawal on 2 occasions, first after chronic, intermittent oral levodopa/ carbidopa and second after 3 to 5 days of continuous intravenous levodopa. continuous intravenous levodopa shifted the dyskinesia dose-response curve to the right, and reduced maximum dyskinesia activity, but did not significantly alter dose response for relief of parkinsonism. improvement in dyskinesia was apparent by the second day of continuous levodopa, during which ratios of plasma dopa/3-0-methyldopa remained constant. our results support the hypothesis that relief of parkinsonism and production of dyskinesias occur by separate mechanisms. continuous dopamine-mimetic therapy should be sought as a therapeutic goal for advanced pd. dopa-responsive dystonia (drd) is a distinct subset of idiopathic dystonia with diurnal fl uctuation and a dramatically beneficial response to l-dopa. it has hitherto been considered an autosomal-dominant disease with reduced penetration (mckusick no. 12823) . we studied an arabic family of 67 members with d r d spanning 6 generations. we examined 43 members and 6 of their spouses. l-dopa was withheld for 24 hours from patients in treatment. five family members had generalized dystonia with diurnal auctuation ( i male, 4 in an arabic family females). dystonia started between the age of 2 and 7 years with gait difficulty and involvement of the legs. mri, eeg, evoked potentials, and screening for wilson's disease were negative. an excellent response to l-dopa was noted in all 5 patients with continued long-term clinical stability for as long as 17 years. the 5 patients were the products of 2 consanguineous marriages, and their 7 siblings were normal. the patients were descendants of the same great-great-grandparents. this pedigree suggests an autosomal-recessive type of inheritance. we believe this is the first report of d r d with an autosomal-recessive type of inheritance. a. achiron, m . gornish, h . goldberg, i . ziv, r. djaldetti, y. zoldan, h. smka, and e. mekzmed, petah tiqva, israel freezing gait is an incapacitating symptom that occurs often in advanced parkinson's disease and also in other neurological disorders, eg., multiinfarct state, multisystem atrophies, and normotensive hydrocephalus. we evaluated, videotaped, and rated 18 patients (15 men, age 74 k 6,60-82 yr) who developed pure progressive freezing gait during 2.5 2 1.9, 0.5-6 years. severity was mild in 4 with sudden motor blocks mainly when confronted with obstacles; moderate in 9 with gait arrests upon any attempt to initiate walking and changing direction, requiring a walking stick or partial external assistance; and severe in 5 with total inability to start walking, requiring a walker, massive assistance, or a wheelchair. in all, freezing was associated with postural instability. they could mimic normal gait when seated or lying prone and could overcome arrests by the "walking over lines" maneuver. neurological examination was otherwise normal with no signs of dementia, parkinsonism, or pseudobulbar palsy. ischemic risk factors including ischemic heart disease, hypertension, and diabetes occurred in 7 and previous strokes in 6. brain c t and mri were normal or showed mild cortical atrophy in 12 and putative lacunae in only 6 patients. none responded to levodopa or dopamine agonists. progressive pure freezing gait should be recognized as a separate nonparkinsonian neurological entity. it may be due to degenerative or ischemic non-nigral brainstem lesions. we describe 19 patients with causalgia and dystonia, triggered by peripheral injuries in 15 patients and occurring spontaneously in 4 patients. the injury was often trivial. the mean age at presentation was 28.6 years. the legs were affected in 12 patients, and the arm was affected in the remaining 7 patients. all had burning pain, allodynia, and hyperpathia, along with vasomotor, sudomotor, and trophic changes. all developed typical dystonic muscle spasms in the affected part. the spasms typically were sustained, producing a fixed dystonic posture, in contrast to the mobile spasms characteristic of idiopathic torsion dystonia. dystonia always followed the causalgia and was painful. there was spread of the causalgia and of the dystonia from its initial site both in the affected limb and to other extremities, the latter in a hemiplegic, transverse, and triplegic distribution. all forms of conventional treatment failed to relieve either the pain or the dystonia. we suggest that functional changes in the corticobasal ganglia-thalamic system are responsible for this painful dystonic syndrome. program and abstracts, american neurological association 247 holiday for parkinson's disease: a controlled clinical trial r. kurlan, c . m . tanner, c. g. goetz, j . sutton, p. carvey, c. deeley, l. cui, c. itvine, and m . mcdemzott, rochester, ny, chicago, il, and san jose, c a the efficacy and mechanisms of levodopa (ld) drug holiday for parkinson's disease (pd) remain controversial. we performed a double-blind, randomized study with 11 advanced pd patients (5 men, 6 women; aged 52-79 yr) with entry criteria of inadequate response to ld plus dose-limiting ld-induced side effects (dyskinesias, hallucinations, and confusion). subjects were assigned to: (1) 100% placebo for ld (complete drug holiday) or (2) 50% ld and 50% placebo for ld (50% drug reduction) for 6 days. after subsequent open-label ld dose optimization, subjects were followed to end point (defined as the time when entry criteria were again satisfied or a maximum of 1 year). median survival time to end point was not significantly different for the complete drug holiday (182 days) and 509% drug reduction (100 days) groups ( p = 3 5 ) . aspiration pneumonia occurred in 2 complete drug holiday patients and no significant morbidity occurred with drug reduction. after a 100-mg dose of ld, clinical and pharmacological responses were no different before and after drug holiday ( p = .75) or reduction ( p = 254). subject to the limitations of our small sample size, we conclude that complete drug holiday is associated with greater morbidity and confers no major advantage over 50% drug reduction. we found no evidence of significant alterations of pharmacokinetic or pharmacodynamic properties of ld after drug holiday or reduction. ( (pc) of the substantia nigra on t2-weighted images. the narrowing of the pc signal has been attributed either to atrophy of the pc or to increased deposition of iron in this region. we have studied details of iron distribution in the midbrain of 8 formalin-fixed human brains by scanning pixe analysis. three p d brains, 1 juvenile pd brain, and 4 control (amyotrophic lateral sclerosis) brains were studied. in the controls, the iron content of the pars reticulata (pr) was almost equal to that of the red nucleus (rn), but that of the pc was less than 50% of the pr. in parkinsonian brains, the iron content in the pc was significantly higher than in the controls. the iron content ratios of pc/pr and pc/rn in parkinsonian brains were significantly higher than in the controls. these findings suggest that iron deposition increases in the pc of parkinsonian brains. the difference in the pattern of iron content corresponds to the intensity profile pattern noted on mri. mri findings in parkinsonian patients may reflect a change in the iron distribution pattern. (jankovic and brin, nejm, 1991) . such resistance within 2 exposures is not likely due to toxin antibody formation. of 61 cd patients evaluated per protocol receiving 2 or more botox tx under multichannel emg monitoring, 7 (11.5%) showed no benefit after the first and second tx, despite mild neck weakness on static muscle testing and, in some instances, emg signs of denervation. the 54 responders (16 men, 38 women) had younger age onset cd (mean 45 yr vs 60 yr), but similar duration (mean 10 yr vs 9 yr) compared to the 1 male and 6 female nonresponders (in contrast to jankovic and schwartz, arch neurol, 1991) . both groups had similar degrees of severity and tx dose (mean 200 iu, range 112.5-300). although disparate group size prohibits statistical analysis, some interesting comparisons include: nonresponders were more apt to have extranuchal dystonic sites (72% vs 33%), antecollis (29% vs 4%), dark eyes (57% vs 19%), women with elevated antinuclear antibody titer (67% vs 24%), history of intracranial operation (29% vs o%), significant for age focal mri abnormality (5 of 6 vs 3 of 19). history of cervical operation (6 patients) did not limit responsiveness. rates of prior remission, perinatal stress, antecedent trauma, left-handedness, and family history of movement disorder were similar for both groups. antecollis presents problems for optimizing tx to affected muscles, but central mechanisms may play a role in why some patients with focal dystonia do not improve with botox tx from the outset. enrico fazzini, new york, n y with parkinson's disease does deprenyl have a symptomatic effect on patients with untreated and l-dopa-treated parkinson's disease (pd)? once deprenyl is started, how long is it before another medication is needed to control symptoms of continued disease progression? there has been controversy over whether deprenyl has effects on delaying disease progression (nejm 1989; 321:1364) and/or in alleviating the symptoms of pd. one hundred seventy-five patients already taking l-dopa (group 1) and 33 patients who had never taken l-dopa (group 2) were treated with deprenyl 10 mg/day. unified pd rating scale (updrs) scores were measured before and after deprenyl. patients were followed until pd symptoms progressed to the point of requiring additional medication. one hundred eighteen of 175 (67%) patients in group 1 (reduced updrs mean activities of daily living [adl) 11 to 9, motor [mtr] 30 to 22) and 29/33 (88%) patients in group 2 (reduced updrs mean adl 11 to 6, mtr 26 to 20) reported symptomatic benefit. an average of 12 months' duration was found in both groups before further medication adjustments were needed. deprenyl provides symptomatic benefit for an average of 12 months in the majority of patients with p d regardless of whether or not they are being treated with l-dopa. yasuo iwasaki, masao kinoshita, toshiya shojima, and ken ikeda, tokyo, japan, and cleveland, oh in parkinsonian patients we measured fasting plasma amino acids in 30 parkinson's disease patients and 30 controls matched for age and sex. all patients were receiving l-dopa and they were free of any medications other than l-dopa. normal controls were free of any medication. there were no differences in diets between patients and controls. fasting blood specimens were collected in heparinized tubes and immediately were centrifuged at 20,000 g for 10 minutes. analysis of plasma amino acids was performed by automated ion-exchange chromatography with lithium-based buffer and an amino-acid analyzer. parkinsonian patients had significant elevations of aspartate, glutamate, and glycine. the other amino acids were not significantly different from those in controls. n o correlation between severity or activity and degree of abnormality in plasma level of amino acids in patients was established. we conclude that excitatory amino-acid metabolism is altered in patients with parkinson's disease. bonnie e. levin, rachel tomer, and william weiner, miami, fl disease there is evidence linking obsessive-compulsive symptoms (ocs) to basal ganglia dysfunction. we investigated the presence and severity of ocs in a sample of 44 patients with an unequivocal diagnosis of idiopathic parkinson's disease (pd) using the leyton obsessional inventory. ocs was found in the majority of the patients, with 24 (55%) scoring above the normative cutoff for the symptom score and 32 (73%) scoring above the normative cutoff for the trait score. when severity of oc symptoms was correlated with a battery of neuropsychological measures, significant relationships were observed between ocs and a preponderance of tests associated with right-hemisphere functions. these findings were observed especially on those tests with a strong frontal lobe component (block design: r = -.50; embedded figures: r = -.534; set shifting: r = -.42; and perseverative responses: r = .58; p < .005 for all measures). in all cases, the more severe oc symptoms, the poorer the performance. a similar trend was observed between the leyton trait scores and the cognitive measures. these findings suggest that ocs is present in a subgroup of pd patients, which may reflect greater compromise of right-hemisphere basal ganglia-frontal lobe pathways. intraclass correlations (iccs) were calculated for the total motor score and for each individual sign. results indicated excellent agreement (icc > .7) for the total motor score, resting tremor, gait, arising from a chair, and speeded, repetitive movements; good agreement (icc > .5) for rigidity, action tremor, posture, postural stability, and bradykinesia; and poor agreement (icc < .2) for speech and facial mobility. a factor analysis was then performed on updrs motor scores for 146 pd patients from a community-dwelling cohort. three factors were extracted by principal components analysis with subsequent varimax rotation, accounting for 63.5% of the total variance: factor 1-balance and stability (posture, postural stability, gait, arising from a chair, and bradykinesia); factor 2-rigidity and motor speed (rigidity, speech, facial mobility, rapid alternating movements, leg agility, hand movements, and finger tapping); factor 3-tremor (resting and action). these results indicate that the updrs motor examination is reliable between raters and measures the cardinal signs of pd. an open pilot study was performed to evaluate the efficacy of botulinum a toxin (botox) injections for disabling hand tremors. a previous report on the use of botox for hand tremors suggested that it was helpful, but relied on subjective clinical rating scales. the extent of normal clinical fluctuations or a placebo response could not be determined. to investigate these issues more objectively, 7 patients with parkinson's disease and 1 with essential tremor with refractory hand tremors underwent electromyographically guided intramuscular injections of botox into wrist flexors and extensors. patients without great medication-related tremor fluctuations were selected. results before and after botox were determined by comparing (1) patient perceptions of functional improvement, (2) clinical assessments using the unified pd rating scale for tremor and the webster rating scales, and (3) physiological measurements using accelerometric analysis of hand tremors of tremor frequency, amplitude, and waveform characteristics. all patients reported some improvement, ranging from mild to marked with a mean of 2.6 on a 0 to 4 (4 = marked) global rating scale. however, only 3/8 patients showed a significant improvement in the clinical rating scales, confirmed by >50% reduction in tremor amplitudes. these findings show that most patients reported improvement not confirmed by the clinical or physiological measures. efficacy of botox injections for tremors is implied, but controlled trials are needed before this procedure can be generally recommended. christopher g. goetz and glenn t . stebbins, chicago, i l we tested whether hallucinations, motor disability, and cognitive decline were risk factors for nursing home placement in advanced parkinson's disease (pd) and whether these effects were independent or synergistic. between 1987 and 1991, we identified 11 patients admitted to long-term nursing homes. using case control methodology, we matched each for age, pd duration, and sex with 2 control pd patients remaining at home. parkinsonism was assessed by the motor and activities of daily living subscales of the unified p d rating scale (updrs); hallucinations and dementia were determined by scores 2 2 on the thought disorder and intellectual impairment items of the updrs. tests of synergy were based on a mantel-hentel model. hallucinations were a significant risk factor with odds ratio = 18.0, x2 = 17.0, p < ,001. motor impairment alone and cognitive impairment alone were not significant risk factors for nursing home placement (x2 for motor severity = ,00084, p > .05, and x2 for cognitive impairment = .0023, p > .05). furthermore, combined odds ratios for hallucinationslmotor severity and hallucinations/cognitive impairment showed no synergy of effect (x2 <1.0 for both,p > .05). of the 3 variables studied, hallucinatory behavior is the most prominent and independent risk factor for nursing home placement in these patients; the data suggest that aggressive control of hallucinations may be warranted to prevent nursing home admission. temperature-sensitive paramyotonia congenita phenotype* louis j . ptacek, philip mcmanis, hzrbert kwiecinski, alfred george, robert barchi, launce gouw. and mark leppert, salt lake city, u t , rochester, mn, warsaw, poland, and philadelphia, pa the periodic paralyses are a group of autosomal-dominant muscle diseases sharing a common feature of episodic paralysis. in one form, paramyotonia congenita (pc), the paralysis is temperature-sensitive, usually occurring with muscle cooling. electrophysiological studies of muscle from patients with pc have revealed temperature-dependent alterations in sodium channel (nach) function. this observation led to the identification of 2 distinct mutations in an s4 segment of a skeletal muscle nach in 3 unrelated pc families. we describe the use of the single-strand conformation polymorphism (sscp) technique to define a third allele specific to pc patients in an additional family. this aberrant pattern, though distinct from the first 2, occurs in the same exon of this nach gene. sequencing is currently underway to define the molecular alteration causing this aberrant pattern. two additional families with the pc phenotype have been sampled and do not demonstrate these 3 sscp variants. we are currently searching for new mutations in these 2 families to define further the molecular heterogeneity of this temperature-sensitive pc phenotype. parag mehta and roger w. kukz, brooklyn, n y abnormal accumulation of calcium (ca) in myofibers is thought to play a role in pathogenic myonecrosis. attempts at reducing intracellular ca content with ca channel blockers in duchenne muscular dystrophy (dmd) have been clinically unsuccessful. dantrolene, however, which acts at the sarcoplasmic reticulum to inhibit ca release from intracellular stores, has produced dramatic reductions in serum creatine kinase (ck) in dystrophic mice and more recently in dmd. we investigated the effect of low-dose dantrolene in a group of 20 patients with limb girdle dystrophy (lgd), dmd, and other myopathic disorders. all subjects received dantrolene in incrementing doses from 25 to 100 mg daily over a 6to 12-week period. mean baseline ck was compared to ck with dantrolene treatment. dramatic reductions in serum ck levels averaging 50% were seen at 50to 100-mg doses in lgd patients (8). dmd patients (3) and patients with other myopathies (9) showed a similar but less dramatic reduction in ck. three of the weakest patients complained of increased fatigue while taking 100 mg, which suggests that higher-dose dantrolene may confound longer-term trials assessing clinical muscle strength and function. dantrolene in dosages well below conventional antispastic doses has a dramatic effect on serum ck and possibly myofiber necrosis in lgd, other dystrophies, and other muscle disorders. p77. antigen-specific therapy in myasthenia gravis: myasthenia gravis (mg) is mediated by anti-acetylcholine receptor (achr) antibodies, believed to be t-cell dependent, and antigen-specific therapy would be preferable to current nonspecific immunosuppression. exposing mouse t-cell clones to mhc class i1 molecules complexed with relevant antigen on planar membranes induced proliferative unresponsiveness (quill and schwartz, 1987) , and soluble mhc class i1 molecules complexed with myelin basic protein (mbp) peptide resulted in unresponsiveness of specific tlymphocyte clones in vitro (sharma et al, 1991) . we have used our well-defined dr4-restricted t-cell clone (ong et a [, 1991 ) isolated from an mg patient and specific for p138-167 of the achr alpha subunit. overnight incubation of these t cells with a soluble p138-167 : dr4 complex substantially inhibited the subsequent response to challenge with soluble antigen and presenting cells. in contrast, antigen response after preincubation with dr4 complexed to an irrelevant peptide (mbp 1-14), soluble dr4 alone, or an experimental approach studied in vitro p138-167 alone (at equimolar concentrations) did not differ appreciably from that in untreated cells. the p138-167:dr4 complex had no effect on other non-achrspecific cell lines/clones. these results suggest that the use of soluble mhc-peptide complexes may be an approach to selective immunotherapy in mg patients. p78. high-dose intravenous immunoglobulin in the shawke a. soueidan and marinos c. dalakas, bethesda, md inclusion body myositis (ibm) is a severe disabling inflammatory myopathy with characteristic clinical and histological features. it is commonly suspected when a patient with presumed polymyositis does not respond to available immunotherapies. the need for an effective treatment in patients with ibm prompted the present pilot study using high-dose intravenous immunoglobulin (hd-ivig), an apparently effective immunomodulating agent in several autoimmune neuromuscular disorders. we treated 4 patients with muscle biopsy-proven ibm with up to 2 monthly infusions of 2 gml kg ivig. after the first infusion, 3 of the 4 patients showed definite functional improvement consisting of independent ambulation, fewer falls, and increased ability to lift weights. the muscle strength of the proximal and less atrophic muscle groups improved by one grade mrc scale (from 4 to 5), whereas the distal and atrophic muscles remained unchanged. the improvement, sustained up to 7 months, was greater in patients with the most severe endomysial inflammation. we conclude that hd-ivig may be the first promising agent that can improve the strength of certain muscle groups in patients with ibm. because ivig is prohibitively expensive, the present encouraging results warrant a large-scale controlled therapeutic study. hays, and n . lutov, new york, n y , and milan, italy anti-myelin-associated glycoprotein (mag) antibodies from patients with neuropathy cross-react with the glycolipid 3-sulfated glucuronyl paragloboside (sgpg). among 24 patients tested by enzyme-linked immunosorbent assay and western blot, 15 had highly elevated antibody titers (56,400) to both mag and sgpg, 2 had highly elevated titers to mag alone, and 7 had highly elevated titers to only sgpg. immunostaining of normal nerve myelin by the antibodies correlated better with anti-mag than anti-sgpg activity. twenty-one of the patients, including patients in all 3 groups, had predominantly sensory or sensorimotor neuropathy, and biopsy specimens revealed deposits of igm and complement on affected myelin sheaths. three patients presented with motor syndromes, all with antibodies specific for sgpg; 1 had a predominantly motor demyelinating neuropathy, 1 had upper and lower motor neuron signs and peripheral neuropathy, and 1 had amyotrophic lateral sclerosis confirmed post mortem. all 3 had deposits of complement on peripheral nerve myelin sheaths. these studies suggest the following: (1) that anti-mag or sgpg antibodies may differ in their fine specificities and biological activities, (2) that anti-sgpg antibodies also may occur in motor neuron diseases, complicating the clinical presentation, and (3) that both mag and sgpg should be used as antigens in testing for autoantibody activity in peripheral neuropathy. david b. williams, john steele, ulla-katrina craig, sandra bryant, peter o'brien, and leonard kurland, newcastle, new south wales, australia, mangilao, guam, and rochester, m n continuing surveillance of neurodegenerative diseases in the mariana islands reveals changes in frequency and clinical characteristics since the 1950s that resemble those in other known western pacific foci (kii peninsula, japan, and irian jaya, new guinea). recent surveys of patients 50 years and older were conducted on rota, tinian, and yigo, guam. possible cases of dementia, parkinsonism, and amyotrophic lateral sclerosis (als) were identified by local trained personnel using a questionnaire, world health organization neurology test, and cognitive screening. those who failed the screening were examined by a neurologist. in the small populations of rota and tinian, there were no definite cases of als compared to i to 3 cases present in previous surveys. the high prevalence of parkinsonism-dementia complex (pdc) was unchanged and dementia was increased compared to earlier surveys. in yigo, als and pdc continue to be prevalent; however, the als patients are predominantly long-term survivors (> 10-year disease duration). in areas of previous high prevalence of als/pdc, dementia (as pdc) was associated with extrapyramidal signs, whereas in areas of previously low prevalence of als/pdc, dementia alone, possibly of alzheimer type, predominated. these observations help to confirm previous reports of changing clinical patterns, but suggest that the geographic distribution of the (presumed) environmental etiological agent for als/pdc remains stable after almost 40 years. p. v . fragokz, 0. frongillo, m. michisanti, g. antonini. derangements of the cardiac conducting system are the most common features of heart involvement in myotonic dystrophy (md). in view of chis 65 patients with various grades of md (43 males and 22 females, mean age 37 yr) underwent 12-lead ecg and holter monitoring. in 31 patients (48%), almost all with a severe grade of md, 1 or more conduction defects were found: first-degree atrioventricular block (i-avb) in 21 cases, second-degree avb in 1 case, right bundle branch block in 3 cases, left anterior hemiblock in 2 cases, left bundle branch block in 2 cases, and trifascicular block in 1 case (pacemaker implanted). an 18-year-old boy had a chronic atrial fibrillation with slow ventricular rate; he died suddenly while awaiting electrophysiological study. thirty-seven patients were followed over a mean period of 40 months (range 11-75 mo). a 54-year-old woman experienced a myocardial infarction and was excluded from subsequent considerations. conduction defects de novo appeared in 6 patients: i-avb in 5 and i-avb plus 11-avb (mobitz i and i1 type) in 1. nine patients, all with i-avb at initial evaluation, showed deterioration of their defects' conduction: a bifascicular block was observed in 6 cases and a trifascicular block in 3 cases (pacemaker implanted). conduction defects may run a malignant course in md, mainly in patients with more severe grades of the neuromuscular disease; thus, a close cardiological evaluation is mandatory for a proper therapeutic approach in single cases. hiroshi mitsumoto, surest5 kumar, kevy h. levin, robert w. shields, jr, michelle secic, asa j . wilbourn, and rajendra g . desai, cleveland, oh, and santa ana, ca twenty patients with amyotrophic lateral sclerosis (als) entered a pretreatment study with monthly quantitative isometric muscle strength tests (4 muscles in each extremity) and quantitative tufts scales including vital capacity, bulbar diadochokinetic rate, timed water drinking, timed rising from a chair, and timed walking 5 meters. after 4 to 6 months of pretreatment observation, the patients received 400 mg/kg intravenous immunoglobulin (ivig) (gamimune-n, miles) every month for up to 12 months. during the study period, 5 patients died and 2 patients withdrew from the study. the slope of each variable's changes over time before and after the ivig treatment were compared statistically. none of the quantitative scales showed significant change with ivig. however, the slope of the upper extremity muscle strength revealed improvement with ivig treatment ( p = .002 and .013, right and left, respectively). when all extremities were combined, the slope was also significantly improved with ivig ( p = .035). lower extremity muscle strength alone showed similar trends but no statistical significance. electrophysiological and immunological data were also analyzed. our results warrant a double-blind, controlled study with ivig for the treatment of als. leber's hereditary optic neuropathy (lhon) is a mitochondrial disorder with predominantly optic nerve abnormality. it can be associated with dystonia, ataxia, encephalopathy, cardiac abnormalities, and other less well-characterized neurological syndromes. we describe 2 members of a family with lhon with a slowly progressive motor polyneuropathy. a 22-year-old man and his 11-year-old sister have had mild motor impairment since early childhood. a gait disorder and distal muscle weakness became evident at puberty. the girl, but not the man, also has blindness, distal numbness, type i diabetes mellitus, and short stature. physical examination showed in both: bilateral foot drop, limb hyperreflexia but absent ankle reflexes, distal sensory loss, and a slight brownish scaly skin discoloration over the forearms. only the girl had clonus and optic nerve atrophy. the man had peripapillary telangiectasias. the jaw jerk was normal in both. motor nerve conductions in both showed absent tibia1 and peroneal responses, whereas other motor and sensory nerve conductions were normal. emg revealed denervation, more so distally. muscle biopsy findings showed recent denervation and previous denervation followed by reinnervation. n o raggedred fibers were observed with the modified trichrome and sdh stains. brain mri was normal in both. cerebrospinal fluid in the girl was normal. blood samples from both patients and maternally related family members revealed a mitochondrial dna point mutation at position 11778 (d. c. wallace). in this family, only 1 male had lhon; 3 females had lhon and 2 others, including the patients' mother, were asymptomatic carriers. this association of chronic motor neuropathy and hyperreflexia with lhon appears to be a distinct syndrome. the pathogenic mechanism by which the mitochondrial dna defect causes the neuropathy (and other neurological deficits) requires analysis. duchennelbecker muscular dystrophy henry j . kaminski, mazen al-hakim, r. john leigh, bashar katirji, and robert l. ruff; cleveland, oh fast-twitch extremity muscle fibers are preferentially affected in duchenne/becker muscular dystrophy (dbmd). since saccades are thought to be mediated by fast-twitch fibers, saccadic velocities would be expected to be decreased among these patients. to investigate involvement of extraocular muscle (eom) by dbmd, we studied with infrared oculography 3 patients who were wheelchair-bound and able to perform only minimal activities of daily living. saccades were slightly slowed but were within 95% confidence limits of normal. all 3 patients showed square wave jerk movements (swj). in 2 patients, the frequency of the swj exceeded that of normal subjects, which suggested central nervous system dysfunction. clinical neuroophrhalmological examination of 7 other dbmd patients was normal. this investigation is the first study of ocular motility in dbmd and demonstrates that eom function is relatively preserved even in far advanced patients. eom is composed of a heterogenous mix of fiber types that differ in anatomical and physiological characteristics from extremity muscle. study of eom in dbmd may prove to be useful in understanding why some muscles are resistant to dbmd and in characterizing properties that limit muscle degeneration. (supported by nih grants ey09186, ey067 17, the department of veterans affairs, and the evenor armington fund.) since patients with myotonic dystrophy (mtd) exhibit a marked resistance to insulin effect on glucose uptake and an impaired handling of the insulin-sensitive amino acids, it is possible that muscle wasting in mtd may reflect a derangement of insulin action on muscle protein metabolism. increased muscle protein breakdown in mtd would be expected if the normal inhibitory effect of insulin on protein catabolism is impaired. the forearm perfusion technique combined with measurements of 3-methylhistidine (3-mh) arteriovenous (a-v) differences by high-performance liquid chromatography provides a unique method to investigate skeletal muscle myofibrillar protein degradation in vivo. we studied 3-mh (a-v) and efflux from the forearm muscles in 8 men moderately affected with mtd and 10 normal men. efflux values (q) were calculated as the product of 3-mh (a-v) times forearm plasma flow measured by the indicator dilution technique. forearm 3-mh release (estimated as {a-v} or q) of mtd patients did not differ significantly from normal controls. we conclude that myofibrillar degradation is not increased in mtd even when measured in a muscle compartment selectively affected by wasting. the possibility of an impaired anabolic action of insulin in mtd has yet to be determined. to study the relationship between the ragged red fibers (rrf) and age, we have reviewed 500 muscle biopsy specimens prospectively. patients with well-established mitochondrial myopathy syndrome and with myopathies known to produce secondary rrf were excluded. the number of ragged red fibers (rrf) was counted under 40 x (lpf) magnification. rrf were identified by the modified trichrome and sdh stain. for the final analysis, the sdh staining was used. the frequency of rrf was analyzed in relation to patients' ages. the frequency of cases with more than 1 rrf increased with aging: 0% in the first decade, 16% in the fourth decade, and 55% in the eighth decade. the frequency of cases with more than 10 rrf also increased with aging: 0% in the first three decades, 4% in the fourth decade, and 19% in the eighth decade. of 25 patients with well-established mitochondrial myopathy syndrome, 24 had more than 10 rrf under lpf. the number of rrf in muscle increases with aging, indicating that mitochondrial activity in muscle is affected by aging. this finding may complicate the diagnostic criteria of mitochondrial myopathy in older individuals. ten rrf under lpf seems to be a reasonable cutoff point for the diagnosis of mitochondrial myopathy. schwartz-jampel, a rare autosomal-recessive syndrome characterized by short stature, myotonia, skeletal abnormalities, and peculiar facies, was reported by aberfeld in 1965. the same sibship was earlier reported by schwartz and jampel in 1962 with emphasis on blepharophimosis. as of this writing about 30 cases have been reported in the literature. most of the features of this syndrome are believed to be secondary to primary muscle disease. several peripheral electrophysiological studies showing features of myotonia have been reported. we describe 4 patients with schwartz-jampel syndrome showing evidence of central conduction disturbance documented by somatosensory-evoked potentials (seps). median nerve seps showed normal latencies to erb's point and n-13 in all. interpeak latencies between n13 and n19 were prolonged in 3 with complete block in 1. emg showed typical myotonic discharges in all. motor nerve conduction velocities, visual and brainstem auditory-evoked potentials, ct, and mri were normal in all. seps in the parents were normal. we believe this is the first report documenting evidence of central nervous system (cns) involvement in schwartz-jampel syndrome. schwartz-jampel syndrome and myotonic dystrophy may have similar cns ''lesion'' as sep abnormalities also have been shown in myotonic dystrophy. epidemiological studies have associated consumption of certain batches of l-tryptophan (lt) with development of the eosinophilia-myalgia syndrome (ems). 1,1 '-ethyledenebisltryptophan) (ebt or peak e), a derivative of lt, is a trace contaminant associated with implicated batches of lt. three female lewis rats received ebt, 4 mg per 100 gm daily, by intraperitoneal injection. four control rats received unimplicated lt. n o peripheral eosinophilia, rash, or weakness were observed in either group. one rat from each group died during the experiment (control-bowel infarct; ebt-death under anesthetic). after 132 days, forelimb and hindlimb muscles of the remaining animals were frozen and fixed for program and abstracts, american neurological association 253 ultrastructural and histological studies. two ebt rats had a myopathy involving soleus with a perimysial infiltrate containing lymphocytes, macrophages and sparse eosinophils, and necrotic fibers; the other showed few necrotic fibers in gastrocnemius. occasional eosinophils were seen in fascia in both animals given ebt but not in controls. fiber-type specific quantitative analysis of the microvasculature showed no decrease in the capillary index. ultrastructural examination revealed an increase in the size of microvessels in ebt animals. no denervation or reinnervation were demonstrated. the perimysial inflammation replicates an important feature of human ems and supports the epidemiological evidence that ebt is the causative agent of the disease. britta ostermeyer-shoaib, bernard m. patten, and tetsuo ashizawa, houston, t x five women (patients 1-5) developed motor neuron disease (mnd) 10 years (range 2-23 yr) after receiving silicone gel-filled breast implants. at explant in 4 patients, 2 had both and 2 had the left implant ruptured with silicone spilled into tissue. one woman (patient 6) developed amyotrophic lateral sclerosis (als) 5 years after numerous injections of free silicone into her face. biceps muscle biopsy specimens in all 6 showed neurogenic atrophy. patient 1 developed als with bulbar involvement and died 7 years later of respiratory failure. she had anti-gm1 antibodies and autopsy findings confirmed the diagnosis of typical als. patient 2 developed als, but also fatigue, myalgia, arthralgia, and skin rash. she had anti-gm 1 antibodies, antisilicone antibodies, positive antinuclear antibodies (ana), and decreased serum igg, iga, and c3, but increased igm and creatine phosphokinase (cpk) and chronic inflammation was revealed in muscle biopsy specimens. patient 3 developed als, but also had hair loss, skin rash, fatigue, headache, sjogren's syndrome, and positive ana. patient 4 developed als, but also had myalgia and arthralgia. patient 5 developed lower mnd, but also fevers, arthralgia, and joint stiffness. she had anti-gm1 antibodies, positive ana, antimyelin antibodies, and decreased serum igg and iga with chronic inflammation shown in nerve biopsy findings. patient 6 developed a steroidresponsive and steroid-dependent als with bulbar involvement. she had a monoclonal gammopathy in the cerebrospinal fluid and increased cpk. we suggest that silicone acts as an adjuvant that damages motor neurons via an indirect autoimmune mechanism. implants and silicone injections into the face p90. silicone adjuvant breast disease: more forty-five women developed mixed sensory-motor neuropathy (35), motor neuron disease (5), multiple sclerosis (2), multiple sclerosis-like syndrome (2), or myasthenia gravis (1) 7 years (range 1 mo-23 yr) after receiving silicone-gel breast implants (38), saline-filled silicone-covered breast implants (6), or direct injections of silicone into the breast (1). most patients had, in addition, severe fatigability, myalgia, arthralgia, morning stiffness, skin rash, lymphadenopathy, sjogren's syndrome, and short-term memory problems. laboratory results revealed in most of the women decreased or increased serum immunoglobulins, autoantibodies, a serum monoclonal gammopathy, or oligoclonal bands in cerebrospinal fluid. at explantation in 34, 14 had both and 7 had 1 implant neurological cases ruptured. biopsy of the fibrous implant capsule in most patients showed foreign-body giant cells containing refractile material consistent with silicone whether or not the elastomer shell was ruptured, indicating silicone bleed. the major finding on surd nerve biopsy was loss of myelinated fibers, on biceps muscle biopsy was neurogenic atrophy, and on pectoralis muscle biopsy was myositis with vasculitis and free silicone in some. we suggest that silicone may provoke damage to nerve and muscle, probably indirectly promoting autoimmunity. james f. howard, jr, m . kathleen donovan. and m. susan tucker, chapel hill, nc urinary symptoms of urgency and incontinence have been reported only rarely in patients with myasthenia gravis (mg) and then most often in association with myasthenic crisis. we report the case of a 31-year-old woman who in december 1987 had the onset of chest pain and was found to have a lymphocytic thymoma. in june 1989 she developed urinary incontinence, was found to have an open bladder neck. and underwent a suspension procedure for stress incontinence in january 1990. eight months later she developed exertional fatigue and a diagnosis of m g was made. in july 1991 there was a recurrence of urinary incontinence. these symptoms clustered toward the end of the day and at trough mestinon dose. neuro-urophysiological studies demonstrated her previous open bladder neck, the inability to sustain a pelvic floor contraction, and increased bladder wall contraction. singlefiber electromyography (sfemg) recordings from the anal sphincter demonstrated a mean consecutive difference (mcd) of 88 ysec, and 11% of fiber pairs had impulse blocking while recordings in the extensor digitorium communis muscle were normal. following a course of plasma exchange, there was significant clinical improvement with a reduction in the frequency of urinary incontinence, and improvement in anal sphincter sfemg studies (mcd, 60 ysec with no blocking). this case demonstrates that in those myasthenic patients with predisposing bladder outlet dysfunction, urinary incontinence may be a manifestation of worsening mg. diana m. escolar, mohamed eldaly, and jaime rich, boston, m a debate still exists as to the role of antibody versus celmediated factors in the pathogenesis of guillain-barre syndrome (gbs). we describe a patient with increased proportion of circulating t cells and a t-cell lymphoma who developed gbs and responded to intravenous immunoglobulin (ivig). a 57-year-old man with t-cell lymphoma drveloped gbs by clinical, nerve conduction, and cerebrospinal fluid criteria. he had an elevated proportion of t cells and markedly reduced b cells with a normal cd4/cd8 ratio. he responded rapidly to ivig, with return of nearly normal motor function in 1 week. three weeks later, he relapsed and his vital capacity dropped. ivig was again administered and within 24 hours he nearly recovered. a third relapse, 2 1 days later, again responded to ivig. he has remained asymptomatic with ivig maintenance. the role of t-cell lymphocytes in initiating experimental autoimmune neuritis has been shown by adoptive transfer experiments. this patient with t-cell neoplasia may represent an analogous model in hu-guillain-barre syndrome mans supporting the role of t-cell (cell-mediated) autoimmunity in the pathogenesis of gbs. ivig therapy may act primarily by inhibiting the t-cell-mediated attack on myelin. p93. sympathetic skin response: age effect it is frequently stated that the sympathetic skin response (ssr) can be elicited in all normal subjects, but the age of the investigated population usually is not considered to be a significant factor. we have examined the ssr in the upper and lower limbs of 100 normal subjects, aged 20 to 88 years (5 5 of them males). the ssr was elicitable in the lower limbs in all subjects under the age of 60 years and in the upper limbs in all subjects younger than 70 years. in contrast, it could be elicited in the lower limbs in only 345% and in the upper limbs in 655% of octogenarians. the amplitude of the response, though highly variable, showed a remarkable decline with age, both in the upper ( p < 0.0001, r = 0.51) and in the lower ( p < 0.0001, r = 0.65) limbs. these results indicate that age affects both the elicitability and the amplitude of the ssr. this has to be taken into consideration when evaluating the autonomic function in the elderly. we reviewed records of patients appearing to have motor neuron disease (mnd) to whom we recommended immunosuppression over 4 years (17 of 2 10 m n d patients). atypical findings engendered hope rhat they might have treatable neuropathy. electrophysiological studies were mainly consistent with mnd, but also showed conduction block or other evidence of relatively mild peripheral nerve disease in 12. sensory symptoms were present in 7 ; 1 or more reduced or absent deep tendon reflexes in 6; elevated cerebrospinal fluid protein in 8; and nonspecific abnormalities on sural nerve biopsies in 6 of 7. anti-gm1 levels were measured in 6 (including 1 who improved), but none was significantly elevated. immunosuppression included cyclophosphamide (12 patients); prednisone (10); plasma exchange (4); intravenous gammaglobulin (1); cyclosporine (1); and total lymphoid irradiation (1). seven treated patients died, 6 worsened, 1 remained stable for 2 years, and 1 improved. two patients declined treatment. one died and the other did not worsen in 3 years. we conclude that immunosuppression by our methods is, at best, rarely effective in atypical mnd. we studied serum antiglycolipid antibodies by enzymelinked immunosorbent assay in 11 patients with typical miller fisher syndrome (mfs), 6 patients with atypical mfs who were lacking in some of the 3 cardinal signs, 4 patients with guillain-barrc syndrome (gbs) with ophthalmoplegia, 20 patients with gbs without ophthalmoplegia, 20 patients with multiple sclerosis (ms), and 17 patients with other immunological disorders (oid) including systemic lupus erythematosus, polymyositis, and mixed connective tissue disorder. all patients with typical mfs had increased activity of igg antibody against ganglioside g q l b in the early phase, and it reduced with time. such anti-gqlb igg activity also was detected in 5 of the 6 patients with atypical mfs and in 3 of the 4 patients with gbs with ophthalmoplegia. in atypical mfs, the only patient without increased anti-gq1 b igg activity demonstrated normal eye movement with ptosis, whereas eye movement was impaired in the other 5 patients. no patients with gbs without ophthalmoplegia, ms, or oid had increased anti-gqlb igg activity. these findings suggest the close association between increased anti-gql b igg activity and impaired eye movement in mfs and gbs. serum anti-gqlb igg activity possibly plays a role in impaired eye movement in mfs. our goal is to develop an assay that can be used to monitor a relevant immune effect of interferon p (ifnp) in multiple sclerosis (ms) patients during the course of ifnp immuno-' therapy, since recombinant ifnp is being tested in multicenter clinical trials. this report extends our prior studies of the inhibitory effect of ifnp on t-cell activation. peripheral blood mononuclear cells (pbls) from 11 healthy donors and 10 clinically stable ms patients were studied. pbl cultures were stimulated with cona, mab to cd3, or with the phorbol ester pma in the presence of the calcium ionophore ionomycin. parallel cultures were studied in the presence of ifnp, 100 uiml. t-cell activation was monitored by determining the percent cells positive for il-2 receptor (il-2r) using facs analysis, or with a sensitive enzyme-linked immunosorbent assay for ifny. ifnp markedly inhibited il-2r expression induced by cona, by mab to cd3, or by pma and ionomycin, which activate t cells via different pathways. the results suggest that ifnp inhibits t-cell activation by actions independent of membrane receptors. we observed significant inhibition of cona-induced t-cell il-2r expression in both ms patients (20.6% inhibition, p < 0.05) and controls (26.8% inhibition, p < 0.05). there was no significant difference in percent inhibition between ms and controls, but there was more variance among the ms patients. variability of biological effects of ifnp on t cells may relate to differential therapeutic responses to exogenously administered ifnp in ms patients. preliminary experiments suggested that ifnp inhibited ifn gamma secretion by pbl stimulated with cona. ifnp inhibits a number of events associated with t-cell activation, in both normal and ms t cells. response to ifnp appears more variable in the ms cases. immunological monitoring of t-cell activation in patients receiving ifnp may assist in understanding the observed therapeutic responses and planning clinical protocols. myelin destruction is associated with many central nervous system disorders, such as multiple sclerosis, head trauma, and ischemic injury. inflammatory cells, monocytes/macrophages, and polymorphonuclear leukocytes (pmn) may me-program and abstracts, american neurological association 255 diate myelin injury, and lipid peroxidation may be an important mechanism. inhibiting myelin oxidation could have substantial benefit, so we evaluated the ability of a 21-minosteroid, u74500a, to inhibit myelin oxidation by monocytes and pmn. fresh rat brain myelin was harvested by multiple sucrose gradient, ultracentrifugation steps, and the final product was confirmed to be pure myelin by sds-page electrophoresis. human monocytes or pmn were obtained from 5 healthy, unmedicated volunteers by gradient separation techniques. monocytes (1.47 x lo6 cells/ml) and pmn (3.40 x lo6 cells/ml), myelin (460 pg protein/ml), and lipopolysaccharide (100 pg/ml) were incubated for 16 hours with or without 100 wm u74500a in 1-ml wells. myelin oxidation was evaluated by a thiobarbituric acid reactive substance assay for production of malondialdehyde (nmol/ ml). myelin oxidation by monocytes was 1.80 +-0.35 (mean 2 standard error of mean) without u74500a and was reduced to 0.76 ? 0.15 by 100 pm u74500a ( p < .005). pmn-mediated myelin oxidation was 1.89 _t 0.44 without drug and 0.64 ? 0.10 with drug ( p < 0.02). these results demonstrate that u74500a markedly inhibits monocyte-and pmn-mediated myelin oxidation and suggest that the 21aminosteroids may help disorders associated with inflammatory cell-induced myelin injury. microglia cells participate in the pathological reactions of the cns to multiple insults including trauma, inflammation, and neuronal degeneration. functional roles for these cells could include mediating tissue in jury, promoting repair, or modulating immune responses. with regard to the latter, we have observed that the majority of adult human-derived microglia express major histocompatibility complex (mhc) class 11 molecules under basal culture conditions, in contrast to astrocytes derived from the same surgical biopsy specimens. all morphological subtypes of the microglia (ameboid, bipolar, and ramified) expressed mhc class i1 molecules, indicating a discordance between morphology and mhc antigen expression as markers of microglia activation. the microglia actively ingest myelin constituents, as assessed using fluorescein-labeled myelin basic protein and laser confocal microscopy. autologous t cells (e') freshly isolated from the systemic blood and cocultured with candida antigen underwent active proliferation in the presence of 1 to 10% microglia, indicating the functional capacity of the microglia to serve as antigen-presenting cells. y-interferon augmented both mhc class 11 expression and functional antigen-presenting capacity. these results indicate the potential of the adult human microglia to promote immune reactivity within the cns. protein (mbp) neutralize anti-mbp purified from multiple sclerosis cerebrospinal fluid active phases of multiple sclerosis (ms) are associated with increased titers of intrathecally produced antimyelin basic protein (anti-mbp). anti-mbp can be purified by antigenspecific affinity chromatography from csf igg of patients with acute relapses of ms. eighteen synthetic peptides of human myelin basic protein (h-mbp) containing between 8 and 25 amino-acid residues and covering the entire length of the molecule were synthesized by the fmoc method. purified anti-mbp was reacted with increasing amounts of h-mbp as well as each of the 18 peptides in an initial liquid phase assay, and subsequently titers of f anti-mbp in all resulting mixtures were measured by a solid-phase radioimmunoassay . purified anti-mbp was neutralized by h-mbp and 6 of the 18 synthetic peptides containing overall residues corresponding to 61 to 106 of h-mbp. the remaining 12 synthetic peptides covering both the amino and carboxyl terminals of h-mbp did not significantly react with purified anti-mbp from these patients. in conclusion, anti-mbp purified from csf of ms patients has affinity for epitopes located between residues 61 and 106 of h-mbp. in a double-blind study involving 70 patients, we recently demonstrated that 4-aminopyridine (4-ap) is superior to placebo in the treatment of multiple sclerosis (ms) (ann neurol, in press). the related agent 3,4-diaminopyridine (dap) also appears to be effective. to enable a preliminary comparison, 14 patients, who in our previous study had not benefitted from 4-ap, were now treated (4 wk) with dap (up to 1.0 mg/kg/day) for 4 weeks in an open-label fashion. instruments for assessment and registration of side effects were the same as in the previous trial. the optimal dose of dap was 56.4 mg/day compared to 30.7 mg/day for 4-ap. significant changes in the edss (1.0 point or more) were not found, whereas significant improvements in neurophysiological parameters were found (no difference between 4-ap and dap, allp > 0.05). subjective side effects during 4-ap (8 patients) mainly suggested cns-function disturbance (dizziness and gait disturbance) and during dap (10 patients) mainly suggested peripheral nervous system-function disturbance (paresthesias). systemic tolerability clearly was diminished for dap compared to 4-ap, with 2 patients withdrawing because of severe gastric complaints and 1 developing liver function abnormalities. these data suggest that 4-ap is more valuable than dap in the treatment of ms. cy clophosphamide/methylprednisolone therapy in multiple sclerosis multiple sclerosis (ms) is a presumed autoimmune disease in which various forms of immunotherapy have been attempted. mri studies show the disease to be more chronically active than is clinically evident, thus a single treatment is unlikely to provide lasting benefit. recently, the northeast cooperative treatment group found that pulse cyclophosphamide (700 mg/m2 every other month for 2 years) slows progressive ms. we initiated a pilot study to determine the effect of a more intensive and prolonged pulse therapy regimen in both progressive and earlier stages of the disease. pulse therapy was given after induction with either iv cyclophosphamide/corticotropin (600 mg/m2 x 5 over 8 days) or iv methylprednisolone (1 gm x 7 over 7 days). patients received a single iv dose of cyclophosphamide (800-1,400 mg/m2) adjusted to produce leukopenia plus 1 gram of iv methylprednisolone monthly for a year, every 6 weeks for the next year, and every 2 months in the third year. another group received pulse methylprednisolone without cyclophosphamide. as of this writing, 128 patients have been treated, of which 24 have completed 3 years. interim analysis shows that patients treated with pulse methylprednisolone were more likely to become treatment failures than those treated with pulse cyclophosphamide/methylprednisolone (78% vs 45%) independent of induction therapy. withdrawal due to toxicity, however, was higher in the pulse cyclophospharnide group. current regimens involve methylprednisolone induction alone followed by pulse cyclophosphamide/methylprednisolone, analogous to lupus nephritis pulse therapy. this regimen can be given solely on an outpatient basis, does not cause alopecia, and is more amenable for use in earlier stages of the disease. to determine the incidence of pathologically confirmed malignancy in multiple sclerosis (ms) patients in funded clinical trials of cyclophosphamide (ctx) and of azathioprine (aza), data were collected longitudinally using telephone interviews, written questionnaires, physical examinations, and medical records for ctx and aza patients from a community in-hospital and out-patient ms clinic in fargo, nd. in the ctx study (goodkin et al, arch neurol 1987; 44: 823-4327) , 5 1 clinically definite (cd), chronic progressive ms patients were enrolled. twenty-four were controls and 27 received a mean induction dose of 6.08 grams. fourteen of the induced patients then received boosters every other month for 24 months resulting in a mean total dose of 15.92 grams. no malignancies were detected. in the aza study (goodkin et al, neurology 1991; 41:20-25) , 54 c d relapsing ms patients participated. twenty-five were controls and 29 received 3 mgtkg of aza daily by mouth adjusted to maintain a white blood count of greater than 3,50o/cmm for 2 years (mean dose 2.6 mg/kg). two of 29 aza patients developed resectable skin cancers: 1 basal cell (bcc) at 18 months and i squarnous cell (scc) at 43 months. the incidence of developing a bcc or scc was not significantly increased after initiating therapies as compared to the untreated ms controls (aza: fisher exact testp value = 0.49). no other malignancy has been detected during 46 to 100 months of clinical follow-up. allergic encephalomyelitis paula dore-dufly, ruth washington, and robert h. swanborg, detroit, m i postcapillary endothelium at sites of inflammation undergoes many changes referred to as activation. activated endothelial cells (ec) exhibit increased surface expression of immunorelevant proteins (icam-1; ncam, elam, and mhc class i and class i1 antigens [ags)). the sequence of events that characterizes ec activation may be important in susceptibility, induction, and perpetuation of experimental allergic encephalomyelitis (eae). in this study we examine expression of ec activation antigens in central nervous system (cns) microvessels in response to interferon gamma (ifn-y). cns microvessels from sjl and bio.s mice were incubated for 18 hours in ifn-y (500 u/ml), fixed, permeabilized, and then stained with an antibody that recognizes class i, class i1 mhc antigens, icam-1, and factor viii. relative fluorescence intensity was determined using a laser cytometer. results indicate that microvessels from all strains tested expressed no detectable icam-1 and class i1 ags. little class i antigen and transferrin receptors were expressed. upon stimulation with ifn-y, sjl microvessels exhibited increased surface expression of all ec activation ags. b1o.s microvessels exhibited icam-1 and class i mhc but mhc class i1 ags were not upregulated. results indicate that there are strain differences in the ec response to ifn-y. resistance of b1o.s mouse ec to activation by ifn may be a factor in decreased susceptibility or induction of eae, or both. protein-t-cell line-mediated experimental to investigate a possible pathogenic role of interferongamma (ifn-y) in experimental allergic encephalomyelitis (eae), an immunocytochemical study was undertaken to localize this cytokine in the spinal cord of lewis rats in which eae was produced by adoptive transfer of myelin basic protein-specific t cells. one pm-thick cryosections of spinal cord were labeled with monoclonal antibodies (mab) db-1 and db-12 recognizing different epitopes of rat ifn-y. in the spinal cord of naive rats, mab db-i, but not db-12, stained processes of astrocytes, suggesting that astrocytes contain a protein with an epitope cross-reacting with ifn-y. in rats with at-eae, numerous ifn-y-positive cells stained with both mab db-1-and db-12-positive cells were present from days 3 to 7 after cell transfer and had disappeared on day 10. at day 2 they entered the spinal cords predominantly through subpial vessels. ifn-y-positive cells could be identified as w3/13+ leukocytes as well as ed1-positive macrophages. as in naive rats, astrocytes in at-eae were labeled only with mab db-1, but not db-12. we never observed labeling of motor neurons with these mab. the transient presence of ifn-y in the rat spinal cord at the onset of at-eae suggests a pathogenic role of this cytokine in acute immune-mediated demyelination of the cns probably as a local stimulus for expression of mhc class i1 antigens and adhesion molecules, as well as for the release of tnf-a and toxic oxygen radicals from macrophages and microglia. immune responses to stress or heat shock proteins are implicated in the pathogenesis of several autoimmune diseases, including multiple sclerosis (ms). we examined the hypothesis that antigens in myelin cross-reacted with stress protein antigens. two techniques were used: immunocytochemistry and western blotting. frozen histological sections were prepared from normal human central and peripheral nervous system tissues. sections were incubated with 4 murine monoclonal antibodies to different mycobacterial stress proteins. antibody binding was determined using avidin-biotin complexed antimurine antibody linked to alkaline phosphatase. program and abstracts, american neurological association 257 a monoclonal antibody to the stress protein sp65 from m . leprae strongly stained both central and peripheral nervous system myelin. no myelin staining was noted with antibodies to sp70 or sp17. proteins from purified central and peripheral nervous system myelin were separated by sds-page. western blots were prepared using a monoclonal antibody to sp65 and a polyvalent rabbit antibody to myelin basic protein (mbp) as primary antibodies. antibody binding was determined using antimurine or antirabbit igg antibody coupled to alkaline phosphatase. strong staining of central but not peripheral mbp by the anti-sp65 antibody was observed. the rabbit anti-mbp antibody stained both central and peripheral nervous system mbp. the presence of antigenic epitopes shared by a stress protein and the potential autoantigen, mbp, supports the hypothesis that immune responses to stress proteins may be involved in the pathogenesis of presumed autoimmune diseases such as ms. (1). of 5 patients with borderline or positive csf lyme titer, 3 received parenteral ceftriaxone. all had later relapses consistent with ms. one patient received a month of oral doxycycline. the fifth patient had a negative western blot and was not treated. we conclude that an incidental borderline or positive lyme serology in an ms patient is unlikely to indicate neurological lyme disease. borderline serologies should be documented to rise on later testing; positive serologies should be confirmed by retest in a different laboratory or by western blot. csf abnormalities suggestive of neurological lyme disease (pleocytosis, protein elevation, intrathecal lyme antibodies) are distinct from those suggestive of ms (ogb, elevated igg index, mbp). in such patients antibiotic treatment may be appropriate, but will not alter disease course. when designing and analyzing therapeutic trials for multiple sclerosis (ms), investigators commonly compare the proportion of patients in the experimental and control groups who worsen one or more steps on the disability status scale (dss) or expanded dss during the study (typically 2 years' duration). however, the intervals between the scores in the dss may not be equal. it may be easier to change by one or more steps in the lower end of the scale (e.g., dss = 1-3) than in the midportion of the scale (e.g., dss = 4-6). to evaluate this possibility, we compared the proportion of patients who worsened by one or more steps in the 2 years after entering our program with dss = 3 or with dss = 6. fifty-one percent (29157) natural history data may be useful for designing therapeutic trials for multiple sclerosis (ms). since 1971, we have collected such data in a standard format on patients in the ucla multiple sclerosis research and treatment program. t o describe the course in our group, we have performed survival analysis (kaplan-meier) of patients with 3 or more assessments who entered the clinic with disability status scale (dss) scores of 1 to 7 (n = 395). an increase of one or more steps in the dss score persisting for more than 3 months defines worsening. median times to worsening for a dds at entry of 1 to 5 were approximately 2 years (range 1.7-2.2); but were 4.6 years for dss 6 and 3.6 years for dss 7. for those starting at dss 6 (n = 129), only 13% worsened by 1 year, 26% by 2 years, and 39% by 3 years. the percent worsening when starting at dss 3 (n = 61) were 41%, 48%, and 54%, respectively. these variable rates of worsening (i.e., time spent at each starting level) influence therapeutic trial design. including patients with dss 6 or 7 will increase the sample size and study duration. for testing nontoxic agents, we recommend enrolling patients with dss 1 to 5. for more toxic treatments, we suggest dss 3 to 5. (partially supported by usphs grant ns 087 1 1, the conrad n. hilton foundation, and various donors.) pi 12. cholinergic antagonists and p-adrenergic agonists inhibit experimental allergic encephalomyelitis in an additive manner mark a. jensen, avertano noronha, and bawy g. w. amason, chicago, il lymphoid organs receive a sympathetic (sns) and possibly a parasympathetic innervation. lymphocytes express padrenergic and cholinergic receptors and thus are sensitive to regulation by these neurotransmitters. the severity of experimental allergic encephalomyelitis (eae) is increased in sns-ablated animals. local parasympathectomy decreases plaque-forming responses in submandibular nodes. p,-adrenergic receptors are upregulated on cds t cells in progressive multiple sclerosis, as are m,-muscarinic acetylcholine receptors on cd4 t cells. we examined the effect of isoproterenol, a p-adrenergic agonist, and scopolamine, a cholinergic antagonist, on the course of eae in lewis rats. eae was induced by injection of 0.1 ml of incomplete freund's ad juvant containing guinea pig spinal cord (25% wlv) and m. tubercdosis (3 mgiml) in one hind footpad. scopolamine (6.6 mglkg, twice daily) and/or isoproterenol(o.15 mglkg, twice daily) or saline were injected subcutaneously starting on the day of immunization. scopolamine or isoproterenol alone reduced severity ( p < 0.05, t test) and duration ( p < 0.05, t test) of disease compared to controls. the combination of scopolamine and isoproterenol further reduced disease severity compared to either agent alone ( p < 0.05, x2 test), suggesting an additive protective effect of cholinergic antagonists and p-adrenergic agonists in eae. antigen-presenting cells a . conrad, v. sanders, p. schmid, and w. w . tourtellotte, los angeles, c a tissue is cryopreserved by the method of tourtellotte; this procedure minimizes or eliminates ice artifacts and preserves surface protein markers. the dissected plaques are lightly fixed in 5% paraformaldehyde and then suspended in 30% sucrose. blocks are mounted in oct, cryosectioned at 20 p,m, and picked up on gelatinized slides. the activity of plaques is determined by the presence or absence of myelin debris (antimyelin basic protein stain or lux01 fast blue) or presence or absence of neutral lipids indicating myelin digestion as seen by oil red 0 (oro) staining and the presence or absence of a class i1 major histocompatibility complex antigen (evidence for an antigen-presenting cell) on macrophages or microglia as seen by immunocytochemically staining for hla-dr (hb104 atcc). the following is our classification of the activity of multiple sclerosis (ms) plaques. type i, the most active, is defined as an area of hypercellularity, positive for hla-dr with no o r 0 staining or staining for myelin debris. type 11, or active, is defined as an area of hla-dr-positive cells that stain mildly with o r 0 at the plaque edge but positive for myelin debris; evidence for demyelinating activity <72 hours (prineas; raine). there is an inner area of plump cells that are positive for hla-dr and oro. type 111, or modestly active, is defined as a "shelf" of plump hla-dr-positive cells at the edge loaded with program and abstracts, american neurological association 259 oro-stained neutral lipid but a paucity of or no myelin debris. a region of hypocellularity is observed at the center of plaque. type iv, least active or inactive, is defined as scattered hla-dr-positive cells at plaque edge with little or no o r 0 staining and no evidence of myelin debris. the frequency of plaque types was determined from a random sample of 97 ms tissue blocks from 23 patients who died of ms. ten percent of the plaques were type i; 20%: were type 11; 209% were type 111. the majority of plaques (505%) were inactive (type iv). accordingly, it is necessary to classify the demyelinating activity of ms plaques for protocols designed to investigate etiopathogenesis. do these results suggest that whatever causes ms can be eradicated in half of the demyelinating areas by the time of death? p114. localization of g d l b ganglioside antigen in the human peripheral nervous system susumu kusunoki, atsuro chiba, tadashi tai, and lchiro kanazawa, tokyo, japan serum antibodies against ganglioside gm 1 and/or g d l b frequently are detected in autoimmune neuropathies such as rnultifocal motor neuropathy, igm paraproteinemic neuropathy, and guillain-barre syndrome. some of them bind to gm1 or g d l b monospecifically but the others cross-react with both of the antigens. to investigate respective localizations of gm1 and g d l b antigens in the human peripheral nervous system (pns), immunohistochemical study of dorsal root ganglia (drg), dorsal roots, ventral roots, and sympathetic ganglia (sg), which were obtained from human autopsy specimens, was performed by using 2 mouse monoclonal antibodies, each monospecific to gm1 and gdlb. ggr12, monospecific to gd1 b, immunostained nerve cell somas and axons of drg, sg, and dorsal and ventral roots. ggrl2 also recognized some myelin, including paranodal areas. however, gmb16, monospecific to gm1, did not bind to either neuron or myelin. thus, serum anti-gdlb antibody can bind to neurons and some myelin in the human pns. further study is necessary to identify the localization of gm 1 antigen, because previous biochemical studies have shown that gm1 is also present in the human pns. the purpose of this study was to compare t4 and t8 lymphocytes in migraine patients versus controls, and a review of the literature was done. fifty-six migraine patients, aged 18 to 53, were tested, as were 19 controls. the t4 :t8 ratio in migraine patients was 2 : 1 1, compared to 1 : 60 for controls. suppressors (t8) were reduced from 918 in controls to 482 in migraine patients. helpers (t4) decreased from 1,436 in controls to 985 in migraine patients, and total ?' lymphocytes decreased from 2,513 to 1,698. previous studies have revealed similar differences in t lymphocytes, with higher t4 : t8 ratios being found in both migraine and tension-type headache patients. in food-induced migraine, an increase in circulating immune complexes was noted, with increased t4 levels. differences in serotonin binding to mononuclear cells have been noted in migraine patients. a decreased sensitivity of the lymphocyte beta-adrenergic receptor in migraine patients was suggested by one study. after lymphocyte incubation with il-2, the natural cytotoxic response is augmented in cluster patients. the percentage of lymphocytes expressing receptors for il-2 was decreased in cluster patients in a fur-review of the literature ther study. this il-2 receptor defect was independent of whether the clusters were present. there is a loss of highaffinity binding sites for serotonin on lymphocytes in both episodic tension and chronic tension headaches. we used positron emission tomography (pet) to measure local cerebral blood flow in 6 volunteer subjects while they performed tasks of memory-guided saccades and a visual fixation control. tasks were performed continuously for 70 seconds during emission scans, after bolus injection of h2lso. eye movements were verified with electrooculography. areas of significant increase in regional blood flow between tasks were matched to three-dimensional reconstructions of brain magnetic resonance images of each subject. compared to the visual fixation control, saccade tasks evoked bilateral activation in the posterior superior parietal lobule with extension into the inferior parietal lobule. activation was also seen bilaterally in an area of frontal cortex immediately rostra1 to the precentral gyrus extending from the superior frontal gyrus to the inferior frontal sulcus. the increased blood flow in the posterior parietal cortex most likely corresponded to enhancement of visual attention required during saccades, while that in the frontal lobe, which included the frontal eye fields, indicated activation for saccade motor output. pamela blake, alexander s. mark, martin kolsky, and jorge kattah, washington, dc fifty patients with third cranial nerve (cn) palsy underwent precontrast and postcontrast mri to assess the utility of this study in this clinical context. mri demonstrated an appropriate lesion in 32 cases. six patients had brainstem lesions (2 infarcts, 1 mass lesion, 1 cryptic vascular malformation, 1 hemorrhagic shearing injury, 1 with compound q toxicity). lesions of the cisternal segment of the nerve were present in 12 patients (4 aneurysms, 4 lymphomas, 1 ophthalmoplegic migraine, 1 viral meningitis, 1 coccidiodomycosis, 1 nerve avulsion), with enhancement of this segment in 7 patients. fourteen patients had cavernous sinus lesions (2 lymphomas, 2 nasopharyngeal carcinoma, 4 tolosa-hunt syndrome, 2 cavernous carotid aneurysms, 3 pituitary apoplexy, 1 aspergillosis). eighteen patients, all with history of diabetes or vascular disease, had normal mri results, suggesting microvascular infarction of c n 111. in patients with cn i11 palsy, mri can detect the presence of brainstem or cavernous sinus lesions and often can suggest their cause. mri with contrast enhancement can demonstrate involvement of the cisternal segment of cn i11 in patients with inflammatory or infiltrative processes that previously could not be radiographically demonstrated. our study suggests microvascular infarction does not cause nerve enhancement on contrast-enhanced mri. we describe 2 patients with acute hyperglycemic, hyperosmolal, nonketotic stupor who had ocular flutter or opsoclonus clinically. these are the fourth and fifth adult patients reported with the acute onset of stupor and opsoclonus; all patients had nonketotic hyperglycemia and hyperosmolality (rapid eye movement sleep also causes stupor and saccadic eye movements). three of the 5 patients had myoclonic jerks in addition to opsoclonus. in the 5, opsoclonus began when glucose and osmolality acutely increased, and completely resolved when glucose and osmolality became normal, showing that opsoclonus is a specific and reversible effect of the metabolic disorder and implying that either acute hyperglycemia or hyperosmolality directly causes opsoclonus. since acute hyperosmolality caused by nacl or sucrose can cause a similar syndrome in experimental animals (trans am neurol assoc 1962; 87:33-36) and infants, hyperosmolality is probably more important. opsoclonus is thought to be due to abnormal activity of saccadic "burst" cells in the pons. acute hyperosmolality may cause spontaneous saccades by disinhibiting burst cells from normal "pause" cell inhibition or by directly activating burst cells. the combination of acute deterioration in mental status and either ocular flutter or opsoclonus should suggest acute hyperosmolality, in particular, nonketotic hyperglycemia. neural cell adhesion molecule (n-cam) and the related cell adhesion molecule l1 play significant roles in axon outgrowth and mediation of cell-cell contact in development, and after peripheral nervous system injury. to understand the role of these molecules after injury in the adult cns, we studied alterations in n-cam and l1 in the rat brain's response to entorhinal cortex (erc) lesion. post lesion, reactive synaptogenesis and axonal sprouting follow a well-defined temporal course in restoring the synaptic density of the dederented outer two-thirds of the hippocampal dentate gyrus molecular layer (ml) to near prelesion levels. we found striking regionand lamina-specific staining of n-cam and l1 in the normal hippocampus and marked alterations in these molecules after injury. embryonic n-cam, present in high amounts during development but expressed at very low levels in the adult hippocampus, was massively re-expressed in the denervated zone; the embryonic form was still heavily expressed 60 days later, when synapse number returned to >so% of prelesion levels. l1 staining, normally evenly distributed through the ml of the dentate, was completely lost in the outer ml, which is denervated by the erc lesion. this staining had not returned by 60 days after lesion. neural cell adhesion molecules play a role in specificity of neural connectivity both in development and after injury. in reactive synaptogenesis and axonal sprouting after injury, both ontogenetic (the reexpression of embryonic epitopes) as well as uniquely adult sequences of repair are utilized. following hemispherectom y" a. pascual-leone, h . t. chugani, l. g. cohen, j . p . brasil-neto, e. m . wassermann, j . and m. hallett, betbesh, md, and los angeles, ca we studied 7 subjects, aged 18 months to 32 years, who underwent hemispherectomy 6 months to 25 years earlier for intractable epilepsy. all had a spastic hemiparesis contralateral to the resected hemisphere, which was present presurgically. we used focal transcranial magnetic stimulation to map the areas of the preserved hemisphere targeting the abductor pollicis brevis (apb), the biceps, and the deltoid ipsilaterally and contralaterally. in 2 subjects who had hemispherectomy after age 10, the same area targeted ipsilateral and contralateral muscles. in the remaining 5 subjects, who were more functional, 2 areas targeted ipsilateral muscles. one area coincided with the contralateral representation, but stimulation induced motor-evoked potentials (meps) of lower amplitude and longer latency in the ipsilateral muscles. the other area, 2 to 4 cm anterolaterally, targeted exclusively ipsilateral muscles and stimulation induced meps of normal amplitude and latency. this separate ipsilateral representation was more distinct in subjects studied a long time after the hemispherectomy and in those who were younger at the time of the operation. these results show evidence of motor reorganization after hemispherectomy. better motor function is associated with topographically differentiated ipsilat-era1 and contralateral representations, which may depend on age at the time of hemispherectomy and the time since then. cynthia l. comella, glenn t . stebbins, nancy brown-toms, and christopher g. goetz, chicago, il in a single-blind, crossover study, we evaluated the effect of an intensive outpatient physical rehabilitation program (re-hab) on the severity of parkinson's disease (pd). the re-hab program consisted of 3 2-hour sessions per week for 4 weeks. sixteen patients completed 2 phases, a rehab phase and a control phase, separated by 6 months. the order of participation in each phase was randomized. all patients were evaluated using the unified pd rating scale with subscales for mentation (ment), activities of daily living (adl), and motor function (mot) by an investigator blinded to the rehab phase of the patient. all patients were evaluated immediately before and after each phase. pd medications were not changed during any phase. following the re-hab phase, there was significant improvement in adl score (pre-rehab 12, post-rehab 8, p = .005 wilcoxon) and in mot score (pre-rehab 26, post-rehab 2 1, p = ,008 wilcoxon), but no change in ment score. after the con-trol phase, there was no significant change in any outcome measure. this is the first controlled, crossover study of an intensive rehab program in pd. it demonstrates that re-hab improves objective motor function and adl scores. sensitive and quantitative measurements of leg weakness, one of the most common deficits in multiple sclerosis (ms) patients, can be made using specialized extremity testing equipment. to determine whether such determinations could be used in clinical trials, 6 ms patients with leg weakness that had been stable for at least 2 months were evaluated every 60 days over a 4-month period. each testing session was carried out at the same time of day and medication dosages and schedules were kept constant (only 1 patient was taking baclofen and his dosing remained constant). quadriceps and hamstrings strengths were measured in isometric contraction in a mechanical testing apparatus (kincom). variability for each series of determinations was expressed as the standard deviation of the mean as a percent of the mean. the overall variability then was expressed as the mean of the individual variabilities. the mean variability for the strength determinations over 4 months was 5.74 k 5.3896, and only one series of determinations out of 28 had greater than 20% variability. these results suggest that quantitative strength determinations might be useful in clinical trials, and early experience in trials of aminopyridines will be discussed. polymyositis (pm) is an inflammatory myopathy of unknown cause, but the accumulating data strongly suggest an autoim-mune pathogenesis. the histological picture is of muscle fiber necrosis and inflammation, whereas in postviral fatigue syndrome (pfs), a disorder characterized by severe fatigue with myalgia and psychiatric symptoms, the histological picture of muscle is essentially normal. enteroviruses have been implicated on epidemiological and serological studies in both. we have used the polymerase chain reaction (pcr) and an enteroviral-specific probe and found persistent enteroviral genomic material in both pm and pfs muscle biopsy specimens. furthermore, we used a radiolabeled full-length cdna probe derived from coxsackie b1 in an in situ technique to look for viral d n a in pcr-positive cases. coxsackie genome was clearly identifiable in the muscle biopsy specimens of patients with pm but negative in pcr enteroviral-positive cases of pfs. the virus excites an inflammatory reaction only in pm. a murine animal model for pfs developed in our laboratory showed positive muscle pcr using enterovirus probes and a conspicuous increase in interleukin 6 within the brain. these results provide major clues in the search for the etiology of these two puzzling disorders. human t-lymphotropic virus type i (htlv-i) is a cause of adult t-cell leukemia and tropical spastic paraparesis. in a specific population of iranian jews originating from the city of mashad, there is a high incidence of htlv-i infection (1 1.5%) and associated t-cell leukemia. we evaluated the incidence of possible correlation between htlv-i infection and spastic paraparesis in israeli mashadi-born jews. we have examined 41 mashadi-born immigrants in a mashadi community center (16 men, 25 women, mean age 66 t_ 13.7 yr) and 40 non-mashadi iranian-born jews. blood samples were tested for htlv-i antibodies by particle agglutination test. the polymerase chain reaction (pcr) was used to amplify htlv-i sequences of d n a from peripheral blood mononuclear cells. twelve mashadi-born immigrants (295%) were seropositive for htlv-i. in 10 of those serologically positive for htlv-i (83%), neurological examination revealed spastic paraparesis of varying severity. none of the non-mashadi iranian jews were seropositive for htlv-i or had clinical signs of spastic paraparesis. these results support other studies of htlv-i-associated myelopathy. the high incidence of htlv-i-associated spastic paraparesis in the mashadi community might be related to their unique history of a high rate of intermarriage among members of this ethnically segregated group. further epidemiological studies are underway to evaluate the incidence of htlv-i in mashadi families as well as in mashadi-originating jews born in israel, to identify whether infection might be genetically transmitted. lymphotropic virus t y p e i-associated acute t-cell leukemia/lymphoma william j . harrington, jr, william a. sheremata, susan snodgrass, and mark raven, miami, fl human t-cell lymphotropic virus type i (htlv-i)-associated acute t-cell leukernia/lymphoma (atl) is thought to produce important c n s disease infrequently. we wish to correct this impression by presenting neurological findings in 15 patients seen between 1989 and the present. all had positive western blots to htlv with polymerase chain reaction confirmation of htlv-i infection. only 2 had a concomitant human immunodeficiency virus infection. all were black, aged 31 to 86 years, 7 were men and 8 women. all but 3 americans came from the caribbean nations of haiti (51, dominican republic (l), jamaica (6), and trinidad (1). sexual transmission was the risk factor for htlv-i for all except for 1 intravenous drug user. all patients were systemically ill. three had preceding neurological abnormality (1, 8 months, and 14 yr) and 8 had major neurological disease concomitantly. two of these had tumor masses demonstrated in brain and 1 in the spinal canal. one had a minor facial sensory abnormality; only 3 had no deficits. we conclude that cns disease is commonly associated with atl, and that in the us atl occurs principally in caribbean natives. a. nath, v . hartloper, and m . furer, winni$eg, manitoba, canada microglia and astrocyte cultures were established from human fetal brain. microglia were infected with human immunodeficiency virus (hiv) strains, hiv,, or hiv,,,, resulting in a rising titer of p24 antigen in the supernatants. multinucleated giant-cell formation, vacuolar changes, and rising levels of lactate dehydrogenase in the supernatants were seen, indicating a cytopathic infection of microglia. astrocytes were infected with free virus or cocultivated with an hiv-infected lymphocyte cell line (hut-78). after a productive phase (rising titers of p24 antigen and detection of hiv antigens by immunocytochemistry), the cells went into a latent phase where hiv could be detected only by dna polymerase chain reaction. a 10-fold increase in astrocytes staining for hiv antigens was seen after cocultivation with hut-78 cells. lymphocytes adhered to astrocytes by 3 hours of cocultivation. no adhesion was seen to microglia. fusion of plasma membranes was seen on electron microscopy. infected astrocytes did not show cytopathic or morphological changes. cell-to-cell contact may be important in viral transmission to astrocytes. hszao-huei chen, steven b. stein, wing kong, and raymond p. roos, chicago, i l one of our goals is tq delineate molecular determinants for disease phenotypes produced by theiler's virus (tv), a mouse picornavirus. the identification of these genes and gene products may clarify viral pathogenesis and also lead to the identification of genes that are important in normal cns function and nonviral cns disease. members of the gdvii subgroup of tv cause an acute, fatal neuronal infection, whereas members of the to subgroup are less neurovirulent and produce a demyelinating persistent infection. our studies of infectious tv cdna clones have demonstrated that the gdvii 1 b(vp2)-2c segment is critical for neurovirulence. several other areas of the genome, including the 5' untranslated region (s'utr), also affect tmev-induced disease. the 5'utr of poliovirus, another picornavirus, has a critical role in paralysis; this effect on neurovirulence is believed to result from an altered translational efficiency related to bind-region ing of neural cell proteins. tv 5'utr has an unusual predicted secondary structure, even for picornaviruses. our studies demonstrate that the tv 5'utr affects translational efficiency and has a distinctive protein-binding pattern. investigations of the tv 5'utr may clarify features of translational regulation of cns genes in general. p129. coronaviruses infect primate brain from g a y f. cabirac, ronald s. murray, galen cai, kristen hoel, and kenneth soike, englewood, co, and covington, la recently, we described finding coronavirus (cv) rna and antigen in active demyelinating plaques of multiple sclerosis (ms) brain tissue (murray et al, ann neurol, in press). molecular analysis showed the cv rna to be more closely related to murine cvs than to human cvs. we then demonstrated that, following intracerebral inoculation, the murine cv jhm and the putative ms isolate cv-sd could infect and cause demyelination in primate brain (murray et al, virology, in press). we now have data showing that murine cv can infect primate brain following intranasal or intravenous routes of inoculation. standard virology, histopathology, and the molecular analysis of viral cytotropism will be presented. we conclude that cvs related to murine cvs can infect primate cns from peripheral routes and warrant consideration as potential human pathogens. probes (gag, pol, or enw). eleven were white and 9 were black. a history of transfusion was obtained in 8, and sexual risk of transmission was present in 8 but not in 4 others. fulminant disease occurred in 4 transfused men 3 months to 4 years later but such disease was only seen in 1 woman (in 1 month). in contrast, 2 of 3 women with multiple sexual partners had rapid progressive disease. the male-to-female ratio was 4 : 4 for transfusion association and 5:3 for those at sexual risk but 0:4 for unknown risk, transfusion is an important risk for tsp/ham and the diagnosis must be considered in all gait problems, regardless of the "diagnosis."transfusion association should decrease with regular testing of blood donors, but this will not affect the risk of sexual transmission. spastic paraparedhtlv-i-associated myelopathy (tsp/ ham). it is unclear why htlv-i infection causes atl in some individuals and tsplham in others. differences in the genome of viral isolates or immunological and host factors have been hypothesized to play a role in disease expression. at present there are no animal models of tsplham and no suitable animal models of htlv-i infection that can address these issues. we transplanted severe combined immunodeficient (scid) mice with peripheral blood mononuclear cells (pbm) from tsplham patients in an attempt to produce htlv-i disease. two weeks after transplantation of pbm from 2 tsplham patients, we detected anti-htlv-i igg in serum samples of 7 of 8 scid mice by enzyme immunoassay using sonicated whole virus. five weeks after transplantation, we detected anti-htlv-i igg to p19, p24, gp46, or gp61168 in serum samples of 5 of 7 scid mice by immunoblot of disrupted virus. these findings suggest that scid mice may be valuable in the study of molecular and pathological determinants of htlv-i-induced disease. theiler's virus produces an encephalomyelitis in susceptible mice. during the course of the disease, specific regions in the cns become infected. compared to the immunocompetent mouse, the nude mouse provides a useful model where viral dissemination can be studied in the absence of functional t lymphocytes and antibodies. we investigated the distribution and spread of the da strain of theiler's virus in the cns of nude mice. by immunohistochemistry, the hippocampus, arnygdaloid nuclei, entorhinal cortex, cingulate cortex, thalamus (anteroventral nuclei), midbrain, and spinal cord all contained viral antigens by 2 weeks after infection. in addition, the olfactory nuclei, mamillary body, hypothalamus, basal ganglia, and nucleus raphe dorsalis often were involved. in the brain, the limbic system was the site commonly infected by theiler's virus. the time course of virus dissemination varied depending on the site of initial virus infection, though the final distribution of virus was the same. olfactory bulb injection, which is a direct inoculation into the olfactory pathway, resulted in more rapid spread than did cortex injection. we demonstrated the constant presence of viral antigen in the limbic system and a different kinetics of viral dissemination between the two different routes of intracerebral inoculations. these results suggest that limbic structures and their connections are important to the dissemination of theiler's virus. 1-associated myelopathy in a northwest native indian d. foti, d. werke, g. dekaban, g. p. a . rice, andj. oger, vancouver, bc, and london, ontario, canada a 59-year-old indian of the oweekeno tribe was admitted for investigation of a myelopathy. initially symptomatic with midthoracic radicular pain, she developed progressive spastic paraparesis over 1 year with mild sensory symptoms and urinary retention. mri of the cord and brain were normal. csf showed elevated protein (930 mgll), 13 lymphocytes, and weak oligoclonal banding with evidence of intrathecal igg synthesis. antibodies to human t-lymphotropic virus type i (htlv-i) were positive by enzyme-linked immunosorbent assay and western blot on both serum and csf. presence of htlv-i was demonstrated by polymerase chain reaction of blood lymphocytes. htlv-i-associated myelopathy, or tropical spastic paraparesis, is endemic in southern japan, the caribbean basin, and several tropical islands but has not been reported in natives of northwest canada. this patient's only risk factors for htlv-i infection were 3 blood transfusions 30 years previously. ongoing familial and epidemiological studies as well as virus sequencing should indicate if this case represents an indigenous or an imported infection. caused by herpes simplex virus type 1 lawy blankensbz) and herbert 0. newton, columbus, oh myeloradiculitis occasionally occurs secondary to herpes simplex virus type 2 (hsv2) infection, but rarely has been reported after herpes simplex virus type 1 (hsv1) infection without encephalitis. we describe a 30-year-old man who developed cervical myelopathy and radiculitis, never developed symptoms of encephalitis, and had positive hsvl spinal fluid cultures. h e initially developed extremity weakness and incoordination, numbness, paresthesias, and neck pain. evaluation was negative except for mri results, which showed a high-signal lesion centrally within the cervical cord. the weakness, sensory loss, and radicular pain progressed over several months. subsequent mri showed extension of the high-signal abnormality and mild enlargement of the cervical cord. symptoms stabilized briefly with dexamethasone but soon worsened, and were accompanied by paroxysmal kinesiogenic dystonic episodes of his arms and right leg. repeat evaluation was unrevealing except for the spinal fluid, which grew out hsv1. the patient was treated with dilantin and a i-month course of intravenous acyclovir, with slow improvement of neurological status and resolution of the dystonic episodes. this case illustrates that hsvl can cause a myelopathy with a subacute and protracted course, requiring serial was more frequent in the middle-aged group ( p < 0.0001, p = 0.001). history of hypertension, previous strokes, diabetes mellitus, and antithrombotic treatment was similar, as were sex ratio, qualifying event type (transient ischemic attack or nondisabling stroke), and angiographic features; stenosis severity in either side and presence of ulceration were all similar. in elderly patients, ecad is associated with symptomatic cardiac disease (scad or af), whereas in middleaged patients it is associated with precursors of generalized atherosclerosis (smoking and hyperlipidemia). to identify the anatomic factors correlating with dementia in patients with lacunar infarctions, we examined digitized ct data on 58 elderly patients (mean age = 71.6 yr; education = 7 yr) who presented with acute lacunar infarction. dementia was diagnosed in 13 patients (22.4%) based on neuropsychological tests given 3 months after stroke onset. the following ct variables were assessed: infarct location and number, total infarct volume, brain parenchymal and csf areas at 3 levels, and width of the frontal horn, third ventricle (tvw), and lateral ventricle plus their ratio to the intracranial width. atrophy and leukoaraiosis were rated semiquantitatively using a standard scoring method. in the group overall, mean infarct volume was 0.64 cc and mean infarct number was 3.8. in univariate analyses, dementia was significantly related to infarct volume, number, tvw, bilaterality, and infarct predominance on the left side, but not to leukoaraiosis or atrophy. in a regression model adjusting for demographic factors, the ct variables correlating independently with dementia status were infarct number (p = 0.37, p = .01) and the presence of left cerebral infarcts (p = 14.17, p = .002). we conclude that the most important ct variables related to dementia in lacunar stroke are lesion multiplicity and the presence of lesions on the left side. brain ischemia results in potassium (k+)-induced voltageregulated presynaptic calcium (ca") accumulation, which may contribute directly to neuronal in jury presynaptically, and also promote excessive release of excitatory neurotransmitters leading to cell damage postsynaptically. k+-induced depolarization of brain synaptosomes may be used as an in vitro model to study the therapeutic potential of pharmacological agents to alter ischemia-induced presynaptic ca2 + accumulation. we preincubated gerbil cerebral cortical synaptosomes in r56865 (janssen pharmaceutical) at concentrations of to lo-' m, subsequently depolarized the synaptosomes with k + , at concentrations of 5 to 6 0 mm, and measured intrasynaptosomal ca2' ([ca2+]) with the fluorescent indicator fura 2. r56865 had no effect on ecaz'i in nondepolarized synaptosomes, but significantly (<.01, student t ) depressed depolarization-induced {ca2+] at to lo-' m in a dose-dependent fashion. the greater the degree of depolarization employed, the greater degree of depression in [ca2+] was seen at each dose of r56865. since r56865 had no effect on [ca2+] when utilizing ca2+-free incubation media, it was demonstrated that r56865 prevents depolaritation-induced [ca2 ' ] increase by blocking voltage-regulated influx. because r56865 appears to block voltage-regulated presynaptic ca2' accumulation, it should be further evaluated as a potential therapeutic agent after cerebral ischemia. sneddon's syndrome (ss) is a focal and diffuse arthropathy affecting mainly the vascular wall of the skin and cerebral arteries. etiology is not determined. we studied 37 patients with ss (27 females, 12 males), aged 15 to 56 years. clinical, radiological, and immunological studies were done. all patients developed cerebrovascular disorders: ischemic stroke in 82%, transient ischemic attack (tia) in 64%, and ischemic stroke and tia in 46%. cerebral scan showed small and medium (less than 3 cm) ischemic lesions in 77%. these lesions were superficial in the cerebral cortex (57%); deeper in the centrum semiovalis, internal capsule, and basal ganglia (18%); and both superficial and deeper (25%). ultrasound and angiogram studies revealed obstruction of intracranial arteries in 30%, and of extracranial arteries in 3%. partial or complete improvement of cerebrovascular symptoms was observed in 81%. immunological studies showed increased content of b-cell lymphocytes ( p < 0.05), increased levels of igm ( p < o.oool), and circulating immunocomplexes ( p < 0.0001). anticardiolipin antibodies were increased (58%) and lupus anticoagulant detected (5 1%). cerebrovascular disorders in ss that lead to small ischemic cortical lesions have a good prognosis. pathogenesis of this syndrome may be related to antiphospholipid antibodies. the cheiro-oral syndrome is characterized by pure sensory deficit limited to the hand and mouth. this syndrome has been described in diverse lesions of the parietal operculum and brainstem, but occurs most commonly due to lesions of the contralateral thalamus, and suggests a humuncular representation of sensation in the ventral posterior lateral (vpl) and ventral posterior medial (vpm) nuclei. we describe a 54-year-old hypertensive woman who presented with sudden onset of numbness of the left side of her body. examination revealed a left hemisensory deficit to all modalities that spared the hand and peri-oral regions. cat scan and mri demonstrated an acute infarction of the posterolateral right thalamus, with a rim of preservation adjacent to the internal capsule. pure hemisensory loss with sparing of the hand and mouth ("inverse cheiro-oral syndrome") has not been reported previously, and complements previously published studies of the cheiro-oral syndrome in demonstrating somatotopic sensory representation in the thalamus. to examine the relationship between depression and dementia after stroke, we administered the 17-item hamilton depression rating scale (hdrs) and neuropsychological tests to 237 elderly patients 3 months after ischemic stroke. using dsm-111-r criteria, we found dementia in 57 (24.1%). hdrs score was 5.0 -t 4.6 overall, and higher in demented compared to nondemented patients (6.2 2 5.0 vs 4.6 t 4.5, p = 0.025). the frequency of depression (total hdrs score >11) was also higher with dementia (17.5% vs 7.8%, p = 0.03). however, demented patients did not differ from nondemented patients on ratings of depressed mood. instead, hdrs items for psychomotor retardation, reduced work activities, and impaired insight best distinguished the 2 groups. in multiple regression analysis, stroke severity (p = 0.23, p = 0.0003) was the most important correlate of hdrs score; dementia status was not correlated independently. mean scores on mini-mental state examination and neuropsychological tests assessing memory, orientation, verbal, spatial, attentional, and abstract reasoning skills did not differ by depression status. although weakly related to intellectual impairment, hdrs score in our stroke sample was most importantly associated with stroke severity. higher scores on hdrs in demented stroke patients may be explained by physical and cognitive symptoms that are expected with dementia. these findings do not support a causal link between depression and dementia, and argue against the importance of "depressive pseudodementia" as an explanation for intellectual decline after stroke. to investigate the pathophysiological mechanism of the white matter lesions in progressive subcortical vascular encephalopathy (psve) of binswanger type, we measured regional water partition coefficient (pc) (reflecting water content) and effective p h (pht) (weighted average of intra-and extracellular ph) with dynamic positron emission tomographic technique using 0-15 co,, o,, and c-11 co,. si-multaneously, regional cerebral blood flow (rcbf) and regional cerebral metabolic rate of oxygen (rcmro,) were evaluated. eight subjects (3 normal, 3 psve, 2 multiple infarction) were examined. in the white matter lesions in psve, corresponding to high-intensity areas in t2-weighted images of mr, the pc increased and pht was unchanged or decreased, whereas both rcbf and rcmroz declined. the ratio of white matter pc to gray matter pc was 0.92 in psve and 0.87 in normals. in the frontal gray matter, the pc decreased in psve, whereas rcbf and rcmroz also decreased. these results suggest that tissue water content increases in the white matter lesions in psve reflecting the edematous status of the damaged regions. elevated pht with high pc may reflect the increase of extracellular water of the tissue. measurement of pc and pht provides useful information about the pathogenesis of psve. stroke has been the second most common cause of death in korea but its risk factors (rfs) have not been studied intensively, so the rfs or causes were investigated prospectively in 1,507 consecutive stroke patients who were admitted to the chungnam national university hospital, taejon, korea, between 1989 and 1991. they included 775 cases of cerebral ischemia (ci) (51.4%), 467 cases of intracerebral hemorrhage (ich) (31.0%), and 265 cases of subarachnoid hemorrhage (sah) (17.6%). control data were obtained from 209 healthy spouses of the patients. multivariate analyses showed that hypertension (ht) was the strongest rf for all stroke types and was followed by old age, diabetes mellitus (dm), smoking, high-density lipoprotein cholesterol, and fibrinogen. the rfs for atherothrombotic ci included old age, ht, dm, smoking, fibrinogen, and cholesterol. for lacunar infarcts, ht, dm, old age, fibrinogen, alcohol abuse, smoking, and female sex were the significant rfs. ht was the cause of ich in 347 (74.3%) and alcohol abuse (44, 9.4%) and vascular anomalies (32, 6.9%) followed. most alcoholassociated ichs occurred characteristically in the posterior fossa. frequencies of hospital admission of ich patients correlated positively with diurnal variation of temperature ( r = 0.5229, p < 0.001). aneurysmal rupture was the cause of sah in 222 patients (83.8%). three major sites of 247 aneurysms identified on cerebral angiograms were the anterior communicating artery (83, 33.6%), the middle cerebral artery (70, 28.3%), and the posterior communicating artery (56,22.6%). thirty-nine patients (14.7%) had no identifiable cause of sah. in korea curvilinear subinsular lesions have been noted on ct but the underlying pathology is unknown. we reviewed the cranial mr scans (1.5 tesla ge machine) of 49 serial patients over the age of 60 who had no cause for mr hyperintensities (hi) other than age or vascular risk factors. seven (14%) had linear subinsular h i (sihi). four of 7 (57%) patients with sihi and 4 of 42 (12%) without sihi had marked periventricular h i compatible with subcortical arteriosclerotic encephalopathy (pvhi) ( p < 0.05). patients with sihi were older (75.3 yr) than patients without sihi (69.1 yr) ( p < 0.05). four of 7 (57%) patients with sihi had hypertension program and abstracts, american neurological association 267 or vascular risk factors. a further patient with diabetes, hypertension, and the opercular syndrome (bilateral facial, pharyngeal, and lingual weakness) had subinsular lesions on ct. the brain arteries were injected postmortem with a lead/ gelatin suspension, and mr of the whole brain and x-ray films of the brain slices were taken. bilateral sihi were seen on mr and corresponded with linear cavitary infarction pathologically, which on microangiograms was found to lie in the border-zone between cortical and basal penetrating arteries. we conclude that sihi are associated with older age and pvhi, and can be due to infarction in a deep watershed territory and can be associated with clinical deficits. hemodilution-treatment results in 12 consecutive cases james l. frey, phoenix, az because precipitous neurological deterioration occurred during blood pressure reduction in a seminal case of lacunar infarction, 11 subsequent patients with partial or evolving lacunar deficits were treated with hemodilution and blood pressure nonintervention to test the hypothesis that lacunar strokes represent perfusion failure. isovolemic hemodilution was performed using hetastarch with target hematocrit of 30 to 33. results of pretreatment ct brain scans, carotid ultrasound, and echocardiograms were normal. nine patients recovered normal neurological function, and 2 regained complete functional independence in close temporal correlation with hemodilution. mri brain scans demonstrated appropriate single white matter lesions in 9 cases. no specific risk factor combination could be identified. n o patient has had recurrent stroke in follow-up from 12 to 30 months. response to hemodilution suggests a hemodynamic pathophysiology. successful treatment requires (1 } blood pressure nonintervention and (2) hemodilution prior to severe clinical deterioration. the hemodynamic classification for the carotid-cavernous sinus fistula (ccf) is important for the implication of prognosis and therapy, but satisfactory objective criteria for such differentiation is still lacking. retrospectively, we studied the application of extracranial duplex sonography in 9 cases of ccf with emphasis on the hemodynamic parameters of resistivity index and flow volume. a correlation was made with the angiographic findings in an attempt to evolve an objective hemodynamic classification by this noninvasive method. the alterations in membrane metabolism and structure could be the primary etiological event in alzheimer's disease (ad) that results in the clinical and neuropathological findings. to investigate in vivo brain membrane phospholipid and highenergy phosphate metabolism in probable ad patients and control subjects, the building blocks (pme) and breakdown products (pde) of membranes and the high-energy phosphates pcr and atp were measured noninvasively by in vivo brain 31p mrs in 11 probable ad patients ( 5 males; 6 females) and 18 controls (9 males; 9 females). all subjects were assessed by mini-mental, mattis, and blessed scales. we found that, at clinical onset, ad females had elevated pme ( p = 0.004), decreased pcr ( p = 0.001), and decreased atp ( p = 0.03). similar changes were not seen in ad males at clinical onset, but the severely demented ad males had increased atp ( p = 0.05). correlation analysis for the ad patients revealed that increasing dementia was associated with decreasing pme ( p = 0.05; r = 0.4), increasing pde ( p = 0.08; r = 0.4), increasing pcr ( p = 0.05; r = 0.4), and increasing atp ( p = 0.02; y = 0.5). similar metaboliccognitive correlations were not seen in the controls. these results demonstrate alterations in membrane and energy metabolism at the earliest clinical stages of ad. increasing dementia correlates with markers of membrane degeneration and decreased utilization of high-energy phosphates. both of these findings suggest the dementia in ad is secondary to membrane changes resulting in synapse loss. alzheimer's disease: postmortem mri and histological correlates fen-lei f. chang, j. e. purisi, c. r. jack+ jr, and r. c. petersen, rochester, mn hippocampal atrophy, defined by mri-derived volumetric measurement, has been useful in differentiating alzheimer's disease (ad) patients from normals. since several studies have demonstrated anatomical and functional gradients along the rostral-caudal (r-c) axis of the hippocampus, it is tempting to speculate on the existence of a differential distribution of morphometric changes along this axis. the hippocampi from 19 patients with clinically and pathologically confirmed ad were studied by postmortem mri and by reconstruction of serial histological sections. there was good correspondence between these two methods. the r-c length of the hippocampus in ad was preserved compared to normal. this length was longer on the left, both in normals and ad. the adassociated atrophy was due primarily to the reduction of the coronal cross-sectional area of the hippocampus. with increasing hippocampal atrophy, volume reduction was more prominent in the rostral area (pes hippocampus). this nonuniform reduction in volume may be associated with different connectivity patterns between rostral and caudal hippocampus. the purpose of this study was to determine the neuropathological validity of nincds-adrda criteria (nac) for probable and possible ad. mckhann et al (1985) provided clinical criteria for the categories probable ad and possible ad. the validity of these categories has not yet been reported. a retrospective, blinded evaluation of the complete neurological history, examination, neuroimaging, laboratory, and psychometric data was done for 68 subjects from the state of florida brain bank. pathological classification, which was blind to clinical diagnoses, was in 3 categories: pure ad, ad + , and other dementias. ninety-three percent of probable ad (n = 42), whereas only 75% of possible ad (n = 26) patients, had ad or a d + ( p = 0.1). pure ad was found in 62% of probable ad and 38% of possible ad patients ( p = 0.1). pathological evidence of coexisting parkinson's disease was present in 14% of all ad brains. these results suggest differential predictive power of nac for probable and possible ad, as suggested by the labels. nac are, therefore, usefui for research and clinical purposes. our prior study of falls in the elderly had shown significantly more white matter low attenuation (wmla) on ct scan among fallers than nonfallers, but no association between wmla and cognitive impairment among nondemented subjects. as these subjects were followed over time, it appeared that fallers were becoming demented at a more rapid rate than nonfallers. as a result, we analyzed the relationship between wmla and rate of change on the blessed test of information, memory, and concentration (bimc) in a combined cohort of 144 subjects from the falls study and from a longitudinal study of dementia and normal aging. we selected 61 of these 144 subjects whose initial bimc score was less than 25 (i.e., not already severely impaired) and who had at least 4 yearly bimc evaluations. ct scans were scored on an 8-point ordinal scale for hemispheric wmla. linear regression was used to summarize the rate of change for each subjects' test scores. the rate of change on bimc was 2.3 points per year with standard error (se) of 0.2 among subjects who eventually became demented; nondemented subjects declined at 0.4 points per year with se of 0.2. multiple regression analysis was performed with initial bimc score and wmla as the independent variables and rate of change of bimc as the dependent variable. wmla accounted for 16% of the variance (partial r = 0.396, t = 3.26, p < .05). these data suggest that elderly subjects with wmla may be at increased risk for rapid cognitive decline. such as g proteins and adenylate cyclase. the activities of adenylate cyclase, and of the g protein-associated enzyme activity, low-km glutamyl transpeptidase (gtpase), were assayed in membranes prepared from the postmortem brains of 8 alzheimer-diseased and 8 age-matched control subjects. both basal and fluoroaluminate-stimulated adenylate cyclase activities were significantly reduced in ad frontal cortex compared to control subjects ( p < 0.01; two-tailed student's t test). in addition, a significant, though smaller, reduction in basal gtpase activity also was detected in ad frontal cortex ( p < 0.05). in contrast, no significant change in the activity of either enzyme was detected in the hippocampus. the stimulation of gtpase activity by muscarinic and gababreceptor agonists was not altered significantly by the presence of alzheimer's disease. however, the degree of stimulation was much lower in human tissue compared to that observed using fresh rat brain, suggesting that the ability of receptors to activate g proteins declines post mortem. these results suggest that alzheimer's disease causes alterations in some key components involved in signal transduction. the association of lobar hemorrhage (lh) with cerebral amyloid angiopathy (caa) and that of caa with alzheimer's disease (ad) are well known. to determine how frequently lh and caa occur in ad, we reviewed 13 patients with cerebral or cerebellar hemorrhage and caa. five patients were treated surgically, none was demented, 2 died, and 1 came to autopsy. eight patients died of lh and came to autopsy. of the 9 autopsied patients, 3 had ad, both clinically and neuropathologically. they comprised 1.2% of 258 cases of autopsy-confirmed ad in our laboratory. none of the other patients were known to be demented. five had senile plaques, with or without neurofibrillary tangles, in the hippocampus, and occasional senile plaques in the cortex, but none met the consortium for establishing a registry for alzheimer's disease neuropathological criteria for ad. ad patients were 70, 85, and 85 years old and the ages of the 10 nondemented patients ranged from 63 to 87 (mean = 73.1 yr). seven were younger than 75 years of age. despite the frequent occurrence of caa in ad, we found that lh was uncommon. in addition, most of our patients with lh and caa were not demented and tended to be younger than ad patients with lh. these results indicate that the hf is involved primarily in acquisition or leaning processes and less so in retrieval of previously learned information. these findings relate to memory and structural brain changes found in normal aging. alzheimer's disease y . stern, l. stricks, g. alexander, 1. prohovnik, and there is an inverse relationship between parietotemporal cerebral blood flow and years of education in alzheimer's disease (ad) patients matched for clinical severity, which suggests delayed clinical manifestation of ad in patients with higher education (stern et al, soc neurosci abs 1771). we classified the lifetime primary occupations of 5 1 ad patients using the dictionary of occupational titles of the us department of labor and derived 6 factor scores describing intellectual, interpersonal, and physical job demands. after controlling for age, education, age at onset, illness duration, and dementia severity (mental status and activities of daily living), relative perfusion in the parietotemporal region (assessed using 133-xenon inhalation) showed significant correlations with job complexity (pl: r = -.36, p < .008) and interpersonal (p3: r = -.44, p < .001) factor scores. in a stepwise multiple regression, job complexity and interpersonal skills increased explained parietotemporal flow variance by 7.5% ( f = 4.7, p < .05) over that explained by demo-graphic and severity indices; physical demands then accounted for another 11.5% of the variance ( f = 8.4, p < .01). we conclude that occupational demands, similar to but independent of education, may provide a reserve that delays the clinical expression of ad. richard mayeux and ming-xin tang, new york, n y risk factors for alzheimer's disease (ad) were collected from 223 patients with ad and 278 healthy elderly controls in an urban community population consisting of 3 ethnic groups: black, hispanic, and white. advanced age (>80 yr) (or = 10.7; 75% ci 6.2-19.1) and head injury with loss of consciousness (or = 2.70; 1.2-7.3) were associated with ad, controlling for all known putative risk factors. factors such as low education (<8 yr) (or = 1.5; 0.8-2.6) and family history of ad (or = 1.7; 0.7-3.0) were not found to be significantly related to ad. head injury occurred in 15.7% of the patients and 6.?% of controls. most (70%) head injuries in the patients with ad occurred after age 50, prior to disease onset. in controls with head injury, 5592 had experienced a head injury before age 50. the duration of unconsciousness was consistently longer in patients with ad than in the controls. the overall effect in each ethnic group was similar (or,, 2.5; 1.3-4.8). these results confirm and strengthen the previously described putative relationship between head injury and ad. we also conclude that both the severity and the timing of the head injury as well as the frequency of head injury in the population at risk may be important factors in understanding the causal relationship between head injury and ad. the purpose of this study was to determine how native language affects the cutoff scores in screening tests for dementia. there is a paucity of data o n this issue at present. screening tests used in the study were: folstein mini-mental state (mms); clockdrawing (clock); preparing a letter for mailing (mail); 4-item grocery list (list); and hamilton depression scale (ham). the subjects included 175 (74 demented) native english speakers (eng) and 72 (22 demented) native spanish speakers (spa) with memory complaints. diagnosis of dementia was determined by neurological, neuropsychological, and psychiatric evaluation. age and gender were unrelated to mms. in spa only, education was positively related to mms. ham scores were higher in deand 0.77 (spa); c d and list did not add discriminative power to mms for eng but did so for list in spa. mms discriminates between demented and nondemented far better in english than in spanish speakers. only mail adds discriminative power to mms. a. heyman, g. fillenbaum, s. mirra, and participating cerad neuropathologists, durham, nc, and atlanta, ga the clinical diagnosis of alzheimer's disease (ad) has become more accurate in recent years due to the application of specific clinical criteria, wider use of neuroimaging procedures, and greater expertise among physicians. we report the frequency of clinical misdiagnosis of ad among 52 patients who at autopsy were found to meet the rigorous clinical diagnostic criteria imposed by the consortium to establish a registry for alzheimer's disease (cerad) study. these patients included 31 men and 21 women (mean ages 78 and 76 yr, respectively) who were among the group of 95 patients who died in 13 cerad medical centers in the us between 1987 and 1991. the clinical diagnosis of ad was neuropathologically confirmed in 47 (88.5%) of the 52 cases. of these 47 cases, varying degrees of concomitant cerebrovascular disease were present in 26% and coexisting parkinson's disease changes were found in 19%. in 4 of the 5 patients without neuropathological evidence of ad, the diagnoses were: lobar atrophy, diffuse lewy body disease, nonspecific neurodegenerative changes, and mesocorticolimbic dementia, respectively. the fifth patient showed no morphological abnormalities. on the basis of these results, it would appear that application of strict diagnostic criteria, as well as the use of brain scans and detailed clinical and neuropsychological tests by experienced clinicians, cannot yet distinguish some types of primary degenerative dementias from alzheimer's disease. we designed a scale that measures an underexplored facet of functional decline in alzheimer's disease (ad): the patient's dependence on others for supervising or performing activities. two hundred twenty-three informants for patients with mild ad (clinical dementia rating [cdr] = 1 for 200; cdr = 2 for 23) were interviewed and dependence was staged from 0 to 5. interrater reliability was assessed by separate interviews of 20 informants; agreement was 100% for dependence stage. dependence stage differed significantly at the 2 cdr levels (chi square = 41.0, p < .01) and correlated significantly with modified mini-mental state (mmms) ( r = -.30, p < .001) and blessed dementia rating scale-part 2 (bdrs) ( y = .41, p < .001). seventy-eight percent of patients in a health-related facility were at stage 3 or higher vs 25% of patients living at home. in a multiple regression model, both the bdrs and dependence scale accounted for unique portions of the variance in mmms, suggesting that they assess unique aspects of functional ability. dependence increased significantly in 118 patients retested at 1 year. we conclude that the dependence scale is reliable and relates to both disease severity and progression. formal assessment of dependence should prove useful for studies of the natural history of ad as well as for clinical trials. cortical-basal ganglionic degeneration (cbgd) is a disorder characterized by an asymmetrical akinetic-rigid syndrome and cortical signs such as apraxia, alien limb phenomena, and cortical sensory loss. dementia has been present in many cases, but always as a late manifestation. we report 2 cases pathologically consistent with cbgd, presenting as primary degenerative dementia, fulfilling nincds-adrda criteria for probable alzheimer's disease (ad). the first patient presented with changes in memory and personality, language dysfunction, decreased verbal output, and shuffling gait. follow-up examinations over 3 years showed progressive dementia, wide-based gait, and frequent falls. the second patient presented with complaints of memory loss. neuropsychological examinations showed progressive deficits in memory, attention, calculations, and visuospatial functioning. no movement disorder developed over 6 years of follow-up. at autopsy, both patients had typical changes of cbgd and lacked pathological features of ad. definitive diagnosis of cbgd rests on both clinical and pathological criteria. cbgd should be considered in the differential diagnosis of patients with dementia resembling that found in ad, especially if extrapyramidal signs are present. a quick, easily administered and scored test for praxis is desirable in evaluation of neurological patients. during 2 months in 1991, each patient seen in the outpatient setting by the principal investigator (e. k.) received 1 of 2 praxis screening batteries. thirty-six patients were tested with a short battery. eleven had normal cognition based on neurological history, examination, and a short test of mental status. twenty-five had cognitive decline (cd). handedness, male/ female ratio, education, and mean age were similar in both groups. mean time of completion of the test was 102 2 10 seconds in normals and 136 * 41 seconds in patients with cd. total scores (maximum 50) were 47.6 * 1.8 in the normals and 41.2 2 9 in the cognitively declined patients. twenty-five other patients, 12 with cd and 13 with normal cognition, were tested with a longer battery containing oral/ facial, upper and lower limb, axial, sequential, and imitation subtests (maximum score 110). normals completed the battery in 297 i 56, and cognitively declined patients completed the battery in 359 ? 53 seconds. of the various subtests, tests of sequential praxis were performed most poorly by patients with cd: 8.3 * 1.8 in normals vs 4.9 * 3.0 in patients with cd. oral/facial praxis was least affected by cd: olivopontocerebellar atrophy (opca) is generally understood to be a nondementing neurodegenerative disorder affecting the cerebellum, lower brainstem, and spinal cord. one of us (s. k.) recently reported that postmortem cerebral cortex from patients with dominantly inherited opca shows a widespread reduction of cholinergic markers similar to that observed in alzheimer's disease (ad). we were interested to determine the status of other neurotransmitter systems in opca postmortem cerebral cortex. samples of frontal, parietal, temporal, and occipital cortex were dissected from 10 confirmed cases of opca and 11 age-matched controls. after processing, neuropeptide levels were measured by radioimmunoassay. concentrations of somatostatin were significantly reduced by 42 to 58% in 3 of the 4 cortical areas of opca brain that were examined. the area that was spared was the inferior temporal gyrus, a region in which somatostatin levels are markedly reduced in ad. levels of neuropeptide y were normal in all 4 areas, while concentrations of cholecystokinin, vasoactive intestinal polypeptide, and substance p were significantly increased in 2 of the 4 areas. these data show widespread neuropeptide changes in the cerebral cortex of opca postmortem brain. in contrast to cholinergic markers, the pattern of neuropeptide changes is different from what is observed in ad. it has been postulated that demise of the corticomotoneuron is the initial event in amyotrophic lateral sclerosis (als) and that the anterior horn cell dies as the result of antegrade glutamatergic excitotoxicity (muscle nerve 1992;15:219). excitability of the corticomotoneuronal system can be tested by measuring threshold-to-cortical magnetic stimulation and the motor-evoked potential (mep)/compound muscle action potential (cmap) ratio, which estimates the number of corticornotoneurons stimulated. cortical threshold and mep/ cmap ratio were measured in 39 patients early in the course of als. the mean time interval from onset of first symptoms was 8.5 months. mean threshold and mepicmap ratio measured 64.2 f 16.6% and 22.0 rfr 21.2%, respectively. in 12 (30.8%) patients, threshold was paradoxically low (<55%, mean 49.1 +. 4.3%) and in 7 (17.9%) patients there was no response. there was a significant ( r z = 0.698) inverse power relationship between cortical threshold and mep/cmap ratio given by 84.1 x mep/cmap-'j. six months later, 7/24 (29.2%) patients still had low thresholds but the mean mep/ cmap ratio had dropped to 24.9 ? 24.5% and in 33.3% there was no response. we conclude that early in als the corticomotoneuronal pathways are abnormally excitable. this may explain early cramping and fasciculation, which characteristically diminishes as als progresses. one of the distinct clinical features in patients with amyotrophic lateral sclerosis (als) is loss of elasticity of skin. however, little is known concerning the biochemical nature of skin elastin in als. in our study, 2 cross-links unique to elastin, desmosine and isodesmosine, were measured and compared in skin tissue (left upper arm) from 10 patients with als and from 7 age-matched controls. the contents of desmosine and isodesmosine were decreased significantly ( p < 0.01 and p < 0.01, respectively) in patients with als (mean * sd, 0.94 ? 0.33 and 0.74 * 0.30 nmol/mg dry weight; range 0.36-1.51 and 0.27-1.33 nmol/mg dry weight, respectively) as compared with those of controls (mean 2 sd, 1.43 * 0.30and 1.17 2 0.21;range 1.11-2.03 and 0.92-1.52, respectively), and were negatively and significantly associated with duration of illness in patients with with amyotrophic lateral sclerosis als ( r = -0.77, p < 0.01, and r = -0.65, p < 0.05, respectively). the ratio of desmosine and isodesmosine was constant (1 : 3) in all samples analyzed. the decline in skin desmosine and isodesmosine is more rapid in als than in normal aging. thus, cross-linking of skin elastin is affected in als. (supported in part by n i h grants de 18522, de 11233, de 08611, ar 19969, ar 30587, and nasa grant nag-2-181.) pl69. natural history of amyotrophic (1) collection of large numbers of twin pairs in disease of low prevalence is difficult. to circumvent this, we devised a new approach termed the "death discordant twin pair" method. eleven thousand deaths from motor neuron disease (mnd) were extracted from the office of population censuses and surveys during 1979 to 1789. birth indexes from 1900 onward were searched for possible twins. for each twin so identified (13 1 pairs), the national health service central registry located the relevant family practitioner committee and thence the co-twin's general practitioner. the search produced: (1) 53 living co-twins; (2) 5 embarked; (3) 60 dying as adults or infants; (4) 3 not mnd; and (5) validity of the accuracy, sensitivity, and specificity of the world federation of neurology (wfn) subcommittee on motor neuron disease working group criteria for the clinical diagnosis of amyotrophic lateral sclerosis (als) has been tested against neuropathological criteria in 36 autopsied patients (neurology, in press). integration of clinical and electrodiagnostic data to meet wfn criteria for possible, probable, and definite als was studied in this samegroup. patients received 1.7 ifr 1.1 (mean * standard deviation) electromyograms (emgs) per patient and included 1.7 2 0.9 emg levels (bulbar, cervical, thoracic, lumbar) per patient. proportionately fewer emgs were performed as the level of diagnostic certainty at presentation increased: suspected (34.3%), possible (31.4%), probable (25.7%), definite (8.6%). in only 4.8% of all patients studied did the first emg alone change the level of diagnostic certainty of the diagnosis of als. only 16.7% of patients presenting with suspected als alone or with possible or probable als were associated with a change in level of diagnostic certainty following 1 or more emgs. however, although increasing the number of emgs performed per patient may be associated with an increasing chance of increasing the level of diagnostic certainty (22 emgdpatient = 33.3%; 2 3 emgdpatient = 60.0%), selection of the level of emg analysis was more crucial. the "el escorial" criteria emphasize the importance of emg evidence of lower motor neuron involvement in a limb with clinical upper motor neuron signs. our analysis of emg studies in autopsy-confirmed als patients suggests that complete evaluation of bulbar and thoracic levels for lower motor neuron changes and complete evaluation of motor unit recruitment patterns are important for the integration of emg data with clinical data in the application of the "el escorial" criteria for the diagnosis of possible, probable, and definite als. sibships on guam annette grefe, john steele, linda flares, and stephen waving, birmingham, al, and umatac and mangikao, guam reports in the 1950s indicated that 40% of guamanian chamorro patients with amyotrophic lateral sclerosis (als) gave october 20 a positive family history. subsequent investigators have inferred that purely genetic factors are not responsible for guamanian als or its clinical variant, parkinsonism-dementia complex (pdc). we report the first 4 chamorro sibships selected in an ongoing study of 17 1 familial aggregations. the basis for the initial selection was that the youngest patient in the sibship had als. age of onset was 30 to 46 years (mean 35 yr). fourteen of 23 persons in these sibships were affected. others in the sibship developed pdc, progressive supranuclear palsy, or pure dementia later in life (mean 61 yr, range 50-74 yr). these cases developed 14 to 47 years (mean 25 yr) after onset of disease in the first sibling. the age at onset of the first case and the intervals between earliest and latest cases in such sibships may help to determine minimal and maximal latency (i.e., interval between exposure to an exogenous agent and onset of symptoms). our observations suggest that exposure may have occurred early (before age 30) with varying and often long latency (up to 47 yr). we also find that variability of clinical expression may be correlated with the age at onset. concentrating on the study of familial cases on guam may enhance the identification of the etiologic agent(s) of this prevalent and tragic disorder. the spinocerebellar ataxias are an uncommon group of genetic disorders that have been well characterized in north america and europe. information concerning these conditions in africa and other parts is scant. to address this problem, a large-scale survey has been undertaken in the cape province of south africa. in this investigation, more than 500 persons in 18 affected families have been appraised and investigated and phenotypic features have been analyzed in detail. linkage studies have been undertaken in 4 families with similar phenotypes in which the condition was transmitted as an autosomal-dominant trait. human lymphocyte antigen (hla) typing was carried out on 79 members of the 4 families and linkage analysis was undertaken using the liped program to analyze the data with a correction factor for age of onset. maximum lod scores were: family a: 4.13 (0 = 0.005); family b: 0.6 (0 = 0.001); family c: 0.50 (0 = 0.30); family d: 0.0 (0 = 0.50). these results indicate linkage to hla in 1 out of 4 families. these findings provide support for the concept of genetic heterogeneity in these phenotypically homogeneous families. pcr typing with the reportedly more closely linked d6s89 locus is now being undertaken in these south african families. h.-p. hartung, g. f. hoffmann, and g. becker, wunburg, heidelberg, germany recently, l-2-hydroxyglutaric acidemia has been described as a novel metabolic disorder in 6 children. we report the occurrence of this disease in adults. one of 2 brothers developed at the age of 10 an abnormal gait and dysarthria; in the other 1, clumsiness and walking delay were noted at age 3. symptoms progressed and at the time of admission, when the patients were 33 and 39 years, neurological examination revealed a spastic ataxic gait, limb ataxia, dysmetria, dysarthria, dystonic posturing, and mental retardation. ct and mr imaging revealed subcortical white matter changes with loss of arcuate fibers, folial atrophy, and leakage in the cerebellar vermis, as well as atrophic changes in the cerebellar hemi-acidemia program and abstracts, american neurological association 273 spheres. on biochemical screening, highly elevated concentrations of l-2-hydroxyglutaric acid were found in csf, plasma, and urine. the pathological accumulation of l-2hydroxyglutaric acid in these 2 adults, along with the clinical picture characterized by cerebellar, extrapyramidal, and pyramidal symptoms and oligophrenia, and the neuroradiological findings of severe loss of myelinated arcuate fibers in subcortical white matter, conform with what previously has been described in the few neuropediatric cases. the biochemical abnormality underlying accumulation of this organic acid remains elusive. this study was undertaken to differentiate primarily affected areas from functionally suppressed areas due to remote effect in aphasic patients with focal brain degeneration, using an activation method with 0-15 water, in comparison with [sf]2-fluoro-2-deoxy-~-g~ucose (fdg) positron emission tomographic examination at rest. the subjects were 2 patients with slowly progressive aphasia showing contrasted clinical symptoms (nonfluent type vs fluent type). regional cerebral metabolic rate of glucose (cmrglu) was measured with intravenous injection of 130mbq of f-18 fdg at rest. regional cerebral blood flow (cbf) was measured with intravenous bolus injection of 1.5gbq of 0-15 water in 3 different conditions: at rest, under repetition tasks, and under naming tasks. changes of cbf were evaluated between a resting condition and task-performing conditions. regional cmrglu was decreased focally in both broca's and wernicke's areas similarly in these cases in spite of the difference in clinical symptoms, whereas the patterns of regional cbf changes were different. the fluent patient showed prominent activation in the bilateral frontal areas on repetition tasks. the nonfluent patient showed, whereas the fluent patient did not show, focal activation in the left occipitoparietal area on a naming task. evaluation with an activation method can provide detailed information about the pathophysiological process and the location of primary lesion. defective complex i activity has been linked to huntington's disease (hd) and parkinson's disease (pd). intrastriatal injection of inhibitors of complex i reproduces the pathological features of hd, and the neurotoxin mpp+ kills dopaminergic neurons by inhibiting complex i. defects in complex i have been reported in hd and pd, but the distribution of this enzyme in the brain is unknown. to map complex i in brain quantitatively, we developed an assay using e3h)dihydrorotenone to label the enzyme in tissue sections. this high-affinity binding is saturable and is displaceable by rote-in brain none and mpp+. using 100 pm rotenone to define nonspecific binding, more than 95% of binding is specific. highest levels of binding are found in kidney, followed by myocardium. moderate levels of complex i are seen in striated muscle and some brain regions. within the brain, binding varies more than 20-fold and is heaviest in the cerebellar molecular layer and dentate gyrus. lower levels of binding are found in cortex and striatum and very low levels are located in substantia nigra. this assay may help to clarify the role of complex i in neurodegenerative disorders. ( in 1988, 4 patients with medically intractable parkinson's disease underwent autologous adrenal medullary-to-caudate transplants at the university of california-los angeles (ucla). these persons had been followed for several years before operation at 3-or 4-month intervals. at each visit, their disability had been rated on the quantified ucla scale and the hoehn and yahr stage of disease. these provided a longitudinal assessment of the progression of disease in each patient, which could be compared to the rate of progression in the cohort of cases followed at ucla for 15 years. in addition, the unified parkinson's disease rating scale provided supplementary data for the immediate preoperative and subsequent postoperative evaluations. the hours "off" also were recorded for the preoperative and postoperative periods. after operation, the same evaluations were performed by the neurologist who previously had cared for the patients. the longitudinal postoperative data revealed that at 1 to 4 months after operation, all 4 patients improved. after 4 years, 3 continue to be less disabled than their preoperative baselines. the progression of their disease, while still evident, is nonetheless proceeding at a slower rate than before transplant. the fourth patient had brief improvement shortly after operation, but then rapidly worsened to his previous level. his disease has continued to progress at a rapid pace, unchanged from progression before operation. individuals at risk for huntington's disease h . p. h . kremer, w. shtybel, b. snow, c. clark, j . theilmann, m . r. hayden, and w. in huntington's disease (hd), caudate hypometabolism as demonstrated by positron emission tomography (pet) is a well-established feature in symptomatic patients. in individuals at risk, however, conflicting findings are reported. since 1984 we have performed 61 pet scans in 44 asymptomatic persons at risk for hd (age 27-76 yr) . linkage analysis with 9 independent dna probes or subsequent evolution to clinical hd (in 5 patients) allowed a risk estimate for 35 subjects. twenty were considered to be at increased risk (?85%), 14 at decreased risk (<15%), and in 1 individual no modification could be given. nine subjects were not tested. a pet scan was considered abnormal if either the caudate/thalamus ratio or the caudate/whole-brain ratio of rcmrglu was more than these criteria, 8 scans in 6 individuals were abnormal. none had received a decreased risk. comparison of the ratios of increased risk, decreased risk, unmodified risk, and control subjects failed to show statistically significant differences (analysis of variance). follow-up of 3 persons with an abnormal scan showed conversion to symptomatic status within 5 years after the first abnormal scan. this result suggests that an abnormal pet scan in a person at risk for h d heralds the onset of choreic movements. robitaille, m . el-awar, b. clark, l. scbut, m. ball, l. young, r. currier, and k. sbannak, toronto, ontario, and montreal, quebec, canada; pittsburgh, pa, minneapolis, mn, portkmd, or, and jackson, ms we measured the levels of dopamine in striatum of 14 patients with end-stage dominantly inherited olivopontocerebellar atrophy (opca). on average, dopamine levels were reduced in putamen ( -5396, as compared with controls), caudate ( -35%), and nucleus accumbens ( -31%). however, individual patient values showed a wide variation (normal to -9996), indicating that striatal dopamine loss is a common, but not constant feature of opca. seven patients had marked putamen dopamine loss (-62 to -8195) but without corresponding severe substantia nigra cell damage; this suggests a "dying-back'' phenomenon in which nerve terminal loss precedes cell-body degeneration. in this regard, opca may offer the possibility of examining nigrostriatal dopamine neuronal degeneration at an early stage. although 2 patients were found to have severe nigral cell loss with near total ( -95 to -99%) striatal dopamine loss, none had depression in parkinson's disease (pd) has been correlated with low cerebrospinal fluid (csf) levels of 5-hydroxyindoleacetic acid (5-hiaa). l-dopa may precipitate or exacerbate depression in 30% of pd patients. to determine if l-dopa affects 5-hydroxytryptamine (5ht) metabolism, 8 patients were studied. four had pd. of these, 2 were taking l-dopa and both were depressed. the diagnoses in the remaining 4 were progressive supranuclear palsy (psp), striatonigral degeneration (snd), normal pressure hydrocephalus, and pseudoseizures with depression. neuropsychological examinations and lps of all 8 patients were done. three patients were started on l-dopa (the 2 previously untreated pd patients and the psp patient) and retested 3 days later. one pd patient started on l-dopa became depressed. mood in the others was unchanged. csf was analyzed for 5ht and 5-hiaa. 5ht could not be detected in the csf of patients who were not taking l-dopa, but was easily detectable in all of the patients who were taking l-dopa. 5-hiaa levels were low in the untreated pd patients, and also in the patients with psp, snd, and pseudoseizures with depression. 5-hiaa levels were even lower in the l-dopa-treated patients. the ratio of 5-hiaa:5ht (an index of 5ht turnover) was lowest in the l-dopa-treated pd patients who were depressed. low csf 5-hiaa in untreated pd may reflect depletion of brain 5ht. l-dopa may induce depression by inhibiting 5ht turnover in 5ht-depleted brain. p18 1. ventroposterolateral medial pallidotomy in the e. fazzani, m. dogali, a. ben;, d. eidelberg, j. gianutsos, t. kay, b. newman, s. loftus, d. samehon, and l. laitinen, new york, n y , and stockholm, sweden in patients with parkinson's disease (pd), as a consequence of low dopamine there exists an increase in inhibitory output from the globus pallidus. ten patients (5 men and 5 women) with pd received unilateral (6 right, 4 left) ventroposterolateral medial globus pallidotomies (vplmp). the average patient age was 61 years (range 55-73 yr), and the average duration of disease was 14 years (range 6-24 yr). patients fluctuated between "on" chorea and "off" parkinsonism. hoehn and yahr stage "on" was i1 in 7 , 111 in 3; and "off" was i11 in 5, iv in 2, and v in 3 patients. unified pd rating scale (updrs) score averages 12 hours off medicines (12hom) were activities of daily living (adl): 20 and motor (mtr): 40 preoperatively (preop). capit score averages preop 12hom were pronation-supination (ps): 3 1 seconds (s), finger tap (ft): 31s, board (b): 39s for the most affected contralateral side, and gait: 57s (2 patients could not walk). re-examination was done 2 to 5 days after pallidotomy. updrs scores 12hom decreased an average of 60%. three patients had major bilateral improvement in bradykinesia. rest tremor, prominent in 3 patients, also was diminished. capit scores 12hom decreased to ps: 19s, ft: 20s, b: 22s; the average gait of the 8 patients who could walk preop improved to 36s. there were no side effects. vplmp leads to an immediate overall significant improvement in patients with pd. s. kish, y . there is a growing interest in the genetic aspects of parkinson's disease and other basal ganglia disorders. we have studied 3 families whose ancestors immigrated to north america from contiguous regions of northern germany and southern denmark. the pedigrees contain 77, 206, and 376 individuals spanning 6, 7, and 8 generations with 7,6, and 9 affected members, respectively. autosomal-dominant inheritance is clearly present in 2 families and probable in the third. typical levodopa-responsive parkinsonism with bradykinesia, rigidity, resting tremor, and impaired postural reflexes uniformly develops in affected individuals from all 3 families. n o downgaze impairment, pyramidal signs, sensory disturbances, cerebellar dysfunction, or orthostatic blood pressure changes have been observed. dementia, however, has developed in a few elderly individuals, especially in 1 family. laboratory studies are normal. mri shows moderately enlarged ventricles and cortical atrophy. 6-fd positron emission tomography demonstrated reduced striatal uptake in 1 examined patient and normal uptake in l individual at risk. autopsy of only 1 subject has been performed (in 1975). brain weight was 1,380 grams and there were no obvious gross abnormaliprogram and abstracts, american neurological association 275 tuesday, october 20 ties, but microscopic examination was limited. further research on these 3 families is planned. electrophysiological study s. maurri, m . cincotta, a. ragazzoni, g. descisciolo, and f. barontini, florence, ltah many neurophysiological examinations were conducted of a 32-year-old woman with familial mirror movements. n o other neurological abnormalities were detected. examination included voluntary electromyographic (emg) activity from various muscles, f-wave as well as short-and long-latency reflex responses of the thenar muscles from electrical stimulation of the median nerve, mapping of motor-evoked potentials (meps) to transcranial magnetic stimulation, movement-related cortical potentials (mrcps), and somatosensory-evoked potentials (seps). emg documented mirror activity in the upper limbs, most marked in the muscles of both hands. onset latency of emg activity in response to an auditory stimulus was identical in active and mirror muscle. long-latency responses from median nerve stimulation were recorded on contralateral as well as ipsilateral thenar muscles. short-latency reflexes and f wave were strictly ipsilateral. unilateral scalp magnetic stimulation evoked bilateral responses at similar latencies in the thenar muscles; midline scalp stimulation activated no responses. scalp distribution of median nerve seps and of mrcps associated with self-paced thumb abduction were normal. our findings suggest that congenital inherited mirror movements in otherwise normal subjects can be generated by corticospinal fibers pro jecting to ipsilateral motoneurons of the spinal cord. we have previously identified dysphagia and constipation (both slow transit and defecatory dysfunction types) as common gastrointestinal (gi) problems in parkinson's disease (pd). since apomorphine has been shown to be capable of terminating off-periods when injected subcutaneously, we have evaluated the effects of apomorphine injection on objective parameters of dysphagia and bowel dysfunction in pd patients. nine subjects underwent the following battery of studies to characterize their pd features, swallowing, and bowel function: gi assessment survey, unified pd rating scale, videoesophagram, colon transit study, defecography, and anorectal manometry. specific abnormalities on the studies were noted and the most abnormal study was repeated after subcutaneous administration of 6 mg apomorphine. all individuals were pretreated with domperidone 20 mg four times daily for 3 days prior to apomorphine administration. improvement in both esophageal motility and deglutition was noted in the 1 individual in whom videoesophagram was repeated. for the other 8 patients, defecography or anorectal manometry was performed. significant improvement in specific parameters was demonstrated after apomorphine administration, but 2 individuals experienced syncope during radiographic procedures. we conclude that subcutaneous apomorphine administration holds promise as a potential therapeutic approach to dysphagia and, especially, bowel dysfunction in pd, but that further investigation and refinement are necessary. asymmetrical effect of unilateral thalamotomy or subthalamotomy on tremor in parkinson's disease nico diedericb, christopber g. goetz, glenn t . stebbins, harold l. klawans, k. nittner, a. kozrlosakis, p. sanker, and v . strum, cologne, germany, and chicago, il in the past, stereotactic operation was a regular treatment for unilateral tremor in parkinson's disease (pd). however, follow-up studies were usually short term and always unblinded. we examined 17 pd patients in long-term follow-up (mean 10.9 yr after operation) who underwent unilateral thalamotomy for parkinsonian tremor. we used videotapes and the unified parkinson's disease rating scale to blindly compare tremor ipsilateral and contralateral to the side of operation. since the patients were specifically selected for stereotactic operation because of asymmetric tremor, we reasoned that a sign of long-term efficacy would be current postoperative reversal of tremor side predominance. upper extremity tremor was significantly better contralateral to the side of operation compared to the ipsilateral side ( z = 3.29; p < 0.023). for the lower extremities the difference was not statistically significant. in chronic follow-up, stereotactic operation improved the absolute magnitude of arm tremor or ameliorated its rate of progression. since asymmetric bradykinesia and dyskinesia were not prerequisites for the choice of surgical side, we cannot make any conclusion about longterm impact of operation on these features. subtle extrapyramidal signs resembles that of patients with parkinson's disease m . richards, k. marder, l. cote, y . stern, and r. mayeux, new york, n y to investigate the relationship between extrapyramidal signs (eps) and cognition, eps severity and neuropsychological function were assessed in 307 normal elderly individuals and 130 nondemented patients with idiopathic parkinson's disease (pd) from a community-dwelling cohort in new york city. multivariate analysis of variance (manova) indicated poorer neuropsychological performance ( p = .001) in pd patients on verbal memory, orientation, verbal fluency, visuomotor construction, and psychomotor speed, but not naming, abstract reasoning, or matching. controlling for eps severity abolished these differences. one hundred fourteen (37%) of the normal individuals had subtle eps (mostly postural abnormality, bradykinesia, or rigidity) but no identifiable neurological disorder. manova indicated poorer neuropsychological test performance ( j = ,001) in these individuals than in normals without eps on verbal memory, orientation, abstract reasoning, naming, verbal fluency, matching, and psychomotor speed but not visuomotor construction. we conclude that: (1) cognitive impairment in pd is specifically associated with eps, and (2) a similar association occurs in individuals with subtle eps but no neurological disorder. whether this represents a preclinical stage of pd or ad is yet to be determined. disease in olmsted county, minnesota emre kokmen, fatma sibel ozekmekci, c. mary beard, and peter c. o'brien, rochester, m n , and istanbd, turkey there have been many studies of prevalence of huntington's disease (hd) in diverse populations around the world. to study the incidence, we took advantage of the availability of detailed health care records for the population of olmsted county, mn, from mayo clinic, its affiliated hospitals, olmsted medical group, county hospital, state hospital, records of solo practitioners, nursing homes, death certificates, and autopsy records. we reviewed all records with a diagnosis of hd, huntington's chorea, chorea major, and chorea otherwise unidentified, and sought evidence for progressive chorea, progressive cognitive and/or behavioral dysfunction, and family history compatible with autosomal-dominant inheritance with onset of symptoms in the period between january 1, 1950, and december 31, 1989 , while the patient lived in the geographic boundaries of olmsted county. we found 3 males and 6 females who met these criteria. average annual incidence rate (age/sex adjusted to 1960 us white population) for hd for this 40-year period was 0.3 cases/ year/ 100,000 population. we also estimated prevalence by taking account of in-migration, out-migration, and deaths. the agelsex adjusted (1960) prevalence for 1-1-60 was 7.51 100,000 and for 1-1-90 it was 2.4/100,000. the small number of cases caused the instability of the prevalence rates, but our rates are similar to rates reported in other populations. alton e . btyant, 111, l. breeden hollis, john a. hamjian, john d. wooten, ill, and francis 0. walker, nc we described 4 patients with unusual episodic movement disorders and normal diagnostic work-ups: a 34-year-old woman who had recurrent episodes of tonic jaw deviation and forced right-eye closure; a 30-year-old woman who developed unexplained pain and subsequent spells of tonic inversion of the left leg; a 61-year-old man who presented with a bizarre episodic right-arm tremor; and a 15-year-old woman who experienced intermittent abdominal undulations. examination of the affected body part provoked or enhanced symptoms in all patients. using suggestion and placebo activation in the form of a medicated patch, intravenous saline, or cervical massage, we first induced and then aborted typical episodes of their abnormal movements. postinduction discussions of the procedure led to a marked reduction in the frequency of attacks in 2 patients. activation procedures are useful in diagnosing psychogenic disorders because they demonstrate that situational, not medical, factors govern the expression of the abnormal behavior. we speculate that patients who are refractory to simple suggestion may respond to induction because it offers the potential of validating their symptoms. as in the case of psychogenic respiratory distress or pseudoseizures, positive induction can assist in counseling and symptom control. had alzheimer's disease with parkinsonism (adp), 1 had essential tremor (et), 1 had cerebellar tremor in multiple sclerosis (ms), and 1 had tardive dyskinesia (td). clozapine was used either to treat psychosis (20 pd, 2 adp, 3 dys, 1 td) or tremor (1 5 pd, 1 et, 1 ms). two pd patients were retrospective analysis of 38 patients counted twice, 1 who was treated for psychosis and then tremor and 1 who was treated on 2 separate occasions for psychosis with different responses. all 3 dys patients improved, 2 with complete resolution of their dystonia on changing antipsychotic drugs. the patients with et (75 mg) and ms (25 mg) improved mildly but sedation and clumsiness caused drug discontinuation in the ms patient. one adp patient (112.5 mg) responded well and the other became sedated and confused (25 mg). the p d responses for psychosis at a dose range of 6.25 to 400 mg daily were good (5), very good (2), and excellent (8), whereas 4 were intolerant. pd tremor responses were good (51, very good (4), excellent (2), and poor (3) at doses of 12.5 to 100 mg daily. one patient died of unrelated causes shortly after initiation of the drug. adverse effects included sedation, weight gain, hypersalivation, fainting, clumsiness, transient granulocytopenia, and "spasms" necessitating discontinuation in 9 patients (7 pd, l td, and l ms). tourette's syndrome and attention-deficit disorder patients s. m. silverstein, p. g. coma, d. palumbo, l. west, and r. kurlan, rochester, n y impaired attention is a common comorbid behavioral feature of tourette's syndrome (ts) and a key clinical feature of attention-deficit hyperactivity disorder (adhd). however, the pattern of attentional impairments reported in adhd has not been observed in ts. we therefore compared 17 ts patients (9 male, 8 female; mean age 32 ? 11 yr), 17 adhd patients (8 male, 9 female; 36 * 12 yr), and 17 normal controls (8 male, 9 female; 3 1 ? 9 yr) on specific neuropsychological (np) and computer-administered tasks of attentional ability. adhd, but not ts, subjects performed significantly worse than controls on the n p tasks (digit symbol, perceptual speed) and had a trend toward poorer performance on a computerized measure of attention. however, both the adhd and ts groups had significantly greater test performance variability on some, but not all, tasks and had more subjects with deviant scores. among ts patients, higher scores on an obsessive-compulsive disorder (ocd) inventory and a greater number of adhd symptoms correlated significantly with poorer performance on the attentional tasks. moreover, ts patients with observed tics during testing had greater attentional impairment than those without tics. these results suggest that: (1) many adult ts patients do not have impaired attention; (2) attentional impairment in ts differs from that observed in adhd; and (3) attentional impairment in ts is associated with the full neurobehavioral spectrum of ts (i.e., tics, ocd, and adhd). frank r. sharp, cathleen miller, thomas rando, and steven greenberg, san francisco and palo alto, c a six patients are described with choreoathetoid movements and marked proprioceptive sensory loss. one patient had a traumatic injury to the right parietal cortex that produced severe proprioceptive sensory loss and choreoathetosis in the left arm. another patient had a left thalamic infarction that resulted in profound proprioceptive sensory loss and chorea on the right side of the body. two patients had cervical spinal cord disease, proprioceptive sensory loss, and diffuse choreoathetosis. another patient had dorsal root ganglionitis associ-a hypothesis program and abstracts, american neurological association 277 ated with small-cell lung carcinoma that produced diffuse loss of all sensory modalities and chorea. the last patient had an ulnar sensory neuropathy and choreic movements of the fifth finger. lesions anywhere along the pathway that transmits limb proprioception may cause pseudochoreoathetosis. furthermore, choreoathetosis without sensory loss caused by focal lesions of striatum may occur because of disruption of cortical proprioceptive inputs to striatum-perhaps explaining why most focal lesions of striatum do not produce chorea. sporadic inclusion-body myositis (s-ibm) and autosomalrecessive hereditary inclusion-bod y myositis (h-ibm) are of unknown cause and pathogenesis. in both there are muscle fibers with rimmed vacuoles containing 15to 21-nm cytoplasmic tubulofilaments (ctfs) and denervation atrophy; in s-ibm, but not h-ibm, there is a varying degree of inflammation. vacuolated fibers contain ubiquitinated inclusions (askanas 1991) and congo-red positivity indicating amyloid (mendell 199 1). because immunoreactive p-amyloid precursor protein (app) and p-amyloid protein (p-ap) are constituents of ubiquitinated senile plaques in alzheimer's disease (ad) brain, we studied immunolocalization of app and p-ap fibers in ibm muscle using antibodies against: (1) non-p-ap fragments of app, viz. (a) c-terminus (residue 676-695 courtesy d. selkoe) and (b) n-terminus (residue 45-62 courtesy b. frangione and d. levartovsky); (2) p-ap (sequence 8-17, courtesy g. glenner, and sequence 1-40 courtesy d. selkoe); (3) ub (chemicon). in 13 of 13 ibm patients, including one h-ibm, 100% of the vacuolated muscle fibers contained large or several small app and p-ap immunoreactive (ir) inclusions, which by double-labeling fluorescence were closely colocalized with each other and with ub-ir. none of 18 control muscle biopsy specimens (including 7 polymyositis) contained app-ir, p-ap-ir, or ub-ir inclusions characteristic of ibm. control experiments utilizing omitted, replaced, or absorbed primary antisera were negative. p-ap, a product of proteolytic cleavage of app, is receiving attention regarding the pathogenesis of ad. our study provides (1) the first demonstration of app and p-ap accumulations in abnormal human muscle, and (2) raises the possibility that in ibm muscle and ad brain rhey may form from similar cellular events. jeffrrey d. rothstein, lin jin, and ralph kuncl, baltimore, m d the pathogenesis of motor neuron death in amyotrophic lateral sclerosis (als) is unknown. accumulating evidence suggests that the disease is characterized neurochemically by a derangement in the control of neurotransmitter glutamate metabolism: csf levels of glutamate and aspartate are ele-of motor neuron degeneration vated and their high-affinity transporter is defective in brain and spinal cord. inefficient glutamate transport, and subsequent chronic increase in extracellular glutamate, could be responsible for selective motor neuron death. to test the hypothesis that chronic defects in glutamate uptake can produce motor neuron toxicity, we developed a tissue culture model employing organotypic rat spinal cord maintained under conditions of chronic glutamate uptake inhibition. slices (300 pm) of lumbar spinal cord from 8-to 14-day-old rat pups were cultured on millicell membranes. chronic uptake inhibition was produced by culturing tissue in the presence of threohydroxyaspartate (tha) or pyrrolidine-dicarboxylic acid, both known to be specific inhibitors of glutamate transport. tha produced chronic elevation of glutamate in the medium and produced motor neuron toxicity after 25 to 30 days in culture using 100 pm tha, and after 18 days using 500 pm tha, as determined by assay of tissue choline acetyltransferase (chat) activity and by histological analysis of 1-micron plastic sections. motor neuron toxicity was completely blocked by the non-n-methybaspartate (nmda) antagonists cnqx or nbqx, but not by the nmda antagonist mk-801. this model demonstrates that the chronic loss of glutamate transport in als can produce motor neuron degeneration and that motor neurons appear to be susceptible to non-nmda-mediated glutamate toxicity. guillain last year, we described a distinct acute paralytic syndrome in children and young adults from northern china and differentiated it from guillain-barre syndrome (gbs) by epidemiological, clinical, and nerve conduction (nc) features. to distinguish chinese paralytic syndrome (cps) from gbs more clearly, we measured nc in 21 cps patients (mean 8 yr, range 1.5-35 yr) and in 21 gbs patients from johns hopkins (mean 14 yr, range 5-24 yr). sensory nc was normal in all (n = 62) but 1 nerve of cps patients, whereas sensory nc was frequently abnormal in gbs patients: median nerve, 63%; ulnar nerve, 87%; and sural nerve, 21%. motor n c also differed between the groups. in all nerves, distal latency (dl) was significantly longer in gbs than in cps. for example, in the median nerve, mean dl was 8.6 ms (se 1) in gbs and 2.8 ms (0.2) in cps ( p < 0.005). motor conduction velocity was significantly reduced in gbs median and ulnar nerves compared with cps nerves. f-wave latency was significantly longer in gbs median nerves than in cps nerves. these data support the distinction both clinically and electrodiagnostically between cps and north american gbs. the use of n c may be especially important in field epidemiological studies in separating the 2 disorders. clinical manifestations and gene analysis of the first japanese kindred yoshihide sunada, teruo shimizu, lchiro kanazawa, and toru mannen, tokyo, japan familial amyloidotic polyneuropathy type iv (fap iv) has been clustered in the finnish population and only a few cases have been reported from the netherlands. denmark, and united states. we describe the first japanese family with fap iv. the family originates from nagano prefecture, a mountainous district in the middle part of japan, and has no relationship to the finnish population. this family has 42 members in 3 generations, and 14 individuals are affected with slowly progressive cranial neuropathy and corneal lattice dystrophy. the genetic trait is autosomal-dominant. polarizing microscopy and immunohistochemistry show abundant amyloid deposits reactive to an anti-gelsolin monoclonal antibody. direct sequence analysis of a dna fragment spanning codon 187 of the plasmagelsolin cdna from the propositus, and restriction analysis using a modified pcr from other family members demonstrate a single base substitution, g to a at the first base of codon 187, which is identical to the mutation of finnish fap iv. this suggests that the mutation causes the fap iv phenotype regardless of ethnic background. gene expression focal puncture injury has been used as a model to study degenerative and regenerative responses of skeletal muscle. previous studies have demonstrated the ultrastructural and metabolic effects of muscle injury. however, the early genomic response to focal injury is presently unknown. we asked whether the immediate early genes (iegs) or early response genes-~$268, c-jun, nur77, and junb-are responsive to muscle injury. these iegs encode transcription factors and are expressed rapidly after cell-surface stimulation. we have previously shown that surgical denervation and neural stimulation of muscle induced differential patterns of ieg expression. in this study, we produced injury of mouse gastrocnemius muscle by injection of 20 c1.1 of normal saline. we used the contralateral (uninjected) muscle as a control and examined the milna levels of each of these 4 iegs. we found that ~$ 2 6 8 and junb levels were increased at 1 and 4 hours and returned to basal levels by 24 hours. in contrast, mrna levels of nur77 and cjun remained unchanged. this pattern of ieg response is distinct from that seen after muscle stimulation or denervation. the selectivity of this pattern suggests that ieg expression may play a role in the response of muscle to injury. amyotrophic lateral sclerosis (als) is a degenerative disease that leads to the restricted loss of motor neurons (mn). the reason for the selective death of mn remains unknown. we hypothesize that mn-enriched or mn-specific genes are important for normal m n function and that their disturbance may play a role in the pathogenesis of als. we have produced clonal hybrid cells derived from embryonic and neonatal spinal cord m n for the study of m n gene properties. some of these hybrid mn clones express traits typical of mn, such as high levels of choline acetyltransferase enzyme activity and message, glycine receptor message, and neurofilament and neural cell adhesion molecule proteins. we are using molecular techniques to identify novel mn-enriched or mn-specific genes in these cells. with this strategy, we have identified several cdna clones preferentially expressed in mn hybrid cells but not in the parental neuroblastoma cells by differential hybridization of an embryonic mn hybrid cdna phage library. we are extending these observations by performing subtraction hybridization experiments. these results suggest that mn-enriched or mn-specific genes can be identified, and may lead to a greater understanding of the etiology of als. there is a syndrome of slowly progressive, mid-adult-onset fasciculating progressive muscular atrophy (pma) affecting upper more than lower limbs, without bulbar or corticospinal signs, more often in males, associated with igm monoclonal gammopathy, and no nerve conduction block. two such men, ages (a) 59 years and (b) 64 years, duration 11 and 3 and one-half years, csf protein 28 and 60, had failed to achieve sustained improvement with: prednisone, cyclophosphamide, total-body irradiation, and multiple lymphoplasmaphereses in a; and interferon alpha 2a in b. intravenous immunoglobulin (ivig), 0.4 gm/kg/day, has provided dramatic benefit, sustained and increasing for >5 and >4 months to date. (there is a continuing base of depotestosterone, 200 mg weekly, which initially alone provided very minimal improvement.) strength increase was evident at 1 and 3 days after the first course of 5 daily ivig infusions. it further increased for 2 to 2 and one-half weeks after treatment, and then began to diminish. repeat 5-day treatment 3 weeks after the first course resulted in summated improvement, now sustained and enhanced by an average of 1 treatment per week. quantitated strength testing by a blinded observer has shown a 2-fold to >loo-fold gradually increasing muscle function in all limbs. patient a regained the ability to feed himself, get out of a chair, walk unaided, and go up steps; quantitated hip flexors increased 2-and 20-fold. patient b regained the ability to feed himself, take care of personal toilet needs, walk securely, and drive 500 miles; quantitated hip flexors increased 5-fold, and biceps flexions increased from 0 with no weight to > 130 reps while holding 10-pound weights. bukhara jews: a new cluster with typical oculopharyngeal muscular dystrophy (opmd) is a rare, late-onset myopathy with autosomal-dominant inheritance. its ultrastructural hallmark is the finding in muscle fibers of intranuclear tubular filaments of 8.5-nm outer diameter. most opmd cases were described among french canadians; in france, the homeland of their ancestors, the prevalence is 1/200,000 (brunet et al, 1990) . in israel's central area live approximately 40,000 jews who have immigrated from the bukhara and samarkand regions in uzbekistan. they represent a homogeneous ethnic group with its own language and community life. among them we have identified opmd in 15 families (55 affected individuals). the inheritance, clinical, electrophysiological, and histological features of these pa-tients are similar to those described in other pdts of the world, with typical intranuclear inclusions seen on electron microscopy. the minimal estimated prevalence of opmd in this population is approximately 1 : 7 5 0 . this cluster of opmd among bukhara jews is the second largest in the world. because many bukharian families are large, they may be suitable for linkage genetic studies. human muscle during ontogenesis e . scarpini, g. conti, p. l. baron, and g. myoblast transfer has been proposed recently as a possible therapy for duchenne muscular dystrophy patients. because immune rejection can represent a major problem in myoblast implantation, immunological characteristics of human muscle should be investigated. previous studies showed that human muscle cells cultured in vitro can constitutively express human lymphocyte antigen (hla) class i, but not hla class 11. furthermore, human y-interferon induces the surface expression of hla class i1 on mononuclear myoblasts, but not on multinucleated myotubes. however, whether the cells produce and present the antigen by themselves or take this material from the environment, where it could be released by infiltrative cells, is not yet clear. in this study, we analyzed hla molecules at the protein level by immunocytochemistry with monoclonal antibodies against different hla-dr epitopes and hla-abc molecules on frozen serial sections of human muscle during development and at the adult stage. human muscle infiltration by macrophages and monocytesmacrophages also were studied with m718and leum3specific monoclonal antibodies at the same stages of development. our results show that during muscle development and maturation, hla-dr and hla-abc antibodies do not label muscle fibers but some m718-and leum3-positive cells within the muscle. these data can be useful to understand the role of infiltrating monocytes-macrophages in the muscle immune response. mounting evidence suggests that excitotoxicity, mediated via the glutamate receptor, is involved in the pathogenesis of amyotrophic lateral sclerosis (als), as well as in other neurological diseases. we therefore initiated an open label, phasen i trial of highdose dextromethorphan (dm), a noncompetitive, selective n-methybaspartate antagonist, in als. patients began with 2 mg/kg/day, divided into 4 doses, and incrementally escalated their medication to 10 mg/kg/day or their maximum tolerable dose. thirteen patients, all extensive metabolizers of dm, were enrolled. total daily doses ranged from 4.75 to 10 mg/kg. major side effects were lightheadedness (8), slurred speech (7), and fatigue (6). no biochemical, hematological, or neuropsychiatric abnormalities occurred after up to 6 months of maximal therapy, except for depression in 1 patient. plasma kinetics of dextrorphan (dt) (the major metabolite of dm) were studied after an acute oral dose of 2.5 mg/kg dm. median elimination halflife was 2.5 hours. plasma dt concentration peaked at a median of 2 hours, with a median cmax of 14.4 pm. median amyotrophic lateral sclerosis cerebrospinal fluid/plasma dt ratio was 9.796. this study demonstrates the feasibility of long-term, high-dose dm therapy. we are now conducting a phase i1 study of highdose dm in als, designed to assess its efficacy. polyneuropathy: a chronic inflammatory demyelinating polyradiculoneuropathy variant? d. cros, k. h. chiappa, s. patel, and s. gominak, boston, ma, we describe 4 patients (3 men, 1 woman) with a pure, adultonset sensory neuropathy. the course was chronic in all cases. three patients had a relapsing-remitting course over 2 to 22 years with several attacks every year; the onset was gradual and followed by a plateau in the fourth patient. all patients had positive and negative sensory symptoms, and 2 had positive motor symptoms (fasciculations). in all patients, muscle power was normal at the time of peak deficit. all were areflexic and had large fiber sensory deficits, and 3 patients had sensory ataxia. three patients had elevated csf protein, whereas the csf was normal in 1 patient. mri demonstrated marked thickening of the lumbosacral spinal roots in 1 patient. motor conduction studies were normal in all patients, and mild f-response abnormalities were noted in 2. neurophysiological investigations of the sensory pathways were abnormal in all. three patients had several studies over a 2-year period. sensory nerve action potentials were unobtainable in 2 patients, and normal in the others. median and tibial somatosensory-evoked potentials showed conduction slowing consistent with demyelinating lesions affecting the peripheral sensory pathways, either globally or focally in the proximal segments. two patients appeared to respond to plasma exchange or intravenous immunoglobulin therapy, or both. glial fibrillary acidic protein cells in experimental motoneuron disease raul n . mandler, pam c. allgood, and james a. wallace, albuquerque, nm neuronal degeneration in human and animal motoneuron disease has been emphasized, but glial phenotype alterations have not been studied as extensively. we carried out a developmental and topographic study of astrocyte expression in the wobbler mouse model of motoneuron disease. wobbler mice and normal littermates were studied at 3, 4 , 5 , and 6 weeks of postnatal development. anesthetized animals were perfused intracardially with paraformaldehyde. spinal cords were dissected and landmarks were identified carefully for systematic study. sections were stained with monoclonal antibodies against glial fibrillary acidic protein (gfap) neurofilament and neuron-specific enolase. cell quantitation was done with video-enhancing microscopy. in symptomatic animals, marked increases in gfap staining were found in rostral and caudal spinal cord areas. quantitation studies revealed a 15to 20-fold increase in gfap+ cells in the wobbler. we conclude that gfap+ cells are markedly increased in the wobbler mouse at cervical, thoracic, and lumbar areas. this cell may also be relevant in motoneuron disease pathogenesis. ( indirect evidence suggests that polio virus may persist in the human cns years after initial infection and may be a cause for the post-polio syndrome. to evaluate whether the polio virus genome can be detected in the cns of patients with previous polio infection, we identified 11 patients who had died with autopsy findings and clinical history consistent with poliomyelitis. rna was extracted from paraffin-embedded sections of brain or spinal cord and subjected to reverse transcription followed by dna amplification by polymerase chain reaction (rt-pcr) using primers specific for heat shock protein 70 (hsp70) and a conserved region of the polio viruses. hsp70 mrna could be detected in all specimens, indicating that amplifiable rna had been isolated. in no specimens could polio virus rna be detected. this study suggests that polio virus does not persist in the human cns in quantities detectable by the sensitive pcr method. with cmt type 11, seen at mayo clinic rochester between 1981 and 1991, for the frequency of selective calf weakness in cmt type 11, the form of cmt most similar clinically to distal sma. anterior compartment weakness exceeded calf weakness in 49 patients (74%); anterior and posterior involvement was equal in 16 (24%). calfweakness exceeded anterior compartment weakness in 1 patient (2%). selective calf weakness in distal sma thus helps distinguish this disorder from cmt type 11, and similarly from distal sma with weakness resembling cmt, in that we are unaware of the 2 distributions in distal sma occurring in the same family. given the possibility of genetic heterogeneity, linkage studies of distal sma probably should include patient selection criteria such that the distribution of leg muscle weakness is homogeneous. p206. conjugal amyotrophic lateral sclerosis: amyotrophic lateral sclerosis (als) is a sporadic neurodegenerative disorder of unknown cause. unusual cases may provide etiologic clues. we report a married couple, both of clue to etiology? whom developed als in 1 year. the couple grew up in southeastern pennsylvania and attended the same schools. they married after high school and have 2 healthy children. in september 1990, a 38-year-old woman noted right-hand weakness and associated fasciculations that progressed to the entire right upper extremity. by january 1991, the lower extremities were asymmetrically weak and fasciculating. she then developed left-arm weakness, d ysarthria, dysphagia, and emotional incontinence. she had hyperreflexia and bilateral extensor plantar responses. then, in may 1991, her husband, aged 38, noted difficulty whistling, which progressed to frank dysarthria. later, he developed dysphagia, emotional incontinence, and weakness, wasting, and fasciculations in the upper extremities. hyperactive gag, jaw, and limb reflexes were present. in both, electrodiagnostic testing revealed widespread evidence of lower motor neuron degeneration. numerous laboratory tests were normal. although these cases may represent a chance association, the development of als in a young husband and wife suggests a possible environmental cause. the authors welcome suggestions about these cases from the neurological community. conduction block in demyelinating neuropathies usually is assessed from differences in the sizes of surface-recorded maximum m-potentials evoked by supramaximal stimulation at successively more proximal sites along the course of motor nerves. as the maximum m-potential is comprised of many bitriphasic surface-recorded motor unit action potentials (muaps), differences in the relative latencies between muaps may lead to phase cancellations, reducing the m-potential size and rendering any quantitative assessment of the extent of conduction block relative to phase cancellation difficult. cooling a muscle (not the nerve), however, by as much as 15â°c increases the negative peak durations of muaps by as much as 2 to 3 times and moves the point at which maximum phase cancellation might occur to some theoretical point well proximal to the spinal roots. in 5 cases of guillain-barre syndrome (gbs) studied to date, cooling produced little change in percent reductions in m-potential negative peak areas between successively more proximal sites of stimulation. this finding suggests that "true" conduction block rather than interpotential phase cancellation best explains reductions in m-potential size at successively more proximal sites of stimulation in gbs. associated with trimethoprim-sul famethoxazole rare cases of primarily motor polyneuropathy have been associated with the use of sulfonamides. the incidence of polyneuropathy has diminished substantially with the abandonment of earlier methylated compounds. we describe 2 patients who developed allergic phenomena, including a skin rash and debilitating, painful sensory and autonomic polyneuropathy within days of receiving trimethoprimsulfamethoxazole. in 1 patient, examination revealed resting tachycardia, marked blood pressure orthostasis and near-program and abstracts, american neurological association 281 syncope, hyporeffexia, urinary incontinence, and reduced sensation distally in the lower extremities. his cerebrospinal fluid was acellular with a protein of 141 mg/dl. the other patient showed a resting tachycardia, sluggish pupils, reduced distal vibration perception, and hyperpathia of hands and feet. conventional nerve conduction studies demonstrated normal motor results in both patients, absent or reduced sensory amplitudes in the first patient, and normal sensory results in the second. autonomic studies identified profound abnormalities in testing of sympathetic skin potentials, sinus arrhythmia, and valsalva's ratio. in both cases, nerve biopsy was not performed for fear of exacerbating the patient's hyperpathia. subsequent hemodynamic and electrophysiological testing showed improvement in autonomic function, paralleling the patients' clinical amelioration. although uncommon, a painful, sensory and autonomic, partially reversible polyneuropathy may develop after the use of trimethoprim-sulfamethoxazole. the remote effects of botulinum a toxin injections into vocalis muscles for treatment of focal laryngeal dystonia were investigated using single-fiber electromyography (sfemg). botulinum a toxin injections have been proven effective therapy for various dystonic disorders including focal laryngeal dystonia, blepharospasm, and torticollis. previous sfemg studies have demonstrated remote effects of the toxin in noninjected muscles after treatment for both blepharospasm and torticollis. these effects include an increase in fiber density, mean jitter (mcd), and percentage of fiber pairs with increased jitter. other researchers have postulated that the distant effects of this toxin may be related in part to the dose of botulinum toxin injected. to investigate this hypothesis we have studied patients treated for focal laryngeal dystonia because the amounts of toxin required are 1/25th to 1/1ooth of the doses used to treat other dystonias. using electromyographic (emg) guidance, bilateral injections of 2.5 or 5.0 mouse units of botulinum a toxin were injected into each vocalis muscle of 11 patients. each patient had significant improvement in phonotory function within 48 hours after injections and have been followed serially (usually within 3 weeks and again at 2 mo) after injections, with sfemg recordings of the left extensor digitorum communis and sternocleidomastoid muscles. five patients have had more than 1 series of injections over the 10 months since we began this study. sfemg studies have revealed no significant change in the fiber density, mean mcd, or percent of fiber pairs with normal jitter in either muscle. in conclusion, our studies support the hypothesis that the presence of remote effects of botulinum toxin may be related, in part, to the amount of toxin used. the c57bl/6/01a mouse exhibits the remarkable characteristic of prolonged survival of axons separated from their cell bodies (slow wallerian degeneration). previous work has demonstrated that the axon itself is responsible for the phenotype of prolonged survival. we investigated whether the lack of rapid axonal degeneration after axotomy in this substrain is due to an inability to break down cytoskeletal components, a process that is normally accomplished by activation of intrinsic calcium proteases. segments of desheathed sciatic nerves from normal and ola mice were incubated for 2 hours under conditions that disrupt the axolemma (freeze/ thaw or in 1 % triton x-loo), allowing external calcium free access to axoplasm. nerves were analyzed by western blot for neurofilament (nf) proteins and by electron microscopy. in high-calcium media (1 mm caci,), nf immunoreactivity was lost and axoplasm was reduced to watery debris in both substrains, whereas in egta-buffered media, axoplasm was preserved. these results demonstrate that calcium-activated proteases are present and can be activated in ola nerves. the defect in these mice that allows for prolonged survival of transected axons is likely in the mechanism for calcium entry into the distal stump. the mechanism by which the analogue of adrenocorticotrophic hormone, acta4-9, prevents cisplatinum (cp) neurotoxicity is unknown. murine n1e. 115 neuroblastoma cells and neural crest-derived, squirrel fish erythrophore cells tuesday, have similar vesicular transport mechanisms to human neural cells. they were used to study the effects of cp and acth4, on cellular transport. differentiated n 1e. 1 15 cells were treated 1 hour prior to observation with serum-free media (sfm, control); sfm/cp 5 pg/ml; or sfm/cp 5 pg/ml and 100 ng/ml acth4-,. organelle transport was studied (7 neurites and 100-140 organelles per condition) using computer-enhanced video microscopy. mean fast anterograde (1.00 k 0.07 pmsec-' vs 1.65 * 0.07 pmsec-') and retrograde (0.67 2 0.04 pmsec-' vs 1.19 +-0.05 pmsec-') transport were decreased in cp-treated compared to control cells ( p < 0.0001). in cp/acth4,-treated cells, mean anterograde (1.46 +_ 0.07 pmsec-') and retrograde (1.13 2 0.04 pmsec-') velocities were greater than in cp cells ( p < 0.0001). velocities in control and cp/acth4, cells were not statistically different. erythrophore pigment granule transport was observed in a blinded study, using similar techniques. mean aggregation velocity was greater in control (1.99 k 0.09 msec-') and cp/acth4, (1.97 f 0.07 msec-')-treated cells compared to cp (1.43 * 0.07 msec-') cells ( p < 0.0001). incubation with cp for 1 or 72 hours affected velocities equally, but acute exposure was more easily reversed by control or acth,, containing media. there is striking inhibition by cp in cross-species models of organelle transport. this can be prevented by acth4,. erythrophores allow future study of individual transport components. neurotrophin to investigate signal transduction pathways involved in neurite growth, the cytoplasmic regions of p7sngfr, the common neurotrophin receptor monomer, were searched for a motif analogous to the predicted secondary structure of the tetradecapeptide mastoparan. potential sequences were modeled using a semi-empirical molecular mechanical force field approach. the sequence rat ~7 5~~~ 367-379 represents a highly conserved amphiphilic domain predicted to be involved in neurotrophin signal transduction via g-protein mechanisms. to test this prediction, peptides containing sequences homologous to p7 5ngfr 367-3 79 were examined for effects on trophic factor-induced survival/differentiation responses of rat pc12 pheochromocytoma cells, chick embryo drg neurons, and chick embryo ciliary neurons. a peptide identical to ~7 5~~~ 367-379 accelerated the neurite growth response to nerve growth factor (ngf) of pc12 cells and drg neurons in a time frame that paralleled uptake into cells, but mastoparan did not influence ngf-mediated neurite growth. millimolar mg+ + and benzalkonium chloride, known to block the actions of mastoparan, blocked the effect of the peptide on ngf-mediated neurite growth by pc12 cells. peptides mutated to alter cationic amino acid relationships or amphiphilicity were less effective than the peptide in accelerating ngf-mediated neurite growth. these observations complement and extend evidence suggesting a pivotal role of ~7 5~~~ in ngf-mediated signal transduction. these studies complement and extend evidence suggesting a pivotal role of p7sngfr in neurotrophin signal transduction and evidence that activation of intracellular signalling processes involving specific g-protein mechanisms are involved in neurotrophin-mediated neurite growth. crushing the hypoglossal nerve causes hypoglossal motor neurons to decrease expression of choline acetyltransferase (chat) and begin expressing p75ngfr, the low-affinity ngf receptor. these changes are evident within 3 days after the injury and continue for several weeks. inhibition of axonal transport by vincristine applied to uninjured nerves causes loss of chat expression without induction of ~7 5~~" . we sought to determine if topical vincristine would alter p7sngf' expression after nerve injury. hypoglossal nerves were surgically exposed unilaterally in anesthetized rats and crushed. one week later, rats were reanesthetized and the same nerves were re-exposed. vincristine or saline was applied at the crush sites by soaking a strip of cotronoid wrapped around the nerves. one week later, rats were anesthetized and perfused with aldehydes. frozen sections from the brainstems were stained by indirect immunoperoxidase to demonstrate chat and ~7 5~~~' . saline-treated controls showed decreased chat and abundant ~7 5~~" in hypoglossal motor neurons ipsilateral to the crush injury. vincristine-treated animals showed no chat and no p7tngf'. we interpret these results as indicating that a signal originating from the injury site maintains ~7 5~~" expression after nerve injury. catecholamines have been reported to be toxic to embryonic-derived rat neurons and glia via the formation of reactive oxygen species (rosenberg, 1988) . we tried to determine whether oligodendrocytes (ol) from adult 6-month-old rat brain are similarly susceptible. toxicity to ol was examined using light microscopy and galactocerebroside immunohistochemistry where the relative number of surviving ol and their extent of process formation were graded. five days of exposure to norepinephrine (ne) and epinephrine (epi) at 10 and 100 fm produced significant toxicity ( p < 0.05, analysis of variance [anova)) to adult rat ol; this toxicity was evident by 24 hours of exposure. treatment with catalase (50 p,g/ml), a free-radical scavenger enzyme, completely prevented the toxicity of catecholamines. to ascertain whether astrocytes, which have free-radical scavenging capacity, could prevent the catecholamine-induced injury to ol, rat ol were seeded on neonatal rat astrocytes. under such conditions, the toxicity of n e and epi was reduced significantly ( p < 0.05, anova). these findings suggest that impairment of this protective function of astrocytes may render ol and its myelin membrane susceptible to free-radical-mediated damage. lyme neuroborreliosis is an increasingly prevalent disorder, but the diagnosis generally has been indirect. thus, the pres-ence of other manifestations of the infection, consistent findings on neurological exam or lumbar puncture, or presence of csf antibody have been used rather than direct isolation or identification of the organism from the csf. we have previously developed polymerase chain reaction with hybridization (pcr/h) to identify borrelia burgdorferi in the blood and organs of infected mice, and found that the assay was equivalent or, in some cases, preferable to culture (ann neurol 1991; 30:302) . the assay used for primers oligos derived from a sequence of genomic b. burgdovfri d n a expressed on a plasmid by rosa and schwan. a two-stage nested pcr was performed on csf samples in which the d n a was isolated in a variety of ways. pcr products were subsequently hybridized with a digoxigenin-labeled internal probe by slotblot hybridization. the sensitivity of the assay was excellent, being <o. 1 fg of purified b. burgdoorfevi dnaiml of csf, and 1 to 10 spirochetes per ml of csf when "spiked" csf was tested. the assay then was applied to a battery of csfs stored over the past 15 years in patients with definite, probable, and possible lyme neuroborreliosis. the lack of pcr/h positivity in some patients with definite and probable disease signifies that the spirochete does not reside in the lumbar csf in all patients with lyme neuroborreliosis, and may be concentrated in the meninges or parenchyma. progenitor cell line on transplantation into the adult murine brain t . kitagwcbi, d.-h. chui, and t . tabira, tokyo, japan several multipotent neural cell lines were generated via retrovirus-mediated v-myc transfer into primary culture cells of the septum of embryonic murine brains (the retroviral vector, kindly provided by d r c. l. cepko, boston, ma). two of those cell lines, when transplanted back into 6to 8-week-old mice by stereotaxic operation, integrated into the septum in a nontumorigenic manner. the implanted cells, which had been labeled with pkh26 dye, could be identified in animals up to at least 10 weeks after transplantation. immunocytochemical analysis demonstrated that the transplanted cells were seen assuming a round morphology and no processes. they did not stain with any glial or neuronal markers except for a2b5 and hnk-i, in the same way as in vitro. interestingly, after 10 weeks of implantation, the cells were located discretely in the transplanted site and displayed a small and round morphology with fine processes. most of the transplanted cells showed immunoreactivity with monoclonal antibodies directed against neuronal markers such as neurofilament and map2. these data indicate that the immortalized cell lines might be useful in characterizing factors that regulate cell type differentiation in the mammalian nervous system. (supported by a grant from the science and technology agency of japan.) related to serum response factor in human brain and muscle dana leifer, dimitri krainc, racbael neve, roger bveitbavt, and stuart a. lipton, boston, m a we have identified cdna clones for a novel transcription factor that is expressed at high levels in human fetal brain and skeletal muscle, but not in a variety of other tissues, as demonstrated by northern blotting. sequence analysis indicates that the clones appear to have 2 alternatively spliced forms and have extensive homology with human serum re-sponse factor (srf) and a family of related transcription factors that has representatives throughout eukaryotic evolution in species from yeast to man. srf is thought to have a role in regulation of immediate early genes and of muscle-specific genes. in gel mobility-shift assays, the srf-like proteins coded for by our clones bind specifically to the myocytespecific enhancer binding factor-2 (mef-2) regulatory element, a dna sequence that has so far been found to be functionally important in the promoter and enhancer regions of a variety of muscle-specific genes. moreover, our srf-like proteins specifically activate transcription of reporter genes containing the mef-2 element. given the abundant expression of our clones in human brain as well as in muscle, our results suggest that these proteins may have a significant role in development not only of muscle but also of brain. a host of quantitative eeg studies, most of which employed variations of the fast-fourier transform, have been made on isolated clinical entities such as the epilepsies, metabolic syndromes, and sleep with varying degrees of satisfactory correlations. using a time domain wave-by-wave computer program that simulated the logical approach of the clinical electroencephalographer, we have studied more than 300 unselected routine neurological clinic and ward patients. the presenting problems ranged from headache to major cerebral involvement. employing the dichotomy of normal and abnormal, the computer-read eegs agreed with the routine eeg, the clinical manifestations (including imaging techniques), and neuropathological findings in 90% of all cases. this high level of correlation, which approached that achieved by welltrained eegers reading the same records, was obtained by solely utilizing the background eeg activity. such results became possible only when the computer program was so organized that the "raw" computed and original oscillograph records were made to match closely. the diagnosis, with topographically diagramed localization, was printed automatically as the final step of the program. our data strongly suggest that routine computer reading of the human eeg is feasible, reliable, and potentially useful. protein accumulation in damaged neurites and microglial cells abnormal accumulation or abnormal processing of amyloid precursor protein (app), or both, may be critical to the development of p-amyloid protein (bap) deposits. however, alzheimer's disease (ad) has another pathological hallmark, which is the appearance of neurofibrillary tangles. the question is, therefore, to clarify the possible relationship between altered app metabolism and neurofibrillary degeneration. one classic method for inducing neurofibrillary tangles is the administration of aluminum salts. although these tangles are morphologically different than those seen in ad brain, this phenomenon has given rise to the hypothesis that aluminum might be an environmental factor in the causation of ad. this theory is controversial, but the animal aluminum model remains one of the few ways that long-lasting neuroskeletal changes can be induced. to explore the effects of aluminum salts on app metabolism, we examined app immunodistribution in rat brain injected intraventricularly or intrastriatally with aici,. we found a long-lasting accumulation of app in affected neurites, as well as in activated microglia/macrophages. abnormal neurites also showed argentophilic changes, neurofilament accumulation, and alz-50 immunoreactivity. the results support the hypothesis that interruption of axoplasmic flow by aluminum salts, as by other means, can lead to both app accumulation and neuroskeletal alterations. p223. nondemyelinating conduction slowing of myelinated fibers due to inactivation of n a channel takanori yokota, yukinobu saito, and tadashi miyatake, tokyo, japan in 4 patients with acute or chronic inflammatory demyelinating polyradiculoneuropathy, the marked improvement of motor-nerve conduction velocity without change of amplitude or configuration of the compound muscle action potentials (cmaps) was observed in 3 days. to investigate the mechanism of the rapid improvement of nerve conduction, the influence of na channel blockade on nerve conduction was studied. in 4 healthy volunteers, the recovery of the cmap and sensory nerve action potential (snap) of median nerve stimulation were recorded after the intravenous infusion of 100 mg of lidocaine. after the loading, cmap and snap were reduced rapidly in amplitude and were slowed in latency. after the recovery of amplitude of cmap and snap, the nerve conduction velocities were improved gradually in 2 hours with the amplitudes and configurations of cmap and snap unchanged. this indicated that myelinated nerve conduction velocity could be slowed by the inactivation of na channels without demyelination or conduction block. the prolongation of rising time in depolarization of axonal membrane potential should be one of the mechanisms of this conduction slowing due to inactivation of na channels. paraneoplastic cerebellar degeneration (pcd) in gynecological and breast cancers frequently is accompanied by an autoantibody response (type i or "anti-yo") reacting with 34and 62-kd cytoplasmic antigens of cerebellar purkinje cells. sakai et al, using a cerebellar library (stratagene), recently have isolated a cdna clone expressing a 52-kd protein recognized by igg from a patient with pcd and uterine carcinoma (sakai et al, ann neurol 1990; 28:692) . this clone is believed to share some homology with the message encoding the 62-kd protein recognized by type i sera. because pcd17 was isolated using serum from a single patient, however, it is not known whether the expressed protein of pcd17 is recognized uniformly by all patients with type i antibody response. e. coli strain xl1-blue transformed with pwr590-2 containing the snabiihindiii fragment of pcd17, pwrsbo-pcdl?sn, was induced using isopropylthiogalactoside. bacterial lysates were electrophoresed on 10% sds-page gels and analyzed by western immunoblot program and abstracts, american neurological association 285 methods using sera and csf from patients with pcd associated with gynecological and breast malignancies who exhibited type i antibody response. the 52-kd expression product was labeled by 818 sera and 414 csf samples tested from antibody-positive patients but was not labeled by sera or csfs from controls. our studies demonstrate that the 52-kd protein expressed by pcd17 contains epitopes that are consistently recognized by both systemically and intrathecally produced antibodies from patients with pcd accompanying gynecological and breast malignancies. tax01 is a novel antitumor drug that has demonstrated impressive clinical activity in breast, ovarian, and lung cancers. although sensory neuropath y has been described secondary to both taxol alone and taxol-cisplatin combination, detailed neurophysiological and pathological studies have not been described. nineteen patients with solid tumors were treated with combinations of taxol (135-350 mg/m2), cisplatin (75-100 mg/m2), and granulocyte colony-stimulating factor (g-csf) (5 pglkglday). sequential neurological examinations, nerve conduction studies (ncs), and quantitative vibration testing (qst) were performed during and after treatment. eighteen of 19 patients developed sensorimotor neuropathy and 3 developed myopathy. thirteen were symptomatic with numbness or weakness and 17 had abnormal results on neuromuscular examination. ncs showed absent or prolonged h-reflexes (14), reduced peroneal motor amplitude (14), reduced sural sensory amplitude (13), and myopathic motor unit potentials in proximal muscles (3). qst results were abnormal in 7 of 15 tested patients. muscle biopsy specimen in a patient with myopathy showed features of a toxic myopathy. the neuropathy was worse with higher cumulative dosages of taxol (>600 mg), with higher single doses of taxol(>300 mg/m2), or with a preexisting neuropathy. we conclude that sensorimotor neuropathy and myopathy are dose-limiting neurotoxicities of combined cisplatin and taxol use, now that neutropenia can be controlled with neuropathy and myopathy g-csf. central nervous system lymphoma casilda balmacedz and lisa deangelis, new york, ny ally periventricular and may seed the csf by direct growth through the ependyma. we reviewed the csf profile of 83 non-acquired immunodeficiency syndrome (aids) patients (pts) with pcnsl. all pts had lumbar puncture (lp) and 46 had multiple samples from an ommaya reservoir. definite lm involvement was identified with a positive csf cytology, lymphomatous lm infiltration on a surgical specimen, or mri with gadolinium showing lm tumor. probable lm lymphoma was diagnosed in pts with suspicious or atypical csf cytology. there were 41 women and 42 men with a median age of 57 (range 20-81 yr). at diagnosis, mean white blood cell count was 49/mm3 (range 0-5,5 10); mean lumbar csf protein was 103 mgldl (range 3-1,893); and mean ventricular csf protein was 32 mgldl (range 4-265). glucose was always normal. nineteen of 57 pts sampled had oligoclonal bands, and 42/65 had elevated pz microglobulin. at diagnosis 43 (52%) had an abnormal csf cytology: 22 positive, 16 suspicious, and 5 atypical. one pt had pathological infiltration of the lm and 1 had lm tumor on spine mri for a total of 45 (54%) pts with definite or probable lm lymphoma. in 43 pts with abnormal cytology, the abnormality was found in 30143 (70%) lps and 32/55 (58%) of the ommaya and ventricular specimens. in 8 pts the lumbar cytology was the only abnormal specimen despite multiple ventricular samples, and in 10 only the ventricular csf was abnormal. thirty-six of 83 (43%) pts developed recurrent tumor afrer treatment. forty-two percent (15136) of all patients with relapse had lm recurrence. lm recurrence was accompanied by brain recurrence in 9 pts, systemic in 1, ocular in 1, both systemic and ocular in 1, and isolated in 3. at diagnosis 59/83 patients received treatment directed against the lm. of these, 8 (14%) had meningeal recurrence whereas 7 of the 24 (29%) patients who did not receive this treatment had lm recurrence. lm involvement by pcnsl is frequent, may be missed on a single csf sample, and requires specific therapy at diagnosis. sixty-three solid cancer patients with a single brain metastasis were prospectively randomized for neurosurgery and radiotherapy combined (arm 1) or radiotherapy alone (arm 2). they were stratified for lung or nonlung cancer and for active versus stable or absent extracranial disease. world health organization performance status was 9. age, sex, performance status, and location of brain metastasis were divided evenly over both groups. one-month mortality was 7% in arm 1 and 6% in arm 2. median survival of 11 months after combination therapy was significantly better compared to 6 months after irradiation alone ( p < .04). it made no difference whether they had lung or nonlung cancer. the largest difference between both treatment arms was observed in patients with stable or absent extracranial disease (12 vs 7 mo, p < .02). when systemic disease activity was present, median survival was 5 months irrespective of treatment arm. functional independent survival was 1 to 2 months shorter than overall survival and was significantly better for patients with stable extracranial disease after combined therapy. multivariate analysis showed that age was also an independent prognostic factor. patients older than 60 years had a hazard ratio for dying of 2.8 (p. 004). we will detail the type and pattern of neurological complications in t-cell non-hodgkin's lymphoma (nhl), and review how they differ from those associated with b-cell nhl, and the lymphomas in general. this study is the first step in a process to characterize these tumors to determine if special staging or cns prophylaxis are indicated in any of the subtypes of t-cell lymphoma. we recently have encountered 5 women with breast cancer and an unusual sensorimotor neuropathy. the neuropathy was the major clinical problem. in 4 women the initial symptom was severe itching, 3 generalized and 1 first localized to the involved breast and then generalized. all developed distal extremity numbness and burning that very slowly progressed proximally, and in 2 became generalized. four complained of painful muscle cramps in the extremities ( 4 ) and jaw (1). all had mild extremity weakness, distal (5) and proximal ( 1 ) . three women developed symptoms up to 21 months prior to cancer diagnosis, 1 shortly after diagnosis, and 1 5 years after diagnosis. four women had disease confined to the breast and regional lymph nodes, and 1 had metastatic disease in remission. although annoying, symptoms were generally not disabling. three women stabilized or had slight improve-associated with breast cancer ment with cancer treatment, and 2 continue to gradually progress while in cancer remission; 1 required a cane to ambulate after 9 years due to sensory ataxia. one who developed cancer relapse had concurrent neurological relapse. one woman treated with high-dose immunoglobulin did not improve. none had significant weight loss. laboratory abnormalities included elevated erythrocyte sedimentation rate (28-60) in 3, antinuclear antibody 1:40 in 1, csf with lymphocytic pleocytosis (7-14 white blood cellslmm) in 3/ 4 and elevated protein (5 1-97 mg/dl) in 414 available. emgi ncv showed mild sensory-to-motor polyneuropathy in 314 available. none had detectable antibodies against peripheral nerve or dorsal root ganglia. the etiology of sensorimotor neuropathy in these patients is unknown, but it may represent a distinct paraneoplastic syndrome that can herald the onset of, and parallel the course of breast cancer. our objective was to determine whether ceramide induces differentiation of anaplastic glioma cells. sphingomyelin hydrolysis resulting in ceramide production has been linked to differentiation of leukemia cells. t9 rat anaplastic glioma cells, seeded at 2 x lo4 cells per well, were grown in serum-a glioma cell line program and abstracts, american neurological association 287 free media. on day 4, cells were photographed, scored for processes longer than one cell body, and counted. c2 ceramide changed plump cells to flattened cells with many long processes: ceramide treatment increased the percentage of cells with processes from 22 2 4% (sd) to 49 * 12% (n = 4, p < 0.01). control cells grew to 6.3 x lo5 cells/well 2 0.6 x lo5 cells; ceramide-treated cells grew to 1.6 x lo5 ? 0.6 x los (n = 4, p < 0.0005). although one ceramide analog reproduced the c2 ceramide-associated changes, the optical isomer of this analog did not, demonstrating stereospecificity. cerarnide did not decrease cell viability by trypan blue. ceramide inhibits proliferation and induces process formation in a glioma cell line, causing it to assume a more differentiated phenotype. cerarnide or its analogs represent possible future therapeutic agents that would inhibit the growth and affect differentiation of anaplastic gliomas. [bashir, mod pathol 1990; 3(4) :429-434)). this is similar to the pattern seen in ebv-infected human b cells and unlike the uniform latent infection seen in burkitt's lymphoma. we tested the hypothesis that long-term passaging of ebv-immortalized human b cells in immunodeficient mice leads to emergence of a uniform nonlytic pattern of ebv infection associated with appearance of the malignant profile. ebv-infected normal human b cells were serially passaged intracerebrally in severe combined immunodeficient cb17 mice (5 x 10' cells per mouse, 5 mice per passage for a total of 10 passages). frozen mouse brain sections from each passage were stained with vca antibody (ebv lytic cycle) and hybridized with biotinylated bamh1-w sequence of ebv. all injected animals developed tumors as previously described (bashir, lab invest 1991; 65(6):702-709) . tumor cells continued to express vca and showed latent and lytic hybridization patterns with bamh,-w after 10 passages despite exhibiting monoclonality (surface immunoglobulins) and random chromosomal changes. lytic infection of immortalized b cells with ebv is stable, resembling brain lymphomas in aids, and unlike the latent infection seen in burkitt's lymphoma. a previously healthy 73-year-old man developed diplopia and incapacitating, diffuse weakness over a period of 6 weeks. examination showed a "one-and-a-half'' syndrome of horizontal gaze paresis, patchy severe weakness with atrophy and fasciculations, absent tendon reflexes in the legs and right biceps, and decreased vibration sense in the feet. csf contained a mild pleocytosis, elevated protein, and oligoclonal igg bands. electrophysiological testing indicated a generalized sensorimotor axonal neuropathy with diffuse denervation. small-cell lung carcinoma was diagnosed by bronchoscopy. prednisone produced mild subjective improvement. chemotherapy was begun but the patient developed fatal septicemia. serum was negative for anti-hu or anti-gm1 with paraneoplastic encephalomyeloneuritis antibodies. serum and csf contained high titers of igg antibodies reacting specifically with a protein antigen of approximately 130 kd in immunoblots of human cerebral cortical neuronal nuclei or of human purkinje cells. this pattern of autoantibody reactivity was not present in sera from any of 37 other patients with small-cell lung carcinoma, 17 of whom had paraneoplastic encephalomyeloneuritis and anti-hu antibodies, nor was it present in many patients with other neurological disorders. the patient's serum has been used to probe a human cerebellum expression library and to isolate a cdna clone that is being characterized. acute encephalopathy is the problem in 17% of neurology consultations reported at mskcc. we studied 94 patients (5 1 prospectively and 43 retrospectively) to determine clinical findings, causes, and outcome. fifty-five were women and 39 were men, and the average age was 63 years. all patients had cancer: lung (20%), gastrointestinal tract (19%), breast (12%), and others (49%), forty-two patients (45%) were delirious on admission and delirium developed an average of 12 days later in 55%. encephalopathy occurred postoperatively in 24%. symptoms included confusion (92%), lethargy (59%), agitation (5 1 %), hallucinations (29%), and seizures (10%). signs included deficits in attention (44%), memory (385%), language (15%), lateralizing signs (50%), and asterixis (33%). the average mini-mental status test (mms) score was 12 (30 = normal). a single cause for delirium was found in only 4% of patients with an average of 4 etiologies per patient. metabolic abnormalities were found in 89% of patients, and were a primary cause in 44%; disseminated intravascular coagulation contributed to delirium in 11%. cns metastases were found in 32% and were a major cause of delirium in all. fifty percent of the patients had fever/ systemic infection, but sepsis was present in only 4%; only 1 patient had cns infection. medication contributed to delirium in 97% but was a primary cause in only 29%. the 30-day mortality rate was 3 1 % and delirium improved in 68% (average mms = 23). patients with cancer have multiple, potentially treatable causes of delirium. delirium is associated with a high death rate, though patients generally improve. radiation therapy for brain tumors d. w. dodick, b. mokri, k. k. unni, g. m. miller, and e. g. shaw, rochester, m n osteosarcoma in a previously normal bone is a rare but recognized remote effect of radiation therapy. any bone in the field of radiation can be affected. involvement of cranial bones is exceedingly rare. we could identify only 4 patients (2 men and 2 women) with postirradiation osteosarcoma of the calvarium seen at the mayo clinic over a 50-year period, from 1931 to 1991. all had received radiation for brain tumor, osteosarcoma had appeared in the field of radiation in all, the interval from radiation therapy to the appearance of sarcoma ranged from 7 to 23 years, and diagnosis of sarcoma was confirmed histologically in all cases. the patients' age at the diagnosis of the brain tumor ranged from 18 to 41 years. the nature of the brain tumor was unverified in 2 cases, was a low-grade ependymoma in the third case, and a pilocystic astrocytoma in the fourth case. one patient is still alive 12 months after the diagnosis of the sarcoma. she received chemotherapy and subsequently underwent resection of the osteosarcoma. one patient died postoperatively after partial resection of the sarcoma. the other 2 patients died 7 months and 15 months after the diagnosis of the osteosarcoma despite additional radiation therapy in the former and aggressive chemotherapy in the latter. element-la2 fusion gene as a potential marker of neural tumor differentiation lawrence recht, chiffon wu, and louis j. degennam, worcester, ma inducing cancers to differentiate into more benign differentiated tumors represents a novel oncological strategy. to establish a model that would permit assessment of this phenomenon at a molecular level, we created and have partially characterized a murine neuroblastoma line that has been stably transfected with a synthetic fusion gene containing the promoter element of the rodent synapsin i gene (synapsin i regulatory element isre)). in vivo, this promoter directs the neuron-specific expression of the synapsin i gene in normal adults. the gene also is expressed in varying amounts in neuronal tumors including neuroblastoma. in the synthetic fusion gene, the sre has been linked to the lacz gene that encodes bacterial p-galactosidase. a simple histochemical assay for p-galactosidase therefore provides a specific marker of the expression of the fusion gene. our preliminary experiments as of this writing have shown that it is possible to detect p-galactosidase activity in the transfected neuroblastoma cells both in vitro and in transplanted tumors. it appears possible therefore that this transfected neuroblastoma cell line can provide a useful model system with which to assess the effects of differentiation therapies. larger lesions (>18 cm2), and larger midline shifts (>4 mm). twenty-eight of 36 (78%) patients with prior has had bt has compared to 25 of 75 (33%) patients without prior has. in 8 patients, their bt h a was similar to their previous ha but was more frequent or severe. we conclude that has in bt patients are common but usually not severe. nausea, vomiting, an abnormal neurological examination, or a change in prior headaches warrant further investigation. cairncross and macdonald showed that procarbazine, lomustine, and vincristine (pcv) are effective for recurrent anaplastic oligodendrogliomas (ao) (ann neurol 1988; 23:360-364) . pcv now has a major role in management of all forms of oligodendrogliomas (0), but the biological basis for this response is unknown. to evaluate one subset of possibilities, we studied 14 patients (6 ao, 8 0) with a ct method that permits measurement of blood-to-tissue transport (kj, tumor-to-blood transport (k2), and vascular volume (v,) (ann neurol 1991; 30:581-587) . pcv was used to treat 11 of the 14 patients. k, (~1 grr-' min-') values were highly variable for whole tumor, ranging from 1.49 to 14.37 (mean 4.87 k 4.17) with no difference between a 0 and 0. k2 and v, were also highly variable. k, of tumor-free brain was 1.40 to 2.69 (mean 1.89 ? 0.50). in comparison to malignant astrocytomas, which have a mean k, in the range of 21.0 with some as high as 33.9, a 0 and 0 appear to be much less permeable. this suggests that the efficacy of pcv may be due to factors other than capillary transport, such as tumor-cell sensitivity. frameless stereotactic localizer gene h. barnett, donald w. komos, and charles p . steiner, cleveland, oh extent of tumor resection has been shown to correlate with prognosis in malignant gliomas. although frame-based stereotactic techniques can provide information regarding tumor margin, they are often unwieldy and require expensive and elaborate computing systems. a frameless stereotactic neurosurgical localizing system was designed that overcomes these liabilities. this armless, frameless, stereotactic pointing device provides real-time three-dimensional localization information during operation. in addition to assisting in placement of a trephine craniotomy, it allows volumetric resection of the tumor with virtually complete excision of even large irregularly shaped tumors. mean error on localizing a point in space using this system has proven to be less than 2 mm. a technical description of the system as well as surgical results are presented. to investigate the effect of age on response rate to chemotherapy and time to progression (ttp) and death ('itd) in patients with recurrent astrocytomas and malignant astrocytomas, we reviewed case records and scans of 143 patients who received chemotherapy at the university of michigan with bischloroethylnitrosourea or procarbazine. three age groups were studied: (1) <39 yr (n = 64); (2) 40-60 yr (n = 56); (3) >60 yr (n = 23). tumors were grouped as grade 2r+ 3 (recurrent grade 2 plus grade 3, n = 72) or grade 4 (n = 7 1). serial computed tomographic or magnetic resonance scans were analyzed in a blinded fashion and graded as progressive disease (pd), stable disease (sd), or partial response (pr, >25% decrease in size). the pr rates for the 3 age groups were 58%/32%/0% for grade 2r+ 3 tumors ( p = 0.023) and 40%/10%/5% for grade 4 tumors ( p = 0.011). median 'itp was 3112316 weeks for grade 2 r + 3 and 221 16/10 weeks for grade 4. median ltd was 53/48/19 weeks for grade 2r+ 3 and 36/31/24 weeks for grade 4. we conclude that age is an important prognostic factor with respect to likelihood of response to chemotherapy, duration of response, and survival irrespective of grade. cheryl p. harris and kurt a. jaeckle, salt lake city, ut intravascular malignant lymphomatosis (iml), a b-cell lymphoma confined to small venules and capillaries, often presents with neurological symptoms. this disease is uniformly fatal (5-month mean survival); no successful treatment has been identified. we observed marked reproducible neurological improvement after plasmapheresis in a 43-year-old woman with iml. presenting with a cauda equina syndrome, she progressed over 1 year with neurological, hepatic, and hematological disease. persistent laboratory abnormalities included a high sedimentation rate (140 mm/hr), coagulopathy, hemolytic anemia, and elevated liver enzymes. extensive evaluations for infectious, autoimmune, and neoplastic processes, including bone marrow examination, were inconclusive. because of neurological progression, empiric therapy with high-dose steroids followed by cyclophosphamide was initiated without response. plasmapheresis (250 ml/kg in 6 exchanges) effected resolution of encephalopathy and normalization of the coagulopathy and sedimentation rate. neurological progression recurred within 2 weeks of pheresis; 6 repetitive courses reproduced neurological response. finally, progressive dementia ensued, and a decision was made to cease pheresis; the patient died 5 days later, 16 months after presentation. autopsy disclosed diffuse intravascular cd-20 positive malignant lymphoma cells in small vessels of all organs. although the mechanism is unknown, the serendipitous discovery of response to plasmapheresis in this patient warrants further consideration. morphine is an effective analgesic in the rat after injection into a number of discrete brainstem regions, including the periaqueductal gray (pag), the locus coeruleus (lc), and the nucleus raphe magnus (nrm). early work with morphine gray and the nucleus raphe magnus established the existence of synergy between the brainstem and the spinal cord in rats. more recently, studies from our laboratory revealed synergy between two brainstem structures, the pag and the lc. in the current study, we explored the analgesic interactions between the pag and the nrm using indwelling cannulae. first, we established morphine dose-response curves and calculated the ed,, independently in the pag (1.9 pg) and the nrm (2.5 pg). we then simultaneously injected various morphine doses into both regions. injecting morphine at 1 pg into either the pag or the nrm did not elevate tailflick latencies above baseline values. however, administered into both regions simultaneously, the 2 1-pg doses produced an 80% maximal response, corresponding to more than a threefold increase of baseline latencies. a fixed morphine dose of 1 pg in the pag shifted the morphine dose-response curve fivefold in the nrm (ed,, 0.5 pg), whereas a fixed nrm dose of 1 fg shifted morphine's dose-response in the pag approximately twofold. together, these results clearly show synergistic interactions for morphine between the pag and the nrm. the presence of synergistic interactions between brainstem nuclei as well as between the brainstem and the spinal cord underscores the complexity of opioid analgesic systems. p244. the glutamate uptake inhibitor ~-trans-2,4-pyrrolidine dicarboxylate is neurotoxic in neonatal rat brain john d. e. barks and faye s. siloerstein, ann arbor, m i important evidence of the neurotoxicity of endogenous glutamate (glu) in mammalian brain was provided by the observation that dl-threo-3-hydroxyaspartate, a high-affinity glutamate uptake (hagu) inhibitor, was neurotoxic in adult rodent striatum (j neurochem 1985; 44:247) ; however, the absence of neurotoxicity in neonatal brain was interpreted as evidence that immaturity of glutamatergic innervation limited the potential role of endogenous glu as a neurotoxin in the immature brain. yet, considerable data provide indirect support for the hypothesis that glu can be neurotoxic at this stage. to resolve this issue, we assessed the neurotoxicity of a novel, selective hagu inhibitor, ~-trans-2,4-pyrrolidine dicarboxylate (l-pdc) (j med chem 1991;34:717), in postnatal day (pnd) 7 rats (n = 8). l-pdc (ph 7.4) was stereotaxically injected into right anterior striatum (str) (568 nrnol, n = 2) or through dorsal hippocampus into posterior str (568 nmol, n = 4; 150 nmol, n = 2). animals were killed 5 days later, and neuropathology was assessed in cresyl violet-stained sections. after anterior injections, focal neuronal necrosis was evident in dorsal str; high-dose posterior injections caused prominent hippocampal lesions with pyramidal layer thinning and focal necrosis in dorsal thalamus, while 150 nmol produced small foci of pyramidal cell loss. in both groups, focal cortical necrosis and callosal cysts were apparent adjacent to the injection track. l-pdc-induced brain injury provides direct support for the hypothesis that endogenous glu may be neurotoxic in the developing brain. (sax et al, ann neurol 1991; 30:311a) . the signs and symptoms of 7 of these patients lessened for 12 to 22 months. furthermore, a patient with a severe oral-lingual biting dyskinesia improved when taking doses up to 300 milligrams per day for 4 months. we noted no-significant adverse reactions, although 4 patients had mild but labile elevations in sgop and sgpt. one patient receiving opioid analgesics for pain inadvertently failed to discontinue the naltrexone but noted no reduction in the pain-alleviating effects of the analgesic. although hyperkinesia, especially of midline functions, as well as quality of life improved for the hd patients, their cognitive deficits remained unaffected. these observations suggest that chronic naltrexone is a safe and effective agent to treat chorea, dysphagia, and oral dyskinesia in hd for periods longer than a year. furthermore, they indicate that naltrexone can be effective in ameliorating oral-lingual biting tardive dyskinesia. these findings support our previous hypothesis that endogenous opioids play a role in rhe modulation of the dopamine system in hyperkinetic stereotypic movement disorders. a. jon stoessl, elizabeth szczutkmuski, and hanna fydvszak, london, ontario, canada we previously have demonstrated (psychopharmacology 1989; 98:372-379 ) that intraperitoneally (ip) administered cholecystokinin (cck)-8s suppresses vacuous chewing mouth movements (vcms, a putative mode1 of tardive dyskinesia) in rats exposed to chronic neuroleptics. as cck is not thought to cross the blood-brain barrier in significant amounts, its site of action in this paradigm is unclear. other behavioral and neurochemical effects of ip cck are blocked by vagotomy. male sprague-dawley rats were administered fluphenazine decanoate (flu; 25 mg/kg im) or its vehicle every 3 weeks for approximately 20 weeks. cck (10, 20, or 50 ng intracerebroventricularly) had no effect on neuroleptic-induced vcms. another group of neuroleptic-treated rats was subjected to bilateral subdiaphragmatic vagotomy or a sham procedure. cck-8s (10, 30, or 50 pg/kg intraperitoneally) suppressed neuroleptic-induced vcms in shamoperated animals, which confirmed our previous results. in vagotomited animals, chronic flu failed to induce vcms and cck was without effect in vehicle-or neuroleptictreated animals. these data suggest that the effects of cck on flu-induced vcms may be mediated peripherally, and that vagal pathways may be important for generating this response. (supported by the ontario mental health foundation and the ontario ministry of health.) p247. excitotoxic amino acids are not involved in dopaminergic neurotoxicity of m p t p eldad mehmed, jutta rosenthal, and avinoam reches, petah tiqva, tel aviv, and jerusalem, israel the dopaminergic (da) neurotoxicity of 1-methyl-4phenyl-1,2,3,6-tetrahydropyridine (mptp) is mediated via its oxidation in cns to mpp + , which enters da neurons and poisons mitochondrial complex i. da neuronal damage induced by direct nigral mpp+ injection is prevented by pretreatment with n-methyl-d-aspartate receptor antagonists, which suggests that excitatory amino acids are involved in mptp toxicity. since local mpp + application may produce nonselective nigral damage, we examined whether excitotoxins have a role in toxicity of systemically administered mptp. c57 black mice were injected intraperitoneally, once, with mptp.hci(40 mg/kg) and decapitated 5 days later. groups of animals underwent the following pretreatments: (i) decortication 1 week prior to mftp; (2) intracerebroventricular injections of the excitatory amino acid receptor antagonists 2-amino-phosphonoheptanoate and d-glutamyl-glycine; and (3) intraperitoneal injections of the calcium channel antagonists nimodipine, diltiazem, and flunarizine 30 minutes prior to mptp. mptp produced marked striatal da depletions. decortication, destroying glutamatergic corticostriatal projections, intracerebral amino acid receptor antagonists, and systemic calcium channel antagonists did not protect mice against mptp toxicity; mptp-induced striatal da decreases were similar to those given the neurotoxin alone. this study suggests that excitotoxins are not involved in the mechanism of mptp toxicity. scopolamine-induced cognitive deficits k . j . meador, m . e. allen, p. franke, e. e. moore, and d. w. loring, augusta, ga a unique neurophysiological role for thiamine in cholinergic systems has been suggested. total thiamine content in cholinergic nerve terminals is comparable to that of acetylcholine, and the phosphorylation state of thiamine changes with release of acetylcholine. thiamine binds to nicotinic receptors and may exhibit anticholinesterase activity. based on these observations, we investigated the effects of pharmacological doses of thiamine on the cognitive deficits induced by the anticholinergic scopolamine in 13 healthy young adults using a randomized, double-blind, placebo-conrrolled, double crossover design. cognitive tests included the p3 eventrelated potential and free recall memory for a verbal paragraph. conditions included baseline (bl), thiamine 5 gm by mouth and scopolamine .007 mg/kg intramuscularly (b1 + scop), and lactose by mouth and scopolamine (plac + scop). testing was performed 3 hours post thiamine or placebo, and 1.5 hours post scopolamine. thiamine significantly reduced the adverse effects of scopolamine on p3 latency (f [i, 121 = 11.84, p 5 .005) and percent recall memory ( f el, 12) = 10.62, p 5 .007). means (+sd) and p3 latency (ms) were bl = 335 (24), b1 + scop = 360 (29), and plac neurol 1990; 27: 186-192) . we previously reported that cff improved in 11 of 17 ms patients (65%) given el-970 orally in divided daily doses ranging from 7.5 to 52.5 mg (stefoski et al, neurology 1991; 41:1344 -1348 . subsequent analysis revealed that in 14 of the 17 patients cff improvements and reversals followed in a phase-locked trend the rising and falling serum concentrations of el-970, including 3 patients whose changes remained below the 15% increase needed to qualify for the improved category. these results resemble the phase-locked effects of temperature on neurological function in ms. the cff changes, because they so closely reflect variations in serum concentration, suggest that el-970 tissue levels closely follow those in serum and that el-970 rapidly crosses the blood-brain barrier. efficacy of el-970 in ms is also predicted to have a close relationship to serum levels. p250. development of a n internal standard detectable by proton and phosphorus-3 1 nmr and hplc w. e. klunk, k. panchalingam, r. j . mcclure, and j . w. pettegrnu, pittsburgh, pa comparison of quantitative results from different analytical techniques can prove difficult due to the peculiarities of the particular techniques and the lack of a common standard applicable to all of the techniques. recently, both in vivo and in vitro nuclear magnetic resonance (nmr) have been applied to the quantification of a large variety of metabolites. although nmr can be applied to the study of living tissue, the question arises of how this technique compares with more traditional techniques such as high-pressure liquid chromatography (hplc). although this question can be addressed partly by studying perchloric acid (pca) extracts, it is difficult to directly compare this in vitro nmr data with results from hplc. to address this question, we have developed an internal standard that can be quantified directly by in vitro phosphorus-3 1 nmr, proton nmr, and by 9-fluorenylmethyl chloroformate (fmoc) derivatization followed by separation by hplc. a variety of aminophosphonic acids were studied by 3'p nmr, 'h nmr, and hplc. promising compounds were added to pca extracts of human brain. the optimal compound was found to be 3-aminopropylphosphonic acid (app, ho3p-ch2-ch,-ch2-nh2). app is easily detectable by all 3 techniques, falls well outside of the region of interest in phosphorus-31 nmr, and is well resolved by proton nmr at 500 mhz. it is easily separable from the phosphomonoesters and phosphodiesters observable by hplc and from the amino acids that occur in brain in significant concentrations. app appears to be a useful internal standard in the study of phosphorus and amino acid metabolites by in vitro 31p nmr, 'h nmr, and hplc. theories of sentence comprehension hypothesize at least a grammatical component that establishes the relationship among words in a sentence, and a semantic component that determines the meanings of these words. we used positron emission tomography (pet) to quantify regional cerebral blood flow (rcbf) in 12 neurologically intact subjects during their detection of a letter target, a grammatical target, or a semantic target in the same written sentences. a mixedmodel analysis of variance (anova) revealed significant main effects for region (f e30, 210) = 19.32; p < .001), condition (f 12, 143 = 3 . 9 6 ;~ < .05), and a significant region times condition interaction ( f {go, 4203 = 1.46; p < .05), but there were no differences between individual subjects. subsequent anovas revealed increased rcbf in a unique set of brain regions during the subjects' response to a grammatical probe when compared to their response to a letter probe of the same sentences. a unique distribution of rcbf also distinguished response to the semantic probe from response to the grammatical probe and the letter probe. other brain regions apparently contributed to performance for several activation conditions. these findings support the hypothesized dissociation of specific linguistic components based on their unique cerebral topographical representation, and that a distributed network of brain regions subserves sentence comprehension. cerebral music processing-a comparison study of musically trained and naive individuals louis s. russo, jr, jachonville, fl we performed topographical mapping of brain electrical activity in 6 right-handed symphony musicians and 5 righthanded, musically naive individuals during various musical tasks; namely, listening to solo piano music, silent singing of familiar music, and silent reading of unfamiliar music. fast-fourier transform ( f r ) of electrocortical activity was carried out during task performance and the eyes-open resting state. data were analyzed using a computer-assisted model. increases in regional beta activity of greater than 3 standard deviations from the resting state were considered significant of activation. during audition, the musicians showed activation in the right posterior parietotemporal region; the naive showed no change from the resting state. during silent singing, the musicians showed bitemporal activation, r > l; the naive showed activation in the right mid-and posteriortemporal regions alone. during silent sight reading, the musicians showed a major activation in both temporal regions, l > > r, the naive showed only a marginal change in the posterior temporal-occipital regions. these data suggest that music processing is primarily a right cerebral function in untrained individuals and a bilateral function in musicians. musicians, in contrast to the naive, show progressively more left brain activation as task complexity increases. the present study analyzes language profiles in 10 patients who presented with primary progressive aphasia (ppa) without global dementia for at least 2 years. language and cognitive impairment were evaluated using the western aphasia battery (wab) and the mattis dementia rating scale (drs). expressive language disability with reduced speech fluency and anomia, but preserved language comprehension and nonverbal cognition, were typical features in early stages. spontaneous speech was significantly more impaired in ppa than in anomic aphasia after left-hemisphere stroke and in language impairment in probable alzheimer's disease (ad) ( p = 0.0004). the profile of aphasia suggests that ppa tends to affect anterior parts of the language-dominant cortex first. neuroimaging generally showed mild to moderate brain atrophy. in 2 patients atrophy involved especially the left frontal progressive aphasia cortex. follow-up examinations that were done in 7 patients 1 or several years after the first assessment revealed continuous, most often rapid deterioration of language impairment. two patients died 3 and 4 years after the onset of ppa. neuropathological examination showed ad in 1 patient and pick's disease in the other patient. beverly clarke, adrian upton, markad kamath, and helene griff;., hamilton, ontario, canada eight patients implanted with a cyberonics neurocybernetic prosthesis model 100 to stimulate the vagus nerve were assessed for changes in cognitive performance. the patients had complex partial seizures for more than 10 years, with more than 6 per month. patients were 34 years * 7.8 sd old. cognitive evaluation included response time to a randomized light signal appearing on a switch box (test a); test b, in which the signal appeared bilaterally; and test c, in which a response to the signal was required while the patient simultaneously ignored a second signal. data were collected and analyzed using an apple i1 e computer and switch pad. all patients were taking therapeutic levels of 3 anticonvulsant medications and dosages were constant. testing occurred 10 times during a day preoperatively (day l), 2 weeks postoperatively with the stimulator on (day 2), and 3 months after turn-on (day 3). patients were randomized into high-and low-frequency stimulation groups (hfg and lfg). hfg parameters were 30 hz, so0 msec pulse width (pw), and lfg 1 hz, 130 msec pw. examiners were blinded as to group. student's t-test analyses of mean differences between groups and individual measurements showed a significant difference between hfg and lfg for test c ( p < 0.05). lfg showed a significant improvement for tests a, b, c between day 1 and 2, and for test c between day 2 and 3. no group effect was seen between day 1 and 3 in the lfg. individual measurements showed improvement for test b ( p < 0.05) for the hfg between day 1 and 2, test b ( p < 0.0s) between day 2 and 3, and tests a and b ( p < 0.01) and ( p < 0.05) day 1 vs 1. the lfg group improved between days 1 and 2 and 2 and 3. between day 1 and day 3, the lfg showed improvement only for test b ( p < 0.001). chronic stimulation of the vagus nerve improves cognitive function in epileptic patients and this improvement is more marked with low-frequency stimulation. a. guidotti, and j. d. rothstein, bologna, itah, washington, dc, and baltimore, m d we reported idiopathic recurring stupor (irs) in a patient with stuporous episodes without known causes and reversed by flumazenil, a specific benzodiazepine (bz) antagonist. ictal plasmdcerebrospinal fluid (csf) showed increased bz-like activity (ann neurol, in press). recently, an endogenous bzreceptor ligand (endozepine [ez]) has been purified from mammalian brain with properties similar to diazepam. it acts like diazepam to potentiate gamma-aminobutyric acidmediated postsynaptic inhibition. we hypothesized that irs might be due to an excess of this substance. irs was diagnosed in 2 patients, 41 and 58 years old, who had recurring stupor or coma episodes lasting hours to days. ictal brain ct/mri, kidney, liver, heart, blood glucose, ammonia, and osmolality were normal. eeg showed fast 13-hz background activity while the patients were unreactive to stimuli, reversed by flumazenil. ictal serum or csf revealed an enormous increase of the ez in both patients, with levels as high as 400 nm, compared to 5 to 10 nm in control serum/csf. interictal csf or serum in irs contained ez levels similar to control csf and serum. irs may be due to excess ez. the cause for increased ez is unknown. parkinson's disease: evidence from word learning murray grossman, jenger mickanin, barbara schaefr, kris onishi, matthew b. stern, steven gollomp, and howard hurtig, philadelphia, pa several reports have suggested that patients with parkinson's disease (pd) have intellectual impairments in several domains such as memory, but few studies have explored difficulties in language processing. we investigated the ability of 20 nondemented pd patients with mild motor impairments to learn about the grammatical and semantic information represented in a new verb. the new verb was presented to patients in a sentence-picture matching context, and we probed their recall of the verb 10 minutes later. a sentence judgment task assessed grammatical knowledge by asking patients to judge the new verb, known verbs, and pseudowords used appropriately or incorrectly in a sentence. we found that 65% of pd patients were significantly impaired in their grammatical appreciation of the new verb (f [i, 331 = 17.03;p < 0.003). this was not related to their motor disorder or neuropsychological performance. a picture classification task used pictures illustrating specific aspects of the new word's meaning to evaluate semantic knowledge. pd patients were as accurate as controls at deciding whether a picture illustrated the meaning of the new verb (f (1, 331 = 0.lo;p > 0.10). only 1 pd patient (5%) had difficulty sorting pictures. selective difficulty recalling only grammatical aspects of a new word suggests that the word learning impairment in pd cannot be entirely explained by poor memory. instead, in agreement with other recent findings, pd patients may be impaired in some aspect of grammatical processing in language. we discuss the hypothesis that defects in the frontocaudate axis in pd underlie this impairment. neuropsychological performance on both verbal and nonverbal tasks is reported to differ between healthy men and women. some of these cognitive differences are postulated to reflect differences in interhemispheric and intrahemispheric cerebral organization. our preliminary study indicated that women with alzheimer's disease (ad) performed worse than men on a composite neuropsychological battery, even after effects of potentially confounding variables were considered (buckwalter et al, j clin exp neuropsychol 1992; 14:23) . to explore further the nature of gender-associated differences in ad, we analyzed data from a verbal and a nonverbal task (the boston naming test and drawings from the spatial quantitative battery supplement to the boston diagnostic aphasia examination) for 22 men and 23 women who met nincds-adrda criteria for "probable" ad. prior to ana-grip strength 9 kg [range 1.5-20 kg]). the electrophysiological examination showed improvement with reversal of conduction block in 3 patients and was unchanged in 4. an apparent response to the placebo was seen in 3 patients. improvement after ivig therapy was maintained for variable durations (3-20 wk) and reoccurred with subsequent infusions. an equally effective response was documented after infusion of a single ivig dose of 1 gm/kg. we conclude that ivig therapy is effective in some patients with cidp, even after long duration of illness. the best responses were observed in patients with recent relapse. a single high-dose treatment may be equally effective. the object of this study was to examine whether borrelia burgdorjeri antigens could be detected in csf in the absence of detectable antibodies to b. burgdorjeri (the etiological agent of lyme disease). osp a is a 31-kd antigen that is specific for 8. duvgdorferi osp a was probed using western (immuno) blot and specific mouse monoclonal antibodies. polyclonal lyme antibodies were detected in csf using standard micro enzyme-linked immunosorbent assay. seven patients had osp a in csf without detectable lyme antibodies. there were 3 men and 4 women aged 20 to 58 years (mean 38 yr). disease duration ranged from 2 weeks to 8 years. neurological syndromes included confusion with acute flulike illness, optic neuritis, hemiparesis with inflammatory brain lesion, encephalitis, headache with erythema migrans, bilateral facial nerve palsies, and encephalomyeloradiculitis. three patients had csf abnormalities. in 4 patients csf parameters were otherwise completely normal. possible explanations for undetectable csf lyme antibodies included early infection (3 patients), prior antibiotics (2 patients), and prior steroids plus antibiotics (1 patient). in 1 patient there was no obvious explanation. we conclude that osp a, a specific antigen of b. burgdorferi, may be present in csf without a detectable humoral response. the diagnosis of neurological infection with b. bwgdorjeri should not require a positive csf serology. mollaret's meningitis: demonstration by polymerase chain reaction a 29-year-old man was seen in september 1991 for his fourth episode of aseptic meningitis over a 4-year period. the episodes conformed to criteria for mollaret's meningitis as published by bruyn, straathof, and raymakers, and subsequently by others; they lasted about 1 week, and were characterized by fever, headache, meningismus, lymphocytic pleocytosis, elevated protein in cerebrospinal fluid (csf), and spontaneous resolution without residua. extensive prior evaluations had failed to uncover a cause. the patient was otherwise well and neither he nor his wife had any history of sexually transmitted diseases. suspicion of herpes simplex virus (hsv) arose due to a single transient, raised skin rash several weeks earlier that failed to yield virus on culture. the patient was treated with acyclovir, which resulted in rapid resolution of symptoms. though culture and immunological studies of csf and blood again were unrevealing, polymerase chain reaction (pcr) studies of csf confirmed the presence of hsv type 2. we suspect that herpes simplex virus is a more common cause of recurrent aseptic meningitis than current culture and immunological techniques would suggest. pcr offers increased diagnostic sensitivity for neurotropic viruses and should be considered in patients with recurrent meningitis of cryptic etiology. differentiation by inorganic lead: a role for protein kinase c j. lutewa, j. p. bressler, r. r. indurti, l. belloni-olivi, and g. w . goldstein, baltimore, m d microvascular endothelial function in developing brain is altered by inorganic lead. this may result from changes in protein kinase c (pkc) modulation. we examined the effects of inorganic lead on an in vitro model of neural endothelial differentiation. astroglial-induced endothelial differentiation into capillary-like structures was inhibited by lead acetate with 50% maximal inhibition occurring at 0.5 pm lead. inhibition was independent of effects on cell viability or growth. we examined the effects of lead on cellular pkc pools under conditions that inhibited capillary-like structure formation. membranous pkc increased in c6 astroglial and neural endothelial cells after exposure to lead acetate. exposing c6 cells to 5 p,m lead for 16 hours increased membranous pkc by 150% as determined by immunoblotting. membranous pkc increased in response to as little as 50 nm lead and saturated at 1 pm. phorbol esters were used to determine if pkc modulation was mechanistically related to lead's inhibition of capillary-like structure formation. 12-myristate 13-acetate (10 nm) inhibited endothelial differentiation by 65 * 5%, whereas 4-alpha-phorbol 12,13didecanoate was without effect. these findings demonstrate that inorganic lead may induce cerebral microvessel dysfunction by interfering with pkc modulation in microvascular endothelial or perivascular astroglial cells. w. f. brown, b. v . watson, j . garland, g . c. ebers, and n . desai, london, ontario, canada gait difficulties in multiple sclerosis (ms) are commonly accompanied by fatigue and dyspnea. possible explanations for the latter include weakness andlor dyssynergia of the respiratory muscles, including possible abnormalities in central pathways regulating respiration. this study examined central and peripheral motor conduction to the diaphragm in 15 ms patients whose gait was notably labored and accompanied by breathlessness. peripheral conduction was assessed by measuring the latency and size of the surface-recorded diaphragmatic maximum m-potential responses to supramaximal stimulation of the phrenic nerve in the neck, and central motor conduction by comparable measurements in response to magnetoelectrical stimulation over the vertex. peripheral motor conduction was normal. the most striking abnormalities were in central motor conduction. cortical stimulus-evoked diaphragmatic responses were absent on both sides in 3 patients, and unilaterally in l patient, whereas in 5 others the latency of the cortical stimulus-evoked response was increased and the size clearly reduced and entirely normal in only 3 patients. these studies show that central conduction program and abstracts, american neurological association 295 to the diaphragm is commonly abnormal and may play a role in the fatigue and dyspnea experienced by ms patients. six men (40-53 yr) developed myelopathy that progressed slowly over several months and was characterized by asymmetrical, incomplete spinal cord syndrome manifested at the sensory level at the trunk, mild spastic paraparesis, and urinary incontinence. the spinal cord lesions at appropriate levels were recognized by mri as enhancing lesions in 4 of the men. coxiella burnetii infection was confirmed in the blood of all patients by immunofluorescence microscopic assay (ifa) and transmission electron microscopy (tem). in 2 patients, we detected c. burnetti by tem and ifa using csf of the patients inoculated onto fresh peripheral blood lymphocytes. four patients who were treated with appropriate antibiotics responded with either partial resolution of symptoms or arrest of further neurological progression. in 3 patients the lesion was shown on mri to have decreased in size. in summary, we report 6 cases of transverse myelopathy associated with c. barnetti infection. this is the first report, to our knowledge, of coxiella-related chronic myelopathy. we present a series of patients with different labyrinthine lesions diagnosed by mri. twelve patients with sensorineural hearing loss were studied by gadolinium-enhanced mri, including 3-mm contiguous t1-weighted images through the labyrinth. ten patients had enhancement of the cochlea or vestibule, or both. all patients with cochlear enhancement had severe neural sensory hearing loss. all patients with vestibular enhancement had severe vestibular symptoms. the patients' final diagnosis included viral labyrinthitis (3 patients), syphilitic labyrinthitis (2 patients), bacterial labyrinthitis (1 patient), and vestibular neuromas (3 patients). one patient had an acoustic neuroma extending in the basal turn of the cochlea. the enhancement in patients with vestibular neuromas was brighter and there was slight mass effect in comparison with the patients with inflammatory labyrinthine lesions. one patient had hemorrhage within the vestibule from an adjacent temporal bone hemangioma. one patient with ct-proven cochlear otosclerosis had pericochlear areas of enhancement on gadolinium mri. mri can diagnose a variety of labyrinthine lesions that correlate very well with the patient's clinical symptoms. gadolinium should be used routinely in patients with suspected labyrinthine disease. the diagnosis of meniere's disease and endolymphatic hydrops remains a diagnosis of exclusion. few radiographic findings have been correlated with the clinical symptoms of this entity. we describe 9 patients with symptoms of hearing loss or vertigo, or both, who demonstrated enhancement of the endolymphatic sac on gadolinium-enhanced mri. no enhancement was noted in a series of 20 controls with no symptoms of hearing loss and vertigo. enhancement in the brain correlates with inflammatory or neoplastic conditions. we thus can speculate that enhancement of the endolymphatic sac reflects an inflammatory process in this location that may interfere with the normal resorption of indulin and secondary hydrops. in addition to excluding an acoustic neuroma and a labyrinthine schwannoma (which clinically may be confused with meniere's disease), contrast-enhanced mri may provide objective evidence in favor of labyrinthine hydrops. it was intermittent (62%) but progressive. the ha was mild to moderate in severity; it was the worst symptom in only 24 (459%) and the first symptom in 32 (60%) patients. has were worse in the morning in 19 (36%) and interfered with sleep in 17 (32%) patients. unlike true tension-type has, bt has were worse with bending over in 17 (32%), with valsalva's maneuver in 12 (23%), and nausea or vomiting were present in 21 (40%) patients. an abnormal neurological exam was found in 38 (72%) patients with has and 43 (74%) patients without has lyzing the effects of gender, we used a hierarchical regression procedure to control for possible effects of subject age, education, age at onset of dementia symptoms, dementia duration, and family history of dementia. significant gender effects were found for the verbal task ( p < 0.005) (mean boston naming test score of 2 1.4 for women and 34.4 for men), but not for the drawing task. we conclude that verbal abilities are more severely affected in women than in men with ad, a difference that may in part reflect premorbid gender-associated differences in cerebral hemispheric organization. hemispatial placement is known to affect line bisection in patients with neglect. whereas placing stimuli in neglected space increases bisection error, placing stimuli in nonneglected space attenuates error. the effects of hemispatial placement on line bisection were examined in 4 patients with chronic neglect (over 5 months after stroke). all patients had large (frontotemporoparietal), unilateral, right-hemisphere lesions. each patient bisected lines of different lengths (24, 26, 28 , and 30 cm) in 3 hemispatial conditions (30 cm left of midline, midline, and 30 cm right of midline). like previous reports, when patients bisected lines in left hemispace, a consistent (20/24 trials) left-sided neglect was observed (2.6 cm). however, when lines were bisected in center space, misbisections occurred on either side of the midline; and, unlike previous studies, when lines were bisected in right hemispace, a consistent (20/24 trials) right-sided neglect was observed (2.0 cm). the magnitude and directional consistency of line bisection errors were significant. neither visual field defects nor limitations in reaching accounted for the results. recovery in chronic neglect may involve a realignment of limited attentional resources favoring the body's midline. consequently, performance in both hemispatial fields can be biased toward midline, resulting in neglect of opposite directions. despite agreement that depression is the most common neuropsychiatric symptom associated with multiple sclerosis (ms), many aspects of this emotional change are unclear. one of the more controversial issues concerns the relationship between severity of ms and depression. this relationship is used to evaluate whether depression is an integral or reactive symptom of ms. examination of this relationship is complicated by the presumed overlap between somatic features of depressive and neurological symptoms in ms. to clarify this situation, we examined the relationship between severity of ms and 4 categories of depressive symptoms using the beck depression inventory (bdi). eighty-nine patients and 47 normal controls were examined. for certain comparisons, patients were classified as mild (extended disability status scale of 0-2) or moderatelsevere (3) (4) (5) (6) (7) (8) . results indicated that total bdi scores and the depressive symptom categories (mood, self-reproach, vegetative, and somatic features) were elevated in patients with ms, but the extent of these elevations was not related to severity of disease. these results suggest that depression in ms is not a simple reaction to physical disability. furthermore, clinical examination of depressive symptoms is straightforward and not confounded by severity of ms. neurological involvement in wegener's granulomatosis was studied in 324 consecutive patients diagnosed at the mayo clinic. one hundred and nine patients (34%) had neurological involvement. peripheral neuropathy was seen in 53 (16.4%), cranial neuropathy in 2 1, external ophthalmoplegia in 16, cerebrovascular events in 13, seizures in 10, and miscellaneous involvement in 25. the mean age and sex ratio did not differ in those with or without neurological involvement. among the patients with peripheral neuropathy, 42 had multiple mononeuropathy, 6 had distal symmetric polyneuropathy, and 5 had unclassified peripheral neuropathy. multiple mononeuropathy was one of the major presenting symptoms in 8 patients. kidney involvement was significantly higher in the patients with peripheral neuropathy compared to those without it (p < 0.001). among the cranial nerves, the second, sixth, and seventh nerves were affected most frequently. multiple cranial nerves were affected in 8 patients. unusual neurological manifestations among the miscellaneous group included spastic paraparesis, temporal arteritis, homer's syndrome, and papilledema. this is the first comprehensive study on the frequency and distribution of neurological involvement in wegener's granulomatosis. chronic inflammatory demyelinating polyneuropathy: a double-blind placebo-controlled crossover study treatment with high-dose intravenous human immunoglobulin (ivig) has been reported to be beneficial in some patients with chronic inflammatory demyelinating polyneuropathy (cidp), yet most observations have been nonblinded. we examined the effect of ivig therapy in 10 patients (6 men, 4 women) with cidp in a double-blind, placebo-controlled crossover study. disease was chronic progressive (n = 5 ) or chronic relapsing (n = 5) and of variable duration (4 mo to 2 1 yr). the diagnosis was confirmed by electrophysiological (10) and nerve biopsy (7) examinations. the trial consisted of two 28-day periods each. patients were randomly treated with ivig (0.4 mg/kg/day) or placebo on 5 consecutive days and followed. function was assessed by a quantitative neurological disability score, functional grade, grip strength measurement, and electrophysiological examinations at the beginning and end of each treatment period. with ivig therapy, significant improvement was documented in 7 / 10 patients (improvement in neurological disability score mean key: cord-005646-xhx9pzhj authors: nan title: 2nd world congress on pediatric intensive care 1996 rotterdam, the netherlands, 23–26 june 1996 abstracts of oral presentations, posters and nursing programme date: 1996 journal: intensive care med doi: 10.1007/bf02316512 sha: doc_id: 5646 cord_uid: xhx9pzhj nan we present the results of a prospective population-based audit of paediatric intensive care activity in two comparable communities with markedly different delivery systems. in the trent region of the uk (4.2 million people), children receive intensive care largely without the supervision of a paediatric intensivist in a variety of hospitals, few of which have designated paediatric intensive care units (picus). critically ill children otherwise receive intensive care in children's wards, special care baby units (scbus) or adult intensive care units. in the australian state of victoria (4.5 million people), children receive intensive care almost exclusively in one centre -a picu staffed by full time paediatric intensivists. the two regions are otherwise demographically comparable. in both groups, data were collected on all children admitted to an intensive care unit between 1/4/94 and 31/3/95 and children who received intensive care (defined by levels of intervention and nurse dependency) in other sites during the same period. values of each variable at first contact with the icu, and the highest and lowest values over the first 24 hours were recorded. the principal outcome was survival to discharge from the intensive care unit. severity of illness was assessed using pim (paediatric index of mortality) and prism. risk-adjusted mortality was compared using flora's z test and logistic regression. the rate of utilisation of intensive care (>1000 admissions in each region) were similar. there was some variation in case mix between the two groups, but crude mortality rates were similar (7.4% in trent and 6.6% in victoria). however severity corrected data and other measures of picu performance were dramatically better in' the centralised delivery system. the substantial excess mortality in the trent region provides strong evidence for the benefits of centralisation of paediatric intensive care services. there are considerable difficulties in evaluating the efficiency and effectiveness oflcare in children presenting with respiratory failure during acute medical illness. optimal outcomes for such episodes include survival and the shortest length of stay (los) in intensive care with negligible risk of readmission. we have tried to determine whether or not the time course of acute severe medical illness with respiratory failure is predictable. study i (n=1000): a retrospective study of intubated and mechanically ventilated children (>28 days, <17 years) with acute severe medical illness. measures: diagnosis, intensive care los in calender days, and survival. results: the underlying diagnosis fell within one of three broad categories: respiratory disease (n=521, mortality 19.2%), central nervous system (cns) disease (n=342, mortality 38.7%), and systemic inflammation or multisystem (sims) disease (n=137, mortality 47.5%. the los in survivors was: respiratory -median (interquartile range) 8(4-16) days, cns 4(3-8) days, £p,4£ 5(7-g) days. 5:i'~'-+cen diag~,~is-rc!ated-grnnp~ (drgs) were identified (8 respiratory, 5 cns, 3 sims disease) and each have been characterised by mortality and los. study ii (n=300): a prospective study of patients supported by the hypothesis that los for the above drgs was predictable (compared with study i data). in certain instances attributable causes for variances in los were identified: e.g. disease severity, timing ofdrug therapy, and associated disease. with daily paediatric risk of morality scoring within each drg, four profiles of instability were identified. discussion: the time course of acute severe medical illness with respiratory failure is predictable and variance may be attributable to specific care or diagnostic factors. we are now developing a means of linking drg-specific clinical care pathways with an integrated computerised decision support and education facility at the bedside. the objective of this open, prospective study was to assess the relation between basic patient characteristics as well as effectiveness of treatment on the one hand and resource utilization in pediatric intensive care on the other. as universal, non-monetary indicators of resource utilization we used the therapeutic intervention score system (tiss) and length-ofstay (los), from which indicators for total resource utilization per admission (tisstot) and average daily resource utilization (tiss-mean = tisstot/los) were obtained. overall 593 admissions, totalling 3130 days, were included. mortality was 8.4%; non-survivors accounted for 14.1% of overall resource utilization. in non-survivors, both total resource utilization per admission and average daily resource utilization were higher, whereas los was not different from survivors'. severity of illness, surgical status, the presence of substantial chronic comorbidity, emergency admission and transfer from another hospital constituted the major predictive determinants of tisstot (r:=0.19) and tissmean (ra=0.45) in multiple regression analysis (p<0.0001). hence these indicators are appropriate non-monetary measures of resource utilization, a considerable proportion of which are determined by a concise set of basic clinical characteristics. subsequently we analysed the relation between effectiveness of care and resource utilization by assessing severity of illness corrected mortality in low, medium and high resource users, respectively. these 3 categories were delineated by percer/tiles of resource utilization (< p20, p20-ps0, > ps0). despite on average long los and high resource utilization in the high risk group, a relatively low standardized mortality was found, probably warranting prolonged intensive treatment in this patient category. summary: objective:the primary purposes of intensive care are to provide treatments to patients with life-threatening physiological dysfunction or to monitor and observe patients perceived to be at significant risk of dying. this collaborative study was performed to describe our patients and their outcome. in order to improve our results we tried to identit~ high risk groups, patients and methods: 13 picus entered the study, the data included all the admissions with >12 hs. during a 60 days period between the l°june and the 30th september 1993. the records included: age, sex, weight, mechanical ventilation (mv), post-operative condition (p.op), malnutrition, diagnosis, length of stay, prism score and outcome. student test, mann-whitney or wileoxon were performed for univariate analysis. fisher exact test or chi square for dicotomic variables. risk group analysis was performed by logistic regression, odds ratio and 95% confidence interval. results: 650 patients entered the study. mean age was 47.6 months (ds hh¢# 60) and median 18 months. we found significant statistical differences in calculated ,is observed mortality rate comparing malnourished with euthrofic patients; mechanical ventilated (mv) with non mv patients. no differences in ter ~,h of stay or di~ noses were found. effect of the un sanctions on the morbidity rate araong the iraqi small children ( below 3 years old of age ) in bagdad. abdulsamad a.abood / institute of medical technology, bagdad. meningitis is essentially a childhood disease (i). the risk of infection are increased by powerty and overcrowding (7). the impah'ed immunity may be an important pathogenic factor underlying the susceptibility to infections in undernourished subjects (5). in general, malnutrition is a man made disease and it begins quite in the womb and ends in the grave (i). 1918 small children, below 3 years of age were admitted to the pediatric hospital in washash with meningitis over 4 cold months in i994, in contrast to only 176 child admitted with meningitis over the same period in1989. all of the children who admitted in 1994 were frankly undernourished, 45% of them were infected with enterobacteriae, because they were exposed to faulty hygiene and lack of asepsis. these facts showed precisely that our small children had suffered at most from the un_ sanctions against iraq, because of food, milk and drug shortage, since 4 years which had resulted a severe undernutrition among them, which impaired their immune status. m wells, of riera-fanego, j lipman. baragwanath intensive care unit, university of the witwatersrand, south africa. background the use of prism or other scoring systems in the icu is of great importance for evaluating the efficacy and efficiency of a particular icu, the prism score was developed and validated in the usa and europe but has recently been shown to be inaccurate in a south american population, a south african population as well as several european studies. part of the poor performance of the prism score is as a result of differences in the case mix between the reference population and other paediatric icus. since scoring systems should generally be used only in populations similar to the reference population from which the prediction model was developed, a modification of the prism score is necessary to improve its discriminatory ability in a wide range of patient groups, aim to improve the predictive power of the prism score in a south african paediatdc icu population. patients & methods we analysed prism, demographic and clinical data collected prospectively from 1528 consecutive paediatrie icu admissions. the prediction of actual mortality by prism was evaluated by standard statistical methodology (goodness-of-fit test and receiver operating characteristic (roc) analysis), the components of the prism logistic regression equation (prism score, operative status and age) and the 14 physiological variables making up the prism score in addition 10 new variables analysed (nutritional index, the need for inotropes and institution of mechanical ventilation) were subjected to discriminant analysis to determine their association with outcome. results the goodness-of-fit test showed a significant failure of prism to accurately predict mortality over a wide range of expected mortality (chi2[8] = 195, p = 0). prism underpredicted mortality at lower prism scores, but overpredicted mortality in patients with high prisms. similarly roc annysis indicated apoor predic~jve power (az = 0.73 ± 0.01), with an area under the curve significantly less than that for the prism reference population (p = 0), prism showed equally poor discriminatory function at all age groups and diagnosfic categories. '~mth the addition of an index of nutrifional status (proportional weight-far-age), and indicators of early respiratory and cardiovascular failure to the logistic regression formula, and a recalibration of the acute physiological score component, the roc can be improved to 0.83 ± 0.02, with a good fit described by the goodness-of-fit test (cn218] = 3, p = 0.89). discussion the prism score is not accurate in our patient population has been recalibrated in view of the poor discriminatory function that we have shown. part of the inaccuracy derives from the different demographic characteristics of our icu population and a different pattern of diseases. in addition to assessments of acute physiological aberrations, an assessment of nutritional status and early respiratory and cardiovascular failure significantly improve the discriminatory ability of the prism score, these parameters have been devised with a view to improving the accuracy of prism in our population, while not decreasing its accuracy in icus similar to the reference population. in interviewing parents regarding how physicians have communicated bad news, the response i have received is that it has not infrequently been done without appropriate care, understanding and compassion. personal experience and the lessons learned from parents, chaplains and others who deal extensively with these situations have provided me with an approach that has been supportive, compassionate, and caring. an especially difficult communication situation for the intensivist occurs when the parents have to be informed of the death of their child. for the parent, death is the hardest loss of all -the ultimate unalterable loss. circumstances surrounding the death are an important consideration (e.g., a fatal crash caused by a drunken driver, a prolonged illness, a suicide, aids). each produces a different grief reaction. the physician needs to inform parents of their child's death sympathetically coming right out with the news and leaving details until later. allow pauses and time for the paren~ to express sorrow and grief, the best communication may be thoughtful silence and a tender touch. there is disbelief that this happened. it is necessary to repeat oneself. acknowledgment of the parent's "feeling terrible" and the physician's acknowledgment of how terrible he/she feels that the life of the child could not be saved is an important first step in the parent's dealing with this tragic loss. with prolonged resuscitation, it is helpful to have a member of the icu team talk to the parents while the resuscitative efforts are ongoing so that the parents are not left unsupported at this time. a progress report should be delivered in a caring, lucid, and sensitive.manner, indicating that every effort is being made to save the life of their desperately injured child. after a child has died, it is helpful to the family if the physician maintains some contact with them. this should take the form of follow-up telephone calls at approximately 6, 12, and 24 months. this can help to screen for depression in the parents. in giving bad news to the family and making every effort to support them through this tragic time, it is necessary to remind oneself that the intensivist has personal needs for dealing with grief and will also require support to pass through this stage. direct evidence that child mortality is lower in specialist pediatric icus comes from 3 studies. a study in oregon (ccm 1981; 19:150-9) found that mortality adjusted for severity of illness was 102% of expected in 3 pediatric units and 139% of expected in 71 general units (p<0.05). a study in holland (ccm 1995; 23:238-45) found that mortality in high risk patients was 85% of expected in 6 tertiary pediatric units, and 143% of expected in 4 nontertiary units (p<0.05). a third unpublished study, has found that children in victoria (who almost all receive intensive care in a pediatric icu) have a much lower standardised mortality rate than children in the trent region of the uk (where many children receive intensive care in adult icus). there is indirect evidence that icus looking after many children are likely, on average, to perform better than icus looking after few children: numerous studies in many specialities have found that units looking after many cases of a particular disease have better results than units with few cases. see luft hs, "hospital volume, physician volume, and patient outcomes", happ, 1990; and farley d, medical care 1992; 30:77-94. compared to general icus, medical and nursing staff in pediatric icus are likely to be better at looking ~fter children, and plcu rmos have greater skills in pediatric intubation, ventilation, iv drip insertion and drug doses. picus are more likely to have appropriate equipment to manage children -especially for uncommon but life-threatening situations. icus in pediatric hospitals are more likely to have physicians and surgeons with pediatric expertise available for consultation at all times. the american academy of pediatrics, the society of critical care medicine, the british paediatric association and the australian nh&mrc have all said that children should receive intensive care in'specialist pediatric units. the weight of authoritative opinion, and direct and indirect evidence is strongly in favour of looking after children in dedicated pediatric icus. neurological deficit showed higher cbf values (125.7/115.2 ml/100g/ rain.) than the 11 patients with good outcome (mean cbf 1 17.5 sd +8.1; cbf 2 19.9 sd _+9.1 ml/100g/rain}. discussion: in asphyxia decrease of ph is due to reduced tissue oxygenation and indicates the severity of metabolic derangements. co2reactivity in newborns with perinatal asphyxia correlates with the lowest ph and therefore may reflect severity of asphyxia. continuous monitoring of cerebral activity is carried out in our unit on all admissions at risk of cerebral dysfunction, a number of monitors are commercially available and we report our experience with the cfam2 which provides in addition to amplitude integrated eeg analysis, continuous raw eeg display and frequency distribution. bilateral recordings are commenced as soon as possible and continued while clinically indicated. forty one children ranging in ages from 4 weeks to 16 years were monitored for periods from 3 hours to i0 days, diagnoses included traumatic brain injury (11), sepsis/meningitis/encephalitis (1 t), status epilepticus (8) and miscellanous others (11). results are tabulated below. patients 13 12 16 status epilepticus 10 4 1 * beta activity 1 8 15 * background voltage 10 3 1 * < i o/zv 2 or more of above 12 2 1 * (*z2 p < 0,001) asymmetry developed in 4 children, all of whom died. positive predictors of good outcome included a mean background activity of >10zzv, the presence of faster frequencies (usually 13) in response to sedative drugs and the absence of seizures. all monitoring is performed by the picu staff and increasing expertise in interpretation has resulted in earlier therapeutic and diagnostic interventions. regional it was previously found that histamine, a vasoactive mediator, accumulated in brain compartments (kov~ics et al 1995 neurosci lett 195:25) , and antihistamines prevented brain edema formation (dux et al. 1987 neuroscience 22:317) in asphyxiated newborn pigs. in the present study we investigated the effect of intracarotid histamine injection on the blood-brain barrier (bbb) permeability, left internal carotid artery of 30 newborn pigs (4-8 h; 1,180-1,530g; ketamine anesthesia, 10 mg x kg 4) was catheterized through the external branch and different doses of histamine (0, 10 -6, 5xi0 -6, 10 -5, 5x104, 104 m, respectively, in 6 groups of animals; n=5 in each) diluted in 1.0 ml isotonic saline was injected into the vessel through 1 rain. bbb permeability was determined for a small (sodium fluorescein, sf, 376 da) and a large (evans blue/albumin, eba, 67 kda) tracer (2%, 5 mlxkg 4, 30 rain circulation time for both dyes) concomitantly in frontal, parietal and occipital cortex, hippocampus, and periventrieular white matter both on left and right sides 1 h after the challenge. then, intravascular dyes were removed by perfusion and bbb permeability for both tracers was quantified by fluorescence spectrophotometry (wavelengths for excitation and emission were 440 nm and 525 nm for sf; and 620 nm and 680 nm for eba, respectively). histamine injection, in doses higher than 10 .6 m, significantly (p<0.05; kruskal-wallis one way anova on ranks followed by dunn's test) increased bbb permeability for both tracers in each brain region. changes in left hemisphere were more intense (p<0.05) than those in right one after the doses of 5xi0 -6 and 10 -5 m in each region, i0 4 m histamine administration induced similar edema in both sides. increased intracarotid histamine levels resulted in a dose-dependent vasogenic brain edema formation. histamine might have a pathogenetic role in neonatal hypoxicischemic cerebral injuries. supported by otka f-12722 and h-u.s,-jfno.392, $162 in coma caused by traumatic brain jnjury, an indication of the likely outcome is provided by the best motor response to pain in the first .$ hours after the insult. in a study in our picu, the proportion of children who died or had a severe disability was 100% in 35 who had no response to pain, 40% in 47 with an extensor response, 14% in 64 with a flexor response, and 1% in 61 who localized in response to pain. the long term outcome of traumatic brain injury appears to be worse in children <4 years old. other risk factors in traumatic brain injury are absent basal cisterns, midline shift or subdural haemorrhage on ct scan (or loss of grey-white differentiation in nontraumatic injury); or an intracranial pressure >30 mmhg despite hyperventilation, mannitol and barbiturate infusion. apart from brain death, there are two findings implying such a poor prognosis that consideration should be given to stopping treatment: first, after traumatic injury, the absence of any motor response to painful stimulus in the cranial nerve distribution (providing drug effects and a post-ictal state have been excluded); and second, in acute brain injury from trauma, infection, hypoxia, or ischaemia, the b{lateral absence of short-latency somatosensory evoked potentials (providing brain stem haemorrhage, subdural and extradural effusions, and decompressive craniectomy have been excluded). in children over 2 months of age, recovery from prolonged coma or a vegetative state is exceedingly rare when more than 12 months have elapsed after traumatic brain injury, and when more than 3 months have elapsed after nontraumatic injury. overproduction of nitric oxide (no) via an inducible isoform of" no synthasc (inos) produces profound vasodilatation in adult septic shock. high nitrate levels have been reported in hypotensive children with sepsis syndrome ]. cardiovascular collapse is a prominent feature of severe meningocoecai disease (mcd). however, systemic vascular resistance (svr) was slightly higher in a group of non-survivors ~ and the rote of no in ivicd remains unclear. children with a presumptive diagnosis of mcd were enrolled. parental consent was obtained. blood was drawn on admission and 12hrly thereafter. plasma was separated immediately and stored at -80°c. the final concentrations reported represent the product of nitrite and nitrate (nox). nox was measured spectrophotometrically using the greiss reaction. 21 children were studied (median age (range); 27m (5-203)). the diagnosis of mcd was confirmed in 18 children, 12 of whom had a glasgow meningococcal score (gms) of" ~8. in this group with severe mcd there were 3 deaths. peak nox was significantly higher (,.54(27-78) vs 96(50-363)nmol/ml, median) and systolic btood pressure was significantly lower in children with severe mcd than mild mcd (p<0.05. wilcoxon rank test). there was a significant correlation between peak nox and gms (spearman's rank correlation r=0.6 (p=0.01)) and prism (r=0.6 (p:0.01)). nox production from adm.ission onwards was also higher in the severe mcd group (p:0.002, kmskal ~wallis). we have demonstrated that plasma nox levels are elevated in children with mcd, correlate directly with the severit 3' of disease and are inversly related to systolic blood presssure. similar to hypotensive septic syndrome, mcd appears to be associated with an up-regulation of the l-arginine-no pathway.. non-survivors with mcd have higher svrs and may be relatively hypovolaemic. in our group of severe mcd there was a significantly lower systolic pressure and increased no formation. excess inos expression at different stages in mcd may contribute to the pathology of the disease. the identification of agents which can boost and/or inhibit no reiease may therefore represent different treatment strategies for mcd. u. merz, th. peschgens, g. kusenbach, m. b6hle, h. h6rnchen in this controlled, prospective study 30 ventilated premature infants with a birth weight < 1250 g were randomized to receive treatment with dexamethasone (dex) either on day 7 of life or on day 14 of life. dex was given over 16 days tapering from 0.5 mg/kg/day to 0.1 mg/kg/day. the infants treated with dex on day 7 of life could be weaned earlier from the ventilator -in median after 14 days (range 10 -34) versus 24 days (range 8 -44) in the [ate treatment group (p = 0.01). the need for supplemental oxygen was shorter in the early treatment group -in median 24 days (range 10 -50) versus 40 days (range 10 -70) (p = 0.2, ns). the incidence of chronic lung disease was lower in the early treatment group -6 of 14 infants (42.9%) versus 10 of 16 patients (62.5%) (ns). to evaluate the long-term efficacy of early dex treatment we performed a respiratory function test in the age of 3 -6 months using an infant whole body-plethysmograph. the intrathoracic gas volume (itgv), the airway resistance (r.w) and the airway conductance (gaw) were measured and no significant differences could be detected between the groups. the frequency of adverse effects due to dex therapy was found to be without significant differences between the early and the late treatment group. we conclude that early dex treatment had short-term improvements in pulmonary outcome in our study population, long-term efficacy however, remained unproven. several factors contribute to the development of chronic lung disease (cld) in premature infants including structural immaturity of the lung, mechanical ventilation, and oxidative stress. reactive oxygen species are formed during normal cellular metabolism but they are generated in higher concentrations during inflammation or inhalation of high oxygen concentrations. to study the relationship between increased oxidative stress, antioxidants and the development of cld we examined 102 ventilated premature infants with birth weights below t500g. 32 infants developed severe chronic lung disease of prematurity (cld), defined by radiological signs of cld and an increased oxygen requirement at a postconceptional age of 36 weeks, and 29 infants had moderate cld with an increased oxygen requirement on day 28 but not at an age of 36 weeks. ventilator settings (fio2, peak inspiratory and mean airway pressure) and the incidence of early-onset-sepsis were significantly higher in the severe cld group than in infants with moderate cld or without cld (n=41) during the first week of life. plasma concentrations of the two antioxidative substances bilirubin and uric acid (ua) were comparable in all groups during the first days of life. however, on day seven bilirubin and ua were significantly decreased in the plasma of infants with severe and moderate cld compared to the non cld group (p<o.001). there was no difference between both cld groups. in serially obtained tracheal aspirate fluids (taf) malondialdehyde (mda) was measured by hplc as an indicator of lipid peroxidation reflecting oxygen injury of the lung. ua was found in higher concentrations in taf than bilirubin. ua has been proven to be a potent antioxidant, capable to react especially with hydroxyl radicals and hydrochlerous acid, which play an important role in the induction of lipid peroxidation. infants with severe cld had significantly higher mdnua ratios in taf from day 5 to 14 compared to the non-cld group (p<o.01). mdnua ratios in taf of infants with moderate cld were significantly higher from day 7 on but still lower than in the severe cld group. in addition, the ratio oxidized / reduced glutathione was significantly increased in taf of infants with cld compared to infants without cld between day 5 and 14. the data support the hypothesis that an imbalance of oxidative stress and antioxidant defense contributs to the onset of cld at the end of the first week of life. introduction. rocuronium bromide (roe), a neuromuscular blocking agent with an onset time dose to that of succinyleholine l'z, has been studied in american society of anesthesiologists' physical status (asa) i or ii pedlatrie patients under non-critical elective conditions. there is a paucity of studies looking at the pharmacodynamics of roc under emergent conditions, involving pediatric patients who are asa iii or iv, without the use of adjuvant inhaled anesthetics ~. methods. with approval of our committee on clinical investigations (irb), roe 1.2 mg/kg was administered to 15 asa iii/iv pediatric intensive care patients (age 40 days to 23 months; m:f=8:7) on intravenous sedation. the time to reach 25% a~d 10% of b~elinc tetanie stimulus response was recorded using a r.elaxogra'ph/qmt-100 nerve stimulator/recorder (datex, helsiaki). depth of clinical relaxation at the 25% level was recorded. results. the time from rapid bolus to 25% was 25.4+12.6 see with a range of 10-50 see; and to 10% was 30.1+17.6 see, with a range of 10-69 see. at the 25% level, excellent clinical relaxation was seen. conduslon. in critically ill children, use of roe at 1.2 mg/kg produces rapid onset of neuromuscular blockade and excellent clinical relaxation, such that roe should be considered for rapid sequence intubation. int anesth clin. 1995;33(1):39-60. anesthesiology. 1994;81 (5) computed tomography of the chest (ct) in mechanically ventilated adults can detect intrathoracic pathology not appreciated on chest radiographs (cxr) and influence intensive care management. no such data exists for ventilated children. aims: 1) to assess if ct provides additional information over cxr regarding extent and nature of intrathoracic disease in ventilated children. 2) to determine whether such information alters clinical management, inclusion criteria :10 ventilated children with cxr changes inconsistent with their respiratory status underwent ct if either a) pao2:fio2 ratio <30 and/or mean paw>15 cm h20 or b) there was an unexplained increase in ventilatory requirement. methods : high resolution ct was performed in 3 patients and spiral ct in 7 patierits, to ensure minimal transport related morbidity, patients were transferred to the ct scanner by a specialised mobile intensive care team. results: in 2/10 patients ct demonstrated greater extent of disease than appreciated on cxr but did not significantly alter clinical management. in 7/10 patients ct provided additional information regarding the nature of disease present, in 2/7 children this involved a further diagnosis and in 5/7 children the exclusion of a suspected pathology. new information led to a positive therapeutic intervention in 2 children, prevented inappropriate manoeuvres in 3, and had no significant effect on acute management in 2 children. conclusions: initial data suggests that in a selected group of mechanically ventilated children chest ct can add to the sensitivity and specificity of intrathoracic diagnosis provided by the chest radiograph and directly influence acute management. case selection criteria and choice of the most appropriate protocol requires further study. pressure control ventilation (pcv) utilizes a decelerating flow pattern which may improve gas distribution and lead to alveolar recruitment. in contrast, volume control ventilation (vcv) employs a constant flow. in children, the effects of pcv as compared to vcv are unclear. the purpose of this study was to determine how these two modes compare in terms of dynamic compliance (cdyn). peak iaspiratory pressure (pip), and mean airway pressure (paw) at equivalent minute ventilation. methods: sixteen infants and pediatric patients ranging in age from 1 day to 13 years were studied. diagnoses included ards (6), postoperative cardiac surgery (7), head trauma (1), and resfrictive lung disease (2). patients were randomized to pcv (9) or vcv (7). initial measurements of gas exchange (abg's) and respiratory mechanics (ventrak, novametrix medical systems) were obtained after a 20 minute stabilizadon period. respiratory mechanics included pip, peep, paw, delivered tidal volume, and cdyn (avolume/apressure). the patients were then crossed over to the alternate mode of ventilation holding delivered tidal volume, peep, inspiratory time, minute ventilation, and fio2 constant. data were collected after 20 minutes, in each mode the absence of intrinsic peep was confirmed. to assure that the measurements were not affected by changes in clinical status, the patients were returned to the initial mode of ventilation and measurements repeated (final) . patients were ventilated with a siemens 900c or sv300. reselts: data were analyzed using 2-way analysis of variance with repeated measures. ~ <0.05 vs. vcv) vcv pcv ~ initial ] final ! cdljn 3.5_+0.7 4.3_+0.8 * 3.7_+0.6 3.9_+0.7 i , pip 32+1.0 30l-_t.0 * 31_+1,0 31+-1,0 paw 9.2_+0.6 10.9i-_0.7 * 9.7+0.7 10.0-!-_0.8 pao2 97_+14 92+-10 87_+9 97_+14 discussion: at the same minute ventilation, the decelerating flow pattern of pcv resulted in a 23% increase in cdyn and an 18% increase in paw while decreasing pip by 6%. the lack of a significant change in oxygenation may be a result of the limited time in each ventilator mode as well as the inclusion of patients with both normal and abnormal lungs. there was no significant difference in initial and final measurements indicating patient stability. the beneficial effects of iecre~l~iug cdyn and paw while decreasing pip indicate that pcv may be a preferable mode of ventilation in patients with lung injury. further randomized studies examining the effect of pcv on respiratory outcome measures in pediatrics are indicated. prolonged positive pressure ventilation following repair of cdh is associated with a high prevalence of iatrogenic lung injury, in our unit dudng 1981-1990 314 late deaths after repair of cdh were due to chronic lung disease. since 1990 babies requiring assisted ventilation for more than 7days following surgery were transferred to a cnep chamber to limit lung injury. cnep of -6cm of h20 was combined with positive pressure ventilation via an endotracheal tube dudng the transition phase. immediate reduction of peak inspiratory and positive end pressures were possible and following extubation respiratory support was maintained by cnep v~th appropriate inspired oxygen. overall outcome: [1981] [1982] [1983] [1984] [1985] [1986] [1987] [1988] [1989] [1990] n=68 deaths before surgery (%) 11 ( ecmo during 1990 -1995 /16 who were ventilated for more than 7 days received cnep and there were no deaths and no chronic lung disease in that group. cnep assisted ventilation may be an important management option for babies who require prolonged respiratory support to avoid the adverse effects of chronic positive pressure ventilation, introduction so far 2 modes of liquid ventilation (lv) have been used in experimental animals and, exceptionally, in humans: 1. total liquid ventilation (tlv)-functional residual capacity (frc) is filled by perfluorocarbons (pfc), and slow tidal volume (tv) breathing is performed by pfc. 2. partial liquid ve,0ti,la~ion (page) -only frc is filled by pfc. gas tv is delivered by conventional mechanical ventilation (cmv), high frequency jet ventilation (hfjv) or high frequency oscillation (hfo). the aim of our study is to present our limited experience with page in newborns and infants. page was used in two groups of infants: 1, in 2 infants with brain death before disconnection from cmv, because recipients for organ transplantation were not available. these infants have relatively normal lungs (fio~ less than 0.4). infants stayed on page for 1 hour, during that period no ventdator manipulations were made. after page, infant were switched to cmv for next 6 hours. 2. very critically diseased infants with ards (rds) -2 on ecmo more than 5 days, 1 before cannulation for ecmo, 4 on hfo because of intractable respiratory failure, preoxygenated rm 101 (miteni, italy) was used in the doses up to 40 ml/kg intratrachealy. blood gases and parameters of pulmonary mechanics were followed (dynamic compliance -c dyn, airway resistance -raw, bicore monitor). page was combined with no inhalation (5-80 p.p.m, in 2 infants). in both groups ad hoc an approvement from e local ethical commission and informed parental consent were obtained. in the first qroud with relatively normal lung parameters of oxygenation drops after pfc instilation intratracheally and stayed depressed for 4-6 hours. slight pco2 retention occured in both cases during page. c dyn increased almost double during page period, raw drops transitorily after pfc instilation but in 10 minutes they were identical like in prepage period, parameters of oxygenation (peo2/fio2) after 4-6 hours after page improved and were better than in prepage period. after that time infants were disconnected and died. in the second group no improvement of oxygenation was seen in one ecmo baby, in spite ()f transient improvement of c dyn. in the second ecmo baby, oxygenation improved and flow of pump could be decreased by more than 20%. none of these babies, however, survived, improvement was only transient in spite of repeated dosis of pfc. in these babies serious problems were to maintain the adequate frc by liquid, because of severe air leak, in 5 babies on hfo/hfjv with severe ards/rds the improvement of oxygenation were seen in all the cases immediately after pfc instiletion for the period of 4-5 hours. after that period, pfc dose had to be repeated. two babies of this group survived. conclusion. page is going steadily from tabs to clinical practice. it is simple, could be performed anywhere, cheaper than tlv. however, because liquivent -perflubren (aliance pharmaceutical) is not available in europe, rm 101 of 82 (mitenti, italy) is the only solution, which could be currently used here. before the widespread use of page in clinics, liquid network among most nicus and picus must be built up, the criteria for page must be defined and ethinal-legal problems resolved as well. after resolution of these particular problems page can be life saving procedure for very special part of critically ill newborns end infants. catherine caronia, peter silver, laura nimkoff, cad quinn, jack gorvoy, and mayer san. division of pediartic critical care, medici,, schneider children's hospital, new hyde park, ny 11040, imroduetiun: cystic fibrosis (cf) patients awaiting lung transplantation present a therapeutic dilenuna when severe respir, aory decompemalion occurs, endotracheal intubation and mechanical ventilation is known to have no long term benefits and is associated with high morbidity and mortality. noninvasive respiratory support appears to be a beneficial alternative. methods: we instituted bipap (respironics, inc,, murrayville, pa) in 9 end-stage cf patients who were admitted to the pediatric icu with severe respiratory decompeusation. all patients were awaiting tung transplantation. after a control period, bipap was applied via a tight fitting nasal or facial mask, using the spo~aneous breathing mode, expiratory pressures were set at 4-8 cm hhzo. inspiratory pressures were started at 8 cm ~i o and increased in 2 cm i-i20 increments until the patient's respiratory comfort was achieved and substantiated by non-invasive monitoring. patients were instructed to use bipap during night sleep and whenever subjectively required, data are reported as mean _+ s.d. results: all 9 patiems utilized nocturnal bipap for 6-10 hours/day during a follow-up period of 2-19 months. compared to their pre-bipap status, the patiems' oxygen requirement and respiratory rate both oz~ cundusion: bipap tl~rapy improves the respiratory status of decompeusatir!g end-stage cf paacnts. it is well tolerated for long term use at home, and provides an extended period of respiratory comfort and stability for cf patients awaiting lung transplantation. l. bindl*, g. kiihl**, p. lasch***, appel**, j.m611er**** and the "arbeitsgemeinschaft ards im kindesalter" background acute respiratory distress syndrome (ards) is a therapeutic challenge in pediatric intensive care in view of the high mortality, in 1992 about 50 german paediatlic hospitals founded a working group aiming on collaborative clinical research in this field. aims and methods the aim of both a prospective and retrospective survey conducted in german pediatric intensive care units in 1993 was to accumulate data on the epidemiology, risk factors, natural history and treatment strategies in a large group of pediatric ards patients who were treated in the tt~ee year period from 1991 to 1993.all patients had acute bilateral alveolar infiltration of noncardiogenic origin and a po2~io2 ratio < 150mmhg. the influence of sex, underlying disease and single organ failure was analyzed using the fischer's exact test, the influence of additional organ failure on mortality was tested with the cochran-mantel-haenszet statistics. results 112 patients were reported giving an incidence of 7 cases per 1000 admissions to pediatric icus. median age was 24 month. in 43% of the cases, ards was associated with a pulmonary, in 39% with a systemic underlying disease. in 20% immunocompetence was impaired. mortality was 46% and not dependent on age, sex and triggering event. the number of associated organ failures, however, strongly influenced mortalib,. mortafity in immuno-compromised patients was 8 t %. the analysis of treatment modalifies employed in the patients revealed a lack of uniform therapeutic strategies. on the other hand, the patients were exposed to interventions not yet supported by controlled trials. conclusions the observation of the lack of uniform treatment strategies led to the elaboration of recommendations on ventilator therapy and patient monitoring within the working group. the data gathered in this survey provide the basis for the design of prospective multicenter studies urgently needed to evaluate innovative treatment modafities in pediatric ards. recurrent apnea and respiratory failnre due to severe lower respiratory tract disorders such as bronchiolitis or pneumonia are the most common reasons for mechanical ventilation during respiratory syncytial virus (rsv) infection. acute respiratory distress syndrome (ards) has been described as a complication of severe rsv infectionj in contrast to the low mortality rates associated with rsv infection (< 5 %), mortality rates in the range of 40-70 % have been reported in pediatric patients with ards. however, studies on ards are usually lumped in respect to causation and the disease course of rsv induced ards has not been previously studied. we examined the lung function abnormalities of 37 infants with rsv induced respiratory failure requiring assisted ventilation, measurements included respiratory mechanics, maximal expiratory flow-volume curves and lung volumes, ards was defined clinically using the criteria which were recently proposed by the american-european consensus conference on ards~: acute disease onset, pao2/fio~ ratio _< 200 mrn hg, bilateral infiltrates on chest radiograph and absence of clinical evidence of left atrial hypertension. we calculated the murray lung injury scores modified for use in pediatric patients 3 from total respiratory system compliance, radiographic findings, ventilator settings and blood gas results. we identified 10 infants with severe restrictive lung disease that fialfilled the clinical criteria fbr classification as ards. all had lung injury scores above 2.5 which is the recommended cut-off for a diagnosis of ards, twenty-seven infants had obstructive disease consistent with a clinical diagnosis of bronchiolitis. the ards patients were significantly younger, had a longer time of assisted ventilation (p <0.05) and a greater proportion of infants with preexisting illnesses (p=0.023, odds ratio =6.67) when compared to the patients with obstructive disease. with the exception of one immunodeficient patient, none of these infants died. given the low mortality despite a clinical picture of severe lung injury, there is evidence that rsv induced respiratory failure may represent a relatively benign cause of ards in pediatric patients, bachmann an audit of patients with severe acute bypoxic respiratory failure (ahrf) receiving highfrequency oscillatory ventilation (hfov) in our unit ( n=32, mortality 75%) revealed that sub-groups with severe underlying disease (n=14, mortality 100%)and those with mu~pie organ failure ( > 2 systems failing, n=7 mortality 100%) accounted for all the deaths beyond the neonatal period. v~ therefore hypothesized that in a modem paedistric intensive care unit (picu): a) children greater than one month of age with ahrf do not die in the absence of severe, pre-existing disease or multi-organ dysfunction syndrome, b) respiratory parameters alone will predict outcome poorly in ahrf. method prospect~/e sty/of all adm~ns to our tertiary picu. data it, citing the respiratory parameters (oxygena~n index [ol] , aiveolar-artedal oxygen tension gradient , pao2/fio2 ratio) were collected hourly from the bedside charts throughout admission. patients were included in the study if ahrf was present at admission either none or in combination with other organ dysfun~on. ahrf was defined as the acute (<48hour) onset of respiratory dysfunctk:~l with a pao2/fio2 ratio.< 200 for six consecutive hours dunng the first 24 hours of admission (with no evidence of left anal hypertension), x-ray review defined a sub-group of patients with acute respiratory distress syndrome (ards) by the presence of bilateral interstitial infiltrates. results to date 59 children (ages 1-168 months, weight 1.2-70 kg) have been admitted in ahrf. 18 of these also had ards. the overall mortality was 23.7% (14/59), and greater in the ards group than the non-ards group (10t18, 55.5% vs, 4141, 9.7%, p< o.01) . it was not possible to predict survivors from non-survivors on the basis of the seventy of the respiratory failure alone, the a-ado2 on the day of admission (best in 24 hours) was not significantly different between survivors and non-survivors: (mean, + sd)(174 mmhg +_108, vs 304 mmhg _+_156). kdl non-survivors were immunodeficient (n=8), previously extmrnsly premature infants (<28140),(n=3) or suffedng fcom chronic metabolic or gastrointestinal disease (n=3). no previously normal child died. conclusion the severity of respiratory failure does not allow predioljon of outcome in our patients. we believe that this reflects that modem picu is so effective at providing respiratory support that pre-existing pathology alone de~ prognosis. this suggests that an abnormally regulated host response or abnormal persistence of a pathogen may be required to induce lung injury of sufficient severity that the resulting respiratory failure cannot be supported in a modem picu. introduction: postural changes (supine to prone) is a therapeutic intervention that could be useful in children with adult respiratory distress syndrome. objective: to determine the effects of postural changes in the oxygenation of young children with ards. method,s: a prospective stud3," was performed in eleven subjects aged 6 to 120 months (mean=33) with the diagnosis of ardsreceiving vendlatory support. (mean peep and fio2 of 9 and 0.75 respectively). postural changes was performed every 8-12 hours, during a period of time ranging from 5 to 16 days. arterial blood gases were determined before and 30-60 n~n after the postural change, no modification in the mechattical ventilation other that changes in the fio2 were performed. the oxygenation was determined by the index pao2/fi02 (p/f). to study the differences between the oxygenation mean, before and after the postural changes the wilcoxon test for paired samples was used, results: 184 changes were performed (104 from supine to prone and 80 from prone to supine). a9% increased p/f ratio was obtained after the change from supine to prune. although, not all the patients receiving postural changes improved their p/f. six of them (group i) showed an improve in the p/f when changed from supine to prone, returning to their base line when positioned from prone to supine. no improvement on the p/f was observed in the remaining 5 subjects (group ii)after postural changes (table 1) . during the maneuver no complications were observed. two patients had a pneumothorax, not related with the postural change. conclusions: postural changes (supine to prone) is an easy way to improve oxygenation in some children with ards. change to prone change to supine introduction: the common noninvasive diagnostic efforts to identify possible obstruction of the intrathorucic airway, are of limited value. invasive procedures such as bronchoscopy and bronchography may also be noncontributory and entail risks. we evaluated the usefulness of 3d-ct in the diagnosis and management of pediatric patients with suspected intrathoracic airway obstruction (itao). methods: we used a diagnostic algorithm (see diagram) in patients with suspected itao resulting in respiratory distress. three-dimensioual imaging of the tracheobronchial tree was reconstructed, following high speed spiral ct scan, by specific computer software (advantage window computer work station, general electric, milwaukee, wisconsin). non-ionic contrast medium was injected, in some patients, to delineate the intrathoracie large vessels.. results: eight patients were studied. in 5 patients the 3d-ct revealed intrathoracic airway abnormalities. these patients underwent further invesive studies which confirmed the following diagnoses: 2 patients had bronchomalacia, 1 had bronchial stennsis due to a dilated pulmonary artery mad 2 patients had subglottie stenosis extending to the thoracic cavity. three patients had no significant disruption in the configuration of the tracheobronchial tree and thus did not require invasive diagnostic procedures. conclusion: computer reconstruction of three dimensional images of the tracheobronehial tree is a safe and reliable diagnostic tool for itao. ards and ecmo; preliminary data from a randomized clinical trial. j fackler, c steinhart, d nichols, d bohn, m heulitt, t green, l martin, k newth, m klein, j ware. many suggest ecmo be considered experimental for ards and undertaken only with careful data collection and reporting. a mtflticenter pediatric rct is in progress to determine whether 1) ecmo and/or 2) permissive hypercapnia, offer significant advantage for the treatment of ards. methods: all patients aged 2 wk to 18 yr (without congenital heart disease) are eligible for study. data collection begins when a patient receives at least 50% oxygen and a peep of 6 cm h20 for 12 hours (stage t). if the predicted mortality reaches 60% within 7 days (stage 2), eligible patients are asked for written consent for randomization. patients are excluded from randomization with significant chronic lung disease, immune compromise, cardiac disease; or profound acute central nervous system damage. the prime outcome variable is survival. at the studies onset, 400 pts were estimated to be required so that 65 pts were randomized per arm. results: 131 patients are enrolled from 9 centers. data are complete on 85. 66 patients never reached stage 2 (i.e. 60% mortality). 47 patients improved and 19 died. of the latter, 13 had randomization exclusion criteria even if stage 2 was reached. 19 patients reached stage 2. 11 had exclusions from randomization and all died. eight patients (4 survivors were eligible for randomization; consent was obtained in no case. two patients received ecmo. overall survival is 60% (51/85). in patients without randomization exclusions, survival is 77% (34/44). morbidity m survivors (discharge -admission popc or pcpc score >_2) was seen in none of the 4 stage 2 surviviors and 15% (7/41) of those who reached only stage !. conclusion: the rct requires completion. the records of hospital in-patients at king faisal specialist hospital and research center who received external cardiac massage as part of their cardiopulmonary resuscitation were reviewed. success of resuscitation was analyzed as (1) short term (restoration of spontaneous circulation), and (2) long term (discharge from hospital). of 234 such patients, 171 (73.1%) survived the initial resuscitation, and 66 (28.2%) were discharged. success of outcome was not related to age, location of patient, time of day, or rhythm at arrest, including asystole. longer resuscitation time was associated with less chance of restoration of spontaneous circulation (p<0.001), but not associated with hospital discharge rate. results for patients with congenital heart disease were similar to those with other medical or surgical conditions. in this series, 36.7% of ward in-patients survived to discharge, compared to two 5"*;'~r ~r;~'9 ,.,.'her,, the r-e~ult~ were 0c/ "'~d ~, ~,°(. overall, 39 7% of patients who survived the initial resuscitation were discharged from hospital. where resuscitation continued for more than 30 minutes, 18.9% of patients had tong term survival. outcome from asystole was no worse than for other cardiac rhythms, we believe that previous reports of poor outcome from asystole in pediatric cardiac arrest should noi influence decisions to stop resuscitation for pediatric in-patients prematurely. successful restoration of spontaneous circulation with long term survival can be achieved after prolonged resuscitation. abdelmoniem~ lindsey jahusou~,mariano fiallos, university of florida, 820 prudential drive, suite 203 jacksonville, florida 32207 usa central acidosis is well recognized as a marker of inadequate tissue perfusiou, and ventilation. however, obtaining central venous blcod is difficult and fraught with complications in the child undergoing cardiopuimonary resuscitation. intraosseous blood may be used instead of central venous blood to judge ph and pcoz during short durations of cardiopulmonary resuscitation and during hemorrhagic shock. the purpose of this study is to compare the ph and pcoz status of intraosseous and central venous during prolonged cardiopulmonary resuscitation after fluid and drug infusion. we hypotbesized that there would be no difference in ph and pco2 values of simultanecusly obtained intraosseous and central venous blood samples. eighteen (18) introduction: cardiopulmonary arrest (cpa) in children is usually preceded by a deterioration of cardiac or respiratory function due to sepsis, dehydration and hypovolemia. early recognition of clinical and laboratory signs followed by immediate intervention are essential for prevention of cpa. the purpose of the present study was to identify factors which contributed to high rates of mortality from cpa in patients admitted to a paediatric intensive care unit (p1cu). methods: a prospective study was done of all non-surgical patients with cpa who were admitted to the picu, hospital baca ortiz, quito ecuador from january to october 1995. clinical and laboratory variables before and after admission to the picu, time from hospital admission to picu admission and the pediatric risk of mortality score (prism) were recorded on a questionnaire designed specifically for this study. results: of the 70 non-surgical patients admitted to the picu, 14 (20%) were admitted after developing cpa on the general pediatric wards. mean age was 16 + 19.1 months, with 13 of 14 patients under 20 months of age. initial diagnoses upon picu admission included meningitis (n=3), respiratory failure (n=2), congenital heart disease (n=2), severe neurological impairment (n=2), end stage neoplastic disease (n=2), hypovolaemic shock (n=l), peritonitis (n=l) and sepsis (n=l). mean time from hospital admission to p1cu admission was 16 _+ 19.2 hours. the mean prism score upon hospital admission was 30+ 13.7 (score > 20 = > 50% mortality). 79% (11/14) of the patients died. one of the three survivors had severe neurologie injury. prior to picu admission, patients experienced tac~,cardia (n=9), hypotension (n=8), neurological deterioration (n=8), respiratory, distress (n=7), oliguria (n=5), bradycardia (n=3), metabolic acidosis (n=7), hyponatremia (n=4), hypokalemia (n=2), hypocalcemia (n=2) and severe hypoglycemia (n=2). there were serious delays from the time of development of clinical and laboratory abnormalities to the time of admission to picu. conclusion: in the critically ill pediatric patient, rapid recognition of clinical and laboratory signs of deterioration, followed by immediate intervention, are required to prevent end stage shock and cpa. we found serious delays in intervention following development of important premonitory clinical and laboratory abnormalities in patients less than 20 months of age on the general pediatric wards, which iikely contributed to the dismal 79% mortality rate. hospitals throughout ecuador should institute immediate improvements in ctinical supervision, and provide training in paediatric advanced life support (pals) to decrease excessively high rates of and mortality from cpa. intraosscous access is recommended by the american heart association and american academy of pediatries as a means of rapid access to the vascular system for childhood emergencies. bone marrow and fat embolism is a concern and has been reported post intraosseous infusion in stable animals but has never been studied in animals subjected to cardiopuimonary resuscitation. we undertook this study to investigate the incidence and magnitude of lat and bone marrow embolism with the use of intraosseous infusion during prolonged cardiopuhaonary resuscitation and after fluid and drug infusion. we hypothesized that there will be no difference in the magnitude of fat embolism between cardiopulmonary resuscitation only and other cxperirnental conditions. thirty-one (31) piglets were anesthetized, mechanically ventilated, and instrumented (carotid artery, pulmonary artery and intraosseous earmulas ). the animals then underwent bypoxic cardiac arrest followed by chest compressions with the mechanical thumper (michigan insmunents) and mechanical ventilation for a minimum of 45 minutes. the animals were divided in groups: a (n=5) which had no intraosseous, ~'oup b (n=6) had intraosscous with no infi~ion, and groups c (n=6), d (n=6), e (n=8) had intraosseous with infusion of adrenaline, normal saline and sodium bicarbonate, at cessation ofcardiopulmonary resuscitation, representative lung samples were collected fi'om upper and lower lobes of each lung, embedded in ocp and firozen immediately. ltmg specimens were stained using oil red-o dye and observed for fat globules and bone marrow elements. the amount of emboli present was rated as a percentage in relationship to iung tissue, by a pathologist blinded to the experimental groups. buffy coat specimens were collected before and at cessation of cardiopuimonary resuscitation, stained with oil red-o dye and observed for fat globules. percentage of fat present were compared using analysis of variance. fat globules were seen in the prebronchial blood vessels and in intravascular areas throughout all lung fields. there was no difference in appearance or distribution of fat globules between groups. quantity varied in the different groups[(a) 45%, (b) 44%, (c) 30% (d) 23%, (e) 25%], but were not statistically significant (p = .097). fat globules in the buffy coat were few and inconsistent with lung findings. fat and bone marrow emboli were present in all experimental conditions, the use of the intraosseous cannula does not increase the magnitude of embolization during cardiopuimonary resuscitation. the decision to use the intraosscous route should not be influenced by the risk of embolization. tzareva iv/,, md*, nedialkova r, md**, *dept. of pathophysiol, *~dept. of child surg. and icu, emergency medical institute pirogov, sofia, among 566 children with blunt abdominal trauma, treated in emi pirogov during the last five years, 79 children had serious disturbances of the basic vital functions, connected with the trauma, and most often with massive haemorrhage, for this reason being an object of reanimation and intensive care. in the group of children who survived -37, predominated the trauma of only one abdominal organ (mainly the spleen, rarely the kidneys, the intestine) and only 15 children had injuries of more than one abdominal organ. in the same group, in 15 children the abdominal trauma was combined with chest or head trauma or bone fractures. in the group of children who died -12, a profound combined trauma was present. the haemodynamic parameters in all children showed a characteristically significant tachycardia along with normal or even high blood pressure, while hypotonia was present in only 64% of the children on the first trauma day. despite the fact that only 13.4% of the children had direct chest injury as well, the gas exchange was considerably disturbed -899'0 of the children were hypoxemic during the first, and 100% during the third trauma day -in 25% significant -below 8.0 kpa (60 mmhg). together with the markable decrease in haemoglobin levels, this determines the pronounced disturbance in oxygen transport. during the first trauma day all the children were acldo~c, and a metabolic alkalosis was present during the following days. twelve of the children with severe combined trauma died within several hours, with the symptoms of irreversible haemorrhagic shock, or in the next 2-3 days, developing multiple organ failure. in conclusion, the intensive therapy of children with severe abdominal and combined trauma, should take in consideration the special haemodynamical trauma answer in children, and requires dynamic monitoring of the most influenced homeostatic parameters -blood gases, acid-base metabolism, haemostasis. introduction: endocrine emergencies, other than diabetic ketoacidosis, are uncommon causes of pediatric intensive care unit (picu) admissions. we report our experience of children diagnosed of adrenal insuficiency (ai) admitted in the picu, during the last four years. subjects: five eases of ai requiring 7 intensive care unit admissions are presented. four females anna 1 male, with ages ranging from 11 days to 7 years, none of them had a previous systemic or endocrine diseases that could suggest al the initial clinical manifestations were: dehydration (5), vomits (3), abdominal pain (2), seizures (2), lethargy (2) and hyperpigmentation in the muco-genitat area in a newborn male and ambigna genitalia in a newborn female. the reason for their admission in the p1cu were: shock in two subjects; three because of hyperkalemia and hyponatremia (k/na: 5.6/123; 9/126; 7,1/134 meq/l); and two with severe hyponatremia (na: 117; 113 meq/l). laboratory findings: severe hyponatremia (5), increased concentration of urinary sodium and chloride (4); metabolic acidosis (4); hyperkalemia (3); increased levels of urea (3) and hypoglycemia (2). in all of them, the electrolytes abnormalities did not normalize with replacement and only normalized after the administration of hydrocortisone. tile ai was due to: autoimmtme disease in two subjects, congenital adrenal hypoplasia, congenital adrenal hyperplasia secondary to 21 alia hydroxylase deficiency and in one no etiology was found, at the present time, comments: aiis an uncommon disease in the pediatric age. anearly diagnosis is crucial, as if the treatment is delayed could lead to patients death. in subjects with arterial hypotension and electrolytes abnormalities refractory to the usual treatment, they should be treated with corticosteroids, if no etiology is found. although, previously samples must be obtained to make the diagnosis, 0: denotes the number of cases. gerbaka b; hakme c; akatcherian c. toxics are frequently involved in domestic accidents during childhood; among non medical products ingestion, carbohydrate poisoning is a serious injury often made possible by inadequate stocking. over 10 years, 43 children aged 10 years and less were examined in the emergency department of hotel-dieu de france hospital for carbohydrate ingestion. 62,8% are boys; age goes from 13 months to 6 years (moan = 2,5years). kerosene is found in 35,8% of cases; all were admitted (mean = 2,8 days). 79,1% were symptomatic on first examination but 93% of all children presented signs of gastric (58%) or respiratory (69,8%) irritation sometime during their history; 37,2% had neurological signs and 41,9% presented some fever. leucocytosis is found in 65% of cases; 25,6% of the children received antibiotics. chest x ray was abnormal in 48,8% of cases: mainly parahilar infiltrates were found, all children survived; 76,7% with a normal course (1,9 days of hospital stay) whereas those who presented complications (severe pneumonia, coma) stayed in the hospital for 6 days (mean) with short course of assisted ventilation for two of them; long term follow up was not possible. we fonnd nick's criteria for hospital admission to be of value: -symptomatic children with normal x ray } 6 to 8 hours monitoring -asymptomatie children with x ray abnormality } -symptomatic children with x ray abnormality: hospital admission -asymptomatic children with normal x ray : no admission. these criteria would have helped to avoid admission in 8 children and would have allowed a short t2 hours stay for 6 more. we found chest x ray to be mandatory in carbohydrate ingestion; other tests were not helpful, aside arterial blood gases measurement in case of respiratory involvement; we now also advocate more restriction in antibiotic use. prevention remains efficient and should be stressed on. severe liver failure [slf] is a rare but severe condition in infants. we report our experience. patients: slf was defined as liver insufficiency with hepatic encephalopathy and a decrease in the level of factor v to below 25 %. between 1984 and 1996, 29 infants (mean : 4 mo) were admitted for slf (neonates excluded). main causes were metabolic disorders (41.3%) (tyrosinemian=5, hemochromatosis n=2, reye's syndrome n=2, other n=3), virus-induced flf (20.6%) and hematologic diseases (13.7%). in 4 cases, the causes remained undetermined. results: olt was contraindicated in 12 cases because of multiple organ failure (n=10), or underlying disease. all of them died within 6 days after admission. 7 patients had no indications for olt, all but one are alive. (1 of them was transplanted later for tyrosinemia and 1 died lately (virus induced-slf). among the t0 infants who underwent emergency olt, 6 are alive and 4 died because of primary non function of the graft. conclusion: slf in infants admitted before their first birthday is a severe condition with an overall mortality rate reaching 60%. inherited metabolic disorders are the first cause of slf at this age. contraindications for olt are frequent because of underlying disease or multiple organ failure. a number of children undergo primary graft failure after liver transplantation. it is unknown if there is any increased morbidity or mortality following retransplantation. this study seeks to explore these issues. methods: a pediatric intensive care/iiver transplant database is in formation. records of all liver transplant patients are reviewed and abstracted. this data is then computerized to allow analysis. this data provides the source for this study. statistical analysis was performed via student's t-test where appropriate. results: of the 350 patients who have thus far received at our center orthotopic liver ransplants, the records of 112 who underwent 140 transplants form the basis for this review. twenty-three patients underwent multiple transplants, 19 required one additional, three required 3 organs, and one patient survived after a fourth organ transplant, there was no significant difference in age at first transplant between those who received multiple organs and those who did not (40 vs, 44 months, p=ns). the anesthesia time for the procedure did not significantly increase tbr subsequent transplants (8.3 vs, 7,3 hours), nor did time in the intensive care unit (t6.6 vs. 22.2 days), nor did time on the ventilator (8.4 vs. 15.3 days) subsequent transplants did not predispose to having more bleeding in the intensive care unit for usage of packed red blood cells or platalets was not significantly altered (299 vs 306 ml and 127 vs 207 ml respectively). patients who required retransplantatior~ did receive mere fresh frozen plasma (ffp)daring their first transplant than in the subsequent ones (275 vs 81 ec, p < 0.05). however ffp use was not significantly different than patients who did not require retransplant. patients who underwent retransplant had a markedly increased mortality (47%) than the overall mortality for liver transplants at our center (20%), conclusion: children who require another liver transplant have a markedly increased mortality. bleeding and prolonged icu stay is not significantly different between the first and subsequent transplants, fulminant hepatic failure and ortothopic liver transplantation.dr.sasb6n,j;centeno,m;entin,e;acarenza,m;ciocca, m:gofii,j;bianco,g;weller, g;imventarza,o. unidad de cuidados intensivos.hospital de pediatria "dr.j.p. garrahan"1245.buenos aires.argentina. introduction:fulminant hepatic failure (fhf) is a clinical syndrome, defined by the development of hepatic encefalopathy within 8 weeks from onset of illness in a previously healthy person.by far,the most comun cause of pediatric fhf in all series, is acute viral hepatitis.we report our experiences with the pediatric fhf and ortothopic liver transplantation (olt) as attemative of treatment. patients:30 childrens with fhf diagnosis were admitted at the picu from 1/1/1993 to 1/12/1995.symptomatic treatment was given to all children and all were put on list for olt,) following the king's college criterion (protrombina time,age,atiologies,bilirrubin,and encefalopathy state). results:etiologic causes corresponded to the 30 childrens were:23, hav (76%); 6, noa nob (20%);1 ,autoinmune (4%).the age was mean:4 years (range:16 month-10 years).seventeen patients were transplanted,13 chidmn were discarded because:no donors:5;withdrow of the list:3,because sepsis in 2 and bleeding of cns 1;and no admission at list:5 because genetic syndrome 1 ,massive intestinal necrosis, 1 ,mitral valvulopathy 1 and sepsis,2. 25 patients (86%) had at least one complication dudng the post operative period.the most frequent was the acute renal insufficiency(ari) and 4 patients requiered continuos hemofiltration.the gtobal mortality rate was 75%.the mortality of patients without olt was 100% and the mortality of patients with olt was 41%,4 patients dayed because sepsis, (2 candidiasis) and the others 3 because mof.the actuarial survival at 1 year is 54% and the follow up of 8 months. conclusions:the fhf is a very severe and frequent disease at picu. supportive treatment only is associated with a very poor prognosis and high mortality rate.the most frequent etiology in our country is the hav. the olt is applicable in this cases and is a valid alternative of treatment (mortality in our series 41%).the ari is the most frequent complication during the post opeative period.in argentina,due the high prevalence of hav,prevention must be considered the main and only way to avoid this catastrophic illness.to assess the efficacy of gastric intramucosal ph (phi) for evaluation of tissular perfusion and prediction of hemodynamic complications m critically ill children. patients and methods: thirty critically ill children (16 boys and 14 girls) whose age ranged from 3 month and 12 years old were studied. a tonometry catheter was placed in the stomach of all patients at their °admission in pediatric icu. intramucosal ph measures were made at the admission and each 6-12 hours during the study: a total of 202 determinations were made. the catheter was removed after extubation and/or checking of hemodyrmmic stability of the patient. the intramucosal ph was derived from application of the henderson-hasselbaeh formula using the pco2 value from the tonometer and the arterial bicarbonate. values of phi between 7.30 and 7.45 were considered normal. the relationship between phi and severity of patient measured through prism, presence of major (cardiorespiratory arrest, shock) and minor (hypotension, hypovolemia or arrhytlmtias) hemodynamic complications, mortality and stay in the picu, was analysed. results: the admission value of phi was 7.48 -t-0.15 (range 7.04-7.68). five patients (16%) had an admission phi < 7.30. no relationship was found between an admission phi < 7.30 and a higher incidence of hemodynamic complications. sixteen patients (53%) showed some values of phi < 730 during their evolution. patients with phi < 7.30 had a higher number of hemodynanuc complications than the rest (p< 0.0001). every cardiorespiratory arrest (cra) and shock cases were related to a phi < 7.30. patients with major complications (cra and shock) had a phi lower (p= 0.03), as well as a higher number of measurements of low phi (p= 0.003) than patients with minor hemodynamie complications. the value of phi lower than 730 presented a 90% of sensibility and 98% of specificity with regard to hemodymanic complications. there was no relationship between phi < 7.30 and prims score and stay in picu. patients with phi < 7.20 presented a prims higher than the rest of patients (p< 0.05). conclusions: the phi value may be an early sign of presence of hem0dyaaimc complications in the critically ill child. we tested the hypothesis that gastric intramural ph (phi) can be used as an early sign of failure m weaning pediatric patients because the blood flow from nonvital areas is diverted to meet the increased demands of respiratory muscles. methods: 24 children (mean age (4.2_+0.3) years + sd) who were thought by their physicians to be weanable from mechanical ventilation (mv.). these patients were ventilated on serve 900c ventilators, receiving ranitidine, and had intestinal tonometer (tonometrics, inc.) 60 minutes before obtaining a sample.. all children were placed on pressure support (ps) at levels judged to overcome the resistance of the endotracheal tube and ventilatory circuit (2 em h.,o). a sample of arterial blood and a sample oftonometer were obtained during vm and weaning (ps). phi, hemodynamic and respiratory data were recorded during vm and weaning we did not interfere with the primary caretaker's decisions regarding extubation. patients were considered to be successfully weaned if they were able to sustain spontaneous ventilation for more than 24 hours after extubation. paired t-test were used to compare the values obtained during mechanical ventilation with those obtained during weaning trials. unpaired ttest were used to compare values from the group that was successfully weaned (a=i5) with those from the group that were not (b=9). results: we did not find statistical differences in any of those variables mesured during mv for patients who were successfully weaned(group a) and those who were not (group b). gastric phi was in group a: 7.35 + 0.03 (vm) and 739 + 0.02 (weaning); in group b: 7.40 _+ 0.04 (vm) and 7.4t _+ 0.02 (weaning). discussion: although we did not find differences in gastric phi during vm, the group a had a lower value than group b because of the number of cardiac patients (70%) and transfusion therapy, in fins group. in group b 75% of patients showed a problem in upper airway (subglottic edema, and enlarged tonsils). we found it after extubation. conclusion: 1) gastric phi is a good predictor of risk in critically ill patients but maybe because of the small size of the sample, in our study is not of practical value as a predictor of failure in weaning pediatric patients from vm. 2) this test is not a predictor of problems in upper airway~ important etiology of failure weaning in children. objectives: i-to determine the prognostic value of the gastric intramueesal phi in mortality and multiple organ dysfunction (sdmo) in critically ill children. 2-to compare this value, with the pediatrics risk index mortality score (prims). methods: aprospective study was performed with 51 critically illcbildren, aged from 1 mouth to 16 years. the athnittiug diagnosis was: 26 post-surgery (13 neurosurgery, 9 spinal fusion and 4 thoracic or abdominal surgery), 7 sepsis, 6 polytraumatism, 5 adult respiratory distress syndrome and 8 with miscellaneous. all the subjects were monitorized on picu admission and treated for their underlying condition. gastric intramucnsal pt{ was measured following the tonometric method, ou admission and every 4-8 hours depending on the patients state. the severity of the clinical condition was evaluated using the the prims, on admission (prims-i) and during the first 24 hours, when the clinical condition deteriorate, the worse score was utilized for the statistical analysis (prims-2). to perform the statistical analysis the subjects were divided in two groups, one with the phi<7.30and the other with phi>7.30.aunivariate analysis (student's tand wilcoxon two tailed test, chi-square) and multivariate analysis were used. results: 12 out of the 51 subjects dyed. of 14 children developing multiorgan failure (mof) 9 expired. 50% of the patients admitted to the picu with sepsis, ards and miscellaneous had a phi < 7.30. in contrast, with 27 % of post-surgical and none of the postqraan~atism. the mortaliry rate, in children with a phi<7.30was 47% (ci 95%:26.16; 69,04) and 11.76% (ci 95%:4,67; 26.62) in children with phi>7.30 (p=0.011). mofwas observed in41,18% of children withphi<7.30v.s, 20.6% with phi >7.30.no relatiouship was observed between the phi and the score of prims-i and 2. perforating an unconditional logistic regression analysis, two independent variables have mortality predictive value: the phi and the prism-2. (table i) following induction of anaesthesia, a laser doppler probe (moorsoft instruments ltd) was inserted 7cm into the patient's rectum, the probe's special design ensuring that the optical prism lay against the mucosa. continuous monitoring of rectal mucosal perfusion ("flux") was continued throughout the operation. after 10 rain cpb at 35°c, "steady state" readings of nasopharyngeal temperature, mean femoral arterial pressure (map) and flux were recorded over a further 5 min before cpbinduced core cooling to 14-24°c. steady state was defined as a 5 rain period with no change in core temperatures or map. other 5 rain steady state recordings were taken immediately prior to low flow, immediately prior to rewarming and after rewarming to 35°c, before initiation of any vasoactive drugs. the cpb flow rate was kept at 100 m l k g -1 min q, the pcv at 25_+3%, the p~co 2 at 5.3+0.5 kpa and the pro2 at 20+5 kpa. results: initial warm and rewarm map (both 46 mmhg) were significantly lower (19=0.008) than during the 2 cold cpb periods (63 & 64 mmhg). the mean cold flux before (152) and after (159) low flow were both significantly lower (p=0.001) than the mean initial warm cpb flux (211). the mean rewarm cpb flux (127) was significantly lower than all other flux values (p=0.001). there were no siglaificant correlations between map and flux except at the first warm cpb period (r=0,33, p=0.04). conclusions: although hypothermia significantly reduces rectal mucosal perfusion, rewarming produces an even greater reduction in gut perfusion which, considering that mucosal oxygen constmaption is highest during this time, may prove crucial in the postoperative development of mof. therapy aimed at improving gut perfusion during cpb should be directed at the rewanning period in particular. abstract this work is aimed at establishing a clinical procedure for the diagnosis of enteritis necroticans (en), even at the communal level, and to define criteria for diagnosis able to distinguish between acute forms. subjects and method : 100 cases admitted at the institute for protection of children's health dpch), having characteristic symptoms, were examined clinically, by roentgenography of the abdominal cavity, with the analysis of the blood (total protein, electrolytes, hematocrite) and cultures of intestinal fluid and faeces. through surgical operations, the pathological lesions were observed and recorded. results: common epidemiological features: the average age is 6-8 years old (3-15) ; male/female : 1.85; in 70% of the cases, the disease occurred after a meal rich in protides. the acute toxic form accounted for 15% : severe shock appearing early, with very severe dehydration associated with profoundly decreased blood protein concentration and lowered natriemia as well. the lesions of the small intestine were expanded, all of them were necrotic. in the surgical form (20%), the predominant feature was an obstruction -peritonitis syndrome, the peritoneal fluid showed a characteristic inflammatory reaction. for the rest of cases 65% were the internal form, the shock syndrome was less severe, the abdominal distention was light and disappears gradually, the inflammatory reaction of the peritoneal fluid was not so characteristic. conclusion (ino) is a selective pulmonary vesodilator that is rapidly inactivated compared to intravenous vasodilators. these qualities make ino an attractive agent for the treatment of pulmonary hypertension (pittn). the efficacy of ino has been studied in persistent fetal circulation, acute respiratory distress syndrome (ards), and congenital heart disease (chd). potential adverse effects oflno include: nitrogen dioxide (no0 toxicity, methemoglobinemia, and platelet dysfimction. our objective was to evaluate the safety of ino in pediatric patients (pts). methods: pediatric pts. with phtn from ards or chd were studied under an established, approved protocol conforming to fda guidelines tbr an investigational new drug. informed consent was obtained for each child prior to treatment. 1no was sequentially titratad from 10 parts per million (ppm) to 20, 40, 60, and 80 ppm at ten minute intervals. parameters monitored before and during therapy included nitric oxide (no) and no~ concentrations (cone.), mean arterial blood pressure (map), and percent methemoglobin (mhg). no and noz levels were continuously monitored using an inline dr~ger electrochemical detection device. ~,litp was continuously measured with an indwelling arterial catheter. mhg was measured by co-oximetry. a mhg level e 5% or no2 cone. ~ 5 ppm were considered adverse effects by study criteria. pretreatment map was compared to map at 40 and 80 ppm ino using paired t-tests. ap value < 0.05 was considered statistically significant. results: thirty-two mechanically ventilated children with phtn (16 with ards, 16 with chd) were studied. five pts. were treated following cardiopulmonary bypass. methemoglobin (met-hb) levels were routinely measured in two prospective clinical studies on no inhalation in 25 pediatric patients with pulmonary hypertension following heart surgery with extracorporeal circulation and in 19 pediatric and neonatal ards patients, the observed differences between the groups prompted in an in vitro study, red blood cells (rbc) of 20 patients sampled before and after surgery with and without extracorporeal circulation (ecc), respectively, were incubated with 32 ppm no for 100 rain, met-hb, atp, and nadht nadph concentrations were compared, during therapeutic exposure no increased met-hb from 0.2 -2-_ 0.1 to 1.2 _+ 0.7 % in cardiac surgery patients and from 0.2 ± 0,1 to 0.5 ± 0.4 % in ards patients (p < 0.01 ). rbc's having undergone ecc were more susceptible to met-hb formation (p< 0,001 ) whereas intracellular coenzymes did not differ neither between the groups (table) nor before and after no exposure. ecc predisposes to increased methemoglobinemia upon exposure to no both in vivo and in vitro. our data suggest a reduced activity of met-hb reducing enzymes rather than diminished availability of energetic substrates, variation of the inhaled nitric oxide concentration with the use of a continuous flow ventilator. anne pmc de jaegere ~, frans im jacobs 2, nico gc laheij 2, john n van den anker t . dept. of paediatrics ~, central instrumentation 2, sophia children's hospital, erasmus university rotterdam, rotterdam, the netherlands. objective: to investigate the homogeneity of nitric oxide (no) concentration in a delivery system with a continuous flow ventilator. design: bench study, setting: biomedical laboratory. interventions: a nitrogen/nitric oxide (njno) gas mixture was injected at three different sites in the patient circuit: just before and just behind the humidifier, and 20 centimetres before the y-connector. ventilator flow (12, 15, 20 l/rain), ventilator rate (40 to 110, increments of 10) and compliance of the testlung (0.36; 0.5; 1.0 ml/cm h20) were changed. carbon dioxide (co2) instead of n2/no was injected at the same points in the circuit. measurements and main results: a) though the flow ratio of the njno and the ventilator gas were kept constant, the no concentration ([no]) raised with increasing ventilator rates. the increase in [no] was up to 40% when the n2/no injection site was close to the y-connector of the ventilator circuit. minimal changes in [no] were noticed when the n~/no was mixed to the ventilator gas before the humidifier. b) analysis of the ventilator flow pattern showed variations at different places in the ventilator circuit. the magnitude cf the p, ow change depended on the meas~:rement site. the closer to the expiratory valve the highest the flow change was. the duration of the flow change was inversely proportional to the adjusted ventilator flow. c) real time measurements of the co 2 concentration ([coz]) showed variations during tile respiratory cycle. these [co2] variations were higher when the co2 gas was blended closer to the yconnector. conclusions: the ventilator flow variations in relation to the fixed side flow of the n2/no gasmixture result in changes of the inhaled [no] during the respiratory cycle. the no concentration during inspiration is always higher then during expiration. this could not be detected with the available monitoring system. to ensure a constant [no] by blending a njno gas balance in a continuous flow ventilator, the site of injection should be as close as possible to the inspiratory outlet. nitric oxide, a potent and selective pulmonary vasodilator, has recently been successfully used to treat pulmonary hypertension of variable etiology in infants and children. side-effects and complications in infants are so far not well known. we describe here two cases in which prolonged (5 and-7 days respectively) high-dose (50 -80 ppm) nitric oxide was used to treat refractor~¢ pulmonary hypertension. one patient was a newborn infant with pulmonary hypertension secondary to a large leftsided diaphragmatic hernia. nitric oxide was begun under conventional ventilation (babylog 8000) at 7 hours of life with a slight initial improvement in oxygenation. he was then placed on oscillation with the same nitric oxide concentration due to worsening respiratory failure. he died on 5th day of life. monitored nitric dioxide concentration never exceeded 4 ppm. the other patient was a 3 months old infant with severe pulmonary hypertension due to a complete atrioventricular septal defect. he required high-dose nitric oxide to come off cardiopulmonary bypass after surgical repair of his heart defect. he slowly improved over the week following surgery but developped suddenly respiratory failure due to massive pulmonary hemorrhage and died. surprisingly, a particular autopsy finding in both infants was a massive acute necrotizing tracheobronchitis. we conclude that nitric oxide is an excellent and sometimes lifesaving treatment of pulmonary hypertension in infants. tracheobronchitis has not yet been reported as a possible complication of nitric oxide administration. we suggest that caution needs to be taken with prolonged high-dose administration and this possible complication to be looked for at autopsy. introduction: permissive hypereapnia (ph) is a beneficial strategy for patients with acute respiratory distress syndrome (ards) to minimize barotrauma by decreasing the peak inspiratory pressure (pip). hypercapnia and hypoxia cause pulmonary vasoconstriction, pulmonary artery (pa) hypertension, and, thus, an increased afterload to the right ventricle. this increased afterload may result in increased right ventricular (rv) work load and subsequent rv dysfunction. one therapeutic approach is the use of inhaled nitric oxide (inn), a selective pa vasodilator. the objectives of this study were to test the hypothesis that in a swine model of ards with ph, inn would improve rv work load and not change intrinsic rv contractility. methods: in 11 swine (25-35 kg), ards was induced by surfactant depletion. hypercapnia was achieved by decreasing the pip while increasing the peep to maintain a constant mean airway pressure, inn was administered in concentrations of 2, 5, and 10 ppm in a random order. pulmonary blood flow (qpa) was determined by an ultrasonic flow probe. rv total power (tp) and stroke work (sw) were calculated by fourier transformation of the pa pressure (ppa) and qpa data. preload recruitable stroke work (prsw), a preload and afterload independent measure of ventriculur contractility, was determined by a shen-subtraction method and vena caval occlusion. respiratory failure with pulmonary hypertension in piglets gerfried zobel*, bernd urlesberger*, drago dacar**, siegfried rtdl*, fritz reiterer* and ingeborg friehs** depamnents of pediatrics* and cardiac surgery**, university of graz,austria objective: to evaluate gas exchange, pulmonary mechanics and bemodynamic data during partial liquid ventilation (plv) combined with inhaled nitric oxide (no) in acute respiratory failure with pulmonary hypertension. design: prospecfive~ randomized, controlled study. setting: university research laboratory. subjects: twelve piglets weighing 9 to 13 kg. interventions: acute respiratory failure with pulmonary hypertension was induced by repented lung lavages and a continuous infusion of the stable endoperoxane analogue of thromboxane. thereafter the animals were randomly assigned either for plv or conventional mechanical ventilation. initially perfhiorocarbon liquid (30ml/kg) was instilled into the endotracheal tube over 5 min followed by 5-10ml/kg~. all animals were treated with different concentrations of no ( 1-10-20 ppm) inhaled in random order. measurements and results: continuous monitoring included ecg, cvp, mpap, map, san2 and svo2 measurements. during plv pao2/fio2 increased significantly from 62_+3.2 mmhg to 193±44 mmhg (p<0.01) within 10 rain, while pao2]fio2 remained constant at 61 -+3.3mmhg. qs/qt decreased significantly from 48-+4% to 25-+5% (p<0.01) during plv and did not change during conventional mechanical ventilation. static pulmonary compliance (cstat) increased significantly ff~m 0.4r±0.07 to 0.75_+0.03 ml/cmh20/kg (p<0.01) during plv and decreased slightly from 0.58_+0.08 to 0.46e0.04 ml/cmh20/kg during conventional mechanical ventilation. the infusion of the endoperoxane analogue resulted in a sudden decrease of pao2/fio2 from 262_+44 to 106_+8.0 mmhg in the plv group and from 71±7 to 52+_2.0 mmhg in the control group. inhaled no significandy improved oxygenation in both groups (pao2/fio2:344_+38 mmhg during plv and 196+_.56 mmhg during conventional mechanical ventilation). during inhalation of no mpap decreased significantly from 57-+2 m 35±2 mmhg (p<0.01) in both groups. there was no significant change in oxygenation and mpap during inhalation of 1 and 20 ppm no. conclusions : plv significantly improves oxygenation and pulmonary compliance in acute respiratory failure. the additional application of inhaled no further improves oxygenation and pulmonary hemodynamics when acute respiratory failure is associated with severe pulmonary hypertension. inhaled no is very effective in improving oxygenation and pulmonary blood flow even at low doses. the work was supported in part by grants of the austrian nationalbank nr 5545. as in neonates, severe respiratory failure in infants and children can be aggravated by pulmonary hypertension, resulting in further deterioration of oxygenation due to increasing intrapulmonary shunting. we analysed the influence of inhalational nitric oxide (ino) in treatment, course and outcome of severe ards in a pediatric population. since 1993 20 infants and children (age: 1-107 months) with ards and oi > 15 (mean value: 32.5± 11) underwent a trial with ino (concentration: 3, 10, 30, 60 and 100 ppm) to prevent further respiratory failure. 11 patients had a significant improvement of their oxygenation (rise of pa09 > 15 mm hg) for at least 24 hours (responders); mean best ~fficient no dose: 24.6 ppm. the non-responders had only a short-term improvement or ino had no effect. in responders and nonresponders there was no significant difference with regard to age, underlying disease, ards severity, time on mechanical ventilation, blood gases and ventilator settings before notrial, nor was there a different grade of pulmonary hypertension (estimated by echocardiography). the only difference was an higher ol in the group of the non-responders: 40.9 ± 9.i vs. 25.6 ~ 6.7, p < 0.002. in the group of the 11 respenders there was a secondary deterioration of lung function after i -6 days on ino in 5 children (transient responders): in these patients, as well as in the group of the non-responders, alternative modalities of treatment (hfov and/or ecmo) became necessary. 6 children (30 %) died: 2 transient respenders and 4 non-responders. in infants and children with ards due to different underlying diseases ino can acutely lead to a significant improvement of oxygenation in about 50 % of the cases. the right selection of patients for no therapy and the influence of ino on the survival rate of ards in childhood has to be evaluated in further studies. and pediatric cardiology, university of graz, a-8036 graz purpose: after fontan procedure cardiac output is critically dependent on the pulmonary vascular resistance. even minor elevations of the pulmonary vascular resistance may significantly decrease cardiac output. inhaled no is an effective, selective pulmonary vasodilator in experimental and clinical situations of pulmonary hypertension. the aim of this study is to evaluate the effects of inhaled no on oxygenation and pulmonm 3, circulation in children after a bidirectional glenn-anastomosis (n-~) or a fontan-like operation (n=9). material and methods: from june t993 to january 1996 13 children with a mean age of 7.1+~2.1 (sem) yrs and a mean body weight of 24.3-+5.8 (sem) kg were treated with inhaled no after glenn-or fontan-like operations. all but one had complex cardiac malformations with single ventricle. all children were mechanically ventilated with an fin2 >0.75. inhaled (no) was applied using a rrdcrdproeessor based system which additionally allowed measurement of no/nox using the chemihimniscence method. methemogtobin concentrations were determined 3 times a day. the major indication for postoperative inhalation of no was a high (>10mmhg) transpulmonary pressure gradient (tpg--cvp-lap). severe myocardial dysfunction of the single ventricle was excluded by echocardiography. results: the mean duration of mechanical ventilation was 8.1_+2.2 (sem) days the. mean dose of inhaled no was 4.4-+0.8 (sem) ppm, the mean duration of no-inhalation was 106_+19 (sem) hours. the mean methemoglobin concentration was 1.2-+0.2 (sem)%. hemodynamic data and arterial oxygen saturation before inhaling no and 15 minutes later are given in table 1 acute hypoxaemic respiratory failure (ahrf) in children occurs in a heterogenous group of diseases with pulmonary pathophysiological processes ranging from reversible physiological intrapulmonary shunting to fixed structural lung damage. we hypothesized that inhaled nitric oxide (ino), a selective pulmonary vasodilator, might identify those patients with potentially reversible disease, i,e, large response may indicate a greater likelihood ef reversibility and thus survival. a retrospective review of the early response to ino in 30 infants and children (aged 1 month to 13 years, median 7 months) with severe ahrf(18 with ards). the mean p(a-a)o2, pao2 / fio2, oxygenation index (oi) and acute lung injury (all) score prior to the commencement of ino were 568 +_9.3, 56 +_2.3, 41 _+3,8 and 2.8 +_0.1 respectively, the magnitude of response to ino was quantified as the % change in oi occurring within 60 minutes of 20 ppm ino therapy. this response was compared to patient outcome data. results. there was a significant correlation between response to ino and patient outcome, kendall tau b r=0,43, p<0.02 (table) conclusion. in ahrf response to ino appears te define a subgroup of patients with improved outcome compared to nonresponders. we speculate that response to ino may be useful in selecting patients with potentially reversible lung disease for special support therapies such as ecmo. randomised controlled trials are needed to define the role of ino in paediatric ahrf. between may 1994 and december 1995, 22 patients (pts) were treated for mas. treatment groups were: group i only 02:6 pts; group i1 conventional mechanioal ventilation (cmv): 11 pts; group ii1 hfo: 1 pt; group iv hfo+no: 4 pts. therapy was stepwise intensified until oxygenation improved ( i -) ii -) iii --) iv). "high volume strategy" was used with hfo (mawp 18-24 cm h20). the initial no-concentration was 20-30 ppm, with rapid reduction down to 5-10 ppm once oxygenation improved. results: one pt (group it) died of hypoxic-ischemic encephaiopathy (termination of therapy); all other newborn babies survived. in group iv pt 1 and 2 showed barotrauma prior to hfo. pt 1,2 and 4 were treated with additional mgci2 (max. mg serum concentration 2.8 -6.5 mmol/i). following the identification of inhaled nitric oxide 0"no) as a selective pulmonary vasodilator (frostell et al 1992) [ 617 .+6,3 626+6.3 data are compared to baseline values within each group. *=p<0.05, **=p<0.03, ***=p<0.0l among 12 patients who fulfilled ecmo criteria, 6 improved with no and did not required extracorporeal life support. tltree out of 6 ecmo patients eventually survived. conclusions: m our study low-dose of irthaled no showed a variable effect on oxygenation in newborns with acute respiratory failure. an acute response to no appeared to be correlated with a better short-term outcome and the avoidance of extracorporeal support in ecmo candidates. differently, lack of acute and/or sustained response was associated with death or need for ecmo. although the nature and severity of the underlying disease or the degree of prematurity may play an important role in these patients, we believe lack of acute response to no may be an early predictor of bad outcome, prompting toward alternative treatments such as ecmo or liquid ventilation. *picea s., °bartuli a.,°dionisi-vici c., *dello strologo l., §villani a., §bianchi r., ^salvatori g.,*rizzoni g, °sabetta g. *div. of nephrology, °div. of metabolism, §intensive care unit, ^div. of neonatology. "bambino gesfl" children research hospital. rome, italy. successful prevention of handicaps or death in newborns with ~ depends on rapidity and efficiency of treatment. poor response to nutritional and/or pharmacological treatment requires extracorporeal removal of nh4. efficiency and cardiovascular tolerance are often difficult to obtain with peritoneal or hemodialysis in neonates. we report the results of cavhd in 3 newborns with hc. methods: vascular access: femoral vessels. blood flow: 10-35 ml/min, dialysate flow: 200-500 ml/h. filter: amicon minifilter plusrm(polysulfone membrane; 0.08 sq.m.). no ultrafiltrate(uf) production, patients: case 1 with carbamoytphosphate synthetase deficiency (body weight -bw-: 3.2 kg) showed hc at day 4, a relapse of hc occurred at day 14 due to an infectious event. case 2 and 3 (bw: 3.0 and 2.8 kg), both affected by propionic aeidemia, showed hc at day 5 and day 7, respectively. plasma nh4 (~tg/dl) decrease is shown in the complications: transitory ischemia of arterial cannulation limb and transitory thrombocytopenia occurred in case 1; surgical repairing of artery after cavt-id was necessary in case 3; no cardiovascular instability was observed during cavhd . outcome,'all patients recovered from hc in less than 1 day: case 1: alive, mild b)iootonia at 34 mos; case 2: dead after 10 days from cavhd withdrawal for pulmonary hemorrhage; case 3: alive, normal development at 7 mos. conclusions: 1) in newborns with hc, ca~q-id provides good cardiovascular tolerance,high efficiency and quick removal of nh4, even without uf production (i.e. only by diffusion). this allows easier management (no need of fluid and electrolyte balance). 2) arterial complications seem frequent in neonates treated by cavhd. venovenous circulation could overcome this problem. vb nguyen, m jokie, c leeaeheux paediatric intensive case service, hospital university centre, avenue c6te de nacre, 14033 caen cedex, france background, the implication of polymorphonuclear neutrophils (pmns) in the physiopathology of children's haemolytic.uraemie syndrome (hus) becomes more and more evident. the purpose of the present study is to role out their impact among other pronostie elements during the course of the disease. patients and methods. diarrheal prodrome and its duration, patient's age, maximal blood nitrogen level, anuria and dialysis time, extra.renal involvements, white enll and pmn counts and thrombopenia duration have been retrospectively analysed in 18 infants with good outcome and in 8 another children with unfavorable outcome. results. neither diarrhoea or its duration, nor children's age, nor blood nitrogen level, nor anuria or dialysis time had any predictive value for the disease evolution in the acute phase of our patients. adversely, extra-nenal involvements was accompanied by severe and complicated courses of the disease (p<0,02). the elevation of white cells and pmns (heyon 20 x 109/i) and pmns (more than 15 x 109/1) as well as its persistence beyon a week were most frequently observed in complicated forms (p<0,001, p<0,001 and p<0,01, respectively). a transient thrombopenia (less than 5 day@ in patients with elevated counts of white cells may be a filrther obvious sign of an unfavorable course of the disease (13<0,02). conclusion. the elevated count of white cells and pmns, either alone or associated to one rapid regeneration of platelets, seems enabled to predict an unfavorable evolution of the hus in children. msud results from an inherited impairement of catabolic pathway of branch chain amino-acids. high leucine blood levels may induce acute brain dysfunction. this dramatic complication led us to propose leucine removal procedures as continuous hemofiltration. patients and methods three newborns in acute msud onset were treated by hf, hdf and hd. extracorporeal circulation was performed through a 6.5 fr catheter, a circuit with a blood pump (priming volume = 40 ml). patients and procedures characteristics are summarized below in the sucralfate (an aluminium salt of sucrose octa sulfate) is used to prevent and treat upper gastrointestinal bleeding in critically ill patients. with minimal absorption, the potential for side effects is thought to be limited, though aluminium toxicity has been reported in patients with chronic renal failure. these patients may already have had high body stores of aluminium. we report 5 critically ill children with high serum concentrations of aluminium following sucralfate therapy. all 5 had renal impairment. the normal aluminium level is < 0.4 gmol/l and in patients with chronic renal failure < 2.2 ].tmol/l. none of these patients had known preexisting chronic renal disease. cpb was conducted under deep hypothermia (t,°16°c) and cardiocirculatory arrest (cca) or under hypothermia (t,°24°c) and low-flow perfusion. continuous holter-electrocardiograms (h-ecg) were recorded from the ilranediate postoperative (po) period on for 72 hours. h-ecg were also recorded prior to the operation and before discharge. following dr were observed: snpraventricutar (sv) and ventricular (v) extrasystoles (es) (>50/24h), sv and v tachycardia (svt and vt), accelerated junctional rhythm (ajr) and junctional ectopic tachycardja (jet), and 2nd and 3rd degree atrioventricular block (avb2 and avb3). the incidence of po dr was 20% in the pre-op h-ecg, 74% on the 1st, 33% on the 2rid, 34% on the 3rd po day and 21% befbre discharge. compared to the pre-op findings, an increased incidence of sves, ves, svt and avb3 on the 1st po day was observed, whereas vt and a jr or jet were exclusively observed po. all types of dr were observed up to the 3rd po day. ty23e of dr before discharge was similar to pre-op findings and there was no definitive avb3. considering patient groups according to the most frequent isolated op-procedure, the incidence of dr on the first po day was 56% after asd ii-closure (n=23), 74% after stthaortal vsd-closure (n=lg), 75% after correction of a complete avsd (n=8), 80% after correction of a tetralogy of fallot (n=20) and 100% after fontan-operation (n=10). incidence and type of dr were not significantly different between groups. longer cpb-dttration and use of cca were risk factors for po ves and vt (p<0,005 and p<0,05, respectively) whereas use of cca and degree of hypothermia were risk factors for the development of a jr and jet (p<0,02 and p<0,0001, respectively). -our results indicate that po dr after cpb in children m'e frequent but mainly transient. in our series, specific cpb-related parameters are of greater influence than surgical procedure itseif for the development of dr and are discriminant risk factors for particular types of dr. the course of anp, cgmp/anp (as indicator for atrial natriurefic peptide biological activity), and no2 and no3 (as indicator for endogenous nitric oxide (no) synthesis) was investigated in i9 infants (median age 4 months) undergoing cardiopulmonary bypass (cpb). patients were divided into 2 groups according to whether they had (group 1, n=13) or not (group 2, n=6) preoperative heart failure (hf) and pulmonary hypertension (pht). group 1 patients had preoperatively significantly higher levels of anp (p<0.005), cgmp (p<0.02) and no2 and no3 (,p<0.02) but had significantly lower cgmp/anp (i0<0.05) than group 2 patients. during cpb, anp was significantly higher in group 1 patients ~<0.02). as compared with prebypass values, cgmp/anp was reduced in both groups during cpb (p<0.0001). cgmp/anp inversely correlated with duration of cpb and aortic clamping time (p<0.001, respectively). no2 and no3 were significantly higher in group 1 than in group 2 patients (p<0.05) without any intraindividual change during cpb. from the early postoperative period on anp, cgmp/anp and no2 and no3 were similar in both groups. after cpb, anp correlated in both groups with blood pressure (p<0,001) and diuresis (p<0.05). no2 and no3 inversely correlated with pulmonary arterial pressure immediately after cpb (19<0.05 patients after a fontan-type of procedure have elevated central venous pressures (cvp) leading to congestion in the gastrointestinal system and often ascites. purpose of this study was to evaluate whether this causes a different postoperative gastric mucosal ph (phi). methods: we evaluated a series of 35 patients, who underwent cardiac surgery with cardiopulmonary bypass (age: 5 days to 16 years (mean 2,2 yrs), weight: 3.2 to 37kg (mean 10.2 kg). a commercially available tonometer (tonometics®) for sigmoidal use in adults was inserted into the stomach after induction of anesthesia. the phi measurements were done according to manufacturer recommendations we compared three groups of patients: 1) aeyanotic (n=20), among them 9 p with vsd and 5 p with avsd; 2) cyanotic (n=10): tof: 6p, tga: 4p; 3) cyanotic after a fontan-type procedure (n=5). phi were measured at picu arrival and after 6h. fudhermore we compared lactat levels at these time points. differences between the groups were evaluated with one way anova on ranks with pairwaise multiple comparisons (dunn's method). the relationship between cvp and phi was investigated by regression analysis. results: the median phi for groups i, 2 and 3 were 7.28, 7.27 and 7.13 at ardval and 7.30, 7.25 and 7.21 after 6h respectively. at picu arrival group 3 was significantly (p<0.05) different from groups 1 and 2. there was no significant difference between the latter two groups, after 6h group 1 was different from group 3, there were no other significant differences. the median lactate levels for groups t, 2 and 3 were 2.2, 3,2 and 4.1 at ardval and 1.6, 3.1 and 3.3 after 6h respectively. at ptcu arrival group 3 was significantly (p<0.05) different from group 1, after 6h there were no significant differences. there was a weak negative correlation between cvp and phi: r= -0.21; p<0.05. conclusion: patients after a fontan-type of procedure have lower phi than patients after other cardiac surgical procedures, however, this is only in part due to the elevated cvp and venous congestion. eleven children were investigated 32 months (median) after postoperative mof. iviof was defined as the failure of at least two vital organ systems (kidney, liver, lung, central nervous system) in addition to cardiac insufficiency and high fever. underlying surgical procedure was repair of tetralogy of fallot (n=3), fontan-(n=7) or seuning procedure (n=l). all patients fulfilled criteria for mof in the 3 first postoperative (po) days. six patients needed peritoneal or hemodialysis for 31 days (median) during the po period. one patient showed cerebral infarction due to thromboembolism in the territory of the right internal carotid artery immediately after the operation. the follow-up protocol consisted of extensive investigations of heart-, renalliver-, and lung functions as well as complete neurological and psychological examinations. all patients had adequate cardiac examination. lung function was normal in all but 2 patients who had an obstructive syndrome. only 1 patient showed an isolated decreased creatinine clearance. abnormalities of the liver ftmction tests were only noticed in patients after fontan procedure. severe neurological sequels such as paraplegia (n = 1) and diplegia (n-i) were observed in 2 of the 11 patients. the remaining 9 children presented with a delayed graphomotorical and speech development associated with normal intelligence. -in our series the most frequent and severe sequels after postoperative mof were neurological. -abnormal liver fimction tests are more likely to be a consequence of the fontan hemodynamics than a sequel of mof. the optimal dosing schedule of surfactant therapy for the treatment of neonatal respiratory distress syndrome (rds) remains unclear. goal: surfaetant function and the concentration of phospholipids (pl) in tracheal aspirates are compared in a prospective randomized trial involving neonates with rds who received either two or more (3 or 4) doses of survanta. methods; ventilated neonates <35w with rds were treated with survanta 1oo mg/kg if fio 2 >_40% or mean airway pressure _>7,5 cm hzo, after 6h a 2nd dose was given (same criteria), if the support still exceeded the criteria 12h after the 2nd dose, the patient was randomized to no extra dose (two}, or to an extra dose of survanta (morel (and a 4th dose 12h later; same criteria), pl was measured in tracheal aspirates and corrected for dilution with the urea method. "active" large aggregates and "non-active" small aggregates of surfactant were separated by centrifugation and quantified. surface tension of the large aggregate fraction was measured by pulsating bubble surfactometer, results: 13 neonates were randomized, 6x two and 7x more (5x3 and 2x4 doses), gestational age was 31,7±2,4w and birth weight 1582±568g. most patients had severe rds with initial ventilation: rate 63.1_+11,1, peak inspiratory pressure (pip) 24,3-+6.4 cm hzo, fio 2 75.3±21.0%. at randomization: rate 63.5±6.9, pip 20.3-+2.5 cm hzo, fio 2 29.5±15.7%, and 24 h after randomization: rate 45.9±17.1, pip 18.7_+2.2 cm hzo, fio 2 26.8±6.6%, without signif, differences between the groups. there was 1 relapse (again fio2_>60% within 72h) in group two and t bpd in group more. in total, 112 tracheal aspirates were analyzed. pl was not signif, different before randomization (two 27.5 ± 15.7 vs more 24.5 ± 11.4 /jmol/ml), but neither after randomization (two 21.2-+ 11.0 vs more 19.3±7,o /~mol/ml). there was no difference in the % small aggregates (two 4.2±1.9 vs more 6.9±5.5%), the surface tensions (ran/m) were not signif, different (each time two vs more): before randomization 10.0±2,3 vs 14.2-+7.2, in the 24h after randomization 12.6±5.0 vs 11.2-+3,8, or 24-48h after randomization 17.0-+5.5 vs 12.8±9.8, or 48-72h after randomization 15.7_+0.4 vs 13.7-+5.6. conclusion: neonates who received more than two doses of survanta did not have higher pl, nor a better surfactant function than neonates who received only two doses of survanta. continuation of the trial is necessary to evaluate clinical outcome. may not indicate need for treatment p.c. clemens s.j. neumann university of hamburg, department of pediatrics, klinikum schwerin, wismarsche str.. 397, d-19049 schwerin. aim of the study: the finding of elevated tsh and decreased t4 in the newborn usually is classified as "transient hypothyroidism", thus the elevation of tsh is classified as consequence of the lowered t4. but on the other hand several data sets show that tsh elevation as well as low t4, one independently of the other one, are associated with different kinds of perinatal stress. each of these laboratory deviations, if not associated with the other value being abnormal too, is generally accepted not to be an indication for treatment. from this we conclude, that more pefinatal stress, as in intensive care neonates, may produce tsh elevation as well as low t4, but only coincidentially, not the tsh elevation being the consequence of low t4, thus not to be classified as "hypothyroidism", thus not indicating treatment. if this hypothesis is right, we should find an association of increasing pefinatal stress with an increasing number of neonates from tsh and t4 normal via tsh or t4 abnormal to high tsh and low t4. method: in the newborn screening program in germa w we determine primarily tsh, and only in the neonates with elevated tsh, in addition we determine t4. thus in our study we asked whether we find an association of increasing perinatal stress with an increasing number of neonates from tsh normal via tsh abnormal while t4 normal to high tsh and low t4. definitions for this study were: tsh elevation = >20 mu/1 (as usual in the german screening programs), t4 lowered = < 6 p_g/dl perinatal stress score was 0 or 1 or 2 or 3 in dependency of the neonate having stress in none to all of the following three categories: (a) forceps or vacuum extraction or sectio co) birth weight below 2500 g (c) at the 5th day existence of a relevant neonatal disorder (rds, ictems gravis, infection/sepsis, vitium cordis with hemodynamic relevance, severe malformation). results: our data of 1131 neonates show a high significant association (chi2 = 84, p <0.001) of, on one hand, perinatal stress score 0 with normal tsh, versus, on the other hand, perinatal stress score 2 or 3 with high tsh and low t4. discussion: facing the background given above, in the intensive care newborn, the constellation of high tsh and low t4 may be only a coincidential addition of two independent abnormalities. in tbese cases -the high tsh not being the consequence of low t4 -the classification as "hypothyroidism" is not justified, thus a therapy not indicated. on the other hand of course there exist rare cases with high tsh as consequence of low t4 thus with hypothyroidism tlms with indication for therapy. unfortunately we have no criteria, that enable a certain discrimination of these two categories thus in respect to the question of therapy or not. conclusion: further research has to be done to learn how to discriminate the coincidential high tsh and low t4 from the causal constellation of high tsh and low t4. until we have certain discrimination criteria we have to treat both groups of neonates. few studies have focused on fa composition of surfactant pc in preterm infants before and after surfactant therapy. methods: tracheal aspirates were collected in 7 venttlated mfants from birth until extubatlon (27/7_1 /twk ga, 859.+ 155g bw). after lipid extraction, t.l.c,, and methylation, fas of pc were quantified by gaschromatography. intralipid a (53.2 % linoleic acid,18:2•6) was started 48h after birth. results: six infants developed respiratory distress syndrome (rds) and received survanta r i00mg/kg (sr), all doses within 18h after birth (ix s r n=l, 2x s r~ n=3, 3x s r n=2). one child did not develop rds. in alt patients, the patmitate % in pc was ~ 65% (before sr<=natural composition), increased to ~ 85% after s r, and remained >80% for i5h after lx s a, 22.3.+i1.8h after 2x, and 38.5.+3.3h after 3 doses. in 4 patients, intubated long enough, the palmitate % decreased with a half-life of 78.7_+42.8h to a new plateau which was still higher than baseline after 1 week. linoleic acid % was 5.85_+2.3 (with rds), decreased after s r~ and returned to baseline due to the decrease in patmitate %. thereafter the linoleic acid % increased linearly with 0.021% per h, in 1 patient even up to 15.1%. other fas did not increase after return to baseline. in neonatal medicine the current parameters, arterial oxygen saturation and arterial oxygen pressure, are poor indicators for oxygen delivery and oxygen demand. the purpose of this study was to obtain venous blood samples from the inferior vena cava in stable neonates with respiratory failure and to determine a parameter that reflects more adequately the balance between oxygen delivery and oxygen demand. "l~e study included 22 neonates requiring mechanical ventilation tbr severe respiratory insufficiency. an umbilical venous and arterial catheter were inserted in the inferior vena cava and in the aorta respectively. paired blood samples were obtained at the time that the patients were hemodynamically stable. fifty paired arterial and mixed venous blood samples were analyzed. 1jnear regression analysis showed the following correlations: in a neonatal intensive care unit adjacent to a delivery room caring for 4000 mothers per year, (with a referral of 400 mostly for preterm delivery), virtually every neonate <ls00g was seen by the same ophtalmologist, j.o. the incidence of retinopathy of prematurity (rop) was in 1976-80 of ii cases (464 preterms <ls00g with 58% surviving to discharge, and 4% rop in survivors; 8% if less than 30 weeks). in 1987-1993, 57 cases of rop were diagnosed by the same ophtalmologist. 679 were born at less than 30 weeks, of which 452 (66%) survived to discharge, and among those survivors, rop was present in 53 (12%), with rates varying from 58% at 24 weeks to 5% at 29. objective: to compare a method of teicoplanine (teico) infusion using an electrical syringe-pump with a manual injection. methods: infusion of teico was simulated through a standart neonatal i.v. system. the infusion system consisted of an life care 4 infusion pump (abbo'it lab.) with its i.v. set for maintenance intravenous fluid (flow < 6 mi/h) connected to a 3-way stopcock. an 1 meter extension tubing (vygon lab.) was placed between the stopcock and a neonatal catheter, an another 1 meter tubing (injection tubing) was connected to the stopcock. the volume of the injection circuit was 2.6 ml. simulations were realised for 2 weights (1 or 3 kg), with a doses of 8 mg/kg and a injected volume of 0,8 ml to 3 ml. our goal was to perform a complete infusion in 10 minutes. we compare one method of infusion with an electrical syringe-pump with 2 manual methods: a: teico was infused with a syringe-pump pilot c (becton & dickinson lab.) according to a protocol using 1) a priming before connecting the syringe to the tubing (for immediate starting of infusion), 2) a programmed volume injected in 5 minutes (the drug volume was greater than the dose prescribed to avoid loss of teico into the syringe), 3) a 5 ml wash out was performed over 5 minutes with the syringe pump. b: teico was manually injected in a few seconds in the tubing followed by a 5 ml wash out over 10 minutes. c: idem as b but a nu site valve (medex) was connected to the proximal end of injection tubing to avoid leakage between removal of the teico syringe and connection of the wash out syringe. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at 10 minutes was calculated and expressed as a perventage of the total amount of teico prescribed. results are a mean of 5 to 8 rons. a b c 1kg 94.2+17,9% 86,8+9.1% 94,4-+6.4% 3kg 95-+4,9% 72-+13,4% 90.9-+6% conclusion: with a drug volume injected < circuit volume and a valve, a direct i.v. administration of the drug in the circuit followed by a wash out seems an accurate alternative to drug infusion conbroled by a syringe pump and is easier to perform. doxapram hydrochloride is a central and respiratory stimulant which is used in neonatal intensive care units to treat caffeine-resistant apnoes of the newborn. routinely, doxapram is administered intravenously. oral administration would be much easier but data on bioavailability after oral administration are limited (two studies) and show a large variation. we therefore studied the oral bioavailability of doxapram in 8 preterm infants. doxapram treatment was started with an intravenous loading dose of 2,5 mg/kg during 15 minutes, followed by a continuous infusion of 1 mg/kg/h. after 24 h the intravenous administration was changed to continuous oral administration with the same dosage, blood samples were collected 24 h after both the intravenous and oral administration and analyzed by hplc-assay. apnoea rates per 6 hours were listed before and after starting doxapram treatment. the median apnoea rate per 6 hours declined from 9 to 2 after both the intravenous and oral administration. the oral bioavailability of doxapram is between 43 and 65%, indicating that the oral route can be used effectively in these infants 2. there were no differences in the decline of the apnoea rate after intravenous versus oral administration of doxapram, infasurf r has been comnared with exosurf r in two studies: one as drodhvlaxis and the other a rescue trial. similar. althouah non-sianificant benefits were found for the natural surfactant. in 6 trials there was a sianificant reduction in dulmonarv air leaks for 0.53: 95% ci 00.41-0.641 for babies treated with natural comnared to svnthetic surfactants. for 7 trials (3554 babies~ comdarina natural and synthetic surfactants for rds {6 comdarina survanta r and exosurf r. and one infasurf r and exesurfr% neonatal mortalitv was sianificantlv reduced (or 0.80: 95% ci 0.66-0.971 with natural compared to synthetic surfactant treatment. in two further trials different natural surfactant drenarations were compared. reduced oxvaen needs for 24 hours after treatment were found for r r infasurf and curosurf respectively when each was compared to survanta r. andarent lonaer-term benefits from these surfactants were not statisticallv sianificant. further trials will be needed to ascertain differences between various surfactant preparations. introduction bacterial meningitis is a common cause of admission in the paediatric age group, and one which still carries a high morbidity and mortality. these complications are strongly associated with a delay in antibacterial therapy. a significant proportion of these patients require mechanical ventilation; it is in this particular group of patients that survival is greatly diminished. the identification of risk factors for mechanical ventilation associated with bacterial meninges may help improving survival by shortening the delay to icu referral. the paediatdc risk of mortality score (prism) is the most widely used scoring system in the paediatric icu literature; the accuracy of prism on predicting outcome in meningitis has been shown to be poor. aim we aimed to describe our population of patients with bacterial meningitis requiring ventilation, and then to identify predictors of survival. methods this study was conducted at the baragwanath hospital in south africa which is an universityaffiliated institution with end average annual paediathc admission of 4500 patients. baragwanath icu admits 250 non-neonatal paediatdc patients per year. a retrospective chart review from january 1991 to december 1995 of 42 consecutive paedistdc icu admissions with bacterial meningitis was performed. results approximately 150 cases of bacterial meningitis are admitted to the general paediatric wards every year; this constitutes ± 3% of all admissions. the mortality of these patients is + 14%. during this time 42 (23m, 19f) patients (7%) were accepted for icu admission, with a mortality of 42.2%. the median age was 9 months (range 15 days to 17 years). the median delay to hospital admission was 48 hours, and the median delay to icu admission was a further 4 hours. the median duration of tcu stay was 48 hours (40 for non-survivors, 120 for survivors). the main presenting features were convulsions (34%), altered mental state (40%), fever (50%), respiratory symptoms (24%), headache (18%), and diarrhoea and vomiting (32%). the most common indications for icu admission were seizures (55%), coma (36%), shock (26%), respiratory failure (29%) and acidosis (21%). in 29% of patients there was a cardiorespirstory arrest prior to admission. the most common organisms in the csf was pneumococcus (57%), haemophilus influenza (15%) and e coli (12%). the presence of leucopenia (wcc < 5), a low platelat count (<100), acidaemia (ph<7.2), and the need for inotropic support were strongly associated with nonsurvival. tachycardia and hypotension were not significantly essorjsted with poor outcome, as has been previously reported. discussion early diagnosis of meningitis and prompt institution of antibiotic therapy requires a high level of clinical suspicion. paediatric patients with bacterial meningitis that require mechanical ventilation have a poor prognosis. there is little evidence to suggest that nomsurviva[ can be predicted prior to icu admission, but a rapid deterioration requiring ventilation and inotrepic support with evidence of severe sepsis (low platelet count, leucopenia) is nmost invariably associated with a fatal outcome. the long term functional outcome of these patients make this disease even more devastating; the rote of icu in the management of these patients has yet to be fully estanished. objective and study design: a retrospective study was pertbrmed for all patients diagnosed with hemorrhagic shock and encephalopathy syndrome (hse) during 1984 to 1994. soroka medical center is the only medical facility in the southern negev region of israel serving a population of -400,000 residents, consisting primarily of jews and bedouins. results: 20 patients (17 bedouins and 3 jews) were diagnosed with hse. main features on arrival included profound shock and coma with con~alsions. active bleeding and/or disturbing coagulation tests with falling heuroglobin levels and thrombocytopenia was noted in every case. all infants developed diarrhea shortly after arrival. elevated urea, creatinine and liver enzymes was noted in all cases. annual incidence tbr inlhnts <1 year of age was 5:10,000 for bedouins and 0.6:10,000 for jews. patients ranged in age from 6-32 wks and arrived at the hospital late night/early morning (2:00am-ll:00am), during winter/early spring (november-april). all were healthy prior to admission, with short prodromal symptoms of upper respiratory tract or gastrointestinal infection noted in 10 cases. most infants had markedly elevated body temperature on arrival. a history of overwrapping and/or excessive hearing was obtained in 4 of 20 infants. bacteriological and virological cultures were negative in all infants. one infant died and neurological sequelae were observed in all survivors. the high prevalence of hyperpyrexia during sleep in the presence of negative microbiological results with no evidence of excessive hearing, and the high incidence of rise among a closed, culturally isolated society known to have a high incidence of congenital malformations, may support previous assumptions that hse results from hyqperpyrexia, originating in most cases from a "physiologic" heat induced trigger which starts and peaks during the night in previously healthy infants with susceptible, predisposing genetic underlie. approximately 10% of hospitalised infants with respiratory syaacytial virus (rsv) infection require mechanical ventilation. our general practice is not to use specific antiviral therapy. we have undertaken studies of rsv-infected mechanically ventilated patients without underlying congenital heart disease or immunodeficiency. study i (n=45): a retrospective review of 45 infants (mean post-conceptual age 48 weeks; median duration of intubation was 8 days (interquartile range 5-11 ). blinded review of chest x-rays during the first three days of mechanical ventilation revealed a spectrmn of lower respiratory tract findings from marked diffiase consolidation in all zones without hyper-inflation (n=10) to gross hyperinfiation without consolidation (n=5), with the remaining patients have an intermediate picture (n=30). death occurred only in patients who were at the poles of this continuum (4/10 consolidation and 1/5 hyperinflation). patients at these poles could be differentiated by gender predominance, birth gestation, alveolar-artarial (a-a) oxygen gradient (p<0.0 l), oxygenation index (p<0.0 l), peak inspiratory pressure (p<0.05), and intubation days (p<0.01). study ii (n=28): prospective audit of infants with the aim of verifying the above differentiation. separating patients based on their early x-rays and a-a gradient we confirmed the above predictable difference in duration of supportive therapy (consolidation v intermediate: 6(4-7) v 14( 12-33 ) p<0.01 ). severe lower respiratory tract rsv-infecrion in young infants results in different distinctive partems of disease with characteristic radiological and clinical features, and each has a predictable timecot~se. conflicting reports on special therapy should be interpreted with respect to these observations before making conclusions about the efficacy of any specific treatment. the clinical data of 186 children wich suffered from a severe mycosis between jan.1990-dac.1994 and wich were treated with amphotericin b in 10 spanish hospitals were collected. mean age was 6+3.9 years; 157 were mate (84%) and 29 female (16%). the most common underlying diseases were leukemimymphoma (31%) and congenital heart defects (20%). the major pathogens isolated were candida albieans (61%), other candida (18%) and aspergillus (17%). and liposomal amphotericin (la) in 68 (37%). in the ca group, the starting dose was 0,3~0,1 mg/kg, reaching a maximal dose of 0.9+0,3 mg/kg after 4.7+3 days. maintenance time was 14+10 days and the cumulative dose: 12~17 rag. in the la group, the starting dose was 1.1±1 mg/kg, reaching a maximal dose of 2.9_+2.4 mg/kg (p<0.01) after 5+5 days. maintenance time was 19~16 days (p<0.05) and the cumulative dose 42_+37 mg (p<0.05). the reasons for la use were: elective in 66% of cases, previous renal failure in 29%, and ca inefficacy in 4%. hepatic or renal function impairment was two times more frequent in la group than in ca group, the antifungal efficacy was 62% for ca and 67% for la. therapeutic failure or toxicity induced withdraw of ca in 7% of cases, vs, 1,5% for la (p<0,01). mortality was not different in both groups (21 vs. 22%), adverse effects were related to ca in 28 events vs, only one in la group (p<0,01). the commonest side effects in ca patients were fever (18%), chilis (10%) and nausea (9%). in ca group, 44 cases (37%) developped analitical anormalities related with amphotericin, vs. 10 cases (15%) in la patients (p<0.001). in the first group, the commonest serum alterations were hypokaliemia (25%), raised creatinine (14%) and bilirrubin (6%). in the second one, hypokaliemia presented in 7% of cases (p<0.01), raised bilirrubin in 6% and creatinine in 3% (p<0,05), the antifungal efficacy of la is at least the same of ca. from the clinical and analitical points of view, la is much less toxic than ca. la can be used at a greater dose than ca and is safe in children with renal failure. laurence desplanques -serge gottot -christian dageville d~artement de sant~ publique -facult~ xavier bichat -16 rue henri huchard 75018 paris -france -the french << reaped ~> network was created to implement a nosecomial infections (ni) quality care program in nicu and picu, the first objective was to describe the annual ni incidence rate in each icu population : all patients stayed more than 48 hours in icu. methods : n] criteria were defined by the reaped group according to cdc criteria. all data were collected by a medical and nursing team. all infection data were validated by an external investigator. results : 4525 patients were admitted over a 14 months period. 68% were newborns. 371 ni were identified among 311 patients. the overall ni incidence rate (ir) was 8.2% and 5.9°/00 person day (from 5.0 to 8.2°/00 according to age, lowest rate for newborns). septicemia (50% of ni) and pneumonia (41% of ni) were the two main ni. according to age, the septicemia ir varied from 6.8 to 10.9°/oo catheter day (lowest rate for newborns) and the pneumonia ir from 3.9 to 7.4°/00 ventilator day (lowest rate for newborns). there were very few other infections (uti : 4%, ir : 7.4°/00 catheter day). gram positive cocci were isolated in 73% of septicemia ( 70% of them were coagulase negative staphylococcal). gram negative bacilli were isolated in 53% of pneumonia (40% of them were pseudomonas). 5% of ni were caused by candida, mostly septicemia. the septicemia and pneumonia ir varied according to unit even after adjustment for age. discussion the aminoglycoside antibiotics are frequently used in newborns for the treatment of severe infection and sepsis due to gram-negative microorganisms. the currently recommended dosage schedule for tobra (2.5 mg/kg q18h) does not take into account differences in gestational or postnatal age during the first 4 weeks of life. we questioned the validity of these recommendations and studied the population kinetics of tobramycin to establish predictive equations that enables the clinician to select the appropriate initial dosing schedule. methods tobra trough (t=0) and peak values (t= 1) were taken on day 2-4 after birth in 460 newborns. tobra was administered as a 30-minute intravenous infusion already in an adapted dosage schedule: 3.5 mg/kg q24h in infants with gas < 28 weeks; 2.5 mg/kg q18h in infants with gas between 28-36 weeks and 2.5 mg/kg q12h in infants with gas > 36 wks, tobra concentrations were analyzed by tdx-assay, a one-compartment model was assumed and non-linear mixed effect modelling (using nonmem) was applied to the data, a trough level < 2 mg/l and a peak level between 6 and 10 mg/l was required, with the present dosage scheme 40% of the trough levels were too high and almost 60% of the peak levels too low. calculations showed that the following dosage schedule should result in optimal levels of tobra. preterm infants gas < 28 wks: 6 mg q48h preterm infants gas 28-36 wks: 4.5 mg q36h preterm infants gas > 36 wks: the currently recommended dosage schedules for toeira result in high trough and low peak levels. prolongation of the dosing interval and increasing the amount of drug per dose according to the above scheme will improve tobra level control. since january 1993 british clinicians have been conducting a randomized controlled trial of neonatal ecmo. mature infants (>-35 weeks gestation and birthweight 2 2 kg) with severe cardiopulmonary failure have been randomized to receive continued care in their referring institution or referral to a designated ecmo centre for further management. we now present the preliminary results which have prompted closure of recruitment to this trial. the final outcome will be assessed as intact survival against death or severe disability at one year of age for all the recruited patients. patients were categorised by diagnosis such as isolated persistent fetal circulation, secondary persistent pulmonary hypertension of the newborn or congenital diaphragmatic hernia and by severity of illness at the point of first contact with the clinical coordinators of the trial -judged primarily by the oxygenation index (240 before randomization). 180 patients were randomized (90 in each arm). hospital outcome data are reported for all patients and 1 year outcomes on t18 (65 survivors). at this stage 26 of the babies allocated to ecmo are known to have died compared to 52 of those allocated to conventional management (rr 0.5; 95% ci 0.35-0.72; p=0.0002). fewer deaths have been obsea-ved amongst ecmo allocated babies in all the diagnostic categories used. a 28% incidence of disability and impah~nent has been observed amongst survivors. this rate is similar in both groups and the survival advantage is not offset by an increased rate of disability or impairment following allocation to ecmo. we consider that these data combined with those available from other studies provide conclusive evidence that the survival to discharge from hospital is substantially higher in patients allocated to ecmo than in comparable infants not so allocated. therefore recruitment to this trial has been closed whist awaiting complete one year outcome data. sigston pe, goldman ap. #keating j. crook r. ~e dj~. great ormond street hospital for children nhs trust, and ~biochemistry department, kings college hospital, london, united kingdom. isoflurane is a safe and effective means of long term sedation in both children and adults in the intensive care setting. the use of isoflurane, by adding it to the sweep gas allows the use of this volatile anaesthetic agent in patients on ecmo, enabling rapid control and weaning of sedation. a potential problem with the long term use of isoflurane is fluoride ion accumulation with the possibility of renal toxicity, the purpose of this study was to assess plasma fluoride levels in patients receiving prolonged isoflurane on ecmo. method: fifteen infants and children (aged 1 day -10 years, median 2 weeks) receiving ecmo support for either cardiac or respiratory failure were recruited to this study. the patients were sedated with isoflurane as well as intravenous agents (morphine and midazolam). isoflurane was administered (0% -3%) via a calibrated vaporiser to the sweep gas, adjusting the level to maintain adequate sedation. blood samples were obtained on a daily basis for plasma inorganic fluoride assay. the relationship between plasma fluoride and amount of isoflurane administered, as %-hours (vaporiser setting in % x hours) was calculated by linear regression. results: the duration of ecmo ranged from 42 to 532 (mean 207) hours, during which the amount of isoflurane administered varied from 7 to 418 (mean 168) %-hours. 75 blood samples were anaiysed, demonstrating individual peak plasma fluoride levels of 2.7 to 16.5#mol/1, mean 7,1p.molli (toxic threshold = 50gruel/f). the plasma fluoride positively co;related with the %-hours of isoflurane (r = 0.65, p = < 0.001). conclusion: this study shows that although there is a dose related accumulation of inorganic fluoride ions in patients sedated with isoflurane on ecmq, the peak fluoride levels are well below the suggested toxic threshold. merzel y, lev a, bar yosef g, halbertal m, lorber a ecmo center, picu, emek medical center, israel. the mortality rate of pediatric patients with acute myocarditis is 20-60% according to the severity of myocardial damage. a 15 month old gzrl presented with high fever, respiratory and cardiac failure. diagnosis of acute myocarditis was made and the patient was ventilated with high pressures and fio2 of 1.0. she required high doses of inotropes. echocardiography revealed a dilated la and lv with severe mr. lvedd was 41 mm and lvsf 9%. calculated oxygenation index was 55. she was resuscitated after a cardiac arrest. she was commenced on ecmo (using biomedicus centrifugal pump and avecor 800 oxygenator) at a flow of 100 ml/kg/mm with immediate improvement of hemodynamlcs, oxygenation and pc02. resptratory assistance and vasoactive drugs were reduced. the patient was transported by air, on ecmo, to the ecmo cevter. she developed arf and cvvh-d was performed. cardiac fimction started to improve after 12 days. ecmo was discontinued on day 18. echo revealed lvedd 34 mm and lvsf 24%. ippv was discontinued on day 20. on discharge, a month later, her lvedd was 29 mm and lvsf 28%. she behaves normally for age without neurologic or other medical sequellae. literature search revealed no case of acute myocarditis, as severe, that was treated successfully. survavors of disease this severe usually suffer dilated cardiomyopathy and permanent disability. the use of ecmo allows myocardial rest which prevents long term myocardial damage. introduction ecmo is increasingly used in the care of critically ill newborns. despite the frequent use of betalactam antibiotics in the treatment of these infants there are no data available on the dispbsition of cefotaxime (ctx) and amoxicilfin (am) d0ring ecmo. the purposes of this study were to determine the pharmacokinetics of these two drugs in infants on ecmo and consequently formulate appropriate dosing regimens. we therefore studied the pharmacokinetics of ctx (100 mg/kg ql 2h) and am (50 mg/kg q6h) in 8 term infants on day 3 after birth, blood samples were taken before (t-o) and 0.5,1,2,4,6 (am) and t2 h (ctx) after the intravenous bolus injection and analyzed by hplc-assays. 2. ctx 100 mg/kg q12h results in adequate serum levels of ctx in fullterm infants on ecmo, am 50 mg/kg q6h results in very high serum trough levels. recalculation based on the known volume of distribution and elimination serum half-life of these infants resulted in the following dosage recommendation: 50 mg/kg q12h. persistent pulmonary hypertension of the new-born (pphn) is characterised by rapid fluctuations in pulmonary artery pressure (pap) and a clinical impression of stifflungs. lung mechanics were measured in 35 term infants, mean age 1.5 +_ 0.7 days who were paralysed and ventilated within the first three days of life. fourteen infants had pphn with systemic or suprasystemic pap measured by echocardiography. in these patients, the respiratory system resistance was 29.4% higher (p < 0.001) and compliance 22.4 % lower (p = 0.03) during systemic or suprasystemic pap compared to when the pulmonary hypertension had resolved. in contrast, there were no changes in resistance in the 14 infants with respiratory distress syndrome (rds) and no pulmonary hypertension or in the seven infants with normal lungs, where two readings were taken 24 hours apart. the changes in lung mechanics interfered with mechanical ventilation, resulting in a 12.5 mmhg rise in paco2 (p=0.007) during pulmonary hypertension. inhalation of nitric oxide 10 ppm resulted in a 16% decrease in respiratory system resistance and an improvement in oxygenation. the bronchial and vascular smooth muscle was increased by 120% in postmortem lung samples from eight infants with pphn compared to six age matched post-mortem controls with normal lungs (p<0.001). these findings suggest a co-constriction and co-hypertrophy of bronchial and vascular smooth muscle during pphn. anatomically the pulmonary vasculature and bronchi lie in close proximity to each other. thus mediators such as endothelin-1 released locally may act on both vascular and bronchial smooth muscle to produce the observed vasoconstriction, bronchoconstriction and smooth muscle hypertrophy. prince of wales children's hospital university of new south wales, randwick, n.s.w. australia. introduction an increasing mortality in asthmatic children has been reported. the increased severity of asthmatic illness leads to an increased demand for icu admission, and a corresponding increased need for mechanical ventilation. geographic end environmental factors are thought to be partly responsible for differences in disease sevedty throughout the wodd. for this reason, epidemiological studies from diverse areas are important, risk factors for icu admission, and for the institution of mechanical ventilation should be identified, to optimise icu admission criteria and to avoid unnecessary delays in admitting at-risk patients. aim to document the clinical characteristics of ventilated and non-ventilated asthmatic patients admitted to icu. methods this is a retrospective study of all paediatric asthma icu admissions from january 1990 to december 1995. results there were 65 patients admitted to the icu for acute severe asthma in the study period. the male:female ratio was 33:32, the mean age 76.1 • 57.3 months, the mean prism 8.5 4-11.1%, and the mean duration of admission 135 4. 129 hours. there was no seasonal variation in admissions. only 40% (26/65) patients required mechanical ventilation. in 22% of all patients this was the first presentation with asthma. there were some significant differences between ventilated and non-ventilated patients (see table) . there was a significantly higher incidence of concomitant and nosocomial pneumonias in the ventilated patients (84.0% vs 21.1%) as well as segmental lung collapse (68.0% vs 26.3%). there were no deaths. discussion the need of mechanical ventilation significantly increases the morbidity of and duration of icu stay of asthmatic patients. younger asthmatic paediatdc patients have a significantly higher risk of ventilation. the need for ventilation is predicted principally from a worsening pco2 and respiratory acidaemia, which is often independently interpreted by the clinician as respira4ory exhaustion. this study has shown that icu admission is important in the management of young paediatdc patients with acute severe asthma and respiratgry fa!!ure. intravenous salbutamoi in the emergency, department management of severe asthma in children. g.j.browne,a. perma,x. phung,m.soo westmead hospital, sydney, australia. it is postulate that if an initial intravenous loading dose of salbutamol is given in severe asthma, a more rapid clinical response will occur, reducing requirements for continued high doses of nebulised salbutamoi with fewer side effects. this double blinded study was conducted in the emergency department of westmead hospital a university hospital in sydney, australia. all children with severe asthma had initial nebuliser therapy (5rag of salbutamol with 4ml of saline). if asthma remained severe 20 minutes later, they were given a dose of intravenous hydrocortisone (5mg/kg) and either normal saline or salbutamol 15microgm/kg intravenously. frequent nebulised salbutamoi therapy continued during the initial first hour if clinically indicated. continuous respiratory and haemodynamic monitoring occurred in the first 2 hours. serum potassium and glucose determinations were made at study commencement and 1 hour after intravenous therapy. salbutamol determination was made at study commencement. children remained clinically monitored for the next 22 hours, with their ongoing treatment determined by clinical response. 29 children with severe asthma 12 months to 12 years of age were studied, with 14 given intravenous salbutamol and 15 given intravenous saline. the intravenous satbutamol group (ivsg) showed rapid reduction in asthma severity scale in the first 2 hours, with reduced need for high frequency nebuliser therapy ( _<2 hourly), occurring 8.78 hours.earlier. no clinically significant side-effects were found in either group, although, tremor more frequent in the [vsg. biochemistry and salbutamol concentrations were similar in both groups. the use of intravenous salbutamol (i5 microgm/kg) in the management of severe childhood asthma is a safe and effective therapy with no significant side-effects and the potential to abort severe asthma attacks in the emergency department. intravenous terbutaline in picu piva j., amantra s, rosso a., zambonato s, giugno k, maia t. introduction: the admission to a picu of children with respiratory failure secondary to an acute obstructive lower airway disease is a common event, especially during winter seasons. these diseases have several causes, but most of them (especially asthma and chronic airway disease) have a good response to the administration of b2-adrenergic drugs. objective: to find the dosis of intravenous terbutaline that is safe, efficient and with minimal adverse effects when used in children admitted to a picu with acute obstructive lower airway disease and respiratory failure. material and methods: we study the records of all children that were admitted to our picu during the winter of 1995. only the patients that had respiratory failure and acute lower airway disease and who needed the use of iv terbutaline were selected. the records were divided in two groups: less than 12 months and more than a year old these two groups were compared in the following aspects: the minimal and maximal dosis, and the length of time of use of iv terbutaline, frequency of tachycardia, hypokalemia, and mechanical ventilation. to establish any difference in the two groups we use the t exact test of fisher and x2, with p< 0.05, results: during the period of study were admitted 367 patients to the picu, and 38 (10,3%) of them used of iv terbutaline. the mean age was 14.2 +12.2 month, used iv terbutaline during 7.24 +3.75 days (0.5 to 17 days), the initial rate was 0.55 +0.26p~g/kg/min, and the means of therapeutic dosis was 2.48 +l.181~g/kg/min (ranged from 0.5 to 4.4). twelve (31.5%) patients had tachycardia art obstacle to the increases in the rate of use of iv terbutaline during any time. mechanical ventilation was necessary in 22 patients (57.8%) and 11 (28.9%) patients died. the children under 1 year of age used initial dosis of iv terbutaline lower than the children up of 1 year old (0.45 p.g/ kghnin x 0.57 ~tg &g/rain, p<0.001), but without difference in the length of use, the maximal dosis, the rate of mechanical ventilation and tachycardia. the frequency of hypokalemia was most common in the group of children under year of age. acute respiratory failure during status asthmaticus may require mechanical ventilation. current therapy includes paralysis, pressure control ventilation (pcv) and permissive hypercapnia to limit pulmonary barotranma and its hemodynamic consequences. asthmatic children exert a significant amount of respiratory effort during exhalation. with paralysis, this expiratory effort is lost. unloading the inspiratory work of breathing while maintaining the patient's expiratory eftbrt using pressure support ventilation (psv), may be beneficial. methods: children receiving pcv (peak inspiratory pressure (pip) = 4 kpa. rate 10 breaths/min) and pco2 > 8 kpa were switched to psv. children were initially ventilated with psv 3.7 kpa and peep = 0.3 kpa (servo 900c). all children received beta agonist therapy, ipratropium and anesthesia with ketamine or inhalational anesthesia, and were breathing spontaneously. respiratory parameters and blood gases are shown be~bre psv, within 30 minutes (start) and when the ph had normalized (during). data are presented as median and range, * p < 0.03 compared to before psv. results: children with hypercarbia during pcv responded to psv, normalizing pcos and ph within 6 hours. the mean respiratory rate decreased from a median of 45 (31-46) to 35 (22-35) while the pip was decreased to 3.2 (2.5-4.0) kpa within 6 hours. the i:e ratio also significantly decreased. conclusion: psv permitted patients to active/y exhale while unloading the inspiratory work of breathing. perhaps this strategy shifts the patient's respiratory effort from inspiration to exhalation, thus permitting the child to meet the excess work of breathing caused by bronchoconstriction. maged z. youssef, peter silver, laura nimkoff, and mayer sagv. division of pediatric critical care medicine, schneider children's hospital, new hyde park, ny 11040. introduction: mechanical vemiladon of patients with severe bronchospasm can be difficult, due to poor chest compliance and increased airway resistance. ketarmne is a cormnonly used anesthetic agent that has been shown to have bronchodilator properties. the purpose of this study was to determine ifa continuous infusion of ketamine had an effect on the oxygenation and chest compliance of children with severe lironchospasm who were mechanically ventilated. methods: a retrospective chart review was conducted of pediatric patients in severe bronchospasm who were mechanically ventilated in our picu and treated with a continuous ketamine infusion. all patients were receiving aggressive bronchodilator therapy and adequate sedation prior to keramine. patients were excluded if any new bronchodilator or sedative agents were started within 24 hours of initiation of ketamine treatment. all patients were simultaneously treated with benzodiazepines. for each patient, the pao2/fio ~ ratio and dynamic compliance [tidal volume/(peak imp. pressure -peep)] was determined immediately prior to ketamine, and at 1, 8, and 24 hours post-ketsmine initiation. data are presented as mean ± s.d., and were a~yzed using one way anova and the multiple comparison method of bonferroni. patients (age 6.0 ± 5.7 yrs.) received * p<0.05 ketamine for severe bronchospastu during mechanical ventilation in our picu. both . .xto-* * the pao2/fio2 ratio and dynamic . . -.... . compliance increased significantly following initiation of the ketamine 200infusion (see figure) . the mean ketamine dose was 32 ± 10 mcg/kg/min, and the -, mean infusion duration was 40 ± 31 too-[/ hours. one patient required glycopyrrotate 6 ~' to control excessive airway secretions, and " one patient required an additional dose of o--j i ~-~4 ~/me diazepam to control hallucinations after i 8 cessation of ketamine. all patients were t~n~,mr~ *~am~ successfully weaned off mechanical ~l~s ~,~s~on ventilation and discharged from the picu. conclusion: continuous ketamine infusion to mechanically ventilated pediatric patients with refractory broncliospasm results in a significant improvement in oxygenation and dynamic compliance of the chest. reports of adults with status nsthraaticus document significant morbidity and mortality, whereas studies in children have had more varied results. different centers report mechanical ventilation (mv) in 10 to 33% of admissions, occurrence of pneumothoraces or paeutuomediastinums in 2 to 11%, and mortality in up to 7% of patients ~'t3. we retrospectively reviewed 113 status asthmaticus admissions to the pediatric intensive care unit (picu) between january 1993 and december 1995. seventy-five of these patients were admitted fr~an the emergency department of chla (er admit). the mean length of stay in the picu was 2.1 days and the mean length of stay in the hospital was 4.6 days. based on 95 patients who had arterial blood analyses, 36 patients had hyperoapnia (pco2 > 45). all patients received oxygen, inhaled albuterol (alb), and cortieosteroid therapy. ninety-five percent of patients also received methylxanthine (mx) therapy. of the 113 admissions, 12 patients (11%) required mv. only 4 of these patients were admitted through our emergency department, whereas the remaining 8 patients were intuhated at outside facilities. twenty-three cases required intr:wenous beta-agonist therapy, either isoproterenol osop) or terbutaline (terb). h~ff of the ea.~es re~%wed were complicated with hypokalemia (k+< 3.5). c,', ,~lications ofpoeumothoraces or pneumomediastinums were seen in 10% of ,'r:u~ported patients, but in only 4% of er admit patients. only 2% of these were in mechanic.all, )atients. there were no deaths in the review. respiratory mechanics measurements 'are useful in mechanically ventilated children to optimize ventilator settings. nevertheless, the transducers used to measure flow (f) and pressure (p) remain expensive. objective. to evaluate the performances of piezoelectric p transducers (350 us dollar) in measuring f and p. methods. we used a previously described monitoring system measuring respiratory parameters [ 1] . in this study f was obtained by a differential piezoelectric p transducer (_+ 12.7 cmi-i20, honeywell) whose sensitivity has been reduced to +_ 2 cmh20 by an electronic amplification equipment and p by a piezoelectric p transducer (_+ 7().3 cmhzo, honeywell) connected to a grid pneumotachymeter &nt) ffleisch 0 or 1 ). volume (v) (5 to 400 ml) obtained by numeric integration off (0.125 to 10 l/rnin ) and p (2 to 70 cmh20) were respectively delivered through a calibrated seringe and an electronical manometer (pic 400 premier) and calculated by the computer. bland and altman analysis was used for assessment of results bias. coefficient of repeatability (cr) was estimated by the standard deviation of repeated measurements of the parameters as calculated in a oneway analysis of variance. results. mean difference (mdi 0 between injected v (5 to 50 ml) and measured v using pnt 0 was 0.15 ml, sd = 0.13 ml. difference and mean v were not correlated. sd of repeated v measurements were not correlated to v. cr was 0.4 ml. mdif between injected v (25 to 400 ml) and measured v using pnt 1 was 3 lrd, sd = 6 ml sd of repeated v measurements were not correlated to mean v. cr was 6 ml. mdif between injected p and measured p was 0.3 cmi-i20, sd 0.4 cm h20 sd of repeated p measurements were not correlated to mean p. cr was 0.3 cmh20. conclusion. inexpensive piezoelectrical transducers can be used to measure f and p and evaluate respiratory mechanics in ventilated children. previous studies have already shown the problem of the reproducibility of pft in preterm ventilated babies. were studied 10 preterm ventilated babies {mean weight 1128 gr) in the first week of life in clinically stable condition, measuring flow, airway pressure and esophageal pressure simultaneously. each baby was studied twice with an interval of one hour and each study was done increasing the rate till 60 to inhibit spontaneous breaths. none sedative has been used. only mechanical breaths were analyzed. compliance and resistence were calculated with a computer system using the linear regression method. we expressed quantitatively the intrapatient variability as the percentage of variation of tidal volume, compliance and resistence between the two studies in each baby. then intraclass correlation coefficient test (icc) was applied to confirm qualitatively our results (total agreement =1, good reproducibjtity > 0.75). we h~£ed, an a6eept~ble ~efiabirl¢, ~-~r;= '~ . during mechanical ventilation, an air leak (al) and plateau phase duration (pl) may influence dynamic and static compliance (cdy and cst, respectively). this study evaluated the effect of al and pl on two methods of measuring c.dy and est. methods. 13 intubated, ventilated patients in a pediatric intensive care unit were evaluated after obtaining informed consent. patients were intuhated with a cuffed endotracheal tube and ventilated with a serve 900(2 ventilator. cdy and cst were determined using the serve ands~rmedics 2600. objective: evaluate the repercussion in respiratory mechanics and arterial blood gases and the impact of the ventilator adjustments on the auto-peep magnitude. material and methods: the measurement of the auto-peep was performed using an eletronic-pneumatic controlled device with a oclasion valve installed between endotracheal canutla and the ventilator circuit. the d~'ice was connected to a solenoid to detecte the end of inspiratuo phase and thus, the activation of the oclusion valve. the signs of pressure and flow were monitorized using a diferential transducer and it was processed using a pc computer and tmeumoview® software. the stud3 were divided in 2 phases: phase a. where the ventilator adjustments was performed using the routine of the unit and phase b, where the targets of mechanical ventilation were to minimize the auto-peep. static compliance (crs) was ineasured by the single-breath occlusion technique, using a mean of ten occlusions for analysis. passive respiratory resistance measurements and the tidal breathing flow-volume loops were also obtained., while the ventilatory settings were siguificantly reduced soon atier ecmo was started. before ecmo crs measured in all patienls was 0.23_+t).03 ml/cmh20/kg (mean_+sem). for each patient the ecmo course was divided into four periods, proportional to the duration of the treatment, and the best ~alue of crs in each period was chosen for analysis. as shown on the figure. crs significantly improved (*p<0,05) from the second half of the ecmo course in the group of patient that finally were successfidly weaned from ecmo. no change ill compliance was measured in the group of patients who failed to respond to the extracorporeal hmg support our data suggest that compliance measurements during ecmo can be useful togelher with overall clinical evaluation to predict both outcome and duration of cxtracorporeai support in the neonatal and pediatric population. objectives: brain temperature determines the amount of neuronal damage caused by hypoxic insults. thus measuring brain temperature at standardised conditions is in request. we investigated whether brain temperature of neonates varies with head insulation environmental temperature, body activity and time course. patients and methods: we investigated non-invasive brain temperature analogues in 19 healthy prematures tess than two weeks of age in an incubator (gestational age 31.5 + 2.1 wks; x + sd, weight 1653 + 370 g). we measured nasopharyngeal temperature (tnasoph) by a thermistor placed in the nasopharynx via a feeding tube, zero-heatflux temperature (zht) at the temple by a thermistor and healflux transducer, insulated by two pads, as well as rectal and incubator temperatures. patient activity was documented by video taping. measurements were performed during periods of increased insulation 1) by turning the head with its measuring site on to the mattress ( (5) 3 (5) -2 (6) 4 (5) 0 (6) 4 (3) 2.5 2 4(5) 25(10) 20{12) 8(5) 5(10) -2(7) 5 6 38 (22) 112(34)i70 (48)51(27) 20 (18) 5(15) 7.5 3 38 (19) 125(21) t85(29) 120(30) 70(30) 30(20) 10 4 53 (30) 133(28) 182(33) 157(24) 154(34) 110(45) web 2170 (lmg/kg) 5 at 30 rain 3 3 (5) -4 (6) 5 (6) 4 (3) 5 (4) -3 (6) the vehicle had no effect. paf caused dose dependent rise in ao and pa pressure and reduction in flow to lpa (up to 80% like the vascular endothelium, the endocardial endothelium (ee) has a significant impact on adjacent myocytes, and may critically alter myocardial function.~ we have previously shown that ee cells are capable of sensing and responding to hypoxia by the release of prostacyclin (pgl). 2 potassium channels in other cell types have been reported to be oxygen sensitive. to determine whether potassium channels modulate the ee hypoxic response, we investigated the effects of three potassium channel inhibitors on hypoxia-induced pg] 2 release from ee cells. methods: ovine endothelial cells were harvested and passaged onto 30 ,~ microcarriers. cells were constantly perfused with normoxic and hypoxic kreb's solution, and with three potassium channel blockers: glibenclamide (gb, 3 #g/ml), tetraethyl-antmonium (tea, 10 ram) and 4 aminopyridine (4ap, i0 mm), perfusate was assayed for prostacyclin (ria). data were compared by analysis of variance. * p<.05 compared to 3normoxic control; # p< .05 compared to hypoxic control. adrenaline is extensively used for resuscitation in neonates with rds. however, effects of adrenaline on systemic, pulmonary and cerebral hemodynamics have not been defined in newborns with rds. thirteen anesthetized, and ventilated newborn piglets were subjected to repeated saline lung-lavage series while mean systemic arterial pressure (abp), mean pulmonary arteriat pressure (pap), mean left atrial pressure (lap) and mean central venous pressure (cvp), cardiac output and blood flow in the internal carotid artery (ica) were measured. systemic vascular resistance (s~), pulmonary vascular resistance (pvr) and cardiac index (ci) were calculated. sixty minutes after luug-lavage, the adrenaline group (a) (n=6) received adrenaline as a continuous infusion of 1.2 lag/kg/mi, while the control group (c) (n=7) received saline. none of the varlables were changed by saline. however, significant increases in abp (p<0.0001), pap (p<0.0001), ci (p<0.001) and svr (p<0.01) were observed after administration of adrenaline, whiie pvr and ica were not modified. mean±sd for abp/pap (p/a), fvr/svr (p/s) and ci (ml/mirdkg) were: ratios of pap/abp and pvpjsvr significantly increased following infusion of adrenaline. these data suggest: 1) the cerebral perfusion is preserved during the infusion of adrenaline; 2) effect of the adrenaline infusion on the systemic circulation is more pronounced than its effect on the pulmonary circulation in newborn piglets with surfactant deficiency. s demirak~a, ch knothe, kj hagel, j bauer department of pediatrics, justus-liebig-university giessen, frg inhaled no is a short acting selective pulmonary vasodilator. we studied the effects of 80 ppm no and 100% oxygen during heart catheterization in 16 children (age 1 -6 years, median 9 years) with heart defects and elevated pulmonary vascular resistance index (pvri) in order to asses the value of no as a tool of decision making for corrective cardiac surgery. patients were eligible for testing when they were more than one year old and had a pathologically elevated pvri in a previous heart catheterization. intubation, 'anesthesia and muscle paralysis were performed in all patients during testing of pulmonary reagibility. calculations of pulmonary vascular resistance and flow were based on the fick method. response to no was assumed when pvri declined more than 30%, 9 of the 16 patients were responders to no. effects of no and oxygen on pvri, mean pulmonary arterial pressure (mpap) and pulmonary vascular flow (qp) in all responders are described in the table below. cardiac surgery was offered to all responders, and 5 of them were successfully operated. surgery is planned in another 3 patients and parental consent for surgery was not given in one patient. in ebstein disease, during the first days of life, the ability of right ventricle to propel blood to the pulmonary artery is impaired due to high pulmonary vascular resistances. the flow is mainly directed to left atrium through tricuspid insufficiency, right atrium and foramen ovale. to decrease pulmonary resistances and increase pulmonary blood flow, high frequency oscillations, mechanical ventilation, nitric oxide and prostaglandin are required. after few days, a forward circulation is normally established. we cared two newborns with ebstein disease where this approach was hindered by a large pulmonary valve insufficiency. both of them were diagnosed in utero, showing a large tricuspid insufficiency with a non opened pulmonary valve and a ductal left to right shunt. one fetus was hydropic. at birth, blood stream from the ductus arteriosus was directed to the right ventricle through the pulmonary valve insufficiency then to right atrium, left atrium and ventricle, aorta and ductus arteriosus. a low pulmonary blood flow was demonstrated by low mean velocities (10cm/sec). a high reverse flow was seen in descending aorta with a negative flow in the renal artery. both of these newborns were oliguric because of ductus arteriosus steal. pulmonary blood flow doppler evaluation allowed different strategies of ventilation, switching between hfo and conventional ventilation, modulation of pge1 doses, inhaled pulmonary vasodilators (nitric oxide) and surfactant. the hydropic baby died, the other survived after 3 weeks of intensive care complicated by supraventricular arythmia (wpw). in conclusion, during neonatal period, in ebstein disease, a large pulmonary insufficiency leads to a vicious circle where lungs are excluded, inducing severe asphyxia and high pulmonary resistances. the blood is backward propeled from the aorta through the ductus arteriosus to the right ventricle and atria, then left cavities to aorta. arec must be considered when pulmonary blood flow does not increase despite optimal therapy. guti~rrez-larraya f*, mandoza a*, velasco jm*, zavaneua (3**, gatindo a ~, s&nchez-andrede r, s&nchez jl***, mellon a***, mar f***. pediatric cardiology*, pediatric cardiac surgery**, pediatric intensive care unit***. hospital 12 de octubre. madrid. background: transesophageal pacing (tp) is effective and sate both for diagnosis and treatment of pediatric arrhythmias. material and methods. eleven consecutive patients are included. a tri or quaddpolar 6 or 7f temporal transvenous catheter with an interpolar distance of 13 to 22 mm was advanced through the nares and positioned to the point with the largest amplitude of atrial deflection, surface ecg and a bi or monopolar electregram were recorded simultaneously, selecting filters when needed (5 to 100 mhz). pacing was performed with a programmable stimulator (medtronic 5328) beginning with 2 ms and increasing ma to 10 and then increasing up to 9.9 ms. narula method was selected to diagnose sinusal node disfunction (snd) and overdrive pacing to treat tachyarrhythmias. results. tp was useful in all the 11 patients and no complications were observed: in 3 patients a snd was diagnosed (one needing a definitive pacemaker), in two patients with atrial ratter (ripe 1) sinus rhythm was recovered, in one patient with a postoperative junctional ectopic tachycadia we were able to get atrial synchrony with marked bemodinamic improvement, and 5 patients with paroxysmal supraventricular tachycardia sinus rhythm was easily and quickly restored (2 of them recquirad repited episodes of tp until pharmacelogycal levels of antiarrhythmic drugs were raised). mean age and weight were 31 months and 12.7 kg (one patient had 2.1 kg). there was a close relation between height and depht insertion (r= 0.98). mean stimulation parameters were 9,1 ms and 13.5 ma. discussion. in experiencied hands tp is an effective and safe way to treat and diagnose cardiac arrhythmias even in newborns. it should be tried before endovenous pacing is stablished and it is faster than pharmacologycal treatment. bailing g., eicken a., sebening w., vogt m., schumacher g., bl~hlmeyer k.; kinderkardiologie, deutsches herzzentrum m0nchen, germany to assess the outcome of balloon valvuloplasty in infants with cardiac failure caused by critical aortic stenosis a retrospective study was performed. between 1986 and 1995 33 neonates, aged 1 -28 days (median 9 d), weight 2.t -4,1 kg (median 3,3 kg) with critical valvar aortic stenosis were dilated by balloon (aovp) as the first line treatment. 21 patients received prostaglandin el, 18 needed inotropic drugs and 16 mechanical ventilation. associated cardiac lesions : persistent ductus arteriosus (pda) in 27 patients (restrictive pda in 8 cases), a mitral regurgitation (mivr) in 27 cases (15 severe and 12 moderate or mild mivr), angiographic findings of endocardial fibroelastosis (efe) in 12 patients, mitral stenosis (mivs) in 8, coarctation of the aorta (coa) in 2, and finally a small musculary ventricular septum defect (vsd) in i patient. vascular approach for ballooning : a. axitfaris in 20 cases (61%) a. femoralis in t 0 (30%) and v. femoralis in 3 cases (9%). the median ratio between inflated balloon and aortic valve diameter was 0,99. dilatation was achieved in all 33 cases. the peak systolic gradient across the aortic valve (pre aovp) ranged from 0 to 137 mmhg (median 50 mmhg) and was reduced to 0 to 55 mmhg (median 15; gradient reduction is significant (p < 0,01)). aortic regurgitation (aovr) was absent or mild in 30, moderate in 2 and severe in 1 patient after aovp. 23 children survived (actual suwival rate: 70%; early mortalffy: n = 3; late mortality: n = 7). mid term follow up (0-8,8 years; mean 2,7 years) showed an increase of the systolic peak doppler gradient across the aortic valve (median 41 mmhg) but no increase of aovr. 10 re-interventions (re-aovp: n = 3, commissurotomy: n = 2, mitral valve replacement n = 2, resection of subaortic stenosis: n = 1, resection of coarctation: n = 2,vsd-closura: n = 1 ) were performed in 6 patients. rv contractility and pulmonary vascular mechanics(pvm) in immature animal models are poorly underslood. we developed an acute rv injury model to measure rv contractility and pvm in response to commonly used cateehalamines. ten anesthetized piglets (9-12kg) were instrumented with micromanometers in the lv, rv, pa, and la. a pulmonary artery flow probe was placed to measure cardiac output(qpa). ultrasonic dimension crystals were sutured to the myocardium and dynamic chamber volumes estimated using shell subtraction methodology. rv injury was induced with 3-7 cryoprobe injuries at -50 to -70°c for 3-4 minmes each. da at 10mg/kg/min, db at 10mg/kg/min, and ep at 0.1 mg/kg/min were infused in random order. rv contractility was evaluated by calculating a load independent measure of contractility, the preload recmitable stroke work(prsw), during vena caval occlusions. to describe pvm, input resistances), characteristic impedance(z0), total pewer(tp), and efficieacy 03f=qimo"p) were measured. measurements were made pre-and post-injury, during infusions, and between infusions. clyoablation decreased prsw (22.8_+7.8 to 13.8+4.1, p<0.001). at the end of the experiment, prsw remained depressed to this level indicating stability of the model. one factor contributing to organ dysfunction for infants undergoing repair of congenital heart defects (chd) is their "inflammatory response" to cardiopulmonary bypass (cpb). this response is characterized by an increase in cytokine release, complement activation and endothelial injury. modified ultrafiltration (muf) is a method for removing tissue water and inflammatory mediators by rapid ultrafiltration followin~ cpb, muf may acutely improve post-operative end organ function. in this study, we evaluated the effects of muf on the pulmonary and cerebral function of infants undergoing cpb for repair of chd. we prosnecrivety randomized 30 infants (.~ 5 mos) to either muf (n=16) or no muf (n=14)(control) following correction for chd. the study intervals were 1) before cpb, 2) immediately after cpb, and 3) 20minutes after cpb. pulmonary function was evaluated by measuring dynamic compliance (cdyn) and airway resistance (raw). for 13 pts (mue=6 pts; control=7 pts) exposed to a period of deep hypothermie circulatory arrest (dhca), cerebral metabolism (cmro2) was calculated at each interval using the xe 133 clearance technique for cerebral blood flow measurements and arterial and jugular bulb saturation measurements to calculate cmro2. a reduction in cmro2 has been consistently demonstrated after dhca. the effects of muf on cdyn and on cmro2 are shown below: p<0.05 vs pre-cpb; # p<0.05 vs post-cpb • p--o.06 vs. post-cpb this study demonstrates that immediately following exposure to cpb, muf will improve pulmonary compliance. raw was not different between groups. there was no significant difference in hours of post-op ventilation for either group. in those pts exposed to dhca a trend towards better cerebral metabolic recovery compared to control was demonstrated. this is the first technique applied to infants undergoing dhca where cmro2 after cpb was greater than precpb measm~s. although this may be beneficial to postoperative hemodynamics, ventilatory management and long-term neurologic recovery, more patients and longer follow up will be necessary to verify such an effect. the effects of conventional mechanical ventilation (cmv) on left ventricular (lv). diastolic filling in neonates are not well established. one approach to improve lv filling is the use of cmv to provide a phasic increase in airway pressure {thoracic augmentation). this phasic increase in airway pressure may result in an increase in lv filling similar to that which occurs with cpr. thoracic augmentation has not been evaluated in neonates with ventricular dysfunction who frequently demonstrate increased heart rates. attempts to maintain low peak airway pressures during cmv may result in a prolonged inspiratory time that occurs over multiple cardiac cycles. this may alter lv filling in the later cardiac cycles. to determine the effects of inspiratory time on lv diastolic filling, 10 infants were examined with doppler echocardiography less than 24 hrs after surgery for the arterial switch procedtme. pulsed doppler recordings of the millal valve (mv) were obtained with the inspiratory time adjusted to occur over 3 cardiac cycles (21 sec.). a pressure transducer was placed in line with the ventilator, and the respiratory cycle was recorded superimposed on the doppler tracing to provide accurate determination of inspiration and expiration. doppler recordings were obtained from the apical 4-chamber view and the following measurements were made: peak e and peak a velocities, eia ratio, and deceleration time. compared to the expiratory phase of cmv, the initial beat during the iuspiratory phase of cmv resulted in an increase in mv peak e (.53 +-.06 vs .65 -+ .08 m/s, p<0.05) and peak a (.47 + .07 vs .63 -+ .09 m/s, p<0.05) velocities with no change in mv deceleration times (p<.01). compared to the initial beat during tile inspiratory phase, the third beat during the inspiratory phase resulted in decreased peak e (.65 + .08 vs .40 + .05 m/s, p<0.05) and peak a (.63 + .09 vs .40 + .05 m/s, p<0.05) velocities with no difference in deceleration times. thus, cmv augments lv filling during the initial phase of inspiration. however, as the increase in airway pressure is distributed over multiple cardiac cycles, lv filling falls below baseline levels. these observations indicate that while thoracic augmentation may be beneficial, to optimize lv filling the inspiratory time of cmv must be < 3 cardiac cycles. energy expenditure in pediatric orthotopic liver tranaplantat~on, to determine the actual calorie requirements of critically ill children and evniuate the correlations between measured, stress-p~lictod and repleted energy exponditttm and the severity of illness. des/gn: a prospective, dinlcal study. se~ng: tertiary care pediatric icu in a university hospital. patients: ten patients aged 6 to 210 months with disorders prompting picu admission, including sepsis, respiratory failure, solid organ transplantation, and cardiovascular surgery. inta~entions: all patients were studied within 24 hrs of major surgery or transplantation, or following acute illness. all patienls were severely stressed clinically and all but two were intubated by cuffed tubes, in three of them, still in a stress state, the study repeated on the third day of the disease, energy expenditure mensurements (mee), as well as illness seventy scoring systems, mtfltisystern organ failure scores and various anthropemetric and clinical indices of nutritional status, the stress-predicted energy expenditure (s-pee), the basal metabufie rote (pbmr), the repleted energy (re) and the recommended dietary allowances (rda) were measured or calculated in each patient. multiple regression analysis was used to analyze the data. measurements and main results: although the mean mee was significantly lower than the mean s-pee (37.6+11 kcal/kg/day vs. 50.35:16 kcal/kg/day, p<.002), it did not differ significantly from the pbmr (mean difference -2.62 kcal/kg/day, range -10.07 to +9.06 kcal/kg/day). the s-pee/mee ratio ranged from 1.04 to 2.07, while the re/rda ratio (21.25:4 kcal/kg/day)/(75.85:7 kcal/kg/dny) ranged from only .1 to .5. the prism/tiss ratio was not correlated better with mee than the diagnostic category (r~=.36 vs..38, respectively). the re was positively correlated withthe mee (rz=.65, i)=.07) while negative oarrelatian has been found between mee and age, mid-arm circumference, triceps skinfotd and the use of vaseactive agents (r~.81, -88, -.67, p<.005 and -.71 resp~lively). concl.m~: if s-pee is used for caloric repletion in the stressed oritic~ly fll el~d, these patients will be substantially overfed by as much as 100%. although pbmr appears to approximate the mee by ±10%, other clinical and nutritional indices should also be ennsidered. objective: to deter .mine..t.he metabpli.c and.nutritional state of mechanically ventilated intants and children m relatmn wlm severity or msease. patients and methods: 37 mechanically ventilated infants and children, median age 7 months (range 3 days to 13years), were studied. severity of illness was assessed using prism, prism-ii~ and fiss-scores. oxygen consumption (vo2), energy expenditure (mee) and respiratory quotient (rq) were determmed by mdirect calorimetry. total urinary nitroger(tun) and creatinine excretion, levels of albumin and crp were aetermmed in 16 patients. in these patients daily caloric intake and substrate utilization were assessed. they were categorized in subgroups: a partial feeding (recent admission to p1cu); b complete feeding. results: mee of the total group (n=37) 0a) i=intake g/kg/day (% total intake); u=utilization g/kg/day (% total production). nitrogenba]ance was negative in all patients in group a (mean -227.7 --176:4 mffkg/day) and positive in all but one patient in group b (.mean 84.9±109.d n~g/..kg/day;p=0.001). no significant correlations were round between creatinine height index, crp, albumine, jun vs v u2/kg conclusions: the mean measured energy expenditure does not exceed predicted resting energy expenditure, but ~ere is a wide range. in a majority ot patients with complete feeding h.igh carbohydrate intake resulted, in high kq and lipogenesis. in patients witla partial teeding the highly negatwe nitrogen'balance suggests that in the early phase of diseasean higher protein intake should be provided. severity of illness scores ann oiocnemicm markers of physiologic stress correlatedpoorly with oxygen consumption. leite,hp; iglesias, s; faria, c; ikeda, a; albuquerque, mp; carvalho, wb pediatric icu -s~o paulo federal university -s~o paulo, brazil objectives: 1 ) to evaluate patterns of use and monitoring of nutritional support in critically ill children; 2) to evaluate an education program in nutrition support given throughout the resident physician training in the pediatric icu. patients and methods: records of 37 patients receiving nutritional support during 1993 were reviewed. aider this first phase, knowledge and understanding of the role of nutrition support was conveyed to the residents through didactic lectures. in a second phase thedata were reevaluated in 35 children who were given nutrition support in 1995. results: from a total of 425 days ofthempy, the single parenteral route was utilized in 80,5%, the digestive route (tube feeding or oral route) in 19,5%. of this time. a previous nutr~ional assessment was performed in 3 children; no patient had the nutr~on goals set. the nitrogen to nonprotein calories ratio ranged among 1:80 and 1:250. only 29,7% of the patients had their estimated caloric needs supplied and this goal was achieved only in those patients who were on enteral tube feeding. patients did not achieved their goals for vitamins. the supply ofoligonleme~s was adequate except the zinc. nutritional monitoring parameters including weight, serum albumin and serum triglycerides were performed in almost all the patients but without uniformity. the reevaluation ofthase parameters showed adequacy of protein and micronutrients supply; however deficiency in nutritional monitoring and infrequent enteral feeding were still detected. conclusion: there were lacks in the implementation of nutritional support, which were partially corrected in the 2rid phase of the study, although the training of residents may have contributed to give them cognitive skills, it didn't changed policies and procedures as desired. we recommend reinforcement of the education program concerning basic nutritional aspects, and the organization ofa multidisciplinary team in charge of coordinating the providing of nutritional support. plasme free fatty acids (ffa) are the meier energy source for mast tissues. during fasting ffa are released from the breakdown af triglycefides in edipose lissue (at). lipalysis, le. the rote of release o/ ffa, has been megsured in humans by means of stable isotope techniques using labeled pa or glyeerd as traces. no information is avoilob!e io dale on the ro of la. we infused albumin hound u13c-pa and u13c-la in 7 critically ill infants, receiving 20 kcel/kg/doy of iv glucose end na oral feeding (weight 3.6,i.,3 kg;, range 1.9-5.8; ego 57:64 days, range 1 149) and measured simultaneously the ra of pa and la from (he isotopic enrichment of plasma fea by gas chromatography-mass speclrome|ry ai 1:50, 2:00 and 2:10 hours from tile shod of the infusion. a subcutaneous gluted at biopsy was obtained far fatty acid (fa) composition. we intended to (1) in fie infants sbjdied atipa ~'os hi9her than attla (~p<o.o01)' and ihe ra of pa was higher then thai of la (~p=0.00 §). however the ratio el the re's to the respeclive fa in at was higher for la than far pa (*p=0.02). in conclusion the ra af la was higher then expected from ~he fa composition of at. we speculate [hat la is preferentially released during tipolysis and its contributuion to the energy metnbolism of the sick infonl could io !orger than what: is normai!y assumed from ihe fa composilion of at and of plasma fea. preoperative starvation can be prevented in infants undergoing non gi surgery by continuing feeds till as long as it is safe to do so. some gi disorders require withholding of feeds for a long period. for these and for infants already suffering from pem~ parenteral feeds are given preoperatively. peroperatively nutrition is maintained by ensuring adequate glucose supply in the infusion fluid and its smooth metabolism. proper placement of feeding tubes are also carried out peroperatively. postoperative early resumption of oral feeds is ensured by new techniques of anaesthesia and pain relief and methods to ensure early return of peristalsis. enteral feeds of pre digested substances and feeds through transanastomotic tubes and through gastrostomies and jejunostomies can prevent starvation in many situations. parenteral feeding is carried out only when enteral feeding is not possible, for example in necrotising enterocolitis~ gastroschisis, short gut syndrome, high enteric fistula and acute pancreatltls. the artedal ketone body ratio (akbr) is established as a valuable tool in the management of adult patients undergoing surgery for severe liver disease.the redox theory emphasises the central role of the liver in preserving homeostasis and the importance of the hepatic mitochonddal redox potential (nad+/nadh) in monitoring liver function and integrity.the akbr (plasma acetoacetate/3hydroxybutyrate) is a measure of hepatic mitochonddal redox status, reduced ratios associated with poorer outcome. the venous ketone body ratio (vkbr) is influenced by peripheral ketone utilisation and therefore thought unreliable in assessing hepatic redox its use has been dismissed as no correlation with the ratio in hepatic venous blood was found. inspite of this. vkbr is used in the diagnosis of lactic acidoses and respiratory chain defects. the objective of this study was to determine the relationship between the akbr and vkbr in a paediatnc intensive care population. 31 children admitted to the paediatdc intensive care unit, with indwelling arterial and central venous lines as part of their routine care, were recruited for the study. the median (range) age was 2.0 years (0-16.6 years) with prism score 10 (0-36), simultaneous akbr and vkbr were measured. suppression of ketogenesis was confirmed using a rapid 3-hydroxybutyrate strip test (ketofilm, genzyme diagnostics) pdor to sampling. the median vkbr 0.50 (range 0.13-1.46) was lower than median akbr 0.56 (range 0.11-1,33), there was good agreement between artedal and venous ratios, bland-altman analysis giving a 95% confidence interval for relative bias of -0.13 to -0.03. there was a significant correlation between vkbr and akbr r 2 0,8271, p,0.001 (intercept 0.02, slope 0,85) conclusions; values for akbr tend to be higher than vkbr, however there is a consistent relationship in critically ill children. in paediatdc patients in whom ketogenesis is suppressed, vkbr may be considered equivalent to akbr. this simple test may prove to be a useful adjunct in predicting mortality in cdt{cally ill children. to understand the present status of pediatric intensive care in china, we conducted a survey between october and december, 1993, involving 20 hospitals in 14 provinces and municipalities. the results showed that there were totally 41 icus for pediatric patients, including 19 pediatric icus (picu), 18 neonatal icus (nicu) and 4 pediatric surgical icus (sicu), with total of 403 beds. the physicians to bed and nurses to bed ratios were 1:1.5 and 1:0.91 respectively. the average number of equipment per bed was 0.47 ventilator, 0.34 multi-fnnction monitor and 0.47 infusion pump. very few of the icus had portable x-ray machine, biochemical and blood gas analyzers, and hemodialysis machines. the most frequently treated diseases/conditions were pneumonia, intracraniat infections, post-operation and sepsis in picus, and neonatal pneumonia, hypoxic ischemic encephalopathy and sclerema in nicus. pneumonia and respiratory failure accounted for 33.29% and 26.50% of all the diseases/conditions treated in the icus and the mean case fatality rate of respiratory failure was 24.50%. the results of the survey suggest that there is shortage of tcu beds and modern equipment, and treatment is often delayed due to excessively strict criteria for mechanical ventilation. a set of simple, and nationally acceptable criteria for evaluation of severity and cure of the diseases/conditions is urgently required. the medical reports of 286 children were reviewed and each admission was analysed in terms of age, sex, diagnosis, management within the hosp~al, length of hospital stay and type of poisoning. the youngest age was 23 days and the oldest was 16 years. hundred and twelve (39.5%) of the children were girls and 174 (60.5%) were boys. the most common (26.5%) reason of admission was intoxication among all of the cases and the greatest group (73.7%) of the poisoned children had ingested medication which was followed by another group of patients (9.2%) who had eaten mushrooms. the peak incidence of drug ingestion was salicylate intoxication (20%). forty drug poisoninigs were accidental while 16 was intentional. the majority (82.4%) of the cases that committed suicide was between 12 and t7 years old, and the main cause of suicide was being unsuccessful at school. we conclude that poisoning -especially salicylate intoxication -is still a major problem in turkey and we believe that emphasis on the need to stere all kinds of drugs in a secure place and re-examination of a chin resistant packaging should help to reduce childhood poisoning significantly which is a preventable condition. included were all patients who died in the hospital, except those treated in the neonatal icu (predominantly premature and sga newborns) and those who died in the emergency room. among a total of 7179 hospital admissions (excluding the neonatal icu and emergency room), 99 patients died (1.4%). of these 99 patients 73 (74%) died in the pediatric icu, 18 (18%) in the ward and 8 (8%) in the operating room. a chronic underlying disease was present in 66 (67%). withholding or withdrawal of therapy was implemented in 48 (48%) children, 27 (27%) died due to failed cpr, 20 (20%) were brain dead and 4 (4%) died following a dnr order. justification for therapeutic restrictions in the 52 patients of the dnr and w/w groups was imminent death in 32 (62%), lack of future relational potential in 12 (23%) and excessive health burden in 8 (15%). withdrawal or withholding of therapy was carried out by extubation in 46%, vasoactive drugs were stopped in 25 %, and mechanical ventilation was withdrawn in 21%, analgetics and sedatives were frequently used (in 73% and 79%, respectively). hence decisions concerning restrictions of treatment are common in pediatric practice, mostly due to imminent death. patients in which treatment was restricted were characterised by a longer hospital stay, a worse prognosis, a higher frequency of chronic underlying diseases and a lower acute mortality risk. despite restrictions of intensive therapy, most patients were allowed to die in the pediatric icu. background microalbuminuria (mca), a subclinical increase in urinary albumin, reflects glomerular and overall vascular permeability 1"2. an increase in urinary excretion of albumin occurs after burns and trauma. transcanillary albumin escape rate is also increased in response to elective surgery 3 and in critically ill adult patients 4. we investigated a possible relationship between urinary albumin levels and clinical instability, as measured by pediatric risk of mortality (prism) scores. method we studied 26 consecutive patients (median age of 13 months, range 2-100). patients whith nephropathies or any abnormality of urine analysis were excluded from the analysis. prism scores, mca (mg.1-1) (immunonepbelometric) and urinary creatinine (cu) (mmol.l -!) (jaffb) (48 hour collection sample) were determined within 48 hours from admission to the picu. the mca/cu ratio (mg.mmol.1 "l) was used to correct for urine output variability. diagnoses included respiratory failure (6), postoperative (5), neurologic (5), sepsis (4), trauma (3) and miscellaneous cases (3). pearson's correlation was performed to correlate data. results and conclusions. mean prism score and mca/cu were 16.9 ± 5.9 sd and 1004-39 sd, respectively. a significant correlation was found between mca/cu and prism scores (r=0.80, p<0.001). our observations show that, independently of the initial insult, the paediatric unstable patient may have increased capillary permeability, which is correlated with the degree of physiological derangement, as measured by prism scores. microalbuminuria can be rapidly determined since it is routinely used in the management of diabetic patients, it is inexpensive, simple to measure and blood-spearing. therefore, it might have a role in the clinical assessment of capillary permeability and transcapillary albumin escape worldwide the demand for paediatric intensive care services exceeds the supply. in developing countries sporadic access to such services alters expectation of care and can lead to children being either mechanically or handventilated in general paediatric wards. the outcome of children requiring ventilation in a major teaching hospital in india was reviewed.children were ventilated on an adult intensive care unit (aicu) if a bed was available, otherwise in the general paediatric wards. over a 4 year period 109 children were ventilated on aicu with 54 deaths. yearly mortality rates varied between 43-58%. over a 3 month period 37 patients were ventilated on the paediatric wards. of the 15 p~tients over 4 weeks of age 11 died (chi squared 0.t >p>0.05) reasons for the higher mortality rate on the paediatric ward likely include the higher patient:nurse ratio, and more limited resources. a predictor of mortality based on simple physiological observations without the need for expensive blood tests and including chronic health status would be a useful tool. the establishment of a paediatric intensive care unit is proposed to redress the balance of care. to assess the performance of the pediatric intensive care unit of hospital dona estef~nia by an international standard score, the authors did a prospective study of 1149 consecutive admissions to the unit during a period of 29 months. mean age was 50.63 _+ 54.07 months; mean lengh of stay was 3.16 + 5.59 days. the effectiveness and efficiency were determined by the admission prism. admission efficiency was defined by two criteria: a) mortality risk > 1% or b) the administration of at least one intensive care unit-dependent therapy. the cumulative observed mortality was 5.57% and the expected mortality was 5.97%, with a standardized mortality ratio (smr) = 0.933. the overall performance of the prism score-based predictive model was found to be good (goodness-of-fit test x2 [5] = 6.387;p=0.271). of 1149 patients admitted, combining the two criteria (icudependent therapy and mortality risk) an admission efficiency of 825 (71.8%) was found, equating to 3263 (89.94%) of 3628 1cu days. conclusion: in our study the assessment of the admission efficiency and of the effectiveness of the unit was possible by using the prism score of admission. there was no significant difference between mean values for otiss and ntiss)in level l patients (p=0.12 paired t-test).for level 2 and 3 patients mean value of ntiss was greater than otiss (p<0.0001). there was a significant correlation between levels using either ntiss or otiss (mean difference level 1 and 2, level 2 and 3, ( p < o.oool). conclusions: a new tiss has been developed and used in a picu. nurses were able to accurately score the interventions on their shift. the assignment of patients to intensive care levels correlates with tiss values allowing a quantitative measure of severity. objective : to compare the rate of cerebral palsy (cp) between monochorionic-twins, dichorionic-twins and singletons born at 25 to 32 weeks' gestation. design : two-year prospective cohort study. setting : geographically defined study (region of franche-comt~., france). main outcome measures : type of plasentation was obtained by anatomopathological, or macroscopic examination of placenta and comparison of 6 twins' blood-groups. neurological assessment was performed at two years of age (uncorrected for gestational age) by family doctor (pediatrician or physician), or neonatologist of the icu at tertiary center. sample : 167 of 17i survivors aged of two years (98% follow-up rate), born between 09/30/90 and 10/01192. triplets and chromosomic malformation were non included. results : thirteen (11%) of the 119 singletons had cp.vs 3/29 (10%) of dichorionic twins and 6/19 (32%) of monochorionic twins (p=0.04). four of the 19 monochorionic twins (21%), 2/29 dichorionic twins (10%) and 4/119 (3%) nngletons suffer from quadriplegia (p<0.01).in a multivariate approach, monochorionic twin placentation was the strongest risk-factor of cerebral palsy (or=9.7, ic 95% = 2a-39, p<6.01). others risk-factors of cp were : lack of father's profession (or 11, p<0 .03), maternal antecedent of abortion (or 3.2, 1-10, p<0.04), vaginal delivery (or 3.4, 1-11, p<0.03), hyaline membrane disease (or 3.4, 1.2-t0, ~0.02). discussion : this is the first population-based study to uplight the role of monochorial twin-placentation as a strong risk factor of cp for premature infants. cp is more severe in monochodonic twins than in other infants. mecanism of cerebrat deficiency is not clear since none of our infants with cp was survivor of an in utero cotwin's death, and none of these infants was exposed to twin to twin transfusion syndrome. were these monochorionic-twins affected by an undiagnosed neurological structural defect that could lead both to prematurity and handicap remains an open question, a vital role of the intensivist is to ensure that knowledge and practice are imparted to trainees in the icu so that patients receive optimal care. teaching effectiveness varies widely leaving gaps in knowledge and practice in the trainee. being an effective teacher should not be a "gift" of a privileged few. the icu provides a fertile ground for using a variety of methods for teaching, e.g. didactic, at the bedside, emergencies, and in the performance ofproeeaures. in this environment, much can be learned. we have embarked upon a program to facilitate this learning process. i) teaching needs to be recognized as the foundation of good clinical care, i.e., patient related, and in its ability to generate discussion and research investigation. 2) teaching structurally has many components including the speaker, audience, varying situations, and the message delivered. 3) establishment of a program using these components to enhance teaching abilities at all levels, a) evaluate base-line teaching skills initially, b) individualize interventions to improve teaching skills, e) demonstration of learned skills with re-evaluation. this process is analogous to the analysis of a clinical disorder in a patient which, once recognized, interventions are then instituted and then re-evaluated. 4) instill the desire to use these attained skills to teach and interest others to teach. teaching excellence should be recognized through awards, honors, and academic advancement. a major emphasis of this program is to provide participants with skills necessary to teach thought processes, decision-making skills (what to do, what to avoid) and implementing appropriate management during stressful emergency situations common to the picu. introduction: many" e-mail based discussion groups exist on the internet to provide medical professionals with a rapidly responsive medium for the international exchange of ideas relating to patient care. several such lists each serve more than a thousand professionals in more than 30 countries, each distributing a dozen or more messages each day to every subscriber. there is very little known about the time being spent by professionals interacting with these lists, and very little known about the impact of the discussions on patient care. we wished to test the hypothesis that these discussion groups provide infortuation which is being used to change the care of individual patients and the general approach to patient problems. methods: in early january 1996 a pilot electronic survey was sent to a small fraction (n=63) of the memberships of 2 e-mail discussion groups, picu@its.mew.edu, and nicu-net@u.washington.edu (the full memberships of both. groups (n=t439 for nicu-net, n=1045 for picu) will be surveyed in early february of 1996). participants were asked for demographic information, experience and skill level relating to e-mail, time spent with the discussion groups, perceived usefulness of different types of discussions, and the ways in which the discussions were used clinically. the pilot study was analyzed for construct validity by correlating an overall assessment question with a summary of the specific questions. scale reliability was measured by cronbach's alpha statistic. results: the pilot survey response rate was 30163 (48%). the majority of respondents were male physicians, with an average age of 39+_5 years, who had completed subspecialty training in intensive care, and were working at a university-affiliated hospital. most had been using e-malt for more than 6 months, and considered themselves moderately adept in that use. 63% felt that the list helped weekly to keep them informed about current issues and practices in their field(s), and 57% felt that, at least monthly, they used information from the list(s) that was not readily available in medical journals. overall, 75% agreed that the list improved their professional competency. when asked to compare the value of 6 months of membership on an e-mail discussion group with more traditional educational media, 34% compared it with attending a national conference, and 26% compared it to a journal subscription. cronbach's alpha was .76, construct validity testing yielded coeff=.50, p <.05. conclusior~: internet-based e-mail discussion groups for health care professionals can be an important part of a strategy for maintaining professional competency. despite the very low cost of this medium for most, the value is felt to be comparable to that of t~r more expensive forums for education. further study will include distribution of the full survey in early february of 1996. fronk shann, tony slater, gale pearson and the pim study group we have developed a new score for predicting the risk of mortality in children admitted to intensive care. the score is calculated from only seven variables collected at the time of admission to icu: mechanical ventilation (yes/no), booked admission after elective surgery (yes/no), the presence of any one of 14 specified underlying conditions, both pupils fixed to light (yes/no), the base excess, the pao 2 divided by the fio2, and the systolic blood pressure. most scores used to predict outcome in intensive care require the collection of a large number of variables (so many icus do not calculate them routinely), and they use the worst value of each variable in the first 24 hours in intensive care. this means they appear to be more accurate than they really are (about 40% of child deaths in icu occur in the first 24 hours -so they are diagnosing these deaths rather than predicting them), and they blurr the differences between traits (a child admitted to a good unit who recovers will have a low score; but the same child who is mismanaged in a bad unit will have a high score -the bad unit's high mortality rate will be incorrectly attributed to its having sicker patients). pim was developed in the picu at the royal children's hospital in melbourne, and has been tested in six other picus in australia and one in the uk. objectives: to study the characteristics of the muhiorgan dysfunction syndrome (mds) in children. methods: a retrospective study with all the children with mds diagnosed from january 1990 to june 1995 is presented. 173 children fulfilled the wilkinson criteria (i). in all of them the number of organs affected and the prims score were determined during the first 24 hours. several groups were performed according to the clinical diagnosis, the hospital of origin and the order of organs affected. results: the 173 subjects studied were an 8% of the pediatric intensive care unit admissions. 100 of them expired (58%). no differences in age, sex and weight were observed between the children dying and the survivals. the most common causes of mds were sepsis, both nosocomial (25%) and medingococcal (i4%) and acute respiratory failure. sixty-fivepercent of the patients were from the hospital wards and the remaining were directly admitted to the pigu from the emergency room. the systems affected were: respiratory (93%), cardiovascular (92%), hematologic (61%), central nervous system (52%), renal (43%) and (hepatic) liver (28%). the organs initially failing were: heart (39%), tung (28%) and central nervous system (18%). the children dying had a larger number of organs with failure than the survivors (3.89 v,s. 3.34, p<0.001).the prmis score was higher in the children expiring than in the survivors (22.4 v.s. 17, p <0.001). s.mmary: the mds is a common pathology in picu, with a high mortality, the mortality is higher in children with a larger number of organs affected and a higher prism score. sepsis is the most common etiulogy. methods : from june ist to july 15th 1995, all patients admitted to the pediatric icu were included. the score was measured at day 1 (d1) and day 3 (d3) and we used 10 variables. for each organ system, we defined 2 categories : dysfunction or failure, which we respectively confered 1 or 4 points. results : 56 patients were admitted : 22 newborns, 34 children. 23 were medical and 33 were surgical patients. 36 (64 %) patients had two or more organ failure at the admission, 12 (21,4 %) patients died, which 6 (50 %) in the first 48 hours. the mortality rate was the same for children with two or more organ faiiure at d1 and d3 : 6/36 (16,6 %) at d1, 4/22 (18,2 %) at d3. the mean score is different for children who survived or who died : 8,6 versus 17,9 at d1 ; 10,6 versus 18,2 at 133. when the score is > 15, the mortality rate is significant. conclusion : in this study, there is a good correlation between the score of severity and the mortality rate but we have few included patients. we need a prospective multicentric study to assess these results and we must compare this score to other scores of severity used in picu. back.qround: injury to the central nervous system is the cause of death in the majority of pediatric trauma victims, studies have identified a wide range of factors associated with poor outcome from brain injury. however, when single features are analyzed, they are not sufficiently accurate predictors. few studies have used a multivariate analysis of these factors and pediatric outcome, methods: clinical and radiographic features of 164 comatose children after traumatic brain injury were analyzed, clinical parameters, the initial cranial ct scan, and demographic characteristics were analyzed for an association with death or vegetative survival at 6 months. a tree diagram in which risk factors may differ within the study subpopulations was constructed using recursive partitioning. results: chitdren with a motor score _<2 had an 11-fold increased risk of poor outcome compared to those with motor scores >2. among patients with scores of _<2, those with abnormal pupillary reflexes experienced a 13-fold increased risk of death compared to those with normal pupillary reflexes. among patients with a motor score >2, an intracranial diagnosis code (no pathology, mild shift _<5 mm, swelling, shift >5 mm, surgical mass lesions, or non-operative mass lesions) was highly predicative of poor outcome at 6 months. children with ct findings other than normal or mild swelling had a 4-fold increased risk of poor outcome. of children with swelling, shift or mass lesions, the pupillary light reflex was associated with outcome. children with abnormal pupils had a 6-fold increased risk of poor outcome. discussion: a few clinical and radiographic features stratified comatose children into fairly distinct risk groups. information available early after traumatic brain injury in comatose children provides useful prognostic information on the likelihood of death or devastating injury. a retrospective study of 70 children with the diagnosis of epidural hematoma was made during 1990-1995 period. ages ranged between 7 days and 17 years (18% less than 1 year, 40% between 1 and 10 years, and 42% older than 10 years), 82% of them were admitted at the picu. 51% of the cases were due to falls, 35% to road traffic accident and 14% to other causes. on admission gcs was less than 8 in 19% of the cases and more than 14 in 53%. diagnosis was made during first 4 hours in 63% of patients and delayed more than 12 hours in 28% of them. neurologic impairment was present at admission in 33% of patients, and delayed in 30%. even so,27% remained without impairment. radiological findings at first ct were skull fracture (68%); epidural hematoma localization was: in the right side (63%), frontal area (24%), temporoparietal (66%) and occipital (t0%). associated lesions were: several (13%) or unilateral (51%) cerebral contusions, diffuse brain oedema (10%), unilateral hemispheric oedema (14%) and 38% showed shifted middle line. four patients died, half of them during the first 24 hours. 41 fully recovered (58.6%) and 25 have sequelae of different nature :7 were left with severe motor disability (10%); at the follow-up t3 have some degree of neurodisability. next datas keep correlation with death or neurosurgical impairment: only were significative multiple cerebral contusion (p=0.002) and brain oedema (p=0.05), gcs less than 8 at the admission (p--0.002), shock (p=0.003) and remaining cerebral contusion in control ct correlated with death or diasability at discharge. on the other hand, neither surgical drainage volume nor first or highest levels of icp (12 cases),nor pupillary abnormalities (10 cases) correlated with worse prognosis. conclusion: gcs equal or less than 8 an shock are main factors related to worse prognosis, also multiple cerebral contusions in ct and diffuse brain oedema. the results of a modified gcs were compared to outcome and intensive therapy in 78 children (mean age 8,5t4,7 years) with head and associated injuries (53,6% of all cases) of different causes (traffic accidents, falls). the gcs was regularly used inn the course of intensive therapy. according to our own and other experiences the gcs was divided in 3 stages: stage 1 (4-8 points), stage 2 (9-12 points) und stage 3 (13-19 points) palhuiugy wile sp, tdhlg c~'lcb1al blood ~0w. sabgcqucntl}. rhc slat,: rerltncd to t1011tl,91 iiltlils. the p0st,~pem~v~ b}i~g wij!!,:q1! ,:_a!~p!ica!j0n~:. 4 ri~;¢ ill the level of sensibflizatjou lo tile cerebn~ anhgrns up to 1t.4-o7 was flofcd iu 9 i,alicnts. there wa.~ al~ iuclt~a~e ill cerebral vdociij,. ~m d~;'ati0a il~ p¢fiphc~ai re~ista/isc of the large ce~'bral ve~ds. neur0h;~c ~:yn'.pt,m~at0!a~, (s::mno!en~', _r_uscu!~r l~:pot0ni& !ryper*'flema) was nbserwed tu lt~ese pal~enls o. cbruc~l ~0nnds. rile ple~c.ut abse~vafion~ suggesl ihal die ~tttdy at" ihe stale ~f hematocr~chcplm/itic bm~ic~ in ckil&en with 31110on emergensy is of abviou.~ !?ece~sib; in co~.te ctin g severe pa~0lo2~-i~mnediately f0u0wing ne ,:~per,'~fion. background: reconstruction of the heart by three-dimensional (3d) echocardiography provided new information on anatomy of complex congenital heart defects, we assessed the utility of 3d ultrasound in detecting morphological changes in cerebral anatomy in newborns before and after cardiac surgery. methods: transfontanel cross-sectional ultrasound, scans were obtained in standardized coronal and median sagittal planes. subsequently, rotational scanning was used to acquire the multiple sequential crosssections of the brain. for rotational scanning, a conventional 5 mhz transducer was rotated 180 degrees.scanning took less than one minute and required no sedation, data was stored in the image processing computer which allowed for off-line three dimensional reconstruction of different brain regions.twelve infants aged 3 -21 (median 7) days were assessed before and after cardiac surgery, results: cavity of lateral ventricle, choroid plexus and the periventricular brain parenchyma could be reconstructed in all. accurate estimation of size and volume of lateral ventricle, aqueduct, and other ultrasonographic visible pathological brain lesions could be performed. reconstruction of various brain areas was accomplished in 3-10 minutes. the localisation and extension of severe periventricular hemorrhage which was detected preoperatively in one infants was better visualized than in conventional ultrasonography. epicortical and subarachnoidal space could be reconstructed in all and allowed detection of hemorrhage in one case which was not detected by conventional ultrasound. conclusion: 3d reconstruction of different areas of the brain may provide additional quantitative information on size and volume of the internal ventricle and choroid plexus, and better understanding of the topographical aspects and the extension of intra-and periventricular hemorrhage than conventional cross-sectional ultrasound. introduction: intracranial cerebral blood has been estimated to be 70% venous, the invasive measurment of venous blood saturation in the jugular bulb provides quantitative information on cerebral oxygen supply and consumption. however, routine oxymetric measurement of blood saturation in the jugular bulb by insertion of a catheter line into the internal jugtdar vein is an invasive procedure which has limited use especially in infants and young children. thus the aim of this study was to investigate the correlation between the non-invasive spectroscopic measurement of rso2 and the oxymetric determination of the blood saturation in the jugular bulb in infants and children undergoing routine cardiac catheterization.. methods: during routine cardiac catheterization 30 infants and children (age 5 day-16 year, median 4,5 year) the rso2 was measured continuously using a two chanel cerebral oxymeter (invos 3100a). the sensor was placed in standardized location at the left temporal head side. after the routine oxymetric blood sampling in the superior vena cava the oxymetric catheter was manupilated into the left jugular bulb. after control of the catheter position simultenuous values of the rso2 were documented. results: over a range of (33-87%) sjo2, a significant linear correlation was found between the spectroscopic measurement of rso2 and the oxymetric determination of venous blood saturation in the jugular bulb (r=0,83, p<0,001) and the superior vena cava (r=0,65, p<0,05). no significant correlation was found between rso2 and the arterial blood saturation in the descending aorta and as well as to the standared hemodynamic parameters. conclusion: meusurement of rso2 by mrs may provide continuous non-invasive information on cerebral venous blood saturation and thereby possibly on cerebral oxygen supply and consumption in infants and children. these may be of clinical value particulary during and immediately after heart surgery by means of non-pulsatile cardiopulmonary bypass. information on refractory status epilepticus (rse) from developing countries is scarce. we analysed 43 cases of rse admitted over last 2 yrs. the objective was to study etiology end evaluate efficacy of diezepam infusion. median age of the patients was 1.25 years irange 1.5 months to t 1.5 yrs); 70% were boys. onset of seizures was 1-t44 hours (median 24 hours) prior to hespitalisation. the glasgow coma scale score ranged from 3.11 (mean+sd 5 + 2). the commonest underlying causes were acute cns infections (26/43, 60%; bacterial meningitis, 16, encephalitis, 10) and epilepsy (8/43, 10%). oiazepam infusion in incremental dose (range 0.01-0.025 mg/kg/min) was used in 38 patients over 3.4_+2.1 days. seizures were controlled n 31 (82%), mechanical ventilation was required in 10 (26%)only, while none had hypotension; 84% patients survived. thiopental infusion (holus 5 mg/kg followed by 0.2 mglkg/min, and increments of 0.1 mg/kg/min till seizure control) was used in 8 patients over 1.7_+0.7 days; seizure were controlled in all, but five patients needed mechanical ventilation, six developed hypotension needing infusion of vasopressoi drugs, 3 out of 8 (38%) died, overall mortality was 26%, mainly due to acute cns infections (n-6) and prolonged se. the patient was a 2-year-old gift di~aosed of dov,~'s s~drom¢, tetralogy of fallot. (t.f.) before admission a vasovagal crisis after coughing and vomiting was seen, and she was taken to the emergency room. mother said she had eyanosis in the mucous membranes of the mouth with exercise.on physical examination, she ~as afebrile, normal fundi and neurologic examination was normal. a harsh systolic murmur was hear~ with decrased intensity during bradycardia. chest rx disclosed a decreased pulmonary vascular markings. ecg: synus rhythm, with bradycardia and nodal escape rhyflmas. she was transferred to our picu because of severe h3,pertomc seizure, lost conciousness, and deeembrate poslamng~ ~t cyancx~is. the episode lasted for ~weral seconds, and ceased v~th diazepam. on admission she was lethargy, and neurologlc exammation showed weakness of left leg without babinski, and normal funduscopic. the patient had two episodes of bradycardia and isoproterenol was begun. during those episodes the patient was cyanotic, and the murmur was heard with the same intensity. act scan disclosed a tight parieto-temporai abscess with midline shift, lnmediately after the diagnostic ct, we administered antibiotics, antiedema treatment and it was drained. the abscess culture was negative. a ct control disclosed air and midlme shift. ~ the next two days she had three episodes of h39oxia and c'yauosis ceased with o@gen, morphine and propanolol the patient died during a fourth episode. discussion: arrhytmias are uncommon in patients with tetralogy of fallot before surgery. in our case the first diagnosis was sick sinus syndrome vs bradycardia secondary to cyanotic episodes. the incidence of cerebral abscess in children with congenital heart disease (chd) is approximately 5%. tetralogy of fallot is the most common associated lesion, and is unusual in children under 2 years of age. conclusion: 1) brain abscess is a rare complication of patients with cyanotic chd, but should be suggested in patients with °'apparent" sick sinus syndrome. in patients with down's syndrome, t.f.,with cyanotic episodes, and difficult neurologic exploration, a brain ct scan is recommended. guillain-ba~re syndrome (gbs) is an acute autoimmune reaction, directed primarily toward the myelin encasing the peripheral motor nerves= this reaction causes a delay or block in nerve conduction. the presentation often can be very subtle but is followed by rapid loss of neuromuscular power, leading to acute respiratory distress, resulting from weakness of muscles and aspiration pneumonia. there were 3 boys -4, 8, and i i years old with gbs, treated in our icu. two of them due to the respiratory distress were intubated nasotracheally and ventilated mechanically with servo-9ooc (siemens-elema, sweden) ventilator. duration of ventilation was i i and 34 days, respectively. plasma exchange was performed in all cases. the numbers of plasma exchange sessions were 2-4 in each case. mean amount of plasma exchanged per session was 28,24 ml/kg. plasma was substituted with albumin, plasma or saline. the most important aspect of the management of patients with gbs in the icu involves the airway care, prevention and treatment of aspiration pneumonia and the mechanical ventilation if respiratory distress presents. endotracheal intubation should be performed whenever there is evidence of retention of pulmonary secretions, refractory to chest physical therapy, weakness of protective reflexes of the airway, leading to aspiration pneumonia and (or) atelecr~sis. cardiac arrhithmias too, is a main threat to the circulatory stability in gbs. therapeutic plasmapharesis has been shown to be beneficial, reducing the time for weaning from the ventilator and for achieving independent ambulation. however, plasma exchange is expensive and not without significant risks for the patient. some authors find that plasmapheresis is not effective for patients with fulminant course of gbs and blocking of nerve conduction. recent studies have demonstrated that intravenous high-dose immunoglobulin can be equally effective. there were no significant complications associated with plasma exchange. all presented patients survived without residual disability. tetraparesis associated with long-term paneuronium use in an infant. paneuronium is a muscle relaxant used in ventilatory management of patients with respiratory distress in intensive care unit. after the end of sedation some patients were found to have severe tetraparesis. paresis was accompanied by complete areflexia and diffuse atrophy of alt extremity muscles. this neuromuscular complication is caused by prolonged high-dosage pancuronium treatment. in the last 5 years, numerous reports have linked the use of pancuronium bromide with prolonged paralysis, disuse atrophy and areflexia. this side-effect is well known in adults patients but rare in a pediatric intensive care unit. we describe one pediatric observation of tetraparesis after prolonged pancuronium treatment in a 9-month-old girl, this female infant developed respiratory distress syndrome and was intubated and mechanically ventilated. to decrease chest wall rigidity pancuronium bromide was administered during 11 days. (she received approximately 120 mg of pancuronium bromide). on day 12 the drug was discontinued and the patient had severe tetraplegia and areflexia with normal head movements. electromyograpliy showed absence of any disorder of neuromuscular transmission. this infant showed a recovely of muscles after 3 months. the other causes of peripheral neuropathies were eliminated. electroencephalograms and head scans were normal. the recovery pattern observed in our patient correspond to the process of regeneration after axonal degeneration. it is suggested that these neuromuscular complications were caused by prolonged high-dosage pancuronium treatment (associated with cortieoid and aminoglucosides). polyneuropathy syndrome in adult lc.u. appeared in literature in 1984 and is extremely common in long stay cases. the etiology of these disorders remains elusive. it is tempting to ascribe them to administration of drugs (muscle relaxants, steroids, aminoglycosidea), plolonged immobility, malutrition, sepsis and ischemia associated with reperfusion injury. to our knowledge there is only one case report of similar condition in a children i.c.u. (pascucci 1990) we present a serie of 16 previously healthy children, aged 9 months to 13 years, who admitted in i.c.u with respiratory failure and who following weaning from m.v, remained in profound diffuse hypotonia with proximal and distal muscle weakness for various length of time, recovery of muscle strength occured in a week or months {the longest i0 months), all children, except one, 3-4 days before admission developed symptoms of either respiratory or upper airway infection with fever. on admission viral and bacterial cultures were positive in 2 cases (haemophilus influenze, herpes virus). during treatment 9 patients became septic. muscle histological and neurophusiological investigations have not been done. considering the multifactorial nature of the aquired nmd in adult critically ill pts, is impossible to attribute the muscle weakness of our pts to any specific cause, in conclusion, our findings suggest the need for further investigation of nmd in critically ill children treated in i.c.u. a van esch, ha van steen~l-m011, ir ramtal, g derksen-lubsen, idf habbema. febrile status epilepticus (fse) is a prolonged and serious febrile seizure. little is known about the outcome of fse in neurologically normal children. this survey involved patients between 6 months and 6 years of age who had visited due to their first fse, the sophia children's hospital during the period of january 1981 till december 1991. patients with a history of neurologic disorders were excluded. 57 patients were identified, 65% were male. the cause of the fever remained unknown in 51% of the cases. in all case the fse was generalized and it most frequently occurred at night (47%). the mean age at fse was t.6 years (0.5-4.7), the mean temperature 39.6°c (38.5-40°c). the mean follow up time was 1.7 year. twelve children (21%) had neurologic sequelea. the neurologic sequelae varied from speech deficit (4 case mild, v2 -1 year delayed; 4 case moderate > 1 year delayed) to severe retardation and epilepsy (4 cases). speech deficit was detected after a mean period of 6 months (range 0-18), age, gender, temperature, family history and time of onset were no significant risk factors for neurologic sequelae. duration of seizure [rr 3.0 (0.8-11.3)] and more than two drugs to treat fse (rr 5.2 (t.5-18.1) were related to neurologic sequelae. we recommend that fse children should be followed for at least a year to detect possible speech disorders properly and start early intervention. unusual presentation of myasthenlg gra%qs ibtza e. modesto ,v~ abe~gochea a, sanch]s 1l all, go l varas k folgado s, garcia e. p.1.c.u. la fe, valencia. spain case report: the patient was a 2-year-o!d gift transferred to our pic because of severe respiratory failure. the patient, convaleseem of ehiekenpox, came into contact with horse manure previous afternoon. in the morning, she was lethargy, and irritability, with poor finding, and ~ an episode of coughing, cyanosis and acute respiratory failure after mucous vomiting when she was drinking milk. on admission she had severe respiratory distress, respiratory acidosis, and the sat 02 was 86%. she was mtubated without difficulty, and was transferred to our p.i.c.u. physical examination reveals stable hemodynamies, pupils equal, round, reactive to light, normal fandi, and muscle relaxation. crusted vesicles diseminats~d. rhonehi over both lungs. hepatomegaly (+) and splenomegaly (+). ~lhe urine, hematologic, and c.s.f. laboratory findings were normal. c.t. scan of the brain, e.e.g., and ekg. revealed no'abnormalities. rx chest disclosed a retrocardiac atelectasis. speci~ts of stool and blood were obtained for cultures and study of c. botul#num toxins. pending receipt of these results, a broad-speotmm antibiotic and acyctovir was begun. the initial differennal diagnosis consisted of laryngospasm associated with aspiraqlon, botulism, and postmfecfious varicella encephalitis. after 15 hours, weatm~ was begun. the neurologic examination showed a low modified glasgow coma ~ale (mgcs), generalized hypotouia and muscle weakness. these data suggested three diagnoses, posfnfecfious encephalitis, residual neuroumsoaar blockade, and excessive doses of sedative and analgesic drugs. after 20 hours she regained skeletal muscle poxver and ufltlcient respiratory effort, the mcgs was acceptable, and blood gases were normal. she was given n~-tigmine and atropine, and her tr~ma was extubated. an acute respiratory failure ocurrs 120 ram. after. chest radioga'aph disclosed a left inferior lobe atelectasis. after 20 hours weaning begun~and the same episode w~as seen. at this point her mother stated that the girl showed weakness of the eyelids or extraneular muscles. it suggested myasthenic syndrome vs ~-barr6 syndrome. c. botul#num toxins were negative, chotinesterase level ~as normal. edrofoinum test ~as positive. anti-acetyleholine receptor antibodies were negatives. e.m.g. confirmed myasthenia gravis (congenital vs juvenile serenegative). pyridostigmine was begun and the trachea was extubated without complications. conclusion: din the differential diagnosis of weamng failure we must consider ~c gravis~ 2)myasthenia gravis could resemble encephalitis, because of low ocs, overall if is triggered by viral infection. 3)in some diseases (this case) gcs could not he an aemuate index of mental state. a burguet*, a menget*, e monnet**, a gasca-avanzi*, c fromentin*, h allemand**, jy pauchard*, ml dalphin*. * r4animation infantile potyvaiente chu st jacques 25030 besancon cedex. ** d~padement de sant6 publique 25030 besancon cedex, france, objective : to point out that strabism is) of one-year-old premature is a good predictor of a poor neurological outcome at two years of age. design and setting : two-year prospective cohort study and geographically defined study (region of franche-comte, france). main outcome measures : neurological assessment was performed at one and two years of age (uncorrected for gestationnal age). a mailing questionnaire was sent to the famity and fuu-filled by thefamily doctor (pediatrician or physician), or neonatologist of the icu at tertiary center, s was diagnosed at one year of age by the examinator but s was not used to diagnose cerebral palsy (cp). sample : 161 of 171 survivors (94%) evaluated at one and two years of age. results : correlation of one and two years neurological evaluation is weak (kappa=0.5). correlation of s at one year and cp at two year is fair (kappa=0,72). the goal of this paper is to review evidence related to hypothesis that the "waiting" axons and cells of the transient subplate zone may participate in the structural plasticity of the human cerebral cortex after perinatai brain damage (kostovic et al, metabot brain res4:17, t989) and to correlate this phenomenon with different forms and mechanisms of structural plasticity. it is our basic assumption that all lesions occuring during cortical histogenesis will lead to more or less pronounced structural reorganization. here we show that various components of the subplate zone participate in several forms of the structural "plastic" responses in the human cortex: modification of convolutional pattern, changes in size of cytoarchitecturat areas~ columnar reorganization, dendritic and synaptic plasticity. the etiological factors which induce lesions and subsequent plastic changes act via the following pathogenetic mechanisms: * disturbances of radial unit formation (rakic); * changes in ingrowth of afferent fibres; * changes in the rate of normally occuring reorganisational events, depending on the critical period for a given histogenetic event. in the present study developmental lesions (localized perlventricular leukomalacia and haemorrhages) were demonstrated by ultrasound in live-born infants ranging between 26 to 40 weeks of gestation. in younger infants (24-34 w) who died shortly after birth, examination revealed lesions of the white matter with the preservation of the subplate zone. in infants who died one week of more after the lesion, we have observed localized micropolygyria, cavities, condensed layer vi -subplate zone, and columnations of the cortical plate. these changes are less prominent if the lesion occurs after diminishment of the subplate zone (after 34 w). since in the fetal cortex the subplate zone serves as predominant source of growing fibers, transient neurons, trophic factors and contains cellular substrata for migration, this zone is the most likely candidate for major types of structural plasticity. in conclusion, cerebral cortex of the low -birthweight infants is more susceptible to the various lesions but shows vigorous structural plasticity and conspicuous functional recovery due to the growing, transiently located neuron at elements. the mortality due to meningoccocal sepsis is high in spite of important progress in emergency and intensive care medicine. during the last decade multiple scoring-systems have been developed in order to establish a therapeutic approach and to evaluate the final outcome of a meningococcal infection. different clinical and biological data (shock, ecchymosis, peripheral wbc and platelet count, coagulopathy, acidosis, meningism, etc) are taken into consideration and the importance given to these data depends on the scoring-system used. a review of the different scoring-systems is given and a clinical case is presented. we report the case of a 4 year old male, who was transfered to our icu 12 hours after onset of temperature and skin rash. the parents described a fast deterioration of his condition. the boy presented wide spread ecchymosis, high temperature, no signs of meningism, circulatory insufficiency and shock, coagulopathy and low peripheral wbc and platetet count. disseminated intravascular coagulopathy developed promptly. the glasgow meningococcal septicemia prognostic score (gmss) was used and the obtained score reached the highest level (15/15). this corresponds to a 100% mortality. the patient required mechanical ventilation for 5 days. at admission he received human albumine, fresh frozen plasma, dexamethason, dopamine, dobutamine and a continuous infusion of adrenaline. antibiotical treatment consisted of ceftdaxone. the evolution was favorable and the infant fully recovered. retrospectively the gmss was compared to other meningococcal scoring scales which gave the same mortality (100%). we conclude that the scoring-systems are important to evaluate the seriousness and to assess the therapeutic approach, but they should be used cautiously even when 100% mortality is predicted by several risk evaluations scoring-systems. the aim of this study was to assess the haemodynamic status on admission and the critical care management of children presenting with meningococcat infection. this was a retrospective study of the charts of 46 consecutive admissions. mean age was 3.43 years (+/-3.46). the average duration of symptoms prior to admission was 20.4 hours (+/-14.09). on admission 17.4% were hypotensive, 45.6% had clinical signs of haemodynamic instability and 54.8% of cases that had a blood gas analysis on admission had a metabolic acidosis (bases excess < -5.q): the mortality rate was 10.9%. 80% of patients that died were hypotensive on admission and all had a metabolic acidosis. of the 41 survivors 9.7% were hypotensive on admission, 39% had clinical signs of haemodynamic instability, 25% required invasive pressure monitoring and 7.3% were ventilated and received inotropic support. this study demonstrates that at the time of presentation with meningococcal infection children had a high incidence of established haemodynamic instability. successful management of this infection is dependent on early presentation and initiation of therapy and on aggressive support of the cardiovascular and vital organ systems. dept. of intensive care medicine and dept of infectious diseases, our lady's hospital for sick children, crumlin, dublinl2, ireland. jude. pediatric intensive care unit, ch&u, 59037 lille-france. more than 10% of children surviving sip (defined as purpura with shock) have snli. objective. to search for a specific hemostatic profile in children with snli. patients and methods. between may 1989 and march 1995, 34 children with sip were admitted to our picu : 6 (17.6%) died and 28 (82.4%) ranged in age from 1 to 185 months (mean : 29) survived, 5 of them (17.8%) with snli (defined as the need of a surgical procedure). in survivors, two hemostasis studies (between h0 and h12, and 24 h later) included the determination of coagulation factors (routine tests), protein c (pc : amidolytic activity, biogenic), total protein s (ps : elisa, stago), c4b binding protein (c4bbp : laurell's technique, stago), antithrombin3 (at3 : chomogenic test, stago), and plasminogen activator inhibitorl (pail : chromogenic test, biopool). three severity scores were determined at admission : french group of pediatric intensive care, gedde-dahl, and crp. statistical analysis used the wilcoxon's test. results. at admission (lst sample) severity scores and at3, pc, ps, c4bbp levels were not different between the group with snli and the group without snli ; quick time (22 4-5% vs 35 ± 14% ; p = .025), vti+x (20 4. 3% vs 30 4-10% ; p = .04i) and pall (105 4-157 ui/m! vs 580 4. 570 ui/ml ; p = .028) were lower in the group with snli. on the 2nd sample there was no difference between the two groups. kinetics of hemostatic abnormalities was not different between the two groups. conclusion. in the literature, intravascular coagulation (dic), low fibronectin and at3 were identified as predictors of snli, and a negative correlation was found between the mean size of the skin lesions and pc activity, at3, and total ps. in this series, apart from dic, there were no specific hemostatic abnormalities that support the use of treatments such as pc, at3, and pail antibodies administration to prevent snli. further studies including more children are needed. the aim of study was to investigate the efficacy of intravenous immunglobulin with enriched igm content pentaglob/n /biotest/. in our pediatric intensive care unit ten septic children /group i/-their average age 2,6 years /sd:o,6/, 7 of them with gramm negative and one with gramm positive blood cultures, and two with unindentified bacteria-were treated with basis sepsis therapy and pentaglobin. the application of pentaglobin was as follows: 1,5 ml/kg loading dose for one hour, followed by a continuous intravenous infusion 0,1-0,4 ml/kg/hour depending on body temperatura /lanser scheme/ for 72-96 hours. another ten septic patients /control-group ii/the mean age 2,5 years/sd:o,65/, their blood cultures were gramm negative bacteria 6, positive 2, and the bacteria was not indentified in two cases -were treated with only the basis therapy. results: the duration of intensive treatment decreased from an average 22,7 days /sd:8, min 12-max 38 days/ to 19,5 days /sd:5,2 min 9-max 25 days/ in the group treated wit pentaglobin. the difference was significant /x 2 p<0,01/. in the group i nobody died, but three in the group ii. conclusion: the pentaglobin therapy can improve the efficacy of the basis therapy of sepsis. sinus bradycardia after an episode of sepsis is a rare symptom complex decribed in children with hematologic malignancies. we present a case of postsepsis bradycardia following severe typhlitis and septic shock in a 12 year old boy with relapse common all. blood and ascitic fluid specimen grew clostridium species and pseudomonas aeruginosa. at surgery there was a necrotic gangrenous terminal ileum and cecum, requiring ileocecal bowel resection with ileostoma. while clinically recovering from sepsis he developed bradycardia for 120 hours. extensive diagnositic procedures was given and the heart rate slowly increased to normal range of age. postsepsis bradycardia in children with hematologic malignancies after an episode of sepsis is self-limiting and after careful differential diagnostics warrants an expectative attitude. nitrate level is known to be enhanced during sepsis. serum nitrate is the stable metabolic end-product of endogenous nitric oxide generation. nitric oxide has demonstrated to be a powerful anti microbial final mediator and also a key molecule driving to the lethality of one of the most common complication of sepsis; the endotoxic shock. such facts prompted us to investigate the possible diagnostic and/or prognostic value of monitoring serum level in high risk, presumptive and confirmed sepsis patients. additionally we have explored the usefulness of this mediator as index of therapeutic response. in our study it is demonstrated that there is an important relationship between nitrate level and the occurrence of neonatal sepsis. septic newborn group showed 6 fold higher nitrate level than that of healthy control group. in addition, the group of patients with high risk of sepsis which finally became septics, exhibited 3 fold higher nitrate level at 24-72 hours before the first symptoms appeared, when compare with those who did not develop sepsis. however in the presumptive sepsis group, there was no difference between the patients which finaliy ,&'ere considered septics and those which not. in all septic cases, after 7 days of a successful therapy with antibiotics, the level of nitrate diminish 3 fold. our results suggest the utility of monitoring nitrate as index for the diagnosis of neonatal sepsis. the potential benefits of exchange transfusion, plasma exchange, and haemofiltration have all been described in children with overwhelming sepsis. however, little hard evidence exists to prove the benefits of any of these techniques. i have treated five patients with plasma exchange (pe), having been asked to see all these patients at a point when it was felt death was inevitable. two of the patients had staphylococcal, two meningococcal and one enterococcal septicaemia. all patients showed a dramatic haemodynamic improvement following pe with improvement in blood pressure, reduction in inotrope requirement and improvement in tissue perfusion. three patients survived. one of the patients with staphylococcal sepsis and both of the patients with meningococeal sepsis had developing gangrene of the limbs which showed remarkable reperfusion with pe. in two of the patients measurements of cardiac output (co) and systemic vascular resistance (svr) showed ~a reduction in co and a rise in svr over the course of a pe despite the reduction or cessation of vasoconstricting inotropes. many believe haemofiltration is of value in septic shock. a trial with a no treatment limb is difficult to achieve. i believe we now have enough evidence to justify a controlled trial of haemofiltration versus plasma exchange in patients with septic shock and unstable haemodynamic status whilst on inotropic support. during the next several days, cough and chest pain suggested pulmonary embolism confirmed by radiologic evaluation. echocardiographic examination showed multiple thrombosis of the superior vena cava, right atrium and ventricle and pulmonary artery. estimated protein c level was 50.7 % (normal range 70-140%); identical deficiency was found in patient's mother and elder sister. cvc was removed, and alter 2-month heparin therapy and supstitution of protein c with fresh frozen plasma, there was almost complete thrombolysis of the great vessels and cardiac chambers. we conclude that invasive diagnostic and therapeutic procedures in such patients may result in higher risk for severe thrombosis at unusual sites, and numeuos further complications bronchopulmonary dysptasia (bdp) is a chronic pulmonary disease of preterm and term babies treated with mechanical ventilation for respiratory problems of different origin and requiring oxygen therapy 28 days after birth. bpd is a disease affecting the growth and development of pulmonary tissue. such pulmonary }esions heal by squamous metaplasia leading to scar formation and fibrous tkssue r~growth, the pediatric intensive care unit makes the survival of babies w~h very low birth weight (500 -999 g) possible. with the increase in their aulyival, the number of complications in low birth weight babies increases as well. bdp is a very serious complication. therefore the importance of early diagnosis and treatment of bdp must be stressed in order to reduce the consequences. babies with bdp must be under medical suveillance for at least 3 years as the disease needs at least that long for complete resolution. tn the icu of pediatric department at madbor teaching hospital: during the past two years (1994-95) 154 newborns were treated with mechanical ventilation. the neonatal and postnatal death rate of all newborns admitted to our icu was 7,1%o.ln the two years from 1994 to 1995, 16 newborns were admitted to our icu (2 %~ of all newborn babies at maribor teaching hospital), with birth weight 500-999 g. in the icu, the survival of these babies and parallel to it the number of complications is increasing. during the mentioned 2-year period, 8 babies with very low birth weight (500-999 g) survived: 5 in 1994 and 3 in t995. in 45-50 %, first or second stage bdp was treated,there was no case of third of fourth stage bdp. the treatment consisted of eary removal from mechanical ventilation, oxygen therapy~ intensive treatment of infection, volume and caloric intake contro}, corticosteroid treatment throught 6 weeks with decreasing doses, diuretic end antioxydant therapy. the children are to be reevaluated at the age of 3 and 6 months and again at i and 3 years. oeure j van der, markhorst do, haasnoot k department of pediatrics, pediatric intensive care unit, free university hospital, amsterdam, the netherlands. case summary a 4%-month 6.5 kg girl of african origin was admitted to the pedfatric irtensive care unit with pneumonia and progressive respiratory irlsuffjderey. she was intubated and ventilated by pressure regulated volume controijed ventilation (servo 300c, siemens, soma, sweden). maximum conditions were inspiratory minute volume 3.2 l, peep 10 cm h~o ahd 100% 0~. chest x-ray showed bilateral interstitial consolidation. material obtained by broncho-alveolar lavage showed preumocystis car}nil htv-serology (elisa and westerll blott) and p24-antigerl were positive, confirming the diagnosis of pediatric aids. she was then treated with high dose co-tllmoxazoie, penthamldine, z{(~ovudire and steroids iv. because of thee x-ray features, high need for o 2 (100%, pad 2 56 mm hg), not responding to elevatiofi of peep (max 10 cm h=o) and pao2/fio = <200 (s6). m acute respiratory distress syhdrome (ards) was diagnosed. because conventional ventilation (cv) failure, hfo-v (31ooa, serisor medics,yorba linda, ca) was initiated. starting mean airway pressure (map) of 19 cm h~o was based or map of the cv, oscillatory pressure amplitude (dp) of 47 was, at ii~itial frequency of 7.5 hz, adjusted ur~til chest wall vibrations were visible, it was required to raise map to 26 cm h20 and dp to 66 before optimal lung volume and ventilation were achieved and need for o 2 reduced within hours, this was monitored by frequent blood-gas analysis and chest x-rays. map and dp could slowly be reduced, after a good response the first day, gradually 02demand reduced and the patient could be weaned from the ventilation. map, dp, fi02 and oxygenation index (map x pa0~jfio 2) are shown in table i. chest x-ray follow-up showed gradually improving lung features, with marked improvement of aereation. after 10 days hf0-v she could be succesfully detubated when a map of 10 cm h20 was acmeved. results : sianificant increase in ventilato~ rate and mean airway pressure was noticed after the change to savi. no differences in oxygenation, co 2 partial pressure and systolic, diastolic or mean blood pressure between imv and savi periods were noted. in 6 infants however an improvement in pao2/p43.ol/ and decrease in paco 2 was observed after the switch to savi. these babies had a lower initial a/a oxygen tension ratio and required higher initial ventilator rate /p<o.05/ in comparison to the rest of the studied patients. conclusion:infants with low a/a po2ratio who need high initial ventilator rate are likely to obtain benefit from savi.. fumimare hatori, haruo uchida, masao katayama, and rika muto department of anesthesia and critical care medicine chiba children's hospital, chiba city, japan. purpose: this study was made to find out whether the heat and moisture exchangers (hme) was effective enough to humidify in the respiratory management for children. patients: the study population consisted of 21 patients who were provided with artificial airway. they were divided into the two groups: ii with heated humidifier (a) and i0 with hme (b). methods: hme could be used for those without pulmonary complication and with less leakage around the endotracheal tube. in both a and b groups, (i) we have measured relative humidity, temperature, and absolute humidity at the endotracheal tube connector. for these measurements, humidity sensor system was utilized. (2) any troubles and complications caused by the artificial airway were investigated. results: (i) in group a, we confirmed the mean values as the relative humidity of 96.5%, the temperature of 32.8~c, and the absolute humidity of 34.0mg/l. in group b, they were 92.7%, 29.5°c, and 28.7mg/l respectively. no difference was noted between the two groups as to the relative humidity, but the temperature and absolute humidity were lower in group b with a significant difference (p<0.0001). (2) in neither of the groups, any respiratory complications such as obstruction or stenosis of the artificial airway were noted. in pediatric icu, hme can be used without any problems under given conditions. titei: objective: evaluate the precision, reproductibility and aplicability of a new device to measure auto-peep in pediatric patients during mechanical ventilation. material and methods: it's an electromc-pneumatic eontolled device with an oclusion valve and a pressure monitor installed between endotracheal canulla and the ventilator circuit. the measurements were performed with a sollenoid conected with to the ventilator to detect the end of inspiration phase and the actwation of the oclusion valve. the signs of pressure and flow were moniturized using a difere~rtial transducer and it was processed using a pc computer and a pneumoviaw® software. the auto-peep also displayed in the ventilator pressure monitor. results: we submitted 17 children with neuromuscular disease or respiratory distress in this study. the incidence of auto-peep was 76%, with variability between 1,5 to 13 cmh20. all the measurements were performed 3 times to verify the precision and the reproduetibility and evaluation of the pressure and flow curves. conclusion: the device is low cost, easy to use and can be used without the pneumotacograph. the auto-peep measurement can be done during mechanical ventilation with time cycled, pressure limited and continuous flow, the most commom ventilator used in pediatric patient. resistance was modeled by 3 endotracheal tube (ett) sizes (2.5, 3, 3,5), and compliance by 2 test lungs (1 and 5 ml/crnh20), for each resistance -compliance arrangement, we measured tidal volume (vt) at various frequencies, peak to peak (p-p) and mean airway pressures. results vt increased when ett size increased with all 3 ventilators in accordance with fredberg results (jap, 1987; 62: 2485-90) . the maximum vt delivered was smaller with the hfv-babyiog 8000 than with the ohf 1 or the sm 3100a at a given frequency (figure on the left). increasing p-p resulted in a linear increase in vt delivery in the 0-30% range of maximum p-p (figure on the right). hfv-babylog 8000 didn't provide significant vt increase when p-p was set above 50% and vt deliven/decreased when mean airway pressure decreased. --i 5~ sm 3100a a number of ventilatory parameters had been analyzed with russia-produced monitor humitemp htm 902 (servisinstrument j,-s. co) in 24 newborn infants with rdsn of t-iv stages on cmv, cppv, imv, and cpap steps using respirators of various kinds (stephan-staxel, bear-2001, newport 8rezee, sechrist). parameters investigated were: temperature of inspired mixture (t), relative and absolute humidity (rh and ah, respectively), static compliance (c), expired tidital volume (vte), expired minute volume of ventilation (mve). the monitor read these parameters in following ranges; rh-from 10 to 100%; ah-up to 55mg/i; mve-up to 3.0 i/mini vte-from 3 to 130 ml; t-accurate to 3%; c-from 0.1 to t0 ml/cm h20. continuous monitoring time ranged from 2 to 96 hours, it was noted, that during this time the monitor and transducers had no malfunctions, and it's using didn't require additional calibration, it was found, that humidifiers mr 498 and mr 410 (fisher, paykel) couldn't maintain parameters t and ah continuously (these values varied from 34,3 to 38.2 c and from 37,5 to 47.1 mg/i, respectively, when heating regulator position was unchanged). changes of parameters c depended clearly on cppv conditions and rdsn severity (with rdsn of stages i-ii c value ranged from 2.4 to 1.2 ml/cm h20; and with stages iit-tv-from 0.3 to 1.1). tn 6 newborn suffering from rdsn of stages ii-ltl and ill-lv with pip>25 mbar, fi02>0,7, peep=4-7 mber, c-from 0.3 to 1.2 ml/cm h20, effectivity of exosurf therapy was studied. in 4 newborns in 4-12 hours of therapy pip decreased to 0.3-0.4, and c increased to 1,7-2.4 ml/cm h20. in 2 newborn infants with aad02>500 mmhg and c from 0,3 to 0.8 mltcm h20 positive effects of exosurf on lung compliance were not observed. in 3 newborns the monitor had revealed decreased of c (from 3.4-2.9 to 1,8-1.3 ml/cm h20), manifested clinically by pneumothorax. in general, monitor htm 902 made possible; 1), to estimate the adequacy of cmv-parameters and regimes in newborn infants; 2). to select optimal t and ah values in the respiratory outline in dependence on lung damage severity and infused volume; 3). to reveal rdsn severity; 4), to optimize indications and adequacy of surfactaot therapy; 5). to diagnostieate the air leakage syndrome; 6). to effects to some agents (broncholytics, spasmolytics); 7). to obtain objective indications for imv/simv and cpap regimes. albano communication is an important aspect of human development and existence, and an inability to vocalise can be a problem in ventilatordependent patients. we present our experience with speaking aids as a means of enhancing verbal communication in four ventilatordependent children in our paediatric intensive care unit. the age of the children ranged from 7 months to 5 years, and the period of ventilation ranged from 3 months to 21 months via a tracheostnmy. they require continuous flow generated pressure limited or control ventilation at rates of 13-20 bpm. the reasons for ventilation include tetraptegia following a shrapnel injury; tetraplegia following congenital cervical spine damage; tetraplegia following atlanto-axial subluxation; and critical illness polyneuropathy following adult respiratory distress syndrome from prolonged ventilation for a severe head injury. the first three patients have passy-mnir one-way speaking valves and the final patient has a bivona foam cuffed tmcheostomy tube with a talk attachment in view of recurrent aspiration. an improvement in quaiity of speech has been shown by independent assessment. we will review the present literature on this subject and discuss the advantages and disadvantages of these two types of speaking aids in the light of our experience. the prognosis of antenatally diagnosed cdh is closely related to the degree of ph. there have been attempts to correlate antenatal or postnatal criteria to mortality: none have been demonstrated to be predictive of lethal ph. the aim of this retrospective study was to determine whether antenatal or early postnatal data could correlate with the findings of post-mortem examinations. patients and methods: between july 1990 and july 1994, 32 cdh patients have been antenatally and postnatally managed at our institution. twentythree infants underwent a post-mortem examination. ph was assessed by using the lung weight to body weight ratio (lw/bw) and the radial alveolar count (rac). antenatal results: cdh diagnosis was made at 24 weeks of gestation (wg) (15-37). twenty-eight patients had a left sided cdh, 3 had a right sided cdh, and one had a bilateral cdh. herniated organs were stomach none (n=21), or liver alone (n=4), or both stomach and liver (n=5 the patient was a 3-yenr-old girl with chronic renal insufficiency see~ to renal dysptasm, two months before admission a kidney trar~ptant was performed. one morah later she showed acute graft rejection with serum ereafinine (cr) level of 0.7 mg%. the rejection was unreslxmsive to an increased steroid dosage, and okt3 was begun with resolution of the rejection. one week arer, new rejection episode was seen marestxmsive to an increased steroid dosage, and transp~ ~s performed five days before admission to our ptc. hemedialysis and peritoneal dialysis (p.d.) each other day, was indicated (g.r.f.< 10 ml/rnin). four days before admission t ~ rose to 38°c. "lhe diagnosis of opporttmistic pneumoma was made on the basis of tach3,pr',e~ hypoxi~ and diffuse interstitial infiltrates. senma ~ was positive for cytomegaloviras (cmv), and stool culture for c albicans. pentamidine, ganciclovir (dhpg), arai-cmv gamma globulin, eritromicine and amphotericin b was administered. on admission in our picu, trachea was mmbated, (a-a) o2 gradient was 600, paofffio~: 65, lung injury score > 3 with peep level of 8 cm hzo. she had normal fiver function. during te next days she had fever and developed ards. bal was negative. p.d. was of little efficiency. we adjusted pentanfdine, and dhpg doses for severe renal failure, with supplements after hero, sis, and at~rp.d.. during ~ next days she was afebrile, and the chest became radiologlcally normal. after ten days on menhani~al ventilation (mv.), the patient was extubated. cr. level was 3.2 rag%, (a-a) oz gradient was 20, and paoyfioz was 375, the patiem was discharged with chronic ambulatory p.d. discussion: opportunistic pneumonia is a major complicalaou in imm~romised children, specially after kidney tvansplaraafion. c m.v. infection can result at~r okt3 administration. in the treatment dhik} dose must be adapted to the degree of renal insu~cieney, with supplements after hemedialysis, and after pd. pneu~y~tis cann# tmeumov~ is ehemeterized by ventilafion-perfusion mistmaeh, decreased pulmonary compliance, hypoxia arld elevated (a-a) oz gradient, with diffuse interstitial infiltrates. in our ease bal was negative. although we did not find the etiology the prevoclons eombh~ation of arairmcrobiat therapy, along with m.v., and supportive measures were the most effective trealme~. conclusion: 1) in patients with severe renal failure and life-threatening infections, we must co~ider drug adjuslments. 2) in our patient we gave dhpg supplements at~r pd. with excett~at results, although p.d. was of little effiele~. introduction: endotracheal intubation and mechanical ventilation have become an important treatmem for many diseases accompanied by respiratory failure. with the frequent use of this treatment modality, an increasing number of complications associated with endotracheal intubation have gained clinical significance. material and methods: a transversal study was realized to find the prevalence of pulmonary aspiration with endotracheat tubes in 36 infants and children. aspiration was assessed by applying two dyes (evans blue, er)¢rosine sodic) on the tongue and searching for the dye during suctioning in the endotracheal aspirate. the factors, that potentially have influenced the aspiration, including weight, age, sex, cause of respiratory failure, main pressure airway (map), level of consciousness, presence of swallowing and body position were evaluated. all the variables studied had their association with aspiration tested by chi-square method with relative risk considering a confidence interval of 95%. the results were adjusted by multivariate analysis. results: the overall prevalence of aspiration was 36.1%. among all children who aspirated, compared to those who did not, there was a statistically significant difference in the presence of swallowing (p=0.005). the odds ratio to aspiration in the presence of swallowing was 38.4 (t.75 -100 c.i.95%) and the relative risk 55.5. aspiration was not significantly affected by sex, weight, age, cause of respiratory failure, map, level of consciousness and position of the body during the ventilation. conclusion: the endotracheal intubated children frequently aspirate as intubated adults and that preventive measures are ineffective. the presence of swallowing movements is the main risk factor to aspiration of oropharingeal content in intubated patients. clinical features and shortterm outcome skling, rp gie pneumonia is the second most important cause of death in young south african children. the clinical features, intensive care course and outcome of children being ventilated for pneumonia in the developing world is unreported. aim: to describe the clinical findings, aetiology and shortterm outcome of children younger than 6 months with pneumonia requiring ventilation. the data of all babies under the age of six months with a lower respiratory tract infection admitted to the paediatric icu for ventilation were prospectively collected over a period of 14 months. tracheal aspirates and blood specimens were submitted for viral and bacterial cultures. results: forty-seven babies aged 14 to 174 days were ventilated for pneumonia. twenty-six infants had been born prematurely; t2 had been ventilated during the neonatal period and 4 had bpd. the median duration of symptoms was 1 day, the most common being cough, tachypnoea, apnoea and cyanosis. five babies (10%) died. the mean duration of ventilation was 8 days (range 1-85 days) and of ward stay after icu discharge 19 days (range 1-161 days), blood euttures were positive in 7 children (15%). viruses were cultured in 14 children (30%). conclusion: 1) fifty-five percent of children below 6 months requiring ventilation for pneumonia were premature infants, of whom 46% had been ventilated during the neonatal period. 2) the median duration of symptoms prior to admission was 1 day. 3) ninety percent of the children survived and were discharged from hospital. 4) viral pneumonia was responsible for 30% of the admissions. mechanical ventilation and atrial natriuretic factor release ulloa santamarfa, e, p6rez navero jl, ibarra de la rosa i, espino hernladez m, velasco jabalquinto mj, frfas p6rez m. picu. reina sofia children's llospital. c6rdoba. spain. mechanical ventilation effects on renal function decreased diuresis and natriuresis due several factors including anf. several studies have demostrated anf released due increaasing pressure in right atrium. on the other hand, mechanical ventilation, overall peep modality, inhibits peptide release althougt cvp increased is found. this study was designed to demostrate anf stimulation is due rigth atrium stretch which be higher during mechanical ventilation instead of atrium pressure. we desing a prospective study including 14 patients, age range 16 months-13 years with congenital heart disease. all of them were admitted at pediatric intensive care unit after extracorporeal surgery and were assisted by mechanical ventilation. hemodinamic state was stabilized in all patients and nor renal neither neurological diseases were found. after 24 hours with mechanical ventilation, plasmatic levels of anf were measurement, pvc, pericardical pressure were assessment; all patient were sedated with midazolan and paralized with neuromuscular blocking agent; mechanical ventilation technique was as follow: imv between 20 and 30, tidal volume and fi o2 enough to mantain respiratory parameters in normal range. afterwards, at least twentyfour hours in spontaneous breathing, the study was made again in each patient. atrial stretch was assesssment according to following equation: transmural pressure= cvp -pericardial pressure. cvp were significantly higher with mechanical ventilation than when the patient was breathing by himself. (5.4+__ 2.2 vs 3.8 + 1.8 mm hg; p<0.01). however, transmural pressure during mechanical ventilation were lower than during spontaneous breathing (8.92 +__ 3.86 vs 11.76 +__ 3.32 mm hg; p < 0.01) equal, plasmatic anf levels were lower during mechanical ventilation ( 87.77 + 46.55 vs 108.92 + 49.06 pg/rnl; p<0.01). in conclusion, anf secretion decreases during mechanical ventilation, even with cvp higher. anf release would depend on atrial stretch meassured by transmural pressure, lower in patients with mechanical ventilation and it would not depend on atrial pressure. the paediatric intensive care unit shaikh zayed hospital, lahore is an acute care area devoted to the care of critically sick children upto the age of 13 years. in a 6 bedded unit with limited equipment, constant care is ensured by the presence of at least one nurse aed one doctor round the clock. in this setup we have the facility to ventilate 2-3 children at one time, between sep. 93 and dec. 95, out of 885 patients admitted to icu, 171 (19.32%) were below 1 yr of age, while 48 (28%) were below 1 month of age. life support was discontinued in 17 (9.9%). total mortality was 56 (32.7%), major mortality was in 0-1 month age group 22 (12.8%), and 1 month to 6 month 15 (8.7%). majority of the patients were of sepsis (36.2%), cns disorder (22,2%) followed by respiratory problems (14.6%). it seems therefore that the major indicatiou for ventilation was overwhelming septicemia leading to multiple organ failure, rather than purely respiratory problems. high frequency oscillation (hfo) in the therapy for ards in pediatric patients requiring aggressive conventional mechanical ventilation (cmv) -routine or experimental mode ef pre ecmo therapy. fedora m., nekvasi~ r, vobruba v., srnsky p,, zapadlo m. dpt. critical care medicine, nicu and ecmo center, university children's hospita! brne, nicu of university hospital prague, czech republic. introduction: 9 pediatric patients (8 males, 1 female, average age 4.7 months, average body weight 5,8 kg) with severe ards ventilated with aggressive regimen of pcv or prvc were connected to hfo (sensormedics 3100) as the last "rescue" therapy due to uncontrollable respiratory failure before intended ecmo. in the course of hfo 2 of them were given no in the concentrations of 5-80 p.p.m., 3 were subjected repeatedly to surfactant replacement therapy (alveofact). results: ecmo was needed in no patient, 8 patients survived, 1 patient was disconnected from the ventilator because of brain death in spite of conspicuous improvement of oxygenation and other parameters, some relevant parameters 48 hours before and 48 hours after starting hfo are given in table 1~ in all the cases, the disconnection from hfo was carried out through the simv regimen, never directly to cpap. table 1 : the levels of blood gases, oxygenation index (oi), aado2,map,fio2 and pao2/fio2 ratio 48 hours before and 48 hours after starting hfo. conclusion: although none of the patient had to be subjected to pediatric ecmo, hfo should be carried out only in workplaces having the immediate possibility of using this method in the case of hfo failure. speculation: should not hfo be used ir pediatric patients with ards earlier than aggressive cmv? can hfo ce considered standard, not experimental method of therapy? refractory hypoxemia in premature patients is characterized in a persistent elevation of pulmonary vascular resistance, with right to left shunt through the ductus arteriosus and or foramen oval. we report the case of a vlbw patient (ga 27w, bw 1010g) who present a severe hypoxemia related to hyaline membrane disease and a pulmonary and systemic infection to group b streptococcus, refractory to conventional ventilatory support and surfactant therapy, associated to hemodynamic failure falling in ecmo criteria used for term infants. a rescue therapy with hfov (sensor medics 3100a) is decided at 5 h of live, the table resume the patient's evolution before and after hfov. at 36w of postgestational age the patient present a fio2 of 0.23 with a chest x ray compatible with a cld type l at discharge no oxygen requirements was needed and actually he's doing well. conclusion: hfov, using an adequate alveolar recruitment strategy, was effective in the rescue of a severe hypoxemic respiratory failure with a rapid off of ecmo criteria entry in our vlbw premature patient, during the united nmioffs embargo ~nst yugoslavia the prevalence of the ast}nnafic ~acks in c~dldren aratsed. the mo~t common causes have beem dramm~e worsening of life standard, ecom~c disaster in global community, gr~ number of refugees from the other parts of former yugodavia. it wm obviom that mcio-ecoumnical conditions took a part in the exacerbations of previously known cldldhood asthra~, ~av~ of micro-and m~mclimaflc changes, psychosocis] and emotional cryses, lack of medics-m~nts for p~ve~on and tl~rspy of acute asflanatic attacks. about 10% of d-dldv~ tmslod in our picu for these year~ exp~dvncod ~vcr~ attack for the flint time iu ~jzeir lifts. it has been cu~ 1~%~ children in mspir~ry picu of our hos~mt. the scut~ revere attack (more ~asn ~/o of hight clinical score) was detected in 62% of all children admitted with respirak~ problems. from tl~ mmlysss we exclu&d: bmncldolifis, ~i anomalies, ~eve~ i~ccqions. concerning our drug supplies (which wc~e reduced), we started our therapy by administration of oxygen, ~ta2-ago~dst inhalations (but sometimes we had the solution for jet nebulizcm only for o~e inhalation per p~cnt), mwinophyllin and mefl~ylpr~ini~done in/ravenously. 48% of ih~ asthmatics needed repea~ doses of muinophyl~n pinch.ally, tnch.,ding the fluids. the bronchodilak)r msponm was poor ~r~cl slow, hospital stay in picu was for 4 days and for 14 days in other units sl~rwsvds. tim ~ of their stable condifio~ was hard at borne (or refugees camps), without p~ventkm, so they came bsvk to hospital for morn than 3 times in 27% of cases, dtrdng ~e4je last motlfl~s file dtustion improved, concerning tim drugs supply for prevention, and we hope that these lifc~restening conditions wouldd~ introduction: the incidence of ards is increasing as survival of critically ill patients is higher. the application of new therapeutic modalities have increased the survival rates in (ards) adult patients. objective: to study the therapeutic efficacy of new tleamlents in children with ards material and methods: a retros~ctive study was conducted from 1990 to 1995. 17 children with severe ards, (lung severity score > 2,5) (r), aged 15 days to 16 years, were included. the diagnosis were as follows: 9 interstitial pneumonitis, 5 non interstitial lung infection, 2 with lung aspiration and 1 with clinical sepsis. 5 patients had different tipes of cancer and 4 to suffer inmunodeficiency disease, the first 8 subjects (group t) were treated with conventional measures. from october of 1994new therapeutic modalities were introduced, including: less agressive ventilatory support, postural changes (prone to supine) in 9 subjects, administration of corticosteroids in 8 patients, rfitric oxide in 3, pe~ssive hypercapnia and administration of exogeans sarfactant in one, pao2/fio2, d(a-a)o2, oxigenation index (oi) and the score of respirator), severity disease were similar in both groups. the two groups evolntiou was compared. results: -ten patients died, 6 from group i and 4 from group ii (75% v.s.44:4%,ns). -the evolution time, either to exitus or weaning from ventilatory support was higher in group ii (22.9 v.s. 13.6days in group i, ns), -the incidence of barotrauma was observed in 12 subjects (70.6%), 6 from group i and 6 from ii. of these patients 75% expired. -during the course of the disease, 15 (88%) patients had more than one damaged organ. only in one subjet mof was considered to be the main cause of death. the majority of the patients expired because of their respiratory disease, although, 80% of them met criteria of mof. -fifty percent of the subjects were infected at the time of death. stmmry: a trend toward a higher survival rate is observed in the subjects receiving the new modalifies therapeutic intervention (corticosteroides, postural changes and permissive hypercapnia). our results are not significative,probably because of the small number of subjects studied. a new doubleaurae~t two-stage et-tube (dl-ett) was desig~aed and tested in the rabbits with acute king injury under conventional mechanical ~entilation_ ventilation efficiency of dl-ett was emrrpared with that of canveniionally t~sed single lumen et-tube (sl-ett). meth~s: dl-ett was specially made out of two sl-ett. vertical crosssections at the distal end of two et-tube (td 3_0 rmn portax) were adhered with each other to form a tracheal stage lumen wifu id 3.0mm the two remained uncut parts of the tubes corlntithted the oval s~ge with two separate imnens. dl-ett and sl-ett were randomly applied to five adult paralyzed rabbits with acute lung injury (by 0.1 nffkg oleic acid. iv). a bird inter 3 vetffttator (bird products corporation) was used for time-cycled pressure-limited ventilation at 40/min of respiratory rate, 10 ern h20 of peak i_~piratory pressure, l: 1 of ire ratio, 6 ljmin. of flow rate and 0.21 of fich. peak inspirntory pressure, mean mrway pressure, posi6ve end-expiratory pressure at tip of et-mbe and bemodynamics were measured and recorded continuously. arterial blood and expired gas were measured ~by avl 993 blood gas analyzer) after each stabilization t.~iod of 30 minntes. _analysis w~as by prated t test. result: dl-ett acaltety improve cos removal at all amman. pa(?oz was decreased by t0.6+_t.5 (p<0.0l) and physiologic dead space fraction (v~zvt) reduced by 22% +-1.8% (p<0.0t), compared with dl-ett. there were no significant change in arterial oxygenation. conelus|on: the double-lumen two-stage et-tabe significantly increases ventilation effmiency with simple operation in rabbits v, ith acute hmg injury, lts availability may influence future clinical management of ~ennated patient~. this ~muly was fimded by the science and technology. commiuee of beijing municipality. analis of hemostasis alterations on different coagulation cascades in 46 children with septic shock has shown that coagulation disorder character is dependent on lung affection rate. the initial manifestation of the respiratory distress-syndrome (rds) are characterized by the obvious activation of blood thrombin potential, moderate coagulopathy and not sharply marked endoteliosis, the witlebrand's factor (wf) increase tot 140-220%. progress in the clinical picture of "shock lung" leads to chronometric and structural hypocoagulation with potential hypercoagulation in "mix-test", high level of firbin derivative, thrombocytopenia with thrombocytopaty and the wf increase to 210~315%, terminal stages of the rds, as a rule, are characterized by potential hypercoaguletion absense, depletion of at-lit and plasminogen, prevalence of antithrombin and antiaggregating activity, obvious endoteliosis (the wf to increase250-540%). the arteriowenous difference according to index of the thromboelastography (teg) in the rds ill-iv rates was 69,8% less than in the 1-11 rates, disorder of lung filtering ability in severe rds is confimed also by minimal arterio-venous difference of activated euglobulin lyses (ael) in children with the rds ill-iv rates is only 11,4%, while the patients whit rds i-i1 rates have the ael-activity in arterial blood 2,1 times as much than in venous blood. the use of then allows to determine the potential hypercoagulation rate, the at-ill level and fibrinogen quantity during the anticoagulant therapy and also the character of the x-factor activation and thrombocytic hemostasis. the effective therapy component of septic genesis rds in children is the controled coagulation method with the use of the individual selected heparin doses in according to desagregants, kryoplasma, proteolisis inhibitors and trombolytics. it is necessary to avoid the heparintherapy for children with the rds complicated with producting coagulopaties and termal phases of blood disseminated intravascular coagulation (dic). bronchoseopy has been used for evaluation of the potential problems of the airways and for investigation the bronchial specimens for diagnostic purposes. regent technical advances result in performing this procedure at the bedside manner and in critically ill patients. we have performed 150 hronehoaeopy during last three years on 1362 pediatric patients with respiratory problems, in 90% of cases the opentube hroneh0seopy was performed (for diagnostic as well as for therapeutic reasons) and collected secretions or bioptic material were examined. the indieatiuns were: acute upper respiratory problems, chronic wheezing, inspiratory strider, tracheal or bronchial bleeding, chronic eongh, retractable atelectssis, severe pulmonary infections, lymph node perforation in lung tuberculosis and soquells like bronehiectssis and fibrosis. our results were: anatomical malformations in 10%, mueosal oedema with chronic inflammation and thick secretions in 56%, easuos masses in 11%, granulation tissue and purulent secretions in foreign bodies and bronehieetasis in 16%, and only 7% of eases were normal finding. our exlxdenees pointed that this invasive procedure in carefully selected patients has important role in establishing the diagnosis and in theintroduction: tbg has been a useful investigation in the management of ventilator-dependent infants in our experience. one ml of contrast was hand ventilated into the respiratory tree via their nasotracheal tubes and their anatomy and dynamics demonstrated on radiological screening. case descriptions: three infants who were difficult to ventilate requiring high airway pressures, high peep and a significant oxygen requirement had tbgs. the ages ranged from 3 to 9 months. two cases were complicated by complex cardiac lesions. in all cases there were frequent episodes of desaturation, where hand ventilation proved difficult and various intermittent lobar collapses occurred. microlaryngobronchoscopies (mlb) performed on the infants by experienced paediatric ent surgeons failed to identify the airway problems. more than one mlb was frequently done. concern about introducing contrast into the airways of infants with limited cardiorespiratory reserve combined with an uncertainty about how much extra intbrmafion would be gained often led to a delay in investigation. when performed these fears proved groundless, the anatomy and pathology of the airways were demonstrated in full and the correct therapeutic plan started. in two cases tracheostomy and peep producing patency of bronchomalacic segments allowed weaning to low levels of ventitatory support. in one case tracheal reconstruction was undertaken and in the cardiac cases the respiratory component of the ventilatory dependence was fully assessed. at the age of 4 months, a baby boy with a history of minor respiratory problems, was admitted to hospital with an upper airway infection and severe dyspnoea. shortly after arrival at the icu he had a total airway obstruction. after intubation there were still difficulties to establish a normal gas exchange, and he was tranferred to the regional picu. ct scan and bronchoscopy verified a congenital tracheal stenosis affecting the whole trachea except the upper 15 mm below the vocal cords. the diameter was estimated to less than 2 ram. an unsuccessful attempt was made to dilate the extremely rigid stenosis with a balloon. after the procedure he had a respiratory and circulatory arrest, and he was put on ecmo as a bridge to surgical correction. after 4 stable days on ecmo, surgery was performed during ecmo with a tracheal homograft transplantation. immediately after surgery, ecmo was discontinued. a silastic dumont type stcnt was inserted inside the homogra~, and a nasotracheal tube was placed inside the stent for assisted intermittent mechanical ventilation. repeated bronchoscopies were performed to remove granulation tissue and secretions. at 9 months of age, the stem was removed with an endoscopic procedure. however, the trachea was still soft and collapsable, and another silicon stent was placed inside the trachea for another 4 months period, after removal he had some respiratory problems and he was treated with nebulized salbutamol, mcemic epinephrine and steroids. he was discharged from the hospital at 14 months of age and his condition is now stable. this is the first procedure of its kind in sweden. it was accomplished by international and multidisciplinary collaboration. ecmo may be a bridge to corrective surgery and long time stenting may be necessary in the postoperative period. post mtubation laryngitis ( pil ) is still a frequent complication, occurmg in l -6 % of intubated patients. inhaled racemic epinephrine has for long been used as an accepted therapy, but this drug is not always available. the authors undertook a randomized, double-blind, placebo-controlled trial to determine the efficacy of inhaled l-epinephrine(le) in the treatment of plu in the period between july/93 and may/95, 289 patients were submitted to endotracheal intubation for ventilatory support. atter the extubation procedure patients were considered for enrollement if they met the following criteria: clinical signs of laryngeal estridor and a downes and rafaelly score for upper respiratory obstruction equal to or higher than 4 patients with primary upper respiratory disease were excluded all patients enrolled reeieved either inhaled l-epinephrine 1% or normal saline. dexametasene ( 0,6 mg/kg/day) was given to all patients in both groups. after 2 inhalations, au patients were monitored for a period of 1-20 minutes and monitoring included cardiac and respiratory rate, mean arterial blood pressure, arterial blood gases and the dowries and rafaelly score. statistical analysis included, qui-square with the fisher correction test and the z-test for paired variables. thirty eight patients ( 13,1% ) met the criteria for enrollment, 18 to the le group and 20 to the placebo group.there were no significant differences in both groups in regard to age, sex, initial score ( 5,05 x 5,1 ) and endotracheal tube diameter. the period of ventilatory support and tracheal intubation was significantly higher in the le group (8,06 x 4,54, p = 0,01). the follow-up score showed a significant drop only at 30 minutes after the inhalations (p = 0,03). re-intubation due to laryngitis, occured in 1 patient of the le group and in 4 of the placebo group with no statistical sxgnificance (p = 0,2). no difference was observed on the monitored hemodynamic variables during the 120 minutes, except for the mean arterial pressure at 60 minutes, being heighar on the placebo group (p = 0,05). we concluded that, although the l-epinephrine group showed a trend in better scores post-inhalation and fewer re-intubations due to laryngitis, the results were not statistically significant. we especulate that the period of intubation may have affected our results. similarlly there were no differences in the incidence of adverse effects between both groups. objectives:to evaluate the complications of endotracheal intubation in children with upper airway obstruction due to epiglottitis or croup. methodes: during a 5 year period (1991 -1995) all patients with epiglottifis or croup were reviewed to determine the complications of endotracheal intubation, especially upper airway obstruction due to granulomas. results: 33 patients were reviewed. in 17 children (mean age 2.5 years) with epiglottitis the mean duration of intubation was 4.0 days (3 -5). no complications were seen. in 16 patients (mean age 2.3 years) with croup the mean duration of intubation until the first extubation was 8.1 days (1 -15 days). elective extubation was performed if an airleak was present or after 7 days without airleak but in the absence of fever and obvious secretion. reintubation was not necessary in 10 children (62.5%). in this group the mean duration of intubation was 6.4 days (1 -12). in 6 patients (37.5%) reintubation was necessary because of severe upper airway obstruction due to granulomas. mean duration of intubation until the first extubation was 10.8 days (6) (7) (8) (9) (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) . there seems to be a difference in duration of intubation between these two groups with croup, however it is not significant (p > 0.1). all the patients with granulomas could be successfully extubated after microlaryngeal surgery, with a mean intubation period of 35.3 days (21 -47). revealed no complications, where as endotracheal intubation in children suffering from croup showed a high incidence (37.5%) of granulomas. however1 laryngeal steepsis and other serious complications were not sesn~ 3 patients (42 days averagely] was obviously seen in ~he peak =one of fl, f2 resonance and in the zone of high freq,-~ncy :r, ~;~e composition while 12 cases(3 day~ average;y] :~bowed no abnormality both clinically and isryngoscopica!~y. 7/10 patients with catheter placement for more than 6 week~ end 1126 p~tie,~ts for less than 5 weeks had t;~ryngeal abnormal change in their larynges,abnormal changes of sound spectrogram were all seen in 3 patients with placement for mope than 5 weeks. our data suggest= ca] the complication of endotracheal intubation was increases with increasing length of time of catheter placsm. entjbut aeriuoa complication is rare i (b] the time limit of pernasal endotraoheal catheter placement is 5 weeks within which the procedure is • comparatively safe and effective means for maintaining e tong term artificial airway. in a 6-year period (1986) (1987) (1988) (1989) (1990) (1991) (1992) we diagnosed tbm as an apparent dilatation of the trachea and main bronchi ih four premature infants on continued mv for respiratory distress syndrome (rds). the infants were three boys and one girl with gestational age (ga) 26-33 weeks and body weight (bw) 1100-1965 g. mv was provided by bourns 2001 cub time-cycled and pressure-limited ventilator to attain normal gas tensions. no jet ventilation was used. chest radiographs were reviewed for a complete evaluation, and for the evaluation of the airway. after the intial subjective diagnosis of tbm, the width of the tracheal and main bronchial air column was measured at the lower level of the first and the third thoracic vertebal body it1, t3) and near the carina; the width of the main bronchi below the carina was also measured. in all infants, tbm became apparent close to the 20lh day, that is, after 2-3 weeks of mv. therefore, for the time period from birth to the 20th day the following ventilatory parameters were reviewed and analyzed: (1) the percentage of total ventilation time when more than 40% o2 concentration was required, (2) the peak inspiratory pressure, (3) the positive end-expiratory pressure, and (4) the duration of high frequency ventilation (80-160 breaths per minute). also noted were the apgar scores (1 and 5 min after birth), the duration of hypotension (systolic bp below 40 mmhg) and circulatory instability, the presence of systemic or tracheal conatal or later infection, the duration of mv, and the final clinical outcome. the records were also reviewed for other possible pertinent data. rigid respiratory endoscopy in children fraga j, amant6a s, piva j, nogueira a, palombini b. introduction: the respiratory endoscopy is an important procedure to diagnose and treat many airway's diseases in children. although have had advances in radiologic investigation exams and pulmonary function tests, the direct anatomic visualization of airway is important to the management of many respiratory problems. objective: evaluation the respiratory endoscopies performed with a rigid bronchoscope in a pediatric reference hospital. material and methods: we study the records of all children that were submitted to respiratory endoscopy under general anesthesia from march 1989 to march 1992. age, sex, clinical to indicate the procedure, diagnosis and complications of endoscopy were registered. results: three hundred and fifty six respiratory endoscopies were performed. the most common indications for endoscopy were strider (52%), suspected foreign body (16%), atelectasis (16%) and difficult tracheal extubation (8%). the most frequent diagnosis were laryngomalacia (36%) and subglottic stenosis (6%) in the glottic and subglottic areas, and foreign body (9%) and tracheomalacia (7%) in the tracheobronchial area. normal endoscopy was performed in 54 (21%) of the children. only three slight complications of the endoscopy were observed. two patients presented bradycardia during the exam, and the third need tracheal intubation due to post-endoscopic subglottic edema. conclusion: the rigid endoscopy in children is efficient and has no serious complications. near drowning; indicators of acute and long term prognosis bernardien t.mj. thunnissen t, reinoud j.b.j. gemke 1, loes veenhuizer?, krijn haasnoot 3, a.johannes van vugh0 department of pediatrics, ~wilhelmina children's hospital, utrecht, 2sophia hospital, zwolle, and ~free university hospital, amsterdam, the netherlands. in this retrospective study factors that affect short and long term prognosis after submersion were analysed. all patients that were admitted to a tertiary pediatric icu between january i, 1986 and january i, 1992 were included. of 34 patients, aged 0-13 years, 8 died in the icu, one after hospital discharge. survivors and non-survivors showed significant differences with respect to central temperature, pupillary reactions, arterial ph, pediatric risk of mortality (prism) score and therapeutic intervention scoring system (tiss) upon admission (p < 0.05). non-survivors more frequently required mechanical ventilation, bicarbonate administration and active reheating. ards was seen in 22 patients (65 %), invariably within 6 hours after admission. no patients with cardiac arrest on" admission snrvived without sequelae. hypothermia appeared to have no protective effect on hypoxic damage. survivors with persistent sequelae _> 6 months after discharge had significantly higher prism and t1ss scores (mean 27 and 34, respectively) than those with complete recovery (mean 14 and 23, respectively). long term cognitive problems were present in 7/25 survivors (28%) and emotional disturbances in 5/25 (20%). in conclusion, a concise number of clinical and laboratory parameters, representing acute severity of illness, are important prognostic indicators for survival and health status of children after submersion. there were 59 (91%) bronchoscopies, and 6 (9%) were oesophagoscopies.the average age was 2,8 years for bronchoscopies, and 4 years for oesophagoscopies. the outcome of the patients was good. no complications were observed. extraction is recomended in every symptomatic patient. orphenadrine is an anticholinergic drug mainly used to decrease symptoms of parkinson disease. orphenadrine has a peripheral and central effect and overdose can result in athetoid movements, convulsions, cyanosis, coma, arrhythmias, shock and cardiac arrest. physostigmine is a specific antagonist of the peripheral and central effects and can be a useful antidote. we report the case of a two and a half year old female who was transfered to our icu for general convulsions. the little girl had, three hours before admission, accidently ingested 400rag of orphenadrinehydrochlodde (disipal®), which was her grandmothers anti-parkinson medication. three hours after ingestion she presented neurological signs: confusion, unstable walking, and periods of aggression. generalized tonic-clonic seizures appeared who were rebel to administration of multiple anti epileptica but ceased after iv administration of diazepam and endotracheal intubation and ventilation. an episode of ventdcular tachycardia responded well to the iv administration of tidocaine. the levels of orphenaddne in the serum were high at admission (3550pg/l) and were present in the blood up to 96 hours after ingestion. high serum levels are, in the literature, associated to a high mortality rate. physostigmine was administered three times at a 0.02mg/kg dose in the first 24 hours. we decribe the noted effects of physostigmine on the different symptoms. the patient survived and could leave the icu after one week. in conclusion: orphenadrine poisoning is a very complicated medical problem associated with high mortality. in severe intoxication, the benefit of physostigmine more than counterbalances its side effects. objective: to define the optimal volume of dilution for endotracheal (et) administration of epinephrine (epi) design: prospective, randomized, laboratory comparison of four different volumes of dilution of endotracheal epinephrine (1.2, 5, and 10 ml of saline) setting large animal research facility ofa universi~ medical center subjects and interventions: epinephrine (0.02 mg/kg) diluted with four different volumes ( 1, 2.5. and i 0 rot) of normal saline was injected into the et tube of five anesthehzed dogs. each dog served as its own control and received all four volumes in different sequences at ieast one week apart. arterial blood samples for plasma epinephrine concentration and blood gases.were collected before and 0.25, 0.5. 0.75_ 1.2.3, 4. 5. 10, 15.20, 25.30 , and 60 minutes after drug administration. heart rate and arterial blood pressure were continuously monitored. measurements and main results: higher volumes of diluent (5 and i0 ml) caused a significant decrease of pao2, from 147:!:8 tort to 106±i0 torr, compared to the tower volumes of diluent (1 and 2 ml), from 136±10 torr tu135+_7 torr (p<0.05). these effects persisted for over 30 minutes. mean plasma epinephrine concentrations significantly increased within 15 seconds following administration for all the volumes of diluent. mean plasma epinephrine concentrations, maximal epinephrine concentration (cmax), and the coefficient of absorption (ka) were higher in the 5 ml and 10 ml groups. the time interval to reach maximal concentration (tmax) was shorter in the 5 ml and 10 ml groups. yet these results were not significantly different. heart rate. systolic and diastolic blood pressures did not differ significantly between the groups throughout the study. conclusions: dilution of endotracheal epinephrine into a 5 ml volume with saline optimizes drug uptake and delivery, without adversely affecting oxygenation and ventilation. the aetiology and outcome of paediatric out-of-hospital cardiac arrest was studied during a 10-year period in southern finland served by physician staffed emergency care units. the files of 100 prehospital patients less than 16 years old without palpable pulse and spontaneous respiration were analysed retrospectively. fifty patients were declared dead on the scene (dos) and resuscitation (cpr) was initiated in 50 patients. the sudden infant death syndrome was the most common cause of arrest (68%) in the dos patients as well as in patients receiving cpr (36%). asystole was the initial cardiac rhythm in 70% of the patients in whom cpr was attempted. eight of the 13 hospitalised patients were discharged, 6 of them with mild or no disability, 1 with moderate disability and one in vegetative state. in multivariate analysis the short duration of cpr (<16 minutes) was the only factor significantly associated with better survival. due to various aetiologies the survival rate from prehospital paediatric cardiac arrest is quite low. on the other hand, hypothermic near-drowning victims seem to have a relatively good prognosis. duration of cpr less than 16 minutes was the best predictor of intact survival, our study supports the previous findings of the importance of early and effective resuscitation efforts for establishing ventilation and perfusion on the scene. in our system well trained physician staffed emergency care units are able to provide immediate and effective als on the scene. on the other hand, these units also appear to be able to refrain from resuscitation when the prognosis is pessimistic. objective: to assess the normal ,gastric intramucosal ph ~hi) by tonometry in healthy children patients and methods: twelve healthy children (6 males and 6 females) with age rmaged from 6 months to 12 years scheduled for minor plastic or urologic surgery. children were previously medicated with midazolam (0.25 mg/kg) and atropine (0.02 mg~) both i.m.. anaesthetic induction was standardized with 02 -n20 (75%) administered via facial mask and increased halotane concentrations (up to 2%). all patients got an endotraeheal tube after iv. administration of femanile (2 mcg:jkg) and vecuronium (0.1 mg/kg) or suxametonio (1 mg/kg), pmaesthesia was maintained with o 2 -n20 (60-75%) and isofluorane (0.5-1%). during surgery, 8 children needed mechanical ventilation and the others maintained spontaneous breathing. ekg, heart rate, blood pressure, and pulse oximetry were moniterized. after anaesthesia, a sigmoid tenometry catheter (tonometrics, inc.) was inserted in the stomach of the patients by direct visualization with laryngoscope and magyll clamps. children were all maintained normoventilated and with normal cardiorespiratery variables. cadet's balloon was £~led with 2.5 ml of saline. thirty minutes after the insertion 1 rrd was extracted and rejected, just afterwards the remanent 1.5 ml was extracted and immediately analyzed. simultaneously an arterial gasometry by puncture was performed. gastric phi was calculated by the henderson-hasselbalch's equation using the pco 2 obtained from the tenometry catheter and the bicarbonate value obtained from the arterial gasometry. results: average gastric phi was 7.34 -i-0.027, range (7.29-7.46). objective: demons~ating intramucesai ph (phi) alterations during transport of patients from operative room to pediatric intensive care unit (picu), material and methods: phi measurements were performed with gastric tonometer catheter in t4 patients undergoing cardiac surgery with cardiopulmona d" bypass (cpb), there was 9 mate and 5 female, the average age = 3yl0ra, average weight = 12,5 kg, average time of cpb = 70 rain. the measurements were made at the end of the surged' and when the patients had arrived in the picu statistical aualysis: average and ~andart deviation and test "t" student. objetive: to asses the efficacy of gastric iatramucosad ptt (phi) and arterial lactate levels to evaluate splacalc tissular perfusion in an experimental model of intestinal ischemia. suneets ~nd methods: twelve piglets weights t3-20 kgs. undergoing orthot~ie liver trasplantation. the intestinal ischemia was induced by aortic damping. tonometry catheter (tonometrics inc.) w~s placed in the stomach after artaesthesia and ot intubation. phi ~s determined 7 times and lactate levels was determined fi times in 3 stages: i) pre-ae~hepatic stage (twice: before surgery and before aortic clamping ); ii) end anhepatic stage (only phi): iii) reperfusion stage (a 30, 90, 120 and 180 minutes). the phi was derived from application of the henderson-hassdbach formula using the pco2 value from the tonometer and the arterial bic~rbonate. all pipets received raaitidiila before sttrgery. values of phi above 7,35 and lactate levels between 6 and 15 mg/dl were considered nortrm. the results were statistically anaj.izated with anova and bonferroni tests. results: the phi was normal on pre anhepatic stage (> 7,35) and lactate levels were slightly increased (21, 5 +_ 8, 9 and 19, 5 ±5, 9mg/dl ns) . in relalion to we-anhepatics values, phi decreased signncatly at the mid of anhevatic stage (7,39_+0,14 vs 6,94_+0,1 p<0,001), phi remain low in stage iii, at 30 rain (6,86+0,12 p< 0,001) and 90 min(g94-+o, 12 p< 0,001). arterial lactate levels increased significatly in relation to levels in stage i, at 30 rain (63,6_+9,7 p<0,o01) arid 90 rain (65,8±9,9 p<0,001) of reperfusion stage. there is a slight improvement on phi and lactate ievels at 120 and t80 rain althought the differences did not reach significance. cnmments: phi and arterial lactate levels propperly reflect hypoperfusion on the experimental model of acute intestinal isdlemia. b~kground : the paediatrie gallbladder diseases generally described are calculous ¢hol~tstitis, cystic duct obstruction, congenital anomaly of the biliary tract, and inflammation. in the neonatal period, noulithogenie gallbladder disease could be also due to erythroblastosis or hyperalimentation. obieetive : we describe an other type of disease affecting the gallbladder in neonates thought to be related to their vascular vulnerability. methods : four patients with abnormal gallbladder ultrasound not related to classical observations were included. we have studied and reviewed the biological and clinical data, the ultrasound findings and their evolutions. results : four patients, 30 to 32 ~.k-old neonates ~ffth a birthweight be~,een 1,3 and 1,9 kg, were intubated and under total parenteral nutrition for 10 to 35 days. none of them were symptomatic on repeated clinical evaluations. one newborn developped hypotensien on umbilical bleeding at 3 hours of life. in two cases, signs of cholestasis were discovered : the total bilirubin level has risen to 5 mg/dl; the direct bilirubin level was 1,5 mg/dl while the urina were dark and the ~o~,ls :mcolour~. the c~mplct~ ~crology as a!! the culvare~ remained negative. the ultrasound explorations were atypical : in the four eases, an initial increasing broad and thickness of the wall of the gallbladder with an hyperecbogenie inside content, which was not sludge, was discovered. in three eases the images resolved in ten to fifteen days. in one ease, an asymptomatie thrombosis of the vena portu which remained patent was discovered. in this case, at one month, the ultrasound showed images encountered in chronic ebolecystitis and, at one year, the gallbladder appeared atrophic. none of them underwent surgery. conelusiou : the gallbladder diseases are multifactorial. besides the prematurity, the infections, the total parenteral nutrition, the premature neonate is exposed to vascular vulnerability affecting also the gallbladder and this may explain our findings. progress in prognosis of pts with b-nhl had followed the use of multimodality chemotherapy (ct). with the prolonged survival, there are comlications due to myetosupression & desease process. the syndrome of neutropenic enterocolitis (ne) is one of the ominous problems because ofpts increased susceptibility to infection & overwhelming sepsis. this material included 25 neutropenic pts (4-14 years) with the stages iil& iv of b-nhl who were treated with the modifired bfm-90 (mtx 1 g/m 2 in 24-h inf.); 22 males, 3 females. seventeen episodes of ne were observed & only after the first 2 courses of ct (13 of 25 after tst, 53%; 4 of 24 after 2nd, 17%). the symptoms existed 3 to 14 days. wbc ranged from 50 to 600 in l~tl (median, 100). the first signs of ne were directly correlated to the beginning of the neutropenia & the recovery of neutrophils led to the disappearance of abdominal recovery of neutrophils led to the disappearance of abdominal pain. the conservative treatment included gastrointestinal tract decompression, broad spectrum antibiotics initially, volume & electrolyte substitution, nutritional support, correction of acid-base balance, symptomatic treatment. sixteen pts were treated nonoperatively, 1 died. on autopsy the transmural bowel necrosis due to thrombosis of branches of a.mes.sup, was found. the bowel perforation occurred in one patient, he was undergone laparotomy & hemicolonectomy & survived. we conclude that ne is a frequent complication in neutropenic pts with the st. lii& iv of b-nhl. it occurs after the induction courses of ct. close observation by surgeons, oncologists & pediatric intensivists is mandatory. conservative treatment is effective & more preferable until leucopenia resolves. operation is necessary only for those.with perforation. near infrared spectroscopy as a tool for evaluation of intestinal perfusionpresentation of an animal model. c. scheibenpflug, p. buxbaum and a.m. rokitansky the recent development of and investigations in the so called near infrared spectroscopy ( nirs --transcutanous emission and simultaneous registration of intensity of spectralcolours depending upon modulations of tissue perfusion ) enable physicians to measure and qualify organ perfusion and nowadays is mainly used to control cerebral as well as skeleton muscular blood flow in trauma patients at intensive care units ( icu ). today intestinal perfusion, hypoperfusion , cell damage caused by reperfusion injury, bacterial and toxin translocation are serious problems in critically ill patients at an icu. paediatric intensive care physicians put major concern on intestinal perfusion, which for. instance gains more and more importance, especially in the neonatal period for example as an etiologic factor for necrotizing enterocolitis. we established an animal model, in which we measured intestinal perfusion by nirs under various invasive and noninvasive conditions. methods and results will be referred. for preliminary conclusion we propose near infrared spectroscopy ( nirs ) also as a potent diagnostic tool to determine early intestinal malperfusion in order to prevent lethal outcome. fm'ther investigations in animals as well in paediatric iritensive care patients should be done to estimate our efforts. introduction: following the acute phase of necrotising enterocolitis (nec) starvation of the gut for a period up to 3 weeks is a generally accepted treatment modality in many centres. objective criteria to refeed these patients are hardly available. recently the double sugar test has become available as a parameter for (ab)normal gut permeability ~'2. aim of the study: to evaluate the changes in permeability of the small bowel in patients with nec and controls before introduction of enteral feeding. methods: a lactulose! rbarrmose (i/r) test was performed in two groups. group 1 was studied 2-3 times within a 5-week period of starvation (n=5, mean gest. age 35, range 31-40 weeks). in group 2 seven different control patients were studied (mean gest.age 33, range 28-38 weeks). the test was performed by giving a patient after at least a 4 hour fast 1 ml/kg bodyweight l/r solution and determination of the 1/r ratio in a 4-hour urine sample by chromatography. results: objective: to evaluate the prognostic factors in the response to nitric oxide (no) in children with acute respirator/ distress syndrome (ards) and/or pulmonary hypertension (pht). patients and methods: 23 critically ill children received no inhaled for ands and/or pht treatment. 14 patient before and after cardiac surgery (2 cardiac transplants), 5 with bronchopneu~onia, 2 multiple trauma, 1 sepsis and 1 cardiorespiratory arrest. 15 patients showed /j~ds and 8 pht, in 4 with associated ards. we analyzed age, sex, diagnosis, pao2, pa02/fi02, oxygenation index, pht, shock, and sepsis as prognostic factors and response factors to n0. results : after no administration oxygenation did not improve in 2 patients (8.6 %) and pht did not diminishe in one children (12 %). 12 patients survived (52 %), 8/15 (53.3 % with /d%ds) and 4 /8 (50 %) with pht. the four patients with isolated pht survived , and the 4 patients with pht and ards dead. patients after cardiac surgery presented less mortality (35.7 %) than the rest of patients (66.6 %). patients with shock presented higher mortality (64.2 %) than the rest of patients (22.2 %). there are no differences in response to no in respect of sex, age, diagnosis, shock, and sepsis. survivors showed higher increase of pao2/fi02 64.3 ± 58.4 to no than non-survivors 48.4 ± 51.1 (n.s). patients with pht showed higher increase in pa02/fi02 to no administration ( 88 ± 47.1) than patients with ards (43.4 ± 50.8), (n.s), but patients with ards showed a higher increase in 0!, 15 ± 6.7, than patients with pht 4.8 ± 4 (p < 0.05). patients with pa02/fi02 < i00 showed less increase in pa02/fi02, 47.8 ± 46.3, than the rest of patients 82.8 ± 65.5 (n.s) conclusions: i. mortality of isolated pht treated with no is less than patients with ap~s. patients with shock and those with pht and ards showed higher mortality. 2. we have not found any clinical or analytical factor to predict clinical response to no administration. 14 patients showed ards, and 9 severe pht after cardiovascular surgery, in 5 with associated ards. we registered respiratory assistance, blood gases, pao2/fi02, the oxygenation index (oil, and mean pulmonary pressure/ mean systemic pressure (pap/sap) before and after no inhalation. we measured continuous concentration of no and no2 by electrochemical method (noxbox, bedfont, airliquide). results: no administration improved oxygenation mean pao2 from 74 ± 17 tm~g to i19 ± 54 ~g (p < 0.01), mean pa02/fi02 fr<xa 83 ~ 30 to 13£± 72 (p < 0.01)and 0i from 28 ± 14 to 20 ± 12 (p < 0.01). 2 patients did not improved with no administration. the oxygenation improved in the first five minutes and the best oxygenation was achieved with 5 -15 ppm. there is no significant change in pac02. pap/sap diminished from 62 ± 17 % to 42 ± 9 % ( p< 0.05), in one patient there is no response. the no administration was maintained between ~5 minutes to 47 days. the effect of no on pulmonary pressure and oxygenation was maintained without change during all the time it was administrated. n02 concentration were always less than 2 ppm y metahemoglobinaemia less than 3.5 %. there are no side effects secondary to no administration. 12 patients survived (52 %). concluaions:l.administration of no improves oxygenation in children with ~/eds and diminishes pht after cardiac surgery. 2.no effect is fast and maintained during the evolution. high frequency oscillatory ventilation in combination with inhaled nitric oxide g~thberg sylvia, md, edberg k e md, phi), dept of paediatric intensive care, children's hospital, s-416 85 g6teborg, sweden background: for man), years severely sick infants with congenital heart malformations or acute lung disorders have died due to pulmonary hypertension, hypoxia and multiple organ failure. today there are several therapeutic facilities coming up for these infants. ecmo progranunes have been introduced in severul centres as well as improved venlllatory techniques, as high frequency oscillatory ventilatior~ (hfov), which provides adequate ventilation with less risk for hmg injury.. in 1987, the endothelium derived relaxing factor was identified as nitric oxide (no), and extensive studies have sho~-a that inhaled no reduces pnimonm3 o vascular resistance and improves oxygenation in hypoxic infants with pulmona~ hypertension. material.. from july 1994 to january 1996, we have treated 13 severely hypoxic children with combined ttfov-no. seven were newborn, 3 with cdh, one with mas, one with irds, one with paediatric ards due to rsv infection and one with poor oxygenation atler open heart surgery. 6 were between 1 month and 9 years and all had ards of differentorigin but one who was hypoxic after open heart surgery. method: hfov was given by means of sensormedics 3100a oscillatory ventilator to 12 patients, and dr~ger babylog 8000 was used in one case. mean airway pwssures varied from 10-34 cm h20. oscillatory pressures varied from 25-85 cm h20 and ventilatory rates from 6-15 hz. fi o2 varied from 0,21 -1,0. no was administered by nomius classic. no and no2 was measured in the inspiratory limb with an electrcchemieal device. noconcentration varied from 2 to 20 ppm and the no2 -concentration between 0-0,2 ppm. methemoglobin was never more than 3,7 % (average 1,7). duration of treatment varied from 1 to 20 days. combined trealment with hfov and inhaled no improved oxygenation and carbon dioxide elimination in 12 out of 13 treated childretl 5 patients died, 3 due to their underlying congenital heart disease, one of asphyxia due to rsv-infection and one of cdh with progressive hypoxia and multiple organ failure. combined treatment with hfov and inhaled no improves oxygenation in severely hypoxic children. treatment should be slarted early to reduce the risk for chronic lung injury following barotranma and high oxygen concentrations. we speculate that the combined hfov-no may reduce the use of ecmo, and that it may improve outcome in ceotres where ecmo programmes are not introduced. apart from its vasodilative properties nitric oxide appears to act also in physiologic immune defense. intracetlular concentrations of no synthesized by macrophages are in the range of 103 above those produced by vascular endothelium. we investigated the bacteriostatic effect of nitric oxide at concentrations used during inhaled therapy for pulmonary vasodilation in neonates. ten different strains of five species were used (staph. anrens, staph. epidermidis, strop. group b [gbs], e. coil and pseudomenas aeruginosa), which are ~e most often tracheally isolated bacteria in mechanically ventilated premature infants and neonates. we compared bacterial growth of cultures applying three different concentrations of nitric oxide (40 ppm. 80 ppm, 120 ppm) m the growth of the same strains in room air for a duration of 24 hours. no bacteriostatic effect was demonstrable at no concentratioes of 40 ppm. e. coil showed decreased bacterial growth at 80 ppm and 120 ppm, however without reaching statistical significance (p=0.058). at nitric oxide concentrations of i20 ppm staph. epidermidis and gbs grew significantly less as compared to colonies of the same strains in room air. no effects were found regarding the growth of staph. aureus and pseudomonas aneruginosa. we conclude that nitric oxide has a selective bacteriostatic effect on some of the most often trachealb, isolated bacteria in premature infants and neonates. this effect appears to be dose-dependant and occurs in the upper range of dosages used with inhaled no therapy. further research is required in order to examine the mechanisms of action as well as specific interactions between different strains of bacteria and nitric oxide. the no,box monitor (bedfont, kent, uk) is used to monitor nitric oxide (no) and nitdc dioxide (no 2) during no administration in ventilated neonates. according to the manufacturers specifications the monitor can be applied in cases where airway pressures range from 5 to 50 mbar. we investigated in-vitro the accuracy of the no monitor in a range of ventilatory conditions. using a dr~ger babylog 8000 we ventilated an artificial lung. no was administered {800 ppm no in 100% nitrogen) with a mass flow controller to the inspiratory tube, at a distance of 20 cm from the y-piece. the no target value was set to 10 ppm. the ventilator was operated in both cpap and ippv modes at different settings. the no sampling tube was placed on two different locations; in the inspiratory tube dose to the y-piece; in the expiratory tube haft way between the y-piece and the ventilator. the no-monitor was ca)ibrated with 84 ppm no at 30 mbar. fig. 1 and 2 show the sensitivity of the no-monitor for respectively static pressure (cpap) and pulsatile pressure (ippv) with the sampling tube located in the inspiratory tube. fig. 3 shows the resur for pulsatile pressure with sampling in the expiratory tube. we conclude that the accuracy of the bedfont no-monitor is dependent upon airway pressure and sampling site, the latter possibly caused by incomplete mixing, pressure and no are linearly related when sampling occured further away from the administration site. based on this study we suggest to place the sampling tube in the expiratory tube. during neonatal care the clinician should be aware of varying inaccuracies depending on the respiratory pressures. hypothesis: availability of therapy with inhaled nitric oxide (ino) decreases ecmo use in patients referred .to a tertiary care hospital for treatment of respiratory, failure unresponsive to conventional therapies. background: at children's hospital of wisconsin (chw) treatment for patients who have failed conventional treatment for respiratory failure, sometimes called "rescue" therapy, has included ecmo since 1986 and high frequency oscillatory ventilation since 1992. ino has been in experimental use at chw since may of i994 and has resulted in the perception of a decreased need for ecmo therapy in those patients referred for rescue therapy. this study was designed to tbst the validity of that perception. study type: retrospective cohort. methods: the medical records of all 105 patients referred to chw from 1/lj93 to 4/1/95 for rescue therapy for severe respiratory failure were included in the chart review. data were collected regarding diagnoses, illness severity, hospital course including interventions and complications, and outcomes. exclusion criteria w~ere the finding of structural heart disease or congenital diaphragmatic hernia as the basis for hypoxemia. qualification for ino treatment included an a-ado2 -600 or oi ~-40 for two hours or -> 25 for twelve hours and echocardiographic demonstration of persistent pulmonary hypertension of the newborn. patients were classified into two groups based on the availability of ino at the time of their hospitalization. results: in the time period of the study, 105 patients were referred for possible ecmo therapy. twelve patients greater than 4 weeks old, 31 with congenital diaphragmatic hernia and 12 with congenital heart disease were excluded from this analysis, leaving 50 patients for study, ino availability reduced ecmo use from 16 of 34 (47%) patients in the ~ino unavailable" group to 2 out of 16 (12.5%) patients in the "ino available" group, p=&026 by fisher's exact test. the fact that the two groups were composed of patients of similar severity of illness is reflected by comparable rates of ecmo and ino rescue therapy (47% vs. 56%). conclusion: by providing an alternative rescue therapy, ino has reduced the need for ecmo in this group of neonates referred for respiratory failure. introduction: true hepatnrenal syndrome (his) is defined an acute renal failure {arf) in the presence of severe liver disease without other known causes of renal failure. hrs is frequently seen in the course of hepatic cirrhosis• in children, cirrhosis is rare; however, arf can be seen in combination with aseites and liver dysfunction• we describe 3 patients with hepatic dysfunction and aseites in combination with ar~ and abnormal sodium-water handling, leading to the diagnosis of hrs. pathophysiology: three factors are considered in the pathogenesis of hr~: i) hepatic dysfunction, 2) deranged hemodynamics, including abnormal blood pressure, reduced effective arterial blood volume and abnormal blood flew distribution, and 3) neuro-humoral dysrsgulatiom, including elevated levels of aldosteron, renin, angiotensin-ll, ade, vasodilatim 9 nitric oxide and vasoconstrictor peptide endothelin-l. the main pathogenetic feature is decreased cortical renal blood flow, decrease of glomerulur filtration rate (gfr), vastly increased sodium retention, uliguria, and azotemia. treatment: therapy is based on counteracting sodium and fluid retention by highdose aldosteron antagonists and loop diuretics, improving renal perfusion by lowdose dopamin, and strict restriction of fluid and sodium. interventions as paracenteals of aacites or n peritoneo-systemic shunt are associated with high morbidity and poor outcome in children. reversal of hem by conservative measures can only be attained at early stages of hrl liver transplantation is the only definitive treatment that can reverse ere at advanced stages. patients: the described patients developed severe ascites with insidious renal dysfunction and abnormal sodium-water handling during admission at picu and fullfilled clinical criteria fur hrs. treated according to the cited principles, all patients showed improvement of gfr, with increased natriuresis and gradual decrease of ascites. eventually, renal function normalised completly. conclusion: ere deserves greater recogmitimn in the picu population; diagnosis can be suspected on clinical criteria. with this increased awareness, therapy tun be instituted at an early phase, with better prospects for recovery. positive outcome of hem depends on early recognition of the clinical picture, understanding of the pathophysiology, and early institution of consistent treatment. mtx is an antimetatxflite widely used as chemotherapeutic agents. high dose ivitx (i to 30~m2) administered as a prolonged intravenous infusion (over 4-42 hours), is often used to treat malignant paediatric diseases. major complications of this treatment are myelosuppression, orointestinal mucositis, dermatitis and impairment of anal function. we report two cases of mtx overd~age occurred in two children (5-year-old. 14 month-old) t~ted for acute lymphoblastic leukaemia. they were treated by cavh and the mtx bhk~d levels rapidly decreasedavoiding multisystemic involvement. establishment of alkaline diuresis and monitoring of plasma mtx levels during treatment is essential to prevent nephrotoxicity. however. leuco',cnn rescue may not prevent the development of potentially lethal toxicities in patients with mtx concentrations persistantl} exceeding t0mm. in theses cases, em'ly treatment of mtx intoxication may pm~cnt myelosuppression and reducerenal damage. the goal is to lower the concentration to below 10 mmoll, at which time rescue agents aleme would be expected to be cllcctive. respective indications of these remo',at mctny.:is are still discussed : hacmt~ialysis t~ eharc(~l haemoperfusion should be prolx',sed for massive and acute intoxication. however, rebound has been reported after combined hcmodialysis and hemoperfusion. exchange transfusion may be proposed as a treatment for prolonged and moderate intoxication. peritoneal dialysis is an incflbedve method for remo~ al of mtx. cavh was used in our icu. cavh is a simple method for blood purification and n':dy iluid control. use of cavh was never be reported in this indication to our knowledge. simplicity, rap~d application and gco.l clinical tolerance are the main advantages of this technique. the technique presents ~peclal advantages in terms of low priming volume of extracorporeal circuit, low blood flow, low rate heparinisation. our results show a decreaseof plasma mtx concentration and a rapid reduction of halfqite of elimination (t5 hours over the period of cavh). moreover, we didn't delec~d rebound after stopping prc,xedure. small size of the i:ratients may present sometime special problems, but these technical problems can be overcome, no severe complication (needing, inlection) were observed during filtration, in summary, aggressive intravenous fluid hydration and alkaliniaation of the urine coupled with careful monitoring of renal function and plasma mtx concentrations during and al'tcr infusion along with lem~overin rescue has reduced the inndcace of life-threatening toxicity after highdose mtx. however, some mtx inu>xication still occurred, leading to se~em toxicity, particularly nephrotoxicity. in these cases, we think that cavh (or cavhd) is a reliable, rapid method without rcix~und increase in plasma mtx concentration or important adverses effects compared to other procedure removal. gouyon jb, germain jf, semama d, pr6vot a, desgres j preliminary limited data suggested that hemofiltration and hemodiafiltration may be valuable in some neonates with decompensation of maple syrup urine disease (msud). venovenous hemofiltration (vvhf) and hemodiafiltration (vvhdf) were performed with a new neonatal hemo(dia)filter (miniflow 10, hospal) on 8 anesthetized rabbits infused with branched-chain amino acids (leucine, isoleucine and valine) and c~-keto-isocaproate. the bcaa and aketo-isocaproate blood levels were close to those previously observed in neonates with msud when extracorporeal blood purification was required. vvhf and vvhdf performances were assessed with two different blood flows (qb = 8.3 and 16.6 ml/min). vvhdf was performed with 4 dialysate flow rates (qd = 0,5, 1.0, 2.0 and 3.0 l/h). thus, each animal was submitted to 10 successive procedures. within each studied period, clearances of the 3 bcaa were strictly similar. bcaa clearances obtained by vvhf were similar to ultrafiltrate rates (respectively, 0.78 4-0.14 and 1.79 4-0.28 ml/min at high and low qb ; p < 0.05). the ~x-keto-isocaproate clearances obtained by vvhf were 0.39 4-0.17 and 0.92 4-0.43 ml/min at low and high qb (not significantly different). whatever qd value, the vvhdf procedures always allowed higher bcaa and c~-keto-isocaproate clearances as compared with the corresponding v'~hf period with similar qb. bcaa clearances obtained by vvhdf with a 0.5 l/h dialysate flow, were 4.1 4-0.5 mljmin and 5.4 4-0.5 ml/min at iow and high qb, respectively. the concurrent a-keto-isocaproate clearances were 2.5 4-,. 0,8 ml/min and 2.9 _+ 1,0 ml/min. at both qb regimens, bcaa clearances provided by vvhdf were markedly higher than values previously obtained with peritoneal dialysis in human neonates with msud. the management of renal failure in the newborn is difficult. when dialysis is instituted peritoneal dialysis (pd) is usually the technique of choice. this is can be problematic and impossible in some patients with pre-existing intra-abdominal pathology. continuous arterio-venous haemofiltration (cavh) has been described in infants but sick preterm infants are not able to support the circuit. i have devised a means of having pumped haemofiltration in small/preterm infants (phis/pi) and describe its use in nine patients ranging in size from 750 to 3000gms for periods of 1 to 7 days. vascular access was achieved through 24 or 22 guage cannulae in either a peripheral artery and a central vein or through two central veins. blood was pumped out using an ivac 572 infusion pump and through a gambro fh22 haemofilter. a second ivac pump was used to remove haemofiltrate from the filter and a third to infuse replacement solution. removal rate was set to give a clearance of 15mls/min/1.73sq.m and blood flow rate set to between 5 and 10 times the removal rate. heparin was infused into the circuit to prevent clotting of the filter. biochemical and fluid balance control was achieved in all infants. guaranteed fluid removal allowed the administration of full nutritional support. four patients died when treatment was withdrawn because of an untreatable underlying problem. one recovered renal function but died some weeks later from unrelated problems, three survived and recovered renal function and one patient is still on treatment. this system allows a secure means of achieving fluid and electrolyte control in the preterm infant. the use of this technique may allow haemofiltration to become as applicable to preterm infants as it is to older children and adults. unibrtunately, children often receive no treatment, or inadequate treatment for pain and painful procedures. this prospective, multicentric study focuses on the efficacy, safety and side effects of novalgin (metamizol sodium) for this indication. patients and method: novalgin was administered to 56 children, aged between 6-16 years, with acute, postoperative or procedural pain. novalgin (10-15 mg/kg) was given 6-8 hourly iv or im respectively, in some cases (15) in combination with opioids (tramadol 10, piritramid 3, butorphanol 2). the pain relief was assessed by six-step verbal rating scale (vrs) from 0 to 5, vital signs were monitored, the side effects, that occured were recorded. results: pain relief was good (vrs less 2) in 53 children -94.6 % of study patients. novalgin was very well tolerated, only one patient had adverse reaction -hyperpyrexia following intravenous application of the drug. discussion: novalgin (metamizol sodium) is safe and effective drug in the management of acute pain in children with low incidence of side effects. obie~qve: a prostx~tive study comparing simultaneous, indepeadent ratings conducted by intensi~4sts using an american (comfort) and an european chartwig) sedation scale for mechanically ventilated pediatric patients. measurements and results: the study comprised 30 observations in 18 mechanically ventilated pediatric patients (aged 16 days to 5 years) in a pediatric intensive care unit (from march 1995 to january 1996 . each patient was sedated by his/her managing physician with opiates, benzodiazepines, barbiturates, used isolated or in combination. each observation consisted of a 3-mid period of oly~ervatien of the patient in his or her pediatric icu bed, after each observation, the comfort (analyses 8 dimensional physiologic and behavioral subscores -range 8 to 40 paints) and hartwig (analyses 4 dimensional behavioral subsenres -range 8 to 25 points) were performed by the intensivist. we established the comfort scores ~ correspanding to adequate (range 17 to 26), excessive (range 8 to 16), and inadequate (range 27 to 40) sedation; and, hartwlg scores z correslxmding to adequate (range 15 to t8), excessive (range 8 to 141, and inadequate (range 19 to 25). statistical mmlysisj: agreement rate (kappa) and p <.01 was considere d s!l~nificant. comfort 18 (60.9%) 2 (6,6%/ 10 (33.4%) hap, twig , 17 (56.6%) 7 (23.4%) 6 (20.0%) to the comfort score, the average for adequately sedated, inadequately sedated, and too sedated was 20.28+-2.78, 2z5_+0.70, and 15a.+_l10, respectively. and to the ha~twig scorn, the average for adequately sedated, inadequately sedated, and too sedated was 16.35:k-'0.77, 20.85-&l57, and 13.0l-0.89, respectively. conclnsion: in our study there were no significantly statistical difference when you apply a more complex scale (conff'ort) or a less complex scale (hartwig) to assess the sedation of mechanically vemilated pediatric patients. the application of local and intravenous morphine infusion after surgery of urinary tract eva nemeth , m.d. semmelweis medical university , first oepartment of paediatrics , budapest , hungary in±roduction:continuous analgesia with morphine may be ~egaroed as a safe and effective method of pain relief during postoperative period. subjects and methods: 24 children /mean age 2.3 years/ underwent elective ureteroneoimplanta±ion were randomly selected to receive either morphin intravenously of lo ug/kg/h /group one/ or bladder morphineinfusion 50 ug/kg/h /group two/ after surgery. all patients were prospectively evaluated during their s±ay in the postanaesthetic care unit. cardiac and respirafory rates,blood pressure,sa 02 ~,degree of alertness,pain perception and complaints of the paticnto ~cr~ recorded hourly. pruritus,nausea and vomiting,voiding difficul-±ies,sedation,dysphoria were systematically sough and quoted. statistical analysis was performed by chi square test. results:postoperative analgesia was the same in the two groups,but side effects were less in the bladder morphine group,because of the lower se morphine concentration.the differentes weren't significant in two groups. conclusions:the administration of bladder morphine infusion is a safe and effective method in children. objetive: compare the evaluations of sedation level made by physicians and nurses with the visual analog scale (vas) and the comfort scale (cs) in pediatrics patients receiving difforents modes of intravenous sedation. material ~ method." file evaluations were made by an attending physician and nurse with the vas and by another physician (always the same) using the cs. the observations were divided following the sedation mode: one drug (fentanyl or midazolan), two continuous drugs, one continuous and one intermi~ent drug and two intermittent drug (fentanyl and midazolan). the groups were compared using the t-student test. the groups also were compared between the percentual of agreement of the evaluations of sedation level made by physicians and nurses with the cs and vas using the x 2 . results: we didnk find any statistical difference between the observations made by physicians and nurses with the vas in the differmts modes of intravenous sedation, the average of the observations using the cs betwom one drug and two drugs modes didnk exhibit also statistical difference. the observations made by physicians mad nurses using the the vas when compared with the cs didn't show statistical difference between the sedation level. we found statistical difference only in percentual of concordance of sedation level between physicians and nurses when compared the one and two drugs modes of sedation. conclusion: we didn't find differences in the observations made by physicians and nurses in the sedation level, only in concordance pereentua/ of observations when compared two modes of sedation. the observations using the cs (more complex) didnk show differences when compared with the vas. effects of age, concurrent administration of other pharmacologic agents, and disease [cardiac(n=31) & pulmonary(n=22)] on the pk & pd of b were evaluated in volume overloaded infants aged 4 days-6 mo (n=53). single doses of 0.005,0.01,0.015,0.02,0.025, 0,03, 0.035,0.05 & 0.10 mg/kg iv were given over 1-2 min after baseline evaluation. age was used as a continuous vadable to determine its effects on the variability in the pk & pd of b. values for pk parameters were compared between patients in cardiac and pulmonary disease groups. hierarchical multiple regression analyses were used to determine the effects of age, disease and other pharmacologic agents on the variability of bumetanide excretion rate (ber) and pd responses, e.g. urine flow rate (ufr) & electrolyte excretion. cit, cir & cinr increased with age (p<0.05) while t,2decreased markedly in the first monthe of life (p<0.05). ber normalized for dose increased with increasing age. patients with pulmonary disease exhibited significantly greater clearance and shorter t~= (p<0.05) than those with cardiac disease whereas vd~ was similar in both groups. the administered dose of b was the primary determinant of ber but increasing age also contributed. penicillin antibiotics decreased ber. dose response curves for ufr and electrolyte excretion were similar between disease groups. more of the variability in ber and pd responses could be accounted for in the pulmonary group than the cardiac group but this was not statistically significant. conclusion: the pk of bumetanide were influenced significantly by age and disease. differences in pk between patients with pulmonary and cardiac disease were primarily due to differences in total clearance. age and the administered dose of b were positive determinants of ber and pd responses while penicillin antibiotics had a negative impact on both, once b reached its site of action, no differences in pd responses were detected between disease groups. the pharmacodynamic effects of bumetanide were evaluated in volume overloaded infants (n=56) aged 4 days-6 months. single doses of 0.005, 0.01,0.015, 0.02, 0,025, 0.03, 0.035, 0.05 & 0.10 mg/kg iv were given over 1-2 rain. bumetanide concentration in blood (n=l 0) & urine (n=6) samples were quantified by hplc. baseline urine samples were collected over 2-4 hours prior to drug administration. determinations of urine volume, electrolytes (na ", k +, ci, ca ++ and mg++), creatinine and osmolality were performed before and at 0-1, 1-2, 2-3, 3-4, 4-6 and 6-12 hours after bumetanide dosing. changes in urine flow rate and electrolyte excretion were plotted as a function of bumetanide excretion rate which was considered the effective dose of the drug. peak bumetanide excretion rate increased linearly with increasing doses of drug and showed no evidence of approaching a maximum. time course patterns for urine flow rate and electrolyte excretion were similar for all dosage groups. urine flow rate and electrolyte excretion increased lineady up to a bumetanide excretion rate of approximately 7 #g/kg/hr and either plateaued (urine flow rate) or declined at bumetanide excretion rates > 10 #g/kg/hr. bumetanide had no detectable effect on serum electrolyte concentrations, conclusion: maximal diuretic responses occurred at a bumetanide excretion rate of about 7 ;~g/kg/hr. higher bumetanide excretion rates produced no increased diuretic effect. peak bumetanide excretion rate of about 7 #g/kg/hr corresponded to bumetanide doses of 0.035-0.050 mg/kg. neonates using an electrical syringe-pump. authors: tr~luyer j.m., sertin a., bastard v., settegrana, c., bourget p., hubert p. background and objective: many problems can be observed with drug administration by i.v. route, especially in neonates. so we evaluate different protocols of teico delivery using an electrical syringe-pump. methods: we simulate infusion of teico with a syrlnge-pump (pilot c, becton & dickinson lab.) trough d standart neonatal i.v. system. for 2 weights (1 or 3 kg) we used 2 doses of teico (8 mg and 16 mg/kg) and a dose volume _<4.2 ml. our goal was to perform a complete infusion in 10 minutes. the infusion system consisted of an life care 4 infusion pump (abbott lab.) with its lv. set for maintenance intravenous fluid (flow _< 6 ml/h) connected to a 3-way stopcock. an 1 meter extension tubing was placed between the stopcock and a neonatal catheter. an another 1 meter tubing (injection tubing) connected the teicoplanine syringe to the stopc, ock. the volume of the injection circuit (from the syringe to the distal part of the catheter was 2.6 ml 4 methods of injections were assessed: a: injection of the predetermined volume of teico in 10 minutes with no wash out. b: idem as a but the teico was injected in 5 minutes, followed by a wash out (5 ml / 5 minutes). c: twice the required volume was introduced in the syringe and the volume to infuse was programed in 5 minutes, followed by a wash out (5 ml/5 minutes). d: ]dem as c but a priming was performed before connecting theteico syringe to the tubing. during each run, serial samples were collected every ten minutes over a one hour period. the samples were assessed using hplc method. results: the amount of drug delivred at 10 minutes were calculated. the results are a mean of 2 to 6 runs and expressed as the percentage of the total amount of teico prescribed. a 2,8 % 6,4 % b 47 % 62,3 % c 82a % 86,8 % d 94,2% 95 % conclusiom for accurate and reliable intermittent drug infusion with a syringe pump it is mandatory to use a precise protocol of administration and to take in account 1) a priming (for immediate starting of infusion), 2) a drug volume greater than the dose prescribed and a programmed volume injected, 3) a wash out of the tubing (with a volume ~ 1,5 x volume of tubing injection) caz is an antibiotic with activity against the major pathogens responsible for neonatal bacterial infections. we previously reported the pharmacokinetics of caz in 136 preterm infants on day 3 of life which showed that the clearance of caz increased with increasing gestationat age (ga). mean serum half-life of infants with gas < 32 wks was 8.7 h. we wanted to investigate the effect of postnatal age on caz pharmacokinetics, we therefore studied caz pharmacokinetics on day 19-21 of life in 10 preterm infants with gas < 32 wks. caz (25 mg/kg) was administered as an intravenous bolus injection. blood samples were coilected before (t =0), and 0.5,1,2,4,8 and 12 h after the caz dose and analyzed by hplcassay, the pharmacokinetics of caz followed a one-compartment open model. during 1995 11 newborns with complex congenital heart defects requiering either htx or palliative staged single ventricle repair were admitted to our hospital: hlh n=8, unbalanced cavsd, tga with hypopl. rv and hypoplastic aoa. tga with hypopl. rv, sas and dextrocardia. 8/i 1 children had been admitted with cardiogenic shuck and mukiorgan failure due to intermittend closure ofductus arteriosus; in 3/8 stabilization failed. parents were informed about the known and unknown risks of the always palliative surgery; in 2 cases parents denied further therapy. one pafiem with hlh underwent orthotopic htx at the age of 5 month after the ducms art. had been stunted in the newborn period. 9 month later he is still in favourable condition and without any sign of acute organ rejection. 5/11 underwent first stage of palliative single ventricle repair: norwood -op. ( 3 ) ( n=3 ), damus-kaye-stansel -procedure ( 2 ). the clue to adequate postoperative management was to archieve a balanced distribution of flow to systemic and pulm circulation, that is to protect the single ventricle from volume overload and to guarantee sufficient oxygenation and pulmonary development as well. with the centralvenous sato2 at about 50% provided maintaining the arterial sato2 at about 75_+5% is corresponding with a qp/qs of 1:1. using modified bt-shunts of3.5mm resp. a central anrtopulm, shunt of 4mm in one case l severe puim. hypertension, surgery at 6 weeks of age ) there was no excessive pulm. blood flow and no need to increase pvr with inspired co2. one child ( norwood at 5 weeks, preexisting pnim_ edema ) developed severe pulur hypertension and parenchymal pulm. dysfunction after prolonged bypass and multiple transfusions due to intraoperative bleeding: hypoxemia could be managed successfully by implanting a second shunt of4mm 18hh later and temporarily using prostacyclin and no; at sternum closure 6 dd later the second shtmt was banded to 3ram. follow-up ranges 5-5 month: all 5 children are at home being assigned for second stage operation at about 6 month of age. establishing clinical practice guidelines has become increasingly important in the current health care environment. significant effort has been focused upon development of post-operetive critical care pathways. however, benchmark data upon which such pathways should be based has not been well reported. length of mechanical ventilation (lmv) and length of stay (los) for children following cardiac surgery, for example, is poorly described. we prospectively recorded the lmv and los in 168 patients who underwent cardiothoracic surgery between 9/1/93 to 6/30/95. only patients who belonged in any one of five categories of congenital heart disease (ventricular septal defect _+ other septal defects (vsd), atrioventricular (av) canal, tetralogy of fallot (tof), transposition of great arteries (tga), and single ventricle physiology (fontan)) were included. eight non-survivors were excluded from the analysis. all patients were admitted to an intensive care unit 0cu) post-operatively where mechanical ventilation was managed by 4 pediatric intensivists. lmv was defined as the period from post-operative admission to planned extubation. length of stay (los) was defined to be from le from the icu. cytokine patterns during and after cardiac surgery in young children. especially in children, cardiac surgery with cardiopulmonary bypass (cpb) can cause a systemic inflammatory response. this process is thought to be mainly a result of inflammation induced by surgery and exposure of blood to an artificial surface, and of reperfusion injury during weaning of bypass. complement activation, degranulation of granulocytes, induction of free oxygen radicals, endotoxemia and release of cytokines, are important contributing factors. we studied cytokine patterns before, during and after cpb in young children admitted for complex surgery or for septal defect correction. in the first group, significant amounts of il-6 and il-lra could be detected preoperatively. these findings could reflect the already existing hemodynamic dysregutation. in both groups, cpb procedure upregulated the circulating pro-inflammatory cytokines il-6/8, but not il-1b. at the same time, il-lra became detectable. therefore, we suggest that in these patients the production of the anti-inflammatory cytokine il-ira was not induced by the preceding acnvity ot pro-inflammatory cytoidnes. during cpb, we noticed a sharp decline in the capacity of the leucocytes to secrete il-6/8. the ex-vivo production of il-lra however, was only slightly attenuated. we conclude that there is a differential regulatory pathway for the induction of il-6/8 and il-lra. in addition, we studied the influence of dexamethasone administration on the cytokine pattern. administration delayed the appearance of il-6/8 and il-ira in the plasma, interestingly, it did only interfere with the ex-vivo production of pro-inflammatory cytokines. the latter supports our hypothesis that production of il-6/8 and of il-lra is regulated by two independent pathways, (60%) of 43 pts. 82% ofpts < 12 months of age developed metabolic alkalosis as compared with 38% ofpts > 12 months of age.the infants with metabolic alkalosis received more citrated blood products and furosemide. following cardiac pulmonary bypass the highest ph-values and be-values were observed 24-48 hours and 48-72 hours, respectively. ii. prospective study: metabolic alkalosis was registerd in 2t children (70%), 8 of those <12 month (75%) developed metabolic alkalosis and 67% of those elder than 12 monms.durmg the postoperative course patients younger than 12 months developed the highest ph-and base excess values after 102 and t05 hours, in the subset of the older patients maximum ph and base excess was found after 48 and 81 hours, respectively. in one case the top level ofph-value exceeded 7.6, the base excess +20 mvalb. conclusion: children undergoing cardiac surgery with cardiopulmonary bypass often develop metabolic alkalosis.in contrast to previous reports, we did not observe an association between metabolic alkalosis and mortality, nor greater frequency of cardiac arrythmias or prolonged mechanical ventilation. in context with decreasing serum lactate levels, our data show positive correlation of metabolic alkalosis with postoperative improvement of liver function. respirator, mechanics and weaning outcome in children undergoing cardipvascular surgery. vassallo j., cernadas c., saporiti a., landry l., rivello g., buamsha d., rufach d., magliola r. mechanical ventilation (mv) and acute respiratory failure are common events in children unergolg cardiovascular surgery (cvs), the development of new techniques helped to measure some of the main respiratory mechanics (rm) in a non invasive fashion. our goal was to evaluate the predictive value of these measurements in weaning (w) outcome in these patients, patients and methods: we prospectively evaluated children considered clinically to be ready for w with < 20 kg and > 24 hs mv. patients with diaphragm paralysis and those who failed w because of upper airway obstruction were excluded. before patient extubation the following measurements were recorded during spontaneous ventilation (cpap/t piece) using the cp 100 neonatal pulmonary monitor bicore (lrvine, ca): total respiratory system static compliance (cssr) and resistance (rts), rapid shallow breathing index (rsbi). maximal inspiratory negative pressure (pi max) was measured using an unidirectional expiratory valve. threshold values predicting w success (ws) were: cssr > 0.5 ml/cm h20, rts < 75 cm h20 /l/sec, rsbi 160 and pi max > -30 cm t120. w failures (wf) -patient reintubation within the following 48 hs, these values were compared between w success and failures using fisher exact test. an apriori level of statistical significance was chosen at p < 0.05. 4 considered, an increase in tnf-a levels is observed after cardiac surgery (p<0.001) with a return to previous values after 24 hours (p<0.005). 72 hours after cpb, similar values are observed in groups ii and ill, but there is a further increase in serum tnf-a levels in group i when compared with both other groups (p<0.03). we found no statistically differences in any other moment. there was a significant correlation between serum tnf-o levels determined 72 hours after surgery and cpb duration (p<0,003). conclusions: cpb in childhood provokes a significant increase in serum tnfa levels, in newborns the inflammatory response is maintained 72 hours after surgery. this enhancement of serum tnf-e levels indicates the existence of a relevant inflammatory response in these patients. introduction: cardiac surgery appears to induce a systemic inflammatory response. we have investigated the behaviour of il-1 i~ and il-6 before and after cardiac surgery. patients and methods: we studied serum il-1 6 and il-6 levels from 20 children with congenital heart disease (10 boys and 10 girls), aged from 7 days to 14 years, undergoing open heart surgery, before cpb (d we found no statistically differences in the il-i levels in the different groups and moments. there is a significant increase in il-6 immediately after surgery (p<0,01) with similar levels 24 hours after cpb and a significant decrease (p<0.01) 72 hours after cpb. preoperatory il-6 levels were higher in the groups i and tl than in group i11 (p<0.05). 24 hours after cpb serum il-6 levels in group 1 were significantly higher when compared with group 111 (p<0.05). conclusions: cpb in childhood induces a significant transient increase in serum il-6 levels, strongly relevant in newborns. cpb was not associated to a significant modification in serum il-1 6 levels. thus, cpb in childhood induces a dissociated behaviour in the proinflammatory il-6 and il-1 & pathways. obiective, to evaluate the effects of amg receipt on the clinical condition during the first 12 hours after birth (t2), the morbidity and mortality in immature outborn neonates. methods. we studied 44 outborn neonates with ga 26 to 29 wks, admitted during the years 1993 to 1995. eighteen neonates exposed to amg (ga:27,6+lwks, bw: 1066_+195g) and 26 neonates did not (ga: 27,7_+1wks, bw: 1042_+187g). results. amg-exposed neonates compared to those not exposed had lower incidence of apgar score at 5 min _< 3 (6% vs 35%, p<.05), lower incidence of ph t2 <7.20 (11% vs 48%, p<.05), decrease need of bicarbonate 12 (22% vs 54%, p<.05), lower fio212 (fio212min>40: 17% vs 48%, p<.05 and fio212max >80: 17% vs 52%, p<.05), lower incidence of intubation (67% vs 92%, p<.05), lower requirements of surfactant (50% vs 79%, p<.05) and lower mortality (11% vs 50% p<.01). there were no differences between the two groups for the following parameters: type of delivery, hypothermia hypoglycemia and anemia during admission, hypernatremia, hypotension 12 (map<30mmhg), need of dopamine and or plasma 12, incidences of ptx pda sepsis nec severe rop major ivh (plus pvl) and bpd and duration of intubation. conclusions. the main beneficial effects of amg receipt on the immature outborn neonates were the decrease of mortality and the decrease of surfactant need. there was no effect of amg receipt upon other severe morbidity in this high risk group of neonates. premature babies are very sensitive on homeostatic disturbances, and often develope intracranial haemorrhage (ich). ultrasound scan of the bram shows four grades of ich: -grade i -only periventricular hyperechogenic areas -grade ii -haemorrhage ham the lateral ventricles -grade ili-dilated lateral ventricles -gtrade iv -intracerebral haemorrhage. the purposes of this study were: 1 to show the incidence of ich in premature babies and its correlation with the gestational age, 2. to determine the severity of ich 3. to present the outcome &those babies. in the study were included 393 premature babies successively-born at the department of gynecology and obstetrics before 37 gestational week (g.w.) and grouped in three groups: less than 28 g.w., 28-32 g.w., 33-36 g.w. to all of them was performed ultrasound scan of the brain. results : 1. the incidence of ich hi premature babies is 49 % and there is ingh level of correlation with the gestational age: -babies born before 28 t~ g.w. have 100% incidence of ich and graduated : i grade -5%, ii grade -65%, iii grade -25%, iv grade -5% -babies old between 28-32 g.w. have incidence of 61% : i grade -24%, i[ grade -62%, iii grade -14%. -babies older than 32 g.w. have incidence of 33%: i grade -46%, ii grade 48%, iii grade -6% 2. sixty of 393 premature babies have died and it is 15.2% lethality. in all died ilffant was confirmed the grade of ich diagnosed by ultrasotmd scan of the brain. d. maksimo~5c. z.braiko~ic, n.vunjak. p. ivanovski (5~iversi~, children's hospital. belgrade, yugosla~, ia infantile intracranial hemorrhage is the most frequent and serious manifestation of late hemorrhagic disease of the newborn caused by ,,~tamm k deficiency in earl?,, ti~fancy. in the last two years, we recorded five cases of infantile intracranial hemorrhage due to "dtamin k deficiency, despite routine prophylax~s (intramuscular vitamin k, 1 mg) , with bpieal clinical presentation: age was 18 -65 days (average 40 days): vomiting, poor feeding, lethar~'irritabiljty, palor, bulging t0ntanelle and convatsiones were present in most cases.two patients developed signs of hemorrhagic shock, with hemoglobin level less than 70 g.1. in 3~5 f \qi level was less than 30 % of predicted value. there was no evidence of head trauma or liver disease in none of patients. four inlants were breast fed, while one, who had diarrheal disea.se, was on adapted milk formula. routine therapy wa.s given (including vitamin k and fresh frozen plasma). two patients were discharged with no sequellae, one developed posthemon'hagic hydrocephalus as a complication and two patients died. late hemorrhagic diseo.se of the newborn is sill/ a significant cause of morbidib' and mortality in earl3' infancy, despite different approaches to prophylaxis developed in recent years. background: neonatal hearing screening in at risk newborns can detect 50% of the children with a congenital hearing loss. automated abr hearing screening (algo-1) has been introduced for healthy newborns. the aim of this study is to test the validity of this algo-1 screener in at risk newborns in a neonatal intensive care unit. subjects: 250 at risk newborns (median gest.age: 30.0 wks, median birthweight 1350 g) selected according to the criteria of the american joint committee on infant hearing. interventions: algo-i automated abr-hearing screening at a level of 35 db was performed in the neonatal intensive care unit. when bilaterally referred, further audiologic screening and/or therapeutic intervention took place. when passed uni-or bilaterally, children enrolled in a) a nation wide screening programme (ewlng) at the age of 9 months and b) in a half yearly follow-up programme in which hearing and speech-and language development were observed according to egan an illingworth. results: screening without disturbance from ambient noise or from routine technical equipment was possible in the incubator, even during nasal cpap therapy. 245 (98%) newborns passed algo-1 screening. 5 (2%) did not pass bilaterally. 1 of 5 with a congenital rubella died shortly after screening.in 4 of 5 bilateral congenital hearing loss of ->35 db was confirmed. 235 of the newborns passed were still alive at the age of 1 year. ewing screening was performed in 183 of 235 (77,9%). 161/183 passed, 15 of 183 had passagere conductive hearing loss, in 7/183 no further investigation was performed. all 235 children enrolled in the i/2 yearly follow-up programme had normal speech-and language development. in this study all 4 at risk newborns with bilateral congeni "tai hearing loss were detected with algo-1 screening. screening results showed no false negatives at follow-up. the algo-1 infant hearing screener can be used as an valid automated abr-screener to detect hearing loss in at risk newborns in a neonatal intensive care unit. gancia gp, bruschi l pnlito e, ferrari g, rondini g -divisione di patologia nc~matate e turapia intensiva -irccs policlinico s. mattco -pavia, italy latrogenic esophageal perforations (iep) in preterm and term infants are seldom reported in litteraturc, in association with difficult endotracheal (et) intubation (with or without stylets), insertion of gastric tube, and pharyngeal suctioning with stiff catheters. crieopharyngeal muscle spasm caused by instrumentation may also lead m a narrowing of lumen, with increased risk of local injury. we report 4 iep observed in intubatcd, mechanically ventilated newborn infants (2 male, 2 female, all outborn). a common feature of iep was inability to pass a nasogastric (ng) tube into the stomach, mimicking e~)phageal atresia.~se 1: birth weight (bw) 185(i g, gestational age (ga) 37 wk, sepsis. before admission to n1cu, the baby underwent multiple et inmbations, because of inappropriate securing of et robe. bloody secretions in pharynx were observed. the endoscopy showed a large lesion at the end of proximal third of the esophagus, case 2: bw 1080 g, ga 32 wk, rds. chest x-ray (cxr) showed a retrostcrnal air leak: the ng tube was stopped }~etwcen d8 and d9 and soluble contrast was seen in upper mediastinum.case 3: bw 76(/g, ga 26 wk, rds. the endo~opy showed an esophageal lesion. cxr showed a paravertebral route of ng tube and a right pneumothorax.case 4: bw 102(i g, cz 22 ,.v!:. rd c. ~!,'.::;;: ::':'_'rvt!~'2s l" ~k':.rvrx. cwr, d,,,,vs ~,,mr~e, ~n rhe upper mediastinum and abnormal route of ng tube through a false passage. surgical intervention is needed in case of mediastinitis or mediastinal abscess: conservative management included broad spectrum antibiotics, total parenteral nutrition, antireflux therapy and, if necessary, drainage of air leaks. enteral feeding has been stopped lor 15 days and cautiously resumed after radiographic study. [x~cal sequelae and death are uncommon, but iep occur in newborns with high risk of death due to prematurity and other diseases. in our patients, et intubation has been performed by experienced personnel: therefore the lack of skills in resu~itative procedures is not always the main factor of iep. prevention of iep requires appropriate materials (et tubes, laryngoscope blades, suction catheters), and procedures (positioning of the infant with correct neck estension, firm et placement). sedation and pain control may help to prevent the muscle spasm. aggressive treatment has improved the tong-term outcome of extremely low birth weight neonates (elbw) but it has also increased the chances of iatrogenic lesions. reviewing the charts of our neonates we observed a high number of vascular injuries. from 1987 to 1994, 2898 neonates were admitted to the neonatal intensive care unit (nicu); 335 of them were elbw (11.5%). studying the charts of these elbw we observed 9 cases (4 m -5 f) with vascular lesions (2.6%). mean gestational age of these patients was 28.7 weeks (rain 24-max33). mean weight at birth was 880g . mean weight at diagnosis was 1825g (1230-2700). in the same period 10 patients with vascular injuries were reported in the 2563 neonates over 1500g (0.3%). the injuries observed in elbw group were: 6 arteriovenous fistula (2 bilateral) at femoral,level, 1 carotid lesion and 2 limb ischemic lesions. aetiology was in 7 cases by venipuncture, in one case umbilical catheter and in the case of carotid lesion a wrong surgical maneuver. no general simptoms were observed. the vessels were repaired with microsurgical technique in six cases: the carotid lesion and five arteriovenous fistula; one case was solved with thrombolitic drugs; an amputation at knee level was required in one case after a long period of medical treatment. the last neonate with an arteriovenous fistula was only observed for parent's will. at follow-up (clinical and by ecodoppler) 7 out of 9 neonates presented normal vascular function without sequelae. from our experience elbw neonates have more chances than older neonates to develop iatrogenic vascular lesions. we advocate an aggressive microsurgery and/or medical treatment to obtain good results and prevent late sequelae. a retrospective comparison between 2 natural surfactants l.j.i.zimmermang m.c.m,van oosten. dept. pediatrics, div. neonatofogy, sophia children's hospital/erasmus university, rotterdam, the netherlands. aim: retrospective comparison of alvofact (in 1993) versus survanta (in 1994) as rescue treatment for neonatal respiratory distress syndrome (rds). methods: both surfactants were given at an initial dose of 100 mg/kg (except for alvofact 50 mg/kg for mild rds grade mi). repeat doses were attowed (survanta 100 mg/kg, alvofact 50 mg/kg) up to a maximum of 200 mg/kg, all parameters and outcome criteria were strictly defined beforehand. the initial response (good,mild,no response,relapse) to surfactam therapy was defined on the basis of the decrease in fio 2. results: there were no signif. differences in patient population and initial parameters: ga (29.9+_2.2 vs 29a _+2,6 wks), birth weight (t332_+431 vs 1227-+444 g), severity of rds (grade ill-iv: 78.6% vs 80.3%), apgar scores, cord blood gases, initial ventilatory settings. in '93 however, the initial surfactant dose was administered earlier than in '94 (14.4-+ 17.4 vs 6.5_+7.8 hrs postpartum, p= 0.025). although the average total cumulative dose was equal in '93 and '94 (169.3-+65,8 vs 167.4_+69 .4 mg/kg), more doses of alvofact were given compared to survanta {2.3_+1.1 vs 1.7_+0.6, p=o.o01) and more patients in '93 received more than two doses than in '94 (46% vs 18 % of patients). there was no difference in the incidence of non-putmonarycomplications. aivofact ( there was a better initial response to survanta and a better respiratory outcome in 1994: in the group < 1250g the duration of ventilation was half in 1994, and in the group >~125og the duration of extra o 2 need was half in 1994 as compared to 1993. we speculate that the main reason for this difference is the earlier and initially higher dosing used with survanta compared to that used with alvofact which was given in the same total cumulative dose but over a larger time span. background: e×ogerlous sur&ct~t raplacem~t treatmem has become rou~ne k~ the t~eatme~t of respira~"¢ dim'~ syndrome (i~ds) of pr~e~tur~, wh~eas its effica w th odi~ respiratory diseoses is sdi1 being wader mvesugatio~. objective: "eac~ mt ereat isto report ottr results of prospect/re, non-randomized "re~-o.e" study oe suffact~t replacement in outhom premamae infa~t~ with rds reruirmg me~aical ventilatioa (nfv). p~tien~ and metho0.s: from j-aly 1993 to june 1995, 18/58; (31%) out~ ~¢ infaats, at a mesa age of 22 z 2,7 horn's ( 13 boys, 5 ~rls; ~ gestafioan age 32-+2.8 weeks, mera~ birth weight 1846 _+ 544 g, ~ 7.2 i" 17 at 5 minutes) with rds, requiring mv, received bov~e-suff~amt (survanta, ros~/aboti, laboratotie~ columbus, ohio) eadotracheally, as was recomm~aded by maaufacturer. as the c,~:ttrol group 19 o~bom premature infants (ot~ of 49; 39%, admitted with rds from euiy 1991 to eune 1991) were saelected ~d who did not receive surfaaam, compared with ~hctant ~'oup they were admitted for treatmeat e~'li~" aft~" daliv~:y (at the age 6.4::2.2 hours vs. 11.7+-13 hours), but they did not diff~ in othe~ baseline dam'a~eri~cs at ~ti~ion. entry crkeda for ~¢fa~aut ~hcadou were fractional i~firat o~ oxtgem r~emeats -fio2 > 0.50 -0.60, ratio au-lerlal to alveolar oxygea pre~are~ao2~ao2 < 0,20 ~ad oxyge~at,~ i~.dex -ol > 10. primary o~comes were deter~caned by ~hanges m exs'ge~ab, c~ ~r~d vmtilatic~ ~ the following variable~; (1) fi'aaic~ of i~spired oxtge~ (fio2); (2) mesa nnvay presmzre (map) (3) pag2 ~ao2 ratio, (4) oxyge~ion index (oi). commo~ comphcadces of prem,musty ~d con~ol mechamcal v~ati]al~on (pater dumas merios.s, intracr~nlal haemcrn:hage, air leak, br onchop ulmrmm'y dy~pl~a ~d death) were reg~ded as sec~d,~y outcomes. r~suas: in warfactaat group we observed slg~5.c~t improve~aeat (p<0.05) in oxygea~thia md veaatilation at 24 hours all~ e~try k~to the m~dy in compari~ion to nons~fa~m" group. compa~on of secondao' outcomes in ~ts with p,.ds showes table l we did not observe ~y major acute hfe fl:u-eattming complicatlola,s m sxlrlhct~mt grou~ tr/lmediately after stu'~actsmt rcplacemev_t therapy. the duramm of mechmucal ven~ation ~ad oxygen lreau~ent m survivals of both groups did not dafter 51gmficautl y a-ore ead~ other. condusion: l!a premature mthats with rds treated with surfaaaat replacemeaat therapy we observed decrease m mc~de~ce of tme'~m~o~oraces add de~th (p<0.01 and p<0.05), whe~e~s m othe~ observed variables thee was uo ,igmfi~t d~=ecce infectious complications during the therapy of respiratory insufficiency in neonates with birth weight less than 1500 g in the course of 3 yearsretrospective study. zitek infants on cmv, cppv, and imv were administered exosurf in dose of 50-60 mg/kg twice endotracheally (see table) . in 32 newborns (86.4%) 2 hours after surfactant admin fi02 value decreased by 20.8%, and after 6 hours -by 28.1% compared with initial value; pip and peep values decreased by 3-5 cm h20 and 1-2 cm h20 after 6 hours, and by 4-7 cm h20 and 2-3 cm h20 after 1 day, respectively accompanied by mean decrease of aado2 from 486,2 to 240.2 mmhg, qs/qt decrease from 24.9 to 13.2% (see table) . mean time of cmv, cppv was 7.8 days, imv-14-36 hours, cpap -10-24 hours. respiratory therapy in 5 newborns (13.5%) was complicated by pneumothorax (bilateral -in 2 infants chorioangioma is a rela~ively rare placentai malformation associated with considerable mortality and morbidity. a chorioangioma can be regarded as an arterio-venous shunt in the circulatory system of the fetus. this causes volume loading eventually resulting in cardiomegaly and high output cardiac failure. a female neonate (gest age 40 wk, birth weight 2290 g, -2.6 sd) was born with an apgar score of 4 and 7 after 1 and 5 rain respectively. the placenta showed multiple chorioangioma. ultrasound of the heart showed a hypertrophic cardiomyopathy. she developed severe hypertension (100/70 mm hg), treated with nitroglycerine and nitropruside. finally blood pressure decreased when enalaprillic acid was given (0.15 mg.kg4). we measuered the activity of the renin-angiotensinsystem. an elevation in renin-angiotensin system is shown probably to compensate for the low resistance circulation before birth, hypothesis: the instantaneous cut off of a large arteriovenous shunt did not result in a fast downregulation of the renin-angiotensin system resulting in hypertension. hypertension should be added to the list of complications of chorioangioma of the placenta. the authors studied 75 cases of children's septicemia with blood culture yielding staphylocucetts aurens. the age of patients varied from 2 months to 15 years (51,3% from 3 years downward), 74% of the children caught their disease in the hot season (may to october). the deaths also occured in this season: 87,5% (21/24). following were the anatomo-dinical lesions. -skin 42%, muscle 60,0%, bone 21,3%, joint 9.3%. -viscera : lung 50%, heart 33.3%, cerebrum 22.6%, kidney 60.6%, fiver 17,3%. -simple lesion skin-muscle-bone joint: 12%, no death in this group. the concomitant lesions of the soft tissue,bone-joint and viscera : 34% with one viscera, 26% with two viscera, 18% with three viscera and 9% with four viscera. -bone lesion : mainly on the long bones (50% on the tibia, 25% on the femur, the remainder being the mandible (3) and the humerus), inflammation of' the hip joint was the main one. -i,ung lesion had forms pneumatocele (4 cases), bronchopneumonia (6 cases), pleural effusion (7 cases), multimicroabcess bursting into the pleura (8 cases), most multimicroabcesses were lethal : 20/22 (90,9%), -heart: all thethreelay~rs got le@~r~, 20% had 2 or 3 layers alrected and death ensued. -cerebrum : the meninges had three forms of lesions purulent meningitis (13 cases), obturafing embolns of brain vessels (2 cases) and cerebral abcess (one case). the characteristic clinical sign was paralysis and meningismus, phlebothrombosis of eavcrnous finus (13 cases)was mually ther~sultofalxil vdfi:h burst there were 6 cases of death with lesion of the meninges and 2 cases of obturating embolns of brain vessels. -the main sign of lesion of the kidney was a change in the components of urine: 60% got proteinuria, 75% had leucocytes in their urine, 42% had erythrocytes in their urine, the urea in their blood increased (over 60rag%) in 21.4% of cases.the lesion of the kidney seemingly had little relation to death. seven cases of ictertts due to an increase of direct bilirubinemia and a decrease of blood-albumin. -the biological characteristics of the pathogen staphylococci showed that all the 75 isolated specimens had positive coagulaza ; the specimens from the dead patients were less semiti~e to, mad ~t to mali~ overag death rate was 34.7 % (24/75). the fungal infection to fusariun species in immunocompromissed child have been reported in the literature with a rare, severe and high, mortality rate in spite.of the use of antifungal drugs. we report a case of successful treatment of a severe disseminated fusariun infection in a ll-year-old boy with acute lymphocytic leukemia (lla-l3), after use a chemotherapy followed by absolute granuloeytopenia. the patient developed fever, skin lesions, pneumonia and fungaemia. fusariun species was cultured from the blood, necrotic skin lesions and lung secretion. the child developed multiple organ system disfunctiou in spite of use broad spectrum antibiotcs and antimycotic therapy needing. uci during 18 days. the patient receive suport treatment (mechanical ventilation, inotropie d~.ugs, diuretics, imunestimulants, blood components, a broad spectrum antibiotes and antifungal agents). we absorved a gradual recovery in the white blood cell count and regression on the sites of infection. the association of preeoce diagnostic and the terapentic with increase in the white blood cell count was the most important in a successful treatment. a 5 year old african-american child suffered a severe pulmonary injury in a house fire. initial survey revealed 1% total body surface burns, soot on the face, and bloody endotracheal secretions. initial chest radiograph revealed diffuse, bilateral infiltrates. severe respiratory failure with an oxygenation ratio of 73 rapidly developed. he developed a pneumomediastinum and subcutaneous emphysema. although transient improvement occurred with inverse i:e ventilation and surfactant, he became more hypoxic (sac2 as low as 47%) and acidotic. on day 2 post injury, he was placed on venc~venous extracorporeal life support (ecls). on ecls day 30 he was decannulated. chest radiograph on ecls day 15 showed an opacity in the left chest. ultrasound of the left chest was consistent with atelectasis rather than pleural fluid. flexible bronchoseopy failed to reveal any obstruction in the left lung. a computed tomography (ct) seen of the chest, which was performed after decannulation, revealed a large loculated collection of fluid in the left, anterior chest. under ct guidance, a 14 f cope loop catheter was inserted and 40 cc of thick blood was removed, follow-up ct performed immediately after this procedure revealed minimal change in the size of the fluid cavity. over the next 48 hr, we instilled urokinase 20,000 units over 20 minutes every two hours. a 30 minute dwell time was allowed before draining the fluid. repeat ct scan done at the end of the urokinase infusion showed a marked decrease in the size of the fluid cavity. act scan was not performed prior to decarmulation because the ecls circuit tubing was too short to allow appropriate positioning of the child in the ct scanner. after a ct scan revealed loculated pleural fluid, a simple drainage procedure was diagnostic but inadequate treatment. we were able to successfully dissolve the thrombus after 48 hr of urokinase therapy even though the thrombus was > 14 days old. we suggest that large loculated plenral thrombi which develop as a complication of ecls therapy may be successfully managed with urokinase infusion. introduction: haemorrhages, particularly intracranial, are major complications experienced in 10-35% of neonates treated with extracorporeal circulation. an induced thrombocytopenia and impaired platelet function play a key role in the increased bleeding tendency observed in these patients. the aim of the present study was to establish a dose-respons curve for the effect of a synthetic protease inhibiting agent, nafamostat mesilate (fut-175), on platelet membrane glycoprotein density and platelet activation during experimental perfusion. methods: two identical extracorporeal life support (ecls) circuits were primed with fresh, heparinized human blood and circulated for 24 h. four different concentrations of fut-175 (7.12 mg/l blood/h; 14.25 mg/l/h; 14.25 mg/l/h+25% bolus at the start of the perfusion and 2&5mg/l/h+25% bolus) were used in different perfusion experiments. a total of eight paired experiments were performed. platelet count, plasma betathromboglobulin levels and platelet membrane density of glycoprotein ib and lib/ilia were followed as well as plasma concentration of haemoglobin. results: a protective effect of the agent on platelet count, plasma concentration of btg and platelet membrane gpib could be observed during the first 3 hours of the perfusion when a bolus dose was added. no positive effect could be recorded with the two lower doses used. plasma concentration of haemoglobin was higher in all the fut-circuits compared to the control circuits. conclusion: the addition of a bolus dose of fut-175 at the start of the perfusion seem to induce a protective effect on platelets during the first hours of perfusion. extracorporeal membrane oxygenation (emco) is a form of invasive cardiopulmonary support that can provide imporary physiologic stabilisation in reversible circulatory failure and or respiratory failure. we reviewed our expierence with extra corporeal membrane oxygenetion in 4 children aged 1 day to 4 year between 1991 and 1995. two neonates was succesfully decanulated, but died 1-2 well after decanulation due to septic complictions. one child 4 years old, one neonates died on day 5 and day" 7 respectively while still on emco. complication which were and encountered were heavy bleeding in case 1 (child), 4 (neonate) and raceway rupture in case 2 (neonate). problems which are specific developing countries like indonisia are: high cost (20.000 us for 7 days) difficulty in transportation (transporting intubated baby) from the orgin hospital, lack of knowledge and understanding of the primary physician and nm-ses and difficulty organizing in 24 hours emco team. resnratory mon1tor/ng in picu z,zjvkovic, s. mihailovic, o, tosev respiratory monitoring in pediatric intensive care unit 0picu) provide the importartt informations for understanding of the pathophysiology of the clinical signs, aid with the diagnosis, and assist in therapeutic management and predicting prognosis. pien in children's hospital for ~flmonary diseases and tuberentosis remained for the t~s't two end a half years relatively limited for diagnomic tools and therapeutic regimens, mostly because of the poor fmnaeial suptx~rt. the number of children admitted for aurae asthmatic at.lzek~ severe pneumonias, bronehiolitis, complicated pulmonary tuberculosis, foreign bodies and exacerbations of ehronit'. pulatonary diseases was t362. for all patients the respirator' monitoring system means: physie~d examination, ehe~ x rays, capillary bltxxl gas mmlyses (vevv few ehiktren experienced itwasive arterial blt~.~'i gases), noninvasive oxyntctry, measuring of the vital capacity in coopo-able patients, as~d capnography. later on, after the imtial critical illness, a complete hmg fimction tests was performed, as well ,~s bronehoscopy in selected eases, (~lr experience revealed that abotrt 60% of ehil&en heos suecessthl outcome, without s~lllens , instead they had been tremted in limited conditions. ']'he rest of our patients were previously diagnosed ~s ettronie pulmonary patients, with high risk score system ibr having seqnells 'llae mortality rate were 0,5%. the continuous blood gas monitor, pasatrend 7 (biomedical sensors, ltd., high wycombe, bucks, england) has the capability of measuring ph, pco2, and po2 via an indwelling optical absorption optodelclark electrode sensor that is placed through an intra-arterial catheter. we evaluated the accuracy of the sensor in radial and femoral locations in critically ill pediatric patients. methods: the simultaneous values of ph, pcoz, and po2 recorded from the paratrend 7 monitor were compared to values measured by standard arterial blood gas analyzer (coming 278, ciba-corning diagnostics, medfield, ma). criteria for the elimination of data points included a core vs. sensor temp. gradient, and sensor pulled back beyond accepted insertion distance. mean time of monitoring per sensor was 108 hours (range 0.75-403.7 hrs). mean time of radial monitoring was 35 hrs (range 0.75-160.5hrs) and of femoral monitoring was 137.2 hrs (range 12.8-403.7 hrs.). linear regression and bland-altman analysis for bias and precision for each parameter were calculated. results: a total of 49 patients (age range 2 weeks to 18 years) had paired samples of ph, pens, and poz made by the sensor and blood g&s analyzer. the range of measurements were ph 6.99-7.66, pco, 16.0-i14.2 t(n r, and po2 34-480 torr. the paratrend 7 monitor demonstrated accuracy that is comparable to the accepted standard of blood gas analysis in a group of critically ill pediatric patients manifesting wide variation in ph, pen2, and poz..this technique appears m be very useful especially in the extreme values of the parameters measured. funding provided by biomedical sensors. understanding of pulse oximetry d.semple, l.e.wilson. royal hospital for sick children, edinburgh, eh9 1lf, scotland, uk. pulse oximetry is a useful, non-invasive monitor, routinely used on the itu and increasingly often on the general wards. we used a questionnaire incorporating questions on the theory and clinical uses of the pulse oximeter to assess understanding of pulse oximetry in medical and paramedical staff doctors indicated grade, speciality, pulse oximetry tuition and neonatology experience. 45 doctors, 15 itu nurses, t9 medical students and 4 physiotherapists completed the questionnaire. some confusion existed between the principles of pulse oximetry and transcutaneous oxygen measurement. wide variations in the lowest acceptable saturation in fit children were seen (80-95%), with around 20% of respondents in all groups accepting values of 90% or less. some potentially serious mistakes were made in the evaluation of oxygen saturations in the clinical scenarios. there were widespread variations in correct responses at all grades of medical staffing. nurses scored well on more clinically-orientated questions but relatively poorly on theory. only 15% of doctors (mostly senior grades) had received tuition in putse oximetry. neonatology rotations appeared to confer little additional knowledge on pulse oximetry. few doctors and nurses receive tuition in the use of pulse oximetry a significant proportion of nurses and doctors, of all grades, exhibited a lack o{" understanding of the principles of pulse oximetry. this may result in unsafe use of the equipment and put patients at risk. one can see from the table that blood composition in uv and ua differens in some characteristics, and similar in sgp magnitude. venous-asterlal gradients "gas functiomals" between uv and ua represent the measure of difference in this characteristics. the gradient cari be positive, zero -order or negative and change both in value and in sign but not reach apo2 (positive) and apco2 (negative) in absolute significance.minimization of "gas functionals" deviations atom the zero is achieved due to"mutual replacement acts" between po2 and pco2 in uv and ua blood. we suggest that presented tests can be useful in full evaluation of gas exchange in newborns. (pap) in the context of pulmonary hypertension is oft desired but rarely achieved. inhaled nitric oxide (no) has been shown to produce this desirable effect, but is relatively difficult to administer or monitor. we wondered whether np, chemicaily related to no but more stable in solution, would produce similar physiologic effects when administered in the convenient modality of nebulization. methods: 9 piglets were anesthetized, mechanically ventilated, and surgically instrumented. systemic blood pressure (bp), pap, and cardiac output (co) were monitored continuously. after postoperative stabilization, 0.9% nac} nebulization was begun, and pulmonary hypertensiorr was induced by reducing fio2 from 0.30 to 0.07. the piglets were monitored for 15 minutes during this hypoxic phase, next, without altering fio2 or ventilator settings, np (10 mg/ml, dissolved in 0.9% nacl, flow 4 ipm) was substitued for 0.9% nacl in the nebulizer circuit. np was nebulized for 15 mins. results: during hypoxia, pao2 fell from 159 to 29 mm hg. pap rose during hypoxia from 14 to 31 torr (p< 0.01). ,^fhile bp and co did not change significantly. pap fell during nebulized np in each piglet, (mean apap = 31 to 21 torr; p< 0.01; mean reduction of hypoxia-induced rise in pap = 61%; range: 36 to 78%; p < 0.01). pvr/svr fell by 28% during np nebulization (p< 0.01), while bp and co did not fall significantly (90 to 86 tort; 653 to 636 mllkg-min), the reduction in pap began within 2 minutes of the onset of nebulized np, and appeared to reach a plateau by 15 minutes. no tachyphylaxis to nebulized np was noted. nebulized np did not significantly affect pap, bp, or co under normoxic conditions. conclusions: 1) like no, np selectively reduced hypoxia-induced pulmonary hypertension without altering systemic bp, 2 ) unlike no, np can be administered by nebulizer, a technique familiar to virtually all health-care providers, and potentially adaptable to both intubated and non-intubated patients. 3 } nebulized np may be beneficial in clinical contexts where inhaled no is impractical. dang phuong kiet and nguyen xuan thu examining 6 cases of purulent pericarditis with various clinical forms treated by surgery, the authors drew the following experiences for their diagnosis. t. clinical factors. purulent pericarditis appeared like a cardiac tamponade in a septicemia due to staphylococci with dassieal symptoms: severe dyspnea, tachycardia, faint heartsound, big liver, prominent cervical vein ; rentgenography of the chest showing enlargement of the cardiac silhouette, a diminution of ventricular pulsations, ~i clear lung field. by an emergency operation, 500ml of diluted blood were drained. purulent pericarditis and pleural effusion appeared at the same time but at first tile symptoms of purulent pericarditis were masked by the predominant symptoms of plearal efihsion. after the pleura was drained, its pus was no more, the general state was relatively stabilized but there still were big liver, dyspnea, enlargement of the cardiac silhouette while central venous pressure increased. purulent pericarditis appeared late. in the first stage (about 2 weeks) there was no suspected sign. later on gradually appeared such symptoms as dyspnea (during serum transfusion for instance). central veinous pressure also raised. the heart chest diametre increased at first (up to 60-65%) then decreased (down to below 50% ) but the liver kept on swelling together with the particular changes of electroeaediegramme. now the pericardium had no more pus but get fibrous (up to 3ram) thus constricting the heart and its main arteries 0ike pick syndrome). 2. diagnostic values of electrocardiograms : common signs of ecg related of these purulent pericarditis were: a diminution of voltage, a widespread elevation of the st segment, the tf wave flattened and inverted. however, what should be stressed was : the diagnostic values of an electrocardiogram for purulent pericarditis was mainly in the dynamics of their signs: in the first week, the voltage diminished corresponding to a pericardium containing pus, while the st segment went up then seemed parallel to the fibrosis of the epicardium, the liver swelled, the central velnous pressure increased, the heart/chest dimension ratio decreased, the st segment went down, the t wave became more flat and inverted. between 1986 and 1995 23 neonates, aged 2 -23 days (median 5), weight 2,38 -4kg (median 3,28) with critical valvar pulmonary stenosis were scheduled for balloon dilation (psvp), 19 children (83%) were on pge1 and 13 (57%) needed mechanical ventilation. after stepwise dilation a final balloon : pulmonary valve (pav) ratio of 114% (25-150) was achieved, there was a significant correlation (p<0,01) between an adequately sized balloon and freedom of reintervention. two valves could not be passed, four neonates underwent surgical procedures (brock n = 3, commissurotomy n = 1), two children (10%) died of sepsis. 17/23 patients (73%) were successfully palliated by psvp in the first month of life. the rv : systemic pressure value fell from 132% (75-231) to 58% (40-87), complications included 2 transient dysrhythmias, 1 transient hypoxia, 3 vessel occlusions;-1 right ventricular outflow tract perforation. in 16/17 patients follow up data is available. the residual systolic peak doppler gradient over the pav on the last out patient visit (5-103 months after psvp) was 10-41 mmhg (median 20). four children needed repea.ted psvp 26 to 72 months after the initial intervention. conclusion: psvp of critically ill newborns is possible. the risk of mortality is relatively low. psvp in neonates with an adequately sized balloon is a challenging alternative to surgical treatment. post hypoxic-ischemic (hi) reperfusion induces the formation of non protein bound iron (npbi), leading to production of the reactive hydroxyl radical. it was investigated if the ironchelator deferoxamine (dfo) could reduce free radical production and improve neonatal myocardial performance after hi. severe hi was produced in 13 newborn lambs and changes from pre-hl values were measured at 15, 60 and 120 min post-hi for (mean) aortic pressure (mean pao), cardiac output (co) and stroke work (sw). left ventricular (lv) contractility and co were assessed by measuring lv pressure (tip-manometer) and volume (conductance catheter), using inferior caval vein occlusion to obtain slope (ees) and intercept of the end systolic pv relationship (v10). npbi, reduced and oxidized vitamine c ratio (vcred/ox) and lipid peroxidation (mda) were measured from sinus coronarius blood. 7 lambs received dfo (10 mg/kg i.v.) immediately post-hi, control lambs (cont) received a placebo. results: mean pao was stable, co and sw decreased up to 60 and 40% respectively in cont as compared to pre-hi. in both dfo-groups co and sw remained within the normal range. ees and v10 decreased in all groups post hi, but did not differ between groups. npbi and mda were higher at 15 min post hi (p<o.05), vcred/ox was lower at 15 min post-hi (p<o.o5) in cont as compared to dfo-group, indicating more oxidative stress in cont. conclusions: dfo reduced the oxidative stress of the heart and prevented co and sw to drop, suggesting a positive effect of iron chelation on the myocardium after h{. from 1987 we published reports with analysis of performance of the heart as a whole organ.while analysing the heart performance as a whole, we recognize three block in it located intrapericardially: l."atrial"block -left (la) and rigth (ra) atriums; 2."aorta-pulmonary" block-aorta 'bulb (a) and pulmonary artery(pa); 3.ventricular "three-chambered" block (vb) consisting of: -left (lv) and right (rv) myocardial chambers, both frith blood outflow into "aorta-pulmonary" block vessels, and -spongy (venous) myocardial chamber with the blood outflow through coronary sinus (cs) and thebesiau vein (tv) into "atrial" block. the following conceps are introduced for vb functions assessment "common" systole and "common" diastole of "three-chambered" vb. the process of normal "common" vb systole: -begins with blood ejection from vb spongy chamber into the "atrial" block; -continues with blood outflow from rv and lv into "aorta-pulmonary" block wi~ venous minimums -x-coiiapses -~btmation iu "a~riai" block; -completes with "three-chambered" vb general emptying. at this period the following blood volumes are transferring: -two-from rv and lv(their stroke volumes)into"aor~o-pulmonary"block; -two-from "spongy" chamber .into "atrial" block; -two-from systemic and pulmonary veins into "atrial" block during the process of so called "systolic" membrane suction (at pulling atrio-ventricular valves into rv and lv chambers as blood ejects out of them). it appears to be the regulation of blood inflow to "atrial" block by blond outflow from "three-chambered" vb into "aorto-pulmonary" block. objective: to evaluate the efficacy and complications of transpyloric enteral nutrition(ten) in critically ill children patients and methods~ from june 1994 to january 1996 23 children (i0 boys and 13 girls), aged from 5 days to 11 years (mean l.8 ± 3.4years) were treated with ten. 18 patients were included after cardiac surgery, 3 with acute respiratory failure, and 2 after cerebral surgery. the indication of ten was mechanical ventilation in 22 patients and failure of nasogastric nutrition in 1 patient.19 children (82 %) had previously received parenteral nutrition. 8 and i0 fg enteral tubes was inserted into duodenus through nasogastric intubation en 21 patients and by endoscopy in 2 patients. rx and ph determination were used as methods to control tube situation. 18 children received adapted formula, 7 caseine hidrolisate, and 3 enteral formulas. (in 5 patients the nutrition formula was changed during ten). 22 patients were supported with mechanical ventilation during ten, 17 received midazolamperfussion(range 2 to 15 mcg/kg/min), 15 fentanyl (i -12.5 mcg/kg/h), and 6 vecuronium (0.1 -0.3 mg/kg/h). resulte: ten was used during 3 to 73 days (mean 18.3 ± 19.3 days). mean maximmnvolume ad~iniateredwas 132 ± 47 ml/kg/day (range 34 208) .patients with midazolam, fentanyl and vecuronitml tolerated ten similar than children without sedatives. complications were diarrhoea 1 patient, abdominal distension and/or important gastric fed residuals 2 patients. pulmonary aspiration or respiratory complications were no registered. ten was ended in one patient due to diarrhoea, in 18 due to change to oral or nasogastric nutrition, 3 children continue yet with ten and 1 was discharged of picuwith ten. conolusion: ten is an useful method of nutritional support in critically ill children with mechanical ventilation and/or nasogastric intolerance. introduction: the enteral nutritional support of the critically ill child may reduce the morbidity and mortality by attenuating, the hypermetabolic and catabolic response, decreasing the gut translocation and the septic complications, improving the bowel mucosa integrity and the wound healing. the aim of this study was to show the safety and tolerance of en. methods: we enrolled 36 consecutive patients admitted to our unit from may to december 1995, mean age 3.4 years (range imonth to i7 years). the prism, mechanical ventilation, inotropic use, opiates and other drugs were recorded. the en was delivered by continuous infusion across a polyuretane tube.we kept the patients head elevated 30 °, and we used cisapride routinely. the gap betweeen admission and the en beginning, average time to meet the nutritional objective, en duration, selected formula, patients outcome and complications were recorded. results: prism groups were 0-1=0 patients; 1-5=1; 5-10=13; 10-15=7; 15-30=12. two patients with mof (multiorgan failure) died. 72% needed mechanical ventilation.the average time elapsed from picu admission to initiation of en was 2.1 days (range 1 to 7 ) and the average duration of the en was 7.3 days (range 3 to t4). the average time to meet the nutritional objective was 2 days (range 1 to 3). the selected formula were: lactose free infant formula in 10 patients, elemental diet in 8, pediasure in 16 and jevity in 2. we recorded vomiting in 4 patients, diarrhea in 5 and constipation in 4. none of them forced the en suspension. we didn't recorded any case of ~spiration or pneumonia. we found no relation between drugs, selected formula and complications. we think that en may be a safe and well tolerated procedure at the picu setting. generation of free radicals in iipid emulsions used in parenterai nutrition (pn) has been described recently. this seems to be due to high polyunsaturated fatty acid content. we studied lipoperoxidation status and antioxidant parameters presurgically and through the postoperative period (5 days) in a group of twelve children (ranging from 4 months to 12 years of age), who underwent heart surgery and received nutritional support with pn. malondiaidehyde (mda), an end product of lipid peroxidation was used as a marker of oxidative stress. it was determined by the yagi spectrofluorometric method. antioxidant activity was measured with an assay based on the inhibition of spontaneous autooxidation of a brain homogenate, and vitamin e in serum by the technique of hansen and warick. erythrocyte mda release fonowing incubation in hzo 2 in vitro was used as a functional measure of tissue vitamin e levels. data were compared using one-way variance analysis. there was not significant differences in the plasma mda production among the values obtained before surgery (3 :t: 0.5 nmol/ml), postoperative pre-pn (3.5 +_ 0.6 nmol/ml) and through the course of pn (3.5 5:0.6 nmol/ml). levels of vitamin e previous to surgery were 5,1 5:1.1 #g/ml and decreased to 3.2 _+ 1.4 #g/ml at 24 hours post-surgery before starting pn. while receiving pn, concentrations of vitamin e increased progressively up to 7 + 4. l #g/ml (p = 0.08). pre-surgicai plasma antioxidaut activity values (72 :i: 11%) dimiuished in the first postoperative day (56 _+ 9.5%) and then showed a clear increasing tendency, directly correlated with that observed in vitamin e levels. the measurements of the maximal percentage of mda release of erythrocytes in vitro, showed an inverse relationship with plasma vitamin e levels and with the plasma antioxidant capacity: preoperative 5.8 + 2.4 % and postoperative descending from 20.5 + 14% to 12 _+ 9.5%. our results indicate that during surgery and within 24 hours postsurgery, a decline in antioxidant defenses occurs, in the postoperative period, while patients are on pn and taldng into account our obtained data: the unaltered mda values, the rise of plasma vitamin e levels, the recovery of both functional erythrocyte membrane antioxidant protection and the plasma antioxidant activity, they do reflect that during the intravenous administration of lipid infusions, oxidative damage does not occur, probably due to the addition of vitamin e to pn solutions in order to avoid autooxidation of lipid emulsions. garnitine is one of the essential nutrient in the diet of newborn infants. mother's milk represents the natural eamitine source for the newborn infants. we studied enteral earnitine intake in 71 premature infants 35 eutrophic (eu) and 36 hypotrophic (hy), fed with mothers milk trough 5 consecutive days-from fifth to tenth day of life. mean gestational age was 33 (range 32-36) weeks for eu and 34 (range 32-36) weeks for hy. birth weight was ranged 1430-2450 g for eu and 1250-2300 g for hy (p < 0,05). breast milk carnitine concentration was 78,88 i.tmol/i in mothers milk delivered eutrophic babies, and singnificant higher mean coenetration 113,88 l.tmol/i, of hypotrophic premature infants (p<0,05). breast milk earnitine concentration was ranged between 39,15-163,71 ~moi,'l, and daily carnitine excretion was between 9,7-165,48 p.mol/i, mean 60,6 +-38,7i p.molll. the daily mean carnitine intake was from 1-1,93 mgkg/d, in eutrophic and 1,23-1,93 mg/kg/d, in hypotrophic premature infants, in milk volumene intake from 150-200 mllkgld., the results of this study suggest that premature infants should be fed with own mothers mitk in eady neonatal pedod in attempt to prevent camitine deficiency. keto-acids and parenteral lipid admlnistration. castorina m., antuzzi d., ricci r., rendeli c., polidori g. pediatric intensive care unit -catholic university -roma (italy). some metabolic studies have suggested that the administration of mediumchain tltgticerides (mct) might induce a marked increase in ketone body concentrations; the aim of this study is to evaluate the effective ketogenetic risk of infusing mct emulsions in total parenteral nutrition (tpn). two groups of seriously infected children were examined: a-12 septic infants were given to tpn with a 100 % of long-chain tryglicerides (100 lct). b-10 septic infants, in wich the lipid source in tpn consisted in a 50-50 mixture of lct and mct. the children in the different groups showed similar severity and therapeutic scores (prism, tiss, ~, f~2, f~3); the lipid intake was the same, corresponding to 1-1.5 g, ckg bodyweight/day. in all patients a sample of urine was taken six times a day for the whole time of tpn the urine samples were screened by the diphenylhydrazone test, and the ketoacids excretion was confirmed by a chromatography. the urinary excretion of 13-keto-acids equivalent to p-ohphenyl-pymvate (mcg/ml urine) is summarized in the no significant increases in frequence and/or in severity of acid-base disturbances were found in all studied patients in consequence of the lipid infusion. the patients of b-group showed a lower excretion of 13-ketoacids. the c~-keto-acids excretion was ever unsignificant and seemed to be correlated with the illness severity more than with the lenght of the tryglicerides chain. this observations let us suppose that the mct, at employed doses, can be safely administred also in childen with metabolic acidosis and/or serious illness. reye syndrome cayetano heredia hospital, lima, peru five patients with reye syndrome were studied; included were those diagnosed from january 1991 to march 1994 and treated at cayetano heredia hospital. the age of presentation varied from z.5 to 7 months. the syndrome occurred more frequently in males (4/5); the time of illness at the presentation varied from 2 to lo days, and the following features were found: fever (3/5), akeration in mental status (5/5), seizures (4/5), gastrointestinal illnesses (diarrhea) (4/5), and respiratory insufficiency (1/5) --in this case ventilator)-support was needed, in all cases hepatomegaly, intracranial hypertension, hypokalemia hyponatremia, metabolic acidosis, hyperammonemia and elevation of hepatic enzymes were found. coagulation blood tests were abnormal in three patients. cerebrospinal fluid (csf) showed hypocellularity in all cases (less than 8 cells/ram3). the cultives were negative, and the final diagnosis was confirmed by hepatic biopsy. no deaths were due to reye syndrome. a contribuhon to the study of reye's syndrome the aulhors analysed 38 records of patients meeting all the clinical, biochemical and anatomic criteria put forward by hutrealoch~ and samaha (1975) who were ireated at the emergency and resusdlation depammlt tithe ipch in 10 years. the average age of the children was 3 years (the 3~umgest 11 monks and the driest 7 year~ most of lhon (34/38) came from lhe countryside to lhe lmfia~ willfin 24 hours of file oulbreak. a few days previously the patients w¢~ld have fever (some of ahem wilh diarrhea or cough) ,,rod vomit then rapidly fidl into coma and c~nvuksien. they ~me to the imtia~ with the signs of typical increased inlracranial pressure ( stages 2-4 according to lovejiy for most cases) but the liver was unllkely big. the main biocheafical dmnge of the blood was acute hepatic thilure -the bllod glucose decreased : (ha the aver~ 23,46n~% (26) ~ not measured in five cases (glucose a"aces). -the blood ammonia ino~ased riven 158 to 275 microg/dl fin lhe average 220, n = 3) -the percentage of p~in was low, in the average 44,5% (n--9), 11% at the lowest (a case ofmekaa lasling five days was ctwed with vitamin k). -got and gpt enzymes increased 3 -4 times (n=14) besides, tht~re was decompcmated addt~is with lhe average valnes ph = 7.19; pcoz = 2~6mmhg and eli = -1~6 ~, (n~). the charadaislic dumge in the ¢~'ebrospinal fluid was a low glucose tx~acenwalien h the average of 1k65mg/dl (3 cases of glucose it'aces) ; meanwhile protein decreased in the average of 14mg/dl (4 cases below 10mg/dl). besides ~here was no inflammatory lesion ~tion) : very serious brain oedona and fatty degeneration of live~ scatteredly or parllally.microso~ically (biopsy and necropsy) in file brain appeared bright space around blood arteries and glioma extended v'lrdmw -robin space, with no inflammatory reaction. liver.-the sa~dure was intact there was no " "mtlammal~s3' cell, the kupffer cells did not show hyperplasia but show a heterogenous deg~nerafion~eart: also showed a fatty degencralion in some areas of the myocard eellkidney: the ihtty degenerati~l scattetedly in the tubular cell. pano~as:fatty degeneration scattetedly in file pancreatic cell. two cases of liver biopsy for lhe 2rid lime (check before leaving file inslitute) found that fatty degeneration was r~tta~ nearty ff~pletely. the exact muse remained unknown. objectives: to analyse whether there exists serum and urine electrolyte disorder in children with respiratory failure, methods: we have made prospective study of 48 children in our icu during a 12 month period, electrolyte concentrations were measured in serum and urine collected during 24 hours (sodium-na, potassium k, chloride-ci, calcium-ca, magnesium-mg and phosphorus-p). results: average values in serum were: na 139.28 +/-3,20 (rv:133-146) mmol/i, k 4.22 +/-0.55 (3.3-5.2)mmol/i), cl 95.20 +/-3.98 (93-106) mmol/l, ca 2.t2 +/-0.12 (2.20 2.65)mm01/i), mg 0.82 +/-0.22 (0.77-1.12)mmol/i. average electrolyte levels in 24 hours urine were: na 64.23 ~/~ 44.11 (42-202)mmol/day. k 22.14 +/-10.33 (22-112)mmol/day, ci 56.14 +/-27.22 (100-244)mmol/day, ca 1.17 +/-0.13 (1.68-6.8)mmol/day and p 11.89 +/-7.12 (11.7-32)mmol/day. conclusions: average serum ci and ca levels were decreased in children with respiratory failure. in urine, average k, ci, ca and mg levels were decreased and urine p concentration was increased. we concluded that serum and urine electrolite disbalance may be expected in children with respiratory failure. the nurse is going to kill me! (icu syndrome) anita duvndam ~, sonia v.d,sluis 2 ~dpt. of pediatrics, div. pediatric intensive care, sophia children's hospital, rotterdam 2dpt. of pediatrics, div. pediatric tntensive care, juliana children's hospital, the hague. content description: this presentation will provide the critical nurse with background information concerning the identification, the prevention and management of the critical ill child who has developed the icu syndrome. the results of a questionnaire concerning the occurrence of icu syndrome on a picu will be presented. behavioral objectives: at the end of this session the participant will be able to: 1. describe four clinical symptoms of the tcu syndrome, 2. identify major sources of picu environmental stress, 3. discuss nursing's unique role in helping the child to cope with the icu syndrome, 4. discuss nursing's unique role in preventing icu syndrome. content outline: the icu syndrome is a situation in which the individual is not able to deal with changes in observation and interpretation of both quantity and of patterns of sensory perceptions. in other words the borders between the inner and outer world becomes unclear for the person. the exact incidence of the icu syndrome in the critical care setting is unknown, we have limited knowledge of the occurrence of the icu syndrome in critical ill children. yet critical ill children in our hospitals sometimes show the symptoms of icu syndromes. to be able to identify the occurrence of icu syndrome we developed a questionnaire. the thesis of the questionnaire was: does the icu syndrome occur in critical ill children in the age between three and ten, who have been intubated and/or ventilated in a picu? eighteen questionnaires have been send out to parents of critical ill children in two hospitals. the response was 90 percent. conclusions: 1. most of the children were anxious (n=11), showed regression (n=8) or had sleeping problems (n-lo) during the stay on the picu. 2. children showed the same problems after discharge. 3. there is no relationship between environmental factors and symptoms of the tcu syndrome during the stay. 4. there is no relationship between preexistential behavior and symptoms of the icu syndrome during the stay. because the lack of a scientific definition for the icu syndrome in children and good criteria for diagnosis, we were not able to get an answer to our thesis. more research is needed. continuous veno venous haemofiltration (cvvh) was adopted as a first line renal replacement therapy in our paediatric intensive care unit (picu) some three years ago. ~/he process of introduction and development of cvvh proved to be an exciting challenge for nurses as indeed it was for the whole multidisciplinary team involved. we have successfully used cvvh in the treatment of over 20 infants and children, weighing between 3-85 kg. the range of conditions treated is ever increasing. to date we have not only used cvvh for patients in renal failure and fluid overload, but also to gain biochemical control in tumour lysis syndrome-and metabolic disorders. other distinct patient benefits in comparison with more conventional means of renal replacement therapies are that, it is a continuous controlled treatment being extremely effective in creating 'space' for nutrition, which is especially important in the fluid restricted, catabolic patient. of paramount importance in providing this level of service is the education and training necessary to impart the skills and knowledge for nurses to become expert practitioners in this field. we now have a teem of highly advanced practitioners who have developed their nursing skills to provide even more holistic care for their patients. this group are embracing new challenges and responding positively to the developing service whilst expanding their knowledge base. this paper will discuss the advantages and disadvantages of cvvh as we have experienced, relating i t to the wide variety of patients we have treated. we wish to share how cvvh has become an accepted role of the picu nurse and how the service has been successfully implemented. integrated care pathways (icp's) define the optimum course of events in the care of a patient with a specific condition, within a set timescale. aims and methods: icp's and case management (cm) were introduced to evaluate and improve clinical practice. icp's were developed for patients undergoing surgery for atrial septal defect (asd) ventricular septal defect (vsd) and fallots tetralogy. they were based on the median experiences of the last 31 patients. 108 patients have been managed using icp's. results: analysis of variation from the icp's shows a reduction in the following potentially avoidable causes of variation: delay in extubation has been reduced from 29% to 10%, and 31 patients (29%) were extubated earlier than the median. prolonged stay on the intensive care unit (icu) has decreased from 13% to 0%, and 24 patients (22%) were discharged to the ward a day earlier than the median. the number of patients receiving inadequate post operative analgesia has decreased from 35% to 15%. delayed feeding after operation has been reduced from 52% to 28%. unavoidable delays in extubation and discharge from icu occurred in 22 patients (20%) because of haemodynamic instability" or lung problems. cm utilising individualised pathways for these patients has reduced variation in care which can improve patient outcomes. pathways have been developed for other conditions and it is anticipated that approximately, 80% of patients will be treated using an icp revision of icp's results in continuous evaluation and improvement of the care provided, conclusions: the use of icp's and cm has improved patient care and decreased avoidable delays and variations. the future development of other icp's, combined with a case managed model for selected patients, is seen as a viable method of continuously improving patient care. this paper is a retrospective audit of 24 children who received continuous veno venous haemofiltration (cwh) whilst on the paediatrie intensive care unit (picu), data was collected over a 21 month period from may 1994 to january 1996. the 9 girls and 15 boys were aged from 1 day to 15 ½ years (median 4½ years) and weighed between 2,5 and 85 kg (median 17.75 kg). length of admission to picu was 2 to 47 days (median 9 days). sepsis syndrome was diagnosed in 11 cases: 4 of these had bowel necrosis and 3 meningoceccal disease. eight patients had an underlying haematological, oncolngical or immune disorder. the remaining children had inborn errors of metabolism (2), nephrotic syndrome (2), or cardiac failure (1). cvvh was instituted for a variety of reasons. muttiorgan dysfunction was present in 46% of patients, 29% had acute renal failure, 12.5% tumour lysis syndrome, 8.5% uncontrollable metabolic acidosis with hyperammoneemia and 4% required fluid management. treatment was continued for between 4 hours and 26 days (median 4½ days). haemofiltration was successful in achieving its desired effect in all except one patient. 87.5% of children with haematological, ontological or immune disorders died despite successful haemofiltration. survival was higher in cases of septicaemia (45.5%), nephrotic syndrome (50%) and errors of metabolism (50%). overall mortality was 62.5%. this was attributed to the severity of the underlying disease process rather than the effectiveness of cvvh as a renal replacement therapy. asynchronous defibrillation and synchronized cardioversion deliver direct currents of high amplitude through the chest, to stop ventricular fibrillation or to convert life-threatening arrhythmias. since the human body is partially conductant, it should be possible that after a brief delay of time, a derivation of this monophasic defibrillation pulse is measurable in regions of the defibrillated body, other than the traject between anodal ("sternum") and cathodai ("ape~;") paddles. one could also estimate that health care personnel in the immediate environment of defibrillatoty shocks, are always at risk to possible electric injury. accidents might occur when health care personnel do not stand clear from the patient during firing and create an additional electric path from this patient through their own body. most likely, the nonisolated parts creating a transversal eiectric path, will be the hands of the caretaker. since defibrillation generates touch voltages up to 5000 v and 60-70 a in ved, short delay's (5 to 10 millisec), the total body resistance during skin to skin or skin to paddle contact, is calculated to be as [ow as 750 ohm (percentile tank 50 for the entire population). an experimental protocol was developed to evaluate the conducted currents during defibrillation. mature pigs with a weight of 100 up to 150 kg. were used as animal models. the:,, had barbiturate anaesthesia, inotropic support with dobutamine at l 0 micmgrams/kg bodyweight and all had a sinasat rhythm at the begining of the test-rounds. synchronized defibrillation at 100 j (approx. 0.75 j/kg) and asynchronized -at 360 j (whenever ventricular fibrillation or ventricular tachycardia occurred), were attempted, through latero-lateral placed and firmly pressed defibrillation paddles and/or adhesive multi-function electrodes. gel pads were choosen as contactmedium to cross the skinpaddle barrier. subdermal electro-myography needle electrodes were put at different parts and regions of the pig's body, but not between the paddles. these electrodes were coupled to a resistance device of 800 ohm and a measuring computer. we measured monophasic and low current pulses up to 0,10 a during the defibrillation burst. thus conducted currents are high enough to produce accidental electric shocks when additional electric paths are created by the caretaker. "llaese are usually harmless, but in some "worst case" (wet or transpiring hands, rings,...) or in association with defectuous equipment, peak currents might be harmfull, and can produce pain, bums, apnae or cardiac (transient or persistant) arrhythmias. maria skogbv. karin mellgren, lars-g6ran friberg, g6sta mellgren, hans wadenvik. g6teborg, sweden. bleeding complications in extracorporeal circulation is partly due to perfusion-induced platelet dysfunction. the aim of this study was to evaluate an in vitro model for investigation of platelet function parameters in an extracorporeat system. study: two complete extracorporeal life support systems were perfused with fresh heparinized human blood for 24 hours. piatetet membrane glycoprotein changes, platelet granule release and platelet count were followed. eight paired experiments were performed. one of the circuits was perfused by a roller pump (polystan) and the other by a centrifugal pump (biomecicus), other components were identical. results: a continuous increase in glycoprotein (gp) ib-negative platelets was seen in both circuits. a marked increase of plasma beta-thromboglobulin concentration and a decrease of the intracellular pool of serotonin was observed, indicating a marked release of alpha as well as of dense granules. the plasma concentration of glycocalioin increased in parallel with a reduced platelet surface expression of gpib, suggesting that the loss of gpib is caused by proteolysis rather than by a downregulation of this receptor protein. conclusion: 24 hours of ecls perfusion induces pronounced platelet degranutation and causes changes of important membrane receptors. this is in accordance with clinical studies, suggesting that our in vitro model does mirror the platelet exhaustion observed in a clinical reality. no significant difference was observed between the two pumps. the purpose of this study was to examine signs of distress exhibited by several patients following the discontinuation of opioids and benzodiazepines (o & b) in a 7-bed pediatric intensive care unit. the authors compiled a list of all cases of possible withdrawal reactions reported by nurses in the study setting over a one-year period. five cases were selected for study in terms of their wide diversity of relevant circumstances. the 5 cases were examined through a retrospective chart review. data pertaining to analgesic and sedative administration, along with nurses' reports of behavioral distress, were transcribed and coded. a remarkable pattern of behavioral distress was clearly associated with discontinuation of o & b. cessation of benzodiazepines was associated with severe distress. these reactions were characterized by various combinations of crying, irritability, tremors, grimacing, gagging, vomiting, or feeding problems. some of these persisted in spite of large amounts of bolus drug administration. these signs were manifested for 2 to 9 days following cessation of o & b. these findings demonstrate that the rapid weaning of o & b infusions, sometimes following short-term therapy, can cause severe withdrawal reactions. the particular course that a specific patient will follow will likely be modulated by underlying manifestations of "icu psychosis" and unresolved pain and emotional distress. hermana tezano8 mt, pilaf orive j, latorre garcia j, lizarraga azparren ma, lopez bayon j ucip hospital de cruces. bilbao. spain a female child, one year old, was referred to our unit from another hospital because she had ischemic syntomsjn her right forearm wich started three days before. she had ~i downs syndrome and fallot's tetralogy with a systemic-pulmonary by-pass. nine days before the admission in our hospital she was undergone to a cardiac catheterization by arterial and venous femoral punctures with no incidences. on the admission to the picu her forearm was cold and pale with absence of cubital and radial pulses and slow capilary filling. treatment with heparine was started unsucessfully in the firsts 24 hours, so uroquinase was added that later was changed to rtpa plus brachial plexus blockade. by the time me arterial tlux became more and more evident (doppi~) il bccuute aiat) evident a regional aedema witch made necessary a fasciectomy &the wrist. she also developped necrotic delimitted areas that included her first and fifth fingers. she was discharged from the picu after 13 days and a week later she went to the operating room where an amputation of the distal phalange of the fifth finger was made. the etiolgy of this ischemic picture can't be attributed to the catheterization itself, but probably it should be due to some attempts in arterial puncture in its course, attempts that could be guess by the little marks noticed at the elbow flexure when she was admitted. long maintenance of cardiovascular funtion by assisted ventricular device with membrane oxigenator hermana tezanos mt, pilar orive j. latorre garcia j, lizarraga azparren ma lopez bay6n j. ucip. hospital de cruces. bilbao. spain a little girl of three and a half years came to the intensive care unit from the operating room. affected of great vessels transposition with a pulmona~' banding corrected vith rastelli technique, it became impossible to discharge her from the by-pass circulation. it was assumed that this factt was due to a transient myocardial disfunction dfter the surgeon x~ent through the technique and found no wrong step in it. at the picu admission she had an ejection fraction belox~ 20% (echncardiografy), and was manteined on veutricular assistance with a circuit consisting ofa plate's membrane oxigenator, a bio-medicus pump and pvc rubber tubes, with monitoring of pulmonary', right and left atrial pressures. initially she needed a ventncular support of 1.2 l/min with dopamine. dobutamine and adrenaline; gradually the ejection fraction rose to 60% aliowing a decrease in the mechanical and inotropic support. the organic function ,.'.-as preserved but x-ray of the thorax showed images of pulmonary aedema with an increase in the 02 needs until a fi02 of 0.4. even though she was placed in a transplant program, she was remouved when the ejection fraction rose to 50% on the 1 lth da 3 of the evolution. there were no signs of infection (profilactic coverage). on the fifhteen postsurgery day. with a good cardiac sound and an ejection fraction of at least 60%. it was considered the withdrawal of the ventficular support, but unsucessfully despite the increase ofinotropic drugs, so she died. we think that our patient is a good example of the posibiti~ to mantain x~ith ecmo during a prolonged period of time a potential transplant receiver without major complicatios. joan wierema; ma0)an mourik. sophia children's hospital, department of pediatric surger,j, rotterdam, the netherlands. the success of an ecmo program is heavily determined by the organizational structure and the daily availability of both well trained nurses and physicians. until now there is no general guideline to determine the optimal training schedule to set up an ecmo program. objective: to evaluate the set-up of an ecmo program in an area without direct availability of perfusionists of cardiothoracic surgeons. description of the progress: during the preparation of the ecmo program which started november 1991, different phases are identified. first phase, acquisition of experience by training abroad of one physician, staff member of the icu, physician acting as a fellow and one icu nurse with theprimary task to serve as an ecmo coordinator and train the nursing start. in the second phase 12 animal experiments were performed by 2 paediatric surgeons, 2 staff physicians, 2 fellows and 12 nurses. third phase, start of the actual ecmo program, priming by one trained nurse and ecmo fellow, daily care of the patient by 2 nurses, 1 icu nurse taking care of the patient related activities, 1 ecmo trained nurse taking care of the circuit. fourth phase, transition of the tasks for priming the system from the ecmo fellow to the ecmo nurse and changing daily care for the ecmo patient now including the circuit by 1 trained icu nurse with special legislation for ecmo. ongoing training of 6 to 8 nurses working for at least half a year in the icu. during an ecmo run direct contact between the ecmo nurse and one of the staff members; patient data: in a 4 year period 52 neonatal ecmo cases were performed with an overall mortality of 74%, ranging from over 95% in meconium aspiration to 45% in congenital diaphragmatic hernia. in 7 other patients pediatric ecmo (age range 1 month -14 months) mortality was 50%. conclusions: ecmo can be established without perfusionists or cardio surgical back up once a predetermined training schedule is available, resulting in comparable results with the international ecmo registry both for neonatal as well as for pediatric cases. mechanical ventilation at home makes normal development of the child with chronic respiratory failure possible. the parents must be encouraged to accept the treatment at home; therefore, they should be enabled to take care of their children all by themselves and the continuous professional support has to be offered to them. it must be stressed that the nurse is the link between the diseased child and his family introducing them into the process of the medical care at home. all the equipment needed for the mechanical ventilation of the child at home (ventilator, suction device, pulse oxymeter, oxygen tanks) has to be provided before the child is discharged. it is paid by the national insurance company. the maintainance service workers will make the necessary installations available and they will renew oxygen and compressed air weekly. the ventilation assembly must not interfere with the childs activities. the related dispensary and nursing service should be notified of the child's condition and the list of the required material (suction tubes, cannulas, desinfectants etc.) has to be made. our experience is so far -from the nursing and medical point of view -satisfactory, however the social status of the parents needs further regulations, omphalocele. mourik m, sophia children's hospital, department of pediatric surgery, rotterdam, the netherlands. in patients with (giant) omphalocde operative closure is impossible due to the lack of intra-abdominal space and a variable degree of pulmonary hypoplasia. consequently conservative treatment allowing epithelialization is the treatment of choice with a high risk of infection and/or sepsis due to a sometimes very long stay in the icu. this conservative treatment consists of daily application of an antibiotic containing powder on the cele which is covered by sterile gauzes. furthermore the enteral intake is started as soon possible. objective: to evaluate whether this treatment renders a high risk for serious infections. patient characteristics: in a 10 year period 23 patients with a giant omphalocele were admitted; mean birth weight 2800g (1500-3990g) mean gestational age 38.5 (33-42 weeks). overall mortality 6 (19%). 11 patients had to be ventilated for a median duration of t6 days (2,5-164). results: patients were discharged at the mean of 68 days following birth (17-260) following complete epithelialization of the omphalocele. following the initial stabilisation period parents were involved in daily care of all patients even during artificial ventialation. enteral intake was started at a median of 2 days (1-18). colonization of the omphalocele was observed within 2 -4 days in all patients. although infectious periods were observed at regular intervals, sepsis was the primarily cause of death in only 3 of the 6 patients who died, in conclusion: nursing care to prevent sepsis in patients with (giant) omphalocele is feasible for a long period of time and can be performed with simple measures, since june 1994, we have been using nasal cpap in the treatment of respiratory disorders in newborn infants (severe apnea syndrom, tachypnea, hyaline membrane disease). in newborns presenting hyaline membrane disease, we have used cpap and administered surfactant therapy to 25 premature babies out of 70. clinical data were : mean ga : 30.8 + 23 weeks. mean bw : 1686 + 551 g. mean administration time was 11 hours. before administration, mean fio2 was 0.4 + 0.07, mean pao2 6.2 + 1.8 kpa and mean a/ao2 ratio 0.21. all babies were intubated for administration of surfactant (curosurf) and were extubated after half an hour to 3 hours after administration. this treatment failed for seven babies and they were ventilated by oscillation ventilation ; all babies survived. complications : we have observed pneumothorax in 2 cases and 1 cerebral hemorrage. mean duration time of nasal cpap was 71 hours for the 18 babies without assisted ventilation. nurses in charge of babies with nasal cpap should be aware of neonatal care, of the possibility of surfactant administration and of complications during this type of treatment. therefore nurses should know very well the use of nasal cpap, the monitoring during this treatment, the fixation of the system on the baby, nursing of the babies during this treatment and finally should take care of the baby physical and psychological well being. as a conclusion, nurses in intensive care neonatal units should know the possibility of treatment of rds by nasal cpap and should be aware of baby-nursing. emco in the postcardiotomy infan_t : a simplified circuit and reduced management grillet lsabelle, bosson christa, goelz andrea, helmer pascale, icu nurses, tschaut rudy perfusianist aldo castaneda institute, clinique de genolier, suisse to improve postoperative survival of infants with repaired cardiac tessions but severe residual cardiopnlmonary dysfunction, emco was used in 4 infants, ranging in age from l0 days to 9 months and in weight from 2,8 kg to 7,8 kg. diagnosis included tga / intact ventricular septum (2) (both subiected to rapid arterial switch operation because of unsuitable lv function) and tga +vsd (2). "['he emco circuit included a sarns roller 15ump, a medtronic minimax plus hollow fiber oxygenator and tubing (1/4 -1/16 inch) with bioactive surfaces, an arterial canula 10 fr., 2 venous canulas : right atrial 20 fr, left atrial 12 fr., an air oxygen mixer and a sarns heater. the act was kept between 180-200 sec. after the infant was connected to emco by the surgical team and the perfusion technologist, the patients were being cared for and controlled exclusively by the 1cu nurse assigned to the patient and the physician on call for the icu, pump flows of 100-150ml / kg / mln were targeted to insure an adequate urine output, a brisk capillary fill and physiologic left and right atrial pressures. sodium nitroprusside was used to control systemic hypertension while all other inotropic drugs were discontinued. inspired oxygen fraction on the ventilator was reduced to 0,25 at a respiratory rate of 10-15 breaths per minute. body temperature was maintened close to normal. when the heart started to eject again, inspired oxygen was increased to about 0,40. the preparation for weaning from emco was done by the icu nurse: including oxygen fraction and ventilator rate. weaning from emcowas coordinated by the medical / surgical team and the perfusion technologist. the duration of emco in the 4 patients ranged from 2 to 9 days. three patients (75%) were saccessflly weaned from emco. one of the three died within 24 hours from neurologic complications, unrelated to the emco. the other 2 patients ( both with tga + vsd ) are long term survivors and are doing well. neither the survivors nor the patients who died bad hemorrhagic complications, despite the fact that 3 of the 4 were placed on emco because of failure to wean from cardiopulmonary bypass. the simplified emco circuit worked reliably throughout this experience and no complications occurred nor could any shortcoming be ascribed to the use of this reduced, cost effective management team. 10 years of praciical experience wiih exiracorporeal membrane oxygenation (echo) -the viewpoint of the nursing siaef monika schindler in 1985 a training program was started for the introduction of echo in the kinderklinik of mannheim/germsny. 2 years later (1987) the first european echo patient, a 3 days old newborn baby, ~as treated successfully in our institution. with echo, more treatment modalities ~ere available after failure of conventional therapy in eases of severe lung diseases like meeonium aspiration syndrome, congenital diaphragmatic hernia, sepsis/pneumonia, primary persistent pulmonary hypertension of the newborn and -in infants and children -ards (acquired respiratory distress syndrome) due to multiple underlying illnesses. in 1989 the first ards patient, a 5 years old girl, was treated successfully ~ith ecmo in mannheim. until now 137 patients (age: i day -10 years) were treated with echo in our institution; 111 additional patients were transferred to us from other institutions for therapy with echo, but could be treated ~ieh alternative moda]ities of therapy like improved conventional ventilatory support, high frequency oscillatory ventilation (hfov) and inhaled nieric oxide (no), unexpectedly the more ~ide-spread use of hfov and no -also in other ~ntensive care units -did not lead to a reduction of the echo frequency in our hospital. due to this long ecmo practice, which is helpful in many critical situations, a certain routine came up in the nursing staff of our intensive care units; but ecmo continues to be a maximum strain for all co-workers and implies an high personnel and material/financial-expense. but in our opinion the improved survival rates in severe respiratory failure-(70 % in neonates and 50 % in infants and children, estimated survival rates under continued conventional management: < 20 %) by the use of echo justifies this expense, even in times of less financial support for public health. • analyse the differences between each urdt. method : ni criteria were defined by the rt~a ped group according to cdc criteria. all data were collected by a nursing and medical team. data 3vere dealed with epi info software. all u-dections data were validated by an external mvestigatol : 4 525 patients who stay more than 48 hours in an icu were included over a 14 months period. 68 % were newborns, 19 % infants and ,13% children. 371 ni were idenlified among sll patients, the overall ni incidence rates was 8,2 % and 5,9 person day, septicemia was the first cause of ni (50 %). staphylococcus epidermidis were isolated in 60 % of septicemia cases. pneumonia was the other main ni (41%) with gram negatwe bacille isolated m 53 % (40 % of them beei,ng fseudomonas) accordmg to age, the septicemia mcidence rate varied from 6,8 ~., to 10.9 %,, catheter/day and pneumonia incidence rate from 3,9 %, to 7,3 % ventilation/daywith the lowest rate for newborns. : this survey was possible thanks to the collaboration between laboratories, bacteriologist, physicians and nurses, and allowed each concerned unit to work together in~tead of every one in his own field. 'lhe results of this survey bring changes in attlhades and empower the different team work the next step is to analyse the ditferent nurses procedures of indwelling central venous catheter in each unit ar)d implement a ni quatity care. program in all nicu anti picu. v~,~jl~j~'v~y : new born in~ra-v~6nous drugs ~md lheir pr~taration mcounter a lot of risk ~)f utters, due to inadapted conditionn~ng to podia)eric and minimal amount injec~.~d, th~ study t~ed to evaluate degrees of do.~age er~o~ dye tt) dru~ preparaek, n i~ nc,:,~atol~gy and to come out w~th ~ method of dihttion able to reduce risk to minima (errors _< 5 %) at the ~eme t~me, ¢o~,~x-tueaces on cost were studioj methnd~ : amikacine was choosen because this antibiotic is regularly ~,~l in neonatology unit and its dosage is easily used by standardiaud method, 30 amikacine doses (15, 23 mg doses and 15, 12 mg doses) were prepared" by 15 nurse~ form 50 mg for 1 m) vial. each dose w'a~ diluted to obtain 2 mi volume, tallowing usual ward method, for each dilution, amikacine con<entrati('m and it,s volume was measured and used equipment for preparation wa~ regi~tred. 10 "first s01utj(m" were prepared diluting ~t'~ mg amikacine pouder inn 51) ml glucnse solution bag (viaflex baxter bag with transfer cap), from tho~e "first solution" 15 doses at 23 mg and 15 doses of ~2 rng were prepared, amik~cine coc, cenir,)tmn for each preparabon and their volume were measured, ai,~n ntttl~,ber of seringe were tounted. first soiuhon staeiiity was conrroieo aher one week conservation at + 4'>c. amjkacine concentration were measured by fluorescence process (tdx abbott) after sample dilurion. on a 10 mg/l sample, tovhnical reliahility show~ > 9~ % of result mpmductlon and < 5 % of variation due to dilutions. results : when amikacine injection werv pro.pared from araikacme 5/) mg for 1 mt vial > 10 % do~ge, ermr~ were found in 19/40 cases ; ~ 30 % in ,t1,to cases. if preparation is done from amikacine "~it'st soltltion", les.--concenvr~tcd, it i~ more preci,,,e and only one dosage error ~ 5 % (6,3 %} is found in eli 30 studied doses. in add)inn to )hal if 10 doses were wep,m-'d from one "first soiatiol~' bag, the cost economy sl~ouid b~" of 32 fr~, and ii 20 dos~$ were prepared tram the same bag the saving mtmey should be o{ i72 its .cencluslon : .ur survey shows th~t h' ntu)nato|ogy the u~ of a "first sohation which can be kept fi~r one week is enable to reduce dosage erroes and i~ co,~tsavmg, regarding [,v. admimst'rahon method the survey is still on, introduction: so-called vein of galen m~iformations ale rare in~racranial embryologycal anomalies, repl~senti~g tess than 1 of symptomatic intracranied artefiovenoas l~alform~tions. the spontlneous prognosis is ~s~u~lly fatal, because of cardiac frilure due to left-to-right shunt thrq~ugh the fistula. recent developments of new techniques of treatment of the malformation and its cardiac consequence have led to a revolution in the practical approach of children w~th galen malformation. our fukfose is to contribute, with our persoaal series of 7s newborns and infal~ts admitted in our unit after endov~,scular embolization, to a better management of these children. such a management requ!res a rnultidisciplinary approach. intensive care are required prior to embollzation for patients with cardiac failure or cardiogenic shock and after cmbolization in order to insure cardiac and cerebral hemodyna.mic stabilities. this overlooking suppose for the nursing team to understand: prior to embolization : heart failure and cardiogenic shock. after cmbolization : evaluation of neurological and hemodynamic consequences of this proccdure, without forgetting the nursing and psychologic aspects, in concl'iision, this last ten yerrs, these new approaches give to the patients and their famitiy a good reason to hope a total recovew, in our exl)erience, the global mortality is 9 % aad 66 % of children #j-e neurologically normal after embolizafion, ii ii~ i ~ii i ii i i l i iiii~ i ~i iii i background: venous oxygen saturation (svo z) reflects the residuai oxygen after tissue oxygen extraction and represents the relation between tissue oxygen supply and demand. we studied svo 2 and arterial lactate during progressive isovolemic anemia to assess the relation between svo2 and tissue hypoxia. subjects: ten 8-10 day old anesthetized ventilated piglets sao 2 and svq were measured continuously by a fiberoptic catheter (oximetrix, abbott lab.) in the carotid and pulmonary a~epy tissue hypoxia was confirmed by a reduced vo, and an increase in lactate. conclusion: svo 2 reflects better a reduced dp obtained by progressive anemia surfactant replacement improves gas exchange in early-stage adult respiratory syndrome (ards) [1,2], but not in late-stage ards [3] . we report the first case of successfull treatment of ards after repeated instillation of surfactant.a ten year old boy, weighing 32 kg, presented with hemorragic shock. biphasic-positive-airways-pressure ventilation was performed (evita ii, dr~ger, germany). he had recieved nine units of packed red blood cells and underwent surgical exeresis of two bleeding gastric ulcus. post-operatively, a cardiac arrest required cardiopulmonary resuscitation for three minutes. hemodynamic status was subsequently stabilised. the chest-radiograph showed infiltrates of both lungs without signs of cardiac failure. on the third day, the patient became severely hypoxic with a pao2/fio 2 ratio of 30. gas exchange was not improved by high ventilator settings. peak inspiratory pressure (pip) and ventilatory rates were 40 cmh~o and 18 breaths/min respectively. inspiratory:expiratory time was 1:1 and the positive end expiratory pressure (peep) 8 cmh20. after increasing the peep level to 11 cmh20, we instilled over 2 minutes, 80 mg/kg of porcine surfactant (curosurf, serene france), in two equal volumes in both main bronchus,the spo~ rose to 97% within 15 rain, the fie 2 could be reduced to 0.6. twenty four hours later, gas exchange worsened again (pao2/fio2 ratio 90). we increased the peep from 8 to 11 cmh20, and instilled a second dose of surfactant (60 mg/kg). again, fie 2 could be reduced within 15 minutes (spo 2 95; fie 2 0.6.). the patient was weaned from the ventilator and extubated on the tenth day. follow-up at four month showed normal lung function.we demonstrate improvement in oxygenation after repeated exogenous surfactant administrations. we assume that in early-stage ards, surfactant may potentiate shunt-reducing effect of peep as it has been demonstrated in experimental model of ards [4] , and allow decrease in fie2. in case of secondary deterioration, we think that a second dose of surfactant should be administered. 1. weg jg, balk ra, tharratt rs, et al. ,lama 1994 : 272: 1433 -8. 2. spragg rg, gillard n, pdchman p, et al. chest t994: 105: 195-202. 3. haslam pl, hughes da, mcnaughton pd. et al. lancet 1994 343:1009 -11. 4. huang yc, caimulti sp, fawcett ta, et al. jappl physiol 1994 76:991-1001 43% (ref) . the aim of this study was to verify these data: patients/~lethods: all pts admitted to our multidisciplinary nicu/picu in 1995 were included if they were in respiratory failure recruiting conventional mechanical ventilation (cmv) with peep >_ 6 and 'fig2 -:2 50% or high-frequency oscillation ventilation (hfo) with mean airway pressure _> t8cm h20 for 12 or more houm. diagnosis, maximal ventilatory parameters, barotrauma, organ/ system failures, mechanism of death and glasgow oulcome scale (gos) 1 and 6 months after study entry were prospectively collected. results: 685 patients were admitted to the unit, o1 whom 337 required mechanical ventilation for a mean duration of 4.0 days. overall mortality was 5%, 22 patients fulfilled study criteria. 17 survivors had gos 5, 2 pts with preexisting neurological impairment survived with gos 3. neonatal diseases included hyaline membrane disease (7), meconium aspiration syndrome (4) and cardiovascular surgery (1), pediatric diseases included bacterial (1) and viral (5) pneumonia, aspiration (1) and cardiovascular surgery beyond the neonatal period (3). 1990 -1994) . patients and methods: cefotaxim was used as a prophylactic agent in 43 patients in life threatening situations (e.g. multitrauma, neurosurgery atc.). more than 85 % children required cefotaxim for the treatment of severe infections (epiglotitis, meningitis, sepsis, pneumonia mainly in immunodeficient and neutropenic patients) in monotherapy or in the combination with the other antimicrobial agents. results: cefotaxim as a prophylactic drug was successful in all 43 cases (100 %). the effectivity of treatment of infections was 82.8 % (313 patients). the change of antibiotic therapy required 9 patients (2.4 %). 40 patients (10.6 %) died, but only in 12 of them (3.2 %) the obduction confirmed infection. conclusion: we conclude that cefotaxim is very effective and safe antibiotic and represents "golden standard" in the treatment of severe infections in childhood. in order to improve nursing quality, we recently adapted nursing care to the "five nursing functions" (activities of daily living, accompagnment in crisis, treatment, prevention and research) as described by the swiss red cross in accordance to the new educational guidelines of the european community, the aim of this study was to document complications of "treatment nursing function".methods: all treatment complications were prospectively collected by the nursing and medical staff. the nursing staff included patient (pt) name, time of occurence and exact description of complication, proposal for prevention and information of parents. the medical staff reported type of complication together with pt information, diagnosis, medication, treatment and interventions, outcome and referral, all complications were discussed in monthly meetings including nursing and medical staff.results: from january until december 1995, 685 pts were admitted to the picu/nicu for 3233 nursing days (81% of total bed occupancy). 337 pts needed endotracheal intubation for an average of 4.0 days and 47 pts required nasal cpap. 26 complications in 21 pts were noted (1 per 26 pi): inadequate check-up of equipment 11; accidental extubation 4 (1 in 85 intubated pts); bedsores 3; false drug dosing 2; wrong drug 2; umbilical bleeding 2; wrong transfusion setup 1; nasal septal necrosis 1). there was no mortality due to these complications. exact documention of treatment complications and their meticulous discussion within the medical and nursing staff may improve "treatment nursing function". however, documentation and evaluation of nursing within all "five nursing functions" will be nessecary in order to achieve optimal nursing care. cardiac output determination by thermodilution, using iced injectate has been shown to be valid and reliable in pediatric patients. it has been demonstrated in adult patients that there is no difference in cardiac output values when using room temperature injectate as compared to iced temperature injectate. the purpose of this study is to examine the effect of injectate temperature on cardiac output values in pediatric patients. our study consisted of sixteen pediatric patients who had oximetric thermodilution catheters in place after cardiac surgery and who had cardiac output determined using both iced and room temperature injectate. with each patient, cardiac output was measured once on the day of surgery and again the following day. in each case cardiac output was measured using both iced and room temperature injectate. statistical analysis included a two-way, repeated measures analysis of variance for each individual injectate administered and no significant differences were found in cardiac output. no statistically significant differences were found between groups with regard to the order of injectate administration or volume of injectate used (i,e., 3 or 5 cc's). the correlation coefficients between groups for cardiac output measurements at each injectate administration time, and for the average measurements across times, ranged between 0.81 to 0.94 (p < .0005). preliminary data analysis suggests that cardiac output measurements for children are not effected by the temperature of injectate. a lenghty stay at a paediatric intensive care unit will always have sideeffects on a child's well-being and will put a high strain on the parents. in order to minimize the side-effects longterm intensive care unit opened in 1990 at the childrens' hospital. admitted children are all ~ongterm-ill and technically-dependent and the ventilatory support can alter from a tracheostoma to cpap or portable volume ventilator. nutritional support is applied by gastrostomies. a homelike atmosphere surrounds the children, they share a dormitory, a living-room and a dining-room the main purpose is to send the child home with or without technical equipment. this can only be implemented by giving structured education (theory and practice) to all categories involved. the multi-disciplinary team consists of one anaesthesiologist, head nurse, clinical specialist, rn nurses, nurses, one habilitation doctor, one social worker and therapists. twenty-four patients have been admitted to licu during these six years. length of stay was from one day to four years. four are presently staying at the trait. the assessment of pain in children (0-3 yrs) is still difficult, because children of this age have limited language and cognitive skills. to standardize the assessment of postoperative pain and distress in the intensive care unit an observational mstrument was needed that met several criteria. it should be easy to use in daily routine care. be suitable for the i.c. situation, and in children of 0-3 hrs of age. the comfort scale, an observational instrument designed to assess distress in infants in i.c. units, met these criteria. to accommodate the use of the comfort scale in the i.c. units and in research, nurses should be trained to use the scale. an additional requirement was that the inter-rater reliability should be sufficiently high, (cohen's kappa > .60). objectives: 1) to introduce the comfort scale in the i.c.u.; 2) to examine whether this instrument can easily, be incorporated into routine care; 3) to investigate the inter-rater retiabtlity. methods: the comfort scale is an 8-item instrument specifically designed for use in pediatric i,c, units and contains both physiological items (heart rate, blood pressure) and behavioral items (e.g., alertness behavior, calmness/agitation, body movement, facial expression respiratory response, muscle tension). the observation period is 2 minutes. the scale is supplemented with an item on crying tbr children who are not mechanically ventilated. groups of 8 t.c. nurses were trained by means of video's and observations at the wards. after the training, each nurse completed 10 scores with other nurses, after which the cohen's kappa was computed. when the kappa's for the items met or exceeded our .60 criterium, a new group of nurses was trained. results: to date, 30 nurses have been trained. nurses find the comfort scale easy" to administer and a valuable addition to routine care in the i.c. unit. the cohen's kappa's were higher than .60 for all items that the inter-rater reliability was high. the comfort scale is feasible in postoperative care in the i.v. and is considered a valuable instrument to improve and maintain high postoperative quality of care in the i.c. unit. introduction:children with neuro-muscular disease are believed to have a higher resting energy expenditure (ree), because of their increasedwork of breathing.the influence of nocturnal nasal mask ventilation on energy metabolism and nutritional state of these children has not been studied so far.objective:l,ls the ree inereased?2.1s there an influence of nasal mask ventilation on the ree?3.what is the nutritional state?4.what is the estimated total energy expenditure(ete) in relation to the caloric intake? methods:a pilot study of 4 patients(12-16 years) .the following measurements were performed:l.anthropometry.2.bioelectric impedance-3.ree was measured by indirect calorimetry during the day (in bed) with and without nasal mask ventuation,ree was compared with predicted ree according to schofield(pee),4.caloric-intake and activities were recorded during 48 hour before measurement.5.total energy expenditure was calculated as follows:measured ree x estimated activity factor. results:tin all children weight for height was too low, <p3.2.aii children had a low % of fat.3.according to the healthy group, ree is not increased.4,nasal mask ventilation lowered ree in 2 patients, in 1 patient we measured a clear decrease.conclueion:l.anthropometry and indirect calorimetry were helpful in evaluating the nutritional state.2.there is no increased ree,in t patient there is clearly effect of nasal mask ventilation.3.when caloric intake was related to ree and level of activity 2 patients had too low caloric intake.4.the influence of nocturnal nasal mask ventilation and nutritional assessment should be evaluated longitudinally. increasing awareness that the neonate can percept pain and suffer following surgical procedures, has major impact on pain management. in our unit continuous morphine infusion (t0/~g/kg/hr) was introduced from january 1990 as a standard medicatton following surgical procedures. before 1990 morphine was given as a bolus (i.m., i.v., rectal) of 100/~g/kg up till four times a day. repeated gifts of morphine were only gwen following observation by the nurse that the child experienced pain. aim of the study: to evaluate pain management before and tbllowing introduction of a continuous morphine infusion for postoperative pain in our icu. patients and methods: term born babies with isolated oesophageal atresia and tracheo-oesophageal fistula were included in the study. the total amount of morphine (/~£/kg/24 hours); number of days morphine was given; duration of artificial ventilation was evaluated in a case control study. res ults: 1985 -1990 1991 -1994 central venous catheters (cvc) have been increasingly used also at our picu, university medical centre ljubljana. besides advantages, the cvc has brought numerous risks of complications; the catheter sepsis occurs most often and can be fatal for the patient. for example, in 1995 we dealt with 400 children aged 0 -12 years or in other words 1.14 cvp per a child treated at our picu. a specialized unit for preparing parenteral natrition started to function in the university medical centre pharmacy in 1977. after that we equipped a special room for preparing other necessary infusion mixtures and organized a team of nurses -"catheter nurses".their tasks comprise: managing cvcs, replacing and installing infusion systems and mixtures made at pharmacy, preparing drugs and some necessary infusion mixtures in special room, permanent training and co-operation with related disciplines, pharmacy, epidemiology, microbiology, etc. all registered nurses at picu have been trained for this work. the routine is as follows: in the morningafter the doctor's visit, we first check the cvc and change the dressings; according to the nurse's observations, the doctor decides whether there is a need to remove or replace the cvc. if the catheter site is inflamed, swollen, or purulent, a swab is taken for microbiological culture and the area cleaned. in case of systemic infection signs, cvc has to be replaced, blood culture taken and the infection treated with antibiotics. the dressings are always changed by two tmcatheter nurses together. afterwards the infusion mixtures for the next 24 hours are prepared for each child. the infusion mixtures which will not be used immediately are kept on +4°c; before application they are, of course, warmed to at least room temperature. finally the "catheter nurse" supplies the cvc with new infusion mixtures made at our pharmacy. our observations show that such work requires responsibility and is demanding; but our pemanent care lessens the number of complications. thus the described scheme fulfilled our expectations. perl-0perative management of neonates with hypoplastic left heart syndrome muir warren, blondel maryse, foltz rhonda, farine martine, icu nurses, the aldo castaneda institute, clinique de genolier, switzerland both the pre-operative and post-operative physiology of patient with hypoplastic left heart syndrome is critically determined by the puhnonary-tosystemic resistance ratio. a high ratio results in minimum volume work for the right ventricle but is at the expense of important hypoxemia. a low ratio is reflected in minimum hypoxemia but an unfavorable increase in excess ventricular volume work. a resistance ratio of approximately 1 results in an arterial oxygen saturation of 75% -80%, a qp/qs of 1, and ventricular volume work only twice normal. this latter physiology appears best for oxygen delivery and systemic perfusion with tolerable volume work. carbon dioxide (co2) in the inspired gas is known to increase pulmonary vascular resistance without significantly influencing systemic resistance in the range of 1 to 20 tort partial pressure. hyperventilation with no co2 in inspired gas decreases pulmonary vascular resistance. thus, managing co2 may be useful to modulate the pulmonary-to-systemic resistance ratio, in the tast 16 months, 20 patients with hypoplastic left heart syndrome were managed by a norwood procedur e. 10 patients with endotracheal entubation pre-operatively had co2 added to inspired gas to modulate the pulmonary-to-systemic flow ratio. 17 patients had co2 added to inspired gas post-operatively. all but 1 patient had characteristically large pulmonaary-to-systemic flow ratio with oxygen saturation mean 90 % preoperatively, even in those patients receiving co2, co2 was accompanied by elimination of metabolic acidosis pre-operatively. the most comlnon partial pressure of co2 added post-operatively was 14 torr. po2 ranged from 25 mmhg to 40 mmhg. all surviving patients developed a metabolic alkalosis (10 mean) when treated with co2. there were 4 deaths, one from drug toxicity, one from excessive post-operative hemorrhage, two from sepsis or mocardial insufficiency. only one patient benefited from catecholamine support which can increase systemic resistance unfaborably. in this experience co2 was felt to be an important adjunct in some patients pre-operatively and most patients postoperatively to faborably modulate the critically important systemic-topulmonary flow ratio, to maximize oxygen delivery and systemic perfusion, while minimizing excessive right vantricular volume work. key: cord-004675-n8mlxe7p authors: nan title: 2019 cis annual meeting: immune deficiency & dysregulation north american conference date: 2019-02-26 journal: j clin immunol doi: 10.1007/s10875-019-00597-5 sha: doc_id: 4675 cord_uid: n8mlxe7p nan a 34 y.o. female was referred to our clinic with a history of multilineage cytopenias/evans syndrome, a history of idiopathic thrombocytopenic purpura, hemolytic anemia, chronic neutropenia, lymphopenia, and hypogammaglobulinemia treated with ivig. our patient was healthy until she was 8 years old; at that time, she developed joint pain, rash, and bruising. she was found to have evans syndrome with idiopathic thrombocytopenic purpura (itp), neutropenia, and lymphopenia. she was initially diagnosed with lupus and was given steroids. her bone marrow biopsy did not conclude myelokathesis. when she was 15 years old, she remained thrombopenic and was started on high dose of immunoglobulin replacement therapy. in 2012 (29 years old), she developed polyarthritis in her upper and lower extremities. in 2013 (30 years old), she had a severe nosebleed, for which she was admitted and treated with amicar twice; her platelets were found to be 2,000 k/ul. she received rituximab weekly for 4 weeks resulting in an increase of platelet count to 90-100k/ul. she recently (march 2017) had a splenectomy to remove her large spleen, and since then, her platelets have rebounded to 400-500k/ul. in 2015, she was placed on long-term immunoglobulin replacement therapy after being hospitalized for bilateral pneumonia for 5 nights requiring iv antibiotics for treatment. in 2017, she developed and was treated for another pneumonia. her family history is characterized by multiple members with autoimmune multilineage cytopenia as well as autoimmune diseases such as multiple sclerosis (mother), thyroiditis and enteropathy. on physical examination, she did not present with any warts and the remainder of her physical examination being unremarkable, except for her scar from her splenectomy and a cervical lymphadenopathy. immunologic evaluations showed igg 601 mg/dl, iga <5 mg/dl, and igm 208 mg/dl. cbc with differential and lymphocyte screen were as follows (cell/mm3): wbc 12.3 x103, hemoglobin 10.2 g/dl, platelets 503 x 103; 3 % neutrophils (anc: 300), 82% lymphocytes, 10% monocytes, 0% eosinophils; absolute total t-cell number was 8884 (750-2500 cells/mcl), cd4+ t-cells 6554 (480-1700cells/mcl), cd8+ t-cells 2185 (180-1000cells/mcl), natural killer cells 206 (135-525 cells/ mcl), and absolute number of b cells was 996 (75-375 cells/ mcl). she came to our clinic with her sister, who also had multilineage cytopenia and hypogammaglobulinemia, treated with monthly ivig; and her nephew whom had neutropenia. based on this family presentation all three underwent whole exome sequencing (wes). the patient, the patients sister and the patients nephew were all found to have a variant on cxcr4 (frameshift mutation on chromosome 2, p.val324fs; refnt: tca; altnt: t). as an important note, the patient had a bone marrow biopsy, which did not conclude myelokathesis. in summary, our patient with trilineage cytopenia and hypogammaglobulinemia, without any warts or myelokathexis, had whim syndrome (warts, hypogammaglobulinemia, immunodeficiency, and myelokathexis), which was discovered by studying her wes. with the identification of her specific diagnosis, this allowed us to discuss the potential future indication of plerifaxor (antagonist of the alpha chemokine receptor cxcr4). and equally important, we discussed family planning and future pregnancies given that the mutation is autosomal-dominant. (4) submission id#555017 taha al-shaikhly, mbchb 1 , kathleen mohan, arnp 2 , matthew basiaga, do, msce 3 introduction: complement component-3 (c3) is shared by the classical, lectin and alternative complement activation pathways. c3, a major opsonin, facilitates phagocytosis of encapsulated microorganisms. inherited c3 deficiency is rare and is associated with increased risk of bacterial infections. subjects with connective tissue diseases (ctd) and c3 nephritic factors can have low and occasionally undetectable c3 levels, yet they are at an underappreciated infectious risk. we hypothesize that excessive c3 consumption in secondary complement deficiency disorders (scd) is associated with higher risk of bacterial infections similar to primary complement deficiency disorders (pcd). objectives: to compare the rate of bacterial infections between pcd and scd patients and evaluate the association between c3 level and bacterial infection risk. methods: we performed a retrospective cohort study. subjects with an undetectable complement activity (ch50) or any of the complement components measured at seattle childrens hospital from 2002-2018 were included in our study. we recorded the number of infections, observation periods, diagnosis (pcd, scd and its underlying etiology), lowest complement component levels, and the immunosuppressive agents used. the date of birth, and date of lowest c3 level were considered as start points to calculate the observation periods for pcd and scd subjects respectively. infections requiring hospitalization or parenteral antibiotics were categorized as serious bacterial infections (sbis). descriptive analyses were performed to determine medians and ranges for continuous variables. differences in rates of bacterial infection were assessed using the chi-square and kruskal-wallis tests when appropriate. among subjects with ctds, we treated every c3 measurement as a single observation (n=1,197) and studied the association between c3 concentration and the 30-day odds of having a sbi. multivariable logistic regression was performed to determine infection risk based on c3 level while controlling for contributing factors. results: we identified 14 subjects with pcd, and 52 subjects with scd. scd consisted of three subgroups (ctd-related (n=44), nephritic factor-related (n=2), and infection-related (n=6)). collectively, ctd subjects had a lower median rate of sbi compared to pcd subjects (p = 0.004). subjects with ctd and c3 level <40 have higher rate of bacterial infection (of any severity) (p = 0.002) and of sbi (p = 0.004) when compared to ctd subjects with c3 >=40 at the beginning of observation period ( figure 1 ). while controlling for immunosuppression level 1 pediatric resident, baystate medical center 2 faculty advisor, baystate medical center introduction: zap70 codes for a 619-amino acid enzyme, zap70, a member of the syk-protein tyrosine kinase family that plays an important role in t cell development and activation. zap70 is phosphorylated at tyrosine kinase residues upon t cell receptor (tcr) stimulation resulting in tcr-mediated signal transduction with src family kinases. zap70 deficiency results in a rare t+b+ nk+ severe combined immunodeficiency (scid). we report a novel compound heterozygous mutation in zap70 leading to presumed absent zap70 function in an infant with a normal trec newborn screen and scid. case description: the patient is a term, fully immunized female, born to non-consanguineous parents who was hospitalized for rsv bronchiolitis at 2 mo. at 4 mo she developed an erythematous, papular rash on her face and extremities, nonresponsive to topical antifungal therapy. at 6 mo she was re-hospitalized with rsv bronchiolitis and subsequently treated with multiple courses of antibiotics for presumed bacterial pneumonia followed by albuterol and oral steroids for possible reactive airways disease. during this course of treatment, her rash resolved. at 8 mo she presented with failure to thrive (wt <0.1% for age), multifocal pneumonia and respiratory failure requiring intubation. bronchial alveolar lavage confirmed pneumocystis jiroveci pneumonia prompting an immune evaluation. total immunoglobulins were normal for age, however antibody titers to tetanus, diphtheria and streptococcus pneumoniae were absent. lymphocyte enumeration revealed elevated cd4 t cells and markedly diminished cd8 t cells, normal b and nk cells. t cell proliferation to mitogens (pha, pwm) and antigens (candida, tetanus) was absent, however t cells proliferated normally to stimulation with pma and ionomycin. trec number was normal by newborn screening, but was 2 std deviations below the mean and would have resulted in a positive screen upon repeat. invitae 18 gene scid panel revealed two variants of unknown significance, c.109c>g (p.arg37gly) leading to substitution of arg with gly and c.1529_1532dupgcat (p.ile511metfs*65) resulting in a premature translational stop signal expected to disrupt the last 109 amino acids of zap70 protein. parental sequencing revealed these variants to be on opposite chromosomes. the patient was successfully treated for pjp pneumonia and has since successfully engrafted a 9/10 matched unrelated donor stem cell transplant. discussion: we report a novel compound heterozygous mutation in zap70 which we presume led to t+ b+ nk+ scid. our patients clinical presentation of failure to thrive, recurrent lower respiratory tract infections, dermatologic findings and pjp pneumonia are consistent with previously reported cases of zap70 scid. her paucity of cd8 t cells, abundance of cd4 t cells and absent proliferation to mitogens are also consistent with previously described cases of zap70. normal proliferation of t cells when bypassing the tcr by stimulating cells with ionomycin and pma confirms a defect in the tcr. we believe this is the second documented case of missed scid by newborn screen in ma since the implementation of trec screening in 2008. pediatric resident (pgy iii), goryeb children's hospital 2 attending physician, pediatric and adult asthma, allergy and immunology, llc introduction: acute otitis media (aom) is one of the most common reasons for antibiotic use in early childhood. we explored the challenges when aom fails traditional therapies and immunologic evaluation does not identify a commonly described immunodeficiency. case description: an eighteen-month-old male presented with 12 episodes of aom and recurrent purulent otorrhea requiring intravenous antibiotics. laboratory evaluation revealed a normal cbc, normal immunoglobulins (igg 588, iga 76, igm 63, ige 12) and igg subclasses. lymphocyte subset panel was normal. initial responses to dtap and prevnar boosters were normal, however, there was rapid decline to tetanus and pneumococcal antibody titers. a sub optimal response to haemophilus influenza type b vaccine was noted. although vaccinated twice for mmr, he never mounted mumps specific igg. mitogen response to pha was normal with decreased responses to cona and pokeweed and no detectable tetanus nor candida responses. further investigation revealed decreased non-class and class switched memory b-cells. the patient was recently vaccinated to pcv23 and at the present time has protective titers. discussion: it has been previously suggested that decreased memory b cells may contribute to decreased antibody responses to select vaccine antigens resulting in recurrent aom in children. our case supports the need to investigate beyond typical immunologic screening for immunodeficiencies. introduction: dna mismatch repair (mmr) system corrects replication errors in newly synthesized dna, and prevent recombination between dna sequences when they were not identical (1) . msh6 is a part of mmr genes, (2) (3) (4) . case: a ten-year-old girl presented with fever, brown spots on her skin, hair loss, recurrent pulmonary infections, arthritis on the left hand and right ankle. she has also been followed up with nf ( figure 1 ). there was a first-degree cousin marriage between her parents. physical examination revealed findings of pneumonia and nf. anti-nuclear antibody, anti-ndna, anti-dsdna, anti-histone, anti ro52 and anti-nucleosome antibodies were positive. in her immunologic assessment showed low igg and iga levels associated with high igm level ( table 1 ). the coexistence of nf, hyper igm syndrome, sle, were considered in the patient. intravenous ig (400 mg/kg, every 3 weeks) treatment was started due to hypogammaglobinemia. the frame shift mutation in exon 2 of the msh6 gene was detected in the boztug's laboratory. in the follow up period, she admitted at 11 years old with back pain. a mass in the left paravertebral area, related to the spinal canal and neural foramina, was detected at the l4-l5 levels in spinal mri. the lymphadenopathy around the liver and hilum and the left parietal bone lesions were developed within two months despite surgical excision of primary mass ( figure 2 ). as a result of pet examination; suvmax was found to be around 6.5 in the mass lesion in the paravertebral region and suvmax values did not exceed 2.5 in other lymphadenopathy and masses. atypical cellular infiltration suggesting neoplastic events, which were including small-medium size atypical pleomorphic mononuclear cells and t cells. since all these formations did not indicate definite cancer, chemotherapy was not started. interestingly, although chemotherapy was not given, progression stopped, and partial spontaneous regression was observed. discussion: the effect of msh6 mutations on patients may significantly vary with the inheritance pattern (2) . leukemias or lymphomas are not common in heterozygote mmr gene defects (5, 6) . however, homozygote mutations in mmr genes show a different pattern. wimmer and etzler proposed the new term constitutional mismatch repair-deficiency syndrome (cmmr-d) for patients who have a homozygous mutation in mmr (3) . cmmr-d characterized by development of childhood cancers, mainly hematological malignancies and/or brain tumors, as well as early-onset colorectal cancers, and neurofibromatosis type 1 (3) . bi-allelic germline mutations in any of the mmr genes in which msh6 is involved increases hematological malignancies by 15% (7, 8) . msh6 mutation has been associated with many cancers since its identification. leukemia, lymphoma, colorectal cancer, endometrial cancer, brain tumors are some of these cancer types (2) (3) (4) 9) . msh6 deficiency is an important disease that can affect different systems at the same time. there is a high risk of malignancy in the cases and therefore they must be closely monitored. this case has also shown that atypical lymphoproliferation may occur in msh6 homozygous mutant cases. (normal rage: 842-1943) background: advances in inborn errors of human immunity have supported the discovery of new syndromes that are marked by striking features of autoimmunity and immune dysregulation often associated with cytopenias, lymphoproliferation, and a predisposition to reticuloendothelial malignancies leading to evaluation with hematologists/oncologists. moreover, hematologists/oncologists have also seen an increasing use of effector cell-based therapies, checkpoint inhibitors, immunomodulatory and targeted therapies resulting in autoimmunity and hyperinflammatory complications. a working knowledge of clinical immunology could help practicing hematologists/oncologists in the identification and management of these conditions. objectives: to support the advancement of aspho members and the field by facilitating education regarding the best practices in diagnosis and management of immunological disorders. to create a platform for the development of collaborative clinical research in patients with hematological/oncological manifestations of immunological disorders or those requiring hematopoietic stem cell transplantation for a underlying immunological disorder. design/methods the aspho clinical immunology sig was initiated based on collaboration with the clinical immunology society (cis). aspho members who are pediatric hematology/ oncology clinicians, clinical researchers, and trainees are eligible to participate. we have established a steering committee with representatives from across the united states and canada with diverse clinical and research expertise. through regular teleconferences and annual in-person meetings, we have developed a platform to provide our members with a network of immunology resources to ensure a strong foundation of knowledge and tools to conduct clinical care and research pertaining to the diagnosis, evaluation, and treatment of patients with immunological disorders. results we currently support over 50 members within our online community. several educational initiatives have been successfully launched. we have submitted an invited review to pediatric blood and cancer which provides a case-based review of primary immune regulatory disorders. we hosted the first immunology for hematology oncology practice (i-hop) cased-based webinar series. this series features case-based discussions of patients with primary immunodeficiency disorders presented by fellow trainees and mentored by senior clinicians. we will also be hosting an aspho webinar focusing on the laboratory evaluation of primary immunodeficiencies and immune dysregulation syndromes. we have also begun the process of laying the groundwork for clinical research initiatives. conclusion: the aspho clinical immunology sig seeks to serve as a collaborative resource for pediatric hematology/oncology clinicians and researchers. through the development of educational and research initiatives, we envision improving the care of patients with immunological disorders that are often managed by pediatric hematologists/oncologists. moreover, we hope to broaden our understanding and application of clinical immunology within pediatric hematology/oncology. we hope that this successful initiative will serve as a blueprint for the development of future collaborations with other specialty societies and patient groups. autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (apeced) is a rare autosomal recessive disease caused by aire gene mutations. clinical diagnosis is established by the presence of at least two components of the classic triad of chronic mucocutaneous candidiasis, hypoparathyroidism, and addisons disease. in europe, the classic presentation is widely recognized and nonendocrine autoimmune manifestations are rarely reported. a recent study of 35 american apeced patients demonstrated a more heterologous presentation, with many nonendocrine manifestations including urticarial eruption, hepatitis, gastritis, intestinal dysfunction, pneumonitis and sjogrens-like syndrome, all uncommon in european reports. within the american cohort, 80% of patients developed a mean of three non-triad manifestations before reaching the classic triad. finding of aire mutations and high-titer antiifn-autoantibodies is seen in both european and american cohorts. we present the case of two siblings, who demonstrate an apeced-like phenotype with both classical and atypical features. they share the same heterozygous c132+1_132+3delinsct aire mutation. the older, an eight-year-old boy, with history of prematurity, bronchopulmonary dysplasia and onychomadesis in infancy, came to medical attention at 16 months of age due to failure to thrive (ftt), in addition to fevers and urticarial rash lasting months after his mmr vaccine. the fevers resolved with anakinra, which was discontinued two years later due to pneumonia. from age 2-4 he developed an alps negative lymphadenopathy which self-resolved. lung issues include chronic cough, initially treated as asthma but with poor bronchodilator response, and frequent lung infections, including 1-2 pneumonias per year. at age five evaluation for ftt revealed growth hormone deficiency. two years later he was diagnosed with primary addisons disease. chronic abdominal discomfort, bloating, cyclical constipation/diarrhea, recurrent rashes, dystrophic nails, and sicca symptoms are also present. his sister, age five, shows ftt, but no growth hormone deficiency. at age one, she too developed a fever and rash syndrome lasting 3 months. severe gerd and constipation started in infancy and are ongoing. at age three she developed a transaminitis, initially diagnosed as ebv, but later thought to be autoimmune hepatitis. she has frequent viral respiratory infections, and pneumonia at age two. she has had a chronic cough, with poor bronchodilator response, for most of her life. evaluation of seizure at age three showed normal brain activity. brain mri revealed partial agenesis of the corpus callosum and microgyria. her brother has similar mri findings. both children have had developmental motor delay and poor tone. brain dysgenesis and neurodevelopmental delay has not previously been described in apeced. although there were both typical and atypical symptoms, the history in combination with genetic findings led to further investigation of an apeced-like syndrome. autoantibody testing confirmed high-titer antiifn-autoantibody typical of apeced in both children and hightiter bpifb1 autoantibodies found almost exclusively in apeced pneumonitis in the brother. whole exome sequencing and copy number variation analyses are underway to further evaluate the patients condition. this case demonstrates the importance of clinical presentation in the evaluation of genetic results and in the guidance of therapeutic management. (12) submission id#570047 rationale: infants with low t cell receptor excision circles (trec) born in queens, nassau, and suffolk counties are referred to our center for further evaluation. this study elucidates the demographic and laboratory characteristics of referred infants with transient or persistent idiopathic t cell lymphopenia (tcl) without clearly identified genetic or acquired etiology. methods: a retrospective analysis was performed from september 2010 (when trec screening started) through the end of december 2017. descriptive statistics were calculated for demographic and laboratory characteristics. t-test or mann-whitney tests were used to compare laboratory variables. pearson or spearman tests were used to determine correlation between initial trec levels and t cell counts. by definition, the cd3+, cd4+, and cd8+ populations of transient tcl patients normalize by age 1 year. results: eighteen infants with transient and 17 with persistent tcl were identified. males comprised 61.1% of the transient and 47.1% of the persistent tcl cohorts. whites comprised 11.1% of the transient and 35.3% of the persistent tcl cohorts. the mean initial trec levels did not differ between the transient and persistent cohorts (67.7 vs. 78.5 trecs/l of blood, p = 0.56). mean initial absolute counts of cd3+ (2149 vs. 1300 cells/l, p <0.0001), cd4+ (1462 vs. 922 cells/l, p <0.0001), and median initial absolute counts of cd8+ (524 vs. 309 cells/l, p = 0.0075), were higher for transient vs persistent cohorts. initial trec level did not correlate with initial cd3+, cd4+, or cd8+ absolute counts. the median age of resolution for the transient cohort was 121.5 days (range 23-244). the absolute cd3+, cd4+, or cd8+ counts rarely exceeded the reported median values for age, and remained closer or below the 5th percentile for age up to 1000 days of life. the majority of both transient and persistent tcl patients demonstrated unremarkable lymphocyte proliferation to mitogens. conclusion: our centers transient tcl cohort appears to be predominantly male and non-white, whereas the persistent tcl cohort is more evenly distributed by sex but still predominantly non-white. the transient cohort had lower initial trec levels, but higher initial t cell counts. both cohorts appear to have relatively intact in vitro function. introduction: primary immune deficiency disease (pidd) is typically considered a pediatric illness, although advances in treatment and diagnosis are changing this paradigm. currently, data on pidd in older patients are very limited. objectives: to characterize the prevalence of pidd among older individuals using a patient database maintained by the consortium of independent immunology clinics (ciic), comprised of 17 specialty immunology outpatient practices in the us. methods: patients with pidd were identified in the ciic database using icd-10 codes d80, d.80. 3, d80.4, d80.5, d80.6, d81.1, d81.2, d82.0, d82.3, and d83 .0. a total of 235 records from 11 geographically-diverse clinics were identified and characterized by age, gender, and pidd diagnosis. results: of the 235 pidd patients in the ciic registry, 73 (31%) were between 60-87 years of age (see figure) . within this age group, most patients were female (n=56, 77%). the most common diagnoses among patients >60 years of age included common variable immunodeficiency with predominant abnormalities of b-cell numbers and function (d83.0; n=41, 56%) and antibody deficiency with near normal immunoglobulins (d80. 6; n=14, 19%) . in comparison, the registry included 36 (15%) patients aged 0-19 years; this age group was predominantly male (n=23; 64%). the most common icd-10 codes within the younger cohort were relatively evenly distributed between hereditary hypogammaglobulinemia (d80.0), antibody deficiency with near normal immunoglobulins (d80. 6) , and common variable immunodeficiency with predominant abnormalities of b-cell numbers and function (d83.0). conclusions: our data suggest that pidd in patients over age 60 may be more prevalent than previously reported. additional research is needed to corroborate these findings, further characterize the nature of pidd in this population, and determine whether there are unique diagnostic and treatment considerations within this demographic. introduction/background: increased susceptibility to invasive infections with neisseria has been well documented in patients with deficiency of terminal complement proteins. the molecular attack complex is constructed with complement components c5 to c9. a deficiency in complement c6 has been described previously in both african american and south african populations. complement c6 deficiency is inherited in a co-dominant pattern, with multiple known mutations. we present a case of a 19-year-old, previously healthy male, who presented with invasive n. meningitides infection. he was found to have a novel mutation noted on genetic sequencing of the complement c6 gene. objective: we present the case of a 19-year-old, previously healthy male, who presented with invasive n. meningitides infection. on genetic sequencing, he was found to have three mutations of the complement c6 gene. two of which have been described previously, and a third novel mutation. methods: a 19-year-old male with no known history presented to us with a 3-hour history of emesis. he was found to be febrile, and quickly decompensated, developing septic shock. blood cultures were drawn, and within 12 hours grew n. meningitides. he was treated with broad spectrum antibiotics upon arrival, and subsequently narrowed to ceftriaxone. his hospital course was complicated by disseminated intravascular coagulation, as well as acute tubular necrosis, leading to endstage renal disease for which he is listed for kidney transplant. results: on immunodeficiency evaluation, he was noted to have an undetectable ch50 (<13, reference range 31-60). complement levels returned with c6 of 10.8 (reference range 28-69) and c1r of 41.5% (reference range 61-102%). complement c6 function screen returned at 0% (reference range 40.7-169%). all other complement levels were within normal limits. genetic sequencing showed the patient to be compound heterozygous for two of known four variants which have been reported to recur in african patients with complement c6 deficiency. this included c.821del and c.1879del, which are predicted to result in frameshift and premature protein termination. he was also found to be heterozygous for sequence c1202g>a, which results in amino acid substitution p.arg401lys. this variant is rare, with one large database reporting it in 6 of 276000 alleles, and not in a homozygous state. it has not been reported in a case of c6 complement deficiency previously. conclusions: we present the case of a previously healthy 19-year-old male with invasive meningococcal disease. he is compound heterozygous for two mutations that have been associated with total complement c6 deficiency; however, he was found to have subtotal c6 deficiency. furthermore, he has a third novel mutation of the complement c6 gene. further investigation is warranted on the significance of this finding and impact on relevance to possible kidney transplant. background: measuring the function of the classical pathway of complement activation is useful in several disease states, including complement deficiency, autoimmune conditions such as systemic lupus erythematosus and certain forms of nephritis. the original method for assessing classical pathway activity was the haemolytic ch50 method, but this assay can be time consuming and has reagent stability issues due to the use of sheep red blood cells. there can also be high lab-to-lab variability due to differences in the protocols used. here we report the assay characteristics of an automated, commercial, liposome-based assay to measure ch50 activity. we also compare the results obtained using the traditional haemolytic method with the automated, liposome-based method used on the spaplus turbidimetric analyser. methods: a linearity study was performed based on clsi guideline ep06-a. the linear range of the spaplus ch50 liposome assay was established by analysis of a series of sample dilutions and evaluation of results against pre-defined goals for recovery and %cv. precision was assessed based on clsi guideline ep05-a2 over 21 days. 4 samples with different ch50 activities (23.7-65.1 u/ml) were run in duplicate, with two runs per day using 3 reagent lots and 3 different analysers. interference analysis was performed by spiking haemoglobin, bilirubin, chyle, ascorbic acid or saline (as a control) into samples before measuring the ch50 activity. for the assay comparison study, sera from 125 routine patient samples were used. samples were collected from chulalongkorn hospital, faculty of medicine, chulalongkorn university, thailand. ch50 classical pathway activity was assessed using a haemolytic method and also using the liposome based ch50 assay for use on the spaplus turbidimetric analyser (the binding site ltd., birmingham, uk). c3 protein concentrations were also available for 116 of these samples. results: the liposome ch50 assay gives a linear response over the range 11.8-95.5 u/ml, covering the measuring range of the assay (12.0-95.0 u/ml) at the standard analyser dilution (neat). the within run, between run and between day %cvs were all 5.4%. the total %cv was 6.8% in all 4 samples. minimal interference was observed with the four common interferents tested. a significant correlation was observed between the two ch50 methods (p<0.0001, r=0.66, y=1.1xâ±0.1), with 90.4% agreement between the methods in determining whether patients were above or below the lower limit of the assay normal range. the 12 individuals in disagreement had normal ch50 results using the haemolytic method, and low ch50 values in the liposome assay. of these, c3 values were available for 10/12, and 5 had c3 concentrations below the lower limit of the assay normal range. conclusion: the liposome ch50 assay for use on the spaplus analyser has passed assay development guidelines based on those set out by the clsi for linearity, precision and interference, and there is a strong correlation between this automated assay and the haemolytic ch50 method used here. five additional patients with low c3 concentrations were defined as having a low ch50 using the spaplus liposome method compared to the haemolytic method. (18) submission id#580179 background/aims: rotavirus vaccine is a live viral vaccine that is part of the routine u.s. childhood immunization schedule. live viral vaccines administered to infants of mothers who received biologic medications during pregnancy can potentially cause vaccine-associated disease. infant death from disseminated mycobacterial infection after vaccination with bacille calmette-guerin (bcg) in infants whose mothers received infliximab during pregnancy has been reported. it is currently recommended that infants born to women who received biologic therapy during pregnancy not receive live viral vaccines, however there is a paucity of information regarding adverse events from live viral vaccines. we report two infants, born to mothers receiving infliximab during pregnancy, who tolerated the complete series of rotavirus vaccine. methods: two infants who received rotavirus vaccine and whose mothers received infliximab (monoclonal antibody against tumor necrosis factor alpha which blocks the inflammatory response) during pregnancy were identified and their charts were reviewed. each mothers chart was assessed for timing of the biologic doses during pregnancy and concurrent immunosuppressant therapy. results: the mother of the first infant had crohn's disease and received infliximab every 6 weeks throughout her pregnancy (final infusion at approximately 35 weeks estimated gestational age [ega] ). she did not take additional immunosuppressive drugs throughout her pregnancy. the infant was born at 39 weeks ega. the infant received rotavirus vaccine at 2, 4, and 6 months of age. the infant did not have coexisting medical conditions or recorded hospitalizations during the first year of life. there were no side effects from rotavirus vaccine documented during well child examinations. the childs growth was normal during the first year of life. the mother of the second infant also had crohn's disease and received infliximab infusions every six weeks during pregnancy until 27 weeks ega. additionally, she took mesalamine (anti-inflammatory) daily. the infant was born at 33 weeks ega. the baby had a brief and uncomplicated neonatal intensive care unit stay. she did not have medical conditions diagnosed at the time of birth, or in the first year of life. the child received rotavirus vaccination at 2, 4, and 6 months of chronological age, and the infant did not experience documented adverse reactions. the child presented to the emergency department twice in the first year of life: once for thrush at 10 months of age and once for viral gastroenteritis at 11 months of age. the childs growth curve was unremarkable. conclusions: we report two infants, whose mothers received infliximab during pregnancy, who safely tolerated the 3-dose series of rotavirus vaccination. neither infant in this case series suffered from minor or severe adverse events as a direct consequence of receiving rotavirus vaccine. this suggests that administration of rotavirus vaccine may be safe in infants whose mothers received biologic therapy. introduction: combined immunodeficiencies (cids) can arise from partial loss of function variants in recognized scid genes, which can lead to relative lymphopenia with poorly functioning and oligoclonal t cells. cids have been most commonly associated with variants of the rag genes, but other genes are also implicated. clinical symptoms may be less severe, and the onset generally is delayed, compared to typical scid presentations. case report: a 28-year-old female presented with a history of recurrent and progressively worsening infections involving multiple microorganisms and organs, starting in infancy and requiring frequent hospitalizations. bacterial or viral infections included rhinosinusitis, otitis media, herpetic stomatitis, dental abscesses, pneumonias, pulmonary mycobacterial abscesses, cmv hepatitis, urinary tract infections, dermal abscesses, and groin hidradenitis. fungal and yeast infections included cryptococcal meningitis, oral thrush, dermatophytosis of the face, osteomyelitis of a finger, and onychomycosis. laboratory tests in 2018 showed: mildly low t cell counts (791/ul) with a reversed ratio of cd4/cd8 t cells (0.22); almost absent b cells (2/ul) ; and low nk cell counts (19/ul). cd4+ t cells were mostly of the memory phenotype (87%). t cell development showed low counts of th17 cells. t-cell stimulation tests demonstrated poor proliferation responses (<30%) to concanavalin a, tetanus toxoid, and candida albicans, with near-normal responses to pokeweed (>13%) and pha (>84%). she had low ig levels (iga 72, igm 23, ige <2), except for igg (872mg /ml; due to replacement since early childhood). limited genetic evaluation at age 9 showed a heterozygous variant in the rag1 gene (g.36595918t>c, c.1064t>c, p.met355thr; nm_000448.2). discussion: loss of function variants in rag1 or rag2 genes are known to cause a t-b-nk+ type scid. more than 100 missense variants have been reported for rag1, with disease-associated variants predominantly in zinc binding regions. the rag1 missense variant in our patient also lies within the zinc binding region (amino acids 354-383). the variant is rare (mean allele frequency 0.0001521 in gnomad) and has been identified in at least one other individual with scid (t-, b cell-, nk+). although classified as a variant of unknown significance, occurrence in at least two individuals with deficiencies of t and b cells-within a functionally important rag1 domainsupports an interpretation that the variant may be pathogenic. most patients with cid with rag variants are either homozygous for a poorly functional allele or have one nonunfucitonal and a second, poorly functional allele. we detected only a single potentially pathogenic allele. our patient has decreased nk cells in addition to t and b cell defects. further genetic studies including whole exome sequencing, are planned to identify further variants in rag1 or other relevant genes. rationale: infants with low t cell receptor excision circles (trec) born in queens, nassau, and suffolk counties in new york were referred to northwell health for further evaluation after abnormal newborn screens. the demographic and immune parameters of infants with transient t cell lymphopenia (ttcl) without clearly identified genetic or acquired etiology are described. tcl is considered transient if the lymphopenia resolves by 12 months of age. similar data from the following infants with low lymphocytes (fill) program of the united states immunodeficiency network (usidnet) are presented. methods: a retrospective analysis of two separate patient cohorts with ttcl are described. cohorts include patients referred to a single center, northwell health, in ny from september 2010 to december 2017 and at usidnet using data tracked by fill from june 2011 to july 2018. results: out of 1,234 referrals at northwell, 18 infants with ttcl were identified. infants were predominantly male (61.1%) and non-caucasian (89.9%). out of 71 fill participants, 9 infants with ttcl were identified. infants were predominantly male (55.6%) and non-caucasian (55.6%). initial laboratory parameters for the northwell versus fill cohorts are summarized: a) median trec levels: 54.5 vs. 47.0 trec/l of blood; b) median absolute cd3+ count: 2135 vs. 1166 cells/l; c) median cd4+ count: 1460 vs. 777.0 cells/l; d) median absolute cd8+ count: 524.5 vs. 440.0 cells/l. initial naã¯ve cd4+ t cell information was available for 0 northwell and 5 fill infants (median 52%). mitogen proliferation studies were performed in 10 (55.6%) northwell and 6 (66.7%) fill infants with 90% of these northwell and 50% of these fill infants demonstrating normal proliferation. genetic testing, such as targeted genetic panels or chromosomal microarrays (cma), was performed in 5 northwell and 0 fill infants. no genetic or chromosomal aberrations were identified. whole exome sequencing (wes) was not performed in either cohort. 11 of 18 (61.1%) northwell and 7 of 9 (77.8%) fill infants did not receive the initial rotavirus vaccine. no fill infants were vaccinated but no adverse effects were reported in 5 of 18 (27.8%) northwell infants who received the first rotavirus dose. of these, 3 of 5 (60.0%) had normal mitogen proliferation while 1 (20.0%) had decreased proliferation to phytohemagglutinin. conclusions: identifying biomarkers for ttcl and developing evidencebased guidelines for the diagnosis and management of ttcl are important knowledge gaps. this descriptive study is limited by small sample size and the constraints of registry-based research. although there appear to be differences between these cohorts, our findings suggest that ttcl may disproportionately affect different segments of the population. ttcl infants with normal mitogen proliferation may be able to tolerate rotavirus vaccination. thus, routinely checking proliferation studies in all ttcl infants may help risk stratify these patients and minimize vaccinerelated adverse events. currently, there is insufficient evidence to recommend more extensive genetic testing such as genetic panels, cma, or wes. systematically collecting information about patient characteristics and outcomes, as well as encouraging increased participation in registries such as fill, may help address these shortcomings. background: systemic lupus erythematosus (sle) is a chronic, inflammatory disease that affects multiple organs. the measurement of anti-dsdna antibodies (abs) is a gold standard serological test used in the diagnosis and monitoring of sle, with higher serum levels associated with worse prognosis. however, not all anti-dsdna abs are pathogenic, and some patients have consistently high levels with low disease activity. one mechanism suggested for the pathogenicity of these antibodies is complement activation. here we describe an assay to measure the c1q binding activities of anti-dsdna abs in sle patients. materials & methods: the concentration of anti-dsdna abs was determined using the quantalite dsdna elisa kit (inova) as per the manufacturers instructions. in order to determine the c1q binding capacity of bound abs, samples were added to the pre-coated plate and incubated. bound anti-dsdna ab/c1q complexes were then detected using a biotinylated anti-c1q antibody (570 ng/ml) and streptavidin peroxidase (1 mg/ml). normal reference ranges were developed in serum samples from healthy controls, and upper limits of these normal ranges were used as cut-offs. the dsdna abs and c1q binding capacity of bound abs was then assessed in 49 sle patients, and compared to other markers and the sle disease activity index (sledai) score. results are displayed as absorbance at 450nm (au). results and conclusions: the 95th percentile ranges for anti-dsdna abs (0.068-0.137 au) and c1q binding activities (0.207-0.313 au) were developed from the measurements generated in 17 healthy serum samples. sle patients with an increased anti dsdna ab concentration (>0.137 au) were then separated into those with low (<0.313 au) and high (>0.313 au) c1q binding activities. patients whose dsdna abs had high c1q binding activity were found to have significantly higher sledai scores (mean 6.70 vs 3.19) . serum c1q concentration, serum dsdna abs (measured by another method) and serum c3 and c4 concentrations were not significantly different between the two groups. this assay suggests that dsdna abs from sle patients differ in their ability to bind complement, and that high complement binding activity of these antibodies may be linked to a more active form of disease. x-linked lymphoproliferative (xlp) is a primary immunodeficiency, caused by signaling lymphocyte activation molecule (slam)-associated protein (sap) deficiency. patients with xlp have severe immune dysregulation, usually triggered by ebv infection, leading to fulminant infectious mononucleosis, dysgammaglobulinemia and lymphoproliferation. without hematopoietic stem cell transplant (hsct) fatality is reportedly 100% by age 40. we report the natural history of xlp in a patient, and describe the lessons learned. our patient was healthy and developed normally until 6-years of age, when he developed progressive respiratory symptoms. lung biopsy revealed mature lymphoplasmacytic infiltrate in the alveolar septa, consistent with lymphoid interstitial pneumonia (lip). he received corticosteroids and cyclophosphamide with significant improvement. at age 12, he developed severe infectious mononucleosis (fever, hepatosplenomegaly, lymphadenopathy, lymphocytosis). he had a protracted clinical course, but eventually recovered and seroconverted to a typical convalescent pattern. he subsequently developed hypogammaglobulinemia, and was started on intravenous immunoglobulin (ivig). during the same year, his 10-year-old brother developed lip, and subsequently hemophagocytic lymphohistocytosis (hlh) and died within 4 months from overwhelming candidiasis. unfortunately, his youngest brother (age 7) then developed lip and died 2 months later from a massive gastrointestinal bleed. both siblings were treated with corticosteroids and cyclophosphamide; they did not have detectable ebv infection. at age 13 years, our patient experienced recurrent strokes and was found to have biopsy-proven cns vasculitis. he was treated with interferon-and recovered with residual left sided weakness, but was lost to follow-up. he continued on ivig, with no other immunomodulatory agents for several decades. he had progressive lung disease and recurrent seizures controlled with anti-epileptics. at age 43, he developed sudden vision change, headache and right-sided weakness, followed by a seizure. mri of the brain revealed small bilateral areas of acute infarction suggestive of a central embolic event, however, no primary thrombus was identified. he did not receive any immunosuppression but was anti-coagulated. eventually he was discharged home with resolution of weakness to his baseline. the patient was referred to our clinic after discharge and we re-evaluated him after 31 years. immune profiles at the time showed therapeutic igg troughs, low/undetectable igm/a/e, normal t/b/nk-cell counts, normal spontaneous, but decreased antibody-dependent nk cytotoxicity, 0% sap protein expression (on cd3+cd8+, cd3-cd56+ and cd3+ cd56+ cells), and deletion on the x chromosome encompassing the sh2d1a gene which encodes sap. his mother was a carrier of the same deletion. his functional status excluded the option of hsct. a year later, he had rapid deterioration with recurrent lung infections, liver failure, and thrombocytopenia. bone marrow biopsy revealed hodgkins lymphoma. he declined chemotherapy and died few days after diagnosis. our case represents a rare patient with xlp surviving to the fifth decade without hsct, particularly having experienced mononucleosis and non-ebv related cns vasculitis. our patient survived decades longer than his brothers (who most likely shared the same genetic defect) without evidence of somatic reversion (0% sap expression in cd3+cd8+) to explain his milder clinical phenotype. this case may help in understanding the natural history of xlp, and confirms that prognosis remains poor without hsct. haematology and oncology, chu de quã©bec ctla-4 is a major negative regulator of immune responses, and ctla-4 haploinsufficiency has been identified as a monogenic cause of primary immunodeficiency in patients presenting with a common variable immunodeficiency (cvid) phenotype with autoimmunity. here we present the case of pb, a 40-year-old man who had been followed by the immunology service of our center for 17 years. a diagnosis of cvid had first been made when the patient presented with atypical transverse myelitis, low immunoglobulin levels, and lymphopenia. over the years, his clinical picture was dominated by various forms of autoimmunity, namely inflammatory demyelinating disorder of the central nervous system, autoimmune haemolytic anemia, immune thrombocytopenia, cryptogenic organizing pneumonia, rheumatoidlike polyarthritis, chronic liver transaminitis with biopsy-proven moderate fibrosis, and lymphocytic colitis with malabsorption. immunoglobulin replacement therapy was started at diagnosis, and autoimmunity was sequentially treated with methotrexate, interferon beta 1-a, cyclophosphamide, mycophenolate mofetil, rituximab, and finally a combination of low-dose prednisone and sirolimus, with stabilization of his neurological condition, the most debilitating complication of his immune dysregulation syndrome. bone marrow transplant had been offered, but declined by the patient due to perceived good quality of life compared to transplant-associated risks. the patient was later referred to our hematology ward in july of 2018 for septic shock complicating febrile neutropenia, which was part of a twomonth, gradual-onset pancytopenia. the diagnosis of immune-mediated aplastic anemia soon became apparent, as demonstrated by a bone marrow biopsy performed in a peripheral center two days prior to admission. the underlying pneumonia and thereafter biopsy-induced staphylococcus aureus iliac osteomyelitis and soft-tissue abscess were treated with broad-spectrum antibiotics as well as multiple surgical interventions. the patient was started on eltrombopag, high-dose corticosteroids and cyclosporin a, the latter promptly switched to tacrolimus due to liver enzymes disturbances, all of which resulted in no significant hematologic response despite over seven weeks of treatment (with concurrent treatment of complicating infection, upper gastrointestinal bleeding, and intensive-care-unite myopathy). during that time, genetic confirmation of ctla-4 haploinsufficiency was received, and the patient was thereafter started on abatacept on day 48 of current hospitalization. administration of equine anti-thymocyte was initially foregone because of perceived infectious risk in the setting of poor iliac wound healing and superimposed adenovirus viremia; however, given the lack of response, it was given on days 52 through 54 of hospitalization. haematologic response began on day 67 of hospitalization with a steady rise in alllineage myelopoiesis up to a complete neutrophil response, platelet near-complete response as well as resolution of transfusion needs by day 101. while waiting for a well-matched bone marrow donor, isolated platelet decrease was observed and attributed to multiple factors, including low-grade thrombotic microangiopathy, inflammatory consumption and drug-related thrombocytopenia, but the patient remained well. to our knowledge, our patients presentation is one of the most severe manifestation of ctla-4 haploinsufficiency to have responded to targeted therapy with abatacept, as a bridge to hematopoietic stem cell transplantation, with resolution of both immune and infectious complications, showing that genetic diagnosis is helpful in optimizing the management of presumed cvid patients. hospital 12 de octubre health research institute (i+12), madrid, spain, dept. of immunology, university hospital 12 octubre. madrid. spain background: xlf/cernnunos deficiency is a rare primary immunodeficiency classified within the dna repair defects. these patients present severe growth retardation, microcephaly, lymphopenia and increased cellular sensitivity to ionizing radiation. here, we describe two unrelated cases with the same nonsense mutation in the nhej1 gene showing significant differences in clinical presentation and immunological profile but a similar dna repair defect. methods: missense nhej1 mutation was identified by targeted next-generation sequencing with an in-house designed panel of 192 genes. for foci experiments, primary skin fibroblasts were irradiated with ionizing irradiation (137cs) or treated with 20mm etoposide for 1 hour. after irradiation, the cells were seeded at a density of 1x104 cells/ml in t75 flasks in triplicate. to evaluate cell sensitivity to gamma-ir (1 and 3 gy),adherent cells were trypsinized and counted 11 days later. pbmcs from patient and healthy controls were irradiated with 10gy, fixed and stained for cd3, cd19 and phospho-histone h2ax. mean fluorescence intensities (mfi) of gamma-h2ax were evaluated on gated cd3+ lymphocytes. results:we report two patients harboring the same homozygous mutation in cernunnos/xlf/nhej1 gene. strikingly, their clinical phenotype ranges from severe combined immunodeficiency to isolated thrombocytopenia followed until escolar age (table 1) . they harbour the same c.169c>t mutation in nhej1 gene but different immunologic features (table 2) . p2 presented with mild t lymphopenia, hypersensitivity and nhej repair defect, typical for patients with xlf/nhej1 defects. on the other hand, p1 presented a more severe phenotype (t-b-) , however hypersensitivity and nhej repair defect was similar to p2.of note, p2 has survived into the first decade of live. both patients are alive and well after hsct. discussion: usually the repair defect in these disorders is assessed by immunofluorescence assays of irradiation-induced gamma-h2ax foci using skin fibroblasts. a high throughput, sensitive and reliable assay to quantify gamma-h2ax foci in pbmcs isolated from blood samples would be a valuable tool to diagnose these patients and perform hsct early. flow cytometry (fc) can be applied as a rapid diagnostic tool for dna repair disorders. patients with the same homozygous mutation (p.r178x) in nhej1 gene have been previously reported. two patients died at 1.5 and 4 years while another of the patients is already 8 years old and is alive (without hsct). however,none of these patients presented severe t lymphopenia as it has been observed in our first patient. conclusions: the assignment of a timely and accurate diagnosis is of paramount importance in the management of patients with defects in dna repair. in the era of nbs an abnormal trec assay should be followed by ngs approach as cernunnos deficiency may present early in life as scid,as other rs-scid defects. since genetic diagnosis takes time,functional radiosensitivity assays in peripheral blood may lead to the correct diagnosis and avoid exposure to alkylating agents during the conditioning regimen prior to genetic diagnosis. it would also be helpful in cancer patients to individualize and to guide the dosing of ionizing radiation (ir) and/or genotoxic agents to avoid accumulation of cells with genomic instability that could accelerate cancer development. figure 1 ). her skin lesions also significantly improved after starting the medication ( figure 2 ). her hospitalizations were complicated by fluid overload and hypertension. both fluid overload and hypertension resolved prior to discharge. she remains on 2mg prednisone daily, cetirizine, ranitidine, cromolyn and benadryl and hydroxyzine prn. to our knowledge, this is the youngest patient successfully treated with midostaurin and she is doing very well on therapy with no apparent side effects. she has had resolution of many of her systemic mastocytosis symptoms including skin lesions, axillary mass and improvement in her diarrhea and growth as well as objective improvements in her tryptase levels. case report: a two-year-old male presented to the hospital with a painful, non-pruritic facial and groin rash. the rash started one week prior to presentation. he had no associated fevers. his history was remarkable for failure to thrive (ftt) and chronic bilateral leg pain with antalgic gait. over the preceding months, he had been diagnosed with hand-foot-mouth disease and varicella. he had also had recurrent cervical lymphadenopathy (lad) for greater than one year requiring incision and drainage. gram stain and gomori methenamine-silver nitrate stain (gms) were negative and pathology showed only acute and chronic inflammation with areas of necrosis. his family history was negative for autoimmune disease or immunodeficiency. infectious exposure history was significant for an incarcerated father with unknown tuberculosis status and history of living in a shelter. on physical examination, the patient was well appearing with multiple erythematous papules, with superficial erosions and scabbing on the face (figure 1 ), lower abdomen, genital area, buttocks and proximal lower extremities. he had large, firm, non-tender submandibular lymph nodes. he also had small palpable axillary and inguinal lymph nodes bilaterally. his laboratory workup revealed normal white blood cell and platelet counts, but microcytic anemia, an erythrocyte sedimentation rate of 140 mm/hr, and c-reactive protein of 7.5 mg/dl. full body magnetic resonance imaging (mri) revealed bilateral cervical, supraclavicular, right hilar and inguinal lymphadenopathy and a patchy right upper lobe consolidation with at least one small area of cavitation ( figure 2 ) and an adjacent smaller area of ring enhancement. it also revealed three small nonspecific hypodense foci within the right lobe of the liver and borderline splenomegaly. given these findings, there was concern for granulomatous diseases. the patient underwent a liver biopsy ( figure 3 ) which showed non-specific evidence of necrotizing granulomatous disease. microbiological cultures and stains for bacteria, acid-fast bacilli and fungi were negative. his infectious work-up was negative for hsv, tuberculosis, hiv, syphilis, histoplasmosis, and toxoplasmosis. superficial bacterial cultures from the face and groin grew mixed gram positive and negative organisms, including methicillin-susceptible staphylococcus aureus (mssa). his immunologic workup revealed borderline elevated iga and igg with normal igm, normal t,b, nk-cell counts and pneumococcal and tetanus titers. a dihydrorhodamine (dhr) flow cytometric test was positive, consistent with a diagnosis of chronic granulomatous disease (cgd). genetic testing confirmed x-linked disease. he was treated with acyclovir and ceftriaxone with resolution of his rash. conclusion: we present a case of a two-year-old male with newly diagnosed x-linked cgd. though he had been seen by multiple healthcare providers for recurrent lymphadenopathy over the preceding year, he had no other history of recurrent viral or bacterial infections or significant family history that might implicate a primary immunodeficiency. at time of presentation, he had diffuse rash which could have caused his palpable lymphadenopathy on exam. a high index of suspicion for cgd in the setting of recurrent lad and ftt prompted sending the dhr, which led to the diagnosis. chronic granulomatous disease (cgd) is an inherited primary immunodeficiency (pid) which results in both inflammatory response dysregulation and an increase in susceptibility to certain bacterial and fungal infections. without curative treatment such as a bone marrow transplant, it remains a chronic disease with daily medication management, intermittent treatment and life-long surveillance. in general, chronic disease involves physical, psychological and social effects which can affect the patients quality of life. although some research has been done on how pid affects quality of life, there is little research in the united states about how cgd affects patients quality of life. to examine the effect of cgd on patients quality of life, as a part of a voluntary research protocol examining the natural history of immune deficiencies, we administered the who qol-bref instrument to adult cgd patients enrolled on a nih irb approved protocol and seen in the infectious disease clinic at the national institutes of health (nih) over a five-month period. the who qol-bref is comprised of 26 items, which measure the following broad domains: physical health, psychological health, social relationships and environment. each item is rated on 5point likert scale. it has been validated cross culturally and has been widely field tested. the survey was interview administered to 35 patients (23 males, 12 females) with genetically confirmed cgd. the age range was 18 -60 years old (mean age 37.6 years) with a distribution of 57 % x-linked cgd and 43% autosomal recessive cgd. results have been obtained and will be presented. rationale: common variable immunodeficiency (cvid) is the most common primary immunodeficiency with an estimated prevalence of 1:25,000. we aimed to analyze the clinical presentations and their associated comorbidities amongst cvid patients in usa. methods: data on 1,546 cvid patients reported in the united states immunodeficiency network (usidnet) from 1992 to 2018 were analyzed based on clinical, immunological and genetic factors. univariate analysis with spearman rank coefficients was done to analyze correlations between disease outcomes. observed survival was estimated using the kaplan-meier method. results: among the 1546 patients, 908 (58.7%) were female and 638 (41.3%) were male. median age at diagnosis was 29 years [mean (sd), 30.1 (20.2); range, 0-82; iqr, 12-47] with median age of onset of 14 years (mean (sd), 20. 3 (19.2) ; range, 0-81; iqr, . females showed a longer delay in diagnosis (9.5 vs. 6.6 years, p=0.006). higher body mass index (bmi) linearly correlated with the age of diagnosis (r= 0.46). in survival analysis, a 5-year delay in age at diagnosis increased the risk of death by 7.4% (hr: 1.07, 95% ci: 0.98-1.18, p=0.14). conclusions: our study suggests a longer delay in diagnosis in female subjects and a strong association with diagnosis of cvid in patients with higher bmi. females may have a longer period without symptoms leading to a diagnostic delay. gender-based and disparities-based inquiry into these trends may need additional study. the physical well-being of those with primary immunodeficiency (pi) and the physical maladies of those with pi are well-documented. since the 1950s, advances in identification and treatment of pi has for many led to lives where the physical infections of these groups of diseases are manageable. however, not as well understood are the emotional and mental health aspects of living with pi. as part of a larger survey project the idf 2017 national patient survey, this study aims to quantify any potential mental health issues or challenges faced by adults with pi. our hypothesis-those with pi, suffer from statistically higher rates of depression when compared to the u.s. general population. the 2017 idf national patient survey was a nationally distributed, unincentivized, mail-based survey of 4,500 persons in the idf patient database identified as being either adults with pi or the parent/caretaker of a child with pi. the questionnaire comprised approximately 44 main questions about pi as well as the validated sf-12v2, brief fatigue inventory and the patient health questionnaire-2 (phq-2) instruments. additional questions asked about current use of prescription medications for anxiety, depression, stress and pain. for the purpose of this study, only adult respondents with pi are included as the basis for analysis. the two-item patient health questionnaire (phq-2) meets the criteria for general screening of depression suggested by the u.s. preventive services task force. scored on a scale of 0-6, a score of three or higher is suggested as the cut-point for depressive screening. according to a 2014 ahrq study that utilized meps data, 2,139 of the 23,770 (9%) respondents scored three or greater. in our survey 211 of the 925 (23%) adults scored three or greater (2 <.05.) overall, those in our survey scored lower on the sf-12v2 mcs scale when compared to the u.s. population (44.3 v.50.0, p<.05) . further, adults with pi who scored three or higher on the phq-2 had an average mcs of 31.8. those who met the phq threshold in our survey were also more likely to report moderate to severe limitations in normal activities as a result of emotional problems than those that fell below the threshold (74% versus 13%, p <.05). not surprisingly, those that met the phq threshold reported much higher use of prescription medications for anxiety, depression, stress (69% versus 33% below threshold, p <.05) as well as a higher reported use of prescription pain medications (33% versus 17% below threshold, p <.05). though moderate to severe fatigue was reported by 68% of those below threshold, 99% of those with phq scores at threshold reported experiencing moderate to severe fatigue (p <.05). health care providers should consider including the phq-2 in the overall health assessments of their patients with pi. those scoring three or higher should be referred to the appropriate professional for further evaluation. (lek et al., 2016) . the w623l is a semi-conservative amino acid substitution, which may impact secondary protein structure. in-silico analyses supported a deleterious effect, located within the sh2 domain, which is a critical functional domain (chandesris et al., 2012; koskela et al., 2012) . it was thus determined that this variant is likely pathogenic. the patients prophylactic treatment was optimized with tmp-smx (800mg-160mg) twice daily for prevention of infections. she was also started on hibiclens (chlorhexidine) baths once per week. she was referred to pulmonology for optimization of pulmonary health in the setting of bronchiectasis and mild decline in dlco. she was advised to followup on a yearly basis to the primary immunodeficiency clinic to assess for recurrent infections and for changes in pulmonary health. finally, targeted testing and clinical evaluation of both of the patients parents was recommended to determine if w623l was inherited or arose de novo. the pathogenic role of the w623l missense change would be further supported if it had occurred de novo or if it segregates with the disease in the family. uploaded file(s) uploads pulmonary function testing results.pdf j clin immunol (2019) 39 (suppl 1):s1-s151 s20 introduction: lipopolysaccharide-responsive and beige-like anchor protein (lrba) deficiency is a rare autosomal recessive disease of the immune systems characterized by hypogammaglobulinemia and decreased ctla4 expression on t regulatory cell (t regs) due to defective intracellular trafficking of ctla4. previous in vitro study has shown a significant increase of ctla4 expression on lrba deficient t cells after overnight culture with chloroquine, an older anti-malarial agent. this effect is likely due to increasing lysosomal ph. however, there is no evidence of such effect in human subjects after administration of weight appropriate doses anti-malarial agents. we are presenting a set of siblings with lrba deficiency who had ctla4 expression measured before and four weeks after starting hydroxychloroquine. case reports: case 1 is a 14-year-old east-indian boy with autoimmune thyroiditis, type 1 diabetes mellitus (dm), short stature, autoimmune cytopenias, and lymphadenopathy. he was referred to immunology clinic at 9 years of age for suspicion of autoimmune lymphoproliferative disorder. primary immunodeficiency genetic panel was sent which revealed a homozygous mutation in lrba gene (c.6480_6481del). this novel variant resulted in a frameshift and created a premature stop codon 18 amino acids downstream from this location which may lead to absent or abnormal protein. lung ct scan showed interstitial lung disease. lung biopsy showed interstitial nodular and diffuse lymphoid proliferation. this diagnosis led to the testing of his sister (case 2) given her history of autoimmune illnesses and the family history of consanguinity. case 2 is a now 13-year-old girl with type 1 dm, autoimmune thyroiditis, lymphadenopathy, psoriatic arthritis, and seizures. her lung imaging showed pulmonary nodules without interstitial lung disease. both cases received hydroxychloroquine while waiting for insurance approval of abatacept. ctla4 expression on tregs was measured prior to and four weeks after starting hydroxychloroquine treatment. at baseline, 8.6% of case 1s cd4 cells were treg (foxp3+ve, cd25hi) and 51.4% of them expressed ctla-4 (in contrast to 94.1% tregs in the healthy control) with mean fluorescence intensity (mfi) of 335. this ratio and mfi did not change after 4 weeks of hydroxychloroquine treatment (6 mg/kg/day). soluble interleukin-2 receptor levels were measured: case 1 had a baseline level of 8510 pg/ml, which decreased to 2228 pg/ml after 4 weeks of hydroxychloroquine treatment. for case 2: 8.4% of her cd4+ t cells were found to be foxp3+cd25hi and 36.1% of these tregs expressed ctla-4. this ratio increased by 7% after one month of hydroxychloroquine. increase in mfi was also noted from 298 to 386. case 2 had a drop in soluble interleukin-2 receptor level from 1265 pg/ml to 950pg/ml after treatment. conclusion: in contrast to the previous in vitro assays, we did not find a significant increase in ctla4 expression on t regulatory cells in vivo after 4 weeks of 6mg/kg/day hydroxychloroquine. interestingly, soluble il-2 receptor levels improved dramatically with hydroxychloroquine. (36) submission id#592574 human nf-kappab2 defect results in defective intrinsic b-cell differentiation, function and class switching introduction/background: autosomal dominant heterozygous mutations in nfkb2 (encoding for the protein nf-kb2) have been identified in the etiology of a form of primary immunodeficiency disorder that presents with hypogammaglobulinemia, defects in b-cell maturation, endocrinopathy, and autoimmune manifestations. in humans, the effects of altered nf-kb2 and mechanisms of immune system impairment have not been fully delineated. objectives: to understand the mechanism of the antibody deficiency in patients with hypomorphic mutations in nfkb2 (c.2564dela; p.lys855serfs*7) by evaluating b-lymphocyte proliferation, differentiation, function, and gene expression. methods: immunophenotyping of primary b-cells from subjects with mutant nfkb2 was completed by flow cytometry. proliferation of b-cells was assessed by cfse stimulation of primary cd19+ b-cells from healthy and nfkb2 mutant subjects. differentiation of healthy and affected naã¯ve b-cells (cd27-cd38-) into plasmablasts (cd27+cd38+) following stimulation was assessed by flow cytometry. the supernatant from these cells were assayed for iga, igg and igm production by elisa. to study the defect in class-switch recombination, naã¯ve b-cells and ebvtransformed b-cells from affected and healthy individuals were stimulated and expression of the aicda gene was quantified by qpcr. in parallel experiments, ebv b-cells from wildtype and nfnb2 mutant individuals were stimulated and aid (activationinduced cytidine deaminase) protein levels were determined by western blot. results: patients with hypomorphic mutations in nfkb2 (c.2564dela) had low memory b-cell (cd19+ cd27+ igd-igm+) and class-switched memory b-cell (cd19+ cd27+ igd-igm-) numbers. in vitro, primary bcells from these patients demonstrated a 50% reduction in proliferation and cell division in response to cd40l and il-10 (p =0.01). compared to healthy naã¯ve b-cells, mutant naã¯ve b-cells had a significant reduction in plasmablast differentiation (p = 0.002) and secreted significantly lower levels of immunoglobulins in response to cd40l and il-21 stimulation. mutant naã¯ve b-cells and mutant ebv b-cells failed to increase aicda expression and aid protein levels in response to cd40l and il-21 stimulation. conclusions: our studies demonstrate that a hypomorphic nfkb2 mutation in humans affects intrinsic b-cell proliferation and differentiation. the mutation impairs transcription of the aicda gene that encodes aid, a key protein involved in b-cell class-switch recombination. the nfkb2 gene defect also impairs immunoglobulin production, as seen in common variable immunodeficiency-like cases. these studies provide unique translational insights into physiological activities of nf-kb2 in downstream immunologic outputs in humans, expanding those suggested by experimental observations in mice. background: few studies have evaluated the quality of life (qol) and patient reported outcomes of primary immunodeficiency disease (pidd) patients, and no studies have assessed medical provider perceptions of their pidd patients qol, neurocognition, physical well-being and psychosocial health. understanding provider beliefs regarding patient reported outcomes is essential to improving clinical management of pidds. here we report our pidd medical provider survey results. methods: providers were contacted via email with the assistance of the clinical immunology society. participants completed adult and/or pediatric-based likert scale survey questions via a secure online survey service. in addition to demographic information, survey questions assessed provider perceptions of patients overall qol and their impression of the impact of disease or its associated treatment on mental health, physical well-being, neurocognition, social relationships and school/work performance. clinicians were expected to make their assessments based on their pidd patient cohort as a whole rather than on specific diagnoses or patients. given the small sample size, a p-value < 0.1 was considered statistically significant; repeated measures anova and paired t-test analyses were used. results: study participants (n=58) were primarily from the united states (64%), born between 1965-1979 (44%) , and trained in allergy/ immunology (77%). 85% of survey takers practiced within an academic center, 52% were female and 95% cared for children with 42% of providers concurrently caring for adults. there was a statistically significant difference (p=0.07) in the perceived overall qol of pediatric versus adult pidd patients with 41% of providers feeling as though their pediatric patients had a good qol while only 25% believed their adult patients had a good qol. clinicians believed adult pidd individuals had more difficulties related to associated co-morbidities rather than their actual pidd compared to pediatric pidd patients (p=0.046). providers felt that the neurocognition and school performance of children were more often negatively affected by a pidd than the neurocognition and work performance of immunodeficient adults (p=0.1). clinicians believe children with pidd more frequently had difficulties related to their concentration than memory (p<0.01). 96% of those who care for pidd adults believe their patients work performance or daily mental functioning is at times negatively impacted. anxiety symptoms and social relationships were viewed as being more negatively impacted by a pidd diagnosis or treatment than anger or depressive symptoms in both children and adults (p<0.01). 38% of pediatric clinicians feel their pidd patients experience anxiety symptoms often or almost always. of physical health parameters, energy, rather than mobility or pain, was deemed to be more deleteriously influenced by an immunodeficiency in adult and pediatric patients (p<0.01). conclusions: our results show that medical providers perceive the overall qol of pediatric pidd patients to be superior to that of adults with pidd, but most clinicians feel a diagnosis or associated treatment regimen for pidd can negatively impact the physical well-being, psychosocial health, school/work performance and neurocognition of both children and adults. [cbm] complex is a critical signalling adaptor that regulates lymphocyte activation, proliferation, survival, and metabolism. primary immunodeficiencies affecting each component (termed cbmopathies) result in broad clinical manifestations ranging from severe combined immunodeficiency (scid) to lymphoproliferation. we present the laboratory and clinical findings of two canadian first nations patients found to be homozygous for the same novel card11 mutation (c.2509c>t; p.r837*). results: we have identified an 8-month-old boy who presented with a severe case of entero/rhinovirus bronchiolitis with interstitial lung disease and a 17-year-old boy with a history of severe pulmonary infections (including pjp), chronic sinusitis, candidiasis, invasive bacteremia, and severe ileo-colitis and oral ulceration requiring total colectomy. both patients possessed absent tregs, absent memory b cells, and hypogammaglobulinemia. however, only the 8-month-old had poor t cell proliferation to pha, cona, and cd3. both patients were found to be homozygous for the same novel variant of card11 (c.2509c>t; p.r837*). the mutation rendered card11 protein expression unstable and it was undetectable by immunoblot. to confirm card11 deficiency, we stimulated patient b cells with phorbol 12-myristate 13 acetate (pma) and ionomycin across a time-course and immunoblotted for various signalling proteins in both the nf-b (ikk/, ib, p65) and mapk (mek1/2, mkk4, jnk1/2, erk1/2) pathways as well as various cleavage substrates of the malt1 paracaspase (relb, cyld, bcl10, hoil1). nf-b and jnk activation were completely absent and malt paracapase activity was lost, but surprisingly, mkk4 (which acts upstream of jnk) was intact. furthermore, co-immunoprecipitation experiments revealed that card11 was required for optimal malt1 association with bcl10 in response to stimulation. conclusions: these two cases highlight the crucial role of card11 in regulating lymphocyte development, function, and humoral responses. in addition, we have identified the oldest known living individual with card11 deficiency and he presented uniquely with inflammatory gastrointestinal disease in addition to scid, further adding to the spectrum of phenotypes associated with card11-related primary immunodeficiencies. abstract: the usidnet registry began in 1992 with an niaid contract with the immune deficiency foundation, which continues today. it aims to provide a resource for clinical and lab research through enrollment of known immunodeficiency patients into a national registry, the usidnet. nih is a major national and international referral center for clinical trials on inborn errors of immunity, or primary immunodeficiency diseases. it is a mechanism for depositing nih data into usidnet. a registry of patient information may help us understand how many people have each disease. the information may improve how we diagnose and treat these conditions. the patient registry is designed to obtain longitudinal data on a large number of patients with primary immunodeficiency diseases who come to nih to participate in research. the data is collected from the nih electronic medical record system, cris and is deposited into a secure registry with restricted and monitored access. all medical information is anonymized for patient privacy. department of biochemistry, emory university, atlanta, ga oas1 is an intracellular sensor for dsrna that generates the second messenger 2'-5'-oligoadenylate to activate rnase-l as a means of antiviral defense. we describe four patients with a complex early-onset autoinflammatory and immunodeficiency disease caused by heterozygous de novo oas1 mutations. patients presented early in life with lung inflammation including pulmonary alveolar proteinosis and interstitial lung disease. they had febrile flares with dermatitis specifically with macular, pustule and bullous features often progressing to ulceration. infants had episodes of bloody diarrhea in 3 patients (assoc. with villous blunting and cryptitis in two patients and oesophagitis in one patient). immunoglobulin igm, igg, and iga levels were low while t cell, b cell, and nk cell numbers were generally in the normal range. exome sequencing identified de novo heterozygous oas1 missense mutations in all patients. one patient had a heterozygous de novo oas1 mutation p.ala76val, with mutant oas1 protein being expressed in ex vivo generated t cell blasts. in sorted primary patient monocytes and b cells, oas1 p.ala76val was associated with spontaneous rna degradation and apoptosis as determined by rna chip technology and flow cytometry, respectively, while t cells were not affected. monocytes displayed disturbed terminal differentiation and functioning as indicated by reduced gm-csf-r expression and signaling. b-cells display reduced class-switch-recombination. proliferation of allogeneic t-cells was reduced in response to sorted oas1 mutated monocytes and b-cells. activation of interferon response genes in pbmcs was detected. two further unrelated patients had a heterozygous de novo oas1 mutation p.cys109tyr, which appeared to compromise protein stability in transformed patient fibroblasts and when transfected. cells transfected with this mutant protein had reduced 2-5 oligoadenylate synthesis compared to wild type transfected cells. immortalized fibroblast lines demonstrated higher levels of inflammatory cytokines and spontaneous cleavage of rnas. a 4th patient with the clinical phenotype had a heterozygous de novo oas1 variant p.val121gly, but has yet to have formal validation of the variant. three patients underwent hematopoietic stem cell transplants in an effort to control their diarrhea and skin inflammation. one patient died with ongoing chronic graft versus host disease, while the two others (p.ala76val, cys109tyr) are alive and reasonably well with a followup of 0.5-7 years. the untransplanted patient died as a result of respiratory failure. in summary, patients with de novo heterozygous oas1 mutations have chronic ongoing inflammation of multiple organs. this is at least in part due to spontaneous rna cleavage, apoptosis and production of inflammatory cytokines and type i interferons. this defines a new category of autoinflammatory disorder. introduction: increased susceptibility to infections is the most common complication of chronic granulomatous disease (cgd). hemophagocytic lymphohistiocytosis (hlh) is a severe disorder resulting from hyperinflammation and hypercytokinemia that can lead to multi-organ system dysfunction (1) characterized by certain criteria: fever, splenomegaly, cytopenias, hypofibrinogenemia or hypertriglyceridemia, hyperferritinemia, increased soluble cd25/il-2ra, evidence of hemophagocytosis, or decreased/absent nk cell cytotoxicity (2) . secondary hlh occurs infrequently but often is preceded by smoldering infection in cgd (3, 4, 5) . we present a case of hlh in a 38-day old male, the youngest reported case with cgd. case: a 38-day old male with previously diagnosed x-linked cgd, due to known family history, presented with fevers. initial evaluation was unrevealing including chest x-ray, urinalysis, and blood and csf cultures. he was admitted and treated empirically with cefepime. ct demonstrated multiple multifocal nodules of the lungs and spleen. after lung nodule biopsy was performed, antimicrobial therapy was broadened to iv meropenem, voriconazole, and micafungin. despite this, he continued to have fever and developed new onset tachycardia, respiratory distress, and lactic acidosis. further decompensation with vasoactive refractory shock was treated with vasopressors and stress dose hydrocortisone. additional laboratory evaluation revealed rising liver enzymes (ast 1670u/l, alt 307u/l), cytopenias (hemoglobin 7 g/dl, anc 90/ul, platelets 96,000/ul), and coagulopathy (fibrinogen 93-135mg/dl). splenomegaly was present on abdominal ultrasound. a diagnosis of evolving hlh was considered and dexamethasone was administered. within 24 hours of clinical decompensation, the patient died of multiorgan failure. subsequent blood cultures returned with gram-negative rods (and ultimately burkholderia cepacia). autopsy confirmed hemophagocytosis within the bone marrow. no mutations were found in genes associated with primary hlh. discussion: patients with cgd are susceptible to infectious complications and auto-inflammation most commonly involving the lungs, gi, and gu systems (6, 7) . patients with cgd can be at increased risk of hyperinflammatory syndromes secondary to infections and chronic inflammation. as shown in the included case, hlh can present in infancy and can be deadly. early consideration and directed treatment of hlh is imperative, even in the setting of sepsis malignant proliferation of gamma-delta t cells include hepatosplenic t-cell lymphoma (hstl), primary cutaneous t-cell lymphoma and t-cell large granular lymphocytic leukemia (t-lgl). the former two have often been associated with splenomegaly and cytopenias. however, reactive proliferation of gamma-delta t cells in spleen mimicking malignancy has only been reported once and has a significant risk of misdiagnosis. a 30-year-old female presented with two years of unintentional weight loss, persistent leukopenia and thrombocytopenia, with leucocytes around 1-2 x 10^9/l and platelets around 100 x 10^9/ l. she also had associated macrocytic anemia (hemoglobin=10-11g/dl) with laboratory evidence of dat (direct anti-globin test) negative hemolysis. physical examination and computed tomography (ct) imaging showed splenomegaly. there was no hepatomegaly or lymphadenopathy. serum liver function test, auto-immune studies, hemolysis and hereditary diseases workup, viral and bacterial serologies were all normal or negative, except for mild hyperbilirubinemia and ldh elevation. bone marrow examination performed four months prior to the splenectomy revealed mildly hypocellular marrow (50%) with trilineage hematopoiesis. flow cytometric analysis and cytogenetics of the bone marrow aspirate and peripheral blood were normal except for small population of large granular lymphocyte and mild low absolute b cell counts in peripheral blood. a laparoscopic splenectomy was performed for diagnostic and therapeutic purposes due to patients worsening luq pain. there was no other treatment given prior to surgery. 24 hours postsplenectomy her leucocytes increased to 13.1 and platelets to 247. her three-month post-splenectomy wbc count and platelet count was 8.9 and 391, respectively. hemoglobin also improved to 14.9. pathology showed red pulp expansion by small lymphocytes (fig. 1 ) and subsequent ihc (immunohistochemistry) was positive for cd3 ( fig. 2) , cd2, cd7, tia-1 and negative for cd8, cd5 and cd56. cd4 was difficult to interpret. eber was negative. flow cytometry ( fig. 3) showed increased gamma-delta t-cell population (20%) with positive cd3, cd2 and cd 7 and negative cd 5, cd4 and cd 8. molecular studies by pcr didnt reveal any t-cell receptor gamma or beta gene rearrangement. cytogenetics was negative for isochromosome 7q or any other abnormalities. she was symptom free at 6 months from her splenectomy. the morphology and immuno-phenotype of these gamma-delta t cells show significant overlap with the malignant cells seen in hstl and t-lgl, such as loss or downregulation of cd5, cd4 and cd8. awareness of this reactive condition is necessary to prevent making a wrong diagnosis of a malignant disease with a potentially benign, spontaneously resolving disease. additional studies of similar cases is needed in order to establish more definitive criterion to separate benign from malignant processes and delineate the role of gamma-delta t cells. uploaded file(s) uploads fig 3. flow cytomtery.pptx background: sex steroids in the human thymic environment influence aire expression as well as interactions with its partners, i.e. genes coding for aire interactors. here we investigated the effects of sex steroids on these interactions during minipuberty the surge of sex hormones that occur along the first six months of life -and up to 18 months of life. we employed a network-based approach for investigating aire-interactors gene-gene relationships and how abundantly co-expressed thymic mirnas covariate with those genes. aire-interactors networks allowed the measuring of gender-related differences in gene-gene expression correlation disclosing relevant differences between minipuberty groups. methods: total rna was extracted from thymic surgical explants obtained from male (m) and female (f) infants -aged 0-6 months (groups mm and mf, for minipuberty) and 7-18 months (group nm and nf, for nonpuberty) and used in dna microarray assays. gene coexpression network (gcn) analyses were performed for aire and its interactors and for mirna-gene coexpression analysis. the set of genes coding for the aire-targeted proteins was previously identified in tecs by abramson et al. (cell 140:123-35, 2010) . aire-interactors networks were obtained for all groups (link strength cut-off for gene-gene > |0.80| and for mirnagene < -0.80). aire expression in mtecs was quantified by immunohistochemistry. these methodologies are described in moreira-filho et al. (sci rep 8:13169, 2018) . results: the mm x mf networks comparison showed that 16 abundantly expressed mirnas are interacting with the different aire interactor genes in both networks. it is interesting to note that network topology were more similar between nm and nf groups, although aire interacts with only one distinct mirna in each network (mir-150-5p in the nm group or mir-7977 in the nf group). conversely, in the non-puberty networks the sets of mirnas and their interacting genes are distinct for each network. immunohistochemistry analysis revealed a higher percentage of mtec aire positive cells in the minipuberty groups: i.e. there is a significant difference between mm x nm (p = 0.0006) and between mf x nf (p = 0.0060). conclusions minipuberty and genomic mechanisms shape thymic sexual dimorphism along the first 6 months of life. this process does not involve changes in aire expression between genders, but differences in the interactions of aire with its partners that persist throughout the non-puberty period, probably regulated by mirnas and also by genetic and epigenetic factors. introduction: neutrophils are presumed to defend against aspergillus species by releasing reactive oxygen species (ros) and neutrophil extracellular traps (nets) to degrade fungal hyphae. triazole antifungals synergistically enhance neutrophil mediated hyphal degradation. patients with cgd are particularly susceptible to aspergillus species likely due to their inability to create ros and nets, and in severe cases may not be amenable to antifungal therapy alone. objective: we present a case of severe disseminated aspergillosis in a patient with cgd in whom gt served as an important adjunct to antifungal therapy and bridge to transplant. results: a 6-year-old boy with known cgd, lost to follow up and nonadherent to prophylaxis, presented acutely with right-sided hemiparesis. neuroimaging revealed an embolic left middle cerebral artery infarction and cardiac magnetic resonance imaging showed extensive vegetations involving both right and left ventricles and atria, with an ejection fraction of 28%. the patient was admitted to intensive care, started on liposomal amphotericin b, meropenem and vancomycin, and underwent debulking of the intracardiac masses on post admission day (pad) 1. operative findings showed severe constrictive pericarditis with multiple abscesses and intracardiac vegetations. thorough debridement of the vegetations was undertaken, however some deep seated abscesses in the myocardium were not amenable. operative cultures were positive for aspergillus fumigatus. clinical status remained precarious, with ongoing requirement for inotropic and ventilator support. antimicrobial therapy was refined to voriconazole, with amphotericin b remaining on board until therapeutic levels of voriconazole were achieved. as effective neutrophils are integral in the immune response against aspergillus, the decision was made to start granulocyte transfusions to aid in clinical stabilization prior to hsct. interferon gamma infusions were not administered because of the risks of adverse effects and potentially increasing transplant rejection. gts were started on pad 6, at a dose of approximately 1x10^10 granulocytes, three times a week. the patient tolerated the infusions well, with no allergic or inflammatory response. neutrophil oxidative burst measured one hour post infusion showed 23.9% mean fluorescent intensity, compared to a baseline of 0% ( figure 1 ). clinical improvement was seen, with inotrope cessation on pad 12 and extubation to bipap on pad 41. human leukocyte antigen (hla) allosensitizaton was tested on pad 12, 6 days after the first gt, with no evidence of hla antibodies. a total of 28 gts were given over 3 months, prior to proceeding to a 10/10 hla matched related donor transplant (pad 69), with two transfusions given before neutrophil engraftment (anc 500) on day +14. the patient is now stable 13 months post transplant, with no evidence of graft rejection. he remains on chronic suppressive antifungal therapy, to continue until full lymphoid reconstitution. conclusion: gt may be a useful adjunct to antifungal therapy in patients with impaired neutrophil function with severe invasive aspergillosis, and potentially provide a life sustaining bridge to hsct. methods: subjects were enrolled in irb protocol 00051692 for rvt-802. rvt-802 was implanted into the quadriceps with immunosuppression. results: subject 1 was normal at 22q11.2 but had hypocalcemia, an asd, pda, and abnormal ears. the subject received a cord blood transplant mismatched at hla-b and hla-c alleles at age 3 months. subsequently mild graft-versus-host disease (gvhd) developed and was treated with antithymocyte globulin, steroids and cyclosporine. donor t cells developed in low numbers. twelve years later, the subject developed epstein barr virus lymphoma and suffered two relapses. while in remission, subject 1 received unmatched rvt-802. two weeks after rvt-802 implantation, the subject developed an adenovirus infection resulting in skin and gut gvhd, presumably from activation of the cord blood t cells. subject 1 was treated with corticosteroids, cyclosporine, cidofovir and infliximab. four years post rvt-802, subject 1 is healthy with 609 genetically recipient t cells/mm3 and 40% naã¯ve cd4 t cells. subject 2 was normal at 22q11.2 but had an asd, pda, hypoparathyroidism, and no t cells at birth. his genetic defect is unknown. subject 2 was treated with a ric myeloablative, allogenic, unrelated, 10/10 cord blood transplant, and a subsequent myeloablative, unrelated 9/10 cord blood transplant. hematopoietic chimerism was established without t cell development. rvt-802 expressed the one allele in the recipient that was not expressed by the second cord donor. the post-thymic transplant course included immune thrombocytopenia requiring rituximab and splenectomy and generalized adenopathy for 3 years but no gvhd. he failed weaning of immunoglobulin replacement. three years post rvt-802, he has 930 cd3, 750 cd4, and 105 cd8 t cells/mm3. he is active in school. subject 3 had absent trecs on newborn screening with 7 cd3+ t cells/ mm.3 a single mutation in foxn1 was identified; she has sparse scalp hair. subject 3 received a 9/10 matched unrelated umbilical cord transplant. the post-transplant course was complicated by significant morbidity, and no naã¯ve t cell development. rvt-802 expressed the one allele in the recipient that was not in the cord blood donor. the subject did not develop gvhd, is healthy and at 9 months has 98 naã¯ve cd4+ t cells. she had resolution of longstanding norovirus and sapovirus gastroenteritis. conclusion: rvt-802 can improve t cell immunity after poor or failed correction with allogeneic hematopoietic transplants. in subject 1, gvhd post rvt-802 was related to an acute viral infection; cord t cells attacked hla mismatches in the recipient. subjects 2 and 3 were given rvt-802 matched to recipient alleles that were not expressed in the hematopoietic donor. we hypothesize that thymocytes developing in rvt-802, if strongly reactive to the recipient-mismatched allele, are deleted by the bonemarrow-donor dendritic cells (that acquire recipient mhc from the recipient-allele-matched thymic epithelial cells) thereby preventing gvhd. rationale: ctla4 haploinsufficiency is an autosomal dominant immune dysregulation syndrome characterized by variable phenotypes. here we present a young woman diagnosed with evans syndrome and lymphoproliferation as a child, found to have a novel ctla4 variant as a young adult, and who developed hypogammaglobulinemia and a bacterial endocarditis while stabilized on ctla-4 replacement therapy. methods: sequencing of 207 genes, including ctla4, in primary immunodeficiency panel. results: our patient was diagnosed with evans syndrome at age 2 with manifestations of anemia and thrombocytopenia recalcitrant to treatment over many years with steroids, cyclosporine, and vincristine. bone marrow biopsy reportedly showed normal trilineage maturation and her symptoms responded for a short time to splenectomy at age 14. symptoms recurred at age 16 when she was also found to have pulmonary reticular opacities, prominent lymph nodes, and elevated b cells. repeat bone marrow and lymph node biopsies at that time were unrevealing. minor responses to treatment with ivig, rituximab, mycophenolate mofetil and gcsf were noted. at age 17, she developed varicella-related encephalitis shortly after vaccination. with a strong suspicion of an immune dysregulation syndrome, immune evaluation revealed normal immunoglobulins with good vaccine responses, elevated b cell numbers, normal t cell numbers, and normal mitogen proliferation. ctla4 sequencing revealed a mutation in exon 2 [c.420c>a, p.tyr140*] causing a premature translational stop signal, which was consistent with previously reported cases of ctla4 haploinsufficiency. she was started on rapamycin initially for her cytopenias but was then transitioned successfully to abatacept with almost complete resolution of her anemia, neutropenia, and pulmonary opacities. after 6 months of stable control, she developed a precipitous drop in her platelets and was eventually diagnosed with streptococcus viridans endocarditis of her native mitral valve. this responded to antimicrobial therapy, but eventually needed surgical intervention due to ongoing insufficiency. around this time, she was also found to be newly hypogammaglobulinemic, necessitating ongoing igg supplementation therapy. during successful replacement of her mitral valve with a biosynthetic prosthesis, it was noted that her aortic valve also had evidence of previous disease, implicating a prior endocarditis as part of her clinical syndrome as well. conclusions: in this patient, the presentation of recalcitrant cytopenias, lymphadenopathy, elevated b cells, vaccine-induced viral infections and lung findings precipitated concern for immune dysregulation syndromes and allowed for identification of a novel deleterious ctla4 mutation. in addition to previously reported clinical findings, our patient presents with the first reported case of repeated endocarditis in the setting of ctla4 insufficiency disease. given the finding in this patient of prior (unrecognized) disease, regularly screening patients with ctla4 insufficiency for evidence of cardiac affectation may be prudent. clinical research nurse, johns hopkins university background: the relationship between elevated serum alpha fetoprotein (afp) concentration and age, mortality, genotype and neurologic outcome in ataxia telangiectasia (a-t) patients has remained inconclusive over the past decades, leaving afp as a useful marker for disease diagnosis without further clinical significance. objective: to examine the relationship between afp levels and age, mortality, genotype and neurologic outcome using a data set larger than any prior study. methods: we retrospectively collected data on 280 a-t patients at johns hopkins medical center (0-34 years of age) with both classical (predicted protein null) and variant a-t. this included 459 serum afp measurements (179 serial levels in 50 a-t patients, max observations 9 per patient). mixed model compound symmetry covariance was used for statistical analysis to examine the effect of age at visit on afp levels. subgroup analysis by mutation type, mortality, feeding/swallowing scores as a surrogate for neurologic function, x-ray induced in vitro chromosomal breakage and serum transaminase levels were similarly analyzed. results: significant association between age and afp level was found such that for every 1 year increase in age, afp level increases 20 ng/ml (p<0.0001). subgroup analysis by mutation type found that the 12 patients with missense mutations showed a negative linear relationship be-tween log afp levels and age (r= -0.10, p=0.03). we found greater afp levels in patients who subsequently died, after controlling for age (least square mean afp level in log scale 0.67 greater in deceased patients versus living patients, p=0.002). we found a significant decline in feeding score by 0.18 units (score range 0-5) per 100 ng/ml afp increase (p=0.05) after adjusting for age. there was no significant relationship between afp levels and serum transaminase levels. conclusion: afp increases with age in a-t patients, though this may not apply to patients with missense mutations. there is a statistically significant increase in mortality and worsened swallowing scores with increasing afp levels, but this remains to be proven clinically significant. here we present a pediatric hae patient who had recurrent abdominal attacks in which constipation, secondary to the adhd medication dexmethylphenidate (focalin), appears to be a trigger. of importance, this is the first pediatric patient with hae to be described as having safely undergone a capsule endoscopy for direct visualization of the gastrointestinal tract. this was done to decrease the risks associated with the more invasive procedure of traditional endoscopy and colonoscopy. case presentation: the patient was an 8-year-old male with hereditary angioedema who presented with 1 day history of diffuse abdominal pain and nausea. in the ed, patient was in no acute distress. abdominal ultrasound showed severe circumferential thickening of the wall of multiple bowel loops and a large amount of simple ascites. x-ray revealed stool in the colon. he was admitted for pain control and hydration. in the next year, he visited the ed five more times for exacerbations of angioedema of his hand, penis, and bowel. each time, he presented he had underlying abdominal pain and constipation. he was seen by gastroenterology and had a workup that was negative for helicobacter pylori, parasites, and other gastrointestinal infections. to further evaluate his abdominal pain, capsule endoscopy was performed and well tolerated. during an admission in january 2016 he received a full inpatient bowel cleanout, after which, his angioedema finally improved. of note, he was diagnosed with adhd and started on dexmethylphenidate (focalin) just prior to this period of recurrent angioedema attacks, and he did not have attacks during the summer months when he was off the medication. discussion: abdominal pain is a common complaint in pediatric hospitals, and further workup consists of endoscopy and colonoscopy. this may be easily accomplished in the general population, however, in patients with hae, these procedures carry greater risk and may be avoided, leading to delayed diagnosis and treatment (2, 4) . a newer and less commonly used alternative for direct visualization of the gastrointestinal tract is capsule endoscopy. some benefits are that it does not require sedation, is less invasive, and is less likely to be irritating to the mucosa (3). additionally, since psychological stress may be a trigger for angioedema attacks, the decreased stress associated with a noninvasive procedure such as capsule endoscopy, makes it safer to use (1) . limitations of capsule endoscopy include dependence on battery life and its inability to biopsy or administer therapy if needed (3) . hereditary angioedema treatment consists primarily of avoiding triggers and managing acute episodes. in this first case of hae in a pediatric patient where capsule endoscopy was used, the procedure was well tolerated without any complications. recognizing constipation as a trigger and capsule endoscopy as a safe method of direct visualization of the gastrointestinal tract will help others to control and decrease the severity of their hae attacks as well. a 45 year old male with past medical history of common variable immune deficiency (cvid) and related autoimmune complications, including granulomatous-lymphocytic interstitial lung disease (glild), hepatosplenomegaly, leukopenia, and thrombocytopenia tolerated monthly subcutaneous immunoglobulin replacement as outpatient for several years with infrequent infectious complications. four months ago, he was found to have elevated liver enzymes on routine chemistry. a liver biopsy two months later showed pathology consistent with nodular regenerative hyperplasia (nrh) without overt cirrhosis. a hepatic venous pressure gradient (hvpg) of 21 mmhg was found, consistent with portal hypertension. his hepatitis viral markers were negative, he did not drink, and portal venogram was negative for thrombosis. in early october, the patient was admitted to the hospital with anasarca and tense ascites. he underwent a diagnostic and therapeutic large volume paracentesis and was also found to have spontaneous bacterial peritonitis (sbp) and bacteremia with group b streptococcus. the patients course was complicated by polymicrobial peritonitis, vre bacteremia, fungemia, variceal hemorrhage, hepatic encephalopathy, and hepatorenal syndrome. his hepatic complications from portal hypertension were out of proportion to his liver parenchymal disease. transjugular intrahepatic portosystemic shunt (tips) was considered to alleviate portal hypertension but was not feasible due to his degree of encephalopathy. immunosuppressants such as high dose steroids were given while in the hospital with plans to start rituximab to treat patients glild after he had recovered from the acute infections. unfortunately, after two months in the hospital, the patient succumbed to sepsis and progressive liver failure. this case emphasizes the importance of systematic screening and continued vigilance for hepatic complications in patients of cvid as studies have shown that nrh of the liver is present in more than 80% of cvid patients who undergo a liver biopsy (pmid: 23219764). a cross-sectional study of patients with primary hypogammaglobulinemia and hepatic dysfunction found that histological findings of nrh were present in 84% of cvid patients and was associated with portal hypertension in 75% of cases (pmid: 17998147). another study estimated the minimal prevalence of nrh in cvid patients as 12% (pmid: 18647320), stating that this was likely a gross underestimate as nrh may also be present in patients with normal liver function tests that are not routinely biopsied. therefore, liver enzyme levels may not anticipate the severity of liver involvement. there is currently no treatment for cvid-related liver disease. other causes of non-cirrhotic portal hypertension, including hepatic veno-occlusive disease and budd-chiari syndrome should be ruled out or treated in cvid patients presenting with hepatic disease. in the case of hepatic nrh in cvid patients, early detection could lead to earlier interventions (such as tips prior to hepatic encephalopathy), to mitigate complications. we describe the application of epigenetic quantification of t regulatory (treg) cells in addition to cd3+, cd4+, cd8+ t cells, b cells, nk cells, monocytes and neutrophils from as little as 50 î¼l of fresh, frozen or dried blood. the method yields identical results to flow cytometry from fresh blood samples of a healthy donor cohort, with the advantage of being more sensitive and precise with limited amount of blood and minimal sample preparation (sci transl med 2018). we have used this method 1) to immunophenotype patients with early onset immune regulatory disorders (pird) and primary immune deficiency (pid), and 2) to evaluate cell subsets reconstitution early after hematopoietic stem cell transplantation (hsct). patients with immune dysregulation, polyendocrinopathy, enteropathy, x-linked (ipex) and ipex-like pird were evaluated by analyzing the treg-specific demethylated region (tsdr) of the foxp3 locus in the total of cd3+ t-cells. despite the dysfunctional foxp3 mutated protein, ipex patients exhibited elevated treg/cd3+ cell ratios which seemed to correlate with disease severity. in contrast, most of the patients with ipex-like symptoms without foxp3 mutations exhibited decreased treg/cd3+ cell ratios -in line with the possible central pathogenic role of treg function and number in pird. using epigenetic quantification of cd3+/b-and nk cells, 23 out of 24 confirmed scid and xla cases were correctly identified within a cohort of 250 newborn dried blood spot (dbs) samples (96% sensitivity, 100% specificity). the method identified one delayed onset scid as well as a xla case that were missed by combined trec/krec testing. epigenetic immune cell quantification missed one scid case with maternal engraftment that was identified by combined trec/krec testing. abnormally elevated treg/cd3+ ratio was also detected in a dbs from a newborn who was subsequently confirmed to be affected with ipex syndrome. when applied to serial blood samples during engraftment and reconstitution post-hsct, the epigenetic method allowed identification of the different blood cell subsets, including treg cells, at earlier time points than flow cytometry according to current clinical practice. this opens the way to a better understanding of the correlation between early immune reconstitution events and graft vs. host disease or viral reactivation, earlier than with the current methods, in different types of hsct. these studies underscore the suitability of epigenetic immune cell quantification for accurately measuring multiple immune cell types from limited blood sample sources. we propose this method as uniquely suitable for novel molecular diagnostic applications in settings with limited fresh blood sample or limited cell number, at the point of care as well as for newborn screening. we evaluated a 5-year-old male with hyperpyrexia, hypertrichosis, conical hypodontia, and a history of illnesses concerning for nemodeficiency syndrome. starting at six months of age, he suffered recurrent episodes of acute otitis media (non-typeable hib and actinobacter iwolffli), pneumonia, and rsv bronchiolitis. whole exome sequencing demonstrated a de novo heterozygous c.1259g>a (p.r420q) mutation in the eda-receptor (edar) gene not present in the parental dna. his physical exam findings and mutation were consistent with hypohidrotic ectodermal dysplasia (hed), a rare genetic condition characterized by abnormal development of skin, teeth, hair, and sweat glands. hed is caused by defects in the ectodysplasin-a (eda)-nfkb signaling pathway but is not typically associated with immune deficiency. consistent with this, immunophenotyping showed normal sub-populations of t-, b-, and nk-cells. immunoglobulin and complement levels were quantitatively appropriate. he had normal mitogen-induced lymphocyte proliferation and normal antibody response to pneumococcal vaccination. nk-cell studies demonstrated robust cytotoxicity. however, nasal mucosa biopsy showed diffuse squamous metaplasia and the absence of ciliated epithelial cells. we hypothesize that recurrent infections in our patient arose from impaired mucociliary clearance due to a ciliary defect. this case raises the possible association between edar variants and ciliary dysfunction. it also underscores the importance of evaluating the immune status of hed patients with recurrent infections which could mimic nemo-deficiency and have broad implications about clinical management. the rapid pace of new gene discovery and phenotype expansion for primary immunodeficiency diseases (pidds) creates challenges for genetic testing and variant interpretation. whereas well-described clinical case reports in published literature have traditionally served as the source of phenotypic data used for variant interpretation, for pidds the causal variants are often private to the patients family and thus the sole source of phenotypic information for a novel genetic variant is frequently the history provided by the clinician on the test requisition form. taking into account such heterogeneous information during variant interpretation requires establishing objective criteria for its inclusion as part of the variant interpretation process. to this end, we adapted our laboratorys preexisting, evidence-based variant classification framework, called sherloc, by developing point-based criteria for the inclusion of clinical information such as a patients phenotype, familial segregation patterns, and whether the variant is inherited or de novo in the patient. as part of this process, we defined clinical criteria for 154 pidd genes. here, we illustrate the application of this method and the importance of integrating clinical information into variant interpretation. between april 2017 and october 2018, our commercial diagnostic laboratory performed 4057 immunological genetic tests, and information about the patients clinical history was provided in 2849 (70%) of these orders. restricting our analysis to just the 154 genes for which case report information is currently used in variant interpretation, these tests revealed 3868 variants, 370 (10%) of which were classified as pathogenic or likely pathogenic (p/lp). information from case report descriptions, segregation patterns, and de novo status were applied for 32%,15% and 4% of p/lp variants, respectively. in 37 (10%) cases, the clinical information provided by the clinician on the test requisition form was used as evidence in the classification of the patients variant as p/lp. ten variants were initially classified as being of uncertain significance and reclassified following receipt of further clinical information or testing of additional relatives. in addition, 35 suspicious variants of uncertain significance were identified in which one or two additional patient case reports would allow for reclassification from uncertain significance to p/lp. these data illustrate the importance of providing good quality clinical information to the genetic testing laboratory both at the time of sample submission and following the receipt of genetic test results. background: cartilage-hair hypoplasia (chh) is a skeletal dysplasia with combined immunodeficiency, variable clinical course and increased risk of malignancy, mostly non-hodgkin lymphoma and basal cell carcinoma. there is a paucity of long-term follow-up data, as well as knowledge on prognostic factors in chh. objective: we conducted a prospective cohort study in finnish patients with chh to describe clinical course and analyze risk factors for adverse outcomes. methods: we recruited 80 finnish patients with chh in 1985-1991 and performed clinical follow-up in 2011-2015. we obtained health information from finnish national medical databases (covering time period of 1969-2016), the finnish cancer registry and the cause-of-death registry of the statistics finland and analyzed all patients' health records. standardized mortality ratios (smrs) were calculated based on the population data. primary outcomes included immunodeficiencyrelated death (from infections, respiratory diseases or malignancies), the development of lymphoma and the development of skin cancer. results: the study cohort included 35 males and 45 females. median age at recruitment was 14.6 yrs (range 2 weeks -49.6 yrs) and median duration of follow-up for the surviving patients was 29.2 yrs (range 25.6 -31.0 yrs). half of the patients (46/80, 57%) had no symptoms of immunodeficiency, while 15 (19%) and 19 (24%) patients manifested symptoms of humoral or combined immunodeficiency respectively, including six cases of late-onset immunodeficiency. in a significant proportion of patients (17/79, 22%), clinical features of immunodeficiency progressed over time. of the 15 patients with non-skin cancer, eight had no preceding symptoms of immunodeficiency. altogether 20 patients had deceased (smr=7.0, 95% confidence interval (ci)=4. [3] [4] [5] [6] [7] [8] [9] [10] [11] including deaths due to pneumonia (n=4), malignancy (n=7, smr=10, 95%ci=4.1-21) and lung disease (n=4, smr=46, 95%ci=9. . malignancy was diagnosed in 21/80 (31%) patients, mostly lymphoma (n=9) and skin cancer (n=15). severe short stature at birth (compared to normal, smr/smr ratio=5. 4, , symptoms of combined immunodeficiency (compared to asymptomatic, smr=19 (95%ci=8.0-36) vs smr=4.8 (95%ci=2. 3-8.9 ), hirschsprung disease (odds ratio (or) 7.2, 95%ci=1.04-55), pneumonia in the first year of life or recurrently in adulthood (or=7. 6/19, , and autoimmunity (or=39, 95%ci=3.5-430) in adulthood associated with early mortality. in addition, recurrent pneumonia in childhood was associated with the development of lymphoma, while warts and actinic keratosis were associated with the development of skin cancer. birth length standard deviation score correlated significantly with the age at the diagnosis of first malignancy (p=0.0029), lymphoma (p=0.011) and skin cancer (p=0.014), demonstrating that patients with shorter birth length developed malignancies at an earlier age. conclusions: patients with chh have high mortality due to infections and malignancies, but also from lung disease. some subjects present with late-onset immunodeficiency or malignancy without preceding symptoms of immune defect, warranting careful follow-up and screening for cancer even in asymptomatic patients. we provide clinicians with the risk factors for adverse outcomes to assist in management decisions. autoimmune lymphoproliferative syndromes (alps and related disorders) are characterized by insufficient apoptosis due to defects in the fas apoptosis pathway. fadd deficiency (omim 602457) is an autosomal recessive disorder resulting from a mutation in fas-associated protein with death domain (fadd), the adaptor protein involved in fas signaling to caspases 8 and 10. we present a case of fadd deficiency identified by whole exome sequencing with a novel genetic mutation we describe two brothers with recurrent febrile episodes accompanied by seizures and respiratory compromise. the older sibling initially presented with status epilepticus following the measles mumps rubella vaccination later experiencing similar episodes until his demise at 18 months of age. the younger sibling, who is unvaccinated, presented at 14 months with fever, rash, vomiting, and diarrhea. he developed status epilepticus with respiratory depression that required intubation. he also had enlarged cervical lymph nodes that regressed with antibiotics and steroids. he recovered from that episode but subsequently had a series of similar illnesses with fevers, altered mental status and seizures. with the exception of elevated hhv6 igg, extensive infectious workup up in all instances was negative. previously described fadd deficiency patients demonstrate an alps like phenotype with increased circulating double negative t cells, lymphocyte apoptosis defects, elevated fas ligand and il10, encephalopathy, functional asplenism but no splenomegaly or lymphadenopathy. our patients clinical and laboratory findings were similar. he had normal igg and iga, decreased igm, and lack of isohemagglutinins. absolute cd3+ count is elevated, with elevated percent of cd3+ tcr+ cd4-cd8-. normal mitogen and antigen t lymphocyte stimulation, but with defect in pokeweed induced b cell proliferation. fas ligand and il10 level are increased (see table 1 ). no hepatosplenomegaly, but howell jolly bodies were detected in peripheral blood indicating functional hyposplenism. whole-exome sequencing revealed two different genetic alterations in the fadd gene: a maternally inherited nonsense mutation predicted to severely truncate the protein and a paternally inherited missense mutation in codon 105. although this paternal mutation has not been described as pathogenic, a different variant in same nucleotide of fadd has been associated with fadd deficiency (reference1). there are very few cases in the literature of fadd deficiency patients and the overall prognosis is poor compared to classical alps patients, as these patients are at significant risk of deadly sepsis from encapsulated organisms or death from neurologic complications. of the fadd deficiency patients described in the literature, several died prior to 5 years old. while pneumococcal prophylaxis may reduce the risk of sepsis, hematopoietic stem cell transplant has been reported for patients with fadd deficiency (reference2), and is being considered for our patient. rationale: hcuvp is a patient product-introduction program that provides cuvitruâ® (immune globulin subcutaneous [human], 20% solution [ig20gly]) free of charge for the first 4 infusions to eligible patients with primary immunodeficiency disease (pid). using patient data from this ongoing program, our analysis described the clinical characteristics and infusion parameters of pediatric and adolescent patients who were initiated on ig20gly through hcuvp. methods: hcuvp eligibility criteria were: patients aged 2 years old, with a primary icd-10-cm code verifying diagnosis of pid, and no current or prior use of ig20gly at program initiation. data from patients who received the first ig20gly infusion between january 1, 2017, and september 1, 2017 were included. data from patients receiving infusions after october 31, 2017 were censored. descriptive statistics were calculated for patients demographic and clinical characteristics and prescribed and actual infusion characteristics by age group (<18 years and 18 years). results: in total, 817 patients who completed all 4 infusions were included in the analysis, of whom 97 were aged <18 years. among those who previously received immunoglobulin (ig) therapy, a greater percentage of patients aged <18 years were treated with intravenous ig therapy (n=46; 73%) compared with adult patients (n=222; 62%) before initiating ig20gly. nine patients aged <18 years were treatment naã¯ve. the mean infusion volume per site was lower among patients aged <18 years (25 years: 17.9 ml; 611 years: 26.4 ml; and 1217 years: 34.6 ml) than among patients aged 18 years (1864 years: 38.5 ml and 65 years: 38.9 ml). however, the mean infusion rate per site was similar between patients aged <18 years ( xmen disease (x-linked immunodeficency with magnesium defect, epstein-barr virus infection and neoplasia) is a primary immune deficiency caused by mutations in magt1 and characterized by chronic infection with epstein-barr virus (ebv), ebv-driven lymphoma, cd4 t-cell lymphopenia, and dysgammaglobulinemia. magt1 gene codifies to magt1 protein, a mg2+-selective transporter, expressed in the human immune system, specifically in the spleen and the thymus. functional studies have established the key role of magt1 in t cells and natural killer (nk) cell activation. upon cd4+ t-cell receptor stimulation, magt1 mediates a transient mg2+ influx that is necessary for phospholipase c gamma 1 (plcy1) activation, which drives ca2+ rise and downstream signaling. this mg2+ influx also regulates cytotoxic functions of nk and cd8 t cells through nkgd2, reason why these patients have impaired cytolytic responses against ebv. eleven male xmen patients have been described. we present the case of a 1-year old hispanic infant with a pathogenic variant in magt1 gene that clinically manifested with early pneumocystis jirovecii and cytomegalovirus (cmv) interstitial pneumonia, and ebv chronic infection with good response to intravenous immunoglobulins supplementation without hematopoietic stem cell transplantation or gene therapy. laboratory study highlights low levels of nkg2d ligands. the objective of this case report is to broaden the spectrum of clinical presentation of xmen disease, that manifests initially as a combined immune deficiency (cid) and evolved with a favorable course of the disease with intravenous immunoglobulins supplementation therapy and chemoprophylaxis with trimethoprim-sulfamethoxazole. introduction: lysinuric protein intolerance (lpi) is a recessively inherited disorder of the cationic amino acids transporter subunit y+lat1 caused by variants in the slc7a7 gene. the disease is characterized by protein-rich food intolerance has a heterogeneous presentation. the clinical findings are a result of depletion of lysine, ornithine, and arginine. symptoms can include hyperammonemia, failure to thrive, protein aversion, neurologic disease, and lung disease. there is also evidence that inflammatory manifestations are mediated through upregulation of nfb, il1, and tnf that occur independent of intracellular arginine levels and can lead to lifethreatening episodes of hemophagocytic lymphohistiocytosis (hlh). case presentation: a 17-year-old male presented with history of anxiety, depression, eating disorder, delayed puberty and complex partial seizures. due to poor nutrition and failure to thrive, a gastrostomy tube was placed. following commencement of enteral feeds, he presented with altered mental status, bilateral mydriasis, hyperreflexia, and agitation which lead to a picu admission. ammonia peaked as high as 181 î¼mol/l and episodes ceased with cessation of enteral feedings. prior to enteral feeds, he had been self-restricting protein in his diet. biochemical testing was consistent with lpi and illumina next-generation sequencing revealed compound heterozygous variants in slc7a7 (p.s396lfs*122 and p.e465dfs*54). hyperammonemia resolved quickly with cessation of protein intake and high rate dextrose infusion without the need for ammonia scavenging agents. he was subsequently started on proteinrestricted enteral feeds. at diagnosis he did not have any respiratory symptoms, ct scan of chest showed patchy areas of groundglass opacification that was suggestive of early pulmonary alveolar proteinosis (pap). bronchoalveolar lavage demonstrated foamy, cloudy pink fluid and elevated bronchioalveolar macrophages on cell differential. his clinical course and slc7a7 genotype led to suspicion for smoldering hlh. the findings of elevated ferritin, hypertriglyceridemia, decreased fibrinogen, splenomegaly, elevated il-2 receptor, decreased nk cell function, along with hemophagocytosis on bone marrow biopsy confirmed the diagnosis. because of his pap and hlh, in addition to dietary modifications, a trial of il-1 beta inhibition (anakinra) at 3 mg/kg/day was initiated. follow up ct scan of chest 2 months after initiation of anakinra showed complete resolution of pulmonary groundglass opacifications and pap. bone marrow evaluation showed continued hemophagocytosis in spite of the normalization in ferritin, soluble il-2 receptor, nk function, and triglycerides levels. overall, he is significantly improved on daily anakinra and no longer meets criteria for hlh or pap. discussion: recent data has shown in y+lat1 models that thp-1 macrophages and a549 airway epithelial cells upregulate il1 and tnf regardless of intracellular arginine content. this suggests that inflammatory manifestations may continue independent of dietary modifications. we present a 17 year old patient with newly diagnosed lpi who was treated dietary modification and anti-il1 therapy resulting in resolution of hlh and pap. more research is needed to see if long-term il1 blockade that can consistently control both the immunologic and pulmonary manifestations of lpi and positively impact morbidity and mortality. learning objective: recognize that symptoms of bartonella endocarditis and associated complications can share features of certain immunocompromising conditions. case description: an 8-year-old caucasian boy with history of repaired pulmonary atresia and aortic root dilation was diagnosed with pancytopenia and splenomegaly during a brief hospitalization for atypical pneumonia. pancytopenia persisted, splenomegaly worsened, and five months after presentation, he developed hypertension and renal insufficiency. he was diagnosed with hypocomplementemic, diffuse sclerosing and crescentic glomerulonephritis and was started on mycophenolate mofetil with improvement in kidney function and stabilization of cytopenias. as part of a comprehensive immune work-up, alps (autoimmune lymphoproliferative syndrome) panel was sent and demonstrated elevated double-negative t (dnt) cells with 3 out of 4 positive immunologic criteria for alps. neither targeted sequencing for alps and alpslike disorders nor whole exome sequencing revealed pathogenic mutations. by age 10, the patient remained on mycophenolate, but developed failure to thrive, with weight dropping from 37th percentile to less than 3rd percentile. he was hospitalized again for low-grade fever, increased work of breathing, left shoulder pain and fatigue and was found to have right lower lobe pneumonia. pancytopenia worsened, and he was started on cefepime and azithromycin without improvement in symptoms. echocardiogram revealed vegetations in his pulmonary conduit and bilateral branch pulmonary arteries, but multiple blood cultures were negative. upon further history, the patient reported contact with kittens. bartonella henselae titers and polymerase chain reaction (pcr) from blood were sent and were both positive. he completed a 2-week course of gentamicin, 1-month course of ceftriaxone, and was transitioned to doxycycline and rifabutin. after initiating antimicrobial therapy, his weight and energy significantly improved, his blood bartonella pcr became negative, and his splenomegaly resolved. approximately one year later, the patient underwent pulmonary artery conduit replacement and bartonella pcr testing of the tissue specimen was positive. he has had sustained weight increase, resolution of hypocomplementemia and splenomegaly, decrease in dnt cell frequency from >2% to 0.9%, and improvement though not resolution of cytopenias. he currently remains on doxycycline and rifabutin and continues treatment with mycophenolate. discussion: alps is characterized by defective lymphocyte apoptosis and clinical features such as lymphadenopathy, splenomegaly, hepatomegaly, cytopenias, and glomerulonephritis. the hallmark laboratory finding is expansion of dnts. our patient met criteria for a probable alps diagnosis based on the presence of both required criteria (chronic splenomegaly and elevated dnt cells) and secondary additional criteria (typical immunologic findings noted on alps panel). pediatric cases of bartonella henselae endocarditis have been associated with splenomegaly, cytopenias, and glomerulonephritis which mimic many features of monogenic immune dysregulatory disorders. the diagnosis of bartonella endocarditis in our patient therefore raises the question of whether his immunosuppression predisposed him to infection or if his entire clinical presentation can be explained by bartonella endocarditis. physicians taking care of patients with immune dysregulatory disorders should consider bartonella endocarditis in the differential diagnosis of onset or exacerbations of immune dysregulation. rationale: while fever is considered a sign of infection, many individuals with primary immunodeficiency (pi) anecdotally report a lower than normal average body temperature. on immune deficiency foundation (idf) friends and idf pi connect research forum online, pi patients report a diminished fever response even when other signs of infection are present. there is limited knowledge about the average body temperature in persons with pi. however, the implications of missing an infection in those with pi is well established. methods: study investigators partnered with patient investigators to design a prospective cohort study to determine whether body temperature differed between persons living with and without pi. three hundred fifty adults with pi were recruited from idf and one adult household member without pi was also recruited. mckesson digital oral thermometers (model 01-413bgm) were provided and used to record temperatures in all participants three times a day for five consecutive days. descriptive statistics were calculated. median body temperatures were compared between the two cohorts at each time point using mann-whitney test. results: data from 254 households were used for analysis (72.6% participation rate). the pi population was largely female (85.8%) with a median age of 49 years and largely caucasian population (97.6%). the non-pi population was largely male (66.9%) with a median age of 53 years and largely caucasian population (92.9%). pi diagnoses included cvid (74.8%), hypogammaglobulinemia (12.6%), igg subclass deficiency (4.7%), selective iga deficiency (3.1%), specific antibody deficiency (3.1%), agammaglobulinemia (0.4%), chronic granulomatous disease (0.4%), combined immunodeficiency (0.4%), and complement deficiency (0.4%). a total of 123 individuals with pi (48.4%) reported a lower than normal non-sick body temperature, while 108 individuals with pi (42.5%) reported a normal (between 97â°f -99â°f) non-sick body temperature. a total of 172 individuals with pi (67.7%) reported absence of fever with infection, while 50 individuals (19.7%) reported a normal fever response with infection. the median body temperature was significantly higher for the pi patients in the morning, but not evening or bedtime, reading in 4 of the 5 days (monday: pi = 97.5â°f vs. non-pi = 97.2â°f, p = 0.0291; tuesday: pi = 97.4â°f vs. non-pi = 97.2â°f, p = 0.0020; wednesday: pi = 97.5â°f vs. non-pi = 97.2â°f, p = 0.0009; thursday: pi = 97.4â°f vs. non-pi = 97.2â°f, p = 0.0575; friday: pi = 97.4â°f vs. non-pi = 97.2â°f, p= 0.0008). conclusions: despite the limitations of this non-clinical study, individuals with pi are knowledgeable about their conditions and can offer unique insights and direction to researchers. this study demonstrates that collaboration with patient advocacy groups may facilitate patient-centered and patient-driven research with high participation among the target population. introduction: familial mediterranean fever (fmf) is a hereditary condition characterized by recurrent episodes of painful inflammation caused by mutations in the pyrin (mefv) gene. alterations in the mefv gene affect pyrin production leading to recurrent fevers and painful inflammation in the peritoneum, synovium, and pleura. amyloidosis may also develop as a complication. arabic, turkish, armenian, and sephardic jewish populations are most commonly affected. homozygosity for mefv mutations are associated with a more severe course. there is a paucity of information regarding pediatric fmf in the literature. case: we present a case of a 2-year-old male with minor speech delay diagnosed with compound heterozygous fmf. patient was initially referred due to recurrent fevers and infections. at 4 months of age, he was hospitalized with septic shock requiring intubation secondary to adenovirus. at 5 months of age, the patient began to have recurrent fevers every 3 to 4 weeks, leading to multiple blood draws and courses of antibiotics prior to referral. at 11, 12, and 22 months of age, he developed three separate episodes of febrile seizures. a total of 10-15 lifetime episodes of acute otitis media occurred prior to bilateral myringotomy tube placement. four episodes of streptococcus pyogenes pharyngitis confirmed by throat culture preceded tonsillectomy. no oral ulcers, joint pain, or abdominal pain were reported. no other infections such as pneumonia, sinusitis, uti, non-viral gastroenteritis, fungal infections, or skin infections were reported. both parents are ashkenazi jewish and a maternal history of early miscarriage was noted. family history was negative for immunodeficiency, malignancy, and autoimmunity. the patients vital signs and physical exam were unremarkable. serology indicated leukocytosis of 18.53 k/l with elevated monocytes of 1390 cells/l, elevated eosinophils of 1200 cells/l, and slightly elevated cd8 t cell count of 2653 cells/l. neutrophil, cd4 t cell, b cell, nk cell enumeration, and immunoglobulin panel were normal for age. tetanus, diphtheria, rubella, streptococcus pneumoniae, and haemophilus influenzae b titers were protective. genetic analysis identified that the patient was compound heterozygous for the e148q and v726 mutations in the mefv gene. family was instructed to keep a fever diary. colchicine 0.6mg once a day was given initially, then increased to 1.2mg once a day for inadequate response. loose stools were observed while patient was maintaining a lactose free diet so he was switched to colchicine 0.6mg bid with resolution of loose stools. apart from two occasions when his colchicine dose was missed, the patient remained afebrile at his follow up visits. conclusion: we present a pediatric case of compound heterozygous fmf (e148q and v726 mefv mutations) in an otherwise healthy 2-year-old male of ashkenazi jewish background, initially symptomatic at 5 months of age. individuals who are compound heterozygous for the e148q and a second mevf mutation are generally symptomatic, although severity cannot be predicted. additional pediatric research on symptomatic heterozygous and compound heterozygous fmf is recommended. natural killer (nk) cells are innate lymphocytes that play a key role in defense against virally-infected cells and in tumor surveillance. nk cells can be divided in two subsets. the majority of nk cells in peripheral blood expressed intermediate levels of cd56 and are referred to as cd56(dim). these nk cells are responsible for nk cell cytotoxicity. a minor population of nk cells express very high expression of cd56 and are referred to as cd56(bright). these nk cells are responsible for cytokine production and are precursors to cd56(dim) nk cells. a few immunodeficiencies have been described in which there are abnormal nk cell subsets, such as autosomal dominant gata2 deficiency where cd56(bright) nk cells are absent and irf8 where there is a paucity of cd56(dim) nk cells and relative expansion of cd56(bright) nk cells. here we present a patient with an absence in cd56(bright) nk cells secondary to cd27 deficiency. our patient is a 6-year-old african american female born to non-consanguineous parents. the patients past medical history is significant for chronic lung disease secondary to prematurity, recurrent acute otitis media, failure to thrive and congenital hypothyroidism. family history is significant for an older sister that presented at age 3 with ebv-associated hodgkin lymphoma whose treatment was complicated by chronic activated ebv infection and who ultimately underwent hematopoietic stem cell transplantation (hsct). our patient presented with pancytopenia, fever, lymphadenopathy and splenomegaly. she was found to have ebv viremia with greater than 550,000 copies in whole blood by pcr. she was treated with two doses of rituximab followed by etoposide and dexamethasone as a bridge to hsct. whole exome sequencing demonstrated a homozygous mutation in cd27. cd27 is a member of the tumor necrosis factor receptor family and influences the function of t cells, b cells and nk cells. in nk cells, cd27 is primarily expressed in cd56(bright) nk cells. cd27 deficiency is an autosomal recessive disorder associated with persistent symptomatic ebv viremia, including ebv-driven hemophagocytosis and lymphoma, hypogammaglobulonemia and specific antibody deficiency. our patients immune evaluation prior to initiation of chemotherapy and immunosuppression was notable for very elevated igg, iga and igm. despite hypergammaglobulonemia patient had only 3 out of 11 protective titers against streptococcus pneumoniae. the patient had pan-lymphopenia with appropriate percentages of lymphocyte subsets. assessment of her b cell subsets showed a slight increase in the percentage of transitional b cells/plasmablast and a nearly complete absence of cd27-expressing b cells. her nk cell phenotyping demonstrated a complete loss of cd56(bright) nk cells with reduced nk cell cytotoxicity, comparable to what has been previously reported in patients with gata2 deficiency. previous reports of patients with cd27 deficiency denote normal nk cell numbers with normal to moderately reduced nk cell cytotoxicity, however, cd27 deficiency causing a specific loss of the cd56(bright) nk cell subset has not been previously reported. cd27 deficiency should be consider in patients with ebv driven disease and abnormal nk cell studies. introduction/background: the transcription factor ikaros is encoded by the ikzf1 gene and plays a crucial role in lymphopoiesis. somatic, and more recently also germline mutations of ikzf1 are associated with a hematologic malignancies, most notably b-cell precursor acute lymphoblastic leukemia. germline mutation in ikzf1 was first reported as a monogenic cause of human disease characterized by marrow failure and immune deficiency in a single neonate in 2012. subsequently, mutations leading to haploinsufficiency were discovered to underlie a proportion of patients with cvid and low b cell numbers, and dominant-negative mutations have been observed to cause more severe combined immune deficiency phenotypes. at this time, there is very little known regarding allogeneic hematopoietic cell transplantation (hct) outcomes for patients with severe dominant-negative ikzf1 mutations. concerningly, ikaros deficiency has been observed to have a negative impact on graft versus host disease in mouse models. objective: to describe allogeneic stem cell transplant outcomes in patients with the dominant-negative ikaros mutation. methods: we collected transplant data from 4 patients who underwent allogeneic hct at transplant centers around the world. results: patients underwent allogeneic hct using a variety of conditioning regimens. patients received bone marrow (n=3) or cord blood (n=1) grafts from an hla-matched sibling donor (n=1) or single allele hlamismatched unrelated donor (n=3). neutrophil engraftment occurred between day +12 and +51 post-transplant. platelet engraftment occurred between day +8 and +167 except in one patient who did not have return of normal platelet counts due to underlying liver dysfunction. all patients were documented to have greater than 99% whole blood donor chimerism at a median of 28 days (range 12-51 days) following transplant and maintained >95% donor chimerism until last follow-up. only one patient developed grade ii acute gvhd. no patients developed chronic gvhd. one patient died approximately 1 year post transplant related to cryptosporidium cholangitis which existed prior to hct. at the most recent follow up of the 3 surviving patients (range: 0.99-7.2y), ivig had been discontinued, antimicrobial prophylaxis had been stopped, and patients had received routine vaccinations. they all had excellent performance status. conclusions: allogeneic hct may be a safe option to consider for patients with dominant-negative ikaros mutation as there does not appear to be an increased risk of death or gvhd. moreover, 3-out-of-4 of the transplanted patients are alive and well and show no features of the disease. however, because of the limited number of patients evaluated and the retrospective nature of this analysis, our data do not allow firm conclusions to be made, and further studies will be needed to evaluate outcomes in larger cohorts. introduction: when evaluating patients with t-cell lymphopenia, we often are concerned about defects in lymphocyte production and function, especially in the setting of frequent infections. here we outline a case demonstrating t-cell lymphopenia due to increased loss, which should be considered in the differential diagnosis. case report: we report a 13-year-old male who initially presented with recurrent, right-sided pneumonias requiring frequent hospital admissions including severe episodes necessitating intensive care unit admission. his work up for the pneumonias included a bronchoscopy revealing normal anatomy with minimal inflammation, and a chest ct with mild peribronchial wall thickening. as his pulmonary disease progressed, he developed a persistent, productive cough with expectorated mucous plugs that were plastic-like in appearance. while his pulmonary symptoms responded to steroids, his mucous plug production persisted. sputum cultures were intermittently positive, isolating cryptococcus neoformans and aspergillus niger. he underwent vats and wedge biopsy, concerning for recurrent aspiration. an immunologic evaluation initially demonstrated normal t-and b-cell counts, but serial evaluation of his lymphocyte population demonstrated low cd4+ cells (ranging 151-367 cells/cumm), and low normal cd8 cells (ranging 101-177 cells/cumm) with normal b-and nk-cell numbers. further t-cell evaluation revealed normal ratios of naive and memory p o p u l a t i o n s ( c d 4 c d 4 5 r a + 6 1 % , c d 4 c d 4 5 r o + 3 9 % , cd8cd45ra+ 74%, cd8cd45ro 33%), normal trec (7768 copies per 10^6 cd3 cells) and normal thymic emigrants (cd4cd31cd45ra+ : 158, normal 150-1500), indicative of sufficient thymopoiesis. mitogen and antigen stimulation assays demonstrated normal responses to phytohemagglutin, concanavalin a, and pokeweed mitogen, with a low lymphocyte response to candida. he had normal quantitative immunologlobulins, normal diphtheria, tetanus and streptococcus pneumonia titers. his dihydrorhodamine flow cytometry and fish for chromosome 21q11.2 deletion were negative. given normal function and thymic output, his immunologic profile was concerning for t-cell loss. our patient was registered with the undiagnosed disease network, and had a second review of his lung biopsy, concerning for plastic bronchitis. subsequent lymphatic imaging demonstrated abnormal lymphatics within the bilateral clavicular space, right greater than left, with questionable partial thoracic duct, explaining his unilateral symptoms. he was diagnosed with plastic bronchitis secondary to abnormal lymphatic drainage, with lymphatic fluid filling his airways and secondary t-cell loss. discussion: plastic bronchitis is a rare and potentially fatal disorder, seen commonly after the fontan procedure for congenital heart disease. this process has resulted in t-cell loss into the airway and subsequent t-cell lymphopenia. in patients with fontan-related protein losing enteropathy, multiple immune abnormalities have been described including reduced immunoglobulins, lymphopenia, and selective cd4 lymphocyte deficiency. similar findings have been reported in patients with lymphatic malformations. although the impact of t-cell loss on adaptive immunity is not entirely known, there is no indication of increased risk for atypical infections. given his normal mitogen assay, our patient did not start prophylactic antibiotics. he continues to have symptomatic episodes with lymphopenia, but has had no opportunistic infections, and remains stable with an aggressive pulmonary regimen. we conclude by reiterating the importance of considering t-cell loss in patients presenting with lymphopenia, particularly with evidence of normal thymopoeisis and t-cell function. introduction: granulomatous disease (gd) has been described with a variable incidence (8.0-22.0%) in patients with common variable immunodeficiency (cvid). an increase in malignancies has been reported in cvid patient cohorts, particularly for lymphoma, reported in 1.6-8.2% of the cvid patients depending on the cohorts. prior analysis of a cohort of 436 cvid patients included 59 patients with gd (gd+). in these, there was a suggestion of more cases of lymphoma (12.5%) when compared to cases without (gd-) (5.0%) although the difference was not statistically significant (p=.07). objectives: compare the frequency of lymphoma in gd+ and gd-patients in the cvid patient cohort from the usidnet registry. methods: we submitted a query to the usidnet registry requesting deidentified data for patients with the diagnosis of cvid, through august 2018. statistical analysis was performed on spss, with comparisons done with pearson chi-square or fisher's exact test, depending on the sample sizes, using an alpha level of .05. results: a cohort of 1395 cvid patients from the usidnet registry was analyzed. ninety-one patients (6.5%) were gd+. overall, 152 patients (10.9%) had a malignancy diagnosis, 47 of these (3.4%) with lymphoma. lymphoma was present in 6/91 gd+ patients (6.6%) versus 41/1304 gdpatients (3.1%) (p=.12). overall malignancy was present in 15/91 gd+ (16.5%) versus 137/1304 (10.5%) (p=.08). discussion: in the cohort of 1395 cvid patients from the usidnet registry, we found a frequency of lymphoma of 3.4%, which is in the range of previously described cohorts. the frequency of lymphoma was 6.6% in patients with gd, higher than the 3.1% frequency for gd-patients, but these differences were not statistically significant. our identified frequency of lymphoma in gd+ patients was lower than the one previously identified in the 436 cvid patient cohort, but with similar proportional differences between gd+ and gd-patients. despite no statistical significance, the frequency of lymphoma, as shown here and elsewhere, was higher in cvid patients gd+ than gd-in both studies, with no full understanding of this increased risk of lymphoma. expanding this analysis to larger groups of cvid patients may help to confirm, or deny a more robust association, which may have a meaningful impact in the outcomes of this particular population. introduction: patients with refractory pericarditis have been treated with intravenous immunoglobulin (ivig) or interleukin 1 receptor antagonist (anakinra) with limited and transient benefit. separate or combined therapy with subcutaneous immunoglobulin (scig) and interleukin (il) 1 inhibitor (rilonacept) for refractory pericarditis in a cohort of patients has not been previously described. case descriptions: 4 patients were referred for recurrent pericarditis refractory to traditional therapies at ages ranging from 16 to 54 years. they all had multiple serious sequelae of their pericarditis and abnormal immune parameters including hypogammaglobulinemia, poor responses to vaccines, poor mitogen induced lymphocyte proliferation, and/or b cell lymphopenia. the patients had varied past medical histories and associated conditions. patients were started on ig, with some initiated on ivig, though all were transitioned to hyaluronidase-facilitated scig (hyqvia). patients were then started on either anakinra or rilonacept with 3 patients continuing on rilonacept and 1 remaining on anakinra. all patients had complete or near complete resolution of their pericarditis on dual therapy for greater than 1 year. the markedly elevated il1 prior to therapy seen in all of the patients normalized post-therapy. some patients had elevated il6 prior to therapy that also improved post-therapy. 1 patient who has also been diagnosed with familial mediterranean fever (fmf) has stopped both therapies for greater than 1 year with no further episodes of her pericarditis. discussion: 4 patients with recurrent refractory pericarditis and signs of immunodeficiency and autoinflammatory disease on laboratory testing responded to dual therapy with hyqvia and rilonacept or anakinra resulting in resolution of pericarditis. inflammasome and immune abnormalities may be implicated or associated with recurrent pericarditis and may respond to targeted therapies. chief, laboratory of clinical immunology and microbiology, idgs, dir, niaid, nih, bethesda, md, usa hypomorphic recombination activating gene 1 (rag1) mutations result in residual t-and b-cell development in both humans and mice and have been found in patients presenting with delayed-onset combined immune deficiency with granulomas and/or autoimmunity (cid-g/ai). recent studies have shed light on how hypomorphic rag1 mutations alter the primary repertoire of t and b cells, but less is known about their effect on immune dysregulation in targeted organs. in order to investigate the role of these mutations in determining intestinal disease, we set out to evaluate gut immunity and microbiota interplay in rag1 mutant hypomorphic mice. we evaluated two mouse models carrying homozygous rag1 mutations (r972q and r972w), corresponding to human mutations (r975q and r975w, respectively) described in patients with cid-g/ai. both mutations fall in the coding flanksensitive region of the rag1 c-terminal domain. on the basis of aminoacid properties and in vitro studies, the r972q mutation has demonstrated a moderate effect on rag1 protein stability while the r972w mutation resulted highly disruptive. analysis of intestinal pathology in rag1 mutant mice (niaid animal protocol lcim 6e) revealed different degrees of spontaneous colitis, with the most severe inflammatory infiltrate observed in mice carrying the most disruptive mutation, r972w. colonic inflammation was characterized by crypt elongation, epithelial hyperplasia, and an abundant inflammatory infiltrate extending to the colonic lamina propria, with occasional crypt abscesses. a significant increase in activated cd44hicd62lcd4+ t cells expressing the gut homing receptor 47 was observed in mesenteric lymph nodes (mlns) of both mutant strains, and was especially prominent in r972w mutant mice. additionally, the proportion of mln cd4+ t regulatory (treg) cells was increased in both mouse models. finally, mln of mutant mice contained a high number of myeloid cells (cd11b+ ) along with a decreased number of b220+ b cells, and these abnormalities were also more prominent in r972w than in r972q mice. in summary, we have shown that rag1 mutant hypomorphic mice present with different degrees of inflammatory bowel disease, with the mouse model carrying the most disruptive mutation presenting with the most severe phenotype. we are currently performing studies to evaluate the impact of rag1 mutations on microbiome composition and diversity in these mouse models of cid-g/ai. background: hypogammaglobulinemia or low serum immunoglobulin g (igg) levels either inherited (primary) or acquired (secondary) is associa t e d w i t h i n c r e a s e d i n f e c t i o n r a t e s . p r i m a r y ( 1â°) hypogammaglobluinemia can be caused by many primary immune deficiencies (pid) including combined variable immune deficiency (cvid), while secondary (2â°) hypogammaglobluinemia can be caused by many acquired conditions such as lymphomas, leukemias, or chemotherapies and other immunosuppressive drugs. immunoglobulin replacement therapy (irt) has been the mainstay of treatment in patients with hypogammaglobulinemia by reducing infection through replenishing the quantitative igg. there are other applications of ig therapy such as in autoimmune diseases, where the mechanism of action is thought to be ig mediated immunomodulation. innate immune cells have shown to be involved in such mechanism, but whether irt modulates adaptive immune cells in patients with hypogammaglobulinemia is not well known. hypothesis: irt has an immunomodulatory effect on t-cell function and proliferation in patients with hypogammaglobulinemia. methods: blood from thirty patients with 1â°(n=12) or 2â°(n=18) hypogammaglobulinemia recruited from the immunodeficiency clinic at the ottawa hospital was drawn for peripheral blood mononuclear cell (pbmc) isolation, before starting irt and minimum 8 weeks after starting irt. data regarding igg level, number and type of infections after receiving irt was collected. pbmcs were analyzed using flow cytometry for quantitation of t-cell subset. cultured and anti-cd3/cd28 stimulated pbmc were also analyzed for extracellular and intracellular cytokine production, measured by e l i s a a n d f l o w c y t o m e t r y, r e s p e c t i v e l y. c o m b i n e d cytomegalovirus, epstein-barr virus and influenza virus (cef) peptides were used to study specific t-cell responses. anti-cd3/ cd28 stimulated pbmc were used for celltrace t-cell proliferation a s s a y s . d a t a w a s g r o u p e d b a s e d o n n a t u r e o f hypogammaglobulinemia i.e. 1â°or 2â°. results were compared between before and after irt using wilcoxon matched-pairs signed rank test. results: irt was not found to significantly alter proportion of treg, cd4+, or cd8+ t-cell populations or activation state as measured by cd45ra/r0 expression. however, irt was found to significantly increase expression of intracellular ifn-y in cd4+ and cd8+ t-cells post-cd3/cd28 stimulation in 2â°(p = 0.007), but not in 1â°h ypogammaglobulinemia patients. there was no change in extracellular il-10 and il-17 cytokine production in both groups. in contrast, cd8+ tcells in 1â°hypogammaglobulinemia patients showed significantly higher expression of intracellular ifn-y and tnf-a post-cef viral peptide stimulation (p = 0.027). cd3+ and cd8+ t-cell proliferation after cd3/cd28 stimulation was found to be decreased after irt for both groups (p = 0.025 & p = 0.049). conclusions: our results suggest that irt can alter cd4+ and cd8+ t-cell function with differential effect in patients with 1â°o r 2â°hypogammaglobulinemia in addition to replenishing serum igg level. more experiments assessing cytotoxicity of t-cells will be conducted to further study t-cell subset function as well as bcell function. these laboratory results will be analyzed for association with clinical outcomes. uploaded file(s) uploads background: severe congenital neutropenia (scn) is a rare immunodeficiency disorder characterised by the extremely low absolute neutrophils count (anc) less than 0.5x109/l. the clinical feature of scn is recurrent bacterial infections and the patients the risk of leukemia development. the incidence of scn is estimated to be 1 in 200 000 individuals. mutations in more than 20 genes have been described causing scn and it is either recessive, dominant or x-linked inheritance. case presentation: we described an 11 years old malaysian girl who presented with recurrent abscesses over the whole part of the body, recurrent oral candidiasis, growth failure and recurrent pneumonias since 4 months old. she also had history of a few episodes of acute tonsillitis, chronic suppurative otitis media and herpes zoster infections. throughout her age, she had persistent neutropenia less than 0.5x109/l but in few occasions, her anc elevated up to more than 1.0x109/l . she was treated as autoimmune neutropenia, respectively due to few positive results of autoimmunity workout such as antinuclear antibodies (ana) and double stranded dna (dsdna) but eventually later to be negative. later at the age 9 years old, whole exome sequencing was performed and confirmed by sanger s e q u e n c i n g , f o u n d a h e t e r o z y g o u s v a r i a n t i n e l a n e gene(c.640g>t; p.gly214ter), an autosomal dominant which was described to cause scn. both parents do not carry this mutation, hence, it is a de novo mutation. currently, she had few on and off recurrent infections. despite that, she is relatively well and on prophylaxis antibiotic. conclusion: to our knowledge, we report for the first time a malaysian girl with scn, with confirmed mutational analysis of the elane gene. the delayed diagnosis might be due to the insufficient awareness of the phenotypic presentation of this rare disease. moreover, the genetic analysis is not available in malaysia and need to be done outside of the country. this case demonstrates the importance of the genetic analysis which may help in improving the diagnosis and management of the patient. (69) submission id#600360 professor of paediatrics and immunology, university college london; great ormond street hospital nhs trust; orchard therapeutics, london, uk background: ada-scid is a rare genetic disorder which causes severe combined immunodeficiency. historically, ada-scid has been treated using enzyme replacement therapy (ert) followed by allogeneic hematopoietic stem cell (hsc) transplant (hsct) from a matched related donor (mrd) or, if none is identified, a non-mrd (matched/mismatched unrelated or mismatched related donor). we developed a self-inactivating lentiviral vector (lv), in which a codon optimized human ada cdna is driven by the short form of the elongation factor-1alpha (efs) promoter (efs-ada lv). the drug product (otl-101), composed of autologous hscs transduced ex vivo with the efs-ada lv, was evaluated in a prospective, historically-controlled phase i/ii clinical trial in ada-scid pediatric subjects. we report safety and efficacy at 24 months in 20 ada-scid subjects treated with lentiviral gene therapy (gt) compared to a historical cohort of 26 ada-scid patients treated with hsct. methods: twenty subjects (9 male, 11 female; 4 mo 4.3 yrs) were treated with gt. autologous cd34+ hscs were isolated from bone marrow and pre-stimulated with cytokines before transduction with efs-ada lv. busulfan was administered at a single dose (4 mg/kg) prior to infusion of otl-101. the control group included 26 patients (0.2 mo 9.8 yrs) treated with allogeneic hsct (mrds n=12, non-mrds n=14) at great ormond street hospital, uk (n=16) or duke university childrens hospital, usa (n=10) between 20002016. results: at 24 months, overall survival (os) and event-free survival (evfs), defined as survival in the absence of ert reinstitution or rescue allogeneic hsct) were statistically significantly higher in the gt group compared with the hsct group (table) . successful engraftment of genetically modified hsc was observed in all gt subjects at 6 months, which persisted over 24 months, based on vector gene marking in granulocytes (median 0.085 copies/cell [range 0.04-2.50] at 24 months) and peripheral blood mononuclear cells (median 0.843 copies/cell [range 0.13-1.86] at 24 months), and was associated with increased red blood cell ada enzyme activity and metabolic detoxification from deoxyadenosine nucleotides. over 24 months, none of the gt subjects required peg-ada ert reinstitution and 90% were able to stop receiving immunoglobin replacement therapy (igrt), whereas 38% hsct patients required rescue hsct or reinstitution of peg-ada ert, and 52% were able to stop receiving igrt (table) . nine subjects in the gt group experienced a serious adverse event (sae), most frequently infections and gastrointestinal events; only one was considered treatment-related. in the gt group, there were no events of autoimmunity during the study. due to the autologous nature of the product, there was no incidence of graft vs host disease (gvhd) in the gt group; whereas 5 patients in the hsct group experienced acute gvhd and 3 experienced chronic gvhd events, one of whom died. conclusions: treatment with lentiviral gt for ada-scid is well tolerated and has a favorable benefit-risk profile at 24 months based on sustained gene correction and restoration of immune function, as well as improved os and evfs compared with hsct (mrd or non-mrd) at 24 months. background: ada-scid is a rare genetic disorder that causes severe combined immunodeficiency, with minimal or absent b cell function. prior to, and often after, treatment with allogeneic hematopoietic stem cell (hsc) transplant (hsct) or autologous ex vivo hsc gene therapy (gt), patients are managed with enzyme replacement therapy (ert) and immunoglobulin (ig) replacement therapy (igrt). we evaluated a gt treatment with autologous hscs transduced ex vivo with a self-inactivating lentiviral vector (lv), in which a codon optimized human ada cdna is driven by an internal short form of the elongation factor-1alpha (efs) promoter ("efs-ada lv"). at 24 months follow-up, 20 pediatric ada-scid subjects treated with gt were compared to a historical cohort of 26 ada-scid patients treated with hsct. here, we report on b cell reconstitution in these cohorts. methods: twenty subjects (9 male, 11 female) aged 4 mo -4.3 yrs received gt. autologous cd34+ hscs were isolated from bone marrow and pre-stimulated with cytokines before transduction with efs-ada lv. genetically modified cells were administered after conditioning with single dose busulfan (4 mg/ kg). the control group included 26 patients aged 0.2 mo to 9.8 yrs treated with hsct at great ormond street hospital (uk) (n=16) or duke university children's hospital (us) (n=10) between 2000 -2016. the hsct patients received an allogeneic transplant from matched related donors (mrds) (n=12) or non-mrds (n=14). subjects continued to receive igrt post-gt until a clinical decision was made to stop, factoring in b cell reconstitution, general medical condition and seasonal infections. results: by month 12, in the gt group, 45% had stopped treatment with igrt compared to 38% in the hsct group overall. by months 18 and 24, higher proportions of gt-treated subjects had stopped igrt (70% and 90%, respectively) compared with mrd hsct patients (55% and 70%, respectively) and non-mrd hsct patients (42% at both timepoints) (table) . in the gt group, vector gene marking was detectable in peripheral blood mononuclear cells within 3 months and persisted at 24 months post-infusion (median 0.843 copies/cell [range 0.13-1.86]), suggesting successful gene modification. as evidence of b cell reconstitution, iga and igm levels in peripheral blood sera more than doubled by 18 months, from 18.5 mg/dl (range 8 to 95) to 48.0 mg/dl (range 20 to 110) and 32.5 mg/dl (range 16 to 107) to 69.0 mg/dl (range 20 to 180), respectively. additionally, antibody response following tetanus vaccination, was evaluated in 3 subjects. all 3 subjects mounted a protective response to the vaccine (median antibody response 3.2 iu/ml [range 0.1 to 3.5]), based on a normal threshold of 0.01 iu/ml (hammarlund clin infect dis 2016) and a laboratory reference range (0.10 to 2.9 iu/ml). conclusions: gt with autologous hscs transduced ex vivo with efs-ada lv resulted in b cell reconstitution, as evidenced by doubled iga and igm production at 18 months, cessation of igrt in 90% of patients by 24 months, and protective specific antibody responses to tetanus vaccine in patients that were evaluated. background: x-linked chronic granulomatous disease (xcgd) results from mutations in cybb encoding the gp91phox subunit of phagocyte nadph-oxidase. attempts to treat xcgd with gene therapy (gt) using transduced autologous hematopoietic stem cells (hsc) transduced ex vivo with a gammaretroviral vector have met with limited efficacy due to transient engraftment of gene corrected hscs, gene silencing, and vector insertion-mediated activation of oncogenes leading to myelodysplasia. we developed a novel self-inactivating (sin) lentiviral vector (g1xcgd lv) with a chimeric cathepsin g/cfes myeloid-specific promoter driving gp91phox expression from a codon optimized cdna. following transplant of g1xcgd lv ex vivo transduced autologous hscs into busulfanconditioned xcgd patients, there was long-term restoration of oxidase activity in peripheral blood polymorphonuclear neutrophils (pmn) at 12 months in 6 of 9 severely affected xcgd patients without evidence of genotoxicity. here we present data about the multiple assays used to assess quality and quantity of restoration of pmn oxidase activity. methods: similar trials of gt with g1xcgd lv were initiated in the uk (n=3, plus 1 compassionate use patient) and usa (n=5). all patients had histories of inflammatory disease and severe, persistent infections (some non-responsive to conventional therapy at time of gt). g-csf plus plerixafor-mobilized cd34+ hscs were transduced with ex vivo g1xcgdlv. subjects received myeloablative conditioning with singleagent busulfan, targeted to net area-under-the-curve of 70,000 ng/ml*hr. freshly prepared or cryopreserved quality-tested genetically-modified hsc, manufactured on-site, were administered intravenously. pmn oxidase activity post-gt was assessed by p-nitroblue tetrazolium (nbt) reduction, dihydrorhodamine (dhr) flow cytometry assay, and quantitative ferricytochrome c assay (ferric) measurement of superoxide generation. results: we report results for 7 patients (aged 2-27 years) with 1-2.5 years of follow-up; two additional patients were treated but died within three months of gt from complications deemed related to pre-existing diseaserelated co-morbidities (severe pulmonary disease and anti-platelet antibodies). within 1 month post-gt, oxidase (+) pmn were present in peripheral blood based on nbt testing and dhr flow cytometry. expression of the corrective transgene was confirmed by flow cytometry using antibody detection of gp91phox. quantitative biochemical measurements of oxidase activity were also confirmed in some samples using the ferric assay, demonstrating quantitative levels of superoxide production per corrected cell that were within the normal range. functional testing of oxidase burst activity using dhr fluorescent assays was applied serially to follow levels of corrected pmn where oxidase activity per corrected cell also were in the normal range. all patients had >15% pmn dhr+ within one month, which remained stable for most patients over the follow-up period ( figure) . follow-up demonstrated sustained stable persistence of 12-46% oxidase burst positive neutrophils in 6 of 7 surviving subjects at 12 months, with restoration to clinically beneficial levels (defined as 10% of pmn being dhr+) in these patients as of december 2018. conclusion: these results demonstrate corrected pmn function within 1 month in x-cgd patients treated with autologous gt. pmn oxidase activity was sustained at levels which restore biochemical function and provide clinically beneficial levels of immunity for 12 months in 6/7 patients. the formulation for igsc 20% was developed based on the knowledge acquired from the formulation of grifols currently licensed 10% immune globulin (human), gamunexâ®-c; however, the protein concentration was increased from 10% to 20% to facilitate efficient subcutaneous administration. gamunex-c has an extensive record of safety and tolerability when administered intravenously and subcutaneously for greater than 15 years in diverse patient populations. the igsc 20% manufacturing process employs the same purification steps as gamunex-c and was demonstrated to be robust and to provide an igg product with the required potency, purity, and quality. the formulation excipient characteristics and compatibility with the drug product have been well established. glycine has been an excipient of intramuscular immune globulin (human) for fifty years and intravenous immune globulin (igiv) for over twenty years. the igsc 20% formulation has low buffering capacity, and a low ph was selected to achieve a product with low aggregates, low fragments and viscosity suitable for subcutaneous administration. to improve visual clarity, the igsc 20% formulation contains a small amount of polysorbate 80 (ps80), which is widely used in biopharmaceutical products. subcutaneous administration of the igsc 20% formulation has been well tolerated in clinical studies. objectives: the goal was to provide the pid population with a new 20% immunoglobulin liquid product for subcutaneous administration (igsc 20%). methods: igsc 20% is manufactured using the current manufacturing process for gamunex-c, followed by an additional concentration step so that the product can be formulated at a higher protein concentration. igsc 20% and gamunex-c batches were produced at full industrial scale and then subjected to a series of analytical testing including assessment of purity, composition and neutralizing activity. results: the igsc 20% and gamunex-c manufacturing processes and formulations have preserved the igg integrity, molecular characteristics and potency. the manufacturing processes have eliminated lipids, alcohols, and acetate and coagulation factor impurities, including fxia, which were undetectable by either specific or global methods. the igsc 20% and gamunex-c batches were 100% gamma globulin by agarose membrane electrophoresis, and have a subclass distribution similar to normal plasma and acceptable specific antibody content. igsc 20% was shown to be primarily monomer plus dimer igg (99â±1%) with minimal aggregate or fragment, which confirms that appropriately gentle processing conditions were used during the concentration of 10% igg solutions to 20% igg. conclusions: igsc 20% is a highly concentrated igg solution with characteristics comparable to gamunex-c, but with twice the igg concentration in order to facilitate subcutaneous administration with reduced volumes and shorter infusion times. analytical testing demonstrates suitable potency, purity, and neutralizing activity for a number of specific antigens. funding: this study was funded and conducted by grifols, a manufacturer of 20% immunoglobulin for subcutaneous administration. disclosure: all authors are employees of grifols. frequent respiratory tract infections and seizures cause recurrent hospitalizations in these children and are typically considered a result of neurological impairment and poor airway clearance. evaluation of these patients for immunodeficiency is not a common clinical practice. here we report combined immune deficiency in 2 patients with mds and recurrent respiratory tract infections. case presentation case 1: a boy with mds was initially referred at age 2 months for an abnormal newborn screen with low t cell receptor excision circles (trec) for severe combined immunodeficiency (scid). initial evaluation revealed moderate cd3+ and cd4+ t cell lymphopenia (figure 1). initial immunoglobulins levels were normal. he was placed on antiseizure medications. he later developed recurrent and severe respiratory tract infections starting in infancy. at 12 months of age, he developed hypogammaglobulinemia ( figure 2 ). in addition, t cell counts progressively decreased and stayed around 600 cells/ul. immunoglobulin replacement therapy started at 18 months of age. hospitalizations due to respiratory tract infections significantly decreased. case 2: a 3-year-old boy with mds had recurrent bacterial and viral respiratory infections which required numerous hospitalizations including intensive care unit stays. newborn screening for scid was negative. he had been on anti-seizure medications. immunologic evaluation at 3 years of age revealed low total cd3+ cells and cd8+ t cells (cd3+: 1284cells/ul[normal range 1400-3700cells/ul], cd8+:278cells/ ul[normal range 490-1300cells/ul]), hypogammaglobinemia (igg: 252mg/dl[normal range 453-916mg/dl]), and non-protective igg levels to tetanus, varicella and pneumococcus serotypes. immunoglobulin replacement therapy started at 3 years of age which resulted in reduced frequency and severity of respiratory infections, and improved quality of life. discussions: t cell lymphopenia and hypogammaglobulinemia were seen in both our cases of miller-dieker syndrome. to our knowledge, immune deficiency has never been reported in mds. one of our cases suggests that low t cell counts may start as early as at birth and may be detected by newborn screening. hypogammaglobulinemia may be primary or secondary due to antiepileptics. both children had reduced frequency and severity of respiratory infections and improved quality of life after immunoglobulin replacement highlighting the importance of screening and early management of immunodeficiency. conclusion: miller-dieker syndrome is likely another syndromic primary immune deficiency disorder. a high index of suspicion with early screening and management of immunodeficiency may be beneficial for children with miller-dieker syndrome. uploaded file(s) uploads this prospective, multi-center, open-label study assessed the pharmacokinetic (pk), safety, and tolerability of immune globulin subcutaneous (human), 20% caprylate/chromatography purified (igsc 20%) in subjects with primary immunodeficiency (pi). the objectives were to determine a weekly subcutaneous (sc) dose of igsc 20% that is noninferior to the intravenous (iv) dose of immune globulin injection (human), 10% caprylate/chromatography purified (igiv-c 10%) and to determine the steady state trough igg levels after igsc 20% and igiv-c 10% infusions. there were 3 possible phases. if not on a qualifying igg regimen at enrollment, subjects (n=44) were required to enter the run-in phase, receiving igiv-c 10% to achieve steady-state before entering the iv phase to determine steady-state area-under-the-curve (auc) of iv infusions. subjects with a qualifying igiv-c 10% regimen (300-800 mg/kg) (n=9) directly entered the iv phase for steady-state iv pk assessments. upon completion of the iv pk assessments subjects entered the sc phase, receiving weekly doses of igsc 20% for up to24 weeks, with steady-state auc determined at the 13th dose. igsc 20% was not associated with any reports of serious local infusion site reactions (isrs). the majority of local isrs were mild-to-moderate. igsc 20% (at a dose conversion factor of 1.37) provided equivalent exposure to igiv-c 10% as assessed by steady-state auc0-7 days, with 33% higher mean igg trough values, lower fluctuations in igg concentrations and the flexibility of at home administration. igsc 20% was well tolerated with a safety profile comparable to igiv-c 10%. clinicaltrials.gov identifier: nct02604810 disclosure: kecia courtney, elsa mondou, and jiang lin are employees of grifols, a manufacturer of igsc 20%. grifols is the sponsor of this study. background: in 2014 two reports described the deficiency of adenosine deaminase 2 (dada2) as early-onset lacunar strokes, intermittent fevers, livedoid rash, and early onset polyarteritis nodosa (pan). since these first reports, the clinical spectrum has dramatically expanded to include antibody deficiency, liver disease, vasculopathy, pure red cell aplasia, cytopenias, and lymphoproliferative disease. methods: forty-two patients were enrolled in an irb approved study at the nih. sequencing of ada2, the gene encoding adenosine deaminase 2 (ada2), was performed in all patients. information was obtained by chart review of all clinical, serologic, and radiographic testing. results: all 42 patients had germline biallelic loss of function mutations in ada2, leading to absent or significantly decreased protein expression and function of ada2. the cohort comprises 20 females (48%) and 22 males (52%). there were 6 sibling pairs and 2 families with 3 affected individuals. twenty-seven patients had a history of at least one ischemic stroke and 6 experienced a hemorrhagic stroke. the average age at the time of first stroke is 5.6 years (range 4 months -24 years), and the average number of strokes is 3 (range 1-11). no new strokes have occurred in patients on anti-tnf therapy. skin manifestations occurred in 86% of patients and include livedo (74%), cutaneous vasculitis resembling pan (64%), and raynauds (19%). hepatomegaly (43%) and splenomegaly (55%) were also notable. portal hypertension was observed in 6 (14%) patients, with 1 patient requiring a spleno-renal shunt for a massive variceal bleed. abdominal mra revealed arteritis and aneurysm in 7/13 patients evaluated; 3 patients developed bowel necrosis. peripheral vasculopathy was seen in 3 patients, with one requiring amputation of gangrenous digits. the most common immune abnormality seen in this cohort is hypogammaglobulinemia (62%); 20 patients have low igg, 20 patients have low igm, and 14 patients have low iga. ten of these patients are on immunoglobulin replacement. specific antibody responses to vaccines were inadequate in 5/16 patients challenged. lymphocyte phenotyping revealed decreased class-switched memory b cells in 23/32 patients (72%) tested. however, there was no relationship between absolute number of class switched memory b cells and hypogammaglobulinemia or infection frequency. hematologic abnormalities include transfusion depended anemia (7%), neutropenia (7%), lymphopenia (5%), and thrombocytopenia (2%). seven patients developed pancytopenia, 1 presented with pure red cell aplasia, and 1 developed aplastic anemia. three patients have undergone bone marrow transplant, with two of those patients requiring a second transplant for graft failure. conclusions: the spectrum of dada2 has expanded from strokes, intermittent fever, and cutaneous manifestations to include portal and systemic hypertension, immune deficiency, cytopenias, vascular abnormalities, and bone marrow failure. while initiation of anti-tnf therapy improves inflammatory markers, and no new strokes have occurred while on therapy, cytopenias do not seem to improve. bone marrow transplantation should be considered in patients with findings of bone marrow failure, although transplant of our patients has been complicated by immune mediated neutropenia. disease manifestations are heterogenous, making a comprehensive evaluation critical to our understanding of this disease. given the increase in neonatal diagnosis of athymia, clinical care is provided by the referring medical centers prior to rvt-802 implantation and patients return to the referring centers earlier after rvt-802. this creates the need for clear, concise guidelines for the care of these patients. primary goals of pre-transplantation clinical care are (1) management of pre-existing medical needs such as feeding difficulties, airway obstruction, congenital cardiac defects and developmental disabilities; (2) management of symptoms related to oligoclonal recipient t cell expansion (autologous gvhd/atypical complete digeorge anomaly) and (3) prevention of infections. most deaths in the pre and early post-transplantation period are secondary to pre-existing infections. necessary surgical and medical procedures (ie cardiac surgery, hearing aids) should not be delayed. for the first 6 to 9 months after rvt802, patients have profoundly low naã¯ve t cell numbers and may require immunosuppression to prevent rejection of rvt-802 by oligoclonal recipient t cells. immunosuppression needs to be closely monitored and titrated for desired effect while minimizing side effects such as renal toxicity, electrolyte abnormalities and hypertension. t cell counts should be performed every 3 months and are used to guide weaning of immunosuppression. most patients with successful transplants develop greater than 100/mm3 naã¯ve t cells by 12 months post rvt-802. infection prevention, clinical stability and optimal nutrition are critical for lasting engraftment. clinical guidelines have been developed to address immunosuppression, management of autologous gvhd symptoms (gut, skin and liver), preservation of renal function, and developmental considerations. after the development of naã¯ve t cells, patients should continue to be monitored regularly by an immunologist. patients may develop autoimmune complications such as thyroid disease and transient cytopenias. while risk of complications related to viral infections is greatly decreased after development of naã¯ve t cells, patients with comorbidities (central venous access device dependence, tracheostomy, chronic lung disease) continue to require complex care from multidisciplinary teams. medical conditions associated with athymia but not alleviated by thymus transplantation, such as hypoparathyroidism or cardiac defects, may require lifelong medical care. lastly, patients must be evaluated for readiness for killed and live vaccines. transplant outcomes are influenced by the clinical condition at the time of rvt-802 implantation and optimization of immunosuppression, nutrition and clinical stability in the first 9 months following rvt-802. clinical care that maintains a well-nourished, clinically stable, infection free patient yields the best chance for successful t cell development. guidance documents supporting these goals ensure patients are best prepared to receive rvt-802 and develop long lasting thymic function. hemophagocytic lymphohistiocytosis (hlh) is a life-threatening disease of immune dysregulation characterized by unchecked inflammatory responses leading to end-organ dysfunction. primary hlh results from inherited mutations that impair capacity for immune regulation whereas secondary hlh arises from inappropriate response to an immune stimulus such as infection, malignancy or autoimmunity. we report a 9-monthold male who presented with symptoms of hlh as an initial manifestation of congenital disorder of glycosylation (cdg) due to mutations in the gene component of oligomeric golgi complex 4 (cog4) resulting in cog4-cdg (cdg-iij). a 9-month-old male with history of mild motor delay presented with 3 days of fever, vomiting, and diarrhea. initial evaluation identified highly elevated ferritin and triglycerides, transaminitis, coagulopathy, and hyperammonemia. he subsequently developed generalized seizures. liver and bone marrow biopsies demonstrated erythrophagocytosis consistent with hlh. immunologic evaluation was notable for mild hypogammaglobulinemia, neutropenia, thrombocytopenia, and anemia. serum cd25 levels and nk functional studies were later found to be normal. the patient was initially treated with ammonia-scavenger therapy and fresh frozen plasma (ffp) for coagulopathy with subsequent intravenous immunoglobulin and dexamethasone several days later. within 24 hours after starting ffp, the patients ferritin level declined sharply. hyperammonemia and transaminitis also resolved, and his fever curve improved. additional immunosuppression was considered, but not initiated due to the patients ongoing clinical improvement. over the next 3 months, the patient experienced two further acute episodes of fever, liver dysfunction, coagulopathy, and sepsis physiology. the second episode was successfully treated with ffp, though no clear infectious trigger was identified. the third episode occurred 4 days after routine vaccinations. the patient had prolonged hypotension requiring ionotropic support that resolved after receiving daily ffp, and hypoxia with pleural effusions that resolved after a single treatment with protein c concentrate. as the patient had met 5/8 clinical diagnostic criteria for hlh, but also had a history of hyperammonemia, he underwent concurrent biochemical and genetic evaluation for both primary hlh and inborn errors of metabolism. whole exome sequencing identified compound heterozygous mutations in cog4, part of an oligomeric protein complex involved in golgi apparatus structure and function. cog4 mutations have previously been reported in two patients with autosomal recessive cog4-cdg (cdg-iij), who were described to have similar clinical symptoms of hypotonia, seizures, coagulopathy, and liver dysfunction, as well as recurrent infections. subsequent immune phenotyping while the patient was healthy was notable for slightly low numbers of nk cells, but normal cd107a mobilization and perforin/granzyme b expression in vitro. our patient represents a novel presentation of cdg due to cog4 defect with associated immune dysfunction manifesting as recurrent episodes of inflammatory crisis with features of hlh. cdg and inborn errors of metabolism should be considered during diagnostic evaluation for patients with hlh symptoms, as cdg patients may develop acute episodes of severe inflammation, in the absence of cellular regulatory defects, for which ffp and protein c concentrate may have therapeutic value. of the 14 deaths with identifiable causes, 10 (71%) were related to infections. the rate of death per person-year was 0.044. the most common autoimmunity-related complication was sweets syndrome, seen in 29 patients (39%) with anti-ifn-g autoantibodies. sixteen of those patients (55%) had recurring sweets syndrome. additionally, 14 patients (19%) developed lymphatic obstruction, which continued to recur in 12 patients (86%). seven patients (9%) in this study did not have anti-ifn-g autoantibodies. the median [iqr] age of autoantibody-negative patients was 38 [27, 54] years and 3 patients (43%) were female. none of the autoantibody-negative patients developed new infections during follow-up. at the end of the follow-up period, none of the patients had active/progressive disease and 2 patients (29%) had died. conclusions: ninety-one percent of hiv uninfected thai patients with disseminated ntm infection with or without other opportunistic infections had detectable anti-ifn-g autoantibodies. about one third of patients with autoantibodies to ifn-g had recurrent infections during follow-up. after approximately 7 years of follow-up, 55% of patients with anti-ifn-g autoantibodies had inactive disease following multi-drug antibiotic therapy while 8% had active/progressive disease and 24% had died. patients with anti-ifn-g autoantibodies are at risk for recurrent infections and autoimmunity-related complications. therefore, longterm follow-up is recommended. life-long secondary antibiotic prophylaxis may be required to prevent recurrence of infection in the setting of persistent anti-ifn-g autoantibodies. the study of early t cell development in patients with severe t cell immunodeficiencies is challenging because of the rarity of these diseases, the difficulty to obtain hematopoietic stem cells (hscs), and limitations in the assays to assess in vitro differentiation of hscs to mature t cells. we recently developed a serum-free system that allows faithful analysis of sequential steps of t cell differentiation. in this system, artificial thymic organoids (atos) are generated, based on the 3d aggregation and culture of a delta-like canonical notch ligand 4 (dll4)-expressing stromal cell line (ms5-dll4) with cd34+ cells isolated from bone marrow (bm) samples of normal donors (nd). in this project, we set out to evaluate the possibility of using the ato system to study t cell differentiation in patients carrying t cell defects, in order to define the exact steps of t cell development affected by different genetic defects. using the ato system, we studied in vitro t cell differentiation from cd34+ cells obtained from patients carrying defects that are intrinsic to hematopoietic cells (rag1, rag2, ak2, il2rg) or that affect thymus development (digeorge syndrome, dgs). the ak2-deficient patient showed a markedly decreased viability in cd34+ cells and a very early defect in t cell development, already at the pro-t cell stage. this defect was very similar to that observed in a patient carrying a null il2rg mutation who was reported to show autologous reconstitution after unconditioned haploidentical hsc transplantation. in contrast, cd34+ cells from a patient carrying a missense il2rg mutation and with a leaky scid phenotype were capable of differentiating into mature t cells in vitro, although with 100-fold decreased efficiency as compared to normal donors (nd). interestingly, in the patient carrying the null il2rg mutation, we noticed very few cells that could reach full maturation, with an absolute number of cd3+ tcrab+ cells around 1000-times less than in nd. at variance with pro-t cells (that failed to express the gc protein), these mature t cells did express normal levels of gc, suggesting that they may have derived from residual cd34+ cells from the bm donor. in addition, cd34+ cells from the patients carrying rag1 and rag2 hypomorphic mutations were able to differentiate to cd4+cd8+ double positive cells, but not to cd3+tcrab+ cells. finally, the dgs patient showed a completely normal in vitro t cell differentiation, confirming that t cell deficiency reflected thymic abnormalities. in summary, our data show that the ato system could be extremely useful in determining whether the lack of t cells in patients with unknown gene defects reflect hematopoietic or thymic intrinsic problems, and may therefore provide critical evidence in deciding whether hsc or thymus transplantation is warranted, even without knowing the actual gene defect. introduction: ataxia-telangiectasia (at) is an autosomal recessive disorder caused by mutations in the ataxia telangiectasia mutated (atm) gene, which aids in detection and repair of dna damage. at is characterized by progressive cerebellar ataxia, oculomotor apraxia, choreoathetosis, conjunctival telangiectasias, variable degrees of t-cell lymphopenia (tcl) and immune compromise. patients are at an increased risk for malignancy, particularly leukemia and lymphoma, and are unusually sensitive to ionizing radiation. with the advent of trecbased newborn screening (nbs) for scid, at patients are being recognized with asymptomatic tcl in early infancy. objectives: we present an older child with at and chronic granulomatous lesions and discuss how this may be avoided in individuals with at diagnosed following abnormal nbs. case report: a 12 y/o male was born at term following an uncomplicated twin pregnancy and delivery, prior to institution of scid nbs. he demonstrated mild gross motor and speech delay as an infant and was diagnosed with at at age 3. he had received all routine immunizations, including live vaccinations. he developed granulomatous skin lesions at age 1, initially small papules on his cheeks and ears, which subsequently formed large disfiguring plaques on sun-exposed areascheeks, arms and hands (fig 1) . following an extensive workup, his lesions were found to be secondary to a mutated vaccine-strain rubella (ra27/3) based on 739bp genotyping, previously described in other immunocompromised individuals [perelygina/sullivan et al. jaci 2016] . his lesions have been refractory to multiple treatments including nitazoxanide. he is currently on daily oral and topical steroids, tmp/smx and ivig. retrieval of his nbs for trec determination revealed that he would have screened positive [mallot/puck et al. j clin immunol 2013] . when first measured at age 3, cd3 t-cells were low, 443/ul, with cd4 227/ul and cd8 140/ul. b and nk cell numbers were normal. since april 2017, 4 cases of at were seen at ucsf in infants with non-scid tcl on nbs. these 3 males and 1 female were all born at term and discharged from well-infant nurseries. at was diagnosed at 2-7 months of age. their initial trecs ranged from 5-12/ul (normal with perkinelmer enlite kit >18), and all had low t-cells on initial flow cytometry (242-1612 cd3/ul, ref range>2500) with decreased cd4 (146-1178/ul) and cd8 (87-403/ul) t-cells; however naã¯ve t-cells were present, ruling out typical scid and raising concern for non-scid tcl. three infants also demonstrated low b-cells (<20-77/ul), while nk cells were normal in all. two are currently receiving ivig, one of whom is also on tmp/smx. all have avoided not only rotavirus but also mmr and varicella live vaccinations. conclusions: at is now often diagnosed in infants with low trecs on scid nbs, prior to neurologic manifestations. benefits of early diagnosis include avoidance of live vaccines, including mmr, which led to the debilitating granulomas in our older patient. additionally, patients receive prompt immunologic monitoring and treatment, avoidance of unnecessary radiation, specialty referrals and family genetic counseling. while there is no cure for at, ongoing research may bring neuroprotective treatments in the future. introduction: subcutaneous immune globulin 20%, ig20gly, was well tolerated in the phase 2/3 north american study in patients with primary immunodeficiency diseases (pidd). here we assess comorbidities, use of concomitant medications, infusion parameters, and tolerability in advanced age patients (60 y) treated with ig20gly in the north american study. methods: patients aged 2 years with pidd received weekly ig20gly infusions at volumes 60 ml/site and rates 60 ml/h/site for~1.3 years in the north american study (nct01218438). the medical history at baseline, medical conditions that were ongoing (defined as comorbid events), use of concomitant medications, adverse events (aes), tolerability, and infusion parameters were assessed by age: in advanced age patients (60 y; n=14), adult (16<60 y; n=39), and pediatric/adolescent patients (<16 y; n=21). results: the mean number of medical history events at baseline was higher in advanced age patients (28.7 events/patient; 402 events in 14 patients) versus adult (16.8 events/patient; 657 events in 39 patients), and pediatric/adolescent patients (6.5 events/patient; 137 events in 21 patients). of these, the medical conditions that were ongoing at baseline (comorbid events) were also higher in the advanced age patients (20.9 events/patient; 292 events in 14 patients) versus adult (12.4 events/ patient; 482 events in 39 patients), and pediatric/adolescent patients (3.4 events/patient; 71 events in 21 patients). in the advanced age patients, neurological comorbidities (51 events) were the most common, followed by those related to eyes, ears, nose, and throat (49 events), gastrointestinal (43 events), and musculoskeletal comorbidities (43 events). concomitant medications were given to treat a preexisting condition in all patients in the advanced age group (225 medications in 14 patients). despite the higher mean number of comorbid conditions, infusion parameters in the advanced age patients were comparable to those in the adult age group. median maximum infusion rates and infusion volumes/site were comparable in the advanced age patients (60 ml/h/site; 47.5 ml/site) and adults (60 ml/h/site; 44 ml/site); lower infusion rates and volumes/site were reported in the pediatric/adolescent patients ( . larger infusion volumes and faster infusion rates were not associated with increases in causally related local aes in the advanced age group, consistent with the trends seen in the pediatric/ adolescent and adult patients. conclusions: despite the higher mean number of comorbidities in advanced age patients with pidd, ig20gly was infused at relatively high rates and volumes and was well tolerated. introduction: hyqvia (ighy; immunoglobulin infusion 10% with recombinant human hyaluronidase [rhuph20]) is an immunoglobulin (ig) replacement therapy approved for patients with primary immunodeficiency diseases (pidd) that allows larger infusion volumes, up to 600 ml/site, and has improved ig bioavailability compared with conventional subcutaneous ig products. a post-authorization safety study is being conducted in the united states to acquire long-term safety data on ighy and to assess prescribed administration regimens in routine clinical practice. infusion characteristics and treatment-related adverse events from an interim analysis are reported here. methods: patients aged 16 years with pidd receiving ighy were included in this ongoing, prospective, non-interventional, open-label, uncontrolled, multicenter study. as a part of routine clinical practice, patients are treated with ighy according to standard medical care and their treatment regimen is at the discretion of the treating physician. adverse events (aes) are collected from enrollment to study completion/discontinuation using a subject diary and assessed at every study visit (every 3 months or standard practice). aes are assessed based on seriousness, severity, and causal relatedness to ighy. the presence of anti-rhuph20 antibody is evaluated on a voluntary basis. treatment preferences for various attributes of ig therapy were assessed annually using a treatment preference questionnaire. results: a total of 175 patients were enrolled at 26 us study sites (data cutoff date: august 21, 2017). infusions were self-administered at home (56%) or at the clinical site (44%) most commonly using 4-week infusion intervals (56.6%). the mean maximum ig infusion rate was 302.8 ml/h and the mean ig dose was 418 mg/kg bodyweight/4weeks. the mean number of infusion sites used for administration was 1.9 and mean infusion duration was 2.8 hours. most infusions (97.3%) were administered without a rate reduction, interruption, or discontinuation due to aes. there were no serious aes (saes) related to ighy. sixteen patients experienced a causally related non-serious local ae (9.1%; 0.43 events/patient-year, 0.07 events per infusion) and 25 patients experienced a causally related non-serious systemic ae (14.3%, 0.88 events/patient year, 0.14 events per infusion). seven of 113 patients who were tested for anti-rhuph20 antibody had 1 positive binding antibody test to rhuph20 (titer 1:160; maximum titer 1:10240 at enrollment, 1:5120 during the study); no neutralizing rhuph20 antibodies were detected. of the patients who responded to the treatment preference questionnaire at the end of year 1, the majority (38/52 [73.1%]) preferred to receive their ig therapy at home; 21.2% (11/52) preferred the doctors office; 3 patients preferred treatment at the hospital, had no preference, or indicated other. almost all patients (51/52 [98.1%]) indicated a preference to continue treatment with ighy. conclusion: this interim analysis of 175 patients with pidd treated with ighy in routine clinical practice supports previous observations that ighy is a well-tolerated and preferred therapy with no reports of treatment-related saes or neutralizing anti-rhuph20 antibodies. background: cartilage hair hypoplasia (chh) is an autosomal recessive chondrodysplasia associated with variable immunodeficiency. pathogenic defects in rmrp, encoding the untranslated rna subunit of ribonucleoprotein endoribonuclease complex (rmrp), result in reduced mrna and rrna cleavage. rmrp c.70a>g is the most common variant, increased in finnish and amish populations. while cellular immunodeficiency is associated with increased morbidity and mortality, there is no established correlation between clinical and immunological phenotype. lymphocyte radiosensitivity has not been described. case: a full-term amish female infant had low trec copies on newborn scid screen. flow cytometry at 3 months-old demonstrated severe t and b cell lymphopenia (cd3+t-cells 413 cells/mcl, range: 2,300-6,500 cells/mcl; cd19+b-cells 214 cells/mcl, range: 600-3,000 cells/mcl) with normal nk quantitation (cd16/56+ 340 cells/mcl, range: 100-1,300 cells/mcl) and cd4+ memory t-cell expansion (33.2%) relative to the naã¯ve subset (67.0%). t-cell functional mitogen responses were normal. she was diagnosed with chh with homozygous rmrp c.70a>g mutation. lymphocyte subset (t, b and nk cells) radiosensitivity was evaluated by flow cytometric analysis of phosphorylated (p) atm, smc1 and gamma-h2ax after low-dose (2gy) irradiation. an increase in gamma-h2ax level was observed in a subset of non-irradiated t cells (17.66% v. 1.36% gamma-h2ax+) and nk cells (23.07% v. 1.04% gamma-h2ax+) in the patient, suggestive of a constitutive defect in dna repair. the relative distribution of t, b and nk cells expressing patm, psmc1 and gamma-h2ax at 1 hour postirradiation (ir) was not significantly different from the experimental healthy control (ehc) or pediatric reference range (prr). however, the kinetics of dephosphorylation at 24 hours post-ir was altered with residual gamma-h2ax expression in a subset of the patients t cells (delta 3.84%, mode ratio mean fluorescence intensity (mfi)=2.58; ehc: delta 0.10%, mode ratio mfi=1.39; prr: delta 2.16%, mode ratio mfi=2.42). a similar finding was observed in a subset of patient b-cells for gamma-h2ax (delta 11.35%, mode ratio mfi=1.48; ehc: delta 0.82%, mode ratio mfi=0.86; prr: delta 1.95%, mode ratio mfi=1.19). the frequency of the patient's lymphocytes with residual gamma-h2ax persistence at 24h post-ir was prominent, with 8.29% t-cells demonstrating persistence of gamma-h2ax (compared to 0.82% in the ehc, and 2.60% in the prr), and 18.02% b-cells gamma-h2ax+ (compared to 1.80% in the ehc, and 2.96% in the prr). there has been lack of follow-up, but verbal report suggests no significant immunological or infectious concerns at 1 year of age. discussion: lymphocyte radiosensitivity is a novel finding in chh with t and b cell lymphopenia. the ability of rmrp to associate with telomerase reverse transcriptase (tert) and function as an rna-dependent rna polymerase, yielding distinct silencing rna sequences, may underlie radiosensitivity in rmrp mutants. systematic characterization of lymphocyte radiosensitivity and immunological phenotype could provide useful information on whether this could serve as a biomarker for the magnitude or complexity of immunodeficiency. assessment of radiosensitivity has implications in conditioning regimen selection for patients requiring allogeneic hematopoietic cell transplantation. we recommend lymphocyte radiosensitivity assessment in chh infants identified by nbs scid and chh patients with significant immunodeficiency and/or malignancy. novel primary immunodeficiency with lymphoproliferative disease due to biallelic defects in nckap1l background: three children from 2 non-consanguineous families and different ethnic backgrounds developed lymphoproliferative disease by 2 years of age. they also had recurrent infections, including pneumonia and bronchiectasis, otitis media, and skin pustules. immune phenotyping revealed low cd4+ t cell percentages, an accumulation of memory-like cd8+ t cells, impaired t cell proliferation, and low total nk cell numbers. methods: the affected individuals, unaffected parents, and other unaffected family members underwent exome sequencing. results: all 3 affected cases had rare and bioinformatically damaging biallelic variants, with appropriate familial segregation, in nckap1l, which encodes hem1. hem1 is an essential component of the wave2 regulatory complex (wrc). immunoblotting confirmed destabilization of the wrc in all patients. immunofluorescence microscopy demonstrated defective f-actin and wave2 localization to immune synapses in nk cells. significant abnormalities were identified in patient lymphocyte and neutrophil migration and morphology, consistent with altered wrc-mediated cytoskeletal dynamics. all patients exhibited impaired inside-out integrin activation. knockdown of hem1 produced deficient proliferative responses and mtorc2-mediated akt activation in control t cells. conclusions: the immunologic and clinical phenotype in the affected individuals recapitulates the phenotype observed in hem1-deficient mice. biallelic defects in nckap1l therefore result in a novel human primary immunodeficiency disease characterized by lymphoproliferation and susceptibility to infections. background: concurrent existence/significance of immunodeficiency with new onset lymphoproliferative disease remains understudied. just two studies to date have evaluated the prevalence of hypogammaglobulinemia in chronic lymphocytic leukemia (cll) and neither studied prevalence and impact of ige deficiency on outcomes in cll [1, 2] . therefore, the objective of this study was to examine the prevalence of hypogammaglobulinemia, examining all isotypes, in newly diagnosed cll patients and to test the hypothesis that patients with hypogammaglobulinemia have a distinct clinical profile and outcome. methods: using the banked sera of 150 newly diagnosed, treatmentnaã¯ve, cll adult patients from the lymphoma molecular epidemiology resource (l-mer), ig (igg, iga, igm and ige) levels were measured. the l-mer was initiated as an observational cohort study of prospectively enrolled newly diagnosed lymphoma patients evaluated at the mayo clinic (rochester, mn) and the university of iowa (iowa city, ia) [3] . igg/a/m levels were measured using immunoturbidimetric assay whereas the ige level was determined using electrochemiluminescence immunoassay. the associations between ig deficiencies and clinical factors were evaluated with wilcoxon rank sum and chi-squared (fishers exact, where appropriate) tests. cox regression models were used to assess the effects of clinical variables on overall survival (os). time was calculated from biopsy to death due to any cause; patients still alive were censored at last contact. all tests were two-sided and assessed for significance at the 5% level using sas v9.4 (sas institute, cary, nc). results: the mean age (sd) of the selected cll cohort was 63.8 (11.0) years with a male predominance (69.3%). 96.2% of the patients were white. with a median follow-up of five years, there were 50 deaths. hypogammaglobulinemia in newly diagnosed, treatmentnaã¯ve cll was common in our cohort with 88 (58.7%) patients having a measurable isotype deficiency. the most common ig deficiency was igm (44.0%, 95% ci 35.9-52.3%), followed by igg (34.7%, 95% ci 27.1-42.9%), ige (16.7%, 95% ci 11.1-23.6%) and iga (12.0%, 95% ci 7.3-18.3%). multiple deficiencies in the same patient were common ( figure 1 ). iga and ige deficiency were associated with higher rai stages (grading system for cll) at presentation (p<0.01 and 0.04 respectively) as well as with higher white blood cell counts at presentation (p=0.02 and 0.01 respectively). a higher proportion of iga deficient patients needed second treatment during follow-up (61% compared to 36%, p=0.04). when comparing predictors of overall survival, higher rai stage [3-4 vs 0, hazard ratio (hr) 2.43, 95% ci 1.08-5.46, p=0.03] and age (hr 1.08, 95% ci 1.05-1.12, p<0.01) correlated with worse overall survival. individual immunoglobulin deficiencies did not correlate with overall survival. conclusions: a significant proportion of treatment-naã¯ve patients with cll have underlying ig deficiencies-both in isolation and a combination of different isotypes. a deficiency of iga or ige was associated with severe disease at presentation. the underlying relationship between these two immunologic disorders deserves further study. background: patients with primary immunodeficiency (pid) have an increased risk of developing autoimmune diseases, including rheumatoid arthritis (ra). management of these patients is challenging as immunomodulators can further increase their risk for infections. additionally, patients with ra that undergo therapy with drug modifying antirheumatic drugs (dmards) may develop a secondary immunodeficiency. there are few studies reviewing the characteristics of patients with a pid who later develop ra, and no studies have been reported comparing these patients to those who develop an immunodeficiency after starting dmard therapy for ra. methods: 65 patients were identified as having inflammatory arthritis and a concomitant immunodeficiency (id) at our institution between 1/1/2000-10/03/2017 using icd-9 and 10 codes. manual chart review was performed to confirm and identify the timing of diagnosis of these disorders. patients were excluded if either there was no definitive diagnosis of id or ra (clinically diagnosed by a practicing allergist/immunologist and meeting acr 2010 criteria for ra with a score of 6 or higher, respectively), or rituximab was administered prior to diagnosis of id . clinical symptoms, treatment, and laboratory data were extracted. fishers exact test was used to compare the categorical variables between the groups; ttest was used to compare the continuous variables. results: 10 patients met the inclusion criteria. 5 patients were diagnosed with an id and developed ra later in life (group 1), and 5 patients were diagnosed with ra and subsequently developed a clinically significant id (group 2). the mean ages of diagnosis of id and ra in group 1 patients were 32.0 years (sd â± 26.9) and 42.6 years (sd â± 19.0), respectively. in group 2, the mean age of diagnosis of ra was 37.8 (sd â± 14.2), compared to 54.8 years (sd â± 12.7) for the diagnosis of id. most patients in both groups were female (60% in group 1 and 80% in group 2). all patients in both groups had a humoral id, including common variable immunodeficiency (cvid) (40% of group 1 patients), specific antibody deficiency (sad) (20% of group 1 and 60% of group 2 patients), and hypogammaglobulinemia (20% of group 1 and 40% of group 2 patients). all patients in group 2 were seropositive for rheumatoid factor (rf) or anti-cyclic citrullinated peptide (anti-ccp), whereas only 20% of patients in group 1 were positive for rf or anti-ccp (table 1 ). most patients in both groups were treated with immunoglobulin replacement therapy. treatment of ra in both groups was similar, but combination dmard therapy was not used in group 1 patients in contrast to group 2 patients. conclusions: our study indicates that even though clinical characteristics and management are similar in patients with coexisting id and ra, rf and anti-ccp are usually negative in patients who develop ra after id, possibly due to impaired antibody production in immunodeficient patients. assistant professor of allergy and immunology, arkansas children's hospital, university of arkansas medical sciences introduction/background: complement deficiencies are relatively rare, comprising less than 1% of primary immunodeficiencies. they are associated with increased risk for infections with encapsulated organisms and autoimmunity. of all complement deficiencies, the rarest are defects in the alternative complement pathway. properdin deficiency is the most commonly described alternative pathway deficiency, with factor b and factor d deficiency more rarely described. fewer than 5 patients with factor d deficiency have been reported with all reported cases being children of consanguineous parents who succumbed to meningococcal sepsis. objectives: to describe a case of factor d deficiency associated with recurrent respiratory infections with streptococcus pneumoniae pneumonia with associated lung abscess and empyema. methods: retrospective chart review was conducted. laboratory investigations included lymphocyte immunophenotyping by flow cytometry, lymphocyte proliferation to mitogen, quantitative serum immunoglobulins, vaccine titers, complement assays and functional evaluation, and genetic evaluation by next generation sequencing. results: a 2 year old marshallese male was transferred from an outside hospital to our facility for further evaluation of worsening pneumonia and was found to have right-sided pleural effusion and pulmonary abscess in the right lower lobe. the abscess was drained and was found to be positive for streptococcus pneumoniae via polymerase chain reaction. he improved after chest tube placement and treatment with intravenous antibiotics. his medical history was significant for recurrent acute otitis media and prior hospitalization out-of-state for pneumonia with empyema secondary to streptococcus pneumoniae, which required chest tube placement and admission to the pediatric intensive care unit at 18 months of age. immunologic work up revealed age-appropriate lymphocyte subpopulations, lymphocyte proliferative responses to mitogens, quantitative immunoglobulin levels, pneumococcal/tetanus/diphtheria titers, and ch50 complement assay. ah50 complement assay was decreased to 44 units/ml. complement testing was repeated -with normal ch50 and ah50 of 0 units/ml. further evaluation revealed normal levels of factors b, h, i and properdin. factor d level was 0.12 mcg/ml, and factor d function was decreased to 2 units/ml, indicating a diagnosis of factor d deficiency. sequencing of the cfd gene revealed a previously undescribed homozygous deletion (c.721_723del and p.lys241del). the parents were not agreeable to personally undergoing genetic evaluation to determine if this was a de novo mutation. the patient was managed with pneumococcal and meningococcal immunizations, prophylactic amoxicillin and intravenous gamma globulin (ivig) without any further infections. unfortunately, after two ivig infusions, he was lost to follow up. conclusion: factor d deficiency is an extremely rare alternative complement pathway deficiency, described in less than 5 patients. all infections described thus far have been secondary to neisseria meningitidis. this case represents not only a novel mutation in the cfd gene leading to factor d deficiency, but also the first description of a patient with factor d deficiency developing invasive infection secondary to streptococcus pneumoniae. background: viral infections are a significant cause of morbidity and mortality in patients with primary immunodeficiency disorders and following hematopoietic stem cell transplantation. adoptive immunotherapy using virus specific t-cells (vsts) has been shown to prevent and treat viral infections in immunocompromised hosts. human parainfluenza virus-3 (hpiv3) is a common cause of severe respiratory illness in immunocompromised patients and has no approved antiviral therapies and has not previously been used as a target for t cell therapeutics. introduction: we previously reported that fatigue is increased in common variable immunodeficiency (cvid). however, in previous studies, fatigue was not defined using validated tools. our aim from this study is to identify the prevalence of patient-reported fatigue, using validated questionnaires, and determine the factors predisposing to fatigue in cvid methods: data from cvid who responded to the idf 2017 patient national survey a were analyzed. fatigue was measured using the brief fatigue inventory (bfi) questionnaire, which includes seven items to identify fatigue, and measure fatigue severity. a total of 555 patients with cvid and responses to bfi were enrolled. demographics, co-morbidities, immunoglobulin replacement therapy (iggrt) route and dose, co-morbidities, infections, depression, quality of life (qol) (using the sf-12v2) and disability were compared between fatigued and non-fatigued. logistic regression was used to identify the significant variables. ebv reactivation without ptld, treated with rituximab. alive and well. j clin immunol (2019) 39 (suppl 1):s1-s151 s58 granulomas are the most significant day-to-day problem for cvid patient management. currently, there are limited options for their treatment and the optimal therapy is unknown. in case reports and small series, infliximab has been reported effective while others found it useless. we here describe a 26yo white male referred for monthly ivig in august 2016. at age 1, he developed large areas of erythematous polymorphic plaques in his cheeks, arms and legs. a skin biopsy showed tuberculoid granulomas negative for bacteria, baar and fungi, with infiltrating cd4+ lymphocytes. a prolonged course of steroids did not improve his skin. he also had multiple pneumonias and bronchiectasis, and oral candidiasis. he received all vaccines, including bcg with no complications. with low immunoglobulins and a poor response to pneumococcal polysaccharides and tetanus toxoid he was diagnosed as cvid and placed on ivig at 7yo with excellent infectious control since then. at age 8, his skin lesions persisted and deepened to the bone on his left leg. broad spectrum antibiotics for 3 months were unsuccessful. at 16yo to 18yo, skin grafts were performed on his arms, legs and both cheeks. two ulcers persisted on his left leg until august 2018 that increased in size, deepened and became erythematous and extremely painful (fig. 1) . in september, two new ulcers appeared on his right cheek and right gluteus, respectively. one week later a third ulcer was found on his left calf. on september 28th, infliximab 5mg/kg (300mg) was administered. on the second infliximab dose, october 12th, the pain was completely gone and all ulcers were shrinking, and those ones in the cheek, gluteus and calf almost completely resolved. by the third dose, on november 23rd the ulcers in his right leg were almost closed (fig. 2) . infliximab 300mg treatment continues every 8 weeks. lab test remained unchanged from 2016 till 2018, when his wounds got worsened. (table 1 ) granulomatous disease in cvid is a challenge. both b and t cell directed therapies are encouraged. we add a new case of an infliximab responsive patient to others already reported. over 20 genes have been reported to cause monogenic cvid. a 4 year old girl presented with recurrent pneumonias and a diagnosis of cvid. the parents sought a second opinion. born at 33 weeks gestational age, she was "always smaller and sicker than her friends," and in the prior 8 months she had 3 episodes of pneumonia with fever to 104f requiring emergency department treatment. two of these were associated with rsv and metapneumovirus, respectively. laboratory evaluation confirmed low levels of igg (326 mg/dl) iga (7) and igm (6) congenital tuberculosis (ctb) is a rare disease most often associated with maternal genitourinary (gu) tuberculosis (tb) or disseminated tb. due to infertility caused by gu tb, ctb is rarely reported even in endemic countries. infants can acquire tb hematogenously via the placenta or umbilical vein or by fetal aspiration of infected amniotic fluid. presenting symptoms include respiratory distress, fever, hepatosplenomegaly, poor feeding, lethargy, and low birth weight. we report a premature female infant conceived via in vitro fertilization (ivf), who was born to indian immigrant parents at 29 weeks of gestation due to preterm premature rupture of membranes. maternal history was significant for pulmonary tb at 9 years of age. she denied abdominal or gu symptoms. infants nicu course was complicated by opacifications in the right lung and leukocytosis with neutrophil predominance, identified during evaluation of frequent apnea and bradycardia episodes at 1 month of age. clinical improvement was noted after treatment with vancomycin, amikacin and piperacillin-tazobactam; however, leukocytosis of unknown etiology persisted. at 1.5 months of age she was discharged to inpatient rehabilitation. at 3 months of age, she was readmitted for fever and respiratory distress. during this admission, an immune evaluation was undertaken due to persistence of symptoms along with unresolved leukocytosis with a peak of 58,000 cells/l with neutrophilia to 42,850 cells/l, and chest ct evidence of progressive multifocal lung disease worse in the right upper lobe despite empiric treatment with broadspectrum antibiotics. infectious work-up was negative, including acid-fast bacilli testing from bronchoalveolar lavage. due to the pronounced and persistent leukocytosis and neutrophilia, a primary immune defect was suspected. immune evaluation included: normal immunoglobulins (ig) g, a, and e, elevated igm, vaccine-specific antibody titers protective to diphtheria and 9 of 13 streptococcus pneumonia strains, mildly elevated t and b cells, a normal flow cytometry for dihydrorhodamine, myeloperoxidase stain and glucose-6-phosphate dehydrogenase level, as well as a peripheral smear with no giant azurophilic granules. her primary immunodeficiency genetic panel was unrevealing. she underwent lung biopsy via video-assisted thoracoscopic surgery, which showed noncaseating granulomas and eventual growth of multi-drug-resistant mycobacterium tuberculosis (mtb). upon treatment with an appropriately adjusted anti-tuberculosis regimen, she showed rapid clinical and laboratory improvement. endometrial samples obtained from mother showed gu tb, confirming the diagnosis of ctb. the slow-growing nature of mtb that resulted in delayed diagnosis, along with the presence of non-caseating granulomas and persistent neutrophilia, prompted an immune work up that was completely normal. this case demonstrates the importance of considering ctb in the differential diagnosis of an infant presenting with severe lung infection, persistent neutrophilia, suboptimal response to broad-spectrum antibiotics and relevant epidemiologic risk factors. furthermore, in the setting of appropriate parental exposures and infertility prompting the use of ivf, maintaining a high level of suspicion of ctb can aid in earlier diagnosis of affected neonates. 15-year-old caucasian male who initially presented with recurrent otitis media, persistent hsm, lad, and hypogammaglobinemia (igg <170 mg/dl) at 2 years of age. he was diagnosed with common variable immunodeficiency (cvid) and chronic arthritis when he was 6 and 9 years of age, respectively. subsequently, he developed hepatitis and recurrent pneumonia with mycobacterium avium complex (mac). his arthritis partially responded to anti-tumor necrosis factor (tnf) agents and tofacitinib, but did not respond to anti-interleukin-6 treatment. a combination of anti-tnf inhibitor, tofacitinib, and low dose prednisone was required to control his arthritis. hypogammaglobulinemia (igg <110 mg/dl), recurrent otitis media, pneumonia, crohn's disease, celiac disease, lad and failure to thrive at 2 years of age with more recent development of hsm. he required only immunoglobulin replacement therapy. case#3 is a 9-year-old caucasian male, the half-brother of case#2, who initially presented with recurrent pleural effusion and bilateral pulmonary infiltrates, hsm, lad, abdominal distension and ascites at 7 years of age. a transbronchial lung biopsy revealed chronic eosinophilic pneumonitis. liver biopsy showed increased eosinophils in the sinusoids with diffuse enlargement of hepatocytes, but without hepatitis. colon biopsy revealed minimal colonic eo-sinophilia. his pulmonary infiltrates and pleural effusion responded to prednisone, and he has not required additional treatment for past 1.5 years. conclusions: the clinical manifestations of the same genetic variant may be variable and unpredictable even in the same family. stat3 gof syndrome should be considered in children with multisystem autoimmune diseases, lad, hsm and low switched memory b cells regardless of presence of hypogammaglobulinemia or history of recurrent infections. background: patients with primary immune deficiencies characterized by severe t lymphopenia and/or poor t cell function and patients posthematopoietic cell transplantation are at high risk of severe viral infections. antiviral medications are expensive, not always effective and associated with significant toxicity and/or long-term side effects. as such, there has been increasing interest in the use of donor-derived or thirdparty virus-specific t cells (vsts), and several studies have demonstrated efficacy of vsts generated using various manufacture strategies. however, in depth immunologic and metabolic characterization of vsts has not been reported, limiting correlative investigations into efficacy. methods: ebv-vsts were generated from apheresis t cells collected from healthy donors using three methods: (1) stimulation and expansion with hla-matched ebv-lymphoblastoid cell lines (lcls) purchased from astarte biologics or sigma-aldrich over a period of 4 weeks, (2) stimulation with ebv peptivator from miltenyi followed by expansion over 9-12 days with different cytokines, and (3) stimulation with ebv peptivator followed by isolation of activated cells using the ifn-gamma capture system from miltenyi. immunophenotyping by flow cytometry was performed using the miltneyi macsquant analyzer. the nanostring ncounter system was used to measure gene expression for metabolic pathway analysis, and the agilent seahorse xf cell mito stress test system was used to measure mitochondrial respiration. results: ebv-vsts generated using lcls or peptivator plus il-15 both resulted in a high percentage of cd8 t cells skewed to the effector memory and terminal effector memory phenotype with high expression of the exhaustion markers pd-1, tim-3, and lag-3. conversely, ebv-vsts generated using peptivator plus il-4 and il-7 and the ifn-gamma capture system resulted in a mixed cd4 and cd8 t cell population with a high number of central memory t cells and lower percentage of cells positive for pd-1, tim-3, and lag-3. stimulation with peptivator followed by expansion with il-2 resulted in an intermediate immunophenotype. nanostring results demonstrated upregulation of the glycolytic pathway in ebv-vsts stimulated with peptivator followed by expansion with il-2 or il-15 compared to ebv-vsts generated using the other manufacture approaches. the seahorse mito stress test demonstrated that the peptivator plus il-2 ebv-vsts had a significantly lower spare respiratory capacity than other ebv-vsts and a low extracellular acidification rate despite upregulation of the glycolytic pathway. the peptivator plus il-4 and il-7 ebv-vsts had the highest basal oxygen consumption rate, atp-linked respiration, and extracellular acidification rate. conclusions: manufacture of ebv-vsts using the various approaches currently employed clinically results in t cell pools with different immunophenotypes and different metabolic profiles. ebv-vsts stimulated with peptivator followed by expansion in il-4 and il-7 and ebv-vsts isolated using the ifn-gamma capture system have immunophenotypes and metabolic phenotypes suggestive of potential greater in vivo persistence, whereas ebv-vsts expanded in il-2 and il-15 have characteristics correlated with increased effector function. however, these vsts are more likely to be short-lived and to have impaired metabolic fitness. these phenotypes will enable better correlation with clinical results and suggest combinatorial approaches depending on clinical indication. introduction: majority of patients with primary immunodeficiencies (pid) require life-long replacement therapy with immunoglobulins (ig) to prevent severe infections and irreversible complications. in addition to safety and efficacy, tolerability and convenience of administration of ig products are essential factors for patients. a new 16.5% ig preparation octanorm (octapharma, lachen; tradename cutaquigâ® in north america) has been developed for subcutaneous administration (scig) derived from the established manufacturing process of octapharmas intravenous ig (ivig) brand octagamâ®. objectives: primary outcome was assessment of the efficacy of octanorm in preventing serious bacterial infections. main secondary endpoints included (among others) evaluation of tolerability and safety of octanorm, the number and rate of other infections, number of days missed at work, and use of antibiotics. methods: a prospective, open-label, non-controlled, single-arm phase 3 study involving 25 adult patients with pid was conducted at 5 russian centers. patients treated with at least 4 infusions of ivig prior to enrollment and with igg trough levels 5.0 g/l underwent an 8-week wash-in/wash-out period followed by a 24week efficacy period. during the study, patients received weekly administrations of octanorm at the same monthly dose as during previous ivig treatment (monthly ivig dose divided by 4 for weekly dose). in total, each patient received 32 scig infusions. results: twenty-four patients completed the study. one patient terminated early (after infusion 7, during wash-in/wash-out phase; personal reasons). mean age was 35.24 years (range 18-64 years). fifteen patients (60%) were female and 10 patients (40%) male. no serious bacterial infections were recorded. during the efficacy period a total of 26 non-serious infections was observed in 14 patients. seventeen infections in 11 patients were of mild and 9 infections in 5 patients of moderate intensity. the infection rate per person-year was 2.37. in total 25 patients received 775 infusions of study drug. the average dose of cutaquigâ® was 0.11 g/kg/week. during the entire study, 59 systemic adverse events were reported (including 34 infections). three of these systemic adverse events were rated as related to study drug, all were non-serious. there was no serious or significant adverse event nor was there an adverse event leading to withdrawal. infusion site reactions were reported for 15% of infusions. serum igg trough levels were nearly constant during the efficacy period. median igg trough levels were 8.15 g/l at screening, 9.52 g/l at the end of wash-in/wash-out period and 10.71 g/l at the termination visit. one patient had a trough level 5g/l at 2 visits during the efficacy period and the dosing was subsequently adjusted for this patient. during the primary treatment period 10 patients (41.7%) used antibiotics in 19 treatment episodes (total of 229 treatment days; range 5-76 days) and 3 patients had 4 absences from work or school due to infections (total of 14 days of absence). conclusion: this study demonstrated that the new subcutaneous human normal immunoglobulin 16.5% is well tolerated, safe and effective in adult patients with pid. background: children with chronic granulomatous disease (cgd) are at high risk for fungal infections (especially with aspergillus species) and these infections usually have contiguous site involvement. most patients have pulmonary presentation. infective endocarditis and fungal osteomyelitis of skull are distinctly unusual. we report one such case. case: a 6-year-old boy, born out of a non-consanguineous marriage, presented with soft tissue swellings of skull for 2 months. his past history was significant with an episode of pneumonia at 1 year and recurrent soft tissue swellings all over the body since 1â½ years of age. on examination he was wasted, had signs of micronutrient deficiency, rickets, pallor, cervical lymphadenopathy and two abscesses, 12x4 cm on right temporo-parietal region and 4x3 cm over left frontal region. he was also found to have hyperdynamic precordium with an ejection systolic murmur. investigations revealed hemoglobin 85g/l; platelet count 7.34x109/l; total leukocyte count 13x109/l(n60/l23/m13/e1); elevated c-reactive protein( 244 mg/l) and a raised erythrocyte sedimentation rate(104 mm 1sthr). chest x ray revealed cardiomegaly (cardiothoracic ratio 67%) and 2d echocardiography showed vegetation of 6x3 mm over the anterior mitral leaflet suggestive of infective endocarditis. blood and urine cultures were sterile. culture from pus over the temporo-parietal abscess showed growth of aspergillus fumigatus. human immunodeficiency virus serology was non-reactive. immunoglobulin profile revealed elevated igg 21.20g/l (5.40-16.10g/l) and iga 5.66 g/l(0.5-2.4g/l); igm was 1.63 g/l(0.50-1.8g/l). in view of strong suspicion of cgd, nitroblue tetrazolium dye reduction test (nbt) was carried out-it revealed no reduction and dihydrorhodamine (dhr) assay showed a low stimulation index (4.34). flow cytometry for gp 47 phox and gp 67 phox was normal and dhr of mother did not reveal x linked carrier state. contrast enhanced computerized tomography (cect) of head showed osteomyelitis of the calvarial bones. contrast enhanced magnetic resonance imaging (cemri) brain showed heterogeneously enchancing soft tissue lesion in the scalp at right fronto-parietal region and left frontal region with underlying bony destruction suggestive of osteomyelitis. he was given intravenous antimicrobials (ceftriaxone, gentamycin, cloxacillin, voriconazole). after 6 weeks of therapy, he showed resolution of findings on mri brain and a repeat 2d echocardiography showed significant decrease in size of mitral leaflet vegetation. conclusion: this case highlights a rare presentation of cgd with infective endocarditis and skull osteomyelitis due to aspergillus fumigatus. to the best of our knowledge, this has not been reported previously. background: genetic defect in il12r1 affect cellular immunity, underlie mendelian susceptibility to mycobacterial disease (msmd) and inflammatory bowel disease (ibd) through different pathways. we present for the first time a patient with il-12r1 deficiency from a consanguine family with two different phenotypes. initially diagnosed as crohn's disease prior to the msmd diagnosis. method and material:patient was referred to the clinical immunology and allergy clinic at the at alzahra university hospital for immunological and genetic evaluation . blood samples from patient, his family and healthy donor controls were collected upon informed consent. in this study, we investigated effect of il12r1 mutation in il-12/ifnaxis by evaluation of patients whole blood cell response to il-12 and ifn-, il-12r1 expression in pbmcs and t cell blasts. also wholeexome sequencing has been performed. result and discussion: a 26 years old male from consanguine family , with history of right sub-axillary bcg lymphadenitis, recurrent mouth ulcers , chronic diarrhea in childhood and appendectomy at age of 5 was investigated. based on his clinical presentation abdominal pain, significant weight loss, chronic and bloody diarrhea , endoscopic and pathological findings treatment for crohn's disease (cd) was started at the age of seven . unfortunately, protracted patient's symptoms ends up to resection of his colon and colostomy two years later. he was presented with multi focal osteomyelitis at the age of 13 . although no bacteria was detected in pcr and tissue culture of the bone biopsy and the patient was not responded to antibacterials , he had a dramatic response to empirical anti mycobacterial treatment and his severe bone pain and lesions were healed. even though the bone manifestations were completely controlled, he continuously was under treatment for his gastrointestinal symptoms. genetic analysis was confirmed segregation of homozygous mutation in 3splice site of exon 15 in il-12r1. expression of gene was completely abolished in pbmcs of patient and the surface expression of il12rb1 was not detectable in t cell derived pbmcs of the patient compared to healthy control. furthermore, did not response to il12 stimulation since we could not detect increase of inf-after stimulation with il12 and bcg. our patient received bcg vaccination at birth and had bcg lymphadenitis as an infant, cd and mycobacterial multifocal osteomyelitis as a child. furthermore there are some evidences which indicate the role of atypical mycobacterial infections as a trigger for cd. conclusion: we reported for the first time contemporary msmd and ibd in 26 years old patient, who had impaired il-12 signaling and abolished il12 r1 expression in pbmcs and t cell blast. however, mycobacterial osteomyelitis is a typical phenotype of msmd patients with deficiency in ifn-r1 or stat, there were no mycobacterial osteomyelitis reported in il-12r1 deficient patients. background: advanced genetic studies help explain the occurrence of many undiagnosed, rare conditions. recently, nbas variants were identified as a causative basis of recurrent liver failure in infants (infantile liver failure syndrome 2, ilfs2). the nbas (neuroblastoma amplified sequence) gene encodes a protein involved in golgi to er retrograde transport. nbas functions seem to be broad and loss of function variants in nbas have been associated with multisystem manifestations. case report: a 5y 9m old chilean male presented to the er with a three day history of vomiting, diarrhea and one day of fever (38.3â°f). on examination he was pale, lethargic, and tachycardic. a chemistry profile revealed markedly elevated liver enzymes, increased bilirubin, and coagulopathy, consistent with the acute hepatic failure (alt 6291, ast >4000, total bilirubin 3.49 (2.82 db), ggt 52, and inr of 2.1). he was hospitalized, given vitamin k, and kept on intravenous fluids, ursodiol, and antipyretics. his liver function improved significantly within 5 days of admission (alt was down to 980, ast 45, total bilirubin 1.62). work-up of possible etiologies including autoimmunity and infectious hepatitis was negative. liver sonogram was normal, but liver biopsy was consistent with acute hepatitis with some necrosis. urine organic acid and plasma amino acid screens were not consistent with any inherited metabolic disorders. his parents recalled two previous episodes of liver failure at ages 3 and 4 years. both were preceded with a mild febrile illness and non-specific symptoms including fever, coughing, vomiting, diarrhea, lethargy, and decreased po intake. these subsequently were followed by jaundice and marked elevation of liver enzymes. flu a and adenovirus were identified as causes of febrile illnesses of the two previous episodes. for this admission, adenovirus was found in the respiratory secretions and a mild ebv viremia was also detected. genetic evaluation in chile was reportedly normal. after a literature review we obtained sequencing of nbas which revealed two variants: c.2827g>t,p.glu943* and nbas c.2951t>g, p.iie984ser. both variants have been previously reported in patients with an infantile onset, recurrent liver failure syndrome. his other clinical features include developmental and speech delays, failure to thrive, and facial dysmorphism. he also has a history of recurrent ear infections and has had 3 sets of tympanostomy tubes. further testing was limited due to the lack of insurance coverage. conclusion: nbas deficiency is a newly described syndrome of recurrent acute liver failure that occurs early in life. once individuals have survived to adulthood they do not seem to develop liver failure with illness. typically, liver crisis is triggered by a common childhood febrile illness. the mechanism of disease is thought to be thermal instability of hepatocytes which improves over time in most cases. however, although spontaneous recovery can occur following the crises, each episode can be fatal or result in permanent liver damage required liver transplantation. increased awareness of this disease will lead to the early establishment of the diagnosis. appropriate and timely management of fever at the onset of illness can significantly improve outcome in this potentially fatal disease. associate prof., infectious diseases and tropical medicine research center, isfahan university of medical sciences, isfahan, iran background: pre-eclampsia, a pregnancy-specific complication, has been shown to be associated with cytomegalovirus (cmv) infection. cmv specific t-cell response plays the major role in cmv infection or disease .we explored whether a change in cmv-specific cell-mediated immunity (cmi) is related to the development of preeclampsia. method: cmv-specific cmi was assessed using cmv-quantiferon (qf-cmv) assay in serum from 35 women with pre-eclampsia as well as 35 normal pregnancy controls retrospectively. participants were matched for gestational age individually. proportion of reactive results, mean value of interferon-level produced in mitogen and antigen tubes were compared between the cases and controls via chi-square, wilcoxon rank-sum tests, respectively. odds ratio (or) and confidence interval (ci) were calculated as well. result: no significant differences observed between demographic characteristics of the case and control groups. the qf-cmv assay turned reactive (qf-cmv [+]) in 22 of 35 of patients (63%) vs. 32 of 35 controls (91.4%) (p = 0.004). women with pre-eclampsia had lower mean ifn-levels in antigen tube (1.57 â± 1.79) compared with normal pregnancy controls (2.40 â± 2.21) (p = 0.028). there was no statistically significant differences in this value of mitogen tube between cases (3.53 â± 1.67) and controls (3.53 â± 1.67) (p = 0.209). women with suppressed cmv-cmi were 6.3 times more likely to manifest pre-eclampsia (or= 6.30, 95% ci: 1.60-24.7). this result even strengthened after adjustment for age, gestational age and gravidity (or = 12.86, 95% ci: 2.68-61.6). conclusion: our finding support an association between suppressed cmv specific cmi and pre-eclampsia. introduction: the triad of susceptibility to infections, auto-inflammation, and cancer in a patients personal and family history are always suggestive of an underlying primary immunodeficiency; however, in some cases the diagnosis might be delayed for years. furthermore, the results of immunological and inflammatory evaluation can also be affected by ongoing immunomodulatory therapy initiated by different specialists upon clinical diagnosis. objective: to describe a unique presentation of auto-inflammatory disease with combined immunodeficiency in an adult patient. case presentation: we report here the case of a 64 year old male, who had a long history of infections including recurrent sino-pulmonary bacterial infections starting during childhood, osteomyelitis at 7 years of age, recurrent tonsillitis requiring tonsillectomy at 21 years of age, recurrent cellulitis, an episode of prostatitis with septicaemia, as well as recurrent varicella zoster and warts. the patient was also diagnosed with sclerosing mesentheritis, and reynauds phenomenon, recurrent oral ulcers, arthritis, uveitis, autoimmune thyroiditis, lung fibrosis and suffered repeated episodes of abdominal pain. furthermore, there is a family history of early childhood death, multiple soft tissue cancers, crohns disease, and autoimmune thyroiditis. upon physical examination, the patient had multiple telangiectasia, baseline erythroderma, and flushing. immunological evaluation showed lymphopenia with significant reduction in both circulating b and t cells, however, assessment of humoral immunity revealed low igg and decreased igm with normal iga levels. at the time of the evaluation he had been on low dose daily prednisone (7.5mg), colchicine, and methotrexate as immuno-modifying therapy. genetic evaluation revealed a heterozygous mutation in nod2 as well as compound heterozygous mutations in the mefv gene. discussion: mutations in nod2 have been described in association with blau syndrome a multisystem auto-inflammatory syndrome which may explain many of the features experienced by our patient. to our surprise next generation sequencing revealed a second aberration in the mefv gene which causes familiar mediterranean fever, another multisystem auto-inflammatory disease, which might lead to the phenotype observed in the patient. conclusion: this is the first report of genetic lesions in two different genes leading to a severe course of auto inflammation. monogenic autoinflammatory syndromes (mais) are a diverse group of disorders characterized by primary over-activation of the innate immune system. induction of the inflammasome complex by innate immune sensors and increased production of il-1b are implicated in the pathogenesis of mais. macrophage activation syndrome (mas) is a life-threatening illness defined by acute hyper-inflammation and unopposed cytokine release. it is considered an acquired condition secondary to infection, rheumatoid disease or malignancy. the early therapeutic use of il-1b inhibition has profoundly improved the prognosis mas. it has recently been shown that increased free il-18 levels in the blood are causatively linked to the development of mas. significant overlap in clinical presentation and laboratory markers between patients with mais and mas led us to explore the role of free il-18 and therapeutic use of il-1b inhibition in a patient with cdc42 mutation. here, we report the case of an 18 months-old female who presented with hydrops fetalis in utero, and later developed failure-to-thrive, splenomegaly, anemia, thrombocytopenia, arthralgias, rashes, frequent febrile episodes and mild facial dysmorphism along with massive increase in crp, esr and ferritin. whole exome sequencing (wes) identified a heterogenous likely pathogenic de novo variant in cell division control protein 42 homolog (cdc42) c.563g>a (p.c188y). cdc42 encodes a small rho family gtpase that regulates multiple signaling pathways controlling cell polarity, migration, endocytosis and cell cycle progression. single allele mutations in the cdc42 gene were recently reported to cause takenouchi-kosaki syndrome manifesting with growth retardation, developmental delay, facial dysmorphism, and thrombocytopenia however systemic autoinflammation has not been described. cdc42 closely interacts with the wiskott-aldrich syndrome protein but little is known about the mechanism underlying immune abnormalities associated with cdc42 mutations. our patient had an inflammamosopathy-like syndrome. because of significant clinical overlap to mas, we measured il-6, il-18, free il-18 and il-18 binding protein, all of which were significantly increased. this increase in free il-18 heightened her risk of developing mas. her il1b level was normal, but an increase in il-1b is hardly ever detectable in the serum despite playing a critical role in this type of inflammation. indeed, chronic il-1b excess in the tissues promotes systemic inflammation and is associated with chronically elevated crp and esr. with this rationale we started the il-1 receptor antagonist anakinra. within 48 hours from starting anakinra, the parents observed an increase in appetite, resolution of arthralgias and improved mobility. over the course of the following weeks, fever, anemia, thrombocytopenia and rash disappeared, the spleen massively decreased in size and the patient started to meet developmental milestones. crp, esr eventually normalized while ferritin and free il-18 are still trending down. conclusions: significant increase in free il-18 and extremely encouraging clinical response to therapy with anakinra in a patient with novel cdc42 mutation suggests a link between mas and defects in cdc42. elucidating the mechanism of inflammasome activation and the drivers of il-18 increase in mas and mais more broadly may shed light on novel therapeutic targets like the use of human recombinant il-18 binding protein. j clin immunol (2019) 39 (suppl 1):s1-s151 s69 maintenance; smarcal1 is enriched in cells that maintain telomeres via the alternative lengthening of telomeres pathway and smarcal1decifient cells demonstrate telomere instability with replication fork collapse and increased telomere-associated dna damage. [1, 2] telomere analysis of 4 siod patients, including one patient who received a hematopoietic stem cell transplant (hsct) 20 years prior, as well as 5 heterozygous family members revealed significantly shorter telomeres in siod patients compared to heterozygous family members and compared to agematched, healthy controls. methods: peripheral blood mononuclear cells were isolated using a ficoll-hypaque density gradient, cryopreserved, then sent to repeat diagnostics in north vancouver, bc. telomere length measurements were performed at a single-cell level using flow-fluorescence in situ hybridization as previously described. [3] telomere length was measured in total lymphocytes, naive and memory enriched t cells, b cells, and nk cells and compared to reference samples from age-matched, healthy individuals. results: compared to age-matched healthy controls, three siod individuals had mean telomere lengths (mtls) less than the 1st percentile for age across all lymphocyte subsets (total lymphocytes, b cells, nk cells, naã¯ve and memory t cells). in comparison, three unaffected family members had normal mtls (10th percentile< x <90th percentile) across all subsets, and two unaffected family members had low mtls (1st< x <10th percentile) in some subsets. the siod individual who received a matched-sibling hsct 20 years prior, had normal mtl in nk cells (10th < x <90th percentile) but low mtls (1st< x <10th percentile) for all other subsets. conclusions: these data show that siod patients have significantly impaired telomere lengths across multiple lymphocyte lineages and support a limiting role for smarcal1 deficiency in telomere maintenance. in comparison, unaffected family members, heterozygous for smarcal1 mutations, have mean telomere lengths that are normal or slightly low for age. this suggests that abnormally short telomeres are seen in individuals with homozygous but not heterozygous smarcal1 mutations. for the individual who received a hsct, we do not have pre and post-hsct telomere data, but these results support obtaining pre and post-hsct telomere length analysis in future cases. abnormally short telomeres have been linked to widespread perturbation of gene expression. [4] we hypothesize that smarcal1 deficiency, by the effect of stalled forks and shortened telomeres, leads to perturbation in the transcriptome of affected tissues. shortened telomeres may explain the reduced hematopoietic bone marrow production in siod, as bone marrow failure is a cardinal feature of dyskeratosis congenita, a disorder of impaired telomere maintenance. future studies to investigate the role of telomere maintenance in siod include measurement of telomerase activity in polyclonally activated t cells and transcriptome analysis using rna-seq background: yellow fever is a potentially fatal disease for which only supportive treatment is available. vaccination is the primary strategy for prevention of this disease and the vaccine is extremely effective, but there are a few specific populations where it is contraindicated. regarding iga deficiency (the most frequent primary immunodeficiency), current recommendations in the literature are controversial. there are no specific studies in this disease, so case series addressing the safety or possible adverse events after vaccination are essential for decisionmaking during epidemic scenarios, as experienced in brazil in the last years. in this context, this study aimed to describe adverse events after the use of the yellow fever vaccine in iga deficient patients. method: a retrospective cross-sectional study was conducted including iga deficient patients followed at a specialized pediatric outpatient clinic between 2017 and 2018. all patients had at least one year of follow-up. immunoglobulin levels, antibody response to vaccines and lymphocyte subset count were evaluated to exclude other immunodeficiencies or the presence of abnormalities that could contraindicate vaccination. demographic data, the presence of infections and comorbidities, use of immunosuppressive medication and adverse events after vaccine administration of the vaccine were described. results: thirty-eight patients with iga deficiency were included in the study and 18 received the vaccine. vaccinated patients had a mean age at the time of the study of 13.7 years (sd â± 3.5y). six out of the 18 presented comorbidities: thyroiditis (n=3), type 1 diabetes mellitus (n=1), celiac disease (n=1) and juvenile rheumatoid arthritis (n=1). all patients were atopic and only one had recurrent infections in the last year despite the use of antibiotic prophylaxis. all 18 patients had normal igg and igm levels for their age, positive vaccine responses for measles, rubella and mumps, and age-appropriate lymphocyte subset count. after 6 months of observation, no immediate or late adverse events were reported. among the 20 non-vaccinated patients, only one had a formal contraindication (systemic erythematosus lupus using immunosuppressive therapy). five out of the 20 non-vaccinated patients reported being afraid of receiving the vaccine, 7 still intended to receive it and for other 7 patients data regarding vaccination was unavailable. conclusion: despite the small number of patients, the absence of adverse events in this case series suggests that immunization with yellow fever vaccine may be safe in iga deficient patients, excluded other contraindications. more studies are essential to confirm the safety and help the decision-making process regarding the vaccine administration for iga deficient patients, especially in this yellow fever outbreak scenario. introduction/backround: immunodeficiency, centromeric instability, and facial anomalies syndrome (icf) is a rare group of autosomal recessive disorders involving the triad of hypogammaglobulinemia, centromeric instability, and facial anomalies. the majority of patients have hypo-or agammaglobulinemia, but t cell defects have also been reported. we present the case of a child with icf-2 who presented with nk deficiency and ultimately developed an ebv-driven malignancy and was successfully treated with bone marrow transplant. methods: whole exome sequencing and nk cell function via 51-cr cytotoxicity assay and phenotyping via flow cytometry were performed at baylor college of medicine and texas childrens hospital. centromeric banding studies were performed at university of pittsburgh medical center. results: the female patient presented at 3 months of age with cmv pneumonitis and persistent cmv viremia requiring treatment followed by prophylaxis with valgancyclovir. she initially had hypogammaglobulinemia and low t, b, and nk cells; she had normal trecs, lymphocyte mitogen proliferation responses and zap 70, mhci and mhcii expression. the hypogammaglobulinemia and t-and b-cell lymphopenia resolved within 9 months after initial presentation as she clinically improved from her cmv infection. she was found to have nk cell deficiency on three separate commercially tested samples. whole exome sequencing revealed a homozygous variant in zbtb24 indicative of icf-2 syndrome that was confirmed with sanger sequencing (c.1492_1493del, p.q498vfs). repeat nk cell studies confirmed impaired function, and phenotyping showed an increase in cd56-bright and a decrease in cd16-positive cells, suggesting either impaired transition from immature to mature nk cells or impaired survival of mature cells. her karyotype and centromeric banding studies were normal, as were centromeric instability studies. she later developed a memory b-cell defect and presented at 34 months of age with persistent fever, respiratory distress, loss of vaccine titers, hypogammaglobulinemia and low b and t cells. she was found to have ebv viremia and an eber-positive diffuse large b-cell lymphoma in her right lung. due to tenuous clinical status, she received rituximab for treatment of ebv prior to definitive lymphoma diagnosis. she was treated with chemotherapy per protocol anhl1131, group b (pre-phase with cop, courses 1 and 2 with copadm, and courses 3 and 4 with cym) and her course was complicated by seizures attributed to methotrexate toxicity. she ultimately underwent reduced intensity conditioning with hydroxyurea, alemtuzumab, fludarabine, mephalan, and thiotepa followed by a cd-34 selected, hla-matched, unrelated donor peripheral blood stem cell transplant. her early post-transplant course was complicated by adeno-, ebv, and cmv viremia, all successfully treated with antivirals and a donor lymphocyte infusion. she is now greater than 8 months posttransplant, off immunosuppression with 100% donor engraftment, no evidence of organ toxicity or gvhd, and with excellent immune reconstitution. conclusions: this is the first reported case of impaired nk cell function and phenotype and ebv-driven malignancy in a patient with icf-2. this case expands the phenotype of icf-2 and suggests that early bone marrow transplant should be considered in these children. it also demonstrates a novel requirement for zbtb24 in human nk cell maturation and function. rationale: common variable immunodeficiency (cvid) is a disorder that affects the production of immunoglobulins and is associated with development of autoimmunity. multiple mutations have been described that are associated with cvid, but plcg2 mutations have only been described in patients with phospholipase c gamma 2 (plc2) associated antibody deficiency and immune dysregulation (plaid) and autoinflammatory plc2 associated antibody deficiency and immune dysregulation (aplaid). we present a case of a 44 y/o male cvid patient with recurrent upper respiratory tract infections, steroid-dependent autoimmune thrombocytopenia, low b cell count, hepatosplenomegaly, and restrictive lung disease. he was found with a variant of unknown significance at the plcg2 gene. in contrast to plaid our patient does not exhibit cold urticaria. method: case presentation of a cvid patient followed in our clinics. patients chart and previous laboratories were reviewed. sequence analysis and deletion/duplication cvid panel testing was performed using invitaeâ© discussion: genetic testing has revolutionized the diagnosis of immune deficiencies, but variants of unknown significance are being increasingly reported. in this case, a variant of uncertain significance was identified which replaces threonine for alanine at codon 829 of the plcg2 protein. this codon is located at the sh3 domain, which is part of a region that provides auto-inhibitory enzymatic functions. plaid mutations have been identified in sh2 domain, but it has been known that both sh2 and sh3 domains facilitate plcg association with other proteins. studies with deletion of plcg2 gene have shown functional abnormalities in b cells, natural killer cells and mast cells. to our knowledge, there has not been any previous report of a cvid patient with a variant mutation at the sh3 domain of the plcg2 gene without being diagnosed as plaid or aplaid. our patient has immunodeficiency, recurrent upper respiratory tract infections, steroid-dependent recurrent autoimmune thrombocytopenia, rheumatoid arthritis, hepatosplenomegaly, early-osteoporosis and restrictive lung disease. he does not have cold urticaria as seen in plaid, but exhibits autoimmunity not observed in aplaid. conclusion: conclusion: plcg2 is an important protein in the pathway of b cell development. a novel mutation in the sh3 domain of the plcg2 gene may be associated with the cvid phenotype of low b cells and autoimmunity. this could lead to a gain-of-function mutation as seen in plaid but without early-onset cold urticaria. functional studies are required to confirm the significance of this mutation. primary (or familial) hemophagocytic lymphohistiocytosis (hlh) is a rare, life-threatening hyper-inflammatory disease affecting mainly young children. it is caused by mutations in genes involved in the granule-dependent cytotoxic pathway, and is characterized by extreme inflammation and massive tissue infiltration by activated t cells and macrophages. to this day, hematopoietic stem cell transplantation is the only available curative treatment with a transplantrelated mortality of 30%. thus, the development of new, more efficient anti-inflammatory treatments would be a significant advancement in the treatment of hlh. here, we hypothesize that combination therapies targeting both jak-dependent and independent cytokines will be more effective than either one alone to reduce the lifethreatening symptoms induced by this pathology. using a perforin-deficient mouse model of hlh, we first compared the effect of targeting individual cytokines with blocking antibodies on the progression of the disease. we show that blocking ifng and il-18, but not il-6, significantly reduces the severity of hlh. targeting the jak-stat signalling pathway with ruxolitinib, a specific inhibitor of jak1 and jak2, downstream of ifng and il-6, but not il-18, is similarly beneficial. more importantly, combination therapies using ruxolitinib and blocking antibodies to either ifng or il-18 show synergistic effects, further mitigating the progression of the disease. these results suggest that jak-dependent and independent cytokines drive the pathogenicity of hlh in perforin-deficient mice. it further supports that ruxolitinib, although effective in reducing the symptoms of hlh, should be used in combination with anti-ifng and/or anti-il-18 antibodies to prevent hlh progression. this is particular relevant since the former were recently approved for the treatment of hlh while the latter (il-18 binding proteins) are in clinical trials for il-18-dependent macrophage activation syndromes. despite the increased risk of opportunistic lung infection in patients with severe t cell dysfunction (e.g. cd40l deficiency) and/or severe cd4 t cell lymphopenia, we are not aware of any reports of disseminated pneumocystis jiroveci infection in non-human immunodeficiency virus (hiv) patients with primary immunodeficiency (pid). we report the first case, to our knowledge, of disseminated pjp in a patient with cvid like/ctla4 haploinsufficiency. he had been diagnosed with common variable immunodeficiency (cvid) in 2009, approximately eight years prior to being referred to us, and was on intravenous immunoglobulin (ivig). he was also diagnosed with multilineage evans syndrome in 2015. his medical history was also significant for potential granulomatous lymphocytic interstitial lung disease (glild) (lung biopsy in the remote past with interstitial disease), significant splenomegaly (29.4 cm), severe portal hypertension, nodular liver disease (likely nodular regenerative hyperplasia) complicated by anasarca, history of chronic diarrhea (potential enteropathy), lymphadenopathy s/p biopsy with nodular lymphoid hyperplasia, and a history of multiple pneumonias. in 2017, he had developed disseminated pjp with lung, liver, and bone involvement. the t2 vertebra pjp invasion was confirmed with a bone biopsy; gomori methenamine silver staining and pcr were performed and concluded pjp. he was treated with trimethoprim sulfamethoxazole (tmp-smx) and steroids, then was continued on tmp-smx prophylaxis. due to his liver damage and his chronic neutropenia, tmp-smx was replaced by atovaquone as a secondary prophylaxis for pjp. his laboratory studies were significant for an absolute neutrophil count of 1.54 k/ul, absolute lymphocyte count of 0.61 k/ul, hemoglobin of 12.7 g/dl, platelets of 78 k/ul, total bilirubin of 2 . t-cell receptor beta chain repertoire analysis showed an oligoclonal distribution. severe combined immunodeficiency panel through ambry genetic testing was negative as was genetic testing for cd40l deficiency. given his complex clinical history, whole exome sequencing was obtained and detected an autosomal dominant heterozygous missense mutation (c.436g>a) implicated in ctla-4 haploinsufficiency and previously reported by schwab et al. our patient is currently undergoing therapy with abatacept (ctla-4 fusion protein), which has been reported to improve glild, splenomegaly and enteropathy in patients with ctla-4 haploinsufficiency. he is improving on this regimen. he has met with the stem cell transplant team, but at this point of time, due to his abnormal lung function, his liver damage and his significant splenomegaly, he is not a good candidate. defects in the nf-b signaling pathway are implicated in the pathogenesis of several primary immune deficiencies in humans. the clinical features of these conditions vary significantly, reflecting the complexity of the pathway, and its broad role in innate and adaptive immune responses, and the development and differentiation of lymphoid organs. here we report the first case of a human pid caused by a homozygous mutation in nfkbid in a 30 year-old male. he was the second child of consanguineous parents, and was diagnosed with possible cvid at the age of 16, after recurrent episodes of pneumococcal pneumonia. however the clinical features have evolved over time; he developed severe ebv infection at age 18, causing hepatitis and pancreatitis. at the age of 20, he presented with an anca-negative systemic vasculitis, manifesting as pulmonary haemorrhage, and acute necrotizing pauci-immune glomerulonephritis. pulsed methylprednisolone and cyclophosphamide induced an initial remission, however, relapse a year later led to end-stage renal failure. he is now dialysis-dependent, and due to the underlying pid, and chronic cmv viraemia, is not a candidate for renal transplantation. genomic dna was subjected to whole-exome sequencing. variants were filtered using a model of autosomal-recessive inheritance and functional analysis of primary cells was performed. we identified a novel, homozygous, single-base deletion resulting in a frame-shift, and premature stop in nfkbid. nfkbid encodes ibns, a non-classical inhibitor of nf-b signaling. at diagnosis the patient had reduced levels of igg2, iga and igm, elevated ige, with absent humoral immune responses to pneumococcal polysaccharide vaccine, and an intact response to tetanus. lymphocyte numbers were initially within normal reference ranges, albeit with an increased proportion of cd4+:cd8+ t cells. however, over time there has been a significant reduction in b cells and cd8+ t cells. cd4+ t cells demonstrated a skewing towards a central memory phenotype (cd45ro+/ccr7+), and cd4 t cell proliferative responses to pha were comparable to a healthy control. functional analysis of primary cells from the proband revealed a complete absence of bns protein expression, dysregulated nf-b signaling, and elevated pro-inflammatory cytokine production. the patient is currently receiving a trial of targeted therapy to modulate the aberrant immune responses. this novel pid highlights the importance of regulation of nf-b signalling, in orchestrating an appropriate immune response, maintenance of self-tolerance, and protection against viral pathogens. primary immunodeficiency diseases (pid) are a heterogeneous group of conditions with variable clinical features that are frequently associated with significant diagnostic delay. accurate diagnosis has significant therapeutic benefit and may lead to personalized therapies. we established the immunology flagship of melbourne genomics health alliance in australia to determine the clinical utility of genomic sequencing for diagnosis and management of individuals with suspected and confirmed cases of pid. 198 adults and children with suspected or confirmed pid (n=153), autoinflammatory disease (n=33) and hereditary angioedema (hae, n=11) were recruited to the melbourne genomics immunology flagship. whole-exome sequencing (wes) was performed, with targeted gene analysis. variant curation and reporting was performed according to the american council of medical genetics guidelines. overall, wes was diagnostic in 15% (30/198), confirming a preexisting diagnosis in 7% (14/198), and offering a new or more specific diagnosis in 8% (16/198). variants of uncertain significance were identified in a further 28 patients (14%) in genes known to be associated with their clinical diagnosis, that warrant further functional validation. in the hae group, diagnosis was confirmed in only 5 patients (45%), suggesting that wes may not be the appropriate technique for genetic diagnosis in this condition. a higher diagnostic rate was observed for autoinflammatory disorders (20%; 8/40) compared to pid (12%; 18/146). of those who received a diagnosis, immediate changes to patient management and treatment occurred for 17/29 patients (59%), including hsct for 3 and specific targeted therapy for 11 (38%) individuals. we have demonstrated the utility of wes for accurate diagnosis of complex immune diseases, with the potential to change diagnoses, guide therapeutic intervention and provide opportunities for genetic counseling. further longitudinal analysis will determine clinical outcomes and health economic implications of genomic sequencing for diagnosis and management of immunological conditions in australia. at birth he had neonatal asphyxia and cerebral palsy. at 4 years old he had presented involuntary movements, left paresis, bilateral horizontal nystagmus. at 8 years of age, he had a right nasal obstruction. it was resected by otorhinolist and informed by biopsy: inflammatory polyp and chronic sinusitis. he has had 3 pneumonias, sinusitis and diarrhea. at the age of 13 years, the ataxia telangiectasia was confirmed by sequencing with pcr (62 exons, 91711 bp) of the atm gene: transition g> a, nucleotide position 2250, codon 750, affecting splicing. alpha fetoprotein 572-606.90 u/ml. brain mri, say cerebellar atrophy. he had igg 685 mg / dl -734 mg / dl, iga 0.00 mg / dl, <1 mg / dl, igm 268 mg / dl -315 mg / dl, ige 0.10 -<1 iu / ml. subclasses of igg: igg3: 0.05 g / dl, igg4: 0.04 gr/dl, low. igg anti hepatitis b 6,22. no seroconversion. hiv negative tcd3 + lymphocytes: 32,40%, = 553 cells / mm3, ltcd4 +: 23,78% = 413,21 cel / mm3, ltcd8 +: 7,69% = 133,5 cells / mm3, cd4 / cd8: 3.09. for all of the above, common variable immunodeficiency was diagnosed. he receives human immunoglobulin. at 16, i arrived at this hospital due to fever, respiratory distress and lymphadenopathy in the neck. ct showed ganglionic conglomerate on right side neck. lymph node biopsy: strong tumors with cd20 and bcl2, weak and moderate diffuse pax-5; negativity with cd68, cd3 and cd10, and a cell proliferation index with ki67 of 50%, diagnosis: diffuse large b cell lymphoma. treated with rituximab and chemotherapy. lymphoma completely remitted. conclusion: the association ataxia telangiectasia and lymphoma is frequent. by contrast, cvid and ataxia telangiectasia are extraordinarily rare. introduction: chronic granulomatous disease (cgd) is a primary immunodeficiency wherein affected patients are susceptible recurrent infections caused by specific bacteria and fungi as a result of defective nadph activity. additionally, inflammatory complications involving the bowel and lungs can cause significant morbidity. currently the only proven permanent cure to cgd remains hematopoietic stem cell transplant. case: a 25-year-old patient was diagnosed in infancy with x-linked cgd. at age 5yrs he received a nonmyeloablative peripheral blood stem cell transplant from his 10/10 non-carrier sister as previously reported (nejm 344:881, 2001) . conditioning was cyclophosphamide (60 mg/kg) on d-6 and d-7; daily fludarabine (25mg/m2) on d-5 through d-1; antithymocyte globulin at 40mg/kg on d-5 through d-2. posttransplant immunosuppression consisted of cyclosporine on d-4 through d+100. he received 7.8x106 cd34+ peripheral blood stem cells which were t-cell depleted with 1x105 add back of cd3+ cells on day 0. after 10 days of neutropenia (anc <500) there were signs of engraftment. per protocol, he received donor peripheral-blood lymphocytes containing 2.0x106 cd3+ cells/kg on d+ 30 after transplantation. since donor t cells constituted less than 60 percent of his circulating cd3+ t cells and he had no graft versus-host disease, he received 1.0â¬107 cd3+ cells/kg on d+60. after the discontinuation of cyclosporine, he received a total of three donor-lymphocyte infusions (1.0â¬107 cd3+ cells/kg) at 90-day intervals achieving 100% t cell and myeloid engraftment at 26 months post-transplant with no acute nor chronic gvhd. at last follow-up 6 years post-transplant (2004) he had 100% and 98% lymphoid and myeloid peripheral chimerisms, respectively. the patient and family declined further periodic followup. then, in october 2018 he presented with malaise, cough and fevers. he eventually was found to have a large consolidation and a bal grew burkholderia cepacia. his dhr showed 12% activity and peripheral blood myeloid and lymphoid chimerisms were 12% and 60%, respectively. discussion: this late graft failure following peripheral blood transplant occurred following a conditioning regimen which is not the current standard for transplant in cgd. in the case series in which this patients transplant is reported (nejm 2001), another patients myeloid chimerism fell to 15% by 3 years post-transplant, remaining stable at that level of chimerism without any serious infections over regular periodic follow up to the present time. current regimens typically include busulfan to enhance engraftment and prevent graft failure. this case reinforces the need for prolonged monitoring of primary immune deficiency patients after transplantation. introduction: with the introduction of severe combined immunodeficiency (scid) newborn screen (nbs) in the state of kansas in 2017, a case of complete digeorge syndrome (dgs) was discovered in an infant born to a diabetic mother with atypical features. this is the first dgs case diagnosed after adding the scid nbs, which emphasizes the need to establish scid nbs in all 50 states. case presentation: the female infant was born via spontaneous vaginal delivery at 39 1/7 weeks to a 31 year old g1 now p1 mother. maternal history was significant for chronic hypertension, obesity, insulin dependent type 2 diabetes, anxiety, depression, and scoliosis. the infant was noted to have a left sided abdominal wall defect and hernia, imaging identifying left renal agenesis, and was initially suspicious for vater syndrome. fortunately, the infant's scid nbs revealed low t cell receptor excision circles (trecs). her initial white blood cell count was 14.1 with an absolute lymphocyte count of 2.679 k/ul. ebv pcr, cmv pcr, and hiv studies were negative. chest imaging discovered absent thymus, abnormal vertebrae with only 10 ribs on the right and 12 ribs on the left, and abnormally formed thoracic vertebrae (t7). echocardiogram detected an atrial septal defect measuring 0.32 cm, possible pfo versus secundum asd. endocrinology was consulted for management of labile calcium and phosphorus levels. fish was negative for 22q11.2 deletion. microarray r evealed a variant of unknown signif icance arr[grch37]2p11.2(86285942_86506132)x3. sequence analysis of combined and severe immune deficiency genes showed a variant of uncertain significance c.544c>a (p.leu182met). management and outcome: additional evaluation included: cd3 67ul (1700-3600ul), cd4 51ul (1700-2800ul), cd8 19ul (800-1200ul), cd45ra 14 cells/ul (1100-5200cells/ul), normal cd 19, and cd 16/ 56, normal immunoglobulin g level, and normal dihydrorhodamine assay. skeletal survey, ct abdomen and chest, and hla typing were performed in preparation for thymic transplant. discussion: patients with complete dgs, a form of scid found in less than 1 percent of patients with 22qds, have absent thymus and a t cell count <3 standard deviations below normal for age (typically <50 naã¯ve cd3+ t cells/mm3). in a large series of patients with complete dgs, only 52 percent had an identifiable 22q11.2 deletion [1] . infants of a diabetic mother have various genetic and syndromic associations including diabetic embryopathy. [2] despite the importance of immunological aspects in pregnancy, few studies have reported on the cellular immune modifications of diabetic embryopathy. diabetes during pregnancy may affect the development of the thymus and thus maturation of the immune system in the offspring. [3] the recent addition of a trec assay to newborn screening can identify such a subset of infants with atypical presentations. scid nbs uses an assay for trecs, a biomarker of t cell development. [4] [5] [6] this initial presentation now places the immunologist in the role of "first responder" with regard to diagnosis and management of these patients, who may present with atypical features. newer genetic and molecular techniques now allow for earlier identification of immune defects in such disorders with life-long clinical concerns. [7] references: introduction/background: goods syndrome is a rare cause of combined b-and t-cell immunodeficiency occurring in association with a thymoma. affected patents are susceptible to bacterial, fungal, viral, and opportunistic infections. an association with autoimmunity has also been reported. current knowledge of goods syndrome is primarily limited to case reports and small series. objectives: to examine the spectrum of clinical and laboratory features of a major cohort of goods syndrome patients in the us. methods: we conducted a retrospective analysis of patients with goods syndrome in the usidnet registry and the mount sinai hospital (msh) cohort. r e s u l t s : we i d e n t i f i e d 2 0 p a t i e n t s w i t h t h y m o m a a n d hypogammaglobulinemia (usidnet, n=11; msh, n=9; median age: 60 years; female: 45%), representing data from 151 patient years. the median age at diagnosis of thymoma and hypogammaglobulinemia were 52 years (range 31-85), and 50.5 years (range 28-86), respectively. two patients were deceased (at age 65 and 70 years, cause unspecified). all patients had low igg (median 313mg/dl, range 47-699). iga and igm were reduced in 90% and 45% of patients, respectively. low cd19+ b cells (median 0.5/mm^3, range 0-28) were reported in all available records. the absence of cd19+ b cells was observed up to 21 years postthymectomy. a wide range of additional laboratory abnormalities were identified: low cd4+ t cells (n=5), low cd8+ t cells (n=2), low cd4/ cd8 ratio (n=6), low nk cells (n=6), and absent peripheral eosinophils (n=8). the most common sites of infections were lower respiratory (70%), upper respiratory (55%), and gastrointestinal (35%). in addition, sepsis (15%), meningoencephalitis (5%), osteomyelitis (5%), and urinary tract infection (5%) were also observed. identifiable infectious agents included: bacteria (35%), virus (35%), fungus (25%), parasites (10%), and protozoa (5%), with opportunistic infections recorded in 25% of patients. opportunistic infections were significantly associated with absolute cd4 lymphopenia (p=0.048, fishers exact test). enterovirus was identified as a previously unreported cause of meningoencephalitis in this population. autoimmune manifestations were reported in 45% of patients, with a higher prevalence of inflammatory colitis (20%) than previously reported. hashimoto thyroiditis, fibromyositis, and bronchiolitis obliterans organizing pneumonia (n=1 each) were identified as previously unreported autoimmune/inflammatory conditions in this population. a case of alopecia areata was also observed. additionally, bronchiectasis was recorded in 20% of patients. all patients were initiated on immunoglobulin replacement, with antibiotics prophylaxis in 20%, and immunosuppressive medications employed in 10% of patients post diagnosis of immunodeficiency. conclusion: goods syndrome is a combined immunodeficiency, with a wide range of autoimmunity in a subset of patients. we expanded upon the spectrum of associated infectious and inflammatory complications through a major us cohort. persistent immune dysregulation was observed up to 2 decades post-thymectomy. introduction: primary immunodeficiencies (pids) constitute a large group of rare disorders that affect the immune systems function. some pid patients develop autoimmunity in addition to having increased susceptibility to infections due to their impaired immunity [917] . (1) case presentation/ management: a 43 year old caucasian female with history of bipolar disorder, factor v leiden deficiency, anti thrombin 3 deficiency, pulmonary embolism, endometriosis, and seasonal allergies was evaluated for chronic granulomatous disease (cgd) in 2007. the main symptoms were inflammatory breast lesions necessitating 4 surgeries on the right breast, and back, facial, genital, ocular, mouth, and scalp sores. biopsy with cultures of the wounds was positive for corynebacterium, coagulase-negative staphylococcus, enterococcus, bacteroides species, and provatella. neutrophil oxidative burst was ordered by the infectious disease specialist and showed normal and abnormal neutrophil populations, a finding consistent with cgd carrier. patient was started on interferon gamma-1b after failing multiple courses of antibiotics. her symptoms were well controlled on interferon gamma-1b 100mcg/0.5ml sq every other day, trimethoprim 100mg tab (2tabs in am and 1 tab in pm), cefixime 400mg once daily, and topical mupirocin as needed except for her recurrent genital ulcers. cgd can be rarely associated with oral ulcers however there is a limited literature describing associated genital ulcers. according to the international study group diagnostic criteria published in 1990 (2), the patient was diagnosed by a rheumatologist as having behcets disease (bd). there are no pathognomonic laboratory tests in bd; as a result, the diagnosis is made clinically. patient failed a trial of colchicine and was later started on cyclosporine, which resulted in decrease of her mouth and genital ulcers. discussion: bd is a rare disease mostly seen along the silk road. the prevalence has been reported as 0.12 (usa) to 370 (in a single village, northern turkey) for 100 000 inhabitants. (3) cgd is a primary immunodeficiency caused by defects in any of the five subunits of the nadph oxidase complex responsible for the respiratory burst in phagocytic leukocytes. patients with cgd are at increased risk of life-threatening infections with catalase-positive bacteria and fungi, and inflammatory complications such as cgd colitis. (4) reports of cgd female carriers with discoid lupus erythematosus, photosensitivity rashes, and other autoimmune phenomena have been published [48, 49] (4) . to the best of our knowledge, this is the first case to report bd in an affected cgd carrier. the treatment of inflammatory disease in patients with cgd poses a difficult balance between therapeutic immunosuppression and the increased risk of severe infection. (5) . high dose intravenous immunoglobulin, and targeted therapies such as ctla4-ig for t cell mediated pathologies, rituximab for b-cell mediated pathologies, and anti-tnf for ibd, may be preferable over the broad immunosuppressive activity of glucocorticoids. in addition, emerging evidence suggests that hematopoietic stem cell transplantation has indication for cases that have been difficult to control using immunosuppression. (1) given all that, our case emphasizes the need to maintain suspicion for autoimmune disorders / immune dysregulation in patients with pid. introduction: cd40-ligand deficiency is an x-linked combined immunodeficiency, characterized by susceptibility to infection, often with associated neutropenia, malignancy, and autoimmunity. central nervous system (cns) manifestations are less commonly reported than respiratory or gastrointestinal complications, but are most often attributed to infection. herein we describe a challenging case of gradual onset episodic memory loss, confusion, and unilateral hemiplegia in a young male with cd40ligand deficiency. case presentation: the patient is a 13-year-old male with cd40-ligand deficiency on immunoglobulin replacement therapy presenting with recurrent, episodic altered mental status (ams) and gradual neurocognitive decline. initial neurologic symptoms began at age 11 years, and included fever, nausea, and eyelid fluttering. initial comprehensive infectious workup at this time, including blood and urine cultures, lyme antibody, serum pcr for hsv, cmv, ebv, respiratory viral pcr including atypical viruses, csf studies including culture, lyme eia, pcrs for enterov i r u s , v z v, e b v, c m v, h s v 1 / 2 w e r e u n r e v e a l i n g . electroencephalogram (eeg) and mri displayed generalized slowing and global atrophy, respectively. definitive diagnosis was not made. the patient continued to decline with worsening developmental delay and memory loss. one year later, at age 12 years, he had a recurrent episode of ams with repeat negative infectious workup including blood and urine cultures, respiratory virus pcr including atypical viruses, csf culture including acid fast bacillus and fungi, cryptococcal antigen, viral encephalitis panel by pcr, and serum pcr for ebv and hhv-6. eeg at this time showed left hemispheric epileptogenic potential, consistent with seizure activity. his presentation, at age 13 years, was notable for right-sided hemiplegia with facial numbness, dysarthria, nausea, and fever. he was found to have anello virus on pcr of csf, abnormal left temporal region on eeg, and global atrophy with stable, diffuse generalized volume loss on mri. he was diagnosed with occult anello virus-induced encephalitis with hemiplegic migraine and discharged on valproate. discussion: here we present the first reported case of anello virus detected by pcr in a cd40-ligand deficient male with neurocognitive manifestations, attributed primarily to hemiplegic migraine. given the anello virus prevalence and relatively avirulent character, it is presumed to be unlikely culprit for encephalitis; however, the significance of this finding is as yet unknown. this case highlights diagnostic challenges in immunodeficiency: infection may go undetected by standard diagnostic techniques; however, the significance of infections identified with advanced techniques may not yet be understood. background: henoch-shã¶nlein purpura (hsp) is an iga-mediated small vessel vasculitis that presents with a tetrad of abdominal pain, arthritis, glomerulonephritis, and purpura. hsp is typically a selflimiting disease of childhood following a viral illness. there is no universal treatment for patients with chronic or recurrent hsp. we report a chronic refractory case of hsp that was successfully treated with a tumor necrosis factor inhibitor (tnfi), etanercept. etanercept functions as recombinant protein that consists of a tnf-alpha receptor ligand-binding region that links to the fc portion of human igg. it is currently approved for use in 5 diseases: juvenile rheumatoid arthritis, rheumatoid arthritis, ankylosing spondylitis, plaque psoriasis, psoriatic arthritis. tnfi are categorized into two broad categories, recombinant receptors (etanercept) and neutralizing antibodies (ex. infliximab and adalimumab). there have been prior case reports of hsp associated with tnfi agents during the treatment of other autoimmune conditions in the adult population. to our knowledge, there have been 3 prior etanercept related hsp reports, one report associated with adalimumab, and one with infliximab. however, there has been no prior report of etanercept use successfully treating chronic refractory hsp. case presentation: a 16-year-old native american male with 3 year history of chronic hsp, hla-b27 positive, and enthesitis related arthritis who was initially treated with steroids, sulfasalazine and methotrexate for symptoms of joint pain and purpura. his iga level was 545 mg/dl prior to therapy. despite treatment for one month of steroids, eight months of sulfasalazine exclusively and eight months of methotrexate and sulfasalazine, he continued to have persistent purpura on bilateral extremities without improvement. he was subsequently initiated on etanercept 50mg weekly and methotrexate was discontinued. approximately one month later, his rash significantly improved. his rash and joint pain recurs when he misses a dose of etanercept. punch biopsies were taken 3 months after initiation of etanercept. the biopsies of a lesion from his left arm showed early leukocytoclastic vasculitis and from his left leg showed weak granular deposition of iga, igm and c3 within vessel walls. there is controversy whether this is a true iga vasculitis. however, we believe that his clinical presentation and the deposition of iga and c3 within blood vessel walls seen on biopsy correlates with chronic henoch-shã¶nlein purpura. conclusion: there is no standard treatment of chronic hsp, but there are reports of benefit with nsaid and corticosteroids. per our literature review, there are no prior reports of etanercept use in the treatment of chronic hsp. tnf inhibitor, etanercept should be considered as a treatment for chronic refractory hsp in the pediatric population as it has showed rapid resolution of purpura in this case report. further studies of etanercept in the treatment of chronic hsp should be conducted given the controversial literature of anti-tnf ab induced hsp during the treatment of other autoimmune diseases. although clinical manifestations of iron overload appear to be quite uncommon in patients who are heterozygous carriers of hfa mutation, we present cases that appear to suggest an increased risk non allergic rhino-sinusitis. case report: we present a 66 year old gentleman with perennial colored rhinorrhea, with facial pressure and tenderness, constant post nasal drip, dry cough and bilateral congestion that had been going on for the past several years. he also had a frequent urge to clear his throat and had frequent episodes of sore throat despite having no history of gerd or lpr. he reported to have multiple sinus infections every year that would progress to pneumonia and eventually require long courses of oral antibiotics. all started in his 40s intensified in the recent past. he had 3 other siblings; one died in his 40s due to liver complications of hh and had a carrier sister and brother with a hx of sino nasal problems exactly similar to the patients. his exam was remarkable for bilateral narrowed nasal passages and moderate edema of the mucosa. his rhinolaryngoscopy showed significant edema and purulent drainage, most notably from bilateral middle meati. his skin test was negative. his cbc showed a wbc count of 6.7/ml with 2% eosinophils and his immunoglobulin panel showed an iga of 236 mg/dl, igg of 1190 mg/dl and ige of 31 mg/dl. patient was placed on alkalol sinus rinses and azelastine nasal spray, which he reported to work pretty well. he left for costa rica and is expected to return back with his siblings to a&i clinic in the coming months. discussion: hh is one of the most common inherited disorders in people of northern european descent with an incidence of 1:200 and carrier rate of 1:10.. most affected hh patients are homozygous for the mutation designated c282y at the hfe gene located at the 6th chromosome. unlike hereditary hemochromatosis, clinical manifestations of iron overload appear to be quite uncommon in patients who are heterozygous carriers. hh patients are at risk for a number of infections with bacteria whose virulence is increased in the presence of excess tissue iron. hh is also a risk factor for acute fulminant frs . here the mechanism is postulated to be due to quantitative or qualitative neutrophil defects as this condition is mostly seen in patients with dm, aplastic anemia, and can happen in patients undergoing antineoplastic chemotherapy. no known increased susceptibility for infections through either mechanism is postulated for patients with the heterozygous carrier state. here we present 3 hh carrier patients who present with recurrent rhinosinusitis with no allergen sensitizations and normal ige levels. since most fungal immunity is at the tissue level and is cytokine driven, it can be speculated that increased tissue levels of iron might interfere with mechanisms of innate immunity. chief, human immunological diseases section, laboratory of clinical immunology and microbiology, niaid, nih, bethesda, md background: dedicator of cytokinesis 8 (dock8) mutations are associated with a combined immunodeficiency disorder marked by atopic features, infectious susceptibility with a striking preponderance of cutaneous viral disease, and a risk for the development of malignancy including lymphoma. almost all cases can be diagnosed by documentation of the loss of dock8 protein expression. methods: we describe a 22-year-old male with a diagnosis of pre-b cell acute lymphoblastic leukemia (all) followed by epstein-barr virus (ebv) associated diffuse large b cell lymphoma (dlbcl). compound heterozygous mutations in dock8 were documented following the completion of whole exome sequencing (wes). the pathogenicity of the variants was assessed. flow cytometric quantification of intracellular dock8 protein was completed. dock8 protein function was assessed by evaluating the morphology of patient lymphocytes when migrating in a 3d collagen matrix. results: a concern for a primary immunodeficiency was raised due to a history of recurrent otitis media which began at 12 months of age. by 4 years of age, numerous warts were noted on his fingers; however, they were transient for a duration of only 2 years. no atopic features were appreciated. at 15 years of age, a diagnosis of pre-b cell all was made. during all therapy, infectious complications were severe including an intestinal perforation, osteomyelitis, and sepsis. at 22 years of age, still in an ongoing remission from his all, an incidental finding of a lung nodule led to a diagnosis of ebv-associated dlbcl. during therapy, however, infectious complications were again severe including a soft tissue infection and sepsis. wes was performed and compound heterozygous mutations in dock8 (c.1128_1132del and c.4474-1g>c) were documented. flow cytometric quantification of intracellular dock8 protein was normal when compared to a normal control. nevertheless, additional functional assessment of dock8 protein was completed. when migrating through a 3d collagen matrix, 45% of the patient lymphocytes studied demonstrated abnormal elongation (stretch ratio > 8 defined by length/width) compared with 10% of lymphocytes from a normal control. he is being evaluated for hematopoietic stem cell transplant. conclusion: autosomal recessive mutations in dock8 are a rare cause of a combined immunodeficiency marked by atopic features, infectious susceptibility with a striking preponderance of cutaneous viral disease, and a risk for the development of malignancy including lymphoma. here, pre-b cell all followed by the development of a subsequent malignant neoplasm (ebv-associated dlbcl) led to the discovery of dock8 deficiency. hence, as our case underscores, for rare instances of high clinical suspicion despite normal dock8 protein expression, additional functional testing is crucial to make a definitive diagnosis and plan treatment. understanding the spectrum of dock8 mutants and their phenotypes will improve our understanding of dock8 deficiency. background: autosomal dominant hyperimmunoglobulin e syndrome (ad-hies) is a rare primary immunodeficiency caused by heterozygous loss-of-function mutations in the signal transducer and activator of transcription 3 (stat3) gene. ad-hies classically characterized by recurrent cold staphylococcal abscesses, pneumonia, eczema, and an elevation of ige level. other additional clinical manifestations of hies have been recognized including skeletal dysplasia (scoliosis, pathologic fractures, delayed dental deciduation), pneumatoceles, coronary-artery aneurysms, brain lesions, and chiari malformations. objective: to describe a unique case of abdominal abscesses in a patient with ad-hies. method: a 22-year-old female with known ad-hies (c.1144 c>t (p.arg382trp)) and a complicated history of early pneumococcal pneumonia and meningococcemia resulting in bilateral amputation below the knees along with loss of several digits, presented for evaluation of skin infection. she had a history of recurrent staphylococcal skin abscesses and presented with inability to use her prostheses due to pain from inflammation around her amputation sites. she underwent imaging and was found to have bilateral extremity abscesses with an associated osteomyelitis of her l tibia (which was found to be mrsa after incision and drainage). while receiving intravenous antibiotics for her osteomyelitis, she developed intractable abdominal pain. imaging showed a thick-walled, multi-septated, paranephric abscess as well as several smaller abscesses scattered throughout her abdomen. she underwent multiple drain placements and drainage of retroperitoneal fluid collections via interventional radiology (ir). purulent fluid from the abdominal abscess drainage grew mrsa. the patient continued to have re-accumulation of abscesses despite multiple drainages. repeat imaging noted increased paranephric abscesses which were not communicating with drains. given lack of response to several ir-placed abdominal drains and to 6 weeks of intravenous antibiotics, she had an open surgical washout with minimal improvement. hospital course was further complicated by development of a left lower lung lobe consolidation and sub-segmental pulmonary embolism necessitating treatment with heparin. finally, after several weeks of escalating antimicrobial therapy and with additional drain placements, the retroperitoneal abscesses started to recede. repeat abdominal imaging several months later while asymptomatic revealed slow but continuing resolution of the abscesses. conclusion: the present case raises awareness of an unusual location for infection in a patient with ad-hies. although the majority of complications of ad-hies are sinopulmonary and skin infections, recalcitrant intra-abdominal abscesses should be considered in the differential of infections in hies. introduction/background: the recent epidemiologic studies have revealed that primary immunodeficiencies (pids) are more common than previously thought. however, there are very few data on epidemiology of pids in korea. objectives: we attempted to estimate the pid epidemiology and disease burden in korea and provide the background information for pid registry for future. methods: to review the previously reported scientific studies, pubmed, koreanmed, google scholar were searched. any studies on pids reported in scientific journal (korean or international) from january 2001 to november 2018 were searched. both korean and english reports were searched. diagnosis for pid was categorized from group i to group xi according to 2017 iuis phenotypic classification. study period was divided into two periods: period 1 from 2001 to 2005 and period 2 from 2006 to 2018, because there was a multicenter study to estimate pid epidemiology from 2001 to 2005. in addition, the number of pid patients and the cost for care were estimated among patients who requested reimbursement to health insurance review and assessment service (hira) korea for one year in 2017. results: a total of 334 pid patients were identified in 75 reports. one hundred and ninety-nine patients (20 reports) and 135 patients (55 reports) were found in period 1 and period 2, respectively. the pids were reported in 11 patients for immunodeficiencies affecting cellular and humoral immunity, 23 patients for combined immunodeficiency with associated or syndromic features, 143 patients for predominantly antibody deficiencies, 33 patients for diseases of immune dysregulation, 113 patients for congenital defects of phagocyte, 1 patient for defects in intrinsic and innate immunity, 4 patients for auto-inflammatory disorders, 6 patients for complement deficiencies, and none for phenocopies of pid. from hira reimbursement data, the number of pid patients were 42 for combined immunodeficiency, 486 for predominantly antibody deficiency, 47 for common variable immunodeficiency, 135 for functional defect of neutrophils, 238 for immunodeficiency associated with other major defects, 272 for other immunodeficiencies. a total of 1,220 pid patients were treated for 14,316 days and $3,351,678 was reimbursed in 2017. conclusions: we performed a systematic review on published studies for pid in medical journals and national open data system of hira to estimate the pid disease burden for the first time in korea. to obtain more information on true pid epidemiology and disease burden in korea, a national multicenter study for pid registry is required in the future. micro-thrombocytopenia is one of the most serious challenges for wiskott-aldrich syndrome (was) and x-linked thrombocytopenia (xlt) patients. thrombocytopenia leads to severe, potentially life-threatening, bleeding episodes, which require frequent transfusions and account for 23% of deaths in patients experiencing was mutations. the gold standard treatment for was patients is hematopoietic stem cell transplantation (hsct) from an hla-identical donor but more recently a number of gene therapy (gt) trials in europe and usa showed promising results. in particular, it has been shown that was patients receiving lentiviral mediated gt, consisting of autologous cd34+ cells transduced with lentiviral vector encoding the human was gene under the control of the endogenous promoter, in combination with a reduced intensity conditioning regimen, have a significant increase in platelet (plt) counts. even though plt counts do not reach normal levels, treated patients decreased the severity and frequency of bleedings. here, in a cohort of 4 xlt and 16 was patients, fifteen treated with gt, the plt phenotype and function were analyzed by electron microscopy, flow cytometry and proteomic profile. the aim of the project is to assess the presence of plt defects in was untreated patients and the impact of gt treatment on the correction of plt behavior. we demonstrate that plts of untreated was patients have reduced size and abnormal ultrastructure along with hyperactivated phenotype at steady state, showing increased expression of cd62p, activated iib3 integrin and cd40l; conversely, activation response to agonist and aggregation capacity are both decreased. analyzing plt samples isolated from treated patients, we found that gt restores plt size and ultrastructure very early after treatment and reduces the hyperactivated phenotype proportionally to was protein (wasp) expression and follow-up length. plts isolated from gt treated patients showed a normal activation response to agonists and restored aggregation capacity in 5 out of 7 analysed patients. by proteomics, various protein pathways were found downregulated in untreated plt samples, mainly involving cytoskeletal-rearrangement proteins, integrins, signal transduction molecules, vesicles-transport proteins; additionally, decreased metabolic capacity were observed. these results are in line with the functional defects observed in plts in terms of activation and aggregation. conversely, the expression of protein-pathways found downregulated in untreated patients is comparable to healthy controls in gt-treated plt samples, reflecting the amelioration of plt phenotype and function. overall, our study highlights the coexistence of multiple defects in the activation and aggregation responses occurring in was patient plts in absence of wasp. gt was able to normalize the plt proteomic profile followed by consequent restoration of plt ultrastructure and phenotype, suggesting gt is responsible for the observed reduction of bleeding episodes in treated patients. introduction: pik3cd is an autosomal dominant genetic disorder of the immune system that results in persistent activation of pi3k. signaling through pi3k is essential for immune cell regulation of metabolism, migration, proliferation and differentiation, leading patient to present with lymphadenopathy, immunodeficiency and senescent t cells. the mutated protein causes t cells to over activate and mature too quickly leading to their death, this over activation also blocks the maturation of b cells. case presentation: a 51-year-old female with a childhood history of failure to thrive, asthma, chronic rhinitis and common variable immunodeficiency on intravenous immunoglobulin replacement, was seen in immunology clinic to establish care. she reported frequent episodes of pneumonia and bronchitis in her childhood. her family history was significant for family members with leukopenia, but no diagnosed immunodeficiency. patient had 1 son who did not report symptoms concerning for immunodeficiency. physical exam was within normal limits with no lymphadenopathy. laboratory examinations exhibited normal iga (185 mg/dl), igg (800 mg/dl), and igm (100 mg/dl). while flow cytometry showed normal absolute cd3 687 (570-2400 cells/ul), cd4 (540 cells/ul), nk cells (151 cells/ul), cd19 (179 cells/ul), cd45ra (160 cells/ul), cd45ro (311 cells/ul), cd2 (757 cells/ul), and hla-dr (173 cells/ul), nonswitched memory cells (9 cell/ul) and class-switched memory cells: (15 cells/ul). (4-62 cells/ul). vaccine response was not pursued as patient had been on ivig. genetic testing was pursued, and revealed a mutation in pik3cd gene, specifically a mutation in the c.2320g>a; p.val774met variant (rs370932461). this mutation though seen in databases, is not currently reported in medical literature as associated with this condition. based on these, ct chest was ordered to screen for bronchiectasis, adenopathy and lymphoma. ct showed no cardiopulmonary disease or adenopathy, but did show an incidental adrenal mass which is now being worked up. while the pattern of inheritance of this mutation is autosomal dominant, her son is asymptomatic and testing of her son has not been pursued, though it was advised for her cousins given history of leukopenia. patient has continued on igg replacement therapy. conclusion: recent publication by the clinical immunology society suggests consideration for next generation sequencing when it can affect future family planning or it has treatment and prognostic implications. this case highlights all aspects of the importance of genetic testing as part of the diagnosis of cvid, since it can affect progeny, it offers the possibility of treatment with immune modulating agents and has implications on screening, since patients are at increased risk for malignancies. background: abnormal v(d) j recombination activity in patients with mutations in the recombination-activating genes 1 and 2 (rag1/2) results in markedly reduced usage of distal vand j genes at the t cell receptor alpha (tra) locus. mucosa-associated invariant t (mait) cells express a semi-invariant t cell receptor containing the distal trav1-2 gene. mait cells can be identified by flow cytometry using a mab directed against valpha 7.2, which recognizes the product of the trav1-2 gene. by performing high throughput sequencing (hts) of tra rearrangements and flow cytometry, we have confirmed lack of t cells using distal valpha genes in patients with known rag mutations. we now report that flow cytometry with mab against valpha 7.2 successfully identified rag deficiency in two patients with an atypical presentation. methods: tra rearrangements were analyzed by hts using gdna from sorted t cell subsets from rag-mutated patients and healthy donors. distal valpha usage was measured in whole blood by flow cytometric analysis with an anti-valpha 7.2 antibody. rag mutations were detected by sanger sequencing. patients were enrolled in niaid protocol 18-i-0041. results: hts of tra rearrangements revealed lack of distal trav and traj gene usage in patients with rag1/2 mutations. the presence of circulating mait cells in controls and patients with known rag1/2 mutations and various clinical phenotypes was analyzed by flow cytometry using mab against valpha 7.2. we found a virtual lack of valpha 7.2 expression in rag mutated patients (<0.5%) compared to controls (2-8%) . we used the valpha 7.2 assay to test two patients with unknown immunodeficiency manifesting as skin granulomas and autoimmune cytopenia, and found nearly absent expression (0.14% and 0.08%). targeted sequencing of rag1/2 revealed that both patients were compound heterozygous for rag1 mutations: p.r112h/p.c328y and p.r410w/p.r507q, respectively. conclusions: patients with mutations in rag1/2 demonstrate a skewing of their tcralpha repertoire. the reduction in recombinase activity in these patients does not allow for rearrangements of the most distal valpha segments. rapid identification of patients lacking valpha 7.2+ t cells by flow cytometry may prompt sanger sequencing and identification of rag1/2 mutations in a matter of days. this assay represents a simple but powerful tool to reduce the cost and time associated with other analysis methods. acknowledgements: supported by dir/niaid/nih. director, centro de inmunologã­a clã­nica dra.bezrodnik y equipo introduction: the fate of effector t cells is strongly dependent on the expression of bcl-6 or blimp-1, which are inhibited reciprocally through a complex signaling pathway. several studies have shown that bcl-6 is a key transcription factor for differentiation towards the follicular helper t cells (tfh) lineage able to collaborate with b lymphocytes (bl). on the contrary, the transcription factor blimp-1 is highly expressed in t lymphocytes th1, th2 and treg, thus regulating the differentiation towards tfh. materials and methods: whole fresh blood and peripheral mononuclear cells from a patient with homozygous mutation in stat5b were analysed by flow cytometry. analysis of ctfh (cd4+cd45ra-cxcr5+), ctfh1 (cxcr3+), ctfh17 (ccr6+), ctfh2 (cxcr3-ccr6-), naã¯ve bl (lb igm+igd+cd27-), memory (mbl) (lb igm+ igd-cd27+), switched (mbl-sw) (igd-igm-) and plasmablast (pbc) (cd27+cd38++) cells was performed. immunoglobulins were measured in serum. results: the patient with stat5b deficiency showed increased values of ctfh (38%) (healthy donors p10-p90: 7,9-17,8 %) that presented an activated phenotype (icos+ and pd-1+) with a skewed to a th17 profile (ccr6+), consistent with her hipergammaglobulinemia and the marked and sustained increase in the switched mbl and pbc subpopulations in peripheral blood over the years. discusion: this immunological phenotype described in the patient with stat5b deficiency could explain in part the pathophysiology of the autoimmune disorders. this patient (as well as the other two patients with mutations in stat5b previously described by our group), have had chronic hypergammaglobulinemia, autoantibodies and consequently autoimmune processes (psoriasis, hypothyroidism, eczema, alopecia and celiac disease, among others). we believe that the link between this clinical symptomatology and the molecular defect relies in the fact that the absence of stat5b promotes a greater expression of bcl-6, which generates a bias towards the production of ctfh cells, that give rise to a greater activation of lb, generation of lbm and plasma cells (dysregulation in the cg), events that manifest as hypergammaglobulinemia and autoimmunity. in summary, we provide promising evidence of the mechanisms that lead to autoimmunity in this type of patients that could also be a consequence of the defect in the regulation of gc, highlighting the crucial role of stat5b in the humoral immune response and maintenance of the tolerance of the immune system. background/introduction: the term primary immunodeficiencies (pid) encompasses a phenotypically and genetically diverse group of conditions. genetic testing for these conditions can guide treatment, reduce morbidity and mortality, allow for genetic counseling, and identification of additional at-risk family members. however, this testing can be complicated by a number of factors, including pseudogenes, high homology, methodology limitations, and the heterogeneous nature of pids. methods: mayo clinic laboratories launched their first set of nine pid next generation sequencing (ngs) tests approximately one year ago. these tests include one single gene assay for gata2 deficiency and eight targeted next generation sequencing panels for: atypical hemolytic uremic syndrome (ahus), autoinflammatory disorders, b-cell disorders, monogenic irritable bowel disease (ibd), phagocytic defects, severe combined immunodeficiencies (scid), and severe or cyclic neutropenia. herein we summarize our first year of experience with these ngs tests, with a focus on the eight targeted panel tests. results: from march 2018 through november 2018 we performed testing for 341 cases. our highest volume of tests was for the ahus panel (127/341 cases, 41%). a variant was reported in 76/341 cases (22.29%). these variants included variants of uncertain significance, likely pathogenic variants and pathogenic variants. the indication with the highest percentage of cases where a variant was reported was scid (9/13 cases, 69.23%). the number of cases that were considered solved, where the genotype likely explains the patients phenotype, varied widely by indication. twenty cases were found to have a pathogenic or likely pathogenic variant or variants; however 2/20 cases were heterozygotes for an autosomal recessive condition and were not considered solved cases. the panel with the highest percentage of solved cases is our scid panel (4/13 cases, 30.77%). conversely, we have yet to solve an autoinflammatory, irritable bowel disease, or telomere defects case; however 20% of cases in each of those three panels have had a variant of uncertain significance reported. we hypothesize that one of the reasons for the low detection rate for these three panels is inappropriate test orders. we are also actively looking for ways to update all 8 panels to increase detection rates and clinical utility, for example expanding the gene list of our ibd panel, including large deletion/duplication detection, and including ncf1, a difficult gene to capture by ngs, on the phagocytic panel. finally, we present the molecular findings from a number of interesting cases that were solved using our targeted ngs panels. conclusions: the launch of our pid ngs tests in march of 2018 has allowed us to aid patients by confirming diagnoses and providing molecular diagnoses that will enable more accurate genetic counseling and risk assessment. we have also uncovered areas for improvement, both on the clinical side: provider education is important to enable better identification of patients who can benefit from molecular genetic testing for pids, and on the laboratory side: introduction of more expanded panels and additional methodologies. the progressive decrease of red blood cells, platelets or neutrophils via a self-directed immune process is jointly termed as autoimmune cytopenias. while autoimmune cytopenias, including autoimmune hemolytic anemia (aiha), immune thrombocytopenic purpura (itp), and autoimmune neutropenia (an), are a common presentation of autoimmunity in the general population, they are particularly frequent and can appear as the first sign in patients with primary immunodeficiencies (pids). possible causes of cytopenia in pids comprise mainly immune dysregulation, bone marrow failure (bmf) and myelodysplasia. our goal is to investigate possible immune mediated mechanisms underlying chronic cytopenia in children in order to achieve an early diagnosis and consequently offer timely and appropriate therapy. we selected 24 patients affected by chronic cytopenia, evaluated with immunophenotyping by flow-cytometry; data were subjected to multivariate analysis by principal component analysis (pca). next generation sequencing (ngs) analysis of genes frequently implicated in pids was performed. among the patients, 5 were affected by bone marrow failure, of which 2 were diagnosed with fanconi anemia and severe congenital neutropenia; 12 were affected by immune-mediated cytopenia and 7 by idiopathic cytopenia. the immunephenotyping showed a typical pattern of cd8 t cell subpopulations expression in patients compared with healthy donors with an increase of naã¯ve t cells and a reduction of central memory (cm) and effector memory (em) t cells levels. we observed a decrease in total b cells, b switched and b memory cells and an increase in cd21low cells. pca showed an overlap between groups, however it revealed a peculiar trend of some single patient, suggesting the pathway involved in immune defect. preliminary results from ngs studies revealed genetic variations in genes previously associated with pids in 10 out of 11 patients investigated. in particular we identify one patient with a mutation in fas, one with a mutation in aire and one with a mutation in ikaros. concerning the remaining patients further studies are ongoing to validate the pathogenicity of the genetic variations. pca is a very effective tool to analyze several parameters at the same time, highlighting patients whose phenotype shows the main peculiarities. the presence of specific lymphocyte subpopulation patterns can be important indicators of immune-mediated cytopenias and helpful signs of specific pids that should promptly be investigated with genetic analysis. the rapid of discovery of novel, monogenic primary immunodeficiencies has been made possible by the broad availability of clinical whole exome sequencing (wes). however, clinical wes has major shortcomings that should be understood by practicing immunologists. focusing on the 2017 iuis list of~330 monogenic primary immunodeficiency genes, we show here limitations in coverage that could significantly impact clinical interpretation. on the agilent whole exome capture kit, the most common wes platform, there are a number of genes with exons that are poorly covered. specifically, there are at least 94 genes with less than 100% exonic coverage, 26 with less than 99% coverage and 5 with less than 90% coverage (e.g. ikbkb, ncf1, taci, unc93b1 and tbx1). beyond this challenging technical issue, there are more subtle issues as well. these include the presence of pseudogenes in at least 17 of our genes (e.g. ak2, c1qbp, cd46, cftr, cr2, msn, ncf1, ncstn, ikbkg, nhp2, pms2, pten, rnaseh2c, rps, sbds and was), which can make accurate sequencing very challenging. finally, there are many known causative intronic (e.g. btk, ctla-4, wasp) and copy number variant mutations (e.g. rag1 and xiap) as well as large deletions (e.g. dock8) that we cannot expect to be optimally covered using wes. this list of genes requires consideration even with a negative exome and may require additional approaches including whole genome sequencing, sanger sequencing, cnv arrays and/or long-read ngs sequencing. wes is a powerful genomic diagnostic tool, but to avoid missing key diagnostic insights using these alternative approaches may be critical when certain genes are in the differential diagnosis. going forward, as pid phenotypes continue to broaden, these issues remain fundamentally important even if these genes are not obviously implicated in a given clinical phenotype. more physicians are utilizing targeted genetic panels to reach a definitive diagnosis for their patients with immunodeficiency. however, this increase in testing also has led to the discovery of many more variants of uncertain significance (vus) in the genes tested. these findings can often leave the patient and the physician with more questions than answers. we present a patient with recurrent infections found to have multiple variants of uncertain significance in several genes associated with primary immunodeficiency. a 13-year-old female who was diagnosed with crohns disease at age 9 after intestinal perforation and jejunal resection experienced two discrete episodes of epstein barr virus (ebv) meningoencephalitis and septic shock. the first episode was diagnosed when patient had fever and altered mental status and occurred prior to her crohns disease diagnosis and the second episode was complicated with altered mental status, disseminated intravascular coagulation (dic) and hypotension requiring picu admission. aside from these two major infections, the family denied any other infections requiring antibiotics in the last 5 years and reported a remote history of repeated streptococcal pharyngitis that have not recurred. immunology was consulted at the time of the second episode of meningoencephalitis and work up was mainly unremarkable with normal immunoglobulins, adequate vaccine response to hib, tetanus, diphtheria, rubella, measles and pneumococcus (18 out of 22 protective titers). she had normal t cell numbers with slightly decreased natural killer numbers for age. neutrophil studies showed normal dihydrorhodamine (dhr) analysis, glucose-6-phosphate dehydrogenase levels and myeloperoxidase (mpo) stain. commercial testing of her toll like receptors (1) (2) (3) (4) (5) (6) (7) (8) showed normal function. invitae primary immunodeficiency panel demonstrated a heterozygous variant in nod2 (c2.104c>t; p.arg702trp) as well as heterozygous variants of uncertain significance in il7r (c.662g>t; p.ser221ile) and tlr3 (c.889c>g; p.leu297val). the patients nod2 variant is known to be associated with an increased risk for crohns disease. even with our patients presentation with recurrent severe viral infections and ibd, it is not immediately clear how these genetic results explain the pathology. innate immune defects probably contribute to her presentation and it is currently unclear if and how the combination of multiple genetic variants has left her immunologically vulnerable. we use this case to demonstrate that even when genetic testing does not elucidate a clearcut diagnosis of primary immunodeficiency, it can still provide helpful insight into a patients underlying immune phenotype. introduction: xiap deficiency is a rare primary immune deficiency characterized by hemophagocytic lymphohistiocytosis, recurrent fever and inflammatory syndromes, inflammatory bowel disease, hypogammaglobulinemia, recurrent infections, and other manifestations. loss of xiap results in abnormal tnf receptor signaling and nlrp3 inflammasome actvity which leads to dysregulated production of il-1beta and il-18. we hypothesized that suppressing the nlrp3 inflammasome with either targeted deletion or pharmacologic inhibition would suppress abnormal production and secretion of inflammatory il-1beta and il-18. methods: bone marrow derived macrophages (bmdms) from control, xiap-deficient, and xiap and nlrp3 double knock-out mice were derived with 1 week of culture in l929-cell conditioned media. bmdms were stimulated with a variety of tlr agonists or tnf-alpha, with or without a variety of inhibitors including the nlrp3 inhibitor mcc950, the cathepsin b inhibitor ca-074, and quercetin, which is a natural flavonoid (antioxidant) found in many fruits and vegetables, and available as a nutritional supplement. il-1beta, il-18, and tnf-alpha were measured in supernatants by elisa, and cell death was evaluated by flow cytometry using pi exclusion. results: as expected, bmdms from xiap deficient mice had markedly increased tlr-agonist-or tnf-alpha-induced il-1beta production compared to normal bmdms. genetic deletion of nlrp3 and the pretreatment of cells with the nlrp3 inhibitor mcc950 greatly reduced abnormal il-1beta production; residual production of il-1beta could be inhibited by caspase-8 inhibition. pre-treatment of cells with the cathepsin b inhibitor ca-074 also decreased cytokine production but was toxic at higher concentrations. quercetin reliably abrogated il-1beta, and also il-18. quercetin was found to inhibit priming of the nlrp3 inflammasome (decreased upregulation of pro-il1beta and nlrp3) and also decreased tnf-alpha secretion following tlr agonist stimulation. conclusion: quercetin suppresses the nlrp3 inflammasome and may be a promising therapeutic option for patients with xiap deficiency. it prevents il-1beta and il-18 secretion. it is a particularly appealing option given that it is a naturally occurring antioxidant, has a great safety profile, and is readily available as a nutritional supplement. human studies are needed. recently, single cell rna sequencing (scrnaseq) analysis in mice has disclosed an unexpected complexity of thymic stromal cells, and medullary thymic epithelial cells (mtecs) in particular. however, the developmental origin, hierarchy, and function of these subpopulations remain ill-defined. moreover, although cortical tecs (ctecs) are thought to represent a more homogeneous population, their characterization has been largely restricted to the adult thymus. we have previously shown that impaired lymphostromal cross-talk in the thymus of patients with combined immunodeficiency (and of corresponding mouse models) is associated with abnormalities of thymic architecture and tec maturation. here, we sought to compare tec distribution and gene expression in wild-type (wt) and in mice carrying rag1 hypomorphic mutations observed in patients with combined immune deficiency and immune dysregulation. methods: multi-color flow cytometry and scrnaseq were used to analyze composition and distribution of ctec and mtec subpopulations in wt and rag1 mutant mice at various weeks of age (niaid animal protocol: lcim-6e). results: we observed that rag1 mutant mice have an excess of ctecs, and that their mtec compartment is predominantly represented by cells with high levels of mhc class ii (mhc-ii) expression, recapitulating the phenotype of neonatal wt thymi. while mhc-iihi mtecs are thought to represent a minor fraction of mtecs in adult wt mice and include mature aire+ cells, a relative abundance of mhc-iihi mtecs is observed also at neonatal age, where they are thought to represent immature mtecs. to define more precisely tec maturation, we performed scrnaseq on sorted cd45-epcam+ cells, and identified 8 and 10 distinct clusters of tecs in wt and rag1 mutant mice, respectively. a large proportion of cells in rag1 mutant mice could be ascribed to the ctec compartment, confirming our previous flow cytometry and histopathology results. furthermore, scrnaseq analysis also disclosed a different distribution of mtec subsets in wt and rag1 mutant mice. to address the hypothesis that this difference in ctec and mtec abundance and subset distribution may reflect different maturation stages in tec development in wt and rag1 mutant mice, we will perform lineage tracing and transplantation experiments, and we will also extend tec scrnaseq analysis to wt and mutant mice of embryonic and neonatal age. in parallel, to evaluate the contribution of thymocyte maturation in shaping the stromal populations, scrnaseq will be performed on thymocytes. conclusions: we have further refined the complexity of tecs, and shown that impaired development of t cells in combined immune deficiency (as exemplified by rag1 mutant mice) has profound effects on the composition and maturation of tecs and may thus contribute to abnormalities of immune tolerance that are often associated with these conditions. the advent of next-generation sequencing (ngs), with the development of whole-exome sequencing (wes) in particular, has allowed the identification of unknown genetic lesions for many diseases and the implementation of specific therapeutic strategies. primary immunodeficiencies (pids) are a group of rare diseases which have benefited from ngs, with the discovery and molecular characterization of previously genetically undefined diseases and the identification of novel molecules involved in the regulation of the immune system. pids are often associated with autoimmune disease due to the dysregulation of the immune system as a whole. the clinical phenotypes are heterogeneous and often overlapping. while a monogenic cause of disease has been identified in a most subsets of patients, the recent application of whole-genome sequencing has found that a polygenic cause is likely. our aim is to investigate the genetic background of patients with immunedysregulations and autoimmunity and to evaluate the possible pathogenicity of the identified gene variants through extensive functional studies. we select 19 patients with sign of immunedysregulation and autoimmunity, extended immunophenotyping and next-generation sequencing (ngs) analysis of 50 genes frequently implicated in pids was performed. in six of them we identify a single gene as responsible of the clinical feature. in particular, we identify two patients with gain of function mutation in stat3, one patient with a mutation in ctla4, one patient with an activating pik3cd mutation, one with a rag1 mutation and one with a fas mutation. in most of them variants in multiple genes have been detected. interestingly, we find that some genes are recurrently mutated in more then one patient such as was, dock8, casp10, casp8, nfatc2 and fcgr3a. further studies are ongoing to validate the effect of the variations identified. our results strongly suggest that the old hypothesis, based on a single gene mutation as a cause of illness, should be revised in favor of the concept that "is the sum that causes the effect" and that a different point of view on pids now seems inevitable. physician, omni allergy, immunology, and asthma introduction/background: immunoglobulin replacement therapy (igrt) may be optimized to reduce the severity and incidence of infections and potentially delay or abrogate the development of pulmonary complications of primary immune deficiencies. pulmonary complications including bronchiectasis are common in common variable immune deficiency (cvid) and contribute significantly to morbidity and mortality in these patients. it remains unclear whether continued obstructive bronchial changes are a result of repeated respiratory infections, associated inflammation and immune dysregulation, or simply lung-damage that is irreversible by the time therapy is initiated. it has also been suggested that under-treatment in addition to the diagnostic delay may contribute to the development of bronchiectasis in patients with pid. lower serum igg levels with any given dose of immunoglobulin replacement therapy have been demonstrated in patients with bronchiectasis compared to those pid patients without this complication. in addition, earlier studies have shown that greater doses of ig (600 mg/kg/ month) may reduce the frequency and duration of infections and help prevent or slow progression of chronic lung disease. objective: to evaluate the prevalence of bronchiectasis in a cohort of patients with a diagnosis of cvid and identify associated ig dosing patterns and clinical outcomes. methods: data were analyzed from the ideal (immunoglobulin, diagnosis, evaluation, and key learnings) patient registry. this is a prospective, longitudinal registry study of patients receiving ig replacement therapy in the home or ambulatory infusion suite with one national home infusion provider. nursing and pharmacy standard of care forms were collected, and dose, infection rate, and prevalence of bronchiectasis were evaluated in patients with a diagnosis of cvid (icd-10 codes: d83.9, d83.1) results: there were 310 patients in the registry with cvid, 14 (4.5%) of which bronchiectasis was also observed. seventy-nine percent (n=246) of the study population was female, and 50% (n=7) of the cases of bronchiectasis were observed in females. the mean age of the patients with concurrent bronchiectasis was 65â±15.8 at start of care compared to 57â±15.8 in those without this observed bronchial obstruction. most bronchiectasis patients (n=11) received igrt subcutaneously every week with a mean dose of 123.8â±22.8 mg/kg/wk. the mean dose of ig in the 3 remaining patients receiving ig intravenously was 506.8â±82.0 mg/kg/month. the average annual rate of infection in ivig and scig patients with bronchiectasis was 1.6â±1.0 and 2.2â±1.3, respectively, however many were serious bacterial infections. at time of analysis, 7 of the bronchiectasis patients remained active in the registry and 7 had withdrawn. reasons for withdrawal included stopping igrt due to the following: patient decision (n=3), physician decision (n=1) insurance change (n=1), and patient expired (n=2). conclusions: there were 14 documented cases of bronchiectasis in our cohort of cvid registry patients, and dosing patterns aligned with standard doses despite the presence of bronchial obstruction. further studies are necessary to assess evolution of lung damage with respect to ig dosing in patients with cvid. background: activated phosphoinositide 3-kinase syndrome type 1 (apds1) is a combined immunodeficiency resulting from gain-offunction (gof) mutations in pik3cd, the gene encoding the catalytic subunit of phosphoinositide 3-kinase (pi3k). this form of pid is characterized by recurrent respiratory tract infections, susceptibility to herpes virus infections, impaired antibody responses, lymphoproliferation and autoimmunity. previous studies showed that patients with apds1 have b cell defects that contribute to the clinical phenotype. furthermore, these patients display t cell abnormalities, including increased numbers of memory t cells and t follicular helper cells (tfh), reduction of naã¯ve t cells and impaired t regulatory cell (treg) function. whether these t cell abnormalities are also associated with perturbations of t cell repertoire in unknown. objective: we aimed to investigate the effects of increased pi3k signaling on the t-cell repertoire of patients with apds. methods: high throughput sequencing was used to study composition and diversity of t-cell receptor (tra) and t-cell receptor (trb) repertoire in sorted treg, tfh, conventional cd4+ (tconv), and cd8+ t cells from 4 patients with pik3cd gof mutations and healthy controls. results: treg cells of patients with apds1 show restriction of tra and trb repertoire diversity, and increased clonality. no repertoire restriction was detected in tfh, tconv, and cd8+ t cells from the same patients. however, the trb repertoire of treg and cd8+ cells was enriched for the presence of hydrophobic amino acids in position 6 and 7 of the cdr3, a biomarker of self-reactivity. conclusion: these data demonstrate that the t-cell repertoire of patients with apds1 is characterized by a molecular signature that may contribute to the increased rate of autoimmunity associated with this condition. furthermore, our result support the notion that the pi3k pathway is a key regulator of treg cell development and homeostasis in humans. j clin immunol (2019) 39 (suppl 1):s1-s151 s87 (4), iii. predominantly antibody deficiencies (2), i. immunodeficiencies affecting cellular and humoral immunity (1), vii. auto-inflammatory disorders (2), ix. phenocopies of pid (1) . two non related cases of ataxia-telangiectasia and one case of schimke syndrome (smarcal1 compound heterozygous mutation) were diagnosed in the last year. we observed a wide range of age (we evaluate adult and pediatric population) with a male:female ratio close to 1: immunodeficiency, immune dysregulation, and systemic autoimmunity. clinical diagnosis of these disorders is complicated by overlapping phenotypes. in april 2017, a 207-gene next generation sequencing (ngs) panel inclusive of copy number variation analysis was launched by a commercial laboratory to facilitate clinical diagnosis of primary immunodeficiency (pid), monogenic autoimmunity and autoinflammatory disorders. we assessed the outcomes of genetic testing utilizing this panel on a cohort of pediatric patients with immunohematologic phenotypes evaluated at our tertiary care center during an 18-month period (5/1/17-10/31/18). eligible subjects were evaluated by at least two of three providers from a multidisciplinary pediatric hematology-immunology team, including a hematology physician, immunology physician and a geneticist or genetic counselor. twenty-three patients met inclusion criteria; 20 (87%) were caucasian, 12 (52%) were male with an average age of 11.7 years. the two most common phenotypic diagnoses included cytopenias, single-or multilineage (leukopenia, neutropenia, anemia, thrombocytopenia) primarily attributed to autoimmune causes or hypogammaglobulinemia. five (22%) were given a definitive genetic diagnosis as a result of panel testing, though in two of these cases, the causative mutations were listed as variants of uncertain significance (vus). diagnoses included common variable immunodeficiency due to a pathogenic variant in nfkb2, stat3 multiorgan autoimmunity due to gain-of-function mutation, and familial cold autoinflammatory syndrome due to a pathogenic mutation in nlrp12. biallelic dnmt3b vus were found in a patient whose phenotype and further laboratory studies (including karyotype) were consistent with immunodeficiency-centromeric instability, facial anomalies syndrome. further, a stat3 vus was identified in a patient with multiorgan autoimmunity and his father with hypothyroidism; studies from an outside research laboratory were consistent with gain-of-function with this variant (private communication). an additional three patients had vus identified that were suspected to be related to their phenotype, prompting eligibility for research studies. four (17%) patients had increased risk alleles in nod2, conferring an increased risk of crohns disease. three (13%) patients had pathogenic or likely pathogenic carrier findings warranting genetic counseling. in addition, 47 vus (an average of 2 per patient) thought to be unrelated to phenotype were identified, necessitating further investigation and counseling. the use of an ngs panel in a cohort of pediatric patients with immunohematologic disorders led to a definitive diagnosis in 22% of previously undiagnosed patients and prompted further research investigation in several more. genetic testing also led to the identification of clinically significant carrier findings, risk alleles and 47 vus unrelated to phenotype, necessitating genetic counseling. our experience illustrates the value of genetic testing for diagnosis of immunohematologic disorders, and the importance of multidisciplinary care, including genetic counseling, for the proper evaluation and management of these patients. background: allogeneic hematopoietic cell transplantation (allohct) is curative for primary immune deficiencies (pid). however, many patients lack a fully-matched unaffected sibling, or may have an unknown underlying genetic defect, rendering it undesirable to use related donors. many pid patients have significant comorbidities at the time they are referred to allohct, precluding the use of myeloablative conditioning. the use of alternative donors with reduced-intensity conditioning (ric) has historically led to increased rates of graft failure, graft-versus-host disease (gvhd), and transplant-related mortality (trm). posttransplantation cyclophosphamide (ptcy) as gvhd prophylaxis immunomodulates the graft through the preferential sparing of regulatory t cells and hematopoietic stem cells from its cytotoxic effects, thus allowing for robust donor engraftment that overcomes the hla barrier while effectively preventing severe acute and chronic gvhd. we report the outcomes of two institutions using a ric allohct regimen with alternative donors and ptcy in patients with pid. design: we transplanted 35 pid patients (table 1) using alternative donors and ric, either serotherapy-free (n=21) or alemtuzumab-based (n=14). all patients received ptcy for gvhd prophylaxis on days +3 and +4, either alone (n=3), or combined with mycophenolate mofetil and either sirolimus (n=21) or tacrolimus (n=11). donors included haploidentical family members (n=16), matched unrelated (n=15), and mismatched unrelated (n=4). stem cell source was t cell-replete bone marrow (n=33) or peripheral blood stem cells (n=2). results: the median follow-up is 17 months (range 0.5-8 years). at 17 months, overall survival is 91%, and event-free survival (defined as alive without graft failure) is 83%. the median days of neutrophil and platelet engraftment are 17 (range 14-42) and 28 (range 15-110), respectively. there were 10 patients who developed acute gvhd, grade 1 (n=5) or grade 2 (n=5), and there were no cases of grade 3 or 4 agvhd. seven of eight patients treated with systemic corticosteroids responded, and one was corticosteroid-dependent, then responded to second-line therapy. one patient developed skin-only chronic gvhd, which responded to corticosteroids and puva light therapy. five patients developed graft failure, either primary (n=1) or secondary (n=4), and four were successfully re-transplanted and remain engrafted. one patient with secondary graft failure had autologous recovery and has not required a second allohct given some durable infection control gained during initial engraftment. there were three deaths prior to day 180 due to infection, and one death at 1.5 years secondary to presumed overdose. in ongoing follow-up of engrafted survivors (n=30), evidence of phenotype reversal has been demonstrated in all patients, with complete or ongoing resolution of some or all of their underlying disease manifestations, including infection, transfusion-dependence, autoimmunity, malignancy, and/or immune dysregulation. discussion: we have observed high rates of engraftment, low rates and severity of acute and chronic gvhd, and low trm in 35 patients with pid transplanted using alternative donors, ric, and ptcy-based gvhd prophylaxis. ric allohct with ptcy shows promise for curing pid, and its use minimizes toxicity and widely expands the donor pool, thus allowing us to offer this curative therapy to many more patients with pid. chronic granulomatous disease (cgd) is a primary immune disorder that involves mutations in the nicotinamide adenine dinucleotides (nadph) oxidase complex (deffert, cachat, & krause, 2014) . two-third of cgd cases are caused by loss-of-function mutations in the cybb gene that encodes the gp91pox subunit of the nadph. the increased in patients' life expectancy thanks to progress in diagnosis and management has underlined the burden of inflammatory manifestations occurring independently of infectious agents (dunogue et al., 2017; marciano et al., 2018) . cgd patients develop inflammatory granulomatous disorders, notably colitis, as a consequence of a dysregulated inflammasome activation. the treatment of inflammatory manifestations remains challenging, as it can be associated with an increased risk of infections. thus, understanding the pathophysiological mechanism of auto-inflammation in cgd could help improve the therapeutic arsenal for the management of these manifestations. to reveal the precise pathophysiological mechanism of auto-inflammation in cgd, we have developed a cellular model that reproduces the cgd phenotype in phagocytic cell. through crispr-cas9 gene-editing we generated a thp-1 c e l l l i n e h a r b o r i n g t h e p r e v i o u s l y d e s c r i b e d mu t a t i o n c.90_92delccginsggt (p.tyr30ter) in the cybb gene responsible for gp91phox knock-out by early termination of translation. this cell line recapitulates the phenotype of cgd phagocytes: (i) decreased h2o2 production (ii) and enhanced inflammatory responses after pma stimulation as evidenced by increased il-1, il-6 and tnfa secretion levels (kuijpers & lutter, 2012) . these features were rescued by complementation through lentiviral transduction of a wild type cybb gene. this new model will help us to investigate the auto-inflammation reported in cgd patients and also to propose new therapeutic targets of inflammatory manifestations in this disorder. interleukin-1 (il-1) driven responses. children with irak-4 deficiency are predisposed to recurrent and invasive infections secondary to streptococcus pneumoniae, staphylococcus aureus and other pyogenic bacteria with high mortality rates in early childhood. the frequency and severity of infections is thought to decrease with age due to the acquisition of humoral immunity and immunologic memory, however due to the rarity of the disease, the natural history of this condition beyond early childhood is not well described. objectives: we present three unrelated irak-4 deficient patients with persistent chronic rhinosinusitis with nasal polyposis that developed in childhood. cases: patient 1 is a 15 y/o male with compound heterozygous mutations in irak4 (p.g75afs*14/c.717-1g>t) with a history of recurrent s. pneumoniae osteomyelitis (left hip at age 9 and left knee at age 10) and c. septicum sepsis at age 9 following acute bowel perforation. additionally, he experienced recurrent aom during infancy and recurrent uti since age 9. despite prophylactic antibiotics and ivig, he has had recurrent polymicrobial (mrsa, s. pneumoniae, h. influenzae, p. aeruginosa, a. fumigatus) rhinosinusitis with nasal polyposis since age 4 refractory to medical management requiring surgical intervention and prolonged courses of iv antibiotics. patient 2 is an 11 y/o female with homozygous deletions (exons 10-12) in irak4 with a history of ruptured appendicitis complicated by pseudomonas abscess and bacteremia at age 2, culturenegative sepsis with septic arthritis and osteomyelitis of the right leg at age 3, and septic shock secondary to mssa bacteremia complicated by rhabdomyolysis and dic at age 5. she has a history of chronic rhinosinusitis, and despite ivig and prophylactic antibiotics, she developed polymicrobial (h. influenzae, b. fragilis) rhinosinusitis with associated nasal polyposis pending surgical management. patient 3 is a 10 y/o female with homozygous mutations in irak4 (q293x/q293x on exon 8) with a history of s. pneumoniae meningitis at 3 months, m. catarrhalis epiglottitis and neck cellulitis at 4 months, rsv bronchiolitis at 6 months, enterococcus bacteremia at 8 months, s. pneumoniae sepsis at age 2 and streptococcus lymphadenitis at age 9. despite ivig and prophylactic antibiotics, she developed recurrent polymicrobial (h. influenzae, b. fragilis, mssa, v. cholera, p. aeruginosa, a. fumigatus) rhinosinusitis refractory to medical management requiring surgical intervention and iv antibiotics. conclusions: in our centers experience, irak-4 deficient patients continue to suffer from infectious complications, most prominently recurrent polymicrobial sinus infections beyond early childhood. the consistent presence of sinonasal polyps in these children is unusual, as it is not typically found in uncomplicated pediatric chronic rhinosinusitis. these infections have occurred despite antimicrobial prophylaxis and ivig, highlighting the role of irak-4 in sinopulmonary epithelium. additionally, the infectious organisms identified in our patient cohort are not commonly associated with irak-4 deficiency. further study of chronic rhinosinusitis and nasal polyposis in a larger cohort of irak-4 deficient patients and other innate immunodeficiencies may help identify pathways for targeted treatment of these patients. introduction: chronic granulomatous disease (cgd) is an inherited phagocytic defect associated with inability to clear catalase positive organisms. infections in patients with cgd are severe and recalcitrant. commonest infections are pulmonary followed by soft tissue infections and suppurative lymphadenitis. osteomyelitis is an uncommon infection in patients with cgd. it poses several diagnostic and therapeutic challenge. we herein report our experience of osteomyelitis in cgd over the last 10 years. material and methods: review of records was carried out to describe the profile of osteomyelitis in cohort of patients with cgd at pediatric immunodeficiency clinic, advanced pediatrics centre, postgraduate institute of medical education and research, chandigarh, india. the diagnosis of cgd was based on nitroblue tetrazolium dye reduction test (nbt) and dihydrorhodamine reduction (dhr) assay. results: of the 63 patients with cgd, 8 (12.7%) had osteomyelitis (6 males and 2 females; age range 1-10 years). most patients had their first episode of serious infection in early childhood (mean age: 1.5 years). stimulation index (si) of dhr assay ranged from 1 to 4.58. mutational analysis was done in 5/8 patients (3 x-linked; 2 autosomal recessive). site of involvement was variable ribs-4; vertebrae-2; radius-1; skull-2; tibia-1. aspergillus fumigatus was the most common isolate (62%; 5/8); others had aspergillus flavus, aspergillus terreus and serratia marcescens each. all 4 patients with rib osteomyelitis had concurrent pneumonia, and fungus was isolated in all of them (aspergillus fumigatus-2, aspergillus flavus-1, zygomyces spp.-1). antifungals (intravenous amphotericin b) were given for a duration of 4-6 weeks and were followed by oral voriconazole in therapeutic doses for 3 to 6 months in majority of them. debridement and resection of ribs was required in one patient, while other patients were managed conservatively. out of 8 patients, 2 (25%) succumbed to pneumonia and respiratory failure. conclusion: osteomyelitis in the context of cgd is usually caused by aspergillus spp. involvement of ribs and vertebra usually occurs with the contiguous spread of infection from the lungs. therapy often requires prolonged duration of anti-microbials, and may require surgical debridement in addition to it. a 29-year-old woman with history of hypogammaglobulinemia and acute liver failure a 29-year-old woman with a 7-month history of nausea, vomiting, and abdominal pain was admitted to an outside hospital with new onset of jaundice and anasarca. liver biopsy was thought most consistent with alcoholic steatohepatitis, and she was discharged with counseling on alcohol cessation and medical management of liver disease. she presented to our facility for a second opinion. over the following days, she developed further rise in direct hyperbilirubinemia up to 19.2 mg/dl, new coagulopathy with an inr 2.06 and hypoalbuminemia to 1.7 mg/ dl in the absence of ongoing alcohol consumption. liver sonography revealed course echotexture and patent vessels. pcrs directed against multiple hepatotropic viruses were negative and copper studies were normal. due to a history of moderate alcohol consumption, she was started on high-dose corticosteroids due to a presumptive diagnosis of alcoholic hepatitis. additional history raised concern for a possible primary immunodeficiency, including idiopathic thrombocytopenic purpura at 11 years of age, multiple episodes of sinusitis treated with antibiotics and sinus surgery, one episode of suspected bacterial pneumonia, and one hospitalization for influenza a during which she developed neutropenia. in her 20s, she developed refractory genital warts, prompting infectious diseases evaluation. initial immune evaluation had revealed low immunoglobulins (iga <7 mg/dl, igg 198 mg/dl, igm 13 mg/dl) with very low responses to tetanus and diphtheria, despite a recent booster dose, and b and t cell lymphopenia (cd19+ 89 cells/î¼l, cd3+ 567 cells/î¼l, cd4+ 345v, cd 8+ 244 cells/î¼l, cd16/56+ 236 cells/î¼l); antigen and mitogen proliferation were not assessed. intravenous immunoglobulin replacement was initiated but discontinued by the patient due to infusion-related adverse effects, and she was lost to follow up until she presented with liver failure. both parents were deceased from cardiovascular disease in their 40s and she had no siblings. she had limited knowledge of family history but no known immune diseases. due to suspicion for genetic etiology of immune disorder and liver disease, we performed next-generation sequencing of a panel of over 200 genes implicated in primary immune deficiencies. patient was heterozygous for a nucleotide substation (c.1752+1g>a) within a splice site at the exon 16/intron 16 boundary of the nfkb1 gene. during the hospitalization, immunoglobulin replacement and trimethoprim-sulfamethoxazole prophylaxis were initiated. an attempt was made to refer the patient for additional immunological evaluation and transplantation evaluation but unfortunately, she developed worsening liver failure and multiple complications, including extended-spectrum beta-lactamase (esbl)-producing e. coli bacteremia, hypotension requiring vasopressors and extensive bowel ischemia, and died in the hospital. in summary, this case highlights both the risk of diagnostic delay in adult patients presenting with a primary immune deficiency and potential for genetic testing to clarify the diagnosis. while the particular genetic change has not been described, other splice site and predicted loss-offunction mutations have been reported as pathogenic in this gene, which have been implicated in autosomal dominant common variable immunodeficiency. this case further expands on the genetic causes and spectrum of disease associated with changes in the nfkb1 gene. introduction: malnutrition and micronutrient deficiency are underrecognized causes of acquired immunodeficiency in adults, and may occur even in patients with high body mass index (bmi). methods: a 46-year-old woman with a medical history significant for one remote urinary tract infection presented to the emergency department after sudden onset of severe right flank pain. the pain was accompanied by urinary frequency and not relieved by ibuprofen; she denied fevers or chills. she was diagnosed with pyelonephritis and discharged on ciprofloxacin, which was later changed to trimethoprim-sulfamethoxazole after her culture grew resistant e. coli. her pain continued despite treatment, prompting her to return to the hospital three days later. upon presentation, she was afebrile with blood pressure of 128/88 mmhg and heart rate of 86 bpm. her body mass index was 32.4 kg/m^2. her physical exam was otherwise notable for right costovertebral angle tenderness. laboratory studies revealed a leukocyte count of 14,300/ul with 83% neutrophils; alkaline phosphatase of 146 units/l and albumin of 2.7 g/dl, but otherwise normal liver function tests; normal lactic acid; and urinalysis with 3,000 wbc/hpf, 40 rbc/hpf, moderate bacteria, and the presence of wbc clumps. ct scan of the abdomen and pelvis demonstrated an obstructing 13 mm right renal stone with hydronephrosis and a right renal abscess contiguous with a right-sided hepatic abscess measuring 7.8 x 6.0 x 7.5 cm. she was treated with ceftriaxone and metronidazole, and underwent imaging-guided drainage of the abscesses. abscess cultures again grew resistant e. coli. she was discharged from the hospital with drains in place and a plan to continue trimethoprim-sulfamethoxazole until definitive management of her nephrolithiasis with ureteroscopy and lithotripsy. discussion: there remained the question of how an ostensibly immunocompetent patient had developed such severe intraabdominal infection with little systemic inflammatory response (e.g. no fever and only mild leukocytosis). a hiv antibody screen was negative. on further interview, she described a 200lb intentional weight loss over the preceding 2 years, accomplished by dietary restriction to less than 600 calories per day. nutritional assays revealed prealbumin, vitamin c, and vitamin b6 levels below the threshold of detection. she had low-normal b12 and b1. out of concern for an acquired immunodeficiency resulting from malnutrition with micronutrient deficiency, balanced nutrition was discussed with the patient who agreed to liberalize her diet. background: the past decade has brought dozens of new mendelian disorders of immunity. yet, the genetic contribution(s) to diverse disorders of the immune system remain largely unelucidated. the majority of research participants referred to the national institute of allergy and infectious diseases (niaid) for what may be a mendelian disorder evade molecular diagnosis. making progress in this area requires a coordinated, systematic, and transparent approach to clinical genomics research which leverages the unique environment at the national institutes of health clinical center (nih cc). methods/design: this study is designed to systematically apply exome sequencing and related technologies with clinical grade interpretation and reporting to niaid research participants at the nih cc under a single protocol in order to facilitate research and clinical genetics care across niaid. we are recruiting approximately 1000 participants per year from approximately 35 intramural clinical investigators. we generate genomic data, collect standardized phenotyping and report clinical interpretation in the medical record, all while providing linked genetic counseling. results: to date, we consented 1287 participants, we sent out 1058 samples for exome sequencing and 183 samples underwent copy number variant analysis. we have completed analysis for 359 families (502 individuals) and finalized and resulted 177 cases. here we present a case series illustrating some of our findings. case 1: a 10year-old female was referred to niaid for neonatal onset multisystem inflammatory disease (nomid). developmental delay and mild intellectual disability were appreciated on clinical evaluation. exome sequencing detected a mosaic novel likely pathogenic variant in nlrp3. chromosomal microarray analysis (cma) showed 㣠5 mb interstitial deletion of chromosome 12 previously associated with developmental delay and intellectual disability. case 2: a 10year-old ukrainian male was referred to niaid for the clinical diagnosis of autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (apeced). exome sequencing and cma did not detect pathogenic variants in aire, but did find a de novo variant in fam111b. defects in fam111b are associated with poikiloderma with tendon contractures, myopathy, and pulmonary fibrosis (poiktmp). the clinical features of the patient were consistent with poikmp. case 3: a 63-year-old man had a history of brain, liver and kidney nocardiosis, disseminated mac infection, prostate cancer and lymphoma. family history was significant for prostate cancer. exome sequencing showed a heterozygous pathogenic variant in brca2, associated with susceptibility to breast-ovarian, male breast, pancreatic and prostate cancer. conclusion: this case series illustrates that multiple diagnoses, unexpected diagnoses, secondary genomic findings, and data sharing helped identify variants in candidate genes. process standardization supports data integrity and efficiency while accommodating the need for investigator flexibility and providing tailored patient care. rationale: activated pi3 kinase delta syndrome (apds) is a primary immunodeficiency caused by dominant mutations that increase activity of phosphoinositide-3-kinase (pi3k). the catalytic subunit p110 is mainly expressed in cells of the hematopoietic system, primarily lymphocytes and myeloid cells, and mutations affect both b-and t-cells. we sought to further evaluate the role of the t-cell receptor (tcr) repertoire in immune dysregulation and the pathogenesis of autoimmunity and lymphoproliferation in patients with apds. methods: we evaluated the tcr repertoire in the peripheral blood in 3 patients with pik3cd mutations and compared these to the peripheral tcr repertoire in 26 patients with common variable immunodeficiency (cvid) and 50 healthy controls to investigate the role of the tcr in disease. the tcr repertoire in affected tissue of 2 patients with pik3cd mutations was also evaluated (tissue included lymph nodes for both patients, in addition to gastrointestinal tract and lung tissue in one patient). a fixed number of tcrs were subsampled (35,000 for blood and 5,000 for tissue) and diversity was calculated using the gini and shannon indexes. results: using the shannon and gini diversity indexes, the tcr repertoire in patients with pik3cd mutations had less diversity/ increased clonality as compared to healthy controls and those with cvid ( figure 1 ). for the two apds patients with biopsy tissue available for analysis, the diversity of the tcrs in tissue was increased as compared to the peripheral blood tcr repertoire ( figure 2 ). conclusions: pi3k plays an important role in the development and function of both b-and t-cells. patients with apds were found to have decreased tcr repertoire diversity in the circulating t-cell compartment compared to healthy controls and other cvid patients. the increased tcr diversity in the affected tissues compared to peripheral blood implicates the pi3k/akt signaling pathway with t-cell trafficking and tissue immune homeostasis, and suggests this pathway may play a role in the development of inflammatory and lymphoproliferative complications in these patients. gain-of-function mutations in pi3kd result in a human primary immunodeficiency, named apds (activated pi3k-delta syndrome), characterized by lymphopenia, lymphoproliferation, respiratory infections and inefficient responses to vaccination. however, what promotes these immune disturbances at the cellular and molecular level remains unknown. we have recently published a mouse model that recapitulates major features of this disease and used this model and patient samples to probe how hyperactive pi3kd fosters aberrant humoral immunity. we found that mutant pi3kd alters the intrinsic function of t and b cells, leading to icos-independent increases in t follicular helper (tfh) and germinal center (gc) b cells, disorganized gcs, and poor class-switched antigen-specific responses to immunization. these phenotypes were associated with increased phosphorylation of akt and s6 in t and b cells, and lower threshold of activation, with altered regulation of foxo1 and bcl2 family members. moreover, b cells showed enhanced responsiveness and proliferation to both antigens and innate stimuli, accompanied by reduced cell death. strikingly, aberrant responses were accompanied by increased reactivity to gut bacteria, and a broad increase in autoantibodies that were dependent on commensal microbial stimulation, as demonstrated by striking reduction of self-reactivity upon antibiotic treatment in mutant mice. we now have further examined b cell function in these mice and demonstrate that altered foxo1 plays a major role in disruption of both b and t cell function. we further provide evidence for altered activation of metabolic pathways in b cells, compared to wt cells, that may contribute to the dysregulated b cell reactivity. our findings suggest that proper pi3kd regulation is critical for ensuring optimal host-protective humoral immunity despite tonic stimulation from the commensal microbiome. this research was supported in part by the intramural research program of the nih, nhgri and niaid. autoimmune cytopenias are seen in a significant proportion of patients with immunodeficiencies affecting antibody production. previous b-cell maturation studies using fluorescence-activated cell sorting (facs) have associated various phenotypes of primary immunodeficiency diseases affecting antibody production with differing levels of b-cell differentiation. in this study we analyzed the peripheral b-cell compartment of 84 patients with a hypogammaglobulinemia and >1% b-cells with and without a history of autoimmune cytopenias. b-cells were isolated from peripheral blood using monoclonal anti-cd19 and these cells were gated to identify the proportion of memory b cell (cd19+cd27+ ), igm+ memory b (cd27+igm+), marginal zone b-cells (igm+ igd+), isotype-switched memory b-cells (cd27+igm-igd-) and transitional cells (igmhicd38hi). pid patients with a history of aic had decreased proportions of total cd27+ b-cell (11.6% vs 25.6%; p=0.0003) and igm memory b cells (8.3% vs 18.4%; p = 0.0018). conversely, the proportion of marginal zone b-cells was increased in this group (82.0% vs 66.5%; p = 0.0043). consistent with previous reporting, the proportion of isotype-switched memory b-cells was significantly lower in the aic group (0.75% vs 2.8%; p = 0.0003). statistically significant inter-group difference was not seen within the transitional b-cell subset. our data suggest that maturation arrest of marginal zone (cd27+igm+ igd+) b-cells may be implicated in the development of autoimmune cytopenias in humoral immunodeficiency. (159) submission id#601984 taissa de matos. kasahara 1 , sudhir gupta, md 2 1 phd student, state university of rio de janeiro and university of californis irvine 2 professor, university of california at irvine, irvine, ca, usa introduction/background: common variable immunodeficiency (cvid) is the most frequent form of primary hypogammaglobulinemia with decreased serum igg and iga levels and variable levels of igm in adults. in addition to decreased serum immunoglobulins, 25-30% of cvid patients present autoimmune manifestations. the mechanisms that lead to a breakdown of selftolerance in cvid are not completely understood. however some differences in b and t cells subsets and autoreactive b and t cells can be detected. elevated expression of surface igd and downregulation of igm receptor are hallmarks of anergic naã¯ve b cells that contain autoreactive receptors in human peripheral blood. moreover, memory b cells that have class switched to igd and present an igd+igm-phenotype are also highly reactive to self-antigens in healthy individuals. the role of these autoreactive naã¯ve and memory b cells in the immunopathogenesis of cvid has not been evaluated. here we investigated the frequency of cd27-and cd27+ b cells expressing igd and igm in peripheral blood of cvid patients. methods: peripheral blood mononuclear cells (pbmc) from cvid patients (n=29) and health subjects (n=32) were separated by ficollhypaque and incubated with anti-human cd19-percp, cd27-fitc, igd-bv510 and igm-apc to identify different subsets of b cells by flow cytometry. cd19+cd27-igd+igm-and cd19+cd27-igd+ igm+ b cells were sorted, loaded with cfse and cultured with cpg and ant-cd40 for 5 days to evaluate the proliferation. results: among the compartment of cd27-b cells, cvid patients showed an increased frequency of igd+igm+ cells and a lower frequency of igd-igm-cells as compared to control group. no differences were observed in the frequency of igd+igm-cells in cd27-b cells between cvid patients and controls. in contrast, in the compartment of cd27+ b cells, cvid patients showed an increased frequency of igd+igm-, igd+ igm+ and igd-igm+ cells and a lower frequency of igd-igm-cells when compared to health subjects. when the patients were divided in two groups based on autoimmune manifestations, the group with autoimmune disease showed an increased frequency of igd+igm+ and igd-igm+ cells in cd27-b cells when compared to the control groups. both patient groups showed an increased frequency of igd+igm-, igd+igm+ and igd-igm+ cells and a lower frequency of igd-igm-cells when compared to health subjects. regarding the proliferation, naã¯ve b cells from cvid patients showed a reduced proliferative capacity in response to in vitro stimulation as compared with naã¯ve b cells from health subjects. conclusion: our results suggest that the increase of cd27+igd+igm-b cells can be related to the susceptibility of autoimmunity in cvid patients. introduction: immunoglobulin g4-related disease (igg4-rd) is a group of immune-mediated conditions where tissues are affected with dense lymphoplasmacytic infiltrations with a predominance of igg4-positive plasma cells and storiform fibrosis, usually in the setting of elevated serum concentrations of igg4. common presentations include autoimmune pancreatitis, sclerosing cholangitis, retroperitoneal fibrosis, salivary gland disease, and orbital disease, among others. symptoms of asthma or allergy are present in approximately 40 percent of patients and they typically exhibit a good initial therapeutic response to glucocorticoids. case presentation: a 61-year-old female with a history of gastroparesis, cutaneous lupus erythematosus and suspected autoimmune pancreatitis was referred to allergy/immunology clinic for evaluation of elevated igg4. she reported a 15-year history of recurrent abdominal pain attributed to recurrent pancreatitis based on previous mild lipase elevations. prior endoscopic ultrasound (eus) of the pancreas revealed edema. there was concern for gallstone pancreatitis but ercp followed by cholecystectomy, biliary and pancreatic sphincterotomy had no change in her symptoms. in 2016, she was noted to have a positive ana and high serum igg4, per patient (values from osh records could not be obtained). symptoms improved with a course of steroids, hence suspicion for autoimmune pancreatitis. in 2018 she developed a rash on her arms and face. biopsies of the affected areas revealed cutaneous lupus erythematosus on the arms and a basal cell carcinoma on the face, which was excised. ana was only 1:80 at that time. at the visit, she complained of severe allergic rhinitis, joint pains, as well as a malar rash, which responded to intermittent courses of prednisone by prior providers. laboratories obtained at initial visit were significant for thrombocytopenia (135 thou/cu mm), positive lupus anticoagulant (56 sec) and elevated igg4 (95 mg/dl; normal range 4-86 mg/dl). c3, c4, c1q, ana, anti-double stranded dna, anti-smith antibodies, antiphospholipid panel, upep and spep were all unremarkable. ct chest and abdomen were also normal. given the patient's history of cutaneous lupus erythematosus, plaquenil was started as a steroid sparing agent. eus of the pancreas with possible biopsy was ordered in an attempt to obtain a histopathologic diagnosis of igg4-rd. conclusion: this case exhibits the association between elevated igg4, pancreatitis of unknown origin, allergic rhinitis, and cutaneous lupus erythematosus, highlighting the value of identifying a pathologic connection between seemingly unrelated disorders in patients with elevated igg4, as they may be manifestations of igg4-rd. in order to make the diagnosis, histopathologic findings showcasing lymphoplasmacytic tissue infiltration consisting mainly of igg4-positive plasma cells and small lymphocytes is essential. the majority of patients respond to glucocorticoids, and while the duration of response is variable, most patients flare during or after glucocorticoids are tapered, as noted in this patient. rituximab has been shown to be effective in some patients and will be considered in this patient if symptoms persist. (161) submission id#602042 rationale: pnp deficiency is an autosomal recessive disorder due to defective purine metabolism leading to severe combined immunodeficiency (scid) and neurological deterioration. newborn screening utilizing t-cell receptor excision circle (trec) assay can detect affected patients before complications arise. herein, we describe an infant initially identified by newborn screening with pnp deficiency and congenital cmv, a previously unreported presentation. methods: cmv quantitative pcr (qpcr) was performed by nebraska medicine, pnp enzyme activity by duke and genetic sequencing by invitae. results: a small for gestational age (sga) male infant was reported to have an abnormal trec assay on day of life (dol) 7. he was hospitalized for further evaluation. initial studies revealed profound lymphopenia, normal lymphocyte proliferation to mitogens and no evidence of maternal engraftment. additionally on dol 10, he had cmv viremia and viruria; thus with sga, failed unilateral hearing screen and head ultrasound with bilateral parenchymal calcifications, congenital cmv was suspected. pnp enzyme activity was abnormal. cmv treatment was initiated with ganciclovir on dol 10. foscarnet was added on dol 13. cmv qpcr levels decreased below the limit of detection by dol 30. genetic testing found a pathogenic homozygous mutation in pnp (c.286-18g>a). the infant has a 10/10 hla-matched, unaffected, cmv positive sibling and will proceed to hematopoietic stem cell transplantation. conclusions: to our knowledge, this is the first reported case of pnp deficiency identified through newborn screening. this novel case of congenital cmv and pnp deficiency highlights the importance of cmv screening and need for treatment strategies for congenital cmv in scid. despite a dramatic increase in the use of next generation sequencing over the last decade, the majority of the more than 50 million identified human genomic variants do not have well-established clinical implications. progress is being made on this complex challenge through multiple approaches, including data sharing. to maximize our understanding of genomic data, platforms that enable effective and responsible data-sharing are essential. this means that genotypic and phenotypic data must be findable, accessible, interoperable, and reusable under conditions that are ethical and transparent. to highlight innovations in data-sharing and their potential to advance discovery, we present three data-sharing mechanisms. for each platform, we will present a case highlighting its key functionality and discuss opportunities and challenges that may arise as each platform is scaled up. (1.) genomic research integration system (gris) is a collaborationengendering web application that facilitates the identification of genetic variants associated with rare immunological disorders. users can access integrated and standardized phenotypic and genomic data that is analyzable within the platform. gris enables systematic and automated capturing, and links patient data from disconnected systems and paperbased records. standardized annotations allow for the comparison of data from different clinical studies. the main goal of this tool is discoverability of other affected individuals enrolled in separate protocols within the niaid intramural research program. this internal database was used to find a second family with a rare variant in a candidate gene. (2.) the genomic ascertainment cohort (tgac) is a resource that aims to improve our understanding of the phenotypic consequence of genetic variation by providing access to aggregate, de-identified genomic data from large nih intramural and related cohorts. participants have provided informed consent to be re-contacted for additional phenotyping in the future. the main goal of this tool is to enable further study of the clinical consequence of variants in a large, unbiased cohort of patients ascertained for many indications. this database was used to investigate findings in participants with previously published pathogenic variants in genes associated with primary immune deficiency based on medical record review. (3.) clingen is dedicated to building an authoritative central resource that defines the clinical relevance of genes and variants for precision medicine and research. through the sharing of genetic and health data, clingen seeks to answer whether a given gene is associated with a disease (clinical validity)?; whether a given variant is causative (pathogenicity)?; and whether the information is actionable (clinical utility)? this resource is meant to convene disease-and gene-specific expert groups to curate the medical literature on mendelian disease to better define gene-disease and variant-disease relationships using many lines of evidence. this resource was used to clarify clinical validity of disease-gene assertions. together these efforts help create a clinical research ecosystem that maximizes the value of clinical research data and ultimately improves patient care. this research was supported by the intramural research program of the nih, niaid. introduction: according to the population reference bureau, the number of elderly americans, defined as age 65 and older, is projected to more than double from 46 million to 98 million by 2060, rising from 15% to 24% of the total population. the impact of immunodeficiency in this important segment of the population remains understudied. methods: the usidnet registry was queried to obtain demographic, clinical data of elderly patients defined as age 65 and older. descriptive analyses were performed on the data. results: 373 participants (7.2%) were eligible out of 5176 total registry participants. the median age of the cohort was 70 years and predominantly female (74.7%) and white (78.0%) with a median bmi of 26.6 â± 6.6.the majority (81.8%) of subjects were living. humoral deficiencies comprised the majority of diagnoses (94.6%), with common variable immune deficiency being the most frequent (76.9%). of the remaining non-humoral diagnoses, immune dysregulation (1.3%) and immunodeficiency with myelodysplasia (1.1%) were the most frequent. the majority (79.1%) of subjects reported having received immunoglobulin replacement therapy (igrt) at some point, with 51.7% reporting via iv route. of the 1275 infections that occurred in this cohort, sinopulmonary infections were the most commonly reported, specifically sinusitis (18.5%), pneumonia (13.8%), upper respiratory infection (6.7%), and otitis media (5.5%). in this cohort, 107 autoimmune, 49 cardiovascular, and 11 granulomatous complications were reported . the number of patients with malignancy was 89, with some patients diagnosed with multiple malignant disorders. of the reported malignancies, the majority (69.9%) were solid tumors. conclusions: compared to the age-matched non-immunodeficiency united states population, this cohort had more females 74.7% (usidnet) versus 56.0% (us population) and fewer whites 78.0% (usidnet) vs 86.0% (us population. humoral immunodeficiencies, specifically cvid, were most common diagnoses, similar to other age groups of immunodeficiency patients. majority of these patients have received igrt, with approximately half via iv route. this cohort reported living with a variety of non-infectious complications, including autoimmunity and malignancies. more research which specifically focuses on elderly patients with immunodeficiency is needed. clinical microbiologist and infectious disease physician, university of calgary x-linked agammaglobulinemia (xla) is a primary immunodeficiency caused by mutations in the bruton tyrosine kinase gene which leads to b cell maturation failure and defective antibody production. this puts patients at risk of recurrent sinopulmonary infections, gastrointestinal infections, and recurrent skin infections including infections caused by helicobacter sp. helicobacter sp are gram negative bacilli commonly found in the gastrointestinal tract of various animals. helicobacter sp. have been linked with gastritis most notably helicobacter pylori causing gastric ulcers in humans. helicobacter sp. has been found in rare cases to cause disseminated infections including pyodermic gangrenosum and cellulitis notably in patients with agammaglobulinemia. infections caused by helicobacter bilis are challenging to diagnosis due to difficulties with culturing the pathogen as well as poor guidelines for antimicrobial management. case report: the patient was diagnosed with x-linked agammaglobulinemia at the age of 16 months with a history of recurrent sinusitis and was started on ivig q3weeks. despite regular ivig, he developed bronchiectasis. at 11 years of age in 2013, he developed a chronic rash around his left knee resembling erythema nodosum. by 2014, he had developed a left knee effusion associated with left sided calf pain. his knee pain was found to improve during courses of ciprofloxacin to treat recurrent lung infections. given case report data of h. pylori causing erythema nodosum in patients with agammaglobulinemia, he was treated empirically for an h. pylori infections with no improvement. in 2015 he was found to have progressive cellulitis with pyomyositis of the left leg. a skin biopsy of a calf nodule was found to be culture negative but 16s pcr was positive for h. bilis. he was started on treatment with ertapenem and levofloxacin with subsequent resolution of his rash. his left ankle pain progressed and by late 2015 and was found to have possible osteomyelitis of the left ankle on mri. in 2016 he was found to be bacteremic with h bilis. due to progressive symptoms with significant impact on function and rising inflammatory markers despite 12 months of antimicrobial treatment, doxycycline and flagyl were added leading to clinical improvement and normalization of his inflammatory markers. he was continued on oral doxycycline and flagyl for 12 months for a chronic osteomyelitis. discussion: h. bilis is a slow growing pathogen which is challenging to culture in the laboratory often requiring special agar plates and prolonged incubation. in patients with agammaglobulinemia and associated chronic skin infections or erythema nodosuma, h bilis should be suspected as a possible pathogen. due to challenges with culturing, 16s pcr or amplification of the 16s ribosomal subunit should be considered to try to identify the pathogen. there are poorly delineated clinical antimicrobial breakpoints to help guide therapy with minimal evidence. case reports suggest prolonged therapy with aminoglycosides and penicillin. other studies have successfully treated patients with a carbapenem, azithromycin and levofloxacin. in the absence of sensitivity data, prolonged treatment (12months) should be considered with a combination of antimicrobials. patients should be followed closely as recurrent infections are not uncommon. chief, human immunological diseases section, laboratory of clinical immunology and microbiology, niaid, nih, bethesda, md introduction: dock8 deficiency is a combined immunodeficiency characterized by eczema, recurrent sinopulmonary infections, viral skin infections, malignancy and early mortality. in recent years, liver disease and vasculopathy have been increasingly recognized as a complication of dock8 deficiency. we clinically characterized our cohort of dock8 deficient patients, with a specific focus on these newly identified areas of disease involvement. methods: chart reviews were performed on patients seen at nih with genetic and clinical diagnosis of dock8 deficiency. patients were all enrolled on irb approved niaid protocols. results: we identified 52 patients from 40 families with dock8 deficiency in our nih cohort, ranging in age from 6-44 years. of the 40 families, 17 had homozygous mutations. of the 52 patients, food allergy was diagnosed in 31 (60%), eczema in 49 (94%), and asthma in 30 (58%). chronic or recurrent viral skin infections were seen in 49/52 (94%). chronic ebv viremia by pcr positivity was seen in 18/46 patients (39%); only 2 patients were known to be ebv immune without viremia. cmv viremia was infrequent. sinopulmonary infections were common, with bronchiectasis occurring in 23 /50 (46%) with available imaging. liver disease was diagnosed in 14 (27%), with 7 having biliary tract abnormalities on imaging and stool positive for cryptosporidia; most patients with cryptosporidia were without diarrhea. the incidence of cryptosporidia is likely under-represented due to more recent availability of sensitive assays for cryptosporidia detection. other liver abnormalities included fatty liver, metastatic disease from malignancy and medication related hepatitis. vasculopathy, predominantly of the aorta and cerebral arteries, was diagnosed in 7, with patients in the last 5 years being prospectively imaged. autoimmunity was rare (5%) including autoimmune cytopenias and hypothyroidism. 36 of 50 with follow-up are alive (70%) with age range 6-44 years. of the 36 living patients, 28 (78%) have had a hsct. causes of deaths include malignancy (6), infection (1) , and hsct complications (7) . long-term follow-up of patients with hsct (up to 6 years) has revealed resolution of the infection susceptibility and eczema, no new cancers, and stabilization of vasculopathy. conclusions: in addition to the well described manifestations of dock8 deficiency including eczema, allergy, recurrent sinopulmonary infections, skin viral infections and malignancy, our cohort revealed a relatively high incidence of liver disease, frequently associated with stool positivity for cryptosporidia, as well as vasculopathy. both of these clinical manifestations should be considered during preparation for hsct as they may affect management through transplant. autoimmunity has likely been over-estimated in prior descriptions of dock8 deficiency. long-term follow-up after hsct is needed to determine the prognosis from the vasculopathy, liver disease, and malignancy risk. (166) submission id#604115 yasuhiro yamazaki 1 , stefano volpi 2 , luigi d. notarangelo 1 introduction/background: extl3 (exostosin like glycosyltransferase 3) is an exostosin family member which initiates heparan sulfate (hs) chain biosynthesis and elongation. we have reported homozygous extl3 hypomorphic mutation (r339w) as a cause of immunoosseous-dysplasia syndrome. fourteen patients who have extl3 homozygous mutation were reported so far. eight of them manifested t cell lymphopenia, and 5 presented with severe combined immunodeficiency (scid) or omenn syndrome. using patient-derived induced pluripotent stem cells (ipscs) as a model, we have previously reported that extl3 mutations affect differentiation to thymic epithelial progenitor cells as well as expansion of hematopoietic progenitor cells. consistent with the latter, previous studies have suggested that mutations in other genes involved in hs biosynthesis affect hematopoietic stem cell (hsc) differentiation. however, the exact mechanisms by which extl3 mutations affect hematopoiesis are not known. objectives: we tried to clarify gene expression difference in hscs derived from wild-type, extl3 hypomorphic and extl3 knock-out (ko) human ipscs. methods: the control bj ipsc line was engineered by crispr/cas9 gene targeting. extl3 ko ipscs were obtained which carried compound heterozygous extl3 mutations (c.1003_1004inst; c.1005_1006insgatattt). hsc differentiation was induced using the stemdiff hematopoietic kit (stemcell technologies). bulk rna from each ips cells and each differentiated cd34+cd43+cd45+ was analyzed by rna sequencing. results: as compared to control ipscs, patient-derived cells showed slightly lower capacity to generate cd34+cd43+cd45+ cells. on the other hand, extl3 ko cells showed no differentiation into cd34+ cd43+cd45+ cells. gene set enrichment analysis showed enriched expression of genes involved in hematopoietic progenitor cell differentiation, regulation of hemopoiesis, and positive regulation of hemopoiesis in both control and patient-derived cd34+cd43+cd45+ cells compared to parental ipscs. moreover, these gene sets were more abundantly enriched in control than in patient-derived cd34+cd43+cd45+ cells. the gene set of response to type i interferon was significantly enriched in control versus patient-derived cd34+cd43+cd45+ cells. conclusions: these results confirm that extl3 plays an important role for hsc homeostasis in human cells. because type 1 interferons play a role in hsc proliferation, the decreased type i interferon signature may account for the reduced number of hscs that we have previously reported upon in vitro differentiation of extl3-mutated versus control-derived ipscs. this study was supported by the division of intramural research, niaid, nih, under protocol 16-i-n139. a case of autoinflammatory syndrome with osteoporosis and specific antibody deficiency autoinflammatory syndromes are inherited disorders with an exaggerated inflammatory response with no specific trigger. the clinical phenotypes of variants of autoinflammatory syndromes may overlap. we report a case of a 13 year old male with prior diagnosis of specific antibody deficiency, periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis (pfapa) syndrome, arthralgia and moderate atopic dermatitis. he was diagnosed at 3 years of age with specific antibody deficiency based on persistently low pneumococcal titers against repeat immunizations. due to recurrent infections, he was placed on immunoglobulin replacement therapy (igrt) at 8 years of age. igrt was discontinued at 13 years of age due to full resolution in infections and patient demonstrated robust response to immunizations. patient had lifelong history of recurrent fevers (every 5 weeks) associated with pharyngitis and aphthous ulcers consistent with diagnosis of pfapa. as he became older these episodes became less frequent. last episode of fever was over a year ago. the father had similar symptoms of recurrent fevers and oral ulcers as a child but currently remains asymptomatic. paternal grandfather died of kidney disease. patient has been generally in good health until recent year with intermittent abdominal pain, arthralgia and several long bone fractures with no history of prior trauma. a bone density scan revealed osteopenia and osteoporosis with a z score of -2.2 of lumbar spine, -4.0 of left femoral neck, -3.1 of left hip. given history of familial autoinflammatory disease, and antibody deficiency genetic testing was obtained which identified a pathogenic heterozygous variant of taci and mefv c.2082g>a (p.met694lle). taci mutation has been linked to antibody deficiency syndromes. genetic study for family members is pending. the mefv gene is associated with autosomal recessive familial mediterranean fever (fmf) and has been reported in autosomal dominant fmf as well. fmf is characterized by recurrent episodes of fever associated with serositis, arthralgia, and arthritis. patients with fmf have elevation in acute phase reactants during attacks with most returning to normal levels during the episode-free periods. multiple studies have shown that patient with fmf have lower bone mineral density and zscores than the general population. inflammation in fmf is thought to be mediated by several different cytokines (il-1, il-2, il-6, il-7, il-8, il-11, il-15 and tnf-). these same cytokines play a role in osteoclast activity and bone resorption. it has been suggested chronic inflammation during acute attacks and subclinical inflammation during the disease-free period lead to bone loss and osteoporosis. regular use of colchicine, the main treatment for fmf, may slow down osteoporosis. beside careful monitoring of clinical and laboratory phenotype, genetic evaluation is an important step in distinguishing between overlapping entities and can prevent complication and promote targeted intervention. a 5 year old previously healthy boy was referred for periodic fever/ pfapa and mosquito bite hypersensitivity. eight weeks earlier he developed fever to 104f, mouth sores and exudative tonsillitis; a rapid strep screen was negative. one week later he developed moderate cervical lymphadenopathy and had a positive ebv early antigen antibody.. one month later he had several severe local reactions to mosquito bites. each manifested 6-8 cm of erythema and induration with a 1+ cm bullae which left an ulcer after rupture and healed with a hypopigmented scar. the bites were accompanied by fever to 104f for 4 days. one febrile episode was treated with low dose prednisolone for presumed pfapa, and the fever resolved within hours. his past history was positive for nasal allergy and mild asthma. his parents are not related: mom is of european-indonesian and dad european-african (creole ancestry. testing prior to this visit showed normal igg, iga and igm, elevated ige (12,000 u/l) and normal cbc. lymphocyte subsets revealed cd3+ 23% (1538/mcl), cd4+ 17% (1109/mcl), cd8+ 6% (363/ mcl), cd19+ 9% (587/mcl), nk cells 67% (4435/mcl). on examination he appeared well with height at 86th%ile and weight at 58th%ile. there was no lymphadenopathy, hepatosplenomegaly or inflammed skin lesions; there was a 1cm round scar on the right plantar surface at the site of a prior mosquito bite. laboratory studies confirmed nk lymphocytosis 64% (5459/mcl) and elevated ige (29,600 u/l). lymphoproliferation to mitogens, cd3/cd28, cmvand hsv were normal, but absent to tetanus and candida antigens. ebv antibodies reflected past infection (vca-igg+, vca-igm-, ebna+); quantitative ebv pcr was >5,000,000 copies/ml whole blood. nk cytotoxicity and cd107a expression were decreased. bone marrow nk analysis suggested conality. the patient was diagnosed with "hypersensitivity to mosquito bites with ebv-associated t-/ nk lymphoproliferation." this disorder represents a subset of chronic active ebv (caebv) that is rarely seen outside of east asia. the lack of organomegaly or lymphadenopathy with hyper-ige and nk lymphocytosis and decreased nk function support the likelihood that nk cells are the target of ebv infection in this patient. this diagnosis may be a precursor to hemophagocytosis, liver necrosis or lymphoma/leukemia, and the only curative treatment is bone marrow transplantation. the patient's sister is a 10/10 hla match. she is seropositive for past ebv infection, and she has no history of extreme reactions to mosquito bites. genetic mutations that cause familial hemophagocytic lymphohistiocytosis have not been reported in caebv, and to the best of our knowledge familial cases of this disorder have not been identified. the response to bmt in this patient is pending. introduction/background: a number of case reports have described symptomatic hypogammaglobulinemia following administration of anti-epileptic drugs (aeds), specifically lamotrigine, carbamazepine, and levetiracetam. the mechanism by which symptomatic hypogammaglobulinemia develops is unclear. we evaluated the prevalence and the clinical significance of hypogammaglobulinemia associated with use of these aeds. objectives: our aim was to characterize the prevalence of aed-induced hypogammaglobulinemia, identify specific aeds associated with hypogammaglobulinemia, and characterize the timeline to development of hypogammaglobulinemia after initiation of therapy. methods: a retrospective, multicenter, electronic medical record review spanning 18 years identified patients with hypogammaglobulinemia who were on aed therapy (lamotrigine, carbamazepine, or levetiracetam). patients were excluded if they had a pre-existing primary immunodeficiency (pid), malignancy, protein-losing enteropathy, or significant proteinuria. patients on chronic immunosuppressive therapy, those without laboratory criteria for hypogammaglobulinemia, or those on one of the aeds for less than one month were also excluded. results: of the 316 cases reviewed, 5 patients met our inclusion criteria. the median age was 35; 80% were adults, 80% were female, and 80% were white. lamotrigine was implicated in 3/5 of the cases, carbamazepine in 2/5, and levetiracetam in 1/5. tetanus and pneumococcal titers were available for 4/5 patients. of those patients, 3/4 had protective titers to both per report with responses to >70% of the serotypes. only one patient reported severe, recurrent infections while the remaining four had little to no symptoms. interestingly, the patient with severe infections did have protective titers. of the five laboratory proven hypogammaglobulinemia patients, one died of an infection, two have continued on the medication due to refractory seizures responsive only to these medications, and two are currently being tapered off of their aed. conclusion: while it appears that aed-induced hypogammaglobulinemia is quite rare, it should be considered in a patient without other secondary causes of hypogammaglobulinemia on aed therapy. many antiepileptics downregulate nfkb signaling suggestive that patients who develop symptomatic hypogammaglobulinemia may have hypomorphic mutations in the nfkb signaling pathway. (170) submission id#604503 autoimmune lymphoproliferative syndrome (alps) results from defective apoptosis of lymphocytes mediated through the fas/fas ligand (fasl) pathway. the hallmark lab finding is an expansion of t cells that express the alpha/beta t cell receptor, but lack both cd4 and cd8 (double negative t cells) in the setting of normal or elevated lymphocyte counts. patients present with chronic, nonmalignant, noninfectious lymphadenopathy or splenomegaly. for definitive diagnosis, patients need to have (1) a pathogenic mutation in fas, fas ligand or caspase 10 or (2) a defective fas-induced lymphocyte apoptosis. we describe a probable case of alps with heterozygous mutation in fas c.287a>g(p.his96arg), a variant that has not been previously reported (his lymphocyte apoptosis assay is pending). unique to this case is the patients castleman disease-like features on pathology. a 15 year-old male referred from hematology clinic presented with an 8 year history of chronic lymphadenopathy, splenomegaly, anemia, and no underlying diagnosis. malignancy had previously been excluded by bone marrow aspirate and biopsy 8 years prior. however, he had a right sided lymph node that had increased in size for the past 4 months. he was otherwise asymptomatic. a lymph node biopsy 7 years prior was reportedly normal. his exam demonstrated significant bilateral lymphadenopathy, greater on right, with an approximately 8 x 6 cm mobile right neck mass. he had splenomegaly palpated 7 cm down and across to midline. he was therefore admitted for excisional lymph node biopsy to evaluate for possible malignancy and labs were sent to evaluate for alps. labs were supportive of alps. he had elevated t cell receptor alpha beta double negative t cells (tcr a/b dntcs) in blood (10.5%). b12 level was elevated (>1000 pg/ml). plasma soluble fasl level was elevated (5517 pg/ml). interleukin-10 (il-10) and il-18 levels were elevated (88 and 909 pg/ml respectively). he had multilineage cytopenias: anemia with hgb of 9.5 g/dl and neutropenia (absolute neutrophil count of 1380 k/ul). he had hypergammaglobulinemia with an igg level of 2010 mg/dl. broad infectious work-up was negative, including hiv, quantiferon, cocci, bartonella, toxoplasma, coxiella burnetii, ebv pcr and, cmv igm. lymph node biopsy showed no evidence of malignancy. immunostains and flow cytometry showed the presence of expanded tcr a/b dntcs in the lymph node, consistent with alps. interestingly, lymph node histology showed morphologic features typical of plasma cell variant castleman disease. numerous castlemanlike follicles showed typical regressive changes with onion-skinning morphology. paracortical hyperplasia with sheets of plasma cells was noted. there was negative staining for hhv8 (a well-known cause of plasma cell variant castleman disease). the diagnosis of idiopathic multicentric hhv8-negative castleman disease was excluded by definition in the setting of alps, per evidence-based consensus criteria published in 2017. in addition, our patient did not show any symptoms typically associated with it, such as fever, night sweats, weight loss, weakness or fatigue. should his fas-induced lymphocyte apoptosis be defective (in 2 separate assays), this would confirm his alps-fas diagnosis and we would start the patient on sirolimus. head of immunology unit, children' s hospital ricardo gutierrez introduction: slc46a1 gene encodes the proto-couple folate transporter (pcft), which supports intestinal folate uptake, and participates in folate transport into the central nervous system. slc46a1 mutations cause pcft defects, resulting in low folate levels in serum and cerebrospinal fluid. hereditary folate malabsorption (hfm) is a rare, autosomal recessive disorder with pcft deficiency resulting in cerebral folate deficiency. most of the patients present megaloblastic anaemia, moderate pancytopenia in the first few months of life, failure to thrive, diarrhoea and/or later onset neurological symptoms including seizures and developmental delay. i m m u n o d e f i c i e n c y i n h f m c a n m a n i f e s t i t s e l f w i t h hypogammaglobulinemia with normal t-cell function. b-cell precursor compartment seems to be particularly vulnerable to folate deficiency in some hfm patients. this immunodeficiency can be restored with specific treatment with folic acid. aim: to describe a female patient with a homozygous pathological variation in the slc46a1 gene. results: a 17 months old girl, born of non-consanguineous parents. she started at 3 months old with diarrhoea due to rotavirus, low weight and bicytopenia with normal bone marrow aspiration. she presented low levels of folic acid 1.5ng/ml (nv 3.1-20.5 ng/ml) at first thought due to secondary to malnutrition. treatment with folic acid supplementation was administrated, improving platelets counts. at 5 months old she presented steatorrhea with severe perianal panniculitis which required surgical treatment. no germs were rescued after a skin biopsy. moreover, she suffered from a respiratory infection due to picornavirus with two episodes of pneumothorax which required intensive care. at that moment ivig treatment was administered due to hypogammaglobulinemia and clinical severity. chronic diarrhoea worsened with bloody depositions. three rectal ulcers were found in the gut biopsy. bowel inflammatory disease was suspected and mesalazine administration was started with weight improvement. furthermore, at 10 months old she presented 3 status epilepticus, with pathological eeg and normal mri; one of them related to a cmv infection, successfully treated. in the immunological evaluation igg and iga were low with normal igm and igd. the protein-antibody response was not evaluated. she presented normal lymphocyte and t cells extended populations, t cells proliferation assay, dhr, treg cells, complement, cd107a expression, alpha-fetoprotein, without autoantibodies a molecular panel testing was done by ngs and a homozygous variant in slc46a1 gene was found, causing impaired intestinal folate absorption. conclusion: hfm should be considered in the diagnosis of patients with cytopenias and hypogammaglobulinemia in order to provide specific treatment. hfm has wide clinical manifestations, not only with megaloblastic anaemia and neurological impairment but also with gastrointestinal and skin manifestations. with folate treatment, clinical and immunological defects can be normalized. introduction: multifocal epithelial hyperplasia (meh), or hecks disease, is a rare, benign infection of the mucosa caused by human papilloma virus (hpv). clinically, meh manifests as numerous painless, soft, sessile papules or plaques, and typically occurs in the labial, lingual, and buccal mucosa. meh lesions are usually associated with hpv types 13 and 32, and seen more commonly in patients of caribbean or central/south american descent. prior studies in adults have shown that tumor necrosis factor alpha (tnf) promotes hpv, and may influence duration of hpv infection. case: we present a five-year-old full term male of haitian descent referred for assessment of multiple flesh colored, papular lesions on the buccal and labial mucosa that had persisted and quantitatively increased over one year, although some lesions regressed. he had no pain or difficulty eating. medical history significant for one seizure; negative for infection. no family history of infection, immunodeficiency, consanguinity, or miscarriage. head and neck examination failed to reveal cervical lymphadenopathy, masses, or hypertrophy in the salivary glands. intraoral examination revealed multiple papular nodules, mostly flat although some were corrugated. the greatest concentration was noted on the lower left labial surface extending to the mucosal vermillion interface, not involving the vermillion or commissure region. lesions extended into the mandibular vestibule and the left buccal mucosa. no other lesions were noted on extremities, genitalia, or any other visualized mucosal surface. based on history and exam, he was diagnosed with meh. white blood cell count, neutrophils, lymphocytes, cd4 and cd8 t cell, b cell, nk cell enumeration, and immunoglobulin panel were normal for age. tetanus and streptococcus pneumoniae titers were protective. cytomegalovirus igg and igm were negative. epstein-barr virus igg was positive, igm and early antigen ab negative. serology was significant for elevated tnf (84 pg/ml; reference range <22pg/ml) while interferon gamma and interleukins 1, 2, 4, 5, 6, 8, 10, 12, 13 , and 17 were normal, as was il-2 receptor cd25. one month after the initial visit, lesions were stable and unchanged. nine-valent hpv vaccination was considered, but not administered. conclusions: meh is a rare but benign disease caused by hpv. awareness of the disease and its course is important to prevent unnecessary expanded immunodeficiency work-up and possible procedures to eliminate lesions. although mucosal immunity can be site specific, especially with hpv, our understanding of t-cell cytokine and chemokine responses to hpv in cervical and laryngeal lesions may be instructive. the mechanism which allows hpv persistence in meh is not characterized, but it likely is due to increased viral persistence and an inability for the host immune response to successfully induce viral latency and successful containment. elevated tnf levels, with normal levels of il-2, il-6, il-8, il-10, may correlate with decreased clearance of hpv and prolonged duration of meh. it remains unclear if viral persistence is the cause of, or the sequela of, increased tnf. longitudinal monitoring of cytokine (tnf, il-2, il-6, il-8, il-10) and chemokine (ccl17, ccl18, ccl19, ccl20, ccl21, and ccl22) serum concentrations may be useful biomarkers for disease resolution. introduction: autosomal dominant hyper ige (jobs) syndrome is a rare primary immunodeficiency characterized by eczema and sinopulmonary infections as well as musculoskeletal and vascular complications. as in all chronic illnesses, patient education is an ongoing need. in the rare disease population, patient education is especially important as patients must be able to explain their unique healthcare concerns in a variety of medical settings. we focused on ad-hies, due to our relatively large cohort of patients, the frequent lack of classic signs of illness often impairing diagnosis of severe infection, and the diverse nonimmunologic clinical features of this disease. objectives: we aimed to increase understanding of the clinical manifestations of ad-hies to promote earlier recognition of symptoms and to increase self-efficacy for symptom management in the adult hies population. methods: adult patients were asked to participate in a patient education project. demographic information was collected from participants. they also completed a 12-item multiple choice test about symptom recognition in ad-hies and promis self-efficacy for managing symptoms, an 8item validated survey. then, patient education handouts that focused on pulmonary symptoms, eczema, bone health, and cardiovascular complications were reviewed with the participant. six weeks later, participants were asked to repeat the 12-item test and the self-efficacy survey. the demographic information, test, and self-efficacy were collected anonymously. results: 33 participants provided demographic information, completed the test and the self-efficacy survey. of the 33 participants, 15 were male and 17 were female. participants ranged in age from 18 to 66 years. 22/33 (67%) reported looking for information about ad-hies using search engines and most patients (91%) report that they have been given information about ad-hies from a doctor. 19/33 (58%) participants identified pulmonary symptoms as the symptom that concerns them most and 10/33 (30%) participants identified more than one symptom of concern. 25 participants returned the second test and second survey. the mean test score increased from 9.08 to 10.28 with 23/25 participants achieving a score of 9/12 or higher. the self-efficacy scores were unchanged with a mean score of 50.08 before reviewing the patient education handouts and 50.13 after. conclusions: participant feedback to this project was generally positive. ad-hies patients are seeking information and an educational intervention can improve their understanding of disease. self-efficacy results were mixed and unchanged overall, but suggest that ad-hies patients manage symptoms as well as other patients with chronic illnesses. patient education should continue at each encounter. this project can be expanded to include more topics, pediatric patients, and other rare disease populations. funded by the nci contract no. introduction: bcl11b plays an important role in the development and maintenance of the immune system and the central nervous system. expression of bcl11b represses nk and myeloid factors while inducing t cell lineage genes in thymocytes at the dn2 stage. conditional loss of bcl11b expression in murine thymocytes leads to t cell deficiency while complete knockout of bcl11b was fatal within a few days of birth. recently, specific heterozygous bcl11b mutations have been reported in 11 individuals with global development delay. however, only 2 of these cases, both carrying heterozygous missense variants, had low trec values with 4 other cases having frequent infections. little is known regarding the impact of bcl11b on human nk and t cell function. methods: we identified a novel heterozygous truncating mutation in bcl11b in an infant who was first detected by trec newborn screening. she subsequently developed severe autoimmune hemolytic anemia at the age of 3 months. we used standard immunoblotting and flow cytometry methods to assess protein expression and the impact of this bcl11b mutant on t cell and nk cell development and function. results: the patient has a novel single base-pair deletion in the bcl11b gene, which is predicted to produce a truncated protein with the loss of 3 of 6 zinc finger domains in bcl11b. immunoblotting of t cell blast lysates revealed a reduced bcl11b expression in the patient consistent with the heterozygous defect in bcl11b but also generated a novel band with a smaller molecular weight that we postulate represents the truncated protein product. while mitogen responses to cona and pha were normal, both cd4+ and cd8+ t cell counts were decreased, especially cd4+ naã¯ve and cd4+cd31+ naã¯ve t cells, suggesting reduced thymic output. the function of th1 cells was skewed with reduced il-2 production but increased ifn levels after pma and ionomycin stimulation. moreover, t regulatory cell counts were below normal range. nk cell counts were normal but these were mostly cd56bright nk cells. of the few cd56dim nk cells that presented, approximately half did not express cd16, the fc receptor for adcc. perforin was only present in cd16 expressing nk cells. as such, anti-cd16 stimulation understandably led to low but not defective nk cell degranulation. function after stimulation with k562 cells was normal when controlled for nk cell counts. conclusion: we report a novel bcl11b truncating mutation with a leaky scid phenotype that manifested with t-cell lymphopenia and autoimmunity. lowered thymic-derived naã¯ve t and regulatory t cells, skewed th1 cytokine response, and incomplete nk cell development suggests that bcl11b is important for the development and differentiation of multiple lymphocyte lineages. introduction: chronic diarrhea is one of the most common gastrointestinal complaints in patients with common variable immune deficiency (cvid) and can lead to life-threatening complications such as malabsorption and malnutrition. chronic diarrhea in cvid could be caused by infections, an inflammatory bowel disease-like picture, as well as malignancy. giardia lamblia is one of the most common parasites causing diarrhea in cvid (up to 40%), and can be refractory in these patients, leading to villous atrophy, weight loss, and failure to thrive. case report: a 41-year-old female with a history of cvid presents with chronic diarrhea and significant weight loss. her cvid was diagnosed by hypogammaglobulinemia (low levels of igg, igm, and iga), inadequate responses to protein and polysaccharide-based vaccines, decreased memory b cells (cd19+cd27+ 0.5%), and recurrent sinopulmonary infections. she was started on immune globulin replacement therapy and had significant improvement in her rate of infections. four years before her presentation to our center, she developed chronic, severe diarrhea. work up revealed giardia lamblia infection on endoscopy and colonoscopy. biopsy showed intraepithelial lymphocytes, villous blunting, and atrophic gastritis with rare plasma cells concerning for non-infectious enteropathy related to her cvid, in addition to the high burden of giardia organisms. she was initially treated with metronidazole for several weeks. however, her diarrhea did not improve, and she developed significant peripheral neuropathy leading to lower extremity weakness and limited mobility. her diarrhea persisted and was associated with approximately a 20-pound weight loss. repeat endoscopy and colonoscopy two years later showed persistent high burden giardiasis of the small intestine, as well as reactive lymphocytic infiltrates and atrophic gastritis. she was treated with nitazoxanide but continued to have diarrhea, and her stool continued to show trophozoites. given the significant inflammation and the lack of response to multiple antiparasitic agents, she was referred to our center for further evaluation. she was started on oral budesonide (9 mg daily) and oral immune globulin (20 grams weekly for 12 weeks). with this regimen, she had significant improvement in her diarrhea with a 10-pound weight gain. repeat colonoscopy showed considerable improvement in inflammation and resolution of her giardia infection, though her stool antigen continues to be positive. conclusions: persistent diarrhea in our patient is most likely due to a combination of cvid enteropathy and giardiasis. a prolonged course of metronidazole and later nitazoxanide did not control her diarrhea and led to significant side effects. switching to an immunomodulatory approach significantly decreased the inflammation in her bowel and may even have helped to reduce the burden of giardia in the gut. targeting both underlying bowel inflammation as well as active infection in cvid patients with chronic diarrhea might be needed to control symptoms. introduction: sphingosine-1-phosphate (s1p) is a lipid chemoattractant that is critical for lymphocyte egress from lymphoid organs. following a s1p concentration gradient maintained by s1p lyase ubiquitously expressed in tissues, lymphocytes within lymphoid organs are drawn to efferent lymph and blood unless their s1p receptor is internalized or downregulated. owing to diminished degradation of not only s1p, but also other sphingoid bases, deleterious mutations in sgpl1 (encoding s1p lyase) perturb sphingolipid catabolism in numerous tissues. correspondingly, human s1p lyase deficiency results in multiorgan dysfunction including kidney, skin, endocrine gland, and neurologic impairment alongside expected lymphopenia. although severe t cell lymphopenia (<300 cells/microliter) rivaling that of severe combined immunodeficiency (scid) can be seen in patients with s1p lyase deficiency, no such patients have been identified by newborn screening of t cell receptor excision circle (trec) counts, which are a surrogate measure of effective t cell production. herein, we describe an infant boy with an undetectable trec count at birth who was found to have two novel, biallelic sgpl1 mutations resulting in s1p lyase deficiency. case description: a 1-day-old boy with a preceding history of fetal hydrops is born at a gestational age of 36 weeks and presents with renal failure, anasarca, and respiratory failure. trec analysis of a dried blood spot obtained at 24 hours of life reveals zero copies/microliter. subsequent peripheral blood studies show profound lymphopenia, with diminished cd3+ t (129/microliter; 96 cd4+, 27 cd8+), cd19+ b (130/microliter), and cd16/56+ natural killer (124/microliter) cell counts. recent thymic emigrants are reduced (11.3% of cd4+ t cells are cd45ra+cd31+), as is the ratio of naã¯ve-to-memory cd4+ t cells (63% cd45ra+, 37% cd45ro+). expedited whole genome sequencing identifies two novel variants in sgpl1 a paternally inherited splice site variant (c.1566+2t>c) predicted to impact a canonical splice donor site, and a maternally inherited missense change (c.854g>a; p.cys285tyr) located in a well-established functional domain of s1p. in addition to nephrotic syndrome and lymphopenia, the patient displays evidence of adrenal insufficiency and has increased plasma levels of sphingoid bases and ceramides. before further analyses could be pursued, the infant dies at 40 days of age due to ongoing complications of renal failure and eventual cardiorespiratory failure. summary: we report the first case of s1p lyase deficiency identified by newborn trec screening for scid. as sgpl1 is not included in most commercially-available, scid-tailored gene panels, s1p lyase deficiency would be missed by conventional genetic testing. therefore, analysis for variants in sgpl1 should be considered in neonates with low-to-undetectable trec counts, nephrotic syndrome, and other suggestive sequelae. w a r t s , hypogammaglobulinemia, recurrent infections, and myelokathexis) is a rare autosomal dominant primary immunodeficiency. it is caused by a defect in the gene encoding the chemokine receptor cxcr4. this receptor, along with the associated ligand cxcl12, regulates leukocyte migration. we present the case of a 40-year-old female, who presented after she self-identified the signature signs of whim syndrome in herself and multiple family members. objectives: we present the case of a 40-year-old female who presented with a history of recurrent warts, leukopenia of unknown cause, and recurrent infections as a child. as a child, she experienced multiple ear and sinus infections, along recurrent warts on her upper and lower extremities that have persisted to this day. furthermore, during a routine examination when she was 14-years-old, she had a complete blood count drawn significant for leukopenia. no further workup was undertaken at that time. when continued leukopenia was noted at the age of 30, referral to a hematologist and a bone marrow biopsy was completed. bone marrow was significant for myelokathexis with borderline hypercellular marrow for patient age (80% cellularity), and normal cell line quantity. a trial of neupoegen was undertaken, without significant improvement. her family history is significant for father and brother with both leukopenia and recurrent warts. results: genetic analysis showed a heterozygous pathogenic variant in the cxcr4 gene, c.1012_1015dup (p.ser339phe fs*6). recent complete blood count was significant for a total wbc count of 1.0 k/ul, with a differential consisting of 30% neutrophils and 57% lymphocytes. lymphocyte subsets were significant for quantitatively low cd3+, cd8+ and cd19+ subsets, with normal numbers of cd4+ and nk cells. immunoglobulin levels revealed an igg of 835 mg/dl, iga of 145 mg/ dl, and igm of 54 mg/dl; igg anti-diphtheria and tetanus titers were protective, however, none of the 23 s. pneumoniae serotype titers were > 1.3 ug/ml. mitogen (pha, cona and pwm) and antigen (candida and tetanus) stimulation of lymphocytes were normal for all stimuli. conclusions: we present the case of a 40-year-old female with a history of recurrent infections, warts, and myelokathexis. on genetic analysis, she is noted to have a pathogenic mutation of the cxcr4 gene. the substitution of a phenylalanine for a serine decreases one of the seven serine phosphorylation sites in the carboxy tail of the molecule that occurs upon binding to its ligand, cxcl12 (sdf1). additionally, the variation generates a premature stop condon terminating the remainder of the carboxy terminal amino acids including ser346-7, known to have a role in carboxy terminial beta-arrestin binding. failure to generate adequate beta-arrestin binding sites leads to prolonged cxcr4 cxcl12 interaction resulting in myelokathexis. background: lacking protective antibodies, patients with primary antibody deficiencies (pad) suffer from frequent respiratory infections leading to chronic pulmonary damage. macrolides prophylaxis has been proven effective to successfully manage chronic lung diseases as cystic fibrosis, bronchiectasis, copd. we conducted a trial to evaluate the efficacy and safety of orally low-dose azithromycin prophylaxis when added to the usual care in pad patients. methods: a 3-year, phase ii, prospective, multicenter, randomized, double-blind, placebo-controlled trial on pad patients (age 18-74 years) with chronic infection-related pulmonary disease. patients received azithromycin 250 mg or placebo once daily three-times a week for 24 months. the primary outcome was the decrease of annual episodes of respiratory exacerbations. secondary endpoints included: time to the first exacerbation, number of hospitalizations, additional doses of antibiotics, health related quality of life measures, and safety. results: forty-four patients received azithromycin and 45 patients received placebo. the mean number of exacerbations was 3â·6 per patientyear (95%ci 2â·5-4â·7) in the azithromycin arm, and 5â·2 (95%ci 4â·1-6â·4) in the placebo arm (p=0â·02). in the azithromycin group the hr for having an acute exacerbation was 0â·5 (95%ci 0,3-0â·9, p=0,03) and the hr for hospitalization was 0.5 (95%ci 0,2-1â·1) (p=0â·04). the rate of additional antibiotic treatment per patient-year was 2â·3 (95%ci 2â·1-3â·4) in the intervention and 3â·6 (95%ci 2â·9-4â·3) in placebo groups (p=0â·004). improvement in hrqofl was observed in intervention group. azithromycins safety prole was comparable with placebo. conclusion: in pad with respiratory exacerbation, azithromycin prophylaxis led to reduction of exacerbation episodes, of additional courses of antibiotics, and of risk of hospitalization. given the deleterious effects of respiratory diseases adding azithromycin to pad treatment should be considered as a valuable option. background: the autosomal-dominant hyper-ige syndrome (hies), is a primary immunodeficiency caused by mutations in signal transducer and activator of transcription 3 (stat3) that leads to defective th17 immunity. adverse reactions following 23-valent pneumococcal polysaccharide vaccine (ppsv23) have been reported in 75% of stat3-hies patients, including severe local reactions that appear to be specific to this vaccine. case report: we present the case of a six-year-old girl, second child of nonconsanguineous healthy parents, that developed an extensive inflammatory skin reaction at the vaccination site following a single dose of ppsv23. the vaccine was prescribed due to history of recurrent respiratory tract infections and an incomplete vaccine calendar with no previously administered pneumococcal vaccines. the reaction began after 2 hours with local erythema and edema at vaccination site, expanding in 48 hours to a phlyctenular lesion with no well-defined borders. within the first 3 weeks, it progressively evolved to a deep necrotic lesion that required surgical debridement. the subsequent skin defect required surgical repair with a split-thickness skin graft from her right thigh as the donor site. the complete wound healing process took about 5 months, leaving a large scar ( figure) . the patient had a longstanding history of recurrent infections with multiple hospitalizations including severe neonatal pneumonia that required respiratory support, a colon perforation with secondary peritonitis and septic shock that required a hemicolectomy at 8 months of age, recurrent oral candidiasis, recurrent pneumonias of different lobes, recurrent acute otitis media, a cervical phlegmon, three episodes of dental abscess and multiple kidney abscesses due to gram-negative bacteria treated with intravenous antibiotics and surgical drainage. family history is notable for an older sibling that died due to sudden infant death syndrome. the patients mother has large and wide nose suggestive of stat3-hies phenotype, but no history of infections. immunological work up showed mild eosinophilia (850 cells/ mm3), elevated ige (1850 mg/dl), normal igg, iga, igm and lymphocyte subsets (cd3, cd4, cd8, cd16, cd56). peripheral th17 cells were markedly decreased (0.6% vs. 3.7% of normal control). specific pneumococcal antibodies evaluated 1 month after psv23 revealed 5/10 serotypes in protective levels. high resolution thorax ct showed multilobar bronchiectasis. echocardiogram and total spine x-rays were normal. stat3-hies was suspected with a national institutes of health score of 40. a novel heterozygous missense variant in stat3 affecting the src homology 2 (sh2) domain (p.lys591glu) was found by next-generation panel sequencing. a variant in the same position (p.lys591met) has been previously reported in a hies patient (clinvar). currently, she is on monthly ivig and prophylactic antibiotics (cotrimoxazole, azithromycin and fluconazole). conclusions: the case presented raises awareness on the risk of severe local adverse reactions to ppsv23 in stat3-hies patients. the etiology of such reactions is unclear and warrants further study. the benefits and risks of immunizing stat3-hies patients with ppsv23 should be weighed carefully by medical providers. abstract (max 500 words) introduction: dock8 deficiency is a rare primary immunodeficiency characterized by susceptibility to viral infections, atopic eczema, defective t-cell activation and th17 differentiation, impaired eosinophil homeostasis and dysregulation of ige. to date, there are no reported cases from malaysia. objective: we aimed to describe the clinical, immunological profile and mutational analysis of three siblings of consanguineous parents, presented with hyper-ige and lymphopenia between the years 1998 and 2012, which were solved by mutational analysis of the second and third siblings. methods: clinical data and investigation results were collated from the medical record. scoring of the symptoms and physical examination findings using nih score was performed. t, b, nk lymphocyte subsets and serum igg, iga, igm, total ige quantification, lymphocyte proliferation test and pneumococcal specific antibody response were performed. mutational analyses were performed in freiburg, germany. result: three siblings presented at different time points over a 20-year span with raised ige levels, recurrent infections, eczema, hypereosinophilia and bronchiectasis. the nih scores for hyper-ige syndrome (hies) ranged from 39 54. we also documented two serious infections in the siblings, which were disseminated cryptococcus neoformans and salmonella sp. immunological results showed t-cell lymphopenia, defective t-cell proliferation, decreased igm, raised ige, hyper-eosinophilia and defective pneumococcal antibody responses present but not in all 3 siblings. we identified a large deletion in dock8 starting from exon 30-48 in 2 of the siblings from mutational analysis performed. we will proceed with next generation sequencing and dock8 protein assay in malaysia to further characterize the defect. conclusion: our on-going study is the first description of dock8 in a family from malaysia. the diagnosis of dock8 should be suspected in cases with raised ige levels, recurrent infections and lymphopenia, despite no warts infection in the history. this study emphasized the importance of international research collaboration and networking in solving complicated cases. the index patient presented at the age of 4 years with increased susceptibility to lower airway and gastrointestinal infections (hospital admissions 5x/year until puberty). she suffered from mumps and varicella disease despite immunization, as well as from recurrent local, partially destructive hsv infections. she was diagnosed with common variable immunodeficiency (cvid) at age 13 and started on immunoglobulin replacement therapy. following a hypoglycemic seizure at age 20, the patient was diagnosed with isolated acth insufficiency with secondary adrenal insufficiency requiring hormone substitution. during and following her first pregnancy at age 25, she suffered from recurrent bronchopneumonias including pneumocystis jirovecii infection, resulting in bronchiectases documented on chest ct at age 30. currently, chronic lung disease is severely limiting her quality of life (table 1) . her daughter was noticed to be hypogammaglobulinemic soon after birth and failed to develop antibody responses to inactivated vaccines. she was started on immunoglobulin replacement therapy. she has not suffered from severe lower airway infections, but developed alopecia totalis at age 10 and nail dystrophy. w h o l e e x o m e s e q u e n c i n g r e v e a l e d a h e t e r o z y g o u s c.2553_2554insacccgag (p.lys855profster33, nm_001077494) mutation in exon 22 of nfkb2 in both mother and daughter. this monoallelic loss-of function frameshift mutation was not found in gnomad, gvs washington or clinvar databases. as previously published, a monoallelic mutation in this c-terminal domain leads to impaired phosphorylation and subsequent reduced nuclear translocation of the nfkb2/p52 active form. pediatricians and internal specialists need to be aware of the combination of hypogammaglobulinemia, acth deficiency, immune dysregulation and ectodermal dysplasia which is unusual for cvid -possibly indicating nfkb2 deficiency. this clinical syndrome may overlap with symptoms and signs found in both apeced/ aire (ar) and eda-id/nfkbia (ad) deficiencies. besides ig and hormone replacement therapy, curative treatment with hematopoietic stem cell transplantation is a therapeutic option for patients with nfkb2 deficiency, although the experience is limited. table 1 introduction: the modes of immunoglobulin (ig) administration for primary immunodeficiency diseases (pidd) differ in pharmacokinetics, infusion parameters, and tolerability. during 3 consecutive clinical studies, a cohort of 30 patients with pidd experienced all 3 modes of administration with the same ig 10% product in sequence from intravenous (iv) to subcutaneous (sc), then to hyaluronidase-facilitated sc (ighy), providing a unique opportunity to assess each administration modality within the same patient cohort treated and observed at the same sites. here we report the rates of infections stratified by igg trough levels, and the rates of adverse events (aes) with the 3 modes of ig administration (ivig, scig, ighy) within this patient cohort. design and methods: this analysis included patients with pidd aged 4 years who participated in 3 clinical studies: in study 1 (nct00546871) patients received ivig 10% every 34 weeks followed by weekly scig 10%; in study 2 (nct00814320), patients were treated with ighy every 34 weeks; in study 3 (nct01175313; extension of study 2), patients continued with the same ighy dose. to assess a potential association between the administration route at comparable igg trough levels and the infection rate, igg trough levels were categorized as 500 <700mg/ dl, 700<900mg/dl, 900<1100mg/dl, 1100<1300 mg/dl, 1300 <1500 mg/dl and 1500 mg/dl. periods where patients had trough levels within these strata were assessed, and the infection frequency was calculated. the time periods for this analysis were 3 months for ivig and 12 months each for ighy and scig 10% (2.25 years) treatments. in order to account for differences in the frequency of administration, rates of systemic and local aes were assessed as aes/patient-year for each mode of therapy. results: for igg trough levels of <1500 mg/dl, the associated annual infection rates were lower or similar for ighy than scig ( the treatment involves the control of infections and immune dysregulation with chemotherapeutic regimens followed by definitive treatment with hematopoietic stem cell transplant (hsct). aim: to describe a female patient with a pathogenic variation in stx11 with normal cd107a expression. results: she was a 2 years old female, the 5th daughter of nonconsanguineous parents, without relevant personal or family records. she was admitted due to a prolonged febrile syndrome, lymphoproliferation, pancytopenia and hepatitis, with hhv6 rescued in bone marrow and blood. gancyclovir treatment started with good response. she was admitted one month later with similar clinical symptoms with relapsed hhv6 infection. furthermore, hemophagocytosis was found in the bone marrow and evaluation of nk cell cytotoxicity demonstrated slightly reduced cytotoxic activity. functional studies for primary fhl were performed: perforin expression and cd107a surface expression were normal. she fulfilled criteria of fhl, and treatment with gancyclovir and steroids was administered. despite this treatment, she persisted with activated macrophagic parameters, and started with hlh2014 treatment protocol. she improved the clinical symptoms and laboratory parameters, but persisted with hhv6 low viremia. three months later, when immunosupression was decreased, she was readmitted with similar clinical manifestations and added neurological symptoms (facial paralysis, abnormal movements and sleep tendency). cerebral spinal fluid was pathological with hhv6 positive rescue. immunosupresive treatment was adjusted, but hhv6 copies in blood increased markedly. foscarnet treatment was administered and immunosupression was suspended for 2 days in order to control viral infection. unfortunately the patient died 6 days later. although specific functional tests were normal, sequencing of stx11 gene by ngs revealed a homozygous variation in c.581_584deltgcc, which is a previously reported mutation responsible for fhl. conclusion: despite the fact that cd107a was normal, the strong clinical and laboratory results must keep the fhl diagnosis in mind and intensive treatment should be early administered; in order to give the patient the opportunity to achieve the curative treatment. objectives: to report and characterize the clinical course of a patient with apeced and specific antibody deficiency. methods: retrospective chart review was performed. the patient was enrolled in niaid irb-approved protocol 11-i-0187. results: the patient is a 13 year-old-girl with apeced caused by homozygous aire c.967_979del13, who manifested cmc, hypoparathyroidism, adrenal insufficiency, sjogrens-like syndrome, autoimmune hepatitis, intestinal dysfunction and autoimmune pneumonitis. she suffered from recurrent sinusitis and severe pneumonias requiring hospitalization and administration of intravenous antibiotics several times per year. at age 9, she presented to our institution with fever and cough, a computed tomography (ct) of the chest revealed bilateral pulmonary infiltrates and bronchiectasis. bronchoscopy showed mucopurulent secretions in the bilateral lower lobes with culture of the bronchoalveolar lavage fluid growing streptococcus pneumoniae. further evaluation for an underlying disorder such as primary ciliary dyskinesia and cystic fibrosis including exome sequencing and sweat chloride testing was unrevealing. quantitative immunoglobulins were normal. despite prior vaccination, specific antibody testing showed negative rubeola igg and protective levels (> 1.3 mcg/ml) to only 3 of 23 pneumococcal serotypes. lymphocyte enumeration showed normal b cell subsets. as approximately 15% of apeced patients may experience asplenia, splenic ultrasound was performed confirming the presence of a 7 cm spleen and peripheral blood smear did not reveal howell-jolly bodies. serotyping of the s. pneumoniae isolate confirmed serotype 33f, which is part of the 23-valent vaccine. follow up vaccine challenge with the 23 valent pneumococcal polysaccharide vaccine showed an inadequate response. hence, she was started on monthly immunoglobulin replacement and over the following 4 years she has experienced a single methicillin sensitive staphylococcus aureus pneumonia. she has missed very few school days and other parameters including linear growth have improved, she is now along the fifth percentile for height and along the tenth percentile for weight. although she continues to experience intermittent cough she remains active participating in sports without limitation. conclusions: we report the evaluation, treatment and outcome of a patient with apeced complicated by autoimmune pneumonitis and specific antibody deficiency. as infectious susceptibility of apeced classically pertains to the signature infectious disease, cmc, patients with invasive or recurrent infections should be evaluated for underlying immune deficiency. investigation should include assessment for asplenia, quantitative immunoglobulins and specific antibodies with response to antigens. in patients with predominate respiratory symptoms, autoimmune pneumonitis should be evaluated given the near 40% prevalence of pneumonitis observed in american apeced patients. acknowledgements: supported by dir/niaid/nih introduction: autoinflammatory diseases are genetically heterogeneous disorders of innate immunity characterized by recurrent fever, rash, and/ or serositis, which generally are considered distinct from autoimmune diseases. we report a case of a patient with lupus-like disease and a mutation of nucleotide-binding oligomerization domain-containing protein 2 (nod2 r702w, yao syndrome) suggestive of an overlap between autoinflammatory and autoimmunity processes. case presentation: a 72-year-old man was evaluated for recurrent pleural effusions, morning stiffness, erythematous rashes, and fever up to 103â°c. history was notable for hashimotos thyroiditis and multiple admissions for presumed pneumonia with recurrent bilateral lung infiltrates and pleural effusions. transbronchial biopsy showed nonspecific pneumonitis and organizing pneumonia. antinuclear and anti-dsdna antibodies were positive. he received prednisone for presumed lupus pneumonitis leading to improvement. prednisone was tapered and hydroxychloroquine was started, but his fevers, pleuritic pain and pleural effusion reoccurred. genetic testing revealed a nod2 sequent variant (r702w) associated with autoinflammatory disease. hydroxychloroquine was stopped and colchicine was added to his regimen, allowing prednisone to be tapered without recurrence of symptoms. further immunological testing revealed increased signaling through the type i interferon receptor (interferon signature). conclusion: although this patient had several clinical (serositis, arthralgia) and immunological (antinuclear and anti-dsdna antibodies, interferon signature) manifestations of lupus, his clinical presentation also was consistent with yao syndrome. in retrospect, he had been having recurrent inflammatory symptoms for many years. recent studies in both mice and humans suggest that inflammasome activation and il-1 production are involved in the pathogenesis of lupus. this case provides further support for the idea that lupus and hashimotos thyroiditis, prototypical autoimmune diseases, may have overlapping autoinflammatory features. background: the implementation of severe combined immunodeficiency (scid) newborn screening by trec assay has played a pivotal role in identifying these patients early in life. the screen has also led to the identification of infants with other immunologic abnormalities, of which the clinical implications have been unclear and there are limited data on their outcomes. objective: to review immunologic and genetic outcomes of infants referred to an immunology service of a tertiary care center with abnormal newborn scid screens. methods: we retrospectively reviewed charts of infants with positive scid screen from july 2014 to november 2018. we excluded patients who had positive screen at <36 weeks corrected gestational age. we classified outcomes into 3 groups including scid, non-scid t-cell lymphopenia (nscid-tcl) and normal t-cell count. idiopathic t-cell lymphopenia was defined as nscid-tcl (cd3+ < 2,500 cells/mcl) with negative chromosome microarray and negative whole exome sequencing/or genetic panel (either genedxâ® scid panel or invitaeâ® primary immunodeficiency panel). results: of 119 infants, 78% were male, 56% were caucasian, and 37% were african-american. fifty-four % and 46% of infants were identified by illinois and missouri screens, respectively. the mean age at initial evaluation was 22 days (4-122 days). 69% of infants had a normal tcell count (n=80) or normal repeat newborn screen (n=2), 25% had nscid-tcl, including mild (cd3+ 1,500-2,500 cells/mcl, n=20) and moderate (cd3+ 300-1,500 cells/mcl, n=10) tcl, and 6% had scid (n=5), leaky scid (n=1) or complete digeorge (n=1). genetic etiologies of nscid-tcl included 22q11 deletion (n=4), trisomy 21 (n=1), and mutations of tbx1 (n=2), foxn1 (n=1), and cd3e (n=1). three of these infants had novel variants at the time of diagnosis. secondary causes of tcl were identified in 1 infant (thoracic infantile fibrosarcoma). one infant had idiopathic tcl. eighteen infants with nscid-tcl were followed clinically without complete genetic testing performed. for scid, mutations were found in jak3 (n=2), ada (n=1), il2rg (n=1), and rag1 (n=1). the patient with leaky scid had negative whole exome sequencing. all patients with scid and leaky scid underwent hematopoietic stem cell transplantation at a median age of 5 weeks (3 weeks -4 months), with successful engraftment in all but 1 patient. of 19 idiopathic and nscid-tcl cases followed clinically, 12 had at least one follow-up visit at median age 5 months (2.6 months 2.2 years) and the majority had improved or stable lymphocyte count without serious infections requiring intravenous antibiotics, though 1 had a hospitalization for rsv infection. the mysm1 patient died after cord blood transplant from unclear etiology. our study had limitations. half of infants with nscid-tcl did not have a complete genetic workup, and only a fifth of patients with nscid-tcl were inpatients, potentially explaining the relatively low number of infants with secondary lymphopenia. conclusions: in our cohort, one-fourth of infants with abnormal scid screen had nscid-tcl. although the majority of nscid-tcl did well, approximately one-third of them had underlying genetic abnormalities associated with their t-cell lymphopenia. (189) submission id#606320 introduction: accumulation of intracellular adenosine and deoxyadenosine nucleotides (daxp) due to adenosine deaminase deficiency results in profound lymphopenia and severe combined immunodeficiency. left untreated this form of scid is uniformly fatal. while allogeneic hematopoietic cell transplant (hct) and autologous gene corrected stem cell therapy (gt) are potential cures for ada-scid , initiating enzyme replacement therapy (ert) immediately upon diagnosis regardless of definitive treatment is standard of care. hct and gt are not therapeutic options for all ada-scid patients and ert offers immediate therapeutic intervention for these patients leading to partial immune reconstitution, and durable survival in most patients treated. adagen (pegademase), approved by the fda in 1990 in the usa, is a pegylated bovine ada (nada) with the enzyme harvested from bovine intestines. this unsustainable production process led to the development of a recombinant enzyme source based on the bovine protein sequence and an improved pegylated linker by using succinimidyl carbamate (revcovitm-(elapegademase-lvlr). methods: a phase ii/iii clinical trial was performed at 5 us sites under institutional irb approval. eligible ada-scid subjects were stable on adagen and without complicating underlying conditions. demographics, medical history, lymphocyte counts, immunoglobulin levels, trough plasma ada activity and rbc daxp measurements were collected. patients were treated with adagen as a single, weekly im dose adjusted to achieve a trough plasma ada activity of > 15 mmol/hr/l and rbc daxp < 0.02 mmol/l (protocol target levels). once patients had achieved this level (3-9 weeks), a seven-day pk on adagen was done and the patients were transitioned to revcovi based on the formula for enzyme equivalent activity of 1mg revcovi = 150 units adagen. after 5 weeks on revcovi, trough ada and daxp were assessed and a seven-day pharmacokinetic study was conducted at week 9. patients were assessed periodically for clinical and laboratory values and evaluation of the study endpoints was done at week 21. subjects subsequently continued on revcovi and were assessed periodically. results: six patients, ages 16-37 entered the trial with initial adagen dosing at 7.7-42.9u/kg/wk (see table 1 ). adagen dosing was adjusted to target endpoints of ada trough activity (>15mmol/hr/l) and rbc daxp (<0.02 mml/l). patients transitioned to weekly revcovi using the aforementioned conversion formula at doses of 0.17-0.285 mg/kg/wk. the spectrum of clinical manifestations range from infections to autoimmunity and inflammation among patients with hypomorphic recombination gene 1 and 2 (rag1/2) pathogenic variants. auto-antibodies targeting cytokines ifn-alpha, ifn-omega and il-12 were reported in a large proportion of these patients and their occurrence often coincides with viral infections. we report the time of emergence and relative frequency of anti-cytokine antibodies in children and adults, and their persistence among patients with hypomorphic rag deficiency. antibodies were measured from plasma samples of patients by enzyme linked immunoassay (elisa). our rag cohort includes 28 patients with rag1 (n=17, 61%) and rag2 deficiency (n=11, 39%). antibodies targeting ifn-alpha (75%) were most common followed by il-12 and ifn-omega (40% each). two asymptomatic patients who were detected by newborn screening for scid and received hematopoietic stem cell transplantation had no detectable anti-cytokine antibodies. in the cohort of young children (ages 11 mo-7 years, n=9), all patients had detectable antibodies to ifn-alpha, prior history of severe viral infection and subsequently developed autoimmune cytopenias. other anti-cytokine antibodies were less common (ifn-omega 44%, il-12 33%). similarly, children between 10-18 yo age (n=9) also had high fraction of anti-ifn-alpha antibodies (89%) with prior history of infections (66%) and continued to have other anticytokine antibodies less commonly (ifn-omega 37%, il-12 62%). in the adult cohort (n=8, ages 25-39 years) the frequency of anti-ifnalpha anti-cytokine antibodies were lower (62%,) and il-12 and ifnomega (50% each) continued to persist. three adult patients had anticytokine (ifn-alpha, ifn-omega and il-12) antibodies tested at multiple timepoints and elevated titers persisted up to 4 years. our data demonstrates that anti-cytokine antibodies, especially those targeting ifn are frequent and emerge early in life in association with viral infections in patients with rag deficiency. a lower fraction of adult patients have detectable anti-cytokine antibodies, and maintain these over several years. anti-ifn-alpha may serve as a useful biomarker for identifying partial rag deficiency among young and adult patients with history of viral infections and autoimmune cytopenias. the role of these antibodies to cytokines is yet to be determined but a specific signature of these antibodies may help to identify an underlying immunodeficiency and initiate early definitive treatment with bone marrow transplantation. anti-cytokine antibodies appear to be a novel tool in evaluation of autoimmune diseases including rag deficiency. introduction: norovirus is one of the most common pathogens causing gastroenteritis in immunocompromised patients, often leading to chronic infection, causing villous atrophy, malabsorption, weight loss, organ failure, need for parenteral nutrition, and death. norovirus treatment in immunocompromised patients is challenging. oral immunoglobulin (poig) has been used to treat norovirus gastroenteritis with variable success. our aim in this study was to determine the outcomes of treating norovirus gastroenteritis in immunocompromised patients methods: electronic medical records were reviewed for patients with norovirus infection confirmed by rt-pcr since january 2012. our initial cohort was focused on patients with primary immunodeficiency (pid), lung, and liver transplant. data on demographics, immunological phenotype, treatment with poig, the number of bowel movements (bm), and virus clearance were collected. descriptive statistical methods were used to describe treatment outcomes. further analysis of patients immunophenotype, immunosuppression medications, and co-morbid illnesses is underway. results: twenty-six immunocompromised patients (27 norovirus infection episodes, as one patient had reinfection) were analyzed twelve females, age range 7 months-50 years. twelve patients had pid diagnosis (3 common variable immunodeficiency, 2 severe combined immunodeficiency, 1 x-linked agammaglobulinemia, 1 wiskott-aldrich syndrome, 1 digeorge syndrome, 1 hyper-igm, 1 stat3 gain-of-function, 1 nemo and 1 lymphopenia in a patient with trisomy 21), 13 patients were status-post liver transplant, and two patients were status-post lung transplant. 13 of26 patients were on ig replacement therapy at the time of the norovirus infection. the average number of bm/day in all patients was 8. 4 (range 2-20) . eight patients received poig (250-500 mg/kg) weekly for a duration from 1-12 weeks. three of those received additional nitazoxanide and 2 received ribavirin. 2/8 patients in the poig group were receiving total parenteral nutrition (tpn), and 4/19 on no treatment group received tpn. the average number of bm/day in poig before treatment was 9.5 (range 4-16), and 8.6 (range 2-20) in those who did not receive any treatment. 5 of 8 (62%) on poig vs. 11 of 19 (57%) in the no treatment group cleared the virus. the average number of weeks to return to baseline bm was 2.6 (range 1-7) in the poig group vs. 1.5 (range 3 days-5 weeks) in the no treatment group. 2 of 8 on poig continued to have chronic diarrhea that is still ongoing. conclusion: despite anecdotal reports suggesting successful use of poig in immunocompromised patients, our data did not show a significant decrease in stool output in patients treated with poig, compared to no treatment. however, poig led to a higher rate of virus clearance. a study with larger sample size might be warranted to identify the patients who benefit from poig in the context of norovirus infection and ensure the appropriate use of ig products, especially given the concerns for the national shortage of ig products. chief medical officer, novimmune sa primary hemophagocytic lymphohistiocytosis (phlh) is a life-threatening, immune regulatory disorder characterized by immune hyperactivation that is driven by high production of interferon (ifn)-. patients with hlh typically develop fever, splenomegaly, cytopenias and coagulopathy. until recently, there have been no fda approved treatments for hlh, and standard dexamethasone/etoposide-based treatment has not evolved significantly in 20+ years. emapalumab-lzsg (ni-0501) is a fully human, anti-ifn-monoclonal antibody that neutralizes ifn-and which was recently approved (november 2018) by the fda for the treatment of adult and pediatric (newborn and older) patients with phlh with refractory, recurrent, or progressive disease or intolerance with conventional hlh therapy. results of the pivotal trial supporting this approval are presented herein. methods: this open-label pivotal study (nct01818492) includes patients 18 years with a diagnosis of phlh and active disease. data presented were from 34 patients, of whom 27 had failed conventional hlh therapy prior to study entry. the initial emapalumab-lzsg dose was 1 mg/kg given intravenously every 3-4 days. subsequent doses could be increased up to 10 mg/kg based on the evolution of response parameters. dexamethasone was administered concomitantly at 5 to 10 mg/m 2 /day and could be tapered during the study. treatment duration was 8 weeks, with possible shortening to a minimum of 4 weeks, or extension up to the time of allogeneic hematopoietic stem cell transplantation (hsct). the primary efficacy endpoint was the overall response rate (orr) at end of treatment, assessed by pre-defined objective parameters, including normalization or at least 50% improvement from baseline of fever, splenomegaly, cytopenias, hyperferritinemia, fibrinogen, d-dimer, central nervous system (cns) abnormalities, and with no sustained worsening of scd25 serum levels. the primary analysis used an exact binomial test to evaluate the null hypothesis that orr be 40% at a one-sided 0.025 significance level. patients were eligible to enter an extension phase for follow-up after completing the main study (nct02069899). the data cut-off applied is july 20 2017. results: patient characteristics are summarized in table 1 and efficacy is summarized in table 2 . disease at study entry was consistent with the broad spectrum of phlh abnormalities. over 30% of patients had signs and/or symptoms of cns disease. orr was significantly higher than the pre-specified null hypothesis of 40%, meeting the primary endpoint. the response rate based on investigators clinical judgement was 70.6%. emapalumab-lzsg infusions were in general well tolerated, with mild to moderate infusion-related reactions reported in 27% of patients. the observed safety events (pre-hsct conditioning) mostly included hlh manifestations, infections or toxicities due to other administered drugs. infections caused by pathogens potentially favored by ifn-neutralization occurred in 1 patient during emapalumab-lzsg treatment (disseminated histoplasmosis), and resolved with appropriate treatment. no off-target effects were observed. conclusions: treatment with emapalumab-lzsg was able to control hlh activity with a favorable safety and tolerability profile in a very fragile population. the majority of patients proceeded to hsct with favorable outcomes. our results indicate that emapalumab-lzsg should be considered as a new therapeutic option in phlh thanks to its targeted mode of action. results: a total of 360 genes were differentially expressed between t cells of 22qds patients (n=13) and healthy controls (n=6) (log 2 fold change range (-2.0747, 15.6724)).when these 360 genes were tested for pathway enrichment, the top 5 pathways in t lymphocytes based on their p value included communication between innate and adaptive immune cells, cross talk between dendritic cells and natural killer cells, allograft rejection signaling, dendritic cell maturation, and b cell receptor signaling. the top 10 biological processes with differential expression included 36 immune response, 31 inflammatory response, 33 apoptotic process, 12 interferon gamma mediated signaling pathway, 14 nucleosome assembly, 16 defense response to virus, 8 lipopolysaccharide mediated signaling pathway, 7 positive regulation of nf-kappa b import into nucleus, 10 type i interferon signaling pathway, and 10 neutrophil chemotaxis genes. we compared gene expression between 22qds participants with low t cell counts (n=7) and 22qds participants with normal t cell counts (n=6) and found 94 genes that were differentially expressed (q<0.05) (log2 fold change range (-4.5445, 5.1297) patient began experiencing recurrent high fevers and developed splenomegaly. elevated transaminases and concern for lymphoproliferative disease prompted a splenectomy and liver biopsy. both the spleen and liver biopsy were positive for ebv but were negative for malignancy. bone marrow biopsy was unrevealing. genetic testing identified a pathogenic variant in xiap/ birc4 (1141c>t), and the patient was treated with high dose oral steroids resulting in an improvement in symptoms. subsequently, therapy with anakinra was started and steroids were tapered. during the steroid taper, he noticed a change in the vision of his left eye consistent with naion, as well as worsening of his colitis. there was loss of the inferior visual field and fundoscopic exam was significant for left optic disc swelling. oct noted superior retinal nerve fiber layer thinning. oral steroids were restarted with improvement in optic disc swelling, but without improvement or change in vision. as of his most recent exam, the patient has persistent bilateral inferior visual field defects with segmental optic nerve atrophy typical of naion. he has continued therapy with anakinra, and subsequently tapered off of prednisone; though he remains on a physiologic dose of hydrocortisone. conclusions: this case demonstrates an unreported ocular manifestation in a patient with xiap deficiency, which clinically appeared sensitive to immunomodulation. our patient is an unusual candidate for naion due to his young age, the average age of onset being the mid to late 60s, and lack of vascular risk factors. we hypothesize that his hyper-inflammatory condition contributed to irreversible vascular damage in the optic nerve head, resulting in naion. therefore, it may be useful to consider the involvement of systemic inflammatory and immune dysregulatory conditions when treating patients with atypical naion. additionally, naion should be considered in patients with xiap deficiency and sudden unilateral vision loss. the importance of de novo mutations in causing severe sporadic immune disease is well described, yet significance of such a variation in less severe and later onset of immune disease is poorly investigated. whole exome sequencing has been a powerful tool to resolve and explain the genetic basis of novel syndromes in immune related diseases. however, proving causation can be complicated due to low number of the affected individuals. we performed whole exome sequencing in a cohort of patients with noncongenital immune defects, along with detailed cellular biochemical phenotyping. we report and describe a novel non-congenital combined immune deficiency arising from a de novo gain-offunction mutation in ikbkb(c.607g>a). this gene encodes ikk2, and activates canonical nfkb signalling. cellular and biochemical studies of the proband revealed that ikk2v203i results in enhanced nf-kb signaling, as well as t and b cell functional defects. ikk2v203 is a highly-conserved residue, and to prove causation, we generated a crispr/cas9 mouse model that carry the precise orthologous missense mutation. we show that mice and humans carrying this missense mutation exhibits remarkably similar cellular and biochemical phenotypes. dysregulation in patients. total rna isolated from cryopreserved peripheral blood mononuclear cells was reverse transcribed to generate cdna. we selected four known gata2 transcriptional targets, gata1, gata2, tal1 and zfpm1 (encoding fog1) and used droplet digital pcr to quantify transcript levels normalized to the low-expressing gene tbp1. we used samples from 9 individuals with wild-type gata2 (wt), 5 known gata2 mutation patients (mut) and two individuals suspected of gata2 deficiency but without identified mutation or allelic imbalance (unk1, unk2). transcript analysis revealed significantly decreased transcript levels of gata1, gata2 and tal1 in mut pbmcs compared to wt. most wt samples had higher zfpm1 transcripts than gata2 mutated patients however it did not reach statistical significance. strikingly, we were able to use this analysis for two individuals suspected of gata2 deficiency. in the first case (unk1) a 51 yr old female with primary lymphedema, hypogammaglobulinemia, recurrent infections and possible family history of leukemia was referred for gata2 testing. no mutation was identified however it was noted that she was homozygous across the gene preventing allelic evaluation. the second patient (unk2), a 24 yr old female, had erethemya nodosa on legs, mycobacteria kansasii and cytopenias. in each of the targets analyzed, transcript levels from unk1 were lower than the wt samples and in a similar range as the gata2 mutation samples while unk2 had a profile consistent with the wt samples. we propose the use of gata2 targets as surrogate markers in cases where a mutation is not identified and allelic expression analysis is uninformative. are often under-reported and under-recognized. we sought to further understand and evaluate the prevalence, type, and association with serum immunoglobulin e (ige) for cvid patients with atopic manifestations. methods: we performed a retrospective analysis of cvid patients with atopic manifestations in the partners healthcare cvid cohort. we evaluated baseline patient characteristics, atopic diagnoses, and serum ige levels. results: in the partners cvid cohort, the average age was 52 years old (â±17) and 64% female. 92/175 (52.6%) of patients had a diagnosis of asthma, with the majority of these diagnosed by an allergist (65%) or pulmonologist (16%). eczema/atopic dermatitis was diagnosed in 47/175 patients (26%), by either an allergist (53%) or a dermatologist (8%). allergic rhinitis was diagnosed in 50/175 (28.5%) with positive skin prick testing in 52% of these patients. food allergy was diagnosed in 5 patients (2.9%). the median cohort serum ige was 7.5 iu/ml. the median serum ige was higher in patients with 2 or more atopic complications compared to those with one or less atopic condition (9 vs. 5 iu/ml), which was statistically significant (p=0.01). conclusions: we report higher rates of atopy than previously described in other cvid cohorts. consistent with previous reports, we find a low median cohort serum ige level in cvid patients compared to the general population. however, we identify a subset of patients with a predisposition towards atopy and higher ige levels within the broader characterization of cvid, and these patients may have a more specific molecular diagnosis that leads to elevated ige and atopic conditions. whole exome sequencing is underway to further evaluate this hypothesis. whim (warts, hypogammaglobulinemia, infections, and myelokathexis) syndrome is a primary immunodeficiency with autosomal dominant inheritance. in most patients, the genetic cause of the disease is a gain-offunction variant in c-x-c chemokine receptor type 4 (cxcr4) that results in arrest of neutrophil migration from the bone marrow. most patients develop hypogammaglobulinemia and early waning of antibody response with vaccination. however, the exact origin of aberrant humoral immunity in whim syndrome patients is yet to be clarified. here we describe a 4-year-old iraqi female with a heterozygous cxcr4 p.ser338ter variant, which is presented with haemophilus influenzae meningitis, history of tetralogy of fallot, early onset intermittent neutropenia, lymphopenia, recurrent bacterial and viral infections. immunologic evaluation revealed hypogammaglobulinemia, elevated igm level and a lack of protective vaccine titers after tetanus and prevnar vaccinations. a bone marrow biopsy was consistent with myelokathexis. immune phenotyping, functional studies and apoptosis assays were performed on peripheral blood cells by flow cytometry in our whim patient and controls. although we found that all lymphocyte compartments were reduced, naã¯ve cd4 t helper cells and switched memory b cells were predominantly affected. spontaneous apoptosis was most pronounced in b rather than t cell compartments in whim patients. in addition, naã¯ve b cells easily activated and died upon activation in vitro. cxcl12, a ligand of cxcr4, induced elevated t helper cell migration and increased actin polymerization in p.ser338ter mutant cells. we conclude that intrinsic b cell abnormalities, such as increased rate of apoptosis and altered activation, might be responsible for defective antibody response in whim patients. although most individuals effectively control herpesvirus infections, some suffer from unusually severe and/or recurrent infections requiring anti-viral prophylaxis. a subset of these patients possesses defects in nk cells, innate lymphocytes which recognize and lyse herpesvirus-infected cells; however, the exact genetic etiologies are rarely diagnosed. plcg2 encodes a signaling protein in nk cell and b cell receptor-mediated signaling. dominant-negative or gain-of-function mutations in plcg2 cause cold urticaria, antibody deficiency, or autoinflammation. however, loss-of-function mutations and plcg2 haploinsufficiency have never been reported in human disease. we examined 2 families with autosomal dominant nk cell immunodeficiency with mass cytometry and whole-exome sequencing to identify the cause of disease. we identified two novel heterozygous loss-of-function mutations inplcg2 that impaired nk cell function, including calcium flux, granule movement, and target killing. although expression of mutant plcg2 protein in vitro was normal, phosphorylation of both mutants was diminished. in contrast to plaid and aplaid, b cell function remained intact. plcg2+/-mice, as well as targeted crispr knock-in mice, also displayed impaired nk cell function with preserved b cell function, phenocopying human plcg2 haploinsufficiency. we report the first known cases of plcg2 haploinsufficiency, a clinically and mechanistically distinct syndrome from previously reported mutations. therefore, these families represent a novel disease, highlighting a role for plcg2 haploinsufficiency in herpesvirus-susceptible patients and expanding the spectrum of plcg2-related disease. we pursued genetic diagnosis, which identified bi-allelic frameshift mutations in the rag1 gene which had not been previously described: c.967delg (p.v323sfsx22) and c.1048_1075del128insaaaagagtg (p.v350kfsx47). taken together, his presentation suggested significant immune dysfunction had evolved since transplant leading to extensive pulmonary nontuberculous mycobacterial infection and possible bronchiolitis obliterans. he therefore will undergo a subsequent unconditioned cd34+ stem cell boost from his sister, the original donor, once he completes mycobacterium abscessus treatment. this case highlights the potential long-term immune dysfunction which may evolve after unconditioned allogeneic stem cell transplant for scid, in which full engraftment in all myeloid and lymphoid compartments is not expected. it also highlights the importance of guideline-driven follow-up of these patients to monitor for said dysfunction, to prevent serious infection and long-term sequelae. somatic hypermutation (shm) in the b cell receptor (bcr) heavy (igh) and light chain genes promotes affinity maturation and also mutation away from self-reactivity, therefore serves as an important peripheral tolerance checkpoint. as an example, unmutated bcr ighv4-34 genes give rise to antibodies that bind to i/i antigen on red blood cells (rbc) and may elicit cold agglutinin disease (cad), a variant of autoimmune hemolytic anemia (aiha). in case of healthy individuals, frequent shms in the i/i binding site of bcr ighv4-34 genes decrease rbc reactivity and cad. patients with primary immunodeficiencies (pid) paradoxically develop autoimmune diseases, including autoimmune cytopenias, especially aiha. it is unclear if impaired shm of bcr, in particular mutation away from i/i binding, is relevant in the development of rbc reactivity and consequently aiha in a pid background. our studies focus on pid patients with hypomorphic recombination activating gene (rag1 and 2), combined immunodeficiency phenotype and history of autoimmunity, in particular aiha (rag cid/ai). we detected increased frequency of unmutated ighv4-34 bcr in memory b cell repertoires of rag-cid/ai patients as well as elevated titer of unmutated ighv4-34 antibodies in the patients' plasma. lower level of shm likely reflect abnormal germinal center (gc) reaction. as rag1 and 2 heterotetramer primarily shapes the pre-immune t and b cell repertoire, we studied the interaction of follicular helper t cells (tfh) and naive b cells via in vitro co-culture experiment. interestingly, tfh cells from rag cid/ai patients exhibited highly activated phenotype with increased expression of cd40l and il-21 compared to healthy controls and were able to initiate exaggerated response (class switching and shm) of healthy donor naive b cells. on the contrary, in vitro activated naive b cells from rag cid/ai patients showed impaired proliferation, class switching and decreased level of shm with diminished induction of genes involved t cell co-stimulation (cd40, il-21r) and shm (aicda, repair enzymes) compared to healthy donor naive b cells indicating intrinsic defect in patient b cells. furthermore, b cells from rag cid/ai patients also showed increased apoptosis and accumulation of gamma-h2ax foci at steady state indicating reduced cellular fitness. these findings suggest that the development of aiha is a multifactorial process in partial rag deficiency. our studies highlight that impaired germinal center reaction is an important tolerance checkpoint with the inability of patient's b cells to respond to hyperactive tfh cells and introduce proper level of shm. hence, we propose that b cell fitness is compromised which impairs proper gc interaction, shm, including mutation away from self and sustains rbc reactivity in hypomorphic rag deficiency. introduction/background: the forkhead box n1 (foxn1) transcription factor is an essential regulator of t cell development, affecting the differentiation and expansion of thymic epithelial cells (tecs). autosomal recessive mutations in foxn1 cause a t-b+nk+ lymphocyte phenotype due to a thymic aplasia in conjunction with alopecia universalis and nail plate dystrophy resulting from keratinocyte dysregulation. this is a classic nude/scid (omim # 600838) phenotype. we report on the identification of two independent patients, identified through newborn screening with absent trecs and with a t-nk+b+ scid phenotype who presented with a t cell lymphopenia who had compound heterozygous mutations in foxn1. notably, these individuals had normal hair and nail beds. objectives: to determine whether distinct compound heterozygous mutations in foxn1 cause a novel t-nk+b+ phenotype in the absence of a classic nude presentation. neutralizing autoantibodies (autoabs) against cytokines increase the susceptibility for selected infections (e.g. anti-ifn-autoabs for nontuberculous mycobacteria and non-typhoid salmonella, anti-il-17-autoabs for mucocutaneous candidiasis and anti-gm-csf-auotabs for infections by cryptococcus, nocardiae and aspergillus spp). however, the role of anti-il-6-autoabs is less clear. il-6 is a key mediator of the acute-phase response and released early in bacterial infections. patients with impaired signaling or affected production of il-6 are at increased risk for severe bacterial infections. only three patients with high-titer and neutralizing anti-il-6-autoabs who suffered from severe infections caused by s. aureus, s. intermedius and e. coli have been described so far. to investigate the prevalence of anti-il-6-autoabs in patients with bacterial infections, we investigated a cohort of 350 patients and identified three further patients, all previously healthy, with neutralizing auotabs against il-6 who hardly developed an acute-phase response. the first patient suffered from life-threatening pneumonia caused by s. pneumonia, the second patient developed a submandibular abscess and septic arthritis caused by s. pyogenes and the third patient suffered from life-threatening pneumonia caused by s. aureus. we also discovered neutralizing anti-il-6-autoabs in two adults among a cohort of patients with autoimmune diseases (n = 564), in one adolescent among a cohort of obese individuals (n = 455) as well as in three mothers of neonates with impaired il-6 signaling. so far none of the later individuals developed a severe bacterial infection. this suggests that naturally occurring and neutralizing anti-il-6-autoabs are a risk factor for severe bacterial infections yet with incomplete penetrance. (215) submission id#606931 persistent transaminitis in copa syndrome 1 researcher, immunodeficiencies research unit, national institute of pediatrics, mexico city 2 social service intern, immunodeficiencies research unit, national institute of pediatrics 3 pediatrics resident, pediatrics hospital, 21st century national medical center, mexican institute of social security 4 researcher, data science department, mexican autonomous institute of technology 5 researcher, department of research methodology, national institute of pediatrics background: inborn errors of immunity constitute a heterogeneous group of over 400 individually rare congenital diseases that involve genes coding for proteins of the immune system, and which result in increased susceptibility to infection, inflammation, autoimmunity, allergy and cancer. the complexity of the diagnostic task, and the intrinsic biases and limitations of the human mind, can be aided by computational tools. among the available machine learning approaches, decision tree algorithms select the best node to split based on entropy and information gain; random forests build hundreds or thousands of decision trees randomly (bootstrapping), to improve accuracy and reduce overfitting. aim: to implement a machine learning-assisted clinical decision support system for the diagnosis of inborn errors of immunity (iei). methods: with a local database of patients with suspected iei, we built a decision tree using c4.5 dtc, and a random forest on python 3 (jupyter notebook, scikit, mathplotlib, pandas, numpy). the database was obtained by conducting an electronic search on medsys of patients with the term immunodeficiency in their electronic medical records, and then hand-picking cases in which an iei had been confirmed or ruled out. it consisted of 234 patients, of which 201 had been diagnosed with iei. we first split the dataset randomly into training (70%) and testing (30%) sets. the decision tree was tasked with classifying correctly pid or not. after running the algorithm in the training set, we evaluated in the testing set. the random forest classified all cases by majority vote into nine groups (0 to 8), according to the iuis pid group. next, we repeated the process on a larger scale with a dataset of 2,400 patients from usidnet. accuracy was assessed by out-of-bag (oob) error estimates. results: accuracy was greater than 95% for the local dataset (pid/ not, 9 groups), and for the usidnet dataset (9 groups). we provide a list of decision nodes and a diagnostic route with those questions that achieved a greater information gain and less entropy. this might help clinicians direct their interrogation and diagnostic approach of suspected iei patients. discussion: we built two classification models. decision trees lend themselves more easily to learning and deriving rules of thumb from their sequences. random forests are more robust and better suited for categoric (as opposed to binary) classification. we next want to develop a chatbot that will ask relevant questions in optimal sequence, and extract undiagnosed patients with suspected iei, based on statistical red flags. 13 researcher, immunodeficiencies research unit, national institute of pediatrics, mexico city dna repair defects are inborn errors of immunity that result in increased apoptosis and oncogenesis. dna ligase 4-deficient patients suffer from a wide range of clinical manifestations since early in life, including: microcephaly, dysmorphic facial features, growth failure, developmental delay, mental retardation; hip dysplasia, and other skeletal malformations; as well as a severe combined immunodeficiency, radiosensitivity and progressive bone marrow failure; or, they may present later in life with hematological neoplasias that respond catastrophically to chemo-and radiotherapy; or, they could be asymptomatic. we describe the clinical, laboratory and genetic features of five mexican patients with lig4 deficiency, together with a review of 36 other patients available in pubmed medline. four out of five of our patients are dead from lymphoma or bone marrow failure, with severe infection and massive bleeding; the fifth patient is asymptomatic despite a persistent cd4+ lymphopenia. most patients reported in the literature are microcephalic females with growth failure, sinopulmonary infections, hypogammaglobulinemia, very low b-cells, and radiosensitivity; while bone marrow failure and malignancy may develop at a later age. dysmorphic facial features, congenital hip dysplasia, chronic liver disease, gradual pancytopenia, lymphoma or leukemia, thrombocytopenia and gastrointestinal bleeding have been reported as well. most mutations are compound heterozygous, and all of them are hypomorphic, with two common truncating mutations accounting for the majority of patients. stem-cell transplantation after reduced intensity conditioning regimes may be curative. 1 department of laboratory medicine, clinical centre 2 immunology, allergy and rheumatology division, department of pediatrics, baylor college of medicine, texas children's hospital, houston,texas, usa 3 laboratory of clinical immunology and microbiology, fungal pathogenesis section, national institute of allergy and infectious diseases, 4 department of intramural research, national institute of allergy and infectious diseases (niaid), national institute of health, bethesda maryland, usa card9 deficiency is an autosomal recessive primary immunodeficiency known to underlay increased fungal infection susceptibility mostly presenting as invasive cns candida infections (in infancy or adulthood) and dermatophyte infections. more recently, a rare card9 variant (c.1434+1 g>c, leading to exon 11 skipping, card9del11) showed a significant protective association towards inflammatory bowel disease (ibd) when present in heterozygosity. at the nih we studied an 8-year-old male patient (p1) born to a non-consanguineous marriage who presented as an infant with recurrent/severe thrush, candida esophagitis, and an episode of tinea pedis; p1 also has mild hypogammaglobinemia (igg 500mg/dl at age 8y). p1s gdna was tested by whole exome sequencing and showed a card9 c.1434+1 g>c mutation in homozygous state. segregation analysis and sanger confirmation determined that both parents and p1s elder brother carried the same variant in heterozygosity, while his asymptomatic younger brother (p2) was also homozygous. as previously described, this variant caused card9 exon 11 deletion as determined in p1 and p2s pbmcs by cdna sequencing and by a lower molecular weight card9 protein by immunoblot evaluation. p1 and p2s pbmcs, as well as the heterozygous parents cells, showed a defective cytokine generation (tnf-, il-1, il-6 and gm-csf) in response to heat killed candida (hkc), but not to lps. while patients pbmcs failed to induce phospho-erk and phospho-p-38 upon hkc-stimulation but presented an intact response to pma+ionomycin; the parents cells responded normally to both stimuli. moreover, t-cell activation and proliferation was affected in response to hkc but not to pha in both patients, whereas the parents exhibited normal results under the same conditions. when hek293 cells were transiently transfected with wt or card9del11 vectors together with a trim62 plasmid (e3-ubiquitin ligase, naturally associated to card9), we confirmed that card9del11 failed to bind trim62 by immunoprecipitation. furthermore, malt1, bcl10 and trim62 were only co-precipitated by wt card9, but no by card9del11, strongly suggesting trim62 is an integral part of the card9/bcl10/malt1 -cbm-complex. in summary, herein we demonstrate that the card9del11 allele fails to bind trim62, and in turn is unable to conform a complete/functional cbm complex. our data also show that card9del11 acts in a dominant negative fashion in terms of cytokine generation (previously reported), but one wt allele seems sufficient to generate normal levels of hkcinduced p-erk and p-p-38, as well as t-cell proliferation. while decreased cytokine generation associated with card9del11 in heterozygosity has been described to be sufficient to protect towards ibd, other defective pathways are affected in homozygosity and likely necessary to confer increased susceptibility to fungal infections. altogether these results suggest that card9del11 acts through a gene dosage mechanism that can dissect pathways that associate ibd protection and fungal infection susceptibility. further work is warranted to explore card9del11 role, if any, in b-cell and t-cell biology. professor, endocrinology, university of michigan medical school background: acquired generalized lipodystrophy (agl) syndromes are a heterogeneous group of diseases characterized by selective dysfunction and loss of adipose tissue after birth. this causes ectopic lipid deposition and deficiency of the adipokine leptin, which promotes metabolic dysfunction through impaired glucose handling resulting in insulin-resistant diabetes mellitus, dyslipidemia and steatohepatitis. while the metabolic effects of altered adipokine secretion are known, the molecular mechanism is less clear. many agl cases are suspected to have an autoimmune etiology. effector and regulatory t cells, dendritic cells and macrophages reside in normal adipose tissue. t cells within adipose tissue highly express pd-1 and regulatory t cells express ctla4, which limits immune activation in the adipose tissue under normal circumstances. thus, inhibition of these immune checkpoints may hypothetically cause immune activation, leading to adipocyte dysfunction and autoimmune destruction. we have encountered two cases that raise clinical concern for this process. patient cases: patient 1 is a 16-year-old female who presented with failure to thrive at 6 months. she was diagnosed with insulin-resistant type 1 diabetes and hypertriglyceridemia at ages 2 and 4 years with progressive subcutaneous fat loss and low leptin levels culminating in a diagnosis of agl. her childhood clinical course was complicated by hypertrophic cardiomyopathy, hepatomegaly, autoimmune hemolytic anemia with massive splenomegaly and severe chronic diarrhea secondary to autoimmune enteropathy. she presented at 14 years with acute liver failure, thrombotic microangiopathy, nephrotic syndrome and progressive kidney insufficiency. evaluation for her multi-faceted autoimmune presentation identified a familial heterozygous pathogenic variant in the ctla4 gene (c.4_5insgttgg,p.ala2glyfster14). despite aggressive immune therapies, including ctla4-ig (abatacept), her kidney disease and enteropathy have progressed. patient 2 is a 55-year-old male diagnosed with localized malignant melanoma of the right neck in july 2014. he underwent excisional biopsy and regional lymph node dissection with negative margins. he relapsed in november 2017 and underwent a modified radical neck dissection with 1 lymph node positive for disease and received external beam radiation from january-february 2017. additionally, he was started on anti-pd-1 therapy with the humanized antibody drug pembrolizumab in april 2017 but discontinued the drug in february 2018 in the setting of toxicities including hypothyroidism. subsequently, he developed up to 7.5% weight loss with progressive loss of subcutaneous fat first in his face, then generalized to the rest of his body. in the ensuing months, imaging with pet-ct demonstrated loss of subcutaneous fat concurrent with elevations in alt and triglyceride levels plus a low leptin level consistent with agl. conclusion: these cases raise concern that inhibition of the immune checkpoints ctla4 and pd-1 may facilitate the development of agl. we hypothesize that these defects significantly increase t cell autoimmune activity in the adipose tissue and/or alter t cell metabolism resulting in agl. disorders of immune dysregulation should be considered in the etiology of agl. similarly, patients with either genetic or pharmacologic inhibition of immune checkpoints should be monitored for the development of agl with careful physical exam and periodic monitoring of glucose and triglyceride levels. background: rosai-dorfman disease (rdd; also known as sinus histiocytosis with massive lymphadenopathy) is a rare non-langerhans cell histiocytosis. it is characterized by proliferation and accumulation of activated histiocytes in affected tissues. classically, rdd presents with bilateral, non-tender, and often markedly enlarged cervical lymphadenopathy. case presentation: a 2-year-old female presented with a 6-week history of asymptomatic, persistent and bilaterally enlarged cervical lymph nodes. she was otherwise healthy with no significant past medical history. operative excision biopsy of the largest lymph node confirmed the diagnosis of rdd. three months following diagnosis, routine bloodwork revealed that she had developed lymphopenia (lymphocyte count 1.4 x 109/l). between 1-year and 2-and-a-half-years post-diagnosis, the patient was hospitalized and treated with intravenous antibiotics for 2 presumed episodes of osteomyelitis and 2 presumed episodes of lymphadenitis. given the recurrent presumed infections and persistent lymphopenia, the patient was referred to immunology for evaluation. she received a full immunologic work-up. lymphocyte immunophenotyping revealed low cd4 (288 cells/mm3) and low cd8 (228 cells/mm3) counts. the rest of her immunologic work-up was within normal limits. approximately 3-and-a-half-years post-diagnosis, the decision was made to initiate treatment for rdd. she was started on a 6-week tapering course of prednisone therapy. within 2-weeks of starting corticosteroid therapy, the lymphadenopathy had diminished, and by 6-weeks, the lymphopenia completely resolved. at her most recent clinic visit, she had been free of serious infections for more than 3-years, and her lymphocyte counts had remained stable and within normal limits for over one year. discussion: in the literature, immune system dysfunction has been reported in rdd, with both auto-antibodies and cellular immunodeficiency implicated. in this patient, the persistent lymphopenia and recurrent episodes of presumed infections appeared consistent with an immunodeficiency. given the known association of rdd with immunologic dysfunction, this was certainly a reasonable assumption; however, when these issues resolved following corticosteroid therapy, we questioned whether her clinical presentation could instead represent a manifestation of her underlying rdd. this case highlights the diagnostic challenge of differentiating between an infection and an rdd exacerbation. the episodes of presumed infections were considered probable but not confirmed with microbiologic or histopathologic specimens. the mechanism underlying lymphopenia in rdd is not clear but may involve decreased production, increased destruction, or sequestration of lymphocytes. to our knowledge, this has not been specifically studied in rdd in the past, however lymphopenia has been linked to lymphocyte maldistribution in other diseases. for example, studies have shown that experimentally altering either the surface of the lymphocyte or the environment through which the lymphocyte travels through can cause sequestration of lymphocytes in various lymphoid organs including lymph nodes. conclusion: we describe the case patient with rdd that developed persistent lymphopenia, and multiple episodes of presumed infections resulting in hospitalization and intravenous antibiotic therapy. her lymphopenia resolved and she had sustained remission of rdd following treatment with corticosteroids. we hypothesize that lymphocyte sequestration in enlarged lymph nodes may have resulted in lymphopenia. this, combined with recurrent rdd exacerbations that clinically resemble infections created a presentation that mimicked an immunodeficiency. background: there is an expanding spectrum of immunodeficiency phenotypes linked to dna repair defects, and some patients may not be diagnosed until adulthood. the most well recognized genetic defect linked to dna repair is in the gene, ataxia telangiectasia mutated (atm), which causes ataxia telangiectasia, characterized by combined immunodeficiency, neurodegeneration, radiation sensitivity, and ocular telangiectasias. however, there are several other dna repair defects associated with immunodeficiency, including some syndromic and severe combined immunodeficiency (scid) disorders. objective: we present the case of an adult patient with prolonged history of recurrent infections, facial abnormalities, and autoimmunity who was found to have radiosensitivity suggestive of a dna repair defect. methods: retrospective chart review, immunodeficiency evaluation, flow-based radiosensitivity assay, gene sequencing. results: a 68-year-old female was referred to our clinic due to a complex history of recurrent infections and immune dysregulation. the patient had a lifelong history of sinopulmonary infections and panhypogammaglobulinemia with low vaccine responses, leading to a diagnosis of common variable immunodeficiency (cvid), necessitating treatment with immunoglobulin replacement. clinical features were also notable for congenital dysmorphia (strabismus, thin and angular face, high arched palate, nasal septal defect, small mouth, missing dentition, clinodactyly, severe equinovarus, and scoliosis). she was subsequently diagnosed with autoimmune features of vasculitides requiring trial of cyclophosphamide, azathioprine, rituximab and belimumab, which was later discontinued due to neutropenia and worsening sinopulmonary and skin infections despite immunoglobulin replacement. in the course of our evaluation she was revealed to have severe b cell lymphopenia (1%), cd4 naã¯ve t cell lymphopenia, persistent iga and igm deficiency one-year post rituximab therapy, and elevated alpha fetoprotein (afp). radiosensitivity assay revealed decreased atm phosphorylation and elevated levels of h2ax 24-hours after low-dose (2gy) radiation in her lymphocyte subsets (t, b and nk cells) . due to the evidence of radiosensitivity and elevated afp levels, there was concern for an atm or other genetic defects in a dna repair pathway. therefore, a targeted (primary immunodeficiency genes) panel was pursued for genetic testing (207 genes, invitae, san francisco). the evaluation did not identify a variant in the atm gene but rather a variant of uncertain significance was identified in the chd7 gene, in exon 38, c.8440g>a (p.gly2814arg), which may be mosaic. this variant has not been reported in population databases. chd7 is typically associated with charge syndrome, and while this patient has some dysmorphic features, she is not typical for charge syndrome. currently, studies on copy number variation (cnv) and deep intronic variants in atm are pending. conclusion: dna repair defects may occur in adult patients with a primary diagnosis of cvid. our patient exhibits some phenotypic features of both a chd7 variant, and atm leading to possible abnormal dna damage responses (ddr). the exact cause of the immune deficiency in our case remains presently unsolved. this case highlights the relevance of both functional studies and genetic evaluation of complex cases of immune dysregulation, for improving our understanding of the phenotypic variability in these immunological disorders. background: womens health issues in patients with immunodeficiency are largely underrepresented in the literature. there are no studies assessing for fertility issues in patients with antibody deficiencies, and there are few sizable studies examining pregnancy and outcomes on progeny in the same cohort. the two largest studies of pregnancy in antibody deficiency, an idf survey and a study of the czech population, provide conflicting data about the safety of pregnancy for these patients. immunoglobulin replacement has been shown to be safe and beneficial in pregnancy for patients with cvid, however, dosing strategies are unguided. we sought to further understand these and other issues associated with fertility and pregnancy in a large cohort of patients with antibody deficiencies. methods: we performed a retrospective chart review of over 100 patients with icd9 and/or icd10 codes of cvid or another antibody deficiency from january 2005 to december 2018. inclusion criteria also comprised of having reached at least 16 years of age, the beginning of child bearing years. data collected included disease characteristics, comorbidities, laboratory values, and outcomes. this was followed by a phone survey to elucidate data regarding fertility, pregnancy, delivery complications, and outcomes of children. this study was irb approved. results: the current age of women included ranged from 16 to 88 years of age, currently being in childbearing years to being post-menopausal. forty percent of the women had been pregnant, delivering an average of 2 babies per woman who had been pregnant. fertility issues were not a prominent factor for women who never became pregnant. a majority of women who had babies (64%) did not receive a diagnosis of antibody deficiency until after their child bearing years. recurrent upper respiratory tract infections, bacterial sinusitis, and urinary tract infections during pregnancy were common even in those not yet diagnosed with antibody deficiency. immunoglobulin levels and dosing of intravenous and/or subcutaneous replacement were recorded for a subset of patients with recent pregnancies. the data re-enforced that increases in dosing are needed in the third trimester. cord blood igg levels were also recorded for baby and were the same or higher than the mothers most recent igg prior to delivery. it was rare for children of our patients to be diagnosed with antibody deficiency or a related condition, although cvid, hypogammaglobulinemia, combined immunodeficiency, lymphoma, rheumatoid arthritis, and other diagnoses were found. conclusion: this is the largest report of outcomes before, during, and after pregnancy for patients with antibody deficiencies in the united states. this report highlights the importance of closely monitoring women during pregnancy for recurrent infections regardless of whether a diagnosis of antibody deficiency is present. it also highlights that close monitoring of igg levels during pregnancy is necessary for women with antibody deficiencies. backgrounds: autoinflammatory diseases (aids) are a group of disorders with an inborn error of innate immunity, characterized by recurrent episodes of fever and inflammatory attacks. the spectrum of aids is expanding, but no data on clinical presentation and symptom variability exist for the iranian population for timely precise diagnosis. this study aims at establishing the first autoinflammatory registry of an iranian population focusing on the clinical and laboratory features that may help clinicians toward a better understanding and diagnosis of these disorders. methods: clinical and laboratory characteristics of patients who clinically and or genetically diagnosed with aids collected. we used the updated version of classification criteria from the eurofever registry for the clinical diagnosis. results: in our retrospective study, clinical and laboratory characteristics of the participants collected. mean age of disease onset, disease course manifestation, the mean duration of episodes, atypical symptoms, laboratory and imaging studies as well as complications, and response to treatment also reviewed. data resulted in 26 patients of whom 16 were male. their age ranged from 2 to 68 years. 5 out of 26 were genetically diagnosed. familial mediterranean fever (fmf) was the most common clinically and genetically approved diagnosis. there were also patients suspected of nlrp12 and nod2 mutations. age at disease onset differed variably and ranged from the neonatal period to adulthood. fever was present in all the participants and the duration of episodes was 1-10 days. the frequency of attacks was between 3 to more than 12 per year. some of the common clinical manifestations were as follows: myalgia or fatigue (77%), arthralgia and arthritis (70%), abdominal pain (65%), aphthous stomatitis (38%), chest pain (34%), chronic gastrointestinal symptoms (38%), skin lesion ranging from urticarial rash and severe nodular acne to pyoderma gangrenosum (50%), exudative and or erythematous pharyngitis (46%), consanguineous parents (42%), symptoms of a type of allergy (84%), lymphadenopathy (27%), splenomegaly (27%), increased acute phase reactant (54%), elevated liver function test (19%) . 10 out of 26 of the individuals reported positive family history and in one of the cases, a patient carrying the homozygous mutation in the mefv gene has shown no clinical manifestation. conclusion: this study highlights the most common manifestations of aids in the population of iranian origin and can be used as evidencebased clinical criteria for their diagnosis. background: the term benign ethnic neutropenia (ben) is used to describe patients of african/arabic descent with absolute neutrophil counts (ancs) less than 1500 cells/ul in the absence of other causes. historically, race has been used to support the diagnosis of ben, but self-reported race is notoriously imprecise. the duffy null phenotype (fya -/fyb-) is a known molecular cause of ben and may be a more reliable marker of ben than self-reported race. in addition, although the anc is known to be lower in patients with ben, the lower limit of ancs is poorly described. it is important to differentiate patients with ben from primary immunodeficiency diseases (pidd) and to recognize their expected anc values. methods: eligible subjects included patients less than 21 years seen at the university of michigan between january 2010-july 2018. duffy null (fya -/fyb-) patients were identified using electronic medical record search engine (emerse) software and search terms duffy and fyab. 105 potential subjects were identified; 67 patients met inclusion criteria including duffy null status and the absence of other conditions or medications, potentially impacting ancs. 251 unique healthy anc values were recorded from the 67 duffy null patients. age and sex matched controls were identified using emerse software with search terms tonsillectomy, department of anesthesiology and absolute neutrophil count. subjects with conditions or medications that might impact the anc or of african/arabic descent were excluded from the control group. asian and caucasian patients included as controls were presumed to be duffy null given that <1% of these populations are expected to be duffy null. 363 control subjects were identified; 134 met inclusion and exclusion criteria. statistical analysis was performed using two-sided two-sample t-test, anova and onesample t-test. results: the median age of the duffy null cases was 4.78 years (iqr: 1.68-11.48) with 61.2% (n=41) male and all of african or arabic descent. mean anc for duffy null patients was 1190 cells/ul (n=251, sd= 650) while mean anc for controls was 4300 cells/ul (n=134; sd=1600) with a mean difference between controls and duffy null cases of 3100 cells/ul (95% ci: 2950-3380; p=0.0001). the anc levels between duffy null individuals and controls were evaluated by five age categories (p=0.0001 for all age categories). however, there was no difference in anc levels between duffy null cases at different age categories (anova, p=0.14196). 54 (21.5%) duffy null cbcs had anc levels in the nonneutropenic range (>1500 cells/ul), 99 (39.4%) cbcs had mild neutropenia (1001-1500 cells/ul), 70 (27.9%) cbcs had moderate neutropenia (500-999 cells/ul), and 28 (11.2%) cbcs had severe neutropenia (<500 cells/ul). conclusions: although neutropenia can be associated with pidds and is often a sign of a compromised immune system, duffy null patients have a wide range of values that are often much lower than previously appreciated. the degree of neutropenia related to duffy null phenotype appears to persists throughout childhood and young adulthood. in the context of patients of african/arabic descent presenting with asymptomatic neutropenia, duffy null status should be assessed, and ben should be considered in the differential. complications, hypogammaglobulinemia and a unique characteristic of decreased susceptibility to enveloped viral infections. objective: to investigate the role of impaired host n-linked glycosylation on viral susceptibility to ebola virus. methods: to mimic the condition observed on cdg-iib patients, we tested in vitro three proprietary iminosugars (emergentbiosolutionsâ©), uv4b, uv001, and uv00128, which act as competitive inhibitors of -glucosidase i and ii. their ability to inhibit the trimming of n-glycans was compared to known n-glycans modifiers as castanospermine, tunicamycin, as well as the bacterial enzyme peptide-nglycosidase f (pngase-f). ebola virus envelope protein gp1 was chosen as a prototype glycoprotein, as it is heavily glycosylated with 15 nglycosylation sites. hek 293t cells were seeded at 1x10^5 cells/well in 12 well plate. after 18h, cells were transfected with pflag-ebolavirus gp1 by coupling with effecteneâ®. after 24h, cells were treated with the inhibitors and harvested 24h after treatment. trimming of n-glycans was evaluated via molecular weight assessment by western-blot. results: all three inhibitors had comparable effectiveness in inhibiting trimming of nglycans from ebola gp1 glycoprotein compared to castanospermine. a greater molecular weight shift was seen with tunicamycin and pngase f as expected. conclusions: chemical inhibition of the n-linked glycosylation pathway was successfully achieved using three new mogs inhibitors. this approach merits further investigation on potential applications on antiviral therapies. investigator, laboratory of human genetics of infectious diseases, necker branch, inserm u1163, necker enfants malades hospital, paris, france 5 head, immunodeficiencies research unit, national institute of pediatrics stat1 gof mutations are associated with infections, autoimmunity and inflammatory manifestations; the rosacea is one of the manifestations described in this disease, however, the etiology rosacea is not clearly established. the characteristics of rosacea are not described in stat gof in the different clinical series. we describe the different characteristics of rosacea in a family with 8 affected members with stat1 gof. a family with eight members with stat1 gof mutation were diagnosed through a first affected member affected with tuberculosis and onychomycosis. seven members more had a clinical history of mycobacterial, viral and fungus infections and autoimmunity disease, in all the seven, was documented the same mutation stat1gof. in six of these adults patients, we documented rosacea, it started after adolescence, it was localized in the face and/or eyes, was progressive and not ameliorated with medical treatment and caused nose deformity. rosacea has been described previously as a unique manifestation, and the etiology is not clear, an autoimmune hypothesis has been proposed. the fact that is present in patients with stat1 gof could suggest that have effectively an autoimmune component. physicians face the patients with rosacea must look for other manifestation presents in stat1 gof mutations. genetic studies in rosacea patients could evidence an new gene defect. introduction: homozygous mutations causing loss of function of the transcription factor forkhead-box n1 (foxn1) underlie autosomal recessive severe combined immunodeficiency with congenital alopecia and nail dystrophy (nude scid). affected humans, like the scid mouse, have small or absent thymus, absent or severely diminished t cells, alopecia, and nail dystrophy. infants with nude scid have had neonatal lymphopenia and severe, life-threatening infections. studies of heterozygous carriers of foxn1 mutations are limited, some having been reported with no phenotype or mild disease manifestations, such as nail dystrophy without lymphopenia or recurrent infections. objective: we describe six infants, including two brothers, with t-cell lymphopenia (tcl) following abnormal california newborn screens (nbs) for scid. each had a single heterozygous variant in foxn1. case reports: six infants (3 female, 3 male) were referred for evaluation after abnormal california nbs for scid (table 1) , with t-cell receptor excision circle (trec) counts from undetectable to 12 (normal >18). all infants were well at the time of initial evaluation. five infants with absolute cd3 t cell counts >400 cells/ul and cd4 t cell counts >250 cells/ul began evaluation as outpatients on home isolation. patient 5, with undetectable trecs, cd3 t cell count 78, and cd4 t cell count 65 was urgently admitted for inpatient evaluation and management and immediately started on antimicrobial prophylaxis. patient 5 further evaluation was significant for lymphocyte proliferation to mitogens that was initially normal but waned with time, prompting treatment with a paternal haploidentical hematopoietic cell transplant at 6 months of age. patients 3 and 5 developed neutropenia within 6 weeks of birth treated with granulocyte colony stimulating factor (gcsf). patient 3 remains well on gcsf but has had persistent growth failure under continued evaluation. patients 1, 2, 4 and 6 remain stable off antimicrobial prophylaxis, but with persistent moderate tcl. as part of an immune evaluation, patients 1 and 3-6 had gene panel testing revealing heterozygous variants in foxn1. only the variant of patient 1 (presumed shared by patient 2, his brother) was predicted to be pathogenic; patient 1 had dystrophic nails and sparse hair most evident after 2 years of age, features shared by his mother and his brother, patient 2. the other patients lack the clinical features of the previously described phenotype of nude scid. their heterozygous foxn1 variants are of unknown significance; the functional role of these variants in the patients clinical phenotype is unknown. conclusion: six infants with abnormal nbs for scid had lymphopenia and heterozygous variants in foxn1. for these infants, variation exists in level of tcl and presence of hair and nail findings. heterozygous variants of unknown significance in foxn1 have been uncovered in others, including infants with abnormal nbs for scid, highlighting the need for functional studies to address the possible role of each heterozygous foxn1 variant in congenital lymphopenia and neutropenia. more work is needed before attributing tcl to a novel foxn1 variant of unknown significance in the absence of family history, abnormal hair or nails, or functional evidence. remains poorly understood. we characterized the intestinal microbiome and metabolome in patients with cgd to determine if intestinal microbiome and metabolomic signatures could distinguish subpopulations of patients with cgd while using the metabolome to add a functional dimension to observed microbiome signatures. methods: clinical metadata and fecal samples were collected crosssectionally from healthy volunteers (hv; n=16) and patients with cgd (n=77). metabolomic profiling and 16s rrna (v4) sequencing was performed on fecal samples (total samples: 108; reads/sample: 15,254 to 191,415; median: 60,816) . results: samples from patients with cgd had distinct intestinal microbiome signatures and metabolomic profiles depending on genotype, presence of cgd-ibd and specific interventions (e.g. treatment with an elemental diet). notably, samples from patients with active cgd-ibd (compared to samples from patients without a history of cgd-ibd) had significantly different alpha-and betadiversities, and were enriched for enterococcus spp. signal transducer and activator of transcription 1 gain of function (stat1-gof) is a primary immunodeysregulatory disease in which a subset of patients have features of autoimmunity and autoinflammation. enteropathy with growth failure and nutrient wasting is a more common feature of immunodysregulation. ruxolitinib is a janus kinase-stat inhibitor that has been shown effective for the treatment of immunodysregulatory features in stat1-gof. our patient is a 13 year old male with stat1-gof (c.983a>g p.h328r) with severe total parenteral dependent enteropathy that led to growth failure (weight 28.5kg). treatment with ruxolitinib led to resolution of diarrhea, return of normal diet, and catch up growth. a dose of 12.5mg twice daily was initially started but was decreased to 12.5mg every morning and 10 mg every evening due to elevated transaminases and thrombocytopenia. over the following year the patient thrived gaining 7.5kg with normal every other day stools. despite weight gain, he remained stable on the same dose of ruxolitinib. as he outgrew his dose, he developed an increased frequency of upper respiratory infections (parainfluenza, coronavirus, rhinovirus). one year after initiation of ruxolitinib, he again developed profuse watery diarrhea that was norovirus positive (weight 36kg, bsa 0.9). he was placed on bowel rest and ruxolitinib was dose escalated with a goal of 15mg/m2/day. when he reached 15mg twice daily, enteropathy completely resolved but liver function tests began to rise. he gained weight and began thriving after 2 weeks of therapy. six months later, enteropathy is controlled, and transaminases have remained elevated (alt 88 iu/l, ast 73 iu/ml) but stable. the appropriate dose and pharmacokinetics for ruxolitinib for the treatment of immunodysregulatory symptoms in pediatric patients has not been thoroughly studied. the dose used was extrapolated from data on the use of ruxolitinib in pediatric myelofibrosis. a dose of 15mg/m2/day appears to provide the most benefit with tolerable adverse effects. this dose should be maintained in order to prevent recurrence of disease related manifestations. abstract clathrin-mediated endocytosis (cme) is the major endocytic pathway by which eukaryotic cells internalize cell-surface cargo proteins and extracellular molecules, thereby allowing for a broad range of biological processes, including cell signaling, nutrient and growth factor uptake, and cell fate and differentiation1. the fbar domain only proteins 1 and 2 (fcho1/fcho2) are involved in the initiation of clathrin coat pit formation. whether fcho1 and fcho2 are functionally redundant or have distinct functions is unclear. we report here the first cases of a severe immunodeficiency due to a genetic defect affecting cme. by using whole exome sequencing and genomic analysis of a targeted pid gene panel, we have identified biallelic loss-of-function fcho1 mutations in five patients from unrelated families of italian (p1), turkish (p2, p3, and p5) and algerian (p4) origin with severe t cell lymphopenia manifesting as recurrent and severe infections of bacterial, mycobacterial, viral and fungal origin. p3 developed ebv-associated diffuse large b cell lymphoma. three patients (p3-p5) died in childhood, whereas p1 and p2 are alive with full donor chimerism at 13 and 1.5 years after allogeneic hematopoietic stem cell transplantation, respectively and have cleared pre-transplant infections. patients p2, p3, and p4 carried homozygous frameshift mutations predicted to cause premature termination. western-blotting analysis of ha-or flag-tagged fcho1 constructs showed expression of truncated products in p2 and p3, whereas no protein was detected in p4, presumably due to mrna decay. p1 and p5 carried homozygous splice-site mutations at the invariant -1 and +1 positions, respectively, leading to skipping of exon 6 in p1's fcho1 cdna. qpcr analysis demonstrated differential expression of the fcho1 and fcho2 genes, with the former being predominantly expressed in lymphoid cells, whereas fcho2 was more abundantly expressed in fibroblasts and k562 cells. analysis of t cell activation in p2 (the only patient for whom pre-transplant pbmc were available) revealed reduced t cell proliferation. while tcr internalization in response to cd3 cross-linking was normal (consistent with recent evidence that tcr internalization occurs through a clathrin-independent pathway), chase experiments demonstrated that transferrin internalization was abolished in activated t cells from p2. we had previously reported that a missense mutation in tfrc, encoding transferrin receptor 1, impairs transferrin internalization and intracellular iron delivery, causing a combined immunodeficiency with defective t cell proliferation. our data identify the first form of severe immunodeficiency due to defects of clathrin-mediated endocytosis, and provide additional evidence in support of the critical role played by iron cellular metabolism in t cell function and homeostasis. natural history of anti-interferon-gamma autoantibody-associated immunodeficiency syndrome in thailand submission id#601826 centralized sequencing initiative at niaid: year 1 therefore, we set out to investigate the pneumococcal-specific responses of igg, igg2, iga and igm to prevnar13â® in igg subclass deficient (iggscd) patients in this study. pneumococcal responses were measured using the vacczyme pneumococcal capsular polysaccharide igg, igg2, iga and igm elisas (the binding site group, birmingham, uk) in control (n=10, median age 57 years, range 27-64) and iggscd patients (n=10, median age 55 years, range 25-65) recruited from the immunodeficiency unit at the karolinska university hospital iga and igm antibodies in response to pcv13 vaccination was observed 4 weeks post vaccination in iggscd patients (median, 2.5th and 97.5th percentile these median concentrations were lower than those observed in control patients (median, 2.5th and 97 pcv13 igg2 71 mg/l, 14-90 however, percentage changes between pre to post vaccination concentrations of igg, igg2 and iga in response to pcv13 in iggscd patients were not significantly different to the control patients u/ml vs 17.1 u/ml, respectively) iga 26 u/ml and pcv13 igm 39 u/ml) responders and non-responders of pcv13 igg iga and igm in response to pcv13 in iggscd patients were generally lower compared to the control population. these results support the fact that in addition to igg and igg2, measurement of iga and igm could also provide useful information for the clinician gain-of-function ikbkb mutation causes human combined immune deficiency submission id#606903 neutralizing anti-il-6-autoantibodies are a risk factor for pyogenic bacterial infections national institutes of health, national institutes of allergy and infectious diseases service of immunology and rheumatology, garrahan national pediatric hospital copa mutations impair er-golgi transport and cause hereditary autoimmune-mediated lung disease and arthritis copa syndrome: a novel autosomal dominant immune dysregulatory disease analysis of pulmonary features and treatment approaches in the copa syndrome expanding the phenotype of copa syndrome: a kindred with typical and atypical features the forest and the trees: machine learning to classify cases of suspected inborn errors of immunity using decision tree and random forest algorithms submission id#607035 card9î�11 gene dosage: from mono-allelic protection to ibd, to bi-allelic increased fungal infection susceptibility yamanaka d 3 , walkiewicz m 4 , lionakis m 3 and rosenzweig s 1 stim1 mutation associated with a syndrome of immunodeficiency and autoimmunity a novel hypomorphic mutation in stim1 results in a late-onset immunodeficiency clinical, histological and genetic characterisation of patients with tubular aggregate myopathy caused by mutations in stim1 gain-of-function mutation in stim1 (p.r304w) is associated with stormorken syndrome gain-of-function mutations in stim1 and orai1 causing tubular aggregate myopathy and stormorken syndrome stormorken syndrome caused by a p.r304w stim1 mutation: the first italian patient and a review of the literature by studying ecs-pre and ecs-post patients we were able to describe the bona-fide effect of gcs on the immune system in general, and t lymphocytes in particular. decreased lymphocyte/thymic output, as well as increased apoptotic tcell death underlies lymphopenia in ecs/chronic gcs-exposed patients. under such conditions, il-21 was significantly decreased in plasma and our in-vitro studies showed that il-21 replenishment was able to increase bcl2 (anti-apoptotic molecule) and bcl6 expression, and efficiently counteract the apoptotic effects of gcs. recombinant il-21 has been explored as a co-adjuvant treatment for multiple human cancers and may offer a treatment option for lymphopenia and its genetic counselor, co-director of personalized medicine, division of hematology/oncology/bmt and the institute for genomic medicine, nationwide childrens hospital 2 genetic counselor, division of hematology/oncology/bmt, nationwide children's hospital acknowledgments. genetic sequencing was kindly provided by drs. raif geha and janet chou at the division of immunology, allergy, rheumatology and dermatology, boston children's hospital, harvard medical school. the following grants are acknowledged: 1. rui 1.1001/cippt/812036 (usm) 2. bmbf 01 eo003 (freiburg) the authors would like to thank the director general of health of malaysia for permission to publish this scientific presentation. while severe viral infections may also be an initial presentation of primary immunodeficiency, an immune evaluation is not always obtained in this scenario. patients with xla have an increased susceptibility to severe enterovirus infections, manifesting as chronic meningoencephalitis, which can be fatal. the following case describes a patient with newly diagnosed xla presenting as suspected coxsackievirus and confirmed hhv-6 meningitis, pseudomonas meningitis and bacteremia. this may be the first reported new diagnosis of xla presenting with both severe bacterial and viral coinfection. case description: a 2 year old, partially vaccinated, hispanic male with a history of febrile seizures presented to the emergency room with fever, oliguria, watery diarrhea, lethargy, meningismus, ecthyma gangrenosum and lower abdominal pain. eight days prior to presentation, he was seen by his pediatrician for facial rash and low grade temperature, and was diagnosed with hand-foot-and mouth disease. he worsened on empiric antibiotics. he had no history of sinopulmonary infections. he did not attend daycare. his vaccines were delayed due to parental choice, and he had not received live vaccines (rotavirus, mmr or vzv). full sepsis evaluation was performed. csf demonstrated pleocytosis, and he was started on empiric antibiotics and transferred to picu. due to worsening abdominal pain, ct of the abdomen was performed, which was consistent with ruptured appendicitis and septic emboli at the lung bases. csf pcr panel was positive for hhv-6 and he was started on gancyclovir. csf and blood cultures subsequently grew pseudomonas aeruginosa. immune evaluation was performed. serum immunoglobulins were undetectable. in addition to iv antibiotics, he received 500 mg/kg ivig and lymphocyte subsets revealed profound b cell lymphopenia (0.23 %, 5 cells/ul). btk protein analysis revealed hemizygous btk pathogenic variant confirming the diagnosis of x-linked agammaglobulinemia. the hospital course was further complicated by brain abscesses and pyoventriculitis. he was treated with 3 additional doses of 500 mg/kg ivig and iv antibiotics. repeat mri of the brain nearly 4 weeks after admission demonstrated significant improvement. there was significant clinical recovery. he was discharged home at baseline neurological status. his igg level upon discharge home was 605 mg/dl with the plan to increase dose to 600 mg/kg per month with close monitoring. conclusion: both severe opportunistic bacterial infections and severe viral infections as the initial presentation of xla have been well reported in the literature. this case describes the first reported severe pseudomonas aeruginosa and hhv-6 co-infection in a newly diagnosed xla patient. this case further highlights the necessity for an increased index of suspicion of primary immunodeficiency in a patient who presents with a severe first infection, despite lack of recurrent infections. we present two patients with dock8 deficiency due to compound heterozygous variants including a copy number loss at chromosome band 9p24.3 spanning approximately .107 mb with partial deletion of the dock8 gene and a novel c.2603c>t (p.ser868leu) missense variant [chr9:379933 (grch37) nm_203447] in dock8. functional data is presented to support the pathogenicity of the missense change, along with a review of the literature on dock8 variants. the proband is a 14-year-old female with elevated serum ige, severe atopic dermatitis, mild persistent asthma, food allergies, and seasonal allergic rhinitis. she is currently healthy following haploidentical bone marrow transplant in june 2018. she has a 17-year-old brother with dock8 deficiency with the same compound heterozygous variants. the brother had later onset of symptoms and a milder presentation of intermittent asthma and seasonal allergic rhinitis. each of the parents is heterozygous for one of the two variants. we evaluated the pathogenicity of the c.2603c>t missense variant with western blots of dock8 protein expression, intracellular flow cytometry, and dock8 stretch assays. flow cytometry showed decreased dock8 protein expression and stretch assays revealed t cells that were stretched in collagen gels. notably, dock8 is a large gene containing 47 exons spanning 190 kb and it is relatively common to be a carrier of a rare missense change. in fact, gnomad has approximately 1500 individuals with rare (<0.002 frequency) missense alleles in dock8. therefore, it is important to demonstrate the potential pathogenicity of any given rare missense change, since few pathogenic missense variants in dock8 have been reported. of the 168 published dock8 variants listed in the human gene mutation database (hgmd) only 13 are missense. the majority are gross deletions, 97 of which were reported in hgmd. the remaining reported dock8 variants include 19 nonsense, 15 splicing, 13 small deletions (all frameshifting), 3 small insertions (all frameshifting), 2 small indels, and 5 gross insertions/duplications. this case demonstrates the relatively infrequent but important contribution of missense changes to pathogenic dock8 alleles. functional validation of missense alleles is critical in the complex evaluation of dock8 deficiency. background: hsct is the only known curative option currently for cd40l deficiency, an x-linked disorder. in cd40l deficiency and other x-linked immune deficiencies, there is an ongoing debate regarding the use of a carrier female sibling or mother as hsct donor. skewed lyonization despite complete donor chimerism has raised concerns for incomplete disease control post-hsct. no data exist regarding the efficacy of related female carrier as hsct donor for cd40l deficiency. we herein report outcomes of three patients with cd40l deficiency who underwent hsct using a related female carrier donor. method: retrospective review of patients who received hsct from carrier female related donor at three separate institutions. results: three patients with cd40l deficiency underwent hsct between 2016-2018. patient 1 had recurrent episodes of pneumocystis jiroveci pneumonia (pjp) despite being on bactrim and immunoglobulin replacement. patient 2 presented with pjp and severe neutropenia. patient 3 presented with acute respiratory failure from severe respiratory viral infections, cmvand had severe neutropenia requiring g-csf treatment. age at the time of hsct ranged from 0.5-15 yrs. all three underwent reduced toxicity hsct with busulfan and fludarabine-based preparatory regimens. two of them received matched sibling bone marrow hsct and one received tcr and cd19 depleted mobilized maternal pbsc haploidentical hsct. donor cd40l expression varied from 37% -67% on activated cd4 cells. immunoglobulin profile and lymphocyte subset were done in two of donors, they were within normal range for age, and none had significant infection history. no history of intermittent neutropenia or oral ulcers noted in donor and the absolute neutrophil count of the donor varied between 2500 6520 /l. donor age ranged from 3.2 yrs 48 years. cd34 dose ranged from 6.1 x 106 -23.1 x 106 cells/kg and cd3 dose ranged from 1 x 105 22.1 x 107 cd3+ cells/kg. gvhd prophylaxis consisted of csa/mmf (n=2) and tcr-a/b depletion and no csa (n=1). neutrophil engraftment ranged from 11-18 days and platelet engraftment ranged from 13 28 days. none of the patients developed acute or chronic gvhd. all three patients maintain full donor myeloid chimerism at the latest testing (9 months 18 months); t cell chimerism was 100% in one and mixed in two patients (91% at nine months, 80% at 12 months). all three patients had excellent t cell immune reconstitution; two patients came off immunoglobulin replacement 5 -11 months post hsct, whereas the 3rd patient is ivig dependent, though iga level was 25 mg/dl at nine months post-transplantation. latest evaluation, 9 18 months post-hsct, revealed 27% -63% cd40l expressing activated cd4 t cells, which correlated with donor cd40l expression and t-cell chimerism. conclusion: our data suggest that hsct utilizing x-linked carrier appears to be safe and results in durable engraftment with excellent humoral and cellular immune reconstitution in patients with cd40l deficiency. longer follow-up and data from a larger cohort is needed to make a definitive determination of safety and efficacy of utilizing female carrier as hsct donors in this disease. chief, immunology service, department of laboratory medicine, nih clinical center, bethesda, md, usa background: ikaros belongs to a hematopoietic-specific zinc-finger (zf) family of transcription factors. after dimerizing and dna binding to pericentric-heterochromatin (pc-hc) regions, ikaros is described as a central regulator of lymphocyte differentiation. somatic mutations/ deletions affecting ikaros n-terminal zf have been identified in b-acute lymphoblastic leukemia (all) patients, and germline n-terminal mutations were reported in cvid patients with progressive lack of b cells, hypogammaglobinemia, autoimmune diseases and b-all. methods: we performed targeted sequencing panel for known inborn errors of immunity disease-causing genes in a previously healthy male pediatric patient with burkitt lymphoma, followed by benign lymphoproliferation, thrombocytopenia and neutropenia. b-cells and immunoglobulin levels were normal. ikaros dna-binding, nuclear localization and protein binding were evaluated by emsa, fluorescence microscopy and immunoprecipitation. protein modeling was also performed. results: a novel heterozygous germline mutation in ikaros c-terminal zf6 dimerization domain (p.r502l) was detected in this patient. this mutant showed normal pc-hc localization but dna-binding was markedly reduced in terms of ikaros dimerization and multimerization. moreover, reduced wt-mutant binding was also detected. mutant/wt cotransfection experiments suggest a haploinsufficient defect. geometry based docking of wildtype ikaros predicted that r502 is within the homodimer interface and may abolish cation-pi interactions and destabilize the ikaros-zf6 dimerization domain. conclusion: a novel germline ikaros c-terminal mutation affecting homodimerization/multimerization and resulting in reduced dna binding to its dna consensus site was detected in a patient with burkitt lymphoma, benign lymphoproliferation and cytopenias. further studies are warranted to formally establish the casual connection between this genotype and phenotype.(210) submission id#606894 patricia pichilingue-reto, md 1 , prithvi raj, phd 2 , igor dozmorov, phd 3 , quan-zhen li, md, phd 4 , edward wakeland, phd 5 , nancy kelly, md 6 , maria teresa de la morena, md 7 , nicolai s. van oers, phd 8 methods: mice were generated by crispr/cas technology to genocopy the foxn1 compound heterozygous mutations identified in one of the human patients. thymopoiesis and hair follicle extrusion was analyzed in the various heterozygous and homozygous mutant mice. gene expression analyses of the hypoplastic and normal-sized thymii and the developing skin were performed. in addition, a structure-function analysis was performed with luciferase reporter assays using 9 distinct and previously unreported foxn1 mutations uncovered in patients who presented with low trecs. results: mice harboring compound heterozygous mutations in foxn1 that match the human patient phenocopy the t-b+nk+ scid phenotype with normal hair and nails. a functional characterization of the diverse foxn1 mutations suggests that the severity of the block in thymopoiesis depends on whether the mutations affect the dna binding or transactivation domains of foxn1. a 5-amino acid segment at the end of the dna binding domain appears to be essential for tec development. however, this segment is not required for normal keratinocyte functions in the skin and nail plate. gene expression comparisons are revealing key targets of foxn1 that suggest a dichotomy in its function in the thymus versus the skin. conclusions: novel compound heterozygous mutations in foxn1 are causal to a t-nk+b+ phenotype with normal hair shaft extrusion and nail plate extension. this differs from the classic nude/scid (omim # 600838) reported for individuals with autosomal recessive mutations in foxn1. assistant professor of medicine and pediatrics, department of allergy and immunology, uva introduction: copa syndrome is a recently described monogenic immunodysregulatory syndrome. the cop protein, encoded for by the copa gene, is expressed in all cell types and is involved in trafficking from the golgi complex to the endoplasmic reticulum (1) . the most common clinical features of copa syndrome are interstitial lung disease, pulmonary cysts or follicular bronchiolitis, pulmonary hemorrhage, arthritis, glomerular disease, and autoantibody development (2, 3) . atypical features of copa syndrome identified thus far include: extrapulmonary cysts in the liver and kidney, renal and neuroendocrine malignancies, autoimmune neurological disorders such as neuromyelitis optica, and infections, such as meningitis (4) . clinical case: we present a case of a 2 year-old male with copa syndrome (de novo heterozygous mutation in exon 9, c.715g>c; p.ala239pro) manifesting as lymphocytic interstitial pneumonitis, peripheral blood b-cell lymphocytosis, mediastinal lymphadenopathy and persistent transaminitis (alt and ast 100-400 u/l, nl ast<35 u/l, alt <55u/l) with normal bilirubin, alkaline phosphatase and pt/inr. the transaminitis was noted prior to diagnosis of copa syndrome, and has persisted despite seven months of therapy with pulse dose steroids, two cycles of rituximab and maintenance therapy with hydroxychloroquine and prednisone. he has had a normal ck and aldolase excluding muscle injury as a source of his transaminitis. a congenital cholestasis panel was normal. markers of autoimmune liver disease including ana, anti-liver kidney microsomal antibody and anti-smooth muscle were negative. serum ceruloplasmin and alpha-1-antitrypsin level were normal and celiac serologies, were negative. liver ultrasound was normal. a liver biopsy did not demonstrate inflammatory changes, hepatocyte necrosis, mononuclear cell infiltrates or fibrosis. nonspecific biopsy findings included occasional intraparenchymal neutrophils. it is unclear if these scattered neutrophils and the transaminitis are due to an early as yet unidentified autoimmune process, perhaps in response to hepatocellular stress exacerbated by the copa mutation. discussion: liver involvement has not been reported in copa syndrome. we describe a child with copa syndrome who has had chronic transaminitis with no clear alternative cause. if the phenotypic spectrum of copa syndrome involves the liver, it may limit immunomodulatory options for the treatment of this disease. background: in humans, biallelic stat1 lost-of-function (lof) mutations lead to a very low or complete absence of the wild-type (wt) protein. whereas, heterozygous mutations can lead to partial loss of function. these patients are susceptible to mycobacteria and herpes virus infections. on other hand, heterozygous gain-of-function (gof) mutations in the stat1 gene result in a hyperphosphorylated state where patients develop recurrent or persistent chronic mucocutaneous candidiasis (cmc), other cutaneous mycosis, bacterial infections, disseminated dimorphic fungal infections, viral infections and autoimmune disease. methods: in this study, we evaluated 4 novel stat1 mutations, three gof and one lof. in vitro, pbmcs from these patients were stimulated with ifn-and ifn-for 30, 60, and 120 minutes and levels of phospho-stat1 were measured by flow cytometry. the stat1 phosphorylation and activity (firefly and renilla luciferase activities) were evaluated in u3a-stat1 deficient cells transfected with a reporter plasmid (for luciferase), wt or mutant-stat1 plasmids. results: we observed higher levels of stat1 phosphorylation after two hours of stimulation from three gof mutations compared to wt. however, a lof mutation showed absent stat1 activation at baseline and in response to ifn-and ifn-. luciferase reporter assay confirmed gain of function and loss of function stat1 activity observed by flow cytometry. conclusions: using flow cytometry followed by a luciferase assay, we confirmed four novel stat1 mutations. measuring phosphorylation of stat1 by flow cytometry is sufficient to determine whether the stat1 mutation is disease causing. this assay can be translated to a clinically accessible test for stat1 related disease. background: variants in recombination-activating genes (rag) are common genetic causes of autosomal recessive forms combined immunodeficiencies (cid) ranging from severe combined immunodeficiency (scid), omenn syndrome (os), atypical scid (as) and cid with granulomas and/or autoimmunity (cid-g/ai). the clinical and immunological presentation is broad, ranging from severe infections secondary to near absence of t and b lymphocytes and hypogammaglobulinemia to the occurrence of autoimmunity with late manifestations with partly preserved immune subsets and near normal immunoglobulin levels and broad spectrum of autoantibodies. objective: we aim to estimate the incidence, clinical presentation, genetic variability and treatment outcome with geographic distribution of patients with the rag defects in populations inhabiting south, west and east slavic countries. due to shared ancestry, we also investigated our cohort for founder variants in rag1 and rag2 genes. methods: demographic, clinical and laboratory data were collected from rag deficient patients of slavic origin via chart review, retrospectively. results. based on the clinical and immunologic phenotype, our cohort of 80 patients from 66 families represented a wide spectrum of rag deficiencies, including scid (n=19), os (n=36), as (n=21) and cid-g/ai (n=4). sixty-six (82.5%) patients carried rag1 and 14 patients (17.5%) carried rag2 biallelic variants. we estimate that the minimal annual incidence of rag deficiency in slavic countries varies between 1 in 180,000 300,000 live birth and it may vary secondary to health care disparities in these regions. in our cohort, 70% of the patients carried rag1 p.k86vfs*33 (c.256_257delaa), either in homozygous (n=17, 26%) or compound heterozygous (n=29, 44%) form. the majority (77%) of patients with homozygous rag1 p.k86vfs*33 originated from vistula watershed area in central and eastern poland, and compound heterozygote cases distributed among all slavic countries except bulgaria. clinical and immunological presentation of homozygous rag1 p.k86vfs*33 cases was highly diverse suggestive of strong influence of other genetic and/or epigenetic factors in shaping the final phenotype. survival of rag deficient patients without hematopoietic stem cell transplant (hsct) (n=3, 8.8%) is poor and dramatically improved in the last decade with access to hsct and tailored conditioning regimens. conclusion: we propose that rag1 p.k86vfs*33 is a founder variant originating from the vistula watershed region in poland, which may explain a high proportion of homozygous cases from central and eastern poland and the presence of the variant in all slavs. our studies in cases with rag1 founder variants confirm that clinical and immunological phenotype only partially depend on the underlying genetic defect. hsct is becoming available for rag deficient patients in eastern europe with improving outcome. clinical immunologist, centre hospitalier universitaire de montrã©al (chum) background: acute gvhd following solid organ transplantation is a rare complication. intestinal and liver transplantation have the greatest risk of gvhd among solid organs due to high number of donor lymphocytes in these organs. prevalence of acute gvhd after liver transplantation is estimated to be around 0,1-2% and has a poor prognosis (1) . chronic neurological gvhd is a rare form of gvhd with three subtypes described: cerebral vasculitis, demyelinating disease and immune mediated encephalitis. acute neurological gvhd has no clear definition and is still considered a controversial entity. case presentation: a 63 year-old male underwent cadaveric liver transplantation for alcoholic cirrhosis and hepatocellular carcinoma. the donor was a 70 year-old man who died from anoxic brain injury. the receiver was induced with basiliximab and then put on prednisone, azathioprine and tacrolimus. he was readmitted 10 weeks later for myalgia, headache, fever and neutropenia. clinical state initially improved with empiric antibiotics. he then developed a skin eruption, colitis and dic. the latter was thought to be tacrolimus-induced. he was switched to cyclosporine. skin and rectosigmoid biopsies were compatible with acute gvhd. he received basiliximab and ivig and developed a refractory convulsive state. csf analysis showed elevated proteins and slight pleocytosis. cerebral mri showed non-specific white matter lesions and conventional angiography was normal. chimerism on peripheral blood was 0% but was 45% donor on csf. with the presence of chimerism on csf, evidence of cutaneous and digestive gvhd and no infectious cause, neurological gvhd was considered the most likely diagnosis. brain biopsy showed non specific change including neuropil spongiosis, microglial activation and reactive gliosis; but no signs of vasculitis or demyelinating disease. he was treated with atg, highdose systemic corticosteroids, cyclosporine, ivig and intrathecal methotrexate and corticosteroids. csf pleocytosis, proteins and chimerism improved with treatment (45% to 2% donor). no improvement was noted regarding his neurological state and he developed pancytopenia. he was then transfer to palliative care and died shortly after (4 month and a half after liver transplant). discussion: to our knowledge, there is only one prior case published of neurological gvhd following liver transplantation (2) . both patients were old, had hepatocellular carcinoma and had at least one hla match. age >50 year, hepatocellular carcinoma and shared hla antigen are known risk factors for gvhd following liver transplantation (1). our patient had only one hla match with the donor. this case is intriguing as there was a great discrepancy between blood and csf chimerism. acute neurological gvhd following transplantation is a real complication. it must be taken into consideration in patients with neurological involvement after transplant, even solid organ transplantations. introduction: hyper-igm syndrome are rare. although no data are available on the frequency of activation-induced cytidine deaminase (aid) deficiency, this disorder is estimated to affect less than 1:1,000,000 individuals. by the year 2012, 110 cases worldwide (1) with such mutation have been described. we describe a patient with hyper igm by mutation in the aicda gene. case report: mvv, 5-year-old boy, born to consanguineous parents, was referred with recurrent pneumonia, which started shortly after discontinuation of breastfeeding at 6 months old. repetitive otitis evolved with bilateral tympanic and partial hearing loss. he was submitted to adenoidectomy without improvement. immunological evaluation showed normal numbers of b and t cells with cd3+ (1290/mm3, 65%), cd4+ (547/mm3, 28%), and cd8+ (259/mm3, 13%). immunoglobulin concentrations were: igg = 138mg/dl (p97). treatment with intravenous immunoglobulin and prophylactic antibiotic was initiated and he had no infections during the follow up except for one episode of sinusitis. at 10 years of age, molecular evaluation was performed and a mutation in homozygosity in the aicda gene (omim * 605257) at position chr12: 8.757.821 was found, confirming the clinical suspicion. conclusion: the role of aid in the immunoglobulin class-switch recombination (csr) and somatic hypermutation (shm) have not been fully elucidated. summarizing within the shm and csr processes, aicda mutation can induce dna lesions in directed sequences in the s and v regions required for dna cleavage. recurrent infections and consanguinity raised the suspicion of inborn errors of immunity in this patient. the literature described late diagnosis as in the second or even the third decade of life. it was suggested that high levels of igm antibodies may provide effective defense, at least, against some infectious agents. it is important to emphasize that the impossibility to obtain genetic diagnosis did not prevent to introduce therapy. * aicda: activation induced cytidine deaminase gene patients with chronic granulomatous disease (cgd) are at risk for recurring infections and non-infectious inflammation, reduced quality of life and life expectancy. conventional treatment with life-long anti-bacterial and antifungal prophylaxis prolongs lifespan but does not eliminate the lifelong risk of infection and inflammation. allogenic stem cell transplantation is currently the only curative option for this disease. although sct with reduced intensity conditioning has improved treatment-related mortality and efficacy, it remains a matter of debate whether all patients with cgd benefit from sct, whether pre-existing infections and non-infectious inflammation are risk factors and at what age sct should be performed. we compared patients with cgd on conventional treatment with those after stem cell transplantation for their prognosis and evaluated potential risk factors for stem cell transplantation outcome followed up in six european centers. frequency of infections, inflammatory complications, hospitalizations, operations and immunomodulative/immunosuppressive therapy, height and weight were compared in patients on conventional treatment /before stem cell transplantation versus patients after sct. correlation between transplantation outcome and patient characteristics or medical history was tested. 105 patients were recruited, 55 on ct, 50 after stem cell transplantation. before/without transplantation 98% of patients suffered from at least one infection, 84,8% from inflammatory complications. patients on conventional treatment developed infection/inflammation/ hospitalization/surgery at a median of 2,28 (range [0,29-21,82] , iqr 2,79) per year, versus 9 (range , iqr 8,5) in the first year after stem cell transplantation but 0 (range [0-15], iqr 0,53) after the first year post stem cell transplantation. there was a significant decrease of all complications after stem cell transplantation (p < .05). growth improved significantly after stem cell transplantation (z-score weight -1,692 versus -0,846 (p.017), z-score height -1,906 versus -1,064 (p.029)). nevertheless, complications post stem cell transplantation are frequent: 88% of patients had at least one infection, 8% had severe acute gvhd, 12% chronic gvhd, 16% had graft rejection, 12% died. preexisting active mold infection increased the risk for complications after stem cell transplantation. in summary infections and non-infectious inflammation are common in patients with cgd on conventional treatment, their growth is significantly impaired. stem cell transplantation, if successful, significantly reduces the risk for infections and non-infectious inflammation. however, treatment related mortality of stem cell transplantation in patients with cgd remains considerable. introduction: development of a diverse t cell repertoire is essential for full immune recovery following definitive treatment for severe combined immunodeficiency (scid), whether by allogeneic hematopoietic cell transplantation (hct); autologous gene therapy (gt); or, in the case of adenosine deaminase deficiency, enzyme replacement therapy (ert). however, the time course and depth of diversity of t cell receptor rearrangements have been difficult to measure directly, necessitating estimates from total and naã¯ve t cell counts and from spectratyping, in which t cell receptor (tcr) beta chain diversity is estimated by the length distributions of cdna amplicons between a series of tcr beta chain variable (v-beta) segments that have productively recombined with the tcr beta-chain constant region. analysis of the actual sequences of rearranged tcrs could indicate more precisely the status of the t cell compartment of these patients, and might reveal oligoclonal expansion of dysregulated t cells, t cell insufficiency, or t cell exhaustion. objectives: we wished to ascertain whether deep sequencing of individual tcr v-beta rearrangements in peripheral blood could be performed sequentially following diagnosis and treatment of scid to differentiate satisfactory immune reconstitution from incomplete or skewed repertoire development that might require further cellular therapies. methods: equal amounts of total rna were obtained from peripheral blood of controls and scid patients pre-hct and at 100 d, 6 and 12 mo, and yearly post-treatment(s). cdna was used as template to semi-quantitatively amplify rearrangements at the tcr-beta locus (trb). raw sequences were filtered to remove pcr errors, and resulting fastq files were converted into fasta format (seqtk software, github, inc), filtered for productive rearrangement, and analyzed for v, d, and j gene composition and length (imgt highv-quest software). the vdj statistics file (past program) was used to calculate a shannon entropy (h) index to measure repertoire diversity, taking into account both abundance and richness of the overall repertoire; and a gini-simpson index of unevenness, measuring inequality in the relative representation of species in a given sample. graphical representations of repertoire diversity were generated by hierarchical tree maps of the trb repertoires (irepertoire software): each dot represents a unique sequence and the dot size corresponds to frequency of that sequence in the total sample. results: tcr v-beta sequence analysis of 3 scid patients (image) showed (top) baseline poor diversity due to pre-treatment ada deficiency followed by improvement to normal complexity (shannon h >7.0) after receiving peg-ada and autologous lentivirus gene therapy at age 3 m; (middle) increasing diversity in xscid after maternal t-depleted unconditioned hct, although b cells did not recover; and (bottom) failure of initial unconditioned maternal t-depleted hct in another xscid patient at 12 m, followed by autologous lentivirus gene therapy with subsequent improvement (shannon h increasing from 3.8 to 6) 12 months later. conclusions: tcr v-beta diversity sequence analysis provided a detailed assessment of repertoire diversity in response to cellular therapies for scid. this method could become a useful predictive tool to measure successful t cell immune reconstitution, both as early as 100 d and in the years following treatment. background: the stim1 (stromal interaction molecule 1) protein, encoded by the stim1 gene, is involved in calcium regulation in the endoplasmic and sarcoplasmic reticulum. pathogenic variants in this gene are associated with three different disorders. homozygous loss-of-function (lof) pathogenic variants in stim1 have been reported to cause autoimmune cytopenias, lymphoproliferation, enamel defects, anhydrosis, and iris hypoplasia. the first described cases had frequent mortality in early childhood due to recurrent life-threatening infections and development of kaposi sarcoma (1), while recently discovered cases have had more prolonged survival, though still with recurrent serious infections (2) . heterozygous gain-of-function (gof) pathogenic variants in stim1 have been associated with both tubular aggregate myopathy (tam) and stormorken syndrome. tam is a clinically heterogeneous progressive muscle disorder with a variable age of onset. muscle biopsy characteristically demonstrates tubular aggregates, with type ii muscle fiber atrophy (3) . stormorken syndrome has a phenotype that includes miosis, thrombocytopenia, intellectual disability, mild hypocalcemia, muscle fatigue, asplenia, and ichthyosis (4) . the thrombocytopenia has not been reported to be immune-mediated; rather it is due to abnormal platelet calcium regulation (5). we report a patient with stim1 pathogenic variant presenting with tam and immune-mediated thrombocytopenia, along with lymphoproliferative features, arthritis, and a mild immune deficiency. case: the patient is a 16-year-old with a history of congenital thrombocytopenia (platelets ranging 60,000-100,000) who presented with acute arthritis of bilateral hand joints after exposure to cold temperatures, which resolved with naproxen. he had back pain without muscle weakness, and preceding sore throat and general fatigue. labs were significant for leukocytosis and elevations in his inflammatory markers and creatine kinase. mri of his lower extremities was negative for inflammatory myositis, but did demonstrate bilateral hip and knee effusions, and significant inguinal lymphadenopathy and hyperintense linear signal changes in the mid-and distal femurs with patchy red marrow signal. abdominal ultrasound could not identify a definite spleen. bone marrow biopsy was negative for malignancy but significant for toxic granulation of neutrophils, evident of inflammation. alpha-beta double negative t cells were not elevated. interferon-gamma was mildly elevated. flow cytometry demonstrated normal t, b, and nk cell absolute counts. circulating antibodies against platelets (both igg and iga) were detected. on lymphocyte antigen and mitogen proliferation testing, he did not exhibit any proliferation when stimulated with tetanus toxoid even though he had been fully vaccinated against tetanus. muscle biopsy demonstrated large vacuoles consistent with tam on both light and electron microscopies. invitaes primary immunodeficiency panel identified a pathogenic variant in stim1 (c.910c>t; p.arg304trp), consistent with a diagnosis of autosomal dominant stim1-related conditions, including stormorken syndrome (6) . conclusion: this patient expands the phenotypic spectrum of stim1 related disease. based on previous evidence, gof pathogenic variants in stim1 are associated with tam and stormorken syndrome, while lof pathogenic variants in stim1 are associated with immune deficiency. however, our patient with a stim1 gof pathogenic variant has features of lymphoproliferation and immune dysregulation in addition to tam. stim1 gof pathogenic variants should be considered in the differential of patients with immune thrombocytopenia and lymphoproliferation. references: introduction / background: card11 is critical for protein binding upstream of nf-kb (nuclear factor kappa b) and mtorc1 (mammalian target of rapamycin complex 1) the signaling pathway involved in t-cell activation and inflammatory response. prior testing of card11 mutations demonstrated variable t-cell dysfunction. in vitro studies have demonstrated reduced interferon gamma cytokine production, interference of t-cell receptor (tcr) signaling, and th2 phenotype skew in t-cells with card11 defects. while homozygous mutation causes severe combined immunodeficiency deficiency, heterozygous card11 defect is associated with atopy by way of inappropriate th2 skewing. heterozygote atopy is characterized by eosinophilia, elevated ige, and severe dermatitis. despite multiple studies demonstrating in vivo consequences of card11 on t-cell function, little is known of the clinical significance. moreover, few studies have demonstrated the impact of card11 mutations on b-cell maturation and development, despite the recognized tcr and interleukin 2 signaling deficits. objectives: this case demonstrates a card11 defect that evolved from atopy to combined immunodeficiency requiring intravenous immunoglobulin therapy. it highlights the poorly understood effect of card11 mutation on t-cell function, and the downstream impact on b-cell quality. methods: 53-year-old male, with past medical history of t-cell lymphoma and no evidence of disease status post autologous stem cell transplant, was found to have card11 e57d missense mutation by genetic testing. consistent with previous literature regarding heterozygous card11 defects, the patient suffered from frequent asthma exacerbations, aeroallergen sensitivity, and eczema. lab work was consistently positive for elevated ige and eosinophilia. family history was positive for a son born with congenital molluscum, and multiple other children with recurrent infections. one child was also identified with card11 mutation. the patient had flow cytometry demonstrating 4% of circulating cells with atypical immunophenotyped cd3+ t-cells, and positive gene rearrangement studies. his qualitative immunoglobulin levels were significant for consistently low igm, but normal quantity igg. in the patients adulthood, he had recurrent bronchitis and pneumonia requiring hospitalization and intravenous antibiotics. given his recurrent infections, the patient underwent immunodeficiency evaluation. despite previous infection with herpes zoster, the patient did not have protective titers. additionally, the patient had received the pneumococcal conjugate vaccine once, and the pneumococcal polysaccharide vaccine four times. the most recent vaccination was one year prior to evaluation. despite repeated vaccinations, titers were unprotective. consequently, the patient was diagnosed with combined immunodeficiency, and initiated on intravenous immunoglobulin therapy. results: in summary, card11 defect is a cause of atopy, observed to become less severe with age. studies of card11 heterozygote mutations have demonstrated in vitro deficiencies in t-cell activation, likely secondary to skewed or decreased inflammatory cytokine production and tcr activation. our patient demonstrates that the variable t-cell dysfunction seen in vitro can have significant clinical implications evidenced by his inadequate vaccine response, and recurrent infections. his combined immunodeficiency poses a connection between card11 defects and, not only t-cell, but also b-cell function. conclusions: further studies are needed to determine deficits in t-cell and b-cell function in the setting of card11 defect, as this case suggests the clinical implications span further than atopy. genetic variants in the scaffold gene card11 cause disorders of the immune system. the clinical course and treatment depends on whether the card11 variant causes gain-or loss-of-function. however, lymphocyte immunophenotyping and proliferation assays in cells expressing card11 variants don't easily distinguish between gain-and loss-of-function. to address this challenge in variant interpretation, we used multiplexed genome editing in a lymphoma b cell line (tmd8) to generate cell populations expressing all possible singlenucleotide variants in the n-terminal 140 amino acids of card11. to assess function in each variant, we tracked its relative abundance over multiple conditions using dna sequencing. since card11 is required for survival of tmd8 lymphoma b-cells, cells expressing clinically identified gain-of-function variants grew faster relative to cells expressing other variants, even in the presence of upstream pathway inhibitors. upon evaluation of the relative abundance of each variant in genomic dna and mrna, we found that clinically identified loss-of-function variants were depleted in mrna, which could be attributed to alterations in splicing or to nonsensemediated decay. to address the impact of splicing, we modeled a newly-identified splice donor mutation (c.358+1g>a) found in two patients from one family diagnosed with combined immune deficiency, autoimmunity and atopy that was also observed in our screen. we show that the variant causes deletion of exon four and that card11 missing exon four exerts a dominant-negative effect leading to decreased nf-kb signaling and cell growth. these experiments demonstrate the utility of multiplexed functional assays for determining variant effect in clinically-relevant genes, which will improve diagnosis and treatment in patients. mutations in the rag1 and rag2 genes in humans cause a wide spectrum of phenotypes, ranging from severe combined immunodeficiency (scid) with lack of t and b cells to omenn syndrome (os), atypical scid (as) and combined immunodeficiency with granulomas and/or autoimmunity (cid-g/ai). here, we sought to investigate the molecular basis for phenotypic diversity presented in patients with various rag1 mutations. methods: we have recently described a novel flow-cytometrybased assay in which mouse rag1-/-pro-b cells containing an inverted gfp cassette flanked by recombination signal sequences (rss) are transduced with a retroviral vector expressing either wild-type or mutant human rag1 (hrag1). the green fluorescent protein expression directly relates to the activity of rag proteins, representing a quick and powerful tool to correlate between defective activity of hrag1 mutant and severity of the clinical phenotype. the genetic variants of hrag1 analyzed in this study were affecting the various domains of the protein: ring, zinc finger ring type domain (amino acids 168-283); nbr (amino acids 387-461); hbr (amino acids 531-763) and the core domain (amino acids 385-1011). using this sensitive assay, we tested the recombination activity of 27 human rag1 variants that have been reported in patients. results: we have demonstrated correlation between the recombination activity of the mutants and the in vivo clinical phenotype of patients. in particular, similarly low levels of recombination activity were observed in patients with scid and os, whereas patients with as and especially those with cid-g/ai carried mutations that retained significant residual levels of activity. conclusions: these data provide a framework to better understand the phenotypic heterogeneity of rag deficiency. here we report a case of a child with b. cepacia lymphadenitis, ultimately diagnosed with takayasu arteritis. takayasu arteritis is a large vessel vasculitis which may have a nonspecific clinical presentation in childhood possibly leading to difficulty in diagnosis. case: a 16-month-old female presented with two weeks of fever, respiratory distress, and lymphadenopathy, and was treated with ivig for presumed atypical kawasaki disease. imaging studies performed due to worsening respiratory distress revealed retropharyngeal abscess with bilateral cervical lymphadenopathy, culture-positive for prevotella oralis and melaninogenica, with improvement following incision and drainage and antibiotic therapy. recurrence of fever and respiratory distress prompted ct imaging of her neck significant for worsening lymphadenopathy. cultures from lymph node biopsy grew b. cepacia. following treatment, she was readmitted with respiratory distress requiring chronic steroid treatment and found to have candida albicans on bronchoalveloar lavage and necrotizing granulomatous inflammation on lung biopsy. an immunologic evaluation was notable for two normal dhr assays. cgd genetic panel was negative for pathogenic variants in cybb (p91), ncf1 (p47), cyba (p22), ncf2 (p67). testing was also notably negative for hiv pcr, bartonella pcr, cryptococcal antigen, histoplasma antigen, bal afb stain and mycobacterial cultures, cmv pcr, ebv pcr, anca, serial blood cultures, and sweat test. lymphocyte subsets were normal for age. mitogen stimulation test, myeloperoxidase antibody igg, serine protease3 igg, c4 level, lad panel, and cytokine panel were normal. autoimmune lymphoproliferative disorders (alps) panel was negative. whole exome sequencing demonstrated heterozygous mutations in cfi and jak3, not considered to be clinically relevant given the patients clinical picture and laboratory evaluation. the patient was then lost to follow-up for over a year. at the age of 3 years, the patient presented with fever and back pain. imaging revealed severe large vessel vasculitis involving the aorta and subclavian, vertebral, mesenteric, and renal arteries. she also had evidence of cardio-embolic strokes on brain mri. she had had no significant interval infections, and her immunologic evaluation remained unrevealing. in the context of her new vasculitis, evaluation for deficiency of ada2 (dada2) was negative. she was ultimately diagnosed with takayasu arteritis and has begun therapy with systemic corticosteroids, aspirin, and etanercept. conclusions: we describe a case of b. cepacia infection in a child without identified immunodeficiency, ultimately diagnosed with a large vessel vasculitis. the presence of b. cepacia infection warrants a thorough investigation. burkholderia has been previously associated with giant cell arteritis, another type of large vessel vasculitis, though causation has not been established. to our knowledge b. cepacia infection has not been associated with takayasu arteritis. christopher santaralas, valentine jadoul, jacqueline squire, john cannon, jessica trotter, susan aja, neil goldenberg, david graham, jennifer leiding background: chronic granulomatous disease (cgd) is a primary phagocytic immunodeficiency secondary to mutations in any of the components of nadph oxidase. in addition to infection susceptibility, patients with cgd can develop auto-inflammatory disease that is difficult to manage. metabolomics is the systematic study of small molecule biomarkers of the clinical phenotype of disease. we sought to investigate plasma metabolic profiles in cgd as we hypothesized that unique signatures may differentiate patients with cgd. methods: plasma collected from 15 subjects with cgd (9 x-linked, 4 p47phox-deficient, 2 p22phox-deficient) and 2 x-linked cgd carriers was analyzed using a targeted multiplex assay by liquid chromatography mass spectrometry (lc-ms) and simultaneously a profiling assay by lcms. sufficient signal was present for 34 metabolites. x-linked cgd and p47phox-deficient groups were sufficiently sized for multivariate and univariate analyses in metaboanalyst. twelve patients had a single time point of plasma metabolomics analysis and three had multiple time points, including one in whom both pre-and post-hematopoetic cell transplantation time points were assessed. post-hoc comparisons were also performed for those with, versus without, clinical comorbidities of autoinflammation. results: plasma from patients with x-linked and p47phox deficient cgd had a differential metabolomic signature at baseline. many metabolites as measured by ion intensity were present at high levels, particularly homocysteine, kyneurine, tryptophan, citric acid, carnitine, methionine, and adenosine. increased values of metabolites reduced to that of normal (compared to post hct). homocysteine levels were elevated among patients with (mean 1.5x105), versus without (mean 6.8x104), clinical comorbidities of auto-inflammation (i.e., colitis, lupus). baseline samples showed elevated kynurenine among all cgd patients, relative to historical normal controls (unmatched, separate analysis). patients with colitis had elevated citric acid levels that were higher among patients with (mean 2.1x106), versus without (mean 4.5x105), colitis irrespective of genotype. conclusions: preliminary data with a small patient subset suggest that patients with cgd have metabolomic signature distinguishable by phenotype. citric acid cycle metabolites are elevated in crohns disease and ulcerative colitis. based on our data, citric acid may too act as a biomarker for inflammatory bowel disease in cgd. analyzing a larger number of samples, across time points, will likely describe a metabolomics profile for cgd and identify biomarkers for auto-inflammation in cgd. no significant medical history in mother; paternal history is unknown and unavailable.no significant medical history in mother or father. rationale: ataxia telangiectasia is a disorder with variable phenotypes characterized by cerebellar degeneration, immunodeficiency, chromosomal instability, radiosensitivity, and cancer predisposition which may correspond to the degree of atm protein expression and/or radiosensitivity. we used in vitro cytometric assessment of atm, smc1 and h2ax phosphorylation to assess dna damage in response to radiation and found that two siblings with the same copy number gain in atm have variable clinical neurologic and immunologic phenotypes. methods: chart review and radiosensitivity assays using cytometric assessment of patm, psmc1, and h2ax expression after irradiation with 2gy. results: patient a is a 6 month old male identified after having low trecs on newborn screening, then found to have lymphopenia and elevated igm. he has diffuse cafã© au lait macules and no neurologic symptoms. his 9 year old sister, patient b, was being followed by neurology for several years for ataxia. she has selective iga deficiency, normal lymphocyte counts, lymphocyte proliferative responses, gammaglobulins, and vaccine specific antibodies. both patients have a 4 copy number gains in atm (exons 48-61). mother and father both have 3 copy number gains in atm and are healthy without neurologic symptoms or recurrent infections. both patient a and b have normal atm protein expression. phosphorylated atm, smc1, and h2ax was assessed in lymphocyte subsets (t, b, and nk cells) after low-dose irradiation to induce dna double-stranded breaks (dsbs). these parameters were assessed at 1 hour post-irradiation when they are expected to be maximal and at 24 hour post-irradiation, when under conditions of normal and effective dna repair, the phosphorylation state returns to baseline. patient a had abnormal patm and psmc1 but normal h2ax expression 1 hour and 24 hours after irradiation of t, b, and nk cells. patient b had normal patm, psmc1, and h2ax expression in t cells but abnormal patm and psmc1 expression in b and nk cells 1 hour after irradiation. patient b, however, had abnormal atm phosphorylation at 24 hours after irradiation of t, b, and nk cells.conclusions: our results indicate that a unique copy number gain in atm within a family can correspond to different clinical and immunologic phenotypes as well as variable degree of radiosensitivity. the persistence of h2ax at 24 hours post-irradiation and impaired phosphorylation of atm and smc1 at 1 hour post-irradiation demonstrates defects in dna dsb repair, and this is variably altered in different lymphocyte subsets. correlation between atm phosphorylation in lymphocytes with outcomes may be an area for future studies and particularly important in counseling patients regarding outcomes. antibodies have been implicated in both protection and pathology of dengue virus infections. however, much of this data is gathered from serum/plasma responses that is a cumulative of historical and ongoing infection. to precisely understand the role of antibodies with respect to the ongoing dengue virus infection, we employed the cutting edge approach of generating of human monoclonal antibodies from individual plasmablasts from peripheral blood of dengue patients that allows us to probe for answers at a single cell level. this method involves ex vivo single cell sorting of plasmablasts from peripheral blood of well-characterized dengue infected patient followed by single cell molecular cloning of immunoglobulin heavy-and light-variable regions into expression vectors containing the defined constant region followed by transient cotransfection of hek 293a cells with the heavy and light chain expression vectors made from genes arising from the same cell. thus far, using this powerful technology, for the first time in india, we have made 140 number of human monoclonals, of which 80 are specific to dengue and 14 neutralize dengue virus at various concentrations. all the neutralizing antibodies are dengue-envelope specific and bind the highly conserved fusion loop of the dengue virus envelope. together, with the ongoing comprehensive analysis of the b cell repertoire and somatic hypermutations, these studies provide a detailed understanding of the dengue-specific plasmablast cell response at a single cell level and create a platform for testing these antibodies for basic research, diagnostic, prophylatic and as well as therapeutic applications. surviving. six of the 13 (46.2%) surviving patients remain dependent on ig replacement despite robust donor chimerism of 99-100% and no active gvhd. all but two received rituximab pre-hsct. of the patients who are independent of ig replacement, only one (14.2%) received rituximab post-hsct, whereas 5/6 of the ig dependent patients received rituximab post-hsct. t cell immune profiling revealed that the absolute numbers of lymphocyte subsets, cd4+ naã¯ve t cells, and cd4+ recent thymic emigrants were not statistically different between ig independent and dependent patients ( figure 1 ). however, there was a marked decrease in the number of total b cells, the percentage of memory b cells (cd27+ b cells), and classswitched memory b cells (cd27+ igd-igm-cells) in ig dependent patients ( figure 1 ). t follicular helper (tfh) cell populations (cd4+cd45ra-cxcr5+pd1+) were evaluated in four patients and the frequency was similar to healthy controls (4.5+/-1.2 vs. 3.9+/-1.4%). the ability of the patients naã¯ve b cells to class-switch was assessed following exposure to il-21, anti-cd40 antibody, and anti-human igm, and revealed normal b cell class-switching and differentiation to plasmablasts ( figure 1) . additionally, t cell ability to provide b cell help was assessed by coincubating naã¯ve b cells with activated cd4+ t cells. this revealed comparable b cell class switching to that of healthy controls. conclusion: the high incidence of poor long-term functional b cell reconstitution following allogeneic hsct for xlp-1 could be related to the use of rituximab in the post-hsct setting rather than pre-hsct. normal tfh numbers and function, and ability of b-cells to class-switch in-vitro suggest that persistent hypogammaglobulinemia is these patients is unlikely from a b or t-cell intrinsic defect. the possibility of rituximab induced acquired lymph nodal stromal defect in these patients is being explored. further studies are needed to understand the biology of persistent hypogammaglobulinemia in xlp-1. additionally, due to the high incidence of persistent hypogammaglobulinemia, exposure of rituximab should be limited post-hsct. background: tandem mass spectrometry (ms/ms) has emerged as a primary platform for many clinical and newborn screening laboratories. the application of ms/ms mainly focuses on the quantification of accumulated small metabolites in plasma resulting from various metabolic defects. however, many disorders do not yield such metabolic markers and would benefit from the direct quantification of intracellular target proteins. unfortunately, the extremely low (e.g., pmol/l range) protein concentrations in blood cells limit their detection via ms/ms. in recent years, peptide immunoaffinity enrichment coupled to selected reaction monitoring (immuno-srm) has emerged as a promising technique for the quantification of low abundance proteins in complex matrices, including dried blood spots (dbs). our lab has demonstrated that immuno-srm methods are able to reliably distinguish affected patients from the normal controls for wilson disease (wd), wiskott-aldrich syndrome (was), severe combined immunodeficiency (scid), and x-linked agammaglobulinemia (xla) (j. proteome res., 2017 and front. immunol., in press). these results demonstrate the utilization of immuno-srm as a sensitive platform for multiplexed quantification of signature peptides in the low pmol/l range. methods: several candidate peptides for each protein were selected based on uniqueness using in silico blast tools and lc-ms/ms response. monoclonal antibodies (mabs) were then generated for peptide enrichment from dbs. blood from normal controls, wd, xla, scid, and was patients was spotted onto filter paper, dried, and stored at -20â°c until use. proteins were extracted from dbs, digested with trypsin, and enriched using mabs bound to magnetic beads. the enriched peptides were then eluted and analyzed using srm mode with a waters xevo tq-xs. results/conclusions: to date, immuno-srm methods have been generated for wd, was, scid, xla, and cystinosis. preliminary data shows immuno-srm methods are able to reliably quantify target proteins using signature peptides and accurately distinguish affected patients from normal controls. analysis of signature peptides found statistically significant reduction or absence of peptide levels in affected patients compared to control groups in each case (was and btk: p = 0.0001, scid: p = 0.05). intra and inter-assay precision ranged from 11 -22% and 11 -43%, respectively, and the multiplexed assay showed a broad linear range (1.39 2000 fmol peptide) . in a blinded sample set of 42 pidd patients and 40 normal controls, immuno-srm-predicted diagnoses showed excellent agreement with clinical or genetic diagnoses. every molecularly-confirmed case of was and btk was also diagnosed by immuno-srm analysis. in addition, 62 randomly selected samples provided by the nbs laboratory of washington state were tested and peptide concentrations were found to be within normal ranges. efforts are underway to validate and incorporate peptide biomarkers for adenosine deaminase deficiency, dock8 deficiency, and ataxia telangiectasia, as well as general markers for nk cells and platelets into a single multiplexed assay. in addition, scid, was and xla samples continue to be run while we focus on reducing assay costs, time, and necessary sample input. our data herein provides proof of concept for the immuno-srm workflow to be extended to various other genetic diseases as potential multiplexed newborn screening methods.(250) submission id#617782the background: the long-term effects of glucocorticoids (gcs) on the immune system have been extensively studied in patients with different underlying conditions (e.g, malignancies or autoimmune conditions), as well as in healthy volunteers receiving short-term courses of these drugs. although these approaches provided highly relevant data, neither of them answered the unbiased/bona-fide effect of long-term gcs use on the immune system. endogenous cushing syndrome (ecs) may be caused by pituitary or ectopic acth-producing adenomas, or by tumors or hyperplasia of the adrenal cortex. patients with ecs present with different gcsdependent manifestations, including those affecting the immune system as neutrophilia and lymphopenia. when tumors are removed, most of the effects of gcs tend to progressively regress. methods: paired samples from 15 patients with ecs due to acth-producing adenomas (age range 7-16y, 8 females) were studied before (ecs-pre) and 6-12 months after tumor removal (ecs-post). extended lymphocyte phenotypes and apoptosis in different cell subsets were evaluated by flow cytometry. cytokine production (elisa) and responses, as well as their effects on cell proliferation and viability, were evaluated using cell trace violet and annexin-v staining. results: among multiple immunophenotypic changes, ecs-pre patients showed significantly reduced naã¯ve t cells and recent thymic emigrants (rte) as well as increased apoptosis in t cells when compared to themselves (ecs-post) or age matched healthy controls. moreover, significantly increased exhausted cd8 t cells were observed in ecs-pre patients. interestingly, ecs-post patients showed full cellularity recovery of t cells and rte with increased proliferation and reduced apoptosis, in addition to correction of most of the other changes evidenced. significantly lower il-21 plasma levels were also detected in ecs-pre when compared to ecspost patients. to determine the role of il-21 in an ecs-resembling condition, healthy control pbmcs were treated with gcs in-vitro and the effect of il-21 and other cytokines was tested. a significant reduction in apoptosis was observed in the il-21-treated cells that almost completely countered the pro-apoptotic effects of gcs; il-21 was also significantly more efficient than il-2, il-7, ifn-alpha and ifn-gamma in rescuing cells from apoptosis. il-21-specific upregulation of bcl2 and bcl6 expression was evidenced in these cells.publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord-011062-ukz4hnmy authors: nan title: poster date: 2020-03-11 journal: j frailty aging doi: 10.14283/jfa.2020.9 sha: doc_id: 11062 cord_uid: ukz4hnmy nan background: frail older adults are at increased risk of postoperative morbidity compared with robust counterparts. simple methods testing frailty such as grip strength have shown promising results for predicting post-operative outcome, but there is a debate regarding the most appropriate and precise frailty assessment method. objectives: we compared the predictive value of multidimensional frailty score (mfs) with grip strength or conventional risk stratification tool for predicting postoperative complications in older hip fracture patients. methods: from january 2016 to december 2018, 277 older hip fracture patients (age >= 65 years) who underwent surgery and comprehensive geriatric assessment (cga) were retrospectively included for analysis. hip-mfs was calculated based on the cga with component of sex, charlson comorbidity index, serum albumin, koval grade, cognitive function, risk of falling, mini-nutritional assessment and mid-arm circumference. grip strength was also measured before surgery. the primary outcome was a composite of postoperative complications (e.g. pneumonia, urinary tract infection, delirium, acute pulmonary thromboembolism, and unplanned intensive care unit admission). results: among 277 patients (mean age 81.7 ± 6.8 years, 73. accordingly, grip strength could be used for screening tool to identify high-risk patients who need for further comprehensive geriatric assessment among older hip fracture patients. information and data suspected of post-operative infections. the diagnostic criteria of infection dealt with grade ii or more of clavien-dindo classification. diagnosis of infectious disease was made with reference to vital sign, blood test, imaging and bacterial test results. surgical site infection (ssi) was evaluated based on the infectious control team surveillance. results: 47 elderly patients were registered with necessary data. the average age was 77.0 years, 25 males and 22 females were included. in the sarcopenia evaluation, there were 15 cases without sarcopenia and 32 cases with it. 12 cases developed some infectious complications postoperatively. the types of infectious complications (including duplication) were 11 cases of some surgical site infections including suture failures, 5 of pneumonia, 2 of urinary tract infection, 4 of pneumonia and 2 cases of sepsis in 12 patients. infectious complications occurred in 4 cases in the non-sarcopenia group and 8 in the sarcopenia group (p = 0.903). the average postoperative hospitalization was 30.2 days overall, 20.8 in the group with postoperative infectious complications, and 61.9 in the group without sarcopenia. conclusion: in this study, there was no relation in the incidence of postoperative infections and preoperative sarcopenia. however, the postoperative hospitalization in the group with postoperative infectious complications was almost tripled. background: hypertension is one of the major risk factors for cardiovascular disease. lowering blood pressure is effective for preventing stroke, heart failure (hf), myocardial infarction and possibly dementia. in france, the prevalence of elderly people treated for hypertension rising leading to a possible increase of potentially inappropriate antihypertensive prescribing (piap) that may cause adverse drug events. objectives: to identify associated factors with potentially inappropriate antihypertensive prescribing (piap) in elderly people. methods: we conduct a retrospective observational study based on a cohort from geriatric day hospital for assessment of frailty and prevention of disability in toulouse, between january 2016 and april 2018. piap was defined with several explicit criteria: the european list of potentially inappropriate medications, alert and control of iatrogenesis (aci) criteria by the french health authority, the french society of hypertension guidelines, screening tool of older people's potentially inappropriate prescriptions (stopp) version two and summary of product characteristics. the piap has been considered as a binary variable (logistic regression) then as a counting variable by number of nonconformities on antihypertensive drugs (negative binomial regression). results: among the 1115 patients, 30% had piap. frailty, polypharmacy, history of angina and hf are associated with a higher risk of piap. similarly: frailty, polypharmacy and history of angina are associated with an increase in the number of non-conformities antihypertensive drugs. analysis of subgroup of patient hf -piap indicated that 42% had aci criteria whose 82% the aci criteria "4 antihypertensive drugs or more" and 68% the aci criteria "2 diuretics or more". analysis of subgroup of patient history of angina -piap indicated that 65% had stopp criteria, focused on loop diuretics. conclusion: our work suggests that some elderly people characteristics are associated with an increase likelihood of piap. targeting these patients would be beneficial in preventing medicine-related illness. background: social frailty was reported to be associated with age, sex, income, education, marital status, and household status. however, mood status including depression and emotion was relatively less investigated. objectives: the aim of this study is to clarify the association between depression and apathy status and social frailty in community-dwelling japanese elderly. methods: a health promotion project (teng tv project) is designed to distribute health promotion programs including enhancement of nutrition and physical activity via cable tv channel for community-dwelling elders. we ran a cross-sectional analysis using baseline characteristics of all participants (n=926). demographic data, socio-economic status, comorbidities, and nutrition evaluated by mininutritional assessment-short from (mna-sf) were recorded. functional capacity was assessed by the japan science and technology agency index of competence (jst-ic). mood status including depression, and emotion was measured by geriatric depression scale (gds-15) and apathy evaluation scale (aes). social frailty was defined by household status (living alone or not), financial difficulty, social activity, and fulfilment of social needs. we defined total deficit scores of 2 or more as social frailty, 1 as social pre-frailty, and 0 as robustness. we used a linear regression model to analyze the association between mood status and social frailty after adjusting for age, sex, education, marital status, comorbidities, bmi, mna-sf, jst-ic. results: at baseline, mean age of all participants (46.9% men) was 75±5.9 years. a total of 34.3% and 22% of all participants were categorized as social prefrailty and social frailty, respectively. the mean scores of gds-15 and aes were 3.4±3.3, 14.3±6.7, respectively. in linear regression model after full adjustment, participants with social pre-frailty and social frailty were associated with increased gds-15 scores (social pre-frailty vs. social robustness: b=0.58, 95%ci 0.01-1.15; social frailty vs. social robustness: b=2.49, 95%ci 1.68-3.29) and aes scores (social pre-frailty vs. social robustness: b=0.04, 95%ci -0.67-1.47; social frailty vs. social robustness: b=1.63, 95%ci 0.22-3.03). in addition, jst-ic was also associated with gds-15 and aes scores. conclusion: social pre-frailty and social frailty were associated with greater level of depression and apathy. future studies are warranted to determine the causal relationship among mood status and social participation. inthira roopsawang 1,2 , hilaire thompson 2 , oleg zaslavsky 2 , basia belza 2 ((1) ramathibodi school of nursing, faculty of medicine ramathibodi hospital, mahidol university, bkk, thailand; (2) biobehavioral nursing and health informatics, school of nursing, university of washington, seatlle, usa) background: frailty is a common geriatric condition with an impact on surgical outcomes. no research has been published on frailty assessment in hospitalized orthopedic patients in thailand. having a valid frailty measure has the potential to improve screening and could enhance quality of care. objectives: to test the ability of the reported edmonton frailty scale-thai version (refs-thai) in predicting hospital outcomes compared with preoperative assessment measures, the american society of anesthesiologists physical status classification (asa) and the elixhauser comorbidity measure (emc) in older thai orthopedic patients. methods: a prospective study was conducted at a university hospital. the hospitalized patients aged 60 years or older scheduled for elective orthopedic surgery were recruited in this study. multiple firth logistic regression modeled the effect of frailty on postoperative complications, postoperative delirium (pod), and discharge disposition, while length of stay (los) was examined by poisson regression. the area under the receiver operating characteristic curve (auc) and mean squared errors (mse) were used to compare predictive ability of the instruments. results: two hundred participants with mean age of 72 (range 60-94 years) were mostly female , 23% were frail, and 58% underwent knee surgery; of which 26.5% had postoperative complications, 12.5 % developed pod, and 11% were unable to be discharged home. average los was 6 days. adjusting for other variables, frailty was significantly associated with postoperative complications (or = 2.38, p = 0.049), pod (or = 3.52, p = 0.034), and prolonged los (relative risk [rr] = 1.42, p = 0.043). applying the refs-thai alone shows good performance in predicting postoperative complications (auc = 0.81, 95% ci = 0.74-0.88) and pod (auc = 0.81, 95% ci = 0.72-0.90). the combination of refs-thai with asa and emc demonstrates improvement in predicting postoperative complications (auc = 0.81, 95% ci = 0.75-0.88 and 0.82 95% ci = 0.75-0.88, respectively) and pod (auc = 0.80, 95% ci = 0.71-0.89 and 0.81 95% ci = 0.72-0.90, respectively). conclusion: frailty assessment using the refs-thai was useful in predicting adverse outcomes in older adults undergoing orthopedic surgery. integrating the refs-thai for preoperative assessment may be useful for enhancing orthopedic care quality. anthony frioux 1 , matthieu faure 2 , margot de battista 2 , benoit roig 1 ((1) université de nîmes, france; (2) université de france) background: the attention of the scientific community to frailty has been drawn over the past several years. frailty is defined as a state of increased vulnerability that may lead to functional disability. if this state is managed soon enough it may be reversible. in parallel, the possibilities of monitoring health status through connected objects such as smartphones are increasing. similarly, it is possible to measure the activity of the inhabitants of a house collecting usage data (water and electricity consumption). our project is in the field of smart home and aging monitoring. objectives: therefore, the objective of our work is to develop an integrative model of frailty based on the contributions of existing scientific tools (fried et al., 2001 ; mitnitski, mogilner, & rockwood, 2001) and current sensors to measure a person's activity. eventually, we are aiming for the detection of the frailty trajectory early on. for example, real-time activity monitoring is used to detect a fall and alert rescue. in our case, these sensors will allow us to identify as soon as possible a dimension that would be abnormal in order to intervene and propose an appropriate intervention. methods: our tool will be able to measure the five fried's frailty criteria which are currently used in clinical practice. we compare the data from the sensors with the results of the evaluation of fried's frailty phenotype. results: we expect to obtain a correlation between our data and phenotype results. conclusion: the main contribution of our tool resides in the possibility to observe deviations from an individual's normal aging trajectory. thus, the evaluation we propose would be more ecological as it will enable us to consider the individual's habits and to have a more detailed assessment of his activity evolution. in conclusion, the holistic aspect of our work will allow the practitioners to base their intervention on a wide range of health data. l. van wagenberg, r.m. wösten-van asperen (department of paediatrics, paediatric intensive care unit. wilhelmina children's hospital, utrecht, the netherlands) background: a frail phenotype is recognized in the elderly population. frailty is associated with a higher mortality for adult intensive care (icu) patients. research in oncology suggests biological age is not the key contributor to frailty, since frailty is also found in the younger population. in paediatrics frailty is an unknown concept and as a consequence, the prevalence and meaning of being frail at young age are unknown. objectives: to assess whether a possible frail phenotype can be found in a critically ill paediatric oncological population. methods: a retrospective cohort study in a paediatric oncological icu population between january 2018 and september 2019. demographic data and need for icu resources (mechanical ventilation, inotropic support and s60 continuous renal replacement therapy (crrt)) were collected. since specific paediatric frailty scores are not available, we addressed patients as having a frail phenotype by textmining their electronic health records on the words "fatigue", "cachexia" and "diminished physical activities" before, during, and after paediatric icu admission. risk factors for a possible frail phenotype (cachexia, use of corticosteroids and lowest serum albumin levels) were collected. primary endpoint was mortality during icu treatment or course of illness. results: 479 admissions were included, of which 74 admissions had a possible frail phenotype. these admissions included 52 unique patients. 52% of patients was male and the median age was 5 years (iqr3-15). patients were predominantly treated for a haemato-oncological malignancy (52%). mortality during icu-admission was 8%, and 23% died subsequently during the course of disease after picu discharge. patients were severely ill, with a mean icu length of stay of 9.9 days (±17), 53% on ventilator support, 34% receiving vasopressor or inotropic support, and 5% on crrt. loss of muscle function or fatigue was present in 54% before icu admission and in 35% acquired atrophy or cachexia was documented during icu treatment. 67% were treated with corticosteroids during picu stay. in 28% a serum albumin ≤2 gram/dl was measured. conclusion: a possible frail phenotype is present in the oncological patient population of a paediatric icu. more research on the contributing factor of frailty on outcome of these patients is needed in the near future. john muscedere 1,2 , amanda lorbergs 1 , jayna holroyd-leduc 3 , anik giguere 4 , leah gramlich 5 , heather keller 6 , ada tang 7 , danielle bouchard 8 , donna fitzpatrick-lewis 7,9 , diana sherifali 7,9 ((1) canadian frailty network, kingston, on, canada; (2) queen's university, kingston, on, canada; (3) university of calgary, calgary, ab, canada; (4) laval university, quebec city, qc, canada; (5) background: despite research evidence related to nutritional and physical activity interventions, there is a gap in provision of evidence-based care focused on preventing and managing frailty among older adults. objectives: to systematically generate evidence-based nutrition and physical activity (pa) clinical practice guidelines to improve health and functioning in older adults with or at risk of frailty. methods: we are using the agree ii guideline development protocol to generate guidelines to improve health and functioning in older adults. for each guideline, systematic review of meta-analyses was conducted by searching three databases for english language citations published since 2001 that included adults aged 65y and older with frailty and/or pre-frailty. nutrition or pa interventions with a comparison group were considered eligible. acceptable study designs included rcts, quasi-experimental trials, and observational cohorts with a comparison group. in a face-to-face meeting with multidisciplinary content experts, healthcare professionals, and end-users we will further appraise the quality and strength of the evidence using the grade approach. this group will use this evidence to form recommendations related to nutrition and pa in this population. results: the nutrition and pa searches resulted in 3158 and 4709 citations, with 119 and 283 eligible for full-text review, respectively. the results will inform guideline recommendations. knowledge translation strategies will be developed to support guideline dissemination and implementation. conclusion: the guidelines will inform health professionals by providing evidence-based nutrition and pa interventions for adults with frailty. ( background: physical and psychosocial factors play important roles in the severity and progression of frailty. frailty screening tools include measures of the more common risk factors, including advanced age, comorbidities, poor diet, weight loss, lower socioeconomic status, and physical inactivity. however, there has been limited standardization in the us on specific frailty screening measures to include in national health surveys or frailty tools/protocols for community health settings. this makes it difficult to monitor frailty incidence/prevalence in the older adult population and to best identify and treat individuals at risk. results: we reviewed the most recent versions of 7 us national health surveys that include older adults, to identify whether frailty screening measures were included in. no national surveys had a battery of measures that would allow for frailty risk screening. most commonly, questions on weight, disability, mental health, physical functioning were included. however, physical functioning measurements such as grip strength or gait speed, measured height and weight, unintentional weight loss, dietary intake or appetite changes were not. further, we used the world health organization criteria for effective community screening programs to review published evidence of the validity, reliability, and feasibility of data-driven screening tools for frailty risk among community-dwelling older adults. of the 10 frailty screening tools reviewed, the frail scale was identified as the most promising, based on test characteristics and cost/ease of use. more community-level s61 research is recommended, particularly on predictive validity of favorable outcomes following physical activity/nutritional interventions. finally, because nutrition plays a significant role in frailty risk, we surveyed registered dietitian nutritionists who work with older adult populations (n=576) to identify their awareness/use of frailty screening protocols/tools and dietitians' potential role in frailty screening. dietitians practicing in the community recognized a potential role, but few dietitians were aware of (<6%) or using (< 4%) specific frailty screening tools. conclusion: future opportunities to better support healthy aging include: addition of frailty screening measures to national health surveys to help prioritize high-risk populations, conduct additional research to validate/recommend a common community-level screening tool, and promote engagement by dietitians and other health professionals who can establish protocols for community-based frailty screening. ming-yueh chou 1,3 , ying-hsin hsu 1 , yu-chun wang 1 , chih-kuang liang 1,3 , li-ning peng 2,4 , liang-kung chen 2,4 , yu-te lin 1 ((1) center for geriatrics and gerontology, kaohsiung veterans general hospital, kaohsiung, taiwan; (2) aging and health research center, national yang ming university, taipei, taiwan; (3) department of geriatric medicine, national yang ming university school of medicine, taipei, taiwan; (4) center for geriatrics and gerontology, taipei veterans general hospital, taipei, taiwan) background: older people with frailty are at risk of adverse outcomes, such as falls, functional decline and mortality, and multi-domain intervention program may prevent those. objectives: the purpose of this study is to evaluate the effectiveness of multi-domain intervention program among those community-dwelling frail older people in southern taiwan. methods: a 12 week multi-domain intervention program were provided for all participants, including physical activity, high protein diet education, medical knowledge education and cognitive simulation activity for 2 hours per week. comprehensive geriatric assessments were performed before and after the intervention program, including basic demographic data, risk for malnutrition (by mna-sf), mood condition (by gds-5), cognitive condition (by mmse) and frailty status according to the definition by the cardiovascular health study (chs) . results: during jan 2018 and may 2019, totally 386 participants were invited for study (75.9% female, mean age 76.0±7.1 years). among them, 31 (9.4%) were clarified as frailty status and 190 (57.4%) as prefrailty status. after the multi-domain intervention program, their mood condition (0.35±0.83 to 0.23±0.71, p<0.001) and cognitive condition (24.40±5.75 to 25.14±5.70, p<0.001) improved significantly. in addition, the walking speed (0.89±0.28 to 0.98±0.49 m/s, p<0.001) and physical activity (13.42±14.51 to 16.31±15.99 mets/week, p<0.001) improved, but not handgrip strength (p=0.850). for the frailty status, those clarified as frailty status decreased from 9.4% to 5.2% and prefrailty status from 57.4% to 41.4% (p<0.001). conclusion: our results showed that through the 12 week multi-domain intervention program, those frail older people could improve their mood condition, cognitive condition, usual gait speed and frailty status. sarah b. lieber 1 , stephen a. paget 1,2 , jessica r. berman 1,2 , medha barbhaiya 1,2 , lisa sammaritano 1,2 , kyriakos a. kirou 1,2 , john a. carrino 3 , dina sheira 1 , mangala rajan 2 , yingtong lyu 2 , lisa a. mandl 1,2 ((1) division of rheumatology, hospital for special surgery, new york, ny, usa; (2) department of medicine, weill cornell medicine, new york, ny, usa; (3) department of radiology and imaging, hospital for special surgery, new york, ny, usa) background: frailty is a clinical phenotype that increases with age, but can occur in younger patients with chronic disease. based on few studies, frailty has been found in up to 27.5% of patients with systemic lupus erythematosus (sle) and is associated with increased mortality. whether frailty is prevalent in other sle cohorts and associated with objective and subjective factors is unknown. objectives: we aimed to determine the prevalence of frailty in a prospective cohort of women with sle and whether inflammatory biomarkers, body composition, and patient-centered domains differed between frail and non-frail women. methods: adult women <70 years old who fulfilled american college of rheumatology sle criteria were recruited from one center. exclusions included pregnancy, dialysis, active malignancy, overlap autoimmune syndromes, and severe sle disease activity. frailty was measured according to fried criteria. patient-reported outcomes (pros) were measured using pro measurement information system (promis) computerized adaptive tests; lupusqol; and disability based on valued life activities. physicianreported sle disease activity and damage indices were collected. inflammatory biomarkers and sarcopenia according to dual-energy x-ray absorptiometry were assessed. differences between frail and non-frail women were evaluated using chisquare tests and kruskal-wallis tests; the association between frailty and disability was determined using logistic regression. results: 71 women enrolled from 8/2018-9/2019. despite age under 70 years old, 21% were frail. frail women had greater disease damage (p=0.01) and were more often smokers (p=0.03). high-sensitivity c-reactive protein (p=0.05) and interleukin-6 (p=0.01) were higher and sarcopenia trended toward greater prevalence (p=0.07) in frail women. significant differences in promis mobility, physical function, pain interference and behavior, and fatigue and lupusqol physical health and pain (all p<0.01) were observed between frail and non-frail women, with frail women reporting consistently worse scores. frail women were 9.5x more likely to be disabled than non-frail women, including after adjustment for age, comorbid conditions, and disease activity/damage. conclusion: the prevalence of frailty was high in this cohort of mid-aged women with sle. frail women had poorer health-related s62 quality of life than non-frail women, including substantially higher disability. if frailty is associated with worse health outcomes, it could be a potential therapeutic target. chariya sumcharoen, supreeda monkong, nuchanad sutti (ramathibodi school of nursing, faculty of medicine ramathibodi hospital, mahidol university, bangkok, thailand) background: bed bound older adults need caring of physical activities, mental, mood, and social from family caregivers. family caregivers usually gets the role strain from caregiving. there are many factors associate with the caregiver role strain but have been rarely reported in bed bound older adults at home. objectives: the study examined age, adequacy of incomes, mutuality, health status, preparedness, and social support influencing caregiver role strain from caregiving activities for bed bound older adults at home. methods: caregiver role strain concept by archbold and colleagues with literature review were used to guide this study. the sample was recruited by purposive sampling consisted of 117 caregivers aged 18 years or older, who have cared for bed bound older adults at home in thailand. data were collected by structured interview using the questionnaires including demographic data, preparedness, health perception, mutuality, social support, and caregiver role strain from the care activities. data was analyzed using descriptive statistics, pearson's product moment coefficients, and multiple regression analysis. results: the most of participants were women (78.33%), age ranging from 26 to 85 years (m= 56.23, sd=11.57) . the result showed that age, adequacy of incomes, mutuality, health status, preparedness, and social support jointly significantly explained 31.9 % of the variation in caregiver role strain from caregiving activities. the regression effects were strongest for health status (beta=-.285, p=.001), followed by preparedness (beta=-.254, p=.002), age (beta=.220, p=.008), and adequacy of incomes (beta=-.214, p=.014) respectively. conclusion: this finding suggests that healthcare providers should find strategies for promoting health status and preparedness of family caregivers for decrease caregiver role strain from caregiving activities. of life, and hospital admissions. objectives: we estimated the prevalence and describe the characteristics of the population with recurrent falls and fear of falling and their association with frailty, physical performance and cognitive fragility. methods: data came from the "salud, bienestar y envejecimiento" (sabe) colombia study, a cross-sectional study conducted in 2015 at the urban and rural research sites (244 municipalities) in colombia. sociodemographic, health, cognitive and anthropometric measures were collected from 23694 community-dwelling adults aged 60 years and older, representative form the total population. frailty was defined using the frailty phenotype proposed by fried. cognitive frailty was defined using the inaa/iagg consensus definition. low performance was evaluated with sppb (short physical performance battery). logistic regression analyses were used to identify factors associated with recurrent falls and fear of falls. results: our study identified 603 elderly who had recurrent falls and 1193 fear of falling (15.6% and 39.5% respectively). young elders (≤ 69 years) had more falls and greater probability for fear of falling compared to older ages. sex had no significant differences. the factor associated with an increased risk of recurrent falls and fear of falling in the elderly were low physical performance, fragility and polypharmacy. chronic illness such as osteoarticular disease, mental disease, diabetes and chronic pulmonary disease were significantly associated with recurrent falls and fear of falling. finally, when adjusted for age, sex, sociodemographic factors and comorbidities in a logistic regression model, frailty was associated with fear of falling and recurrent falls, while cognitive frailty and low physical performance only were associated with fear of falling. conclusion: recurrent falls have a significantly association with frailty. there are cognitive, physical performance and clinical factors associated with fear of falling that could be preventable and treatable. rubbieri gaia 1 , ceccofiglio alice 1 , mazzeo nicla 1 , pupo simone 2 , cartei alessandro 1 , rostagno carlo 1 , mossello enrico 2 ((1) department of perioperative medicine, careggi hospital and university of florence, italy; (2) department of geriatric medicine, careggi hospital and university of florence, italy) background: the prevalence of frailty in patients with hip fracture is high, but little is known about the choice of the best frailty tool in terms of prediction of functional recovery. objectives: the aim of this preliminary study was to determine the most predictive validated frailty tool in older people with hip fracture and to determine whether frailty can predict functional recovery during the hospital acute phase. methods: this study was observational prospective cohort study. participants aged 65+ admitted to hip fracture units in florence, were assessed pre surgery (t0), and post surgery. each participants underwent a comprensive geriatric assessment and frailty was defined using: clinical frailty scale (csf), frail scale (fs), reported edmonton frail scale (refs), postal frailty screening (pfs). the outcome was functional recovery, evaluated by a score of postoperative performance on the cumuleted ambulation score (cas). data recorded included pre-recovery barthel index (bi), charlson comorbidity index (caci), handgrip strenght test (hg), asa score, mini nutritional assessment short-form (mna-sf), delirium. results: sample included 114 patients (mean age 85±8 years, female 75.4 %). cfs was the most predictive frailty tool, with a 88% sensitivity and a 50% specificity (auc = 0.80, cut off >3). dividing the sample according to premorbid bi, while bi itself had the highest predictive value when premorbid level was <80%, cfs was the best predictor of functional outcome in the 80%+ subsample (auc= 0.67). conclusion: frailty defined by cfs can predict short-term functional recovery during acute phase following hip fracture. this appears particularly relevant for subjects with a higher pre-morbid functional independence. s64 52% were women. 385 individuals had data for all five frailty measures. nine percent of participants were non-frail by all instruments, 20 % were frail by all measures and thus 71 % had discordant frailty measurements. 91% were frail by at least one measure method. the prevalence of frailty ranged from 34 % to 75% for the different measures. those classified as frail by cfs and non-frail by bp were more likely to be men, be co-living, have lower cognitive function and a higher dependency in iadl compared to those classified as frail by bp and non-frail by cfs. conclusion: frailty measures cannot be used interchangeably. specifically the cfs might not identify physical frail women, with high cognitive ability who lives alone. factors contributing to the heterogeneity of groups classified as frail by different measures need to be further explored. background: polypharmacy is increasingly common amongst older, multimorbid adults. in these individuals, studies have shown a high prevalence of frailty. identification of frailty can be performed using comprehensive assessments registering accumulation of deficits like in the frailty index, or using single-trait markers of frailty like gait speed and handgrip strength. polypharmacy is recognized as an independent risk factor for the development of frailty, and the subgroup of psychotropic drugs may be particularly important in the development of this syndrome. objectives: our objectives were to study the relationship between the total burden of polypharmacy on frailty status using three different measurements of frailty, and specifically the influence of psychotropic drug use on frailty status. our overall aim was to explore whether either of these could be used as independent predictors of frailty. methods: we used data from a 2-year follow-up study of older people living in the community and receiving home care nursing, i.e. the cascade-study. data collection was completed in june 2018. all 210 participants were aged >65 years (mean 84 years). a 34 item frailty index was calculated based on results from a comprehensive geriatric assessment performed in the patients' own home. a fourmeter gait speed test was performed, as well as measurement of handgrip strength. information on regular medications was collected from the patients if they administered own medications, or from the home care nursing service if they were responsible for administering the patients' medications. psychotropic drugs were selected based on beers 2019 criteria. results: we found a significant association between the use of psychotropic drugs and frailty index, and frailty index increased by 0.03 for each psychotropic drug added (p<0.001). one additional psychotropic drug decreased gait speed by 0,03 m/s (p<0,05). there was no statistically significant association between psychotropic drug use and handgrip strength. conclusion: our study showed that psychotropic drug use was a significant predictor of increased frailty index and reduced gait speed. this was not the case for handgrip strength in our material. laetitia beernaert 1 , frédéric schuind 2 , sandra de breucker 1 ((1)department of geriatrics, hôpital erasme -université libre de bruxelles, belgium; (2) department of orthopedics, hôpital erasme -université libre de bruxelles, belgium) background: anemia is a condition whose prevalence might reach 50% in the geriatric population. anemia and frailty are two prognostic factors for patients admitted for a hip fracture. objectives: we analyzed retrospectively if preoperative frailty and anemia were independently predictive of postoperative complications and mortality in old patients admitted for hip fracture. methods: ninety-seven patients above 65 years old have been admitted for urgent surgery for a hip fracture during 2016 and 2017. we excluded patients with a pathological fracture or fractures due to high energy trauma. preoperative anemia was defined as an hemoglobin level under 12g/dl for women and 13g/dl for men. frailty was assessed with the isar (identification of seniors at risk) score. results: seventy-five percents of patients were considered as frail (isar score>2). the prevalence of preoperative anemia was 37%. we found no statistically significant correlation between anemia and frailty (r = -0.18-p = 0.071). in multiple regression logistic analysis, the only independent parameter associated with anemia was the presence of comorbidities (or 1.12 (1.04-1.20)-p = 0.02), and the only parameter associated with frailty was the presence of malnutrition (or 28.2 (2.8-28.9)-p = 0.005). neither anemia nor frailty was associated with postoperative complications and mortality. conclusion: preoperative anemia and frailty are not interrelated in patients admitted for hip fracture. anemia is associated with comorbidities, but not postoperative mortality. frailty is associated with preoperative malnutrition. the isar score may not be ideal to screen for frailty in old patients admitted for hip fracture, an item being attributed to the current loss of autonomy. settings. m martinez 2 , maria montoya 1,2 , davide angioni 1 , lizeth canchucaja 2 , natalia ronquillo 3 , maria luz gallego 2 , claudia bejar 4 , emmanuel gonzalez 2 , olga vazquez 2 , anna renom 2 ((1) institute de viellisement toulouse, france; (2) hospital del mar, barcelona, spain; (3) hospital de terrasa, barcelona, spain; (4) parc tauli, barcelona, spain) background: frailty is a common critical geriatric syndrome which has been associated with poor health outcomes.a wide variety of frailty indices (fis) have been developed. frail-vig («vig» is the spanish/catalan abbreviation for comprehensive geriatric assessment).it contains 22 simple questions that assess 25 different deficits. it has been inspired by the rapid geriatric assessment. objectives: the aim is to compare the prediction capacity of clinical rockwood index frailty (rif) and frail-vig index (vif) for poor health outcomes (pho) defined as: emergency department visits and/or hospital admission and/or mortalityamong elderly patients. methods: a retrospectiveobservational study was conducted with a followup up to 15 months or pho occurred. patients were admitted in acute geriatric unit care and geriatric day hospital at hospital del mar; barcelona; spain during august 2018 and march 2019. the inclusion criteria were the admission ones. frailty was measured at admission. survival analysis was conducted; cox proportional hazards regression was used to build a pho predictive model based on both indexes. best model according to contrast of hypothesis log-rank ,aic; bic and c harrel was selected.diagnoses of the chosen model was done. results: a total of 49 patients were included, mean age was 78 and 46.9% female. the mean of follow-up was 9.78 , 51% patients presented a pho. 24.4% died, 32% were admitted at emergency department, 26.5% were hospitalized and 22% presented more than one event.survival curves for frail and non-frail according to pho showed statistically significance for vif (x2=6.77 p=0.0093)but not for rif (x2=0.62 p=0.4315). cox proportional hazards regression showed vif hazard ratio 3.44 (p=0.0406) and rif hazard ratio 1.27 (p=0.607). predictive capability resulted in a model for vif containing cognition and sex, with harrel c of 0.735. as for rif the most parsimonious model rif would be absent and harrel c 0.503. the diagnoses of the model showed time covariate variable test with p=0.429, p=0.297, p=0.640 for each predictive variable; squared linear predictor with p=0.39 of and 2 outliners. conclusion: the vig frailty index performed better; compared to rockwood clinical index; in predicting a composite outcome composed by mortality, hospitalization and visits to emergency departments in patients admitted in acute and outpatient settings. after hospital discharge. methods: this study was conducted in the departments of internal medicine and neurology of the university hospital of araba (basque country, spain). participants were >=70 years, scoring >=20 on the mmse test and able to stand and walk independently for at least 4-meter. participants performed twice-weekly moderate intensity group sessions of multicomponent exercise at the hospital during 12-week, followed by a home-based intervention (12week) . both were focused on balance, aerobic capacity and strength. taking together both interventions, participants completed 24-week of physical exercise. at the beginning and the end of the program, frailty was measured though fried´s index1 and sarcopenia with different criteria2: muscle strength (5-chair stand), muscle quality (dxa) and physical performance (sppb). we compared the results before and after the intervention by mcnemar test. results: 55 patients (27 females, 49%) were enrolled, 26 were lost to follow-up at the 24-week time point and 29 people finished the intervention. the intervention decreased significantly the percentage of frail individuals (p<0.001) according to fried´s index, and the percentage of people who met sarcopenia criteria for sitto-stand (p=0.031) and sppb (p=0.031). however, there were no differences in the percentage of people with low appendicular muscle mass. conclusion: our study showed that a multicomponent exercise program is effective for posthospitalization patients because after 24-week intervention there were significant reductions in frailty and improving results in muscle strength and physical performance. we did not find changes related to muscle mass. references: 1. background: alcohol addiction can impact every part of the body, including bones. research shows that chronic heavy alcohol use, especially during adolescence and young adult years, can dramatically affect bone health and increase the risk of osteoporosis and bone fracture later in life. objectives: the purpose of this study is to compare data from international scientific literature with data from the study of patients admitted for alcohol dependence, to assess whether there are significant connections between alcohol dependence and unrecognized fractures. methods: we analyzed 34 meta-analysis's studies from the pubmed search engine to evaluate the association between bone fractures with alcohol use disorders. only humans studies from the last 5 years have been analyzed. subsequently, data related to patients admitted for an alcohol rehabilitation cycle were analyzed. results: scientific literature show that there is a close correlation between alcohol abuse and greater frequency of bone fractures. this is partly due to association between alcohol consumption and both osteoporotic fracture and bone density, and partly to the fact that there is an increased risk of falls in alcohol intoxicated patients compared to the general population. 1145 patients were considered: 71% male and 28.2% female. the average age was 48 years. of these 1145, 5.38%, 61 patients, had unrecognized fractures. conclusion: intoxicated patients admitted in alcoholic rehabilitation with recurrent falls anamnesis often did not perform any diagnostic assessment. this is due to the lack of pain perception in the patients or due to family members or emergency physicians who placed the state of drunkenness before any consequences caused by repeated falls. there is an increased risk of unacknowledged fracture in the patients admitted in alcohol rehabilitation this is partly due to the fact that alcohol intoxicated patients often do not perceive the pain and therefore do not investigate any falls that occurred in a state of drunkenness, in part it is due to the damages that alcohol causes on the bone. our data show that alcohol dependence and unrecognized fractures can often be associated. studies in the literature confirms that there is an increased risk of non-cone fractures in patients with alcohol dependence. zamudio-rodríguez, hélène amieva, luc letenneur, karine pérès (centre de recherche inserm u1219 université de bordeaux -isped, bordeaux, france) background: although conceptually distinct, frailty and disability are very common among older adults. both are multifactorial conditions and share some risk factors and pathophysiological mechanisms, such as inflammation or sympathetic-parasympathetic balance alteration. furthermore, each individual component of the frailty phenotype defined by the cardiovascular health study (chs) has been associated with disability in basic and instrumental activities of daily living. objectives: the present study aimed to determine whether pre-frail and frailty are part of the natural history of the disability process. methods: a sample of 894 people aged 75 of the three cities (3c) study in bordeaux were followed for four years. pre-frailty and frailty were defined according to the original phenotype proposed in the chs. disability was defined using the basic (adl) and instrumental (iadl) activity of daily living scales. seven mutually exclusive hierarchical groups were distinguished at inclusion: 1) robustness (no frailty or disability); 2) pre-frail (without disability); 3) frailty (without disability); 4) iadl (without pre or frailty or adl) 5) pre-frail with iadl (no adl); 6) frailty with iadl (no adl); 7) frailty with iadl and adl. results: 177 deaths (19.8%) occurred during the four years follow-up. compared to the robust group, all other hierarchical subgroups had an increased risk of death, with an increasing gradient: pre-frailty (hr= 1.84; ic 95 %= 1.00 -3.39); frailty (hr= 3.46; ic 95 %= 1, 53) , iadl disability (hr = 3.21; ic 95 %= 1.28 -8,05); pre-frailty with iadl disability (no adl) (hr= 4,08; ic 95%= 2,16 -7.70); frailty with iadl disability (no adl) (hr= 5,42; ic 95%= 2.84 -10.34); frailty with iadl and adl disability (hr= 10,58; ic 95%= 5.39 -20.77) were significant after adjustment by age and sex. conclusion: there is a gradual risk of mortality across the different groups ( i.e., 1) robust; 2) pre-frail; 3) frail; 4) iadl disability without pre or frailty; 5) pre-frail with iadl disability; 6) frail with iadl disability; 7) frail with iadl and adl disability) thus suggesting a hierarchical relationship. this study could have important clinical implications since pre-frailty and frailty are assumed more effectively reversible conditions in order to interrupt the continuum at the early phase of the disability processes. background: joint replacement provides significant improvement in pain, physical function, and quality of life in patients with osteoarthritis. with a growing body of evidence indicating that frailty can be treated, it is important to determine whether targeting frailty in joint replacement patients is feasible and improves post-operative outcomes. objectives: to examine the feasibility of a preoperative multi-modal frailty intervention (mmfi) compared to usual care in pre-frail/ frail older adults undergoing elective unilateral hip or knee replacements. methods: in this pilot randomized controlled trial (rct), participants who are 1)>=65 years old; 2) pre-frail (score of 1-2; (fried frailty phenotype (ffp)) or frail (score of 3-5; ffp); 3) having elective unilateral hip or knee replacement with surgery wait times between 3-10 months were recruited from the regional orthopaedic clinic mcmaster university, ontario canada. the mmfi included tailored exercise, protein (20-40 gm/day), vitamin d (1000 iu/day) supplementation, and medication review with recommendations sent to family physicians. frailty and mobility were assessed at baseline and 6-weeks post-operative using ffp, short performance physical battery (sppb) and oxford hip/knee score (ohs/ oks) respectively. results: we recruited and randomized 69 participants between september 2016 and may 2018. of those, 78.3% were referred for total hip replacement and 21.7% for knee replacement. the included participants' mean age (standard deviation (sd)) was 73.9 (7.5) years; 68.1% were women; 30.0% lived alone, body mass index was 31.9 kg/ m2 (7.2) and 44.9% were former smokers. at the baseline assessment, on the ffp, 64% were prefrail, 36% were frail and the sppb was 7.0 (2.2). for participants with hip osteoarthritis, ohs mean (sd) was 19.5 (7.3) and for participants with knee osteoarthritis, oks mean (sd) was 24.5 (7.2). the study recruitment rate was 54.8%, and the retention rate was 87%. eighty three percent of participants of the intervention group completed the intervention. self-reported adherence to the intervention components was as follow: 1) exercise sessions: 68.4%, 2) protein supplement: 87.5%, 3) vitamin d supplement: 85.7% and 4) medication review completion: 100%. conclusion: this is the first study to examine the feasibility of a multi-modal frailty intervention in pre-frail/frail older adults undergoing joint replacement. this study showed that frailty screening, assessment and management is feasible for older adults undergoing joint replacement in orthopaedic surgery clinics. results have informed the current multi-centre rct to determine effectiveness. christine tocchi 1 , sathya amarasekara 2 , michael cary 3 ((1) school of nursing, duke university durham, nc usa; (2) school of nursing, duke university durham, nc usa; (3) school of nursing, duke university durham, nc usa) background: inpatient rehabilitation facilities (irfs) provide intensive rehabilitation therapy to patients to reduce functional impairment, enhance independence and return patients to the community. determination of eligibility for irf is currently based on preadmission screening. subpopulations of older adults may require special consideration in determination of irf admission due to greater risk for poor functional recovery such as those with pre-existing functional limitations and those who are frail. frailty, a pervasive characteristic in older adults with hip fractures has not been examined as a clinical factor influencing discharge destination outcomes in irfs. objectives: 1) determine the prevalence of frailty among older adult with hip fracture receiving inpatient rehabilitation; and 2) determine the association between frailty and discharge destination among hip fracture patients receiving inpatient rehabilitation. methods: a retrospective cohort study design using cms 2014 inpatient rehabilitation facility-patient assessment instrument file. multivariate regression models were performed to examine the association between frailty and discharge destination. frailty status was measured using a frailty index of 30 items with the following cut-off points: 0 -0.20 robust/non-frail; 0.20 -0.35 pre-frail; and 0.35 or greater as frail. the final sample included 26,134 hip fracture patients. results: frailty, pre-frailty, and nonfrail were present in 0.33% (n=86), 7.6% (n=1976), and 92% (n=24071) of hip fracture patients, respectively. the majority (65%) of the frail hip fracture patients were discharged home. there were significantly greater proportion of females than males discharged home and those of white race, 65 to 74 years of age, and with higher functional status. regression analysis showed significantly lower functional status at discharge (p < .0001) for patients with these characteristics: males, non-white race, and older age. additional factors that influenced discharge destination included: marital status, living in the community prior hospitalization, and length of stay. conclusion: frailty was the most common frailty status on admission to irf. home is the most common discharge destination for all frailty status groups. frailty status could be used to identify hip fracture patients at high risk for adverse outcomes. future studies should be used to explore the potential of frailty to provide valueadded utility to clinical settings such as irfs. background: front-line care providers are seeking direction on how frailty measures may be integrated into existing or future care pathways to enhance the experience of individuals who live with it. multidimensional frailty measures such as the edmonton frail scale offer the potential for case-finding, estimation of severity, and definition of frailty components. objectives: test the feasibility of the implementation of a multidimensional frailty order set into acute care. methods: in 2016, we conducted a literature search to identify existing frailty guidelines and systematic reviews related to frailty in acute care. an expert panel graded the quality the evidence, then generated recommendations, graded by strength to inform the generation of a clinical knowledge and content management (ckcm) topic for dissemination throughout alberta health services (ahs). ahs is the largest province-wide, fullyintegrated health system in canada. this ckcm would include graded statements and recommendations, clinical decision support, electronic alerts, and a frailty order set. results: four guidelines, 60 systematic reviews, and one scoping review informed the development of the frailty ckcm. from this, we developed eight recommendations, covering topics such as prevention, case-finding, estimation of severity, definition of components, triggers for expert assessment, and linkage to care processes. the recommendations also addressed safeguards to avoid labelling and other unintended consequences. an order set employs the clinical frailty scale, electronic frailty index, and edmonton frail scale to support a clinician to develop a personalized care plan. the order set empowers front-line clinicians to administer these frailty measures, based on cut points that prompt personalized recommendations on diet, activity, fall prevention, bladder management, and infusions. depending on the frailty component of concern, clinicians are also prompted with specific options to address cognitive impairment, functional dependence, falls and immobility, social isolation, nutritional risk, polypharmacy, urinary incontinence, chronic pain, and constipation. in preparation for the conversion to a province-wide electronic medical record (emr) in november 2019, the ckcm was released in may 2018 and the frailty order set was built into the emr by september 2019. conclusion: development and implementation of a multidimensional frailty order set in the setting of acute care is feasible. masayo kojima 1 , toshihisa kojima 2 , yuko nagaya 3 , yasumoto matsui 1 ((1) national center for geriatrics and gerontology, obu, aichi, japan; (2) nagoya university, nagoya, aichi, japan; (3) nagoya city university, nagoya, aichi, japan) background: prevention programs for frailty at community usually target healthy older people. to further prolong healthy life expectancy, we need to approach those who already have got chronic diseases such as rheumatoid arthritis (ra). objectives: the aim of this study is to assess the prevalence and factors associated with frailty in japanese ra patients. methods: ra patients aged 40-79-yearold who visited two university hospitals between march and july 2019 were consecutively invited to join the study. those who agreed to participate the study provided written consent forms. frailty was assessed by the total score of the kihon checklist >=8. self-report questionnaires were used to evaluate patients' demographic characteristics, perceived degree of pain, depression (the beck depression inventory-ii) and physical function (the health assessment questionnaire, haq). rheumatologists' global assessment of disease severity, swelling and/or tender joint counts, years of ra duration, frequency of arthritis surgery and crp level were also measured. results: total of 389 ra patients were included in the study (312 women, average age: 64.5 ± 9.7 years, average disease duration: 15.8 ± 11.8 years), and the prevalence of frailty was 25.6%. the higher the age and the longer the duration of the disease, the higher percentage of ra patients with frailty was observed. 18.4% among ra patients of working age (40-64 years), were frail, whereas 28.0% and 39.3% were frail among those aged 65-74 years and >=75 years, respectively. stepwise logistic regression analysis revealed that age, haq, depression severity and trust in neighbors were independently associated with frailty in ra. no significant gender difference was observed. conclusion: frailty is common even among working age in ra patients. physical function, depression and social capital were suggested to be independently associated with frailty. on-going followup study will disclose the influence of frailty on fracture, dependency, and mortality among ra patients. background: frailty is an important modulator of ageing and might impact on clinical presentation and progression of parkinson's disease. objectives: to evaluate the prevalence of frailty and correlation with motor and non motor symptoms as well as mri atrophy and white matter hyperintensities in parkinson's disease. methods: consecutive parkinson's disease patients underwent a comprehensive motor and non motor evaluation and geriatric assessment using multidimensional prognostic index (mpi). a subset of 60 patients underwent mri with assessment of atrophy and white matter hyoperintensities by visual rating. results: 125 pd outpatients (mean age 69.5 y, mean disease duration 4.6 years) entered the study. pre-frailty assessed by mpi was presented by 20% of patients and correlated with age and disease duration. when adjusting for these ariables, mpi correlated with updrs-iii, non motor symptoms assessed by umsar, prevalence of prevalence of orthostatic hypotension, rbd and depression. the mri assessment showed a correlation between global atrophy and frailty indipendently from mmse and educational levels. no association between frailty and wm hyperintensities was found. conclusion: frailty is a possible important modulator of pathology and brain vulnerability in parkinson's disease and could explain different severity in motor and non motor symptoms. longitudinal studies are warrented to evaluate the impact of frailty in disease progression. background: accidental falls in older adults have been associated with worse health-related outcomes especially in the frailest individuals, such as nursing home (nh) residents. in this special population of older adults, falls have been related to greater morbidity and mortality, but their impact on nutritional status is still unclear. moreover, so far there are no data on the potential role of unmodifiable (e.g. cognitive impairment [ci] ) and modifiable factors (e.g. assistance from informal caregivers) in influencing the impact of falls on nutritional status in older residents. objectives: we aimed to evaluate the changes in body weight during the six months after the occurrence of a fall in nh residents, and the possible influence of severe cognitive impairment, depressive symptoms and of the assistance from informal caregivers on such variations over time. methods: the sample included 148 older residents who experienced at least one fall since nh admission. for each participant, we collected data on sociodemographic information, mean frequency of visits from informal caregivers, medical history, and cognitive and functional status at nh admission. severe ci was defined as the presence of a physician-based diagnosis of ci or a mini-mental state examination <18 points. the frequency of the visits from informal caregivers was categorized as none or 1 (low) vs >1 (high) per week. falls' date and characteristics were obtained from structured forms completed by physicians. monthly body weight in the six months before and after the fall were derived from the nh medical records based on nurses' assessments. linear mixed models were used to evaluate the body weight changes after a fall, as a function of the presence of severe ci and low visits' frequency from informal caregivers, alone or in combination. results: the mean age of our sample was 81.8±8.4 years and 72% were women. more than half (54.7%) of residents involved had severe ci and 51.7% had low visits' frequency from informal caregivers. after adjusting for potential confounders, the presence of severe ci (b=-0.4, se=0.1, p<0.001) and the report of low visits' frequency from informal caregivers (b=-0.2, se=0.1, p=0.03) were associated with steeper decline in body weight during the six months after the fall. when combining these variables, we found an additive effect of severe ci and low visits' frequency from informal caregivers in influencing weight loss (b=-0.44, se=0.13 for residents with severe ci and high visits' frequency, and b=-0.65, se=0.13 for those with severe ci and low visits' frequency; p<0.001 for all). conclusion: our results suggest that cognitive impairment may worsen the impact of falls on nutritional status in nh residents, and that this effect may be exacerbated by scarce assistance from informal caregivers. (2) tokyo women medical university, tokyo, japan, japan; (3) department of geriatic medicine, kyorin university medical hospital, tokyo, japan; (4) tokyo metropolitan institute of gerontology, tokyo, japan) background: in consideration of the future rapid aging of the society, to achieve healthy and active aging is indispensable. because especially the major issue is to prevent "multi-faceted frailty", it is necessary to reconsider regarding nutrition, physical activity and sociality/sociability in the elderly. sarcopenia is associated with adverse health outcomes, such as frailty, limited physical function, falls, disability and loss of independence. objectives: our aim to notice evidencebased new information, leading to frailty prevention, and let the community-based activity by elderly citizen only promote as a voluntary motion in each community. methods: we have already established many new evidences from our on-going japanese large-scale longitudinal study 'kashiwa study'. these evidences include the impact of overlapping of slight oral dysfunction, namely "oral frailty", as well as unbalanced diet and inadequate physical activity in early-stage sarcopenia. furthermore, we found the negative impact of several social disengagements including eating alone, so-called "social frailty", leading to subsequent sarcopenia. we developed a simple screening tool, ''frailty check-up activity'', which elderly citizen supporters only can operate in each small gathering place (e.g. community salon) via support by its local government. results: based on the concept of all-including three pillars, 1) nutrition (i.e. dietary food intake including diversity and adequate protein intake, and treatment/maintenance against oral frailty), 2) physical activity (not only exercises but also social daily activity) and 3) social participation, the newly citizen activity ''frailty check-up'' has developed. after elderly citizen supporters received training fully, they could implement this activity completely and repeatedly in each local municipality. elderly participants could learn how to improve/conquer by themselves with raising their self-awareness for the importance of early frailty/sarcopenia prevention and could change their behavior modification. in addition, using big data combined with preexisting database of new-onset regarding care needs and/or all-cause mortality, we found the new cut-off point in our frailty check-up activity. conclusion: we could confirm that our interdisciplinary "action-research" can raise the citizen's early awareness and affect their behavior modification via elderly citizen supporter system for frailty prevention, consequently leading to extend healthy life expectancy. saguez, carlos márquez, bárbara angel, mario moya, lydia lera (inta, universidad de chile, santiago, chile) background: physical phenotype of frailty has been associated with quality of life deterioration and some studies have calculated cost-effectiveness of interventions on frailty in quality-adjusted life years (qalys), however studies on the direct burden of frailty expressed in qualys lost in community dwelling older adults are scarce. objectives: to forecast qalys lost caused by frailty in older chileans and describe health profiles as determined by euroqol (eq-5d) in community-dwelling older chileans with and without frailty. methods: cross sectional study in 630 (72,4% women, mean age 72y±6.7) community dwelling people >=60years participants in alexandros cohorts. the frailty phenotype was defined as having >=3 from the 5 following criteria: weak handgrip dynamometry, unintentional weight loss, fatigue/ exhaustion, five chair-stands/slow walking speed and low physical activity. qol was evaluated trough euroqol (eq-5d) five dimensions: mobility, self-care, usual activities, pain/ discomfort and anxiety/depression and self-rated health trough eq5-visual analogue scale (eq-5d-vas). qualys were calculated by the eq5-d time trade-off (tto) method. to estimate life expectancies (le), multistate methods based on the follow-up of alexandros cohorts, were employed. results: frailty was identified in 31,7% of the sample. selfrated health according to eq-5d-vas was lower in frail than non-frail people (63.9±21.2 vs 73.6±18.0, p<0,01). after adjusted multinomial logistic regression, the eq-5d dimensions of anxiety/depression (very depressed rrr= 6.24;95%ci:2. moderate rrr=4.19; 95%ci:2, 23) and pain (much pain rrr=7.89; moderate pain rrr=2.44; had the highest association with frailty. the valorisation of years in qualys was lower in frail than in non-frail people (0.77±0.29 vs. 0.87±0.23 qalys per year, p<0,05) and among those frail, much lower in people >=80y than in the group 60-69y (0.48±0.30 vs. 0.83±0.26, p<0,05). the qualys remaining years were lower in frail people than in non-frail:total le at 60-69y was 22,5y corresponding to 18,8 qalys in frail and 20,5 qalys in the non-frail; in the group >=80y tle was 8,3y corresponding to 3,98 qalys in frail people and 6,72 in the non-frail. conclusion: the high burden of frailty on qalys, mostly related to pain and anxiety/depression makes compulsory its early detection and treatment. its knowledge allows calculating cost-effectiveness of interventions. background: + agil barcelona is a real-life a multicomponent intervention against frailty implemented in a primary care center, which promotes a comprehensive and coordinated approach between primary care, geriatrics teams and community resources, to detect and reverse frailty in the older adults. objectives: we aimed to assess the 3-months impact on physical function of +agil barcelona in community-dwelling frail older adults with cognitive impairment. methods: the study population was driven from the +agil barcelona program population. we included participants with cognitive impairment or dementia past history and those who performed a minicog test < 3 points. after frailty screening by the primary care team, a geriatric team performed the comprehensive geriatric assessment. according to cga results, a tailored and specific multidisciplinary intervention for each person was designed. the intervention could include a) multi-modal physical activity (pa) sessions, b) promotion of adherence to a mediterranean diet c) health education and d) medication review. the physical performance was assessed at baseline and at 3-omths follow-up by the short physical performance battery (sppb) and gait speed. the pre/post intervention analysis was done by a paired sample t-test for repeated samples for continuous variables and chi-square for categorical variables. results: we included 54 participants (mean age= 82.2±5.2, 70.2% woman and 29.8% lived alone). despite being independent in daily life, 36.8% had fallen the past year, 77.2% were vulnerable or frail according to the csf. physical performance was impaired: sppb=7.29±2.5 and gait sped=0.67±0.20m/sec and 46.9% had balance impairments. after 3 months, 73.2% of participants completed >=7.5 physical activity sessions. the mean improvements were +1.15±1.27 points (p<0.001) for sppb, +0.06±0.12 m/ sec (p<0.001) for gait speed, -4.4±8.53 sec (p<0.001) for chair stand test, and 47.6% (p 0.001) improved their balance. additionally, psychoactive treatment was withdrawn in 25.9%. conclusion: according to our results, a multidisciplinary and comprehensive geriatric intervention for frail elderly people with cognitive impairment of the community improves physical function and could reverse fragility at 3 months. clarence mwelwa patrick chikusu, amritha narayanan, joel james (ashford and st peter's nhs foundation trust, chertsey, uk) background: frailty and muscle strength are a critical component of walking ability and presence of these can result in high prevalence of falls. it also results in increased morbidity and mortality among the elderly. despite sarcopenia being very common and a reversible condition in its early stage it is a frequently overlooked and undertreated geriatric syndrome a greater understanding of sarcopenia and frailty among healthcare professionals could have a dramatic impact on outcome and quality of life of the elderly. objectives: this study aimed to assess the current knowledge about the concept of sarcopenia and frailty among the healthcare professionals working in an nhs district general hospital in surrey. methods: this longitudinal study included nhs healthcare professionals (n = 50) who were asked to complete a questionnaire regarding awareness of concept, risk, diagnostic strategy and management of frailty and sarcopenia. results: 63.27% of healthcare professionals stated to know the concept of sarcopenia, 20% indicated to know how to diagnose sarcopenia and 20% had seen patients with suspected sarcopenia in the last one month. only 20 % knew the risk associated with sarcopenia. 83.33% used sarc f questionnaire as diagnostic method for sarcopenia. 100 percent of the cohort experienced bottle necks during the implementation of diagnostic strategy. lack of awareness and time (41.76%) was the main reason for this .97.96 percent heard the term frailty and 76.16% knew that sarcopenia and frailty is not the same .77.55 percent was aware of the scoring methods for the frailty and 76.32 % used clinical frailty score as the method. 65.31% was aware of the frailty pathway but only 53.06% knew whom to contact regarding managing frailty. 57.14% heard the term comprehensive geriatric assessment. only 24.49% was aware of key recommendations of managing frailty in the acute settings. conclusion: although concept of sarcopenia and frailty is familiar to most nhs healthcare professionals, the practical and clinical application is limited due to a lack of awareness regarding the diagnostic methodology, risks as well as time constrains. as such the benefits and potential treatment options may be overlooked and we aim to improve awareness so that these measures can improve outcomes for patients. mahtab alizadeh-khoei 1 , fatemeh sadat mirzadeh 1 , reyhaneh aminalroaya 1 , fati nourhashemi 2 ((1) gerontology & geriatric department, medical school, tehran university of medical sciences, ziaeian hospital, tehran, iran; (2) department of internal medicine and clinical gerontology, toulouse, france) background: frailty is a potentially reversible geriatric syndrome associated with geriatric risk factors. detecting risk factors is a useful purpose to predict frailty levels incidence to plan for institutional or home care services. objectives: the aims were finding frail and prefrailty frequency in iranian geriatric outpatients' and determining demographics related factors and geriatric syndrome predictors on frailty levels, based on frailty fried index. methods: in this cross-sectional study 364 elderly >=60 years old, selected by convenience sampling from geriatric day clinics in the area of tehran university of medical sciences. the effect of risk factors (adl and iadl dependency, obesity, and polypharmacy) and geriatric syndromes (falling, chronic pain, sleep problems, vertigo, vision and hearing impairments, incontinence, dementia, and depression) were evaluated on frailty fried index. predictor factors by logistic regression model were analyzed, according to demographic risk factors and geriatric syndromes. results: the mean age was 67/3±6/2 years old, majority were male (62%). prefrailty was 37.6% in men and 47.1% in women based on fi. the significant risk factors in elderly prefrail women were depression (82.1%), polypharmacy (48.3%), visual impairment (47.2%), and chronic pain (56.6%); although, in prefrail men were vertigo (57.6%), falling (52%), sleep disorder (49.5%), and incontinence (52.1%). in prefrail older adults>=70 years, only sleep disorder was significant. in logistic regression model, six significant predicted factors were included depression, iadl dependency, falling, chronic pain, vertigo, and age. depression increased the risk of prefrailty by 2.8 times, dependency in iadl increased 3.5 times; moreover, chronic pain and vertigo increased prefrailty risk about 2 times. dependency on iadl increased the risk of frailty 5.8 times, and chronic pain and falling increased the risk of frailty about 1.65 times. by logistic regression model, 58% of prefrail outpatients elderly could be diagnosed. conclusion: geriatric syndromes in outpatients' elderly could predict prefrail more than frail elderly. in the iranian community dwellers prevalence of prefrailty was high, so the on-time screening and outpatients' interventions can help to prevent frailty. background: frailty is a key condition to be screened among elderly oncological patients. nevertheless, the use of the frailty index (fi) in onco-geriatrics is still limited. objectives: aim of our work is to measure the functional and prognostic value for 1-year mortality of the frailty index (fi) in a cohort of older women with gynecological cancer. methods: the prognostic value of fi was tested in 200 older women with gynecological cancer (mean age = 73.5 years). fi was retrospectively calculated following the rockwood model[1]. spearman's rho test was used for correlations with other oncological scales: eastern cooperative oncology group performance status (ecog); karnofsky performance status (kps); vulnerable elders scale-13 (ves-13). cox proportional hazard models and roc curve were performed to estimate prognostic role of 1-year mortality. sensitivity and specificity were also calculated. results: fi is normally distributed and descriptive statistics define our population as frail (mean = 0.25±0.11, range 0.08-0.51). 0.7 is confirmed as an upper limit compatible with life. fi doesn't significantly correlates with age, ecog and kps while it positively correlates with ves-13 (r=0.7, p < .01). fi is the strongest predictor for 1-year mortality confirmed after all adjustments for confounders (or 3.40; 95% ci 1.55-7.45, p < .01) and by roc curve analyses (0.66, 95% ci 0.51-0.81, p=.01). conclusion: frailty index is a useful tool to detect vulnerability in onco-geriatrics and it predicts 1-year mortality. it predicts negative health-related outcomes (mortality) better than other traditional scales. its adoption may support a more efficient identification of patients in the need of adapted and personalized care. further studies are needed to confirm and extend these findings. background: frailty has been studied in the old population due to its association with negative outcomes but more information is needed about frailty in very old samples. the fried frailty phenotype (ffp) has been widely used and includes a set of objective indicators: weakness, slowness, unintentional weight loss, exhaustion and low physical activity. objectives: to determine which sociodemographic, functional and health-related variables predict ffp in a sample of community-dwelling individuals aged 80+yrs. methods: data from 142 individuals living in the metropolitan area of porto were considered: sociodemographic information (age, sex, education level, living status), ffp (0-5), functionality (basic and instrumental activities of daily living), health information (nr. medicines, nr diseases, nr. falls, cognitive impairment, and self-perception of health). descriptive and correlational analysis were conducted and followed by a linear regression analysis (stepwise method) of variables significantly associated with ffp. results: participants' mean age was 88.1 years (sd=5.3), they were mainly women (73.9%), with 1-4 years of education (52.8%) and living with a relative (63.4%). high disability levels were found both for basic and instrumental activities of daily living. the mean of medicines intake was 6.8 (sd=3.5) and of diseases 6.4 (sd=2.1); 41.1% of the participants rated their health as poor. the median number of falls in the last year was 1 (iqr=2). participants scored on average 19.4 points (sd=6.4) in mmse. gender or age were not associated with ffp. basic and instrumental activities of daily living, selfperception of health and cognitive performance significantly predicted ffp. in the adjusted model (r2=0.311), the stronger predictor was the higher dependency for basic activities of daily living, followed by worst self-perception of health and lower scores of cognitive performance. the dependency for instrumental activities of daily living lost its significance in the adjusted model. conclusion: our results identify three main predictors of ffp (basic activities of daily living, selfperception of health, and cognitive performance) in participants with advanced age. these results provide relevant information for further understanding of frailty and the ffp among the oldest old. background: unplanned hospital readmissions are associated with poorer prognosis and increased risk of functional decline and dependence in older people. identifying major risk factors and assessing clinical risk scores can help to distinguish patients at risk of worse outcomes and rehospitalization, allowing the proposal of preventive measures. the aim of this study was to compare the accuracy of different instruments and risk factors in predicting readmission, functional decline and death in hospitalized older patients in a brazilian geriatric unit. methods: in a cohort study performed at a geriatric unit, 198 patients, 65 years old or over were included. demographic data, functional status, prisma 7 scale, geriatric depression scale, mini mental state examination, timed get up and go test, gait speed, mini nutritional assessment, palmar prehension strength, charlson comorbities index, frailty score of the cardiovascular health study and the senior index risk for rehospitalization were assessed at study admission. all patients received a follow-up telephone call at 90 days after discharge to assess potential readmissions, deaths and functional status. results: mean age was 79.1 years (sd +-8.63) and the mean barthel adl score was 71.43 (sd +-33.0). altered barthel (5.39; ci95% 2.6-11.4; p<0.001), chs score (11.57; ci95% 1.5-87.4; p<0.001), isar-hp (3.27; ci95% 1.1-9.9; p=0.02), tgug (7.85; ci95% 1.8-34.1; p<0.001), palmar prehension (3.84; ci95% 1.3-11.3; p=0.01) and gait speed (2.94; ci95% 1.6-6.9; p=0.01) were associated with higher mortality 90 days after discharge. the risk of functional decline at 3-month follow up evaluation was higher in patients with altered barthel (4.62; ci95% 1.54-13.9; p<0.001), lawton (5.66; ic95% 1.3-25.2; p=0.01), chs score (4.6; ci95% 1.9-11.0; p<0.001), isar-hp (3.88; ci95% 1.8-8.4; p<0.01), prisma 7 (2.23; ci95% 1.2-4.3; p=0.02), tgug (5.22; ci95% 2.36-11.55; p<0.001), palmar prehension (3.49; ci95% 1.7-7.0; p<0.01) and gait speed (1.98; ci95% 1.13.7; p=0.03). conclusion: altered iadl, frailty chs score, isar, tgug, palmar prehension strength and gait speed are predictive of functional decline and mortality 90 days after hospital discharge. these tools can be useful to pinpoint frailty in older patients, allowing the implementation of preventive interventions to avoid functional decline. more research is needed to evaluate the role of these tools in predicting rehospitalization. to limit the strain on available resources and prevent an unnecessary increase in patient burden. objectives: this study aimed to improve patient selection for multi-disciplinary care by identifying risk factors for disability after cardiac surgery in elderly patients. methods: two-centre prospective cohort study in 537 patients aged >=70 years undergoing elective cardiac surgery. before surgery 11 frailty characteristics were investigated. outcome was disability at three months defined as world health organisation disability assessment schedule 2.0 >=25%. multivariable modelling using logistic regression, concordance statistic (c-statistic), and net reclassification index were used to identify factors contributing patient selection. results: disability occurred in 91 (17%) patients. ten out of 11 frailty characteristics were associated with disability. a multivariable model including euroscore ii and preoperative haemoglobin yielded a c-statistic of 0.71 (95% ci 0.66 -0.77). after adding prespecified frailty characteristics (polypharmacy, gait speed, physical disability, preoperative health related quality of life, and living alone) to this model the c-statistic improved to 0.78 (95% ci 0.73 -0.83). net reclassification index was 0.32 (p<0.001) showing improved discrimination for patients at risk for disability at three months. conclusion: using preoperative frailty characteristics improves discrimination between elderly patients with and without disability at three months after cardiac surgery and can be used to guide patient selection for preoperative multi-disciplinary team care. fabiola valero 1,3 , henry tapia 1,3 , enrique valencia 1,3 , tania tello 1,2,3 ((1) facultad de medicina, universidad peruana cayetano heredia, lima, peru; (2) instituto de gerontología, universidad peruana cayetano heredia, lima, peru; (3) hospital cayetano heredia, lima, peru) background: frailty is increasingly recognized as a risk assessment to detect vulnerability and complexity. currently, there are limited tools to predict adverse perioperative outcomes for the geriatric population with hip fracture. objectives: to determine frailty and functional dependence as predictors of intrahospital adverse events in hospitalized older adults with hip fractures in the orthogeriatric unit of a general hospital in lima, peru. methods: we conducted a prospective cohort involving 218 patients aged 60 years or older who were admitted to the orthogeriatric unit with hip fracture from june 2017 to june 2019. data were obtained at the time of admission to our unit: frailty was assessed with the frail scale, function ability with the barthel scale, cognition with the short portable mental state questionnaire (spmsq) scale of pfeiffer, comorbidities, socio-family assessment and geriatric syndromes. patients were followed up to discharge, and adverse events were evaluated during this period. univariate models were performed, and logistic regression was done subsequently. results: 218 patients with hip fractures were evaluated, the mean age was 80.4 (8.9) years, 73.8% (161) were women and 2.7% (6) came from nursing homes. hypertension was the most frequent comorbidity in 41.2% (90). 56% (122) had a history of functional dependence on basic activities of daily living (abvd), 54% (104) had some degree of cognitive impairment, 13.7% (30) had social problems, polypharmacy in 21.5% (47) and 43.8% (139) history of falls in the last year. according to frail scale, 18.3% (n = 40) were robust, 29.3% (n = 64) were pre-frail and 52.3% were frail (n = 114). 31.8% (69) had an adverse event while hospitalized (pneumonia, uti, delirium, acute renal injury, pet), of whom 15% (6) were robust, 31.2% (20) pre-frail and 38% (43) frail (p = 0.02). 73.9% of patients with functional dependence on abvd presented adverse events. in the multivariate analysis, the factors associated with in-hospital adverse events were functional dependence in abvd, or: 2.72, (ci: 1.3-5.7); frailty with an or: 1.51 ic (0.5-4.5) and social problem, or: 2.72 ic (1.1-6.2). conclusion: older adult patients hospitalized for hip fracture who had frailty, functional dependence, and social problems had significant adverse events at a general hospital in lima, peru. aiko inoue 1 , chi hsien huang 1,2 , chiharu uno 1 , kosuke fujita 1,2 , tomoharu kitada 1,3 , joji onishi 2 , hiroyuki umegaki 2 , masafumi kuzuya 1,2 ((1) institutes of innovation for future society, nagoya university, japan; (2) department of community health and geriatrics, nagoya university graduate school of medicine, nagoya, japan; (3) department of business administration, seijoh university, aichi, japan) background: social frailty was associated with age, sex, income, education, marital status, and household status. however, the risk factors of social frailty relatively less investigated. objectives: the aim of this study is to clarify the risk factors of social frailty in community-dwelling japanese elderly. methods: a health promotion project (nagoya-teng project) is designed to distribute health promotion programs including enhancement of nutrition and physical activity via cable tv channel for community-dwelling elders. of all participants (n=926), 500 participants with complete baseline information (mean age 75.0±5.9 years, 242 men (46.9%)) were included in our cross-sectional analysis. at baseline, demographic data, socio-economic status, geriatric depression scale (gds-15), japanese version of european health literacy survey questionnaire (j-hls-eu-q47) were obtained. social frailty was defined by household status (living alone or not), financial difficulty, social activity, and fulfilment of social needs. total deficit scores of 2 or more were defined as social frailty,1 as social pre-frailty, and 0 as robustness. results: a total of 234 (46.8%), 172 (34.4%), and 94 (18.8%) of all participants were categorized as social non-frailty, pre-frailty and social frailty, respectively. in multivariable logistic regression model after adjusting for age, sex, bmi, and education level, living without a spouse is a significant risk factor (p<0.001) for social pre-frailty (or 2.95, 95% ci 1.78-4.88) and social frailty (or 4.31, ). low gds-15 scores were associated with high risk of social prefrailty (or 1.16, 95% ci 1.07-1.26) and social frailty (or 1.43, 95% ci 1.30-1.57). in addition, health literacy was inversely associated with social frailty (or 0.92, 95% ci 0.88-0.96). age, sex, and education level were not associated with social frailty. conclusion: regardless of age and sex, living with a spouse and depression which is associated with activity of daily living and quality of life are associated with social frailty. low health literacy is also a risk factor of social frailty. in literature, loneliness and social frailty were associated with functional decline and mortality in the elderly. future approaches incorporating health literacy interventions are warranted to prevent social frailty in the aged society with increasing number of physical frail older adults. background: frailty increases the risk for morbidity and mortality after cardiac surgery. the influence of frailty on postsurgical functional outcomes is largely unknown. objectives: the aim of this research was to study the association of preoperative frailty characteristics on adverse functional outcomes and to investigate the trajectory of functional recovery among frail and non-frail elderly patients up to one year after elective cardiac surgery. methods: a prospective two-centre observational cohort study in 555 elective cardiac surgery patients aged >=70 years. preanaesthesia assessment was supplemented with 11 frailty tests covering the physical, mental, and social domain. functional outcomes were assessed at one year and included change in health related quality of life (hrql) measured by the short form 36 and disability measured by the world health organisation disability assessment schedule 2.0. adverse functional outcome was considered when worse physical or mental hrql or disability was present after surgery. results: frailty characteristics were present in 468 (86%) patients of whom 406 (73%), 214 (39%) and 231 (42%) showed frailty in the physical, mental or social domain respectively. adverse functional outcome at one year after surgery occurred in 257 (46%) patients. patients with an adverse functional outcome were more often frail (92 (36%)) than patients without an adverse functional outcome (47 (16%) p<0.001). worse physical or mental hrql occurred in 134 (24%) and 141 (25%) patients respectively. the most important frailty characteristic associated with worse physical hrql was high preoperative physical hrql (β -0.56 per point (95% ci -0.7 to -0.5). preoperative mental hrql showed the strongest associations for worse mental hrql (β -0.55 per point (95% ci -0.7 to -0.4)). disability was reported by 120 (22%) patients and associated with preoperative polypharmacy, gait speed, health related quality of life, living alone or dependent living. gait speed had the strongest association (β 2.2 per second (95% ci 1.6 to 2.8)). conclusion: preoperative frailty characteristics were common and predictive for adverse functional outcome one year after cardiac surgery. frailty screening can be used to improve risk stratification and decision making in older cardiac surgery patients. background: frailty frailty has many elements and these can be characterised as physical, nutritive (including body composition), cognitive and sensory (including hearing and seeing). the relative prevalence and importance of these elements are not known. objectives: to estimate the prevalence of frailty and relative contribution of physical/ balance, nutritive, cognitive and sensory frailty to important adverse health states (falls, physical activity levels, outdoor mobility, problems in self-care or usual activities, and lack of energy or accomplishment) in an english cohort. methods: analysis of 9803 community-dwelling older people. the sample was drawn from a random selection of all people aged 70 or more registered with 63 general practices across england. data were collected by postal questionnaire. frailty was measured with the strawbridge questionnaire. we used cross sectional, multivariate logistic regression to estimate the association between frailty domains and adverse health outcomes. some models were stratified by sex and age. results: mean age of participants was 78 years (sd 5.7), range 70 to 101 and 47.5% (4653/9803) were men. the prevalence of overall frailty was 20.7% (2005/9671) and there was no difference in prevalence by sex (odds ratio 0.98; 95% confidence interval 0.89 to 1.08). sensory frailty was the most common and this was reported by more men (1823/4586) than women (1469/5056; odds ratio for sensory frailty 0.62, 95% confidence interval 0.57 to 0.68). men were less likely than women to have physical or nutritive frailty. physical frailty had the strongest independent associations with adverse health states. however, sensory frailty was independently associated with falls, less frequent walking, problems in selfcare and usual activities, lack of energy and accomplishment. conclusion: physical frailty was more strongly associated with adverse health states, but sensory frailty was much more common. the health gain from intervention for sensory frailty in england is likely to be substantial, particularly for older men. sensory frailty should be explored further as an important target of intervention to improve health outcomes for older people both at clinical and population level. background: it live independently. our goal is to encourage independent living, wellbeing and to relieve health and care services budget pressure. longevity is one of the biggest achievements of modern societies. by 2020, a quarter of europeans will be over 60 years of age. combined with low birth rates, this will bring about significant changes to the structure of european society, which will impact on our economy, social security and health care systems. the most problematic expression of population ageing is the clinical condition of frailty. frailty develops because of age-related decline in multiple physiological systems. it is estimated that a quarter to a half of people over 85 years are frail , and this is set to reach epidemic proportions over the next few decades. while frailty increases, the average amount of health spending increases as well with the frailty level in a range from 1,500 to 5,000 €/person year, depending upon the frailty status and the setting of care. frailty usually comes along associated with another risk facto; loneliness. then, ageing, frailty and loneliness constitute overlapping conditions submitted to multiple health and care interventions. ecare project aims to deliver disruptive digital solutions for the prevention and comprehensive management of frailty to encourage independent living, wellbeing and to relieve health and care services budget pressure, throughout the implementation of a pre-commercial procurement scheme. pre-commercial procurement is an ideal framework for the delivery of innovative solutions. the ecare network of procurers and the service providers are often on the frontline as new needs emerge. this pcp will allow the procurers to voice out their unmet needs, create a new demand to access sustainable products of higher quality, and develop new applications with lower life cycle costs. the demand and the supply side will work together to co-create and co-design the solutions and validate their functionalities against the specific challenges outlined in the pcp call for tender. this will clearly maximize the engagement of innovation in health and care services. solutions should improve outcomes for frailty in old adults entailing the physical and the psychosocial factors. the target group are the pre-frail/frail old adults with emphasis on those that feel lonely and/or isolated. the project will procure the development, testing and implementation of digital tools/services and communication concepts to facilitate the transition to integrated care models across health and social services and country-specific cross-institutional set-ups, including decentralised procurement environments and collaboration across institutions. objectives: the project objectives are: • newly development easy-to-use and reliable solutions that facilitate early detection of frailty based on the most efficient standards and methods. • improve the understanding of the factors affecting frailty and the feelings of loneliness and isolation, and how they do correlate (e.g.: gender dimension, social context, etc.). • deliver personalised intervention plans taking into account the end-user societal context. • innovative and meaningful means to tackle the feelings of loneliness and isolation. • new approaches to engage patients as active self-managers of their own health. • new technology developments designed and oriented to the target end-user. • and among all, investigate to deliver cost-efficient solutions, affordable to the payers involved. methods: ecare procurers will proactively organize the requirements of the demand for care solutions in a coherent way. the procurers (buyers' group) will assess the solution adequacy to the targets. the preferred partners will contribute with solid knowledge of innovative procurement paths to the innovation procurement tender. the project partners will do this by: • providing a solid and informed base for dialogue between stakeholders by determining a coherent picture of the market state of the art of the sector based on practical experience of customers and suppliers. • enabling a genuine and credible dialogue between the supply-chain and customers to determine the practical policy and procurement actions required to deliver the ecare solutions. • defining the common unmet needs, communicating these to stakeholders and initiating a mobilization plan for a pcp addressing ecare needs. the pcp may be summarized in a series of actions: • convey the relevance of innovation procurement to public procurers: encouraging suppliers to offer novel solutions to address ecare challenges rather than the lowest price solutions. • analyze the state of the art of the market with all potential suppliers, as well as the main problematic and barriers faced in the sector and that need to be overcome a set of actions involving both the supply and demand sides will be carried out: a coordinated first analysis of the state of the art conducted by all project members followed by a coordinated market sounding through all dissemination channels managed by the consortium will be undertaken to spread project results aiming to receive feedback from all key market players. for this, the role of procurers is vital to replicate and stretch the impact of the project. • providing public procurers with procurement know-how to improve public sector procurement efficiency and increase public sector market power by giving support to apply the methodologies of innovation procurement. market sounding will provide an opportunity for engagement and two-way dialogue with innovative companies that can offer solutions and guidance on how to overcome the procurement barriers. • launching an agreed, realistic and validated joint pcp tender. results: the ecare consortium is immerse in a deep process of unmet needs detection. our goal is to be extraordinarily concrete when defining what the end users and the healthcare professionals are willing for. those unmet needs will be critical for the definition of the requirements and uses cases that the it suppliers will have to follow to design the ict solutions. then… what a better way to know their needs that asking them personally? the vision of providing tailored fit solutions and tools to the end users led to the consensus in creating and facilitating focus group sessions across the 4 procurers regions -campania (italy), barcelona (spain), santander (spain) and wroclaw (poland)-. these sessions will be involving end users, health and social care professionals, and it internal departments of the procurers' organisations. -the focus group script for the end users sessions integrates as main topics the specific condition and related symptoms; experiences of services and care provided; experiences of managing condition when progressing rapidly ; needs for symptom management and how these can be met ; integration of it supportive tools in the management of frailty and loneliness. -the professionals are invited to reflect and discuss the topics of common symptoms and actual care model; experiences of monitoring elderly when condition is progressing rapidly; views about the supportive care needs of elderly and caregivers; early integration of the new care in the management of frailty and loneliness; integration of it supportive tools in the management of frailty and loneliness. -the identified and proposed topics for the it staff would be the state of the art of the relation in between it and social/healthcare; state of the art of interventions on frailty and loneliness. all the four procurers were challenged to organize, at least, 3 focus sessions, one with each specific target group. so far, all the procurers already organized and scheduled the sessions that will occur until the end of january. in terms of impact, 119 participants are expected to be involved (56 end users, 42 healthcare professionals and 21 it people). all the representative of the procurers reported so far that the participants have been considering the sessions so interesting and useful. in fact, new topics have been put in the table for discussion in all the different sessions, adding more important information for the definition of the unmet needs. the journey of the project so far has been providing very powerful insights and evidences that people and professionals appreciate to be involved and e(motionally) cared. conclusion: ecare will progress beyond the state of the art by approaching older people not just in terms of their diseases but also in terms of physical, cognitive and psychosocial care and support to prevent functional decline, frailty and disability. the project key components to address frailty are those that define also integrated care, with the addition of targeting high risk frail individuals, an enablement attitude and a focus on outcomes most relevant to frail individuals and their caregivers. for these, a multimodal comprehensive system able to provide the most effective care will need to be provided. background: maintaining autonomy as life progresses has become a challenge for the health systems. this objective can only be achieved by moving the axis of health policies and health care practice from the disease to the preservation of functional capacity. objectives: the aim of this study is to design and pilot a model for the assessment and support of functionality for community dwelling older people. methods: a space in which nurse and social worker jointly assess the functional capacity of older people and identify and provide responses to the detected deficits was proposed. this study was performed in osi donostialdea (gipuzkoa, spain). three main tasks were carried out: 1. definition of the joint assessment procedure of functionality. 2. identification of the existing resources and community assets to give answer to the identified needs. 3. piloting the model in a sample of older people. the identified needs and the availability of resources to respond to them were obtained from the pilot phase. results: in the initial version of this integral assessment were included, functional capacity, physical activity, cognitive capacity, sense organs, nutritional status, social assessment and housing and environmental conditions. a total of 49 individuals (69% women; mean age 82 years, sd=5.8; barthel index, mean 97.0, sd=4.2; 47% living alone; 76% without cognitive impairment) were recruited during the pilot. the following needs were identified: personalized workout routines, fine motor skill exercises, visual and efficient diets adjusted to each patient, make sure resources reach the community, promote the use and design of gadgets to assist the needs of basic and instrumental activities of daily living, improve strategies to prevent cognitive function impairment, ease loneliness and avoid or minimize physical and environmental barriers to access home, to walk the streets and, particularly, to use public transport. there were no resources available for all the identified needs. conclusion: this study will allow the development of a model for the integral assessment of functionality for the aged population, based in a multidisciplinary team, a space and a new way of working in primary care. mónica machón 1-3 , maider mateo-abad 2,3 , mercedes clerencia-sierra 2,4,5 , carolina güell 1,6 , beatriz poblador-pou 2,5 , kalliopi vrotsou 1-3 , antonio gimeno-miguel 2,5 , alexandra prados-torres 2,5 , itziar vergara 1-3 ( (1) background: multimorbidity and frailty are often present in older people and are found to be associated to increased risk of adverse health events. it is necessary to improve the knowledge of the characteristics of such populations to design adequate clinical guidelines seeking to avoid or delay the onset of dependence. objectives: the aim of this study was to identify clusters of chronic diseases in robust and frail individuals and compare sociodemographic and health characteristics between these clusters. methods: this was a cross-sectional study based on data from two longitudinal studies. the sample was composed of functionally independent community-dwelling older people with multimorbidity living in gipuzkoa (basque country, spain). information from electronic health records (diagnose diseases and medication) and a baseline assessment (sociodemographic characteristics, functional status, self-perceived health, cognitive status, sight and hearing impairments, history of falls and nutritional status) was used in the analysis. the timed up and go test of physical performance was included as a measure of frailty. multiple correspondence and cluster analyses were performed to identify groups. results: the study population consisted of 813 individuals (55.1% women; mean age 77.4 years, sd=5.0). frail individuals (n=244) were older, had a lower educational level and a poorer health status than robust individuals (n=569). three clusters were obtained in robust (rc1, n=348; rc2, n=139 and rc3, n=82) and four among the frail individuals (fc1, n=164; fc2, n=23; fc3, n=44 and fc4, n=13). in rc1 and fc1, none of the chronic diseases had a higher prevalence than in rc2-rc3 and fc2-fc3-fc4, respectively. individuals pertaining to rc2 and fc2 presented more frequently diseases related to mobility limitation or limb pain compare to the other clusters. higher rates of cardiovascular diseases and risk factors were seen in rc3 and fc3. in frail individuals a new cluster emerged, fc4, containing individuals with higher rates of cognitive and eye problems and a clearly poorer health status. conclusion: the findings obtained in this exploratory study may provide insight for the designing of more specific health interventions for older patients with multimorbidity, even though the chronic diseases cluster identified were similar in robust and frail individuals. background: older african americans (oaa) are at high risk for becoming frail in later life. interventions can reverse or delay frailty, yet oaa have largely been excluded from frailty intervention research. many interventions are also time and resource intensive, making them inaccessible to socially disadvantaged oaa. objectives: we present results of a feasibility trial of a low dose frailty prevention intervention among 60 community-dwelling, pre-frail oaa aged 55+ recruited from a primary care clinic between june 1st and october 31st 2018. methods: using a 2-arm rct, participants were assigned to the intervention, which was delivered by an occupational therapist (ot) and comprised of four sessions over four months (an ot evaluation, and sessions on healthy dietary practices, increasing physical activity, and maintaining a healthy lifestyle), or enhanced usual care (publicly available information about healthy lifestyle, home safety, and local elder services). feasibility criteria were set a priori at 75% for participant retention (including attrition due to death/ hospitalization), 80% for session engagement, 2 participants/ week for mean participant accrual, and 90% for program satisfaction. results: participants were 65% female with an average age of 76.58 years, 51.67% of which lived alone and 51.67% lived off of less than 15k per year. feasibility metrics were met. the study recruited 2.5 participants per week and retained 75% of participants who attended 95% of scheduled sessions. mean satisfaction scores were 93%. the treatment also resulted in positive trends in the expected direction in the treatment group for the following outcomes (d = effect size): global health (d = .45), mental health (d = .26), qol (d = .18), social functioning (d = .68), depression (d = .24), and pain reduction (d = .43). descriptively, treatment group participants were also less likely to experience a progression (deterioration) in three frailty status indicators at 4-months compared to controls: weight lost, walking speed slowness, and grip strength weakness. conclusion: the intervention was feasible to deliver. qualitative findings from exit interviews suggested changes to the program dose, structure, and content that could improve it for future use. background: it is well known that frail patients are potentially most at risk of functional decline following a hospital admission. objectives: to measure the effects of an augmented prescribed exercise programme versus usual care, on physical performance, quality of life and healthcare utilisation for frail older medical patients in the acute setting. methods: this was a parallel single-blinded randomised controlled trial. within two days of admission, older medical inpatients with an anticipated length of stay >=3 days, needing assistance/aid to walk, were blindly randomly allocated to the intervention or control group. until discharge, both groups received twice daily, monday-to-friday half-hour assisted exercises, assisted by a staff physiotherapist. the intervention group completed tailored strengthening and balance exercises; the control group performed stretching and relaxation exercises. length of stay was the primary outcome measure. blindly assessed secondary measures included readmissions within three months, and physical performance (short physical performance battery) and quality of life (euroqol-5d-5l) at discharge and at three months. time-to-event analysis was used to measure differences in length of stay, and regression models were used to measure differences in physical performance, quality of life, adverse events (falls, deaths) and negative events (prolonged hospitalisation, institutionalisation). results: of the 199 patients allocated, 190 patients' (aged 80 ±7.5 years) data were analysed. groups were comparable at baseline. in intention-to-treat analysis, length of stay did not differ between groups (hr 1.09 (95% ci, 0.77-1.56) p=0.6). physical performance was better in the intervention group at discharge (difference 0.88 (95% ci, 0.20-1.57) p=0.01), but lost at follow-up (difference 0.45 (95% ci, -0.43 -1.33) p=0.3). an improvement in quality of life was detected at follow-up in the intervention group (difference 0.28 (95% ci, 0.9 -0.47) p=0.004). overall, fewer negative events occurred in the intervention group (or 0.46 (95% ci 0.23 -0.92) p=0.03). conclusion: improvements in physical performance, quality of life and fewer negative events suggest that this intervention is of value to frail medical inpatients. its effect on length of stay remains unclear. background: to propose a simple frailty screening tool able to highlight frailty profiles, already since the initial screening phase. methods: a 9-item questionnaire (lorraine frailty profiling screening scale, lofpross), constructed by an experts' working group, was administered by health professionals to participants >70 years old (n=817) and living at home, in 3 different clinical settings: a primary care outpatient clinic (rural population, n=591), a geriatric day clinic (day-clinic population, n=76) and healthy volunteers (urban population, n=147). a multiple correspondence analysis (mca) followed by a hierarchical clustering of the results of the mca performed in each population was conducted to identify participant profiles based on their answers to lofpross. a response pattern algorithm was resultantly identified in the rural (main) population and subsequently applied to the urban and day-clinic populations and, in these populations, the two classification methods were compared. finally, clinically-relevant profiles were generated and compared for their ability to similarly classify subjects. results: the response pattern differed between the 3 subpopulations for all 9 items, revealing significant intergroup differences (1.2±1.4 positive responses for urban vs. 2.1±1.3 for rural vs. 3.1±2.1 for day-clinic, all p<0.05). five clusters were highlighted in the main rural population: "non-frail", "hospitalizations", "physical problems", "social isolation" and "behavioral", with similar clusters highlighted in the remaining two populations. identification of the response pattern algorithm in the rural population yielded a second classification approach, with 83% of tested participants classified in the same cluster using the 2 different approaches. three clinically-relevant profiles ("non-frail" profile, "physical frailty and diseases" profile and "cognitive-psychological frailty" profile) were subsequently generated from the 5 clusters. a similar double classification approach as above was applied to these 3 profiles revealing a very high percentage (95.6%) of similar profile classifications using both methods. conclusion: the present results demonstrate the ability of lofpross to highlight 3 frailty-related profiles, in a consistent manner, among different older populations living at home. such scale could represent an added value as a simple frailty screening tool for accelerated and better-targeted investigations and interventions. (3) homburg/saar/germany, saarland university medical center, neurology, homburg/germany) background: frailty is the most important short and long term predictor of disability in the elderly. no study to date evaluate the impact of frailty on short and long term independently from neurological outcome measures. objectives: the aim of the study was to evaluate whether diagnosis frailty predicts short and long-term mortality and neurological recovery in old patients who underwent reperfusion acute treatment in stroke unit. methods: consecutive patients were older than 65 years who underwent thrombectomy or thrombolysis in a single stroke unit from 2015 to 2018. predictors of stroke outcomes were assessed including demographics, baseline nihss, time to needle, treatment and medical complications. premorbid frailty was assessed with a comprehensive geriatric assessment (cga) including functional, nutritional, cognitive, social and comorbidities status. at 3 and 12months, all-cause of death and clinical recovery (using mrs) were evaluated. results: 102 patients, of whom 31 underwent mechanical thrombectomy and 71 venous thrombolysis (mean age 77.5, 65-94 years) entered the study. frailty was diagnosed in 32 out of 70 patients and associated with older age (p=0.001) but no differences in baseline nihss score or treatment strategies. at follow-up, frail patients showed higher incidence of death at 3 (25% vs 3%, p=0.008) and 12 (38% vs 7%, p=0.001) months. frailty was associated with worse neurological recovery at 3 month (mrs 3.4 + 1.8 vs 1.9 + 1.9, p=0.005) and one year followup (mrs 3.2 + 1.9 vs 1.9 + 1.9) for free survival patients. conclusion: frailty is an important predictor of efficacy of acute treatment of stroke beyond classical predictors of stroke outcomes. larger prospective studies are warranted in order to confirm our findings. background: frailty becomes increasingly common as adults age and has known associations with activity limitations and injurious falls among older adults. while it is believed that frailer older adults are less socially connected than their more functional counterparts, less is known about the relationship between frailty and social isolation among community-dwelling older adults. objectives: the purpose of this study was to examine associations of frailty indicators on self-reported social isolation risk among community-dwelling adults age 60 years and older. methods: the upstream social isolation risk screener (u-sirs) was developed to assess social isolation risk among older adults within clinical and community settings. comprised of 13 items (cronbach's alpha=0.80), the u-sirs assesses physical, emotional, and social support aspects of social isolation. using an internet-delivered survey, data were collected from a national sample of 4,082 adults age 60 years and older. participants completed the u-sirs and additional items on sociodemographics and other health risks. theta scores for the u-sirs serve as the dependent variable, which were generated using item response theory. an ordinary least squares regression model was fitted to identify frailty indicators associated with social isolation risk. results: participants' average age was 69.6 (±5.2) years. the majority of participants was female (58.5%) and lived with a partner/spouse (56.9%). twenty eight percent of participants reported difficulty walking or climbing stairs, 4.3% reported difficulty dressing or bathing, and 16.2% reported a fall in the past year. higher u-sirs theta scores were reported among males (b=3.82, p<0.001) and those with more chronic conditions (b=9.34, p<0.001). participants who reported difficulty walking or climbing stairs (b=3.96, p<0.001), difficulty dressing or bathing (b=3.43, p=0.001), or a fall in the past year (b=4.27, p<0.001) also reported higher u-sirs theta scores. further, higher u-sirs theta scores were reported among participants who had not left their home in the past three days (b=10.62, p<0.001). conclusion: findings suggest frailer older adults and those with functional limitations may have greater risk for social isolation. this highlights the critical demand for easy-to-administer and practical assessments for frail older adults that identify their social isolation risk and link them to needed resources and services. background: peak expiratory flow (pef) has been linked to several negative health-related outcomes in older people, but its association with frailty is still unclear. objectives: this study investigates the association between pef and prevalent and incident frailty in older adults. methods: data come from 2559 community-dwelling participants of the swedish national study on aging and care in kundgsholmen (snac-k), aged >=60 years. baseline pef was expressed as standardized residual (sr) percentiles. frailty was assessed at baseline and over six years, according to the fried criteria. associations between pef and frailty were estimated crosssectionally through logistic regressions, and longitudinally by multinomial logistic regression, considering death as alternative outcome. obstructive respiratory diseases and smoking habits were treated as potential effect modifiers. results: our crosssectional results showed that the 10th-49th and <10th pef sr-percentile categories were associated with three-and fivefold higher likelihood of being frail, than the 80th-100th one. similar estimates were confirmed longitudinally, i.e. adjusted or=3.11 (95%ci: 1.61-6.01) for pef sr-percentiles<10th, compared with 80th-100th. associations were enounced in participants without physical deficits, and tended to be stronger among those with baseline obstructive respiratory diseases, and, longitudinally, also among former/current smokers. conclusion: these findings suggest that pef is a marker of general robustness in older adults and its reduction, exceeding that expected by age, is associated with frailty development. background: as consistently reported in the literature, muscle strength (ms) decreases at a higher rate than muscle mass (mm) during aging resulting in a decreased muscle quality (mq). loss of mq has been associated with loss of mobility, falls, frailty and an increased risk of mortality. however, the degree of muscle declines is varying throughout the population leading to 3 states: successful, normal or pathological. it has been proposed that healthy life habits such as be physically active, having a healthy diet etc. could reduce the muscle aging decline. thus, identifying if life habits could counteract or maintain muscle quality during successful aging is important to better characterize aging and to intervene more specifically. objectives: the aim of the present study was to identify whether a physically active lifestyle could attenuate the effects of aging on mq. methods: active young were compared to active older men. to be considered active, young and older men need to practice voluntary physical activity at least 150min/week since 5yrs. body composition (dxa; mri) and maximum knee extension strength were measured. mq was calculated as the ratio of ms to mm. aerobic capacity (vo2max; moxus©) and muscle contractility (emg) were also measured. muscle biopsies were performed to determine fiber typing, size, intermuscular adipose tissue (imat) and intramyocellular lipid content (imcl). results: absolute mm (p<0.001) and ms (p=0.005) was greater in young participants compared to their older counterparts while mq was similar between them. even if total (p=0.04) and type iia (p=0.024) fiber size were greater in ya than in oa, muscle fiber proportion, muscle contractility and lower limb fat mass (imat, imcl) were similar between both groups (p>0.05). conclusion: mq was similar between younger and older physically active men suggesting that being physical activity may have mitigated the loss of mq with aging and delayed some physiological age-related changes (muscle composition, contractility). i r a t x e e g a ñ a , itxaso mugica 1,2 , nagore arizaga 2 , maider ugartemendia 1 , nagore zinkunegi 1 , janire virgala 2 , maider kortajarena 1 ( (1) and sppb test (p<0,01). similar results have been found in other researches. the parameters that have higher influence in cognition are handgrip test (p<0,01) and frailty (p<0,01). in other investigations, they got the same results; better cognition is related to better physical capacity and less fragility. in regards with functionality, the values of tug test (p<0,01) and gait speed (p<0,01) are the ones that show stronger relation. in other investigations, they observed that physical state and functionality were related. conclusion: the quality of life, the functionality and moca test are interconnected and the parameters that have the strongest statistical relationship are fragility and physical state. the greater the physical capacity of the older person is, the greater the functional capacity is too and the fragility decreases. in conclusion, the quality of life is better. kazuki kaji 1 , jun kitagawa 2 , takahiro tachiki 3 , naonobu takahira 2 , masayuki iki 4 , junko tamaki 5 , etsuko kajita 3 , yuho sato 6 , jpos study group 4 ((1) national center for geriatrics and gerontology, obu, aichi, japan; (2) nagoya university, nagoya, aichi, japan; (3) nagoya city university, nagoya, aichi, japan) background: the skeletal muscle mass index (smi), which is the appendicular skeletal muscle mass (asm) adjusted for height squared (kg/m2), is used to assess skeletal muscle mass. we reported at this conference last year that smi was overestimated by height loss due to aging in elderly women. furthermore, age-related changes in smi were inconsistent with changes in physical function such as grip strength and walking speed. objectives: the purpose of this cross-sectional study was to investigate the effects of height loss on agerelated changes in smi and physical function in japanese women aged 50 or older. methods: this study was part of the 15/16-year follow up survey of the japanese population-based osteoporosis (jpos) cohort study conducted in 2011/2012. the jpos study was started in 1996. the subjects of the 15/16year follow-up were 710 women (mean 65.3±10.0 years). we divided the subjects into quartiles based on 15 years of height loss (q1: the lowest, q2, q3 and q4: the highest). asm was measured by dual x-ray absorptiometry (qdr4500a, hologic, usa). grip strength, maximum walking speed, and timed up and go (tug) were also measured. results: the mean change in height during the 15/16-year follow-up was -1.6±1.6 cm. mean changes in height in q1 (n=191), q2 (n=171), q3 (n=172) and q4 (n=176) were -0.2±0.41 cm, -1.0±0.20 cm, -1.8 ±0.26 cm and -3.7±1.84 cm, respectively. the trend test demonstrated significant increases in the mean age and smi from q1 to q4. on the other hand, there was a significant decrease in asm from q1 to q4. the mean grip strength and maximum walking speed significantly decreased from q1 to q4. tug results were similar, suggesting that greater height loss led to longer times. conclusion: in japanese elderly women with height loss, asm and physical function decreased with age, but the smi adjusted for height increased. it may be necessary to establish a muscle mass parameter other than smi to investigate the relationship between muscle mass and physical function. kota tsutsumimoto 1 , takehiko doi 1 , sho nakakubo 1 , satoshi kurita 1 , hideaki ishii 1 , hiroyuki shimada 2 ((1) section for health promotion, department of preventive gerontology, center for gerontology and social science, national center for geriatrics and gerontology, aichi, japan; (2) center for gerontology and social science, national center for geriatrics and gerontology, aichi, japan) background: sarcopenia was defined as decline in skeletal muscle mass and muscle function, leading to serious health problems including disability. the modifiable risk factors of sarcopenia should be elucidated to contribute to develop intervention from sarcopenia. objectives: to examine the association between anorexia of aging and sarcopenia among community-dwelling elderly japanese individuals. methods: population-based, cross-sectional cohort study in japanese older adults was conducted and participants were identified from the database of the national center for geriatrics and gerontology-study of geriatric syndromes. anorexia of aging was assessed via a simplified nutritional appetite questionnaire. handgrip strength and walking speed were tested, and skeletal muscle mass was assessed using a bio-impedance analysis device. subjects with sarcopenia were defined as those who met the criteria of the asian working group for sarcopenia. the association between anorexia of aging and sarcopenia was then analyzed via multiple regression analysis. results: in total, 9,496 elderly japanese individuals were evaluated. the prevalence of sarcopenia and anorexia of aging was 4.0% and 9.8%, respectively. in multivariable logistic regression model adjusted for the covariates except for nutritional status such as albumin, anorexia of aging was independently associated with sarcopenia (or: 1.45, 95% ci: 1.07 to 1.95; p = 0.015). this significant association remained even after adjusting for all covariates including nutritional status (or: 1.42, 95% ci: 1.06 to 1.92, p = 0.020). conclusion: anorexia of aging is associated with sarcopenia among japanese older adults. further studies are needed to determine whether a causal association exists between anorexia and sarcopenia. background: low grip strength is consistently associated with higher rates of mortality, disability and other age-related health outcomes, and is a key characteristic of sarcopenia. grip strength has thus been proposed as a general biomarker of ageing. life expectancy in russia is substantially lower than in norway but whether this is reflected in differences in grip strength across adulthood, as observed in previous comparisons of older adults from russia, denmark and england, needs to be established and explained. objectives: we aimed to compare grip strength in norwegian and russian populations by age and gender, and investigate whether any observed differences were explained by contrasts in height, weight, smoking or education. methods: we used harmonised cross-sectional data on grip strength for 10,112 men and women aged 40-69 years. this comprised participants from the russian know your heart study (n=4,147) conducted in the cities arkhangelsk and novosibirsk in 2015-18, and from wave 7 of the norwegian tromsø study (n=5,965) conducted in 2015-16. grip strength was assessed using the jamar+ digital dynamometer in both studies, and the maximum of six measurements (three in each hand) was used. the association between grip strength and covariates was assessed using linear regression. results: norwegian males had stronger grip than russian males at all ages, for example they were an average of 3.2kg (95% confidence interval (ci) 2.3, 4.1) stronger at age 40 years and 3.3kg (95% ci 2.6, 4.0) stronger at age 69 years. among women, corresponding numbers were 2.0kg (95% ci 1.2, 2.8) at age 40 and 1.5kg (95% ci 0.9, 2.1) at age 69. adjustment for weight, education and smoking did not affect the results, but height attenuated the between country differences, especially at older ages. among women aged 60+, differences in height between countries fully explained the differences observed in grip strength. conclusion: norwegian 67-year-olds had the grip strength of 60-year-old russians suggesting that russians are ageing more rapidly in terms of muscular strength than their norwegian counterparts. the important role of height in explaining these differences, especially at older ages, suggest contrasts in early life circumstances may be of key importance. eleanor lunt 1,2 , paul greenhaff 2,3 , adam l gordon 2,4,5 , john rf gladman 1,2 ( (1) background: frailty is a state of vulnerability to stressors resulting in adverse clinical outcomes including falls and fragility fractures. identifying biomarkers associated with these outcomes may help target interventions. objectives: to compare parameters of body composition, muscle thickness and muscle strength between patients and healthy older and young volunteers. methods: six young (18-35 years) and 11 older (>= 70 years) healthy female volunteers were recruited by advert from community groups. 15 female patients (>=70 years) with an acute fragility fracture were recruited from hospital wards and measured during first week of admission (median 4th day (iqr 2-6)). frailty was determined by the 5-item frail scale. height, weight, handgrip (jamar dynamometer) and knee extension (lafayette manual muscle tester) were assessed. body composition was estimated using whole body bioelectrical impedance (bodystat quadscan 4000®). midpoint vastus lateralis (vl) muscle thickness and mid-thigh subcutaneous fat thickness were assessed using ultrasound (mylab gold, esaote biomedica, italy) with a 14hz linear-array probe. oneway anova and post hoc tukey's test were used to compare end-point measures between groups. results: frailty was significantly more prevalent in the patient group (53% frail, 40% pre-frail, 7% robust) than the healthy older group (100% robust, p<0.001). the patient group was older (83 ± 7 years vs 78 ± 6 years, p<0.05) and had more co-morbidities (p<0.001). there were no significant differences between the patient and healthy older group in weight, height, bmi, percentage body fat or subcutaneous fat thickness of lateral thigh. vl muscle thickness was lower in the patient group compared to healthy older and young volunteers (1.27±0.43cm, 1.75±0.30cm and 2.09±0.41cm respectively, p<0.01). the patient group also had lower handgrip strength (9.2±5.5kg, 19.9±5.8kg, 41.3±15.6kg respectively, p<0.001) and lower knee extension strength (4.3±1.4kg, 7.8±1.3kg, 9.5±1.3kg respectively, p<0.001). vl muscle thickness associated with muscle strength (knee extension r=0.70, p<0.001 and handgrip r=0.71, p<0.001) and was significantly lower in the frail compared to pre-frail or robust participants (0.98±0.30cm, 1.53±0.27cm, 1.76±0.29cm respectively p<0.001). conclusion: female patients presenting to hospital with a fall and fragility fracture have lower muscle thickness in the thigh compared to non-frail older women, despite no difference in other body composition variables. register, health technology assessment, nhs economic evaluation database) were searched from inception to april 12, 2019. cross-sectional and cohort studies that reported adjusted risk ratios with 95% confidence intervals (ci) for frailty with serum level of total testosterone, free testosterone, sex hormone-binding globulin (shbg) were selected. a metaanalysis was carried out by using fixed effects and random effects models to calculate the or of relationship between low level of testosterone and risk of frailty. results: the crosssectional study concluded 9 articles, there was statistically significant association between lower level of total testosterone and risk of frailty (or=1.59; 95%ci, 1.28-1.98, i2=80%), as well as free testosterone (or=1.59; 95%ci, 1.21-2.08,i2=78% ), the highest level of shbg was no significant associated with the risk of frailty(or=1.05; 95%ci, 0.84, 1.30; i2=62%). the prospective cohort studies obtain 4 articles, no significant were found between frailty and low total testosterone and frailty (pool or=1.12; 95%ci, 0.99-1.32, i2=14%). conclusion: the meta-analysis indicates that low level of serum testosterone is significantly associated with the risk of frailty in the crosssection studies. however, we found no significant relationship between low total testosterone and frailty in the cohort studies. more research is needed to address the underlying mechanisms to explain this relationship and to determine whether testosterone supplementation is effective for preventing frailty syndrome. background: although frailty and abdominal obesity are known risk factors for disability in older persons, few studies have investigated the interaction between both factors on the association with disability. objectives: to investigate the association of frailty and abdominal obesity with disability in older persons. methods: we used data from 13,787 participants (41% men) in the prospective, population-based singapore chinese health study cohort, who were interviewed and examined for frailty, abdominal obesity and disability at mean age of 74 (range 63 to 97) years from 2014-2017. we defined frailty as having three or more features of weak handgrip strength, slow timed-up-and-go test, low energy level, multiple comorbidities, and difficulty carrying out usual activities. we defined abdominal obesity by waist circumference using sexspecific cut-offs, and assessed disability using the lawton instrumental activities of daily living (iadl) scale. we used multivariable logistic regression models to compute the odds ratio (or) and 95% confidence interval (ci) for the association between frailty/abdominal obesity and disability. results: about 7.6% of participants were frail and 58.4% had abdominal obesity. frailty was associated with increased or (95% ci) of 7.78 (6.64-9.12) for disability. conversely, the or (95% ci) for the association between abdominal obesity and frailty was only 1.13 (1.01-1.27). compared to participants who were neither frail nor abdominally obese, the or (95% ci) for disability was 6.19 (4.71-8.14) in those who only had frailty, and 1.10 (0.98-1.24) in those who only had abdominal obesity. however, participants who were both frail and abdominally obese had markedly increased or (95% ci) of 9.57 (7.75-11.81) for disability; p-value for interaction between frailty and abdominal obesity was 0.047. furthermore, while men who were both frail and abdominally obese had increased or (95% ci) of 4.67 (3.27-6.67) for disability compared to their counterparts who were neither frail nor obese, the corresponding or (95% ci) was much higher at 14.92 (11.34-19.65) in women; p value for heterogeneity by sex <0.001. conclusion: frailty and abdominal obesity interacted synergistically to increase the risk of disability in older persons, and the combined effect of both factors on disability was much stronger in women than in men. background: as the world's population ages, the prevalence of cognitive impairment associated with age increases exponentially. objectives: objective of this study was to investigate the longitudinal association of physical activity and cognitive function in two deferentl populations; older adults from mexico representing latin america and south korea representing asia. based on two large population-based longitudinal studies. methods: this is a secondary analysis of two surveys, mhas and klosa, designed to study the aging process of adults living in mexico and south korea. participants>50 were selected from rural and urban areas. here we investigate the longitudinal association of exercise and cognition using the two waves of each study. cross cultural cognitive examination and mini-mental state examinarion were used to analyze the association between physical activity and cognition in mexican and korean older adults. multivariate logistic regression models were used to evaluate the said association. results: in mexico, the prevalence of physical activity was 40.68%, physical active older adults obtained a higher score in ccce (0.099 ± 1.01) p-value < 0.001. they also had more years of education (5.63 ± 4.61 vs. 5.10 ± 4.27) p-value <0.001, had depression (31.55% vs. 35.25%) 0.0090 and consumed less alcohol (89.91 vs. 93.03) p-value <0.001. in korea, the prevalence of physical activity was 35.57%. the physical active group performed better in mmse (-0.123 ± 1.05 vs. 0.046 ± 0.90) p-value <0.001. the no physical active group had a higher proportion of women, less alcohol consumption (50.01 vs. 55.22%) p-value <0.001, fewer years of education p-value < 0.001 and a higher prevalence of depression (5.12% vs 3.64%) p-value 0.0090. in the multivariate analysis an independent association was found in the korean population between physical activity and mmse score even after adjusting for confounders (0.0866 (0.0266 ; 0.1467) p value 0.0047). conclusion: physical activity could have a protective effect on the cognitive decline associated with ageing. background: aging is related to the increase of several chronic diseases, such as, osteoarthritis, osteoporosis, diabetes, hypertension and sarcopenia. sarcopenia (progressive loss of muscle mass and physical performance) is related to difficulties in treating other comorbidities, whether pharmacologically or non-pharmacologically. it's important to understand the relations between muscular strength (w), muscular mass and the phase angle (pa) of bioimpedance, in sarcopenic subjects to prescribe more accurate treatments. objectives: to study the relations of skeletal muscle index (smi) with w, pa and the presents of comorbidities (nc) in elderly subjects. methods: a prospective, observational secondary analysis of data from the "the sarcopenia screening and health related issues in the region of algarve", was performed. community independent living elderly subjects were recruited. body composition was measured by bioimpedance (seca analytics 115), knee flexion and extension isokinetic strength (60º/sec) (humac norm). a screening questionnaire was used to determine the presence of comorbidities. smi levels were assessed using european working group on sarcopenia in older people cut-off points. results: a total of 46 female and 12 males, were included, mean age 73,7 (± 7,64 sd). subject were divided into 3 groups according to smi: normal (n=21), moderated impairment (n=18) and severe impairment (n=19). pearson correlation were calculated within each group for w; pa and comorbidities. normal smi level, were correlated to knee extensors w in both legs (right: r=0,510, p<0,05 and left r=0,506, p<0,05) . no significant correlations were found with pa. moderate smi level: were correlated to knee extensors w in both legs (right: r=0,742, p<0,001 and left r=0,708, p≤0,001), and also with knee flexors w (right: r= 0,677, p< 0,005; left: r= 0,659, p<0,005). a moderate correlation was also found in this group with pa (r= 0,472, p< 0,05). severe smi level: no correlations were found, in this group, with w. a moderate correlation was found with pa (r= 0,565, p< 0,05). comorbidities did not have any correlations with smi levels. conclusion: our results seem to indicate that isokinetic strength (work) may have in the future a role in understanding sarcopenia, once it is related to smi. also, pa may indicate moderate and severe smi impairment. background: body characteristics as low muscle mass and high fat mass (fm) affect the physical function of older people. physical function is a fundamental component for the performance of daily activities and for the maintenance of the independence of older adults. however, the relationship between body composition and physical performance varies in different studies and still demands further research. objectives: this study aimed to investigate the association of fat mass index (fmi) determined by dual-energy x-ray absorptiometry (dxa) with physical performance in brazilian communitydwelling older adults. methods: a cross-sectional study with a sample of 55 participants aged 60 years and older, living in ribeirão preto, brazil, including both men and women, was conducted. fm was measured by dxa and fmi was calculated as fat mass/height2 (kg/m²). the physical performance was assessed by the 6-minute walk test, and walking distance was recorded as the main parameter, considering the distance predicted by sex. the kolmogorov-smirnov test was used to verify the normality of data distribution. the association of physical performance and fmi was analyzed using the pearson's correlation test and statistical significance was set at p ≤ 0.05 (two-sided). results: the participants were aged 70.13±6.3 years, fmi was 9.88±3.1kg/m2 and distance walked was 454.6±83.2m. there was a significant negative association (r = -277, p = 0.040) between fmi and distance walked, showing that higher fat mass index is associated with worse performance in the 6-minute walk test. conclusion: high fat mass index is associated with worse physical performance in brazilian older adults. background: sarcopenia and physical frailty have been shown to be risk factors for mortality and major morbidity in older adults suffering from various forms of cardiovascular disease. ultrasound measurement of quadriceps muscle thickness (qmt) is an emerging biomarker for sarcopenia, which we hypothesized could be conveniently acquired during the routine echocardiographic exam. objectives: to demonstrate the feasibility of measuring qmt at the time of echocardiography, and determine the association between qmt and clinical indictors of frailty. methods: adult inpatients and outpatients undergoing a clinically-indicated echocardiogram for known or suspected cardiovascular disease were recruited for this cross-sectional study at the jewish general hospital. prior to the echocardiogram, trained research assistants measured height, weight, and three clinical indicators of frailty: rockwood's clinical frailty scale, handgrip strength (jamar dynamometer), and bioimpedance phase angle (inbody 770). at the conclusion of the echocardiogram, cardiac sonographers blinded to the preceding assessments acquired a biplane image of the anterior thigh midway between the anterior superior iliac spine and knee, and measured qmt as the combined thickness of the rectus femoris and vastus intermedius muscles. a cardiac ultrasound machine and probe were used (ge vivid e9/e95, 1.5-4.5 mhz probe). results: the cohort consisted of 301 patients, of which 290 had an available measure of qmt. the acquisition and measurement of qmt added 1-2 minutes to the echocardiographic exam. the mean age was 65+/-15 years with 56% females. the mean qmt was 30+/-9 mm, similar in men and women, with the lowest quintile being <22.2 mm. higher age and lower body mass index were associated with lower qmt. after adjustment for age, sex, and body mass index, qmt was found to be associated with the multivariate composite of frailty indicators (p<0.001), particularly with the clinical frailty scale (beta -0.03 per mm; ci -0.04, -0.01) and bioimpedance phase angle (beta 0.02 per mm; ci 0.01, 0.03). additional adjustment for heart failure and inpatient status did not alter results. conclusion: qmt can be efficiently measured during a routine echocardiographic exam and can add incremental insights about frailty in a diverse group of patients with cardiovascular disease. background: frailty is a clinical syndrome whose signs and symptoms are predictors of health complications, making this a major public health problem. objectives: this study aims to evaluate the prevalence of frailty, in communitydwelling older adults enrolled in a physical exercise program in the north region of portugal, based on fried's phenotype, its association with other variables. methods: in this crosssectional analysis, we used data from 419 individuals who were enrolled in physical exercise programs. gender and age standardized prevalence and the association between frailty and sociodemographic (age, gender, marital status, education, shortage of money) physical (self-perceived health, polypharmacy, physical fitness, vision, hearing), cognitive (memory), social (emptiness, loneliness and abandonment) and psychological (depression and anxiety) variables were evaluated. results: of the 419 participants, the mean age was 72.4±5.5 years old, and 69.2% were female. prevalence of pre-frailty and frailty were of 46.8% and 5.0%, respectively. from the 5 fried's phenotype criteria, exhaustion is the most common reported by 58.2% of the pre-frail and 76.1% of the frail participants. age, marital status, self-perception of health, physical fitness, memory and depression were found to be independently associated with pre-frailty, while age, education, self-perception of health, physical fitness and anxiety were independently associated with frailty. conclusion: we reported lower prevalence of pre-frailty and frailty compared with other studies, showing that physical exercise may delay the progression of frailty. interventions aimed to prevent frailty must address the diversity of the associated variables. background: frailty is related with ethnicity and impaired physical capacity which is also affected by diabetes. however, little is known about how physical health indicators of frailty are associated with each other in older hispanics with diabetes. objectives: the goal of this study was to investigate the relationship between physical health indicators of frailty in older hispanics with diabetes. methods: thirty-eight older hispanics with diabetes (29 women, 9 men, age = 79±7 years) participated in the study. the variables included age, weight, body mass index, body composition (% of muscle mass and body fat -bio-impedance), fear of falls (falls efficacy scale international -fes-i), chair stands in 30 sec, grip strength (jamar® dynamometer), balance with eyes open and closed (force plate), preferred walking speed, gait velocity during regular and reduce time street crossing simulations (gaitrite®). results: characteristics: body mass = 75±16 kg, % of muscle mass = 25±5%, % of body fat = 40±11%, fes-i score = 29±11 points, chair stands = 8±4 repetitions, grip strength = 21±6 kg, center of pressure area with eyes open = 5±3 cm2 and with eyes closed = 8±6 cm2, preferred walking speed = 81±22 cm/s, gait velocity during regular = 100±29 cm/s and during reduced time street crossing = 124±34 cm/s. there were significant correlations (*p<0.05, **p<0.01) between age and gait velocity during regular street crossing (r = -0.34*); grip strength and % of body fat (r = -0.51**) and % of muscle mass (r = 0.56**); chair stands and preferred walking speed (r = 0.63**), gait speed during regular (r = 0.68**) and during reduced time street crossing (r = 0.60**) and center of pressure area with eyes closed (r = -0.36*), and between fear of falls and center of pressure area with eyes closed (r = 0.56**). conclusion: gait speed during street crossing simulations decreased with age. greater grip strength was associated with lower % of body fat and higher % of muscle mass. people who completed less chair stands in 30s also walked slower and had worse balance, and those with poor balance had increased fear of falls. britta c arends, lisa verwijmeren, peter g noordzij, douwe h biesma, leon timmerman, eric pa van dongen, heleen j blussévan oud-alblas (st. antonius hospital -nieuwegein, netherlands) background: chronic pain after cardiac surgery is common and has a negative impact on quality of life. frailty is an important risk factor for adverse surgical outcomes. the influence of frailty on chronic pain after cardiac surgery is unknown. objectives: this study aimed to address whether frailty characteristics were associated with chronic pain after cardiac surgery in an older population. methods: this study was based on the anesthesia geriatric evaluation (age) and quality of life after cardiac surgery study, which included 560 patients >= 70 years undergoing elective cardiac surgery. preoperatively, frailty was tested in physical, mental and social domains. pain was evaluated with the short form 36 questionnaire (sf-36) preoperatively and one year after surgery. multivariate logistic regression was used to investigate the association between frailty and chronic pain. change in health related quality of life (hrql) was analyzed to evaluate the impact of chronic pain. results: 426 (78%) patients were included in the analysis. 84/426 patients (20%) reported new or increased pain one year after surgery. in 356 patients (84%) at least one frailty characteristic was present and 118 patients (28%) were frail in two or more domains. after adjustment for possible confounders in multivariate analysis, patients with single status and polypharmacy were at increased risk for new or increased chronic pain (aors 1.86 (95% ci 1.01 -3.41) and 2.13 (95% ci 1.11 -4.11). new or increased chronic pain was associated with a worse hrql (aor 2.81; 95% ci of 1.61 -4.90). conclusion: frail patients are at risk for chronic pain and worse hrql after cardiac surgery. future research should focus on perioperative interventions to reduce chronic pain in elderly patients. background: frailty is a vulnerability state that is associated with negative outcomes such us falls, in-hospital admissions and mortality. many factors can contribute to the pathogenesis of frailty and nutritional status is playing and important role. that´s why undernutrition and frailty must be overview in older adults before surgical procedures in order to treat them earlier. objectives: identify the relationship between physical frailty and undernutrition in older adults undergoing elective abdominopelvic surgery in a general hospital in lima-perú. methods: this is a secondary database study from the original "physical frailty and adverse events in older adults undergoing elective pelvic abdominal surgery in a general hospital, lima-perú", it was realized between august 2017 and march 2019, using validated face to face questionnaires. physical frailty was determined with fried criteria, undernutrition by mini nutritional assesment (mna). in adition, they also evaluated functional status and cognition. univariate models were performed, and logistic regression was done subsequently. results: 171 older adult met inclusion´s criteria, the mean age was 68.7(+6.8) years old, 50,0% (86) were female, 29,7% (51) had hypertension, 12,2% (21) were diabetic, the mean number of comorbidities were 2.4 (+0.7), 11,1% (19) had functional impairment, 9,5%(16) had cognitive impairment. the mean bmi was 27.41 ± 4.80. 16,57% (28) were underweight, 49.70%(84) normal ,17.75%(30) overweigth and 15.98% (27) obese. by mna 31 % (53) had risk or undernutrition, 22.64% (12) of them had functional impairment in contrast with 5,9%(7) who weren´t at risk or undernutrition; p=0.002. also, 16.98 %(9) who had risk or undernutrition had cognitive impairment in contrast with 5.93%(7) who weren´t at risk or undernutrition; p=0.014. by fried criteria, 29% (49) were frailty, 66 % (113) prefrailty and 5,3% (9) robust. the frailty patients 53% (26) had risk or undernutrition vs 23,08%(26) in prefrailty and 1.11%(1) in robusts; p=0.000. conclusion: there is an increased risk of undernutrition in frail older adults undergoing abdominopelvic surgery at a general hospital in lima, peru. background: cognitive frailty increases the risk of dementia, dependency and mortality in older people. moderatevigorous physical activity (mvpa) improves frailty syndrome and cognitive functions in older people, but being physically inactive is still prevalent. walking is the most common and inexpensive form of physical activity in older people and brisk walking is a form of mvpa. m-health has been successful in changing health behaviours in many populations. however, its effect in treating cognitive frailty through promoting mvpa in older people is not known. objectives: the aims of this study were to examine the effects and feasibility of an m-health intervention. methods: a pilot randomized controlled trial was employed. eligibility criteria include 1) age > 60 years, 2) living in community, 3) having cognitive frailty, and 4) mobility at "outdoor walker" level. the study was conducted in community settings. subjects were recruited in the elderly community centres. subjects were randomized into either intervention or control at a 1:1 ratio. in the intervention groups, the subject received a smartphone pre-installed with physical activity tracking and social media applications. they received a course of brisk-walking in daily living training, health education, and a 12-week behavioural change intervention on the smartphone platform. in the control group, participants received a course of brisk-walking in daily living training, health education, and telephone follow-up. the outcomes were frailty (ffi), cognitive function (moca) and mvpa (actigraph). we targeted at recruiting totally 30 subjects. nonparametric tests were used to compare the effects within and between groups. missing values were replaced by last observed values. results: this study recruited 33 subjects (intervention: n=16, control: n=17). significant improvements in frailty (p<0.01), cognitive function (p<0.01), and mvpa (p<0.05) were observed in the intervention group after the completion of the intervention. only cognitive function was also observed to be improved in the control group (p<0.01). the compliance of wearing devices (i.e., smartphones and actigraphs) and the usage of the smartphone applications were highly satisfactory. three subjects withdrew from the study (intervention: n=1, control: n=2). conclusion: m-health intervention is feasible to treat cognitive frailty in older people. it is more effective to ameliorate frailty and increase mvpa in older people with cognitive frailty when compared to conventional training. background: the prevalence of dementia and associated healthcare cost increases with aging population. population health management and proactive screening with increased emphasis on primary risk reduction may reduce the overall prevalence of dementia. motoric cognitive risk syndrome (mcr) has been increasingly studied as a pre-dementia stage to identify older adults at risk of transiting to dementia while few studies explored the association between mcr and functional capabilities. objectives: the aims are to investigate the prevalence of mcr and its associated factors among community-dwelling older adult and also to examine possible impact of mcr on functional capabilities. methods: data for 546 older adults aged above 60 years old staying in northwest region of singapore was used. mcr was defined as slow gait speed over 4m (1 sd below population mean) with subjective memory complaints in the absence of dementia. functional capability was determined by administering the lawton instrumental activities of daily living (iadls). differences in demographics, socioeconomic and lifestyle factors between mcr positive and mcr negative groups were found using independent t-test and chi-square test. risk factors of mcr and impact of mcr on functional capability were examined using logistic regression. results: the prevalence of mcr in the studied population was 7.1%. after adjusting for demographics and socio-economic factors, indians (adjusted or = 5.79, 95% ci = 1.36-24.57, p = 0.017), increasing age (adjusted or = 1.09, 95% ci = 1.04-1.14, p <0.01), higher bmi (adjusted or = 1.12, 95% ci = 1.05-1.20, p <0.01) increased likelihood of mcr while increased years of education decreased likelihood (adjusted or = 0.91, 95% ci = 0.84-0.99, p = 0.028). the odds of having at least one impairment in iadl after adjusting for demographics, socio-economic and health factors amongst those with mcr were 3.65 (adjusted or = 3.65, 95% ci = 1.37-9.72, p = 0.01). conclusion: our study found 1 in 14 to have mcr, the pre-dementia stage. indian ethnicity, those with increased age and higher bmi are at greater risk of having mcr. as mcr is also associated with functional impairment, it can serve as a useful screening tool to identify those at risk of progressing to dementia. background: sleep disturbance has been found in older persons with dementia, which impact on the quality of life of older persons and on the caregiving burden of the family. little is known about the sleep patterns and sleep problems of older persons with dementia. exploring these data would provide basic information to develop interventions for this population. objectives: to explore sleep patterns and sleep problems in community-dwelling older persons with dementia. methods: the sample recruited by purposive sampling consisted of 88 community-dwelling older persons with any stage of dementia who used healthcare services at outpatient departments of a university hospital, thailand. data were collected using a demographic data questionnaire, a sleep diary recorded by caregivers, and an electronic wrist activity tracker to assess sleep data for 3 consecutive nights. the data had been collected for three months and were analyzed using descriptive statistics. results: the sample had an age range from 65 to 101 years (m= 82.33, sd = 7.15). the total sleep data of the 88 older persons with dementia consisted of 264 episodes. almost all of the sleep data showed the polyphasic sleep pattern (sleeps for several periods of time a day), but a few had monophasic and biphasic sleep patterns. the total sleep time per night ranged from 3 to 13 hours with a mean of 9 hours. the mean sleep latency was 35 minutes, by which two-thirds of them had sleep latency less than 30 minutes. three-quarters of the data woke up at night. the mean duration of waking up at night was 26 minutes. two-thirds of the data had sleep problems, including insomnia, waking after sleep onset, and excessive daytime sleeping. also, most of them had snoring (74%), followed by sleep talking (53%). conclusion: the polyphasic sleep pattern was found mostly in older persons with dementia. also, they had sleep problems of insomnia at night and excessive sleeping during the daytime. healthcare providers may use the results from this study to understand the sleep patterns and then find strategies to promote the sleep quality of older persons with dementia. yumi umeda-kameyama 1 , masashi kameyama 2 , taro kojima 1 , masaki ishii 1 , shinya ishii 1 , mitsutaka yakabe 1 , kiwami kidana 1 , tomohiko urano 1,3 , sumito ogawa 1 , masahiro akishita 1 ((1) department of geriatric medicine, the university of tokyo school of medicine, tokyo, japan; (2) department of diagnostic radiology, tokyo metropolitan geriatric hospital and institute of gerontology, tokyo, japan; (3) department of geriatric medicine, international university of health and welfare, narita, chiba, japan) background: «perceived age» of facial appearance in elderlies was shown to be a robust biomarker of aging that predicts survival, telomere length, and dna methylation. it is also reported to correlate with carotid atherosclerosis and bone status. objectives: this study aims to determine whether perceived age is a better biomarker than chronological age for a variety of aspects in dementia assessment, which includes general cognition, vitality, depressive state, and selfsupportability. methods: one hundred twenty-six patients admitted to the department of geriatric medicine, the university of tokyo hospital with suspect of cognitive decline were enrolled. mmse, vitality index, gds15, iadl, and barthel index were performed. ten geriatricians and clinical psychologists determined the perceived age of subjects based on their photographs. results: the average values of 10 rates showed excellent reliability (icc(3,10)=0.941). perceived age showed significantly better correlation with mmse (female), vitality index (total, female), and iadl (total) than chronological age by steiger's test, but not with gds15 and barthel index. conclusion: perceived age was demonstrated to be a better biomarker for cognitive assessment than chronological age. l a u r a t a y 1 , h u d a m u k h l i s 1 , jolene ho 1 , aisyah latib 2 , eeling tay 3 , shimin mah 3 , candy chan 4 , yeesien ng 1 ((1) department of general medicine, sengkang general hospital, singapore; (2) office of regional health system, singhealth, singapore; (3) department of physiotherapy, sengkang general hospital, singapore; (4) dietetics, sengkang general hospital, singapore) background: cognitive frailty is characterized by co-existence of physical frailty and cognitive impairment. earlier studies reported aggravated health outcomes attributable to cognitive frailty over physical frailty alone. objectives: we examine risk factors for cognitive frailty, and its impact on physical performance and health outcomes, compared with isolated occurrence of cognitive impairment or physical frailty. methods: cross-sectional analysis of 757 communitydwelling older adults who completed multi-domain geriatric screen assessing for social vulnerability, mood, cognition, functional performance, nutrition, physical frailty (frail) and sarcopenia (sarc-f). cognitive impairment was defined using locally validated education-adjusted cut-offs on modified-chinese mini-mental state examination. participants underwent physical fitness tests comprising grip strength, gait speed, lower limb strength and power, flexibility, balance, and endurance. health outcomes included hospitalization, emergency department visits, falls and self-rating of health. each participant was categorized as robust-cognitive intact (pf--/ ci-), pre-frail/ frail only (pf+/ ci-), cognitive impaired only (pf-/ ci+), and cognitive frailty (pf+/ ci+). results: mean age of study cohort was 67.6(6.7)years. 523 (69.0%) were pf-/ci-, 122 (16.1%) pf+/ci-, 73 (9.6%) pf-/ci+, and 39 (5.2%) pf+/ ci+. in multi-nomial logistic regression referenced to pf-/ci-, older age significantly increased risk for pf-/ci+ and pf+/ci+. cognitive frailty contributes to worse physical performance and poorer health outcomes compared to physical frailty and cognitive impairment in isolation. while social vulnerability and depression were differentially associated with isolated frailty status, malnutrition and sarcopenia should be targets for preventing frailty and cognitive impairment. osamu katayama, sangyoon lee, seongryu bae, keitaro makino, ippei chiba, kenji harada, yohei shinkai, hiroyuki shimada (department of preventive gerontology, center for gerontology and social science, national center for geriatrics and gerontology, japan) background: cognitive frailty is a condition recently defined by operationalized criteria describing coexisting physical frailty and mild cognitive impairment (mci). however, there is no consensus on the definition of cognitive frailty for use in clinical and community settings. objectives: this study aimed to use latent class analysis (lca) to discover potential subtypes of cognitive frail older people. in addition, we explored the relationship between the identified cognitive frailty subtypes, and their demographical, neuropsychological, body composition, and lifestyle activity characteristics. methods: a total of 7309 community-dwelling older adults aged >= 60 years participated in the study. we characterized physical frailty as >= 3 of the following criteria: slow walking speed, muscle weakness, exhaustion, low physical activity, and weight loss. we used tests of word list memory, attention, and executive function, and processing speed to screen for cognitive impairment. the presence of >= 1 cognitive impairments were defined as mci. we defined the condition where physical frailty and mci coexist as cognitive frailty. lca was applied to characterize classes or subgroups with different cognitive frailty phenotypes. subsequently, we performed multinomial logistic regression analysis with cluster membership as dependent variable and dichotomized demographics and lifestyle activity characteristics as independent variables. results: lca identified eight distinct subgroups included three different cognitive frailty phenotypes: cognitive frailty composed of physical frailty and amnestic mci (acf), cognitive frailty composed of physical frailty and non-amnestic mci (nacf) and, cognitive frailty in which physical frailty and global cognitive impairment (gcf). cognitive frailty subtypes were associated with distinct demographical, neuropsychological, and lifestyle activity characteristics. in particular, the acf cluster was associated with younger age and also related to the inactivity of productive and cognitive activities (p<0.05). the nacf cluster was related to the inactivity of social and cognitive activities (p<0.05). finally, the gcf cluster was associated with older age (p<0.05). conclusion: using lca, we identified eight distinct subgroups included three different cognitive frailty phenotypes in a large sample of community-dwelling older adults. cognitive frailty subtypes were associated with distinct demographical, neuropsychological, and lifestyle activity characteristics. sara g aguilar navarro, alberto j mimenza alvarado, itzel aparicio gonzález, clarita cabrera juárez, alejandra samudio cruz, monsal alexa, ja avila funes, teresa juarez-cedillo (instituto nacional de ciencias médicas y nutrición salvador zubiran, ciudad de méxico, mexico) background: the prevalence of mild cognitive impairment (mci) ranges between 14-18% and is 4 times more frequent than dementia. the dcl has been associated with cardiovascular risk factors, mainly changes at the executive level. the apoe4 genotype, on the other hand, is a gene that confers susceptibility to alzheimer's disease in addition to participating in lipid metabolism, giving greater risk of atherosclerosis and cardiovascular risk. however, given the genetic heterogeneity of the mexican population, this association is not clear. objectives: to establish the strength of association between the different types of dcl (amnesic and non-amnesic) in mexican mestizo older adults according to their carrier status of the apoe4 allele and cardiovascular risk factors. methods: 83 patients in a memory clinic were evaluated from 2017 to 2019, older than 75 years, without sensory deficit, psychiatric diseases or uncontrolled metabolic pathology, separating them into 3 mutually exclusive groups: healthy controls, group with amnesic mci, group with nonamnesic mci, performing geriatric and neuropsychological evaluation. parametric and nonparametric statistics (x2, anova, multivariate linear regression analyzes) were used to find statistical differences between groups. results: multivariate linear regression analyzes were performed to examine the relationship between vascular risk factors, the presence of the apoe ε4 allele, and cognitive change. apoe genotype significantly modified the associations between both hypertension and cardiovascular disease and a decline in language abilities as well as diabetes and decline in verbal memory, attention, and visuospatial abilities in non-amnestic mci. associations between increased vascular risk burden and greater cognitive decline were observed among apoe ε4 carriers but not non-carriers with mci. conclusion: the present study revealed an increase in the association between non-amnestic mci (apoe ε4 carriers with vascular risk factors) and suggests that the treatment of vascular risk factors could contribute to reducing the risk of progression of cognitive impairment, particularly among patients with apoe ε4 mexicans. background: a number of cross-sectional and longitudinal studies have demonstrated an association between physical frailty and cognitive impairment (1). many mechanisms have been suggested to explain the presence of cognitive impairment in frail subjects, such as cardiovascular risk, hormonal disturbances, chronic inflammation or nutrition (2, 3). another hypothesis is that cognitive impairment in frail patient may be due to alzheimer's disease (ad) (1, 2, 3). however, the link between frailty and amyloid deposition has to date never been studied in vivo. objectives: (1) to examine the prevalence of cerebral amyloid pathology as measured with amyloid positron emission tomography (pet) or amyloid-β-1-42 level in cerebrospinal fluid, among frail and pre-frail individuals presenting an objective cognitive impairment (2) to characterize the cognitive and clinical progression of frail cognitively impaired patients according to the amyloid status. methods: cogfrail is a monocentric observational prospective study of 345 cognitive frail and prefrail older participants (according to fried criteria), aged >=70 years, with an objective cognitive decline (defined by a clinical dementia rating (cdr) scale scoreat 0.5 or 1). the participants will be followed up every 6 months, during 2 years. in addition to cerebral amyloid pathology (measured by amyloid positron emission tomography (pet) or amyloid-β-1-42 level in cerebrospinal fluid), measurements include cognitive performance, physical function, nutritional status, depressive symptoms biology, nutrition, magnetic resonance imaging (mri), and body composition to better understand the mechanisms and progression of cognitive frailty. results: the study is currently being recruited. to date, 272 patients were included. 156 mri 170 pet scan and 10 lumbar puncture have been performed. 43 subjects completed the study. conclusion: this study will allow us to determine, for the first time, the prevalence of amyloid pathology, a marker of ad, among frail and pre-frail patients presenting objective memory impairment. the results will help characterize the cognitive decline in frail and pre-frail patients, with important implications for the detection, management and ultimately prevention of neurocognitive disorders among frail old individuals references: 1) kojima g, taniguchi background: cognitive impairment is a well-known risk factor for falls in older adults. the risk of falls is increased in those with diminished executive function and reduced processing speed. while participants with cognitive deficits are more prone to falling, it is unknown whether risk of falling on cognitively intact individuals placing them at higher risk for future cognitive decline. objectives: to ascertain the incident development of cognitive decline in those at higher risk for falls using the center for disease control's fall risk assessment tool, steadi (stop elderly accidents, deaths, and injuries) in community dwelling individuals >65 years of age. methods: we identified individuals >=65 years old using the longitudinal national health and aging trends study (nhats) that consists of eight years of follow-up. these individuals did not have cognitive impairment at baseline. fall risk was defined using the algorithm from the center for disease control's steadi initiative. participants were classified at baseline in three categories of fall risk (low, moderate, severe). impaired global cognition was defined as nhats-defined impairment in either the alzheimer's disease-8 score, immediate/delayed recall, orientation, clock-drawing test, or date/person recall. the primary outcome was the risk of incident cognitive impairment over time. cox-proportional hazard models and linear mixed-effects modeling ascertained the incidence of cognitive impairment, adjusting for age, sex, smoking status, education, co-morbidities and an ability to walk. our referent variable was individuals at low steadi fall risk. results: of the 5,822 participants (55.7% female), median age category was 75-80 years. prevalence of baseline fall risk using the steadi measure in participants was low (55.2%), medium (36.2%) and high (8.5%). the rate of cognitive impairment in our sample was 45.7%. in our fully adjusted model, the risk of developing cognitive impairment was hr 1.12 [95%ci:1.00 -1.26] in the intermediate risk group, and hr 1.78 [95%ci: 1.51 -2.11] in the high risk group. using linear mixed-effects modeling yielded similar results. conclusion: steadi fall risk at baseline was predictive of higher rates of cognitive decline in those with normal cognition. elevated fall risk by steadi may suggest need for more thorough cognitive assessment. background: the concept of cognitive reserve (cr) has been developed as a potential factor able to describe individual differences in vulnerability to cognitive, functional, or clinical decline along aging. the progressive reduction of cognitive and functional performances represents an outcome commonly associated with aging. objectives: the aim of this crosssectional study is to investigate the association of cr with cognitive and functional outcomes in a sample of elderly outpatients. methods: subjects aged >=65 were consecutively recruited. patients who were unable to undergo the execution of required tasks due to severe cognitive, functional or sensory impairment were excluded. mini mental examination (mmse), brief intelligence test (tib) and cognitive reserve index questionnaire (criq) were administered. handgrip strenght, gait speed and daily life autonomy were measured; a frailty index (fi) was eventually calculated. results: data from 105 patients were analyzed. criq was significantly correlated with mmse (r = 0.378, p <0.01), handgrip (r = 0.347, p <0.01) and gait speed (r = 0.220, p= 0,024). furthermore, criq was correlated with badl (r = 0,270, p=0,005), iadl (r= 0,330, p= 0,001) and inversely with fi (r= -0.335, p <0.01). significant correlations were found between tib and mmse (r = 0.280, p <0.05), between tib and criq (r = 0.524, p <0.01), and between tib and iadl (r = 0,197, p= 0,043). conclusion: this preliminary report highlighted that patients with higher cr showed not only better overall cognitive functioning, but also better functional status and a lower degree of frailty. in the light of a multidimensional geriatric assessment, the integrative evaluation of cr in elderly might offer the opportunity to track possible trajectories of aging, since it appeared related either to cognitive status, either to functional oucomes and to frailty. background: the clinical syndrome of "physical" frailty has been conceived without regard for cognitive decline. nevertheless, it has been suggested that frail elders exhibit frailty-specific cognitive impairments, and that the cognitive correlates of frailty may be dementing in their own right. meanwhile, we have used confirmatory factor analysis (cfa) in a structural equation model (sem) framework to construct a latent dementia phenotype, "δ". our approach is modular and can be redirected to other clinical targets. objectives: in this analysis, we create a δ ortholog representing the "cognitive correlates of frailty" (df). methods: first, we constructed a frailty index (if) from wave-5 data collected as part of the hispanic established population for epidemiological studies in the elderly (h-epese). a δ ortholog targeting if was then constructed from a cognitive battery that included the mini-mental status exam (mmse) and clox: an executive clockdrawing task (clox). results: the model fit the data well and df exhibited factor determinance. dfrailty was strongly indicated (r = 0.64, p<0.001) by if and explained 41% of the index's variance. it was also significantly indicated by mmse and clox scores. df was strongly correlated (r = 0.90, p<0.001) with instrumental activities of daily living (iadl), independently of age, gender and education. the remaining 59% of if's variance had no significant association with iadl. the orthogonal latent variable "g'", df's residual in spearman's general intelligence factor "g", was strongly indicated by all three cognitive performance measures. nevertheless, it was weakly associated with iadl. measure specific cognitive performance, residual to both df and g', had no independent: association with iadl. conclusion: these results suggest that the frailty syndrome does indeed have specific cognitive correlates. these are strongly associated with iadl and therefore potentially "dementing". like δ, the cognitive correlates of frailty are extractable from spearman's g, which may constrain the biology and psychometric properties of frailty-specific cognitive changes. independently of df, cognition has little association with iadl. this suggests that frailty may be a major determinant of iadl performance in elderly ma, and possibly a major etiology of "all cause" dementia in that population. background: cognitive-frailty has been proposed as a distinctive entity which preludes dementia. objectives: we aimed to examine the relationship between physical frailty, cognitive status, and gait performance as predictors of cognitive decline and incident dementia. methods: cohort study of 252 community older adults free of dementia at baseline with a 5 year follow-up. inclusion criteria: > 65 years, english speaking, able to ambulate one city block. exclusion criteria: hip/knee joint arthroplasty in past 6 months, parkinsonism, major depression, and diagnosis of dementia (dsm-iv criteria). cognition was assessed using the moca, the mmse, and the clinical dementia rating (cdr) scale was performed. physical frailty was defined using the phenotypic criteria described by fried and walston. cognitive-frailty was defined as the simultaneous presence of physical frailty with objective cognitive impairment, and absence of concurrent dementia. the main outcome measure was all-cause dementia (dsm-iv criteria). cox proportional hazards models were used to estimate the risk of cognitive decline and incident dementia. results: over a 5-year follow-up, 53 participants experienced cognitive decline and 27 participants progressed to dementia (global incidence rate (ir): 73 per 1000-person/y). participants with frailty had a higher prevalence of cognitive impairment (77%) compared to those without (54%, p=0.02) but the risk of progression to dementia was not significant. adding cognitive impairment to the frailty phenotype (cognitive-frailty) predicted further cognitive impairment and progression to dementia. dementia ir for frailty was 61 per 1000 person/y and for cognitive-frailty, 80 per 1000 person/y. however, when slow gait was combined with baseline cognitive impairment, it showed the highest risk of progression to dementia (hr: 35.9, 95%ci: 4.0-319.2; p = 0.001) with an ir of 130 per 1000 person/y. conclusion: frailty and cognitive impairment are common and often coexist in the same individuals. however, slowing gait seems to be the frailty component driving the association with future dementia. background: assisted bathing requires the most hours of home care. for the frail elderly and their caretakers, the bathroom presents the most risk factors for falls and injury. bathroom adaptation is the primary reason for consultation in community occupational therapy and available resources cannot meet the increasing demand. the hygiene 2.0 (h2.0) website (https://algo.grismoir.com/) addresses this need by offering a structured questioning to identify bathing assistive technology for the frail elderly living at home. objectives: our actionresearch protocol aims to establish a partnership between actors in the home care social economy enterprises (eésad), the home care programs offered through the healthcare system and the private sector (e.g., assistive technology providers). this implies: 1) adapting h2.0 to the home care service workers' needs; 2) designing an implementation model for h2.0 in order to formalize a partnership in the community; 3) conducting pilot testing in two eésad. methods: 1) user-centered design and a multiple case study where a case represents a home care worker (n=9) from a eésad (québec, canada) offering bathing assistance for the elderly. during testing, the home care worker will explore the h2.0 prototype with an elderly in his or her home, sharing their thoughts out loud. the unit of analysis is the usability of h2.0, allowing improving to the prototype after every three participants. 2) all collaborators will participate in the iterative modification of a preliminary logic model for the implementation of h2.0. modifications suggested will be integrated to the model throughout three meetings, or until a consensus is reached. 3) the adapted version of h2.0 (obj. 1) will be tested according to the implementation model developed (obj. 2). a pilot project using mixed methods in collaboration with two eésad will be conducted with 20 older adults having difficulty bathing. results: anticipated results: responsive h2.0 website adapted to the users' needs, an implementation model and pilot data allowing scaling-up technology meeting needs of frail elderly and their caretakers issues during bathing. li-ning peng 1,2,3 , fei-yuan hsiao 4,5,6 , wei-ju lee 1,2,7 , shih-tsung huang 4 , liang-kung chen 1,2,3 ( (1) background: the theory of cumulative deficits using big data to develop the multimorbidity frailty index (mfi) has become a widely accepted approach in public health and healthcare services. however, constructing the mfi using the most critical determinants and stratifying different risk groups with dose-response relationships remain major challenges in clinical practice. objectives: this study aimed to develop the mfi by using machine-learning methods that select variables based on the optimal fitness of the model and to further establish four entities of risk using a machine-learning approach as well as to ensure the dose-response relationship and the best distinction between groups. methods: in this study, we used taiwan's national health insurance research database to develop a machine-learning multimorbidity frailty index (ml-mfi) using the theory of cumulative diseases/deficits of an individual older person. compared to the conventional mfi, in which the selection of diseases/deficits is based on expert opinion, we adopted the random forest method to select the most influential diseases/deficits that predict adverse outcomes for older people. to ensure that the survival curves showed a dose-response relationship with overlap during the follow-up, we developed the distance index and coverage index at any time point to classify the ml-mfi of all subjects into the categories of fit, mild frailty, moderate frailty and severe frailty. survival analysis was conducted to evaluate the ability of the ml-mfi to predict adverse outcomes, such as unplanned hospitalizations, intensive care unit (icu) admissions and mortality. results: the final ml-mfi model contained 38 diseases/deficits in this study. compared with conventional mfi, both indices had similar distribution patterns by age and sex; however, among people aged 65-69, the mean mfi and ml-mfi were 0.037 (standard deviation (sd) 0.048) and 0.0070 (sd 0.0254), respectively. the difference may result from discrepancies in the diseases/deficits selected in the mfi and the ml-mfi. a total of 86,133 subjects aged 65 to 100 years were included in this study and were categorized into 4 groups according to the level of the ml-mfi. both the kaplan-meier survival curves and cox models showed that the ml-mfi significantly predicted all outcomes of interest, including all-cause mortality, unplanned hospitalizations and all-cause icu admissions, at 1, 5 and 8 years of follow-up (p<0.01). in particular, a doseresponse relationship was revealed between the four ml-mfi groups and adverse outcomes. conclusion: the ml-mfi consists of 38 diseases/deficits that can successfully stratify risk groups associated with all-cause mortality, unplanned hospitalizations and all-cause icu admissions in older people, which indicates that precise, patient-centered medical care can be a reality in an aging society. to return home. understanding the home environment prior to discharge is crucial. occupational therapists (ots) often depend on client's verbal descriptions, pictures and sketches when planning rehabilitation exercises and suggesting adaptations. the information obtained is therefore partial. mapit is a new mobile application which scans a room producing a 3d representation with virtual measurements of environmental elements. this could provide a more complete representation of the home needed by inpatient rehabilitation ots. objectives: to target mapit's clinical applications for inpatient rehabilitation of the frail elderly. methods: multiple case study where mapit was introduced in three inpatient geriatric rehabilitation units over 40 days. five ots maintained a logbook and participated in four individual semi-structured interviews. a deductive thematic analysis of the logbooks and interview transcripts was corroborated by two additional ots. results: mapit is useful for ots in rehabilitation settings by allowing them to 1) see it: see the home environment, 2) measure it: take measurements of desired environmental elements, 3) document it: have a copy of the environment on hand, 4) communicate it : facilitate exchanges with the client and with colleagues. with mapit, ots gain a better understanding of the environment, which informs the rehabilitation intervention. better communication could also improve the client's implementation of the therapeutic strategies. conclusion: mapit is a useful resource to optimise intensive rehabilitation for the frail elderly. sonia jiménez-mola 1 , javier idoate-gil 1 , david idoate 2 , maría plaza carmona 3 ((1) geriatric department, complejo asistencial universitario, león, spain; (2) university of salamanca, salamanca, spain; (3) urgency department, complejo asistencial universitario, león, spain) background: as the age of the population increases, the incidence of osteoporosis and its direct consequence, fragility fractures, are also increasing. hip fractures are associated with the greatest number of complications, functional deterioration, and mortality of up to 30% one year after the fracture. objectives: the aim of this study is to determine the prevalence of previous diagnosis of osteoporosis in elderly patients who suffer hip fracture and its relationship with age distribution (75-84, 85-90 and >90 years old), gender, type of fracture and funtionality. methods: we enrolled 534 patients with hip fracture, aged 75 years or older in an orthogeriatric unit between december 2013 and november 2014. underwent comprehensive geriatric assessment that evaluates comorbidities, medication use, ability to perform basic activities of daily living, place of residence, anesthesia risk as measured by the asa score, type of fracture, type of surgery and anesthesia and in-hospital mortality. spss®, v.22.0. results: the mean age was 86.1±7.3 years (75-105 years). 75.4 % female. 55% pertrochanteric fractures. (93%) underwent surgery. only 11.6% received general anesthesia. 64% walked independently, 69% had barthel >60, 132 (25%) had a previous diagnosis of dementia, and 26% live in nursing home prior to fracture. we found a previous diagnosis of osteoporosis in 58 patients (10.9%). in these patients, statistically significant differences were shown for sex p<0.05 (12.8% female vs 5.2% male), age distribution p<0.05 (14.8%(75-84) vs 10.6% (85-89) vs 6.7% (>90) and the presence of anti-osteoporotic treatments p<0.001. all other measurements (barthel index, cognitive degree, type of fracture, asa score and type of surgery, did not show statistically significant differences (p>.05). conclusion: patients in very advanced age showed neither significantly higher percentage of diagnosed osteoporosis, not significantly higher amount of preexisting osteoporosis-related medication. although the prevalence of osteoporosis increases with age, the diagnosis and treatment prevalence decreased in higher age groups. background: aging is associated with a decrease in bone density, muscle mass and a gain in fat mass which increase physical disabilities and falls. nevertheless, the impact of obesity on bone density and architecture is still controversial. furthermore, protein intake appears to be associated with maintenance of muscle and physical function, but also with bone density and architecture. however, the role of initial protein intake in osteopenic-obese older adults is still unclear. objectives: to examine the influence of initial protein intake on muscle and bone function in osteopenic-obese older adults. methods: cross-sectional a-posteriori matched study design. fourteen obese (total fat (%): men >25; women: >35) osteopenic (bmd t-score <-1.5) older adults (age >60 years old) were divided in 2 groups according to their initial protein intake (prot-(n=7): <1g/kgbw/d or prot+ (n=7): >1.2g/ kgbw/d) and were matched for age (±2years) and gender. body composition (fat, fat-free and bone masses, dxa), muscle composition and bone architecture (qpct), muscle function (grip strength, knee extension strength, muscle power), physical performance (walking speed (4m), tug (3m), unipodal balance, stair and chair tests), cardiorespiratory function (6min walking test) and lifestyle habits (physical activity level: 3-axial accelerometer and nutritional status: food record) were assessed. results: our groups (prot-vs. prot+) were similar (p>0.05) in terms of age (66.3±3.8 vs. 65.4±2.2 years), bmi (26.9±5.2 vs. 26.3±3.9 kg/m2), body fat (total(%): 33.4±5.9 vs. 37.6±4.0), muscle quantity (fat-free mass or limb muscle area) and quality (intra & submuscular adipose tissues), bone density (total hip or spine) and architecture (marrow, cortical or total area, and compressive or torsion strength), physical performance (walking speed(m/s): 0.75±0.13 vs. 0.75±0.06), cardiorespiratory function, lifestyle habits (steps: 7734±2867 vs. 8032±3418), except (by design) for the initial amount of protein intake (0.8±0.2 vs. 1.4±0.2 g/kgbw/d) respectively. conclusion: the initial protein intake does not seem to influence bone architecture, muscle function, or physical performance in elderly osteopenicobese. obesity but also the level of protein intake above the official recommendation (>0.8g/kgbw/d) could explain these conclusions. thus, future studies are needed to confirm our preliminary results. background: the glim definition of malnutrition is the first intended to be used globally. glim uses five criteria (two phenotypic and three etiologic) for the diagnosis of malnutrition, which is made when at least one etiologic and one phenotypic criterion are present. mna-sf is a validated widespread screening tool used in geriatric settings. glim and mna have not been compared in acute geriatric care. objectives: to measure the prevalence of malnutrition in older patients admitted to an acute geriatric unit using glim criteria and to assess the accuracy of the mna-sf in predicting glim defined malnutrition. methods: a prospective study was conducted among all patients older than 80 years old admitted to an acute geriatric unit. end-of-life situations and wearers of pacemakers were excluded. glim criteria and mna-sf were assessed on admission. muscle mass (one of the glim criteria) was estimated by bioimpedance (thresholds for low muscle mass: <21.4 kg in men; <14.1 kg in women). results: 171 patients were included (mean age 92.9±3.7 years, 72% women). on admission, 55.6% were malnourished according to the glim criteria (84.2% met at least one etiologic criterion, 63.2% met at least one phenotypic criterion). 53.8% were malnourished using mna-sf. however, there was no correlation between glim and mna-sf (correlation coefficient r=-0.05, p=0.076). mna-sf had low sensitivity (51.6%) and low specificity (43.4%) to detect malnutrition diagnosed with the glim criteria (roc curve auc=0.475). conclusion: more than half of the very old patients admitted to an acute geriatric unit were malnourished according to the glim diagnostic criteria. a very similar proportion of patients had a mna-sf suggesting malnutrition. however, mna-sf had a low reliability to detect patients with glim defined malnutrition. corina naughton 1 , rachel simon 2 , tj white 2 , darren daly 3 ( (1) background: hospitalised older adults are at risk of hospital associated decline (had). optimising nutrition intake is an important modifiable factor in protecting against had and promoting recovery, but food intake and the quality of mealtimes are frequently overlooked nursing activities. objectives: the study aim was to undertake an in-depth analysis of mealtime practices and to identify patient and mealtime factors associated with low food intake (<eating 50% of meal provided). methods: we carried out structured observation of mealtimes using a validated tool examining patient positioning, mealtime set up and assistance. the primary outcome was food consumption categorised as 0, 25%, 50% 75% or 100% based on visual inspection of food trays. data were also collected on patient characteristics. data analysis used descriptive statistics and univariate logistic regression to examine the association between low food intake and mealtime and patient factors. results: we included 295 mealtime observations on 63 patients aged 65 years and older. at 41% (n=122) of meals, patients ate half or less of the food provided. meal time factors with a weak association with low intake were: allocated red tray (an indicator of nutrition risk), modified diet, and needing assistance. breakfast time was the most important meal for food intake. nearly half of the patients (31/63) ate 50% or less of the food provided on two or more occasions over a 48-hour period. patient frailty and a moderate to high nutrition risk score were independently associated with low food intake. conclusion: patient factors are the strongest predictors of low food intake. increasing the quality of the mealtime experience and more tailored nutrition plans could improve nutrition intake in frail older adults. were hospitalized at least once, 149 (40.7%) fell at least once, and 35 (9.6%) had at least one fracture during the 4-year follow-up. no association was found between malnutrition and 4-year risk of institutionalization, hospitalization, falls, or fractures (p>0.05). conclusion: malnutrition according to glim criteria was associated with a 4.4-fold higher mortality risk; double that of the espen criteria, during a 4-year followup. no association was found between malnutrition according to these two criteria and incidence of other adverse health consequences. glim criteria anticipate outcome and might guide interventions, with important implications for clinical practice and research. background: older adults are at high risk of developing cardiovascular disease. pre-clinical studies indicate that resveratrol (rsv), a polyphenol present mostly in grapes and red wine, may prevent development of cardiovascular disease. objectives: our hypothesis was that rsv will reduce biomarkers of cardiovascular disease risk in obese, rather healthy older adults in a dose-dependent manner. methods: older participants (65 years and older) were randomized to a 90 day rsv treatment with 300mg (n=10), 1000mg (n=9) or placebo (n=10). we measured levels of atherosclerosis development risk biomarkers i.e. oxidized low-density lipoprotein (oxldl), soluble e-selectin-1 (se-selectin), soluble intercellular adhesion molecule-1 (sicam-1), soluble vascular cell adhesion molecule-1 (svcam-1), total plasminogen activator inhibitor (tpai-1). statistical significance was set at p<0.05. results: changes in svcam-1 300mg vs. 1000mg vs. placebo: (-10.4±43.8 ng/ml vs. 130.2±38.2 ng/ ml vs. 15.1±51.4 ng/ml) and tpai-1 300mg vs. 1000mg vs. placebo (-1.6±5.1 ng/ml vs. 15.2±3.5 ng/ml vs. 4.9±5.9 ng/ ml) indicate significantly higher levels in a 1000mg group compared to a 300mg and a placebo groups. other biomarkers (300mg vs. 1000mg vs. placebo: oxldl, seselectin-1 and sicam-1) followed the same trend toward higher levels in the 1000mg group compared to the 300mg and placebo groups, without reaching statistical significance. conclusion: this pilot project suggests that a higher dose of rsv may increase the levels of cardiovascular disease risk biomarkers in overweight older adults. given no change in the cardiovascular disease risk biomarkers in response to a lower dose, future studies should test the effects of different doses of rsv on reduction of cardiovascular disease biomarkers in overweight, rather healthy older adults. background: actual nutrition is a factor that continually effects physiological capacity and workability, the functional aging rate of an elderly persons. objectives: the purpose of this study was to determine the relationship between nutrition and physiological abilities, the work performance, functional aging rate, residual working capacity and frailty of the elderly. methods: it has been studied anthropometric and functional parameters of respiration, physical performance, mental capability, sensory skills, as well as the rate of functional aging in different aging groups: 20-30 years -43 persons, 60-89 years -120 persons, 90 -104 years -36 persons. we have also analyzed the professional history, social status, and factual nutrition (according to the questionnaire proposed by the who and adapted for ukraine) of the elderly. results: the nutrition or diet factors influence on the problems dealing with working capability, reduction of the hand grip strength and endurance, independence and frailty (for elderly) in overall 10.53% for all mentioned factors. right and left hand grip strength associate with protein consumption (r = 0.253; r = 0.248; p < 0.01 accordance) with variety of cereals (r =-0.224; r =-0.227 p < 0.05 accordance) also with variety of vegetables (r = 0.209; r = 0.196; p < 0.05 accordance)variety of fruits (r = 0.254; p < 0.01; r = 0.216; p < 0.05 accordance). it was studied features of an actual food at 36 centenarians of ukraine which not only have lived to this old age, but also have the relatives who have lived to age of centenarians. it was established, that meals of ukrainian centenarians include high percentage of vegetables, fruits and dairy products. meanwhile menu has been deprived practically all basic alimentary pathology risk factors which accelerates biological age, creates certain preconditions to preservation of health and longevity. conclusion: as a result of a comprehensive study and mathematical modeling was developed a quantitative method for assessing the residual working capacity for elderly persons. background: age-related decline in olfactory function has implications for health and nutrition due to reduced appetite and decreased sensory perception of food. several studies have investigated olfactory performance in the elderly, but studied mostly single odour components often less related to food and meals. food odours are composed of multiple odorants and compensation for specific perceptual losses among elderly may occur. therefore, it is relevant to study olfactory perception of complex food odours to improve understanding of odour perception in the context of foods and meals. objectives: to develop a test method to screen young and elderly (60+) subjects on their olfactory capacity for everyday food odours. the method included a series of sniffing sticks with relevant and familiar complex food odours from primarily essential oils. methods: the olfactory sniffing sticks test kit was developed in four steps: 1) selection and validation of relevant, familiar and diverse food odours, evaluated on perceived familiarity. 2) standardization of an iso intensity reference level for the food odours in relation to n-butanol. 3) assessment of shelf-life stability for the sniffing sticks within an 8 weeks period. 4) evaluation of test-retest reliability for intensity and identification of the odours within a 2 weeks period. results: 16 food odours were selected due to their diverse sensory characteristics. they were provided from a french manufacturer which may have compromised the familiarity in a danish context as only 12 out 16 obtained satisfactory familiarity score. however 14 out 16 showed reliable results in a test-retest procedure. n-butanol, in two concentrations provided a satisfactory reference frame for the iso intensity scaling. furthermore the food odours were overall shelf-life stable within an 8 weeks period. conclusion: a new odour test kit for everyday food odours was developed and validated for screening olfactory capacity (intensity perception, familiarity and identification) in elderly subjects. based on the evaluations, 15 odours were included in the final test kit. this olfactory test reflects the complex stimulation of the olfactory system, when stimulated by eating a food, compared to odour test kits with single or few components which makes it relevant when customizing of meals for elderly to improve nutrition and wellbeing. background: nordic nutrition recommendations (nnr) (2012) suggest protein intake >=1.1 g/kg body weight (bw) to preserve physical function in nordic older adults. however, no published study has used this cut-off to evaluate the association between protein intake and frailty. objectives: this study examined associations between protein intake, and sources of protein intake, with frailty status at the 3-year follow-up. methods: participants were 440 women aged 65-72 years enrolled in the kuopio osteoporosis risk factor and prevention -fracture prevention study. protein intake g/kg bw and g/d was calculated using a 3-day food record at baseline 2003. at the 3-year follow-up (2006), frailty phenotype was defined as the presence of three or more, and prefrailty as the presence of one or two, of the fried criteria: low grip strength adjusted for body mass index, low walking speed, low physical activity, exhaustion was defined using a low life satisfaction score, and weight loss >5% of bw. the association between protein intake, animal protein and plant protein, and frailty status was examined by multinomial regression analysis adjusting for demographics, chronic conditions, and total energy intake. results: at the 3-year follow-up 36 women were frail and 206 women were prefrail. higher protein intake >=1.1 g/kg bw was associated with a lower likelihood of prefrailty (or=0.45 and 95% confidence interval (ci) =0.01-0.73) and frailty (or=0.09 and ci=0.01-0.75) when compared to protein intake <1.1 g/kg bw at the 3-year follow-up. women in the higher. conclusion: protein intake >=1.1 g/kg bw and higher intake of animal protein may be beneficial to prevent the onset of frailty in older women. background: sarcopenia is a geriatric syndrome with increasing importance due to the aging of the population. progressive resistance training and protein supplementation are currently recommended for the prevention and treatment of sarcopenia. however, elderly are less responsive to these anabolic stimuli compared to healthy adults. inflammation is considered an important contributor to this age-related anabolic insensitivity. therefore, anti-inflammatory strategies, such as omega-3, are a promising strategy to combat sarcopenia. furthermore, omega-3 were also shown to improve muscle anabolism though activation of the mtor signalling pathway and reduction of insulin resistance. objectives: firstly, we performed a narrative review of literature that gives an overview of the current knowledge about omega-3 intake and sarcopenia defining parameters (grip strength, gait speed, muscle strength or physical performance). secondly, we provided an overview of data on omega-3 supplementation and sarcopenia defining parameters. methods: a literature search was conducted in november 2018, using electronic bibliographic databases (pubmed and embase). the reference lists of all full texts retrieved during the search process or as identified in already published (systematic) reviews were scanned. results were published in a narrative review (dupont j. et al. 2019 aging clin exp res.) results: seven observational studies described the associations between omega-3 intake and sarcopenia defining parameters. four interventional studies looked at the effect of omega-3 supplementation alone and suggested an improved muscle protein synthesis, improved gait speed and increased muscle strength and physical performance. three studies combining exercise with omega-3 supplementation suggested an enhancing effect of the supplement on the exercise-induced gains in muscle mass and strength. we found one study combining omega-3 and protein supplementation with exercise, but omega-3 dosage was too low for conclusive results. conclusion: observational data on omega-3 intake and sarcopenia remain conflicting. from current interventional data we conclude that there is growing evidence for a beneficial effect of omega-3 supplementation in sarcopenic elderly, which may add to the effect of exercise and/or protein supplementation. however, the exact dosage, frequency and use (alone or combined with exercise and/or protein supplementation) in the treatment and prevention of sarcopenia still need further exploration. background: with the growing incidence of cancer in older persons, malnutrition rates have increased. tumor-related malnutrition is a risk factor of treatment side effects. it reduces the quality of life and increases morbidity and mortality. therefore, malnutrition screening and diagnosis are mandatory to implement proper nutritional support. objectives: this study aimed to evaluate and compare the short form of mini nutritional assessment (mna-sf) nutritional screening tool with the new global leadership initiative on malnutrition (glim) diagnostic criteria for malnutrition among elderly patients with cancer. methods: patients >=70 years old, with a g8 screening tool ≤14, were referred to an oncogeriatrics consultation between february and september 2019. the data recorded comprehended, demographic variables (age, sex), type of tumor, functional (barthel, lawton index, fac) and mental (mmse, yesavage) status, nutritional (mna-sf, glim criteria) and social assessment and number of drugs. if-vig, cirs-g, rockwood-ms, cci-sf, sppb and handgrip strength were used to estimate frailty. the roc curve was used to evaluate the ability to accurately distinguish malnourished patients. to determine diagnostic concordance between the assessment and the new glim diagnostic criteria of malnutrition, retrospectively analyzed, cohen's к statistic was calculated. results: 34 patients were included, mean age 84.9±5.6, 41.2% were women. gastrointestinal (29.4%) and gynecological (26.5%) neoplasms were most prevalent. 91.2% were independent or had mild dependence on badl, 85.3% on iadl. 70.6% had no cognitive impairment and 50.4% had no depressive symptoms. frailty scales showed a pre-frail patient profile, with good social support and a 7.6±4 drugs on admission. according to the new glim diagnostic criteria for malnutrition, 50% of the patients were malnourished. with the use of mna-sf, 76.5% of the patients were found to be at risk of malnutrition. the roc curve of mna-sf had an area under the curve (auc) of 0.15. no concordance was found between the mna-sf and the malnutrition diagnostic results (к=0, p<0.001). conclusion: in this small sample, most cancer patients were male, >80 years old, with low frailty index, good functional and mental status and at risk of malnutrition. the mna-sf scale detected more risk cases so preconditioning and nutritional recommendations before specific oncological therapies could be made. concentration is associated with muscle mass and strength in healthy elderly. however, there are several confounders, including body composition, nutrient intake, physical activity level and blood parameters which may also influence muscle mass. previous studies have not thoroughly examined the relationship between serum 25(oh)d concentration and muscle indices by comprehensively considering the potential confounders in healthy elderly. objectives: the purpose of this study was to investigate the relationship of serum 25(oh) d concentration with muscle mass and strength in healthy japanese elderly. methods: this cross-sectional study included 100 healthy elderly in shiga prefecture in japan (age: 68.2 ± 5.2 years, m = 44, w = 56). total fat-free mass (tffm) and appendicular (affm) were measured using dual-energy x-ray absorptiometry. in addition, handgrip strength and leg extension power were measured. a blood sample was collected in an overnight fasted state, and serum 25(oh)d concentration was assessed. habitual dietary intake and physical activity were assessed. protein intake, carbohydrate, and vitamin d intakes were adjusted for energy by the residual method. association of serum 25(oh)d concentration with tffm, affm, handgrip strength, and leg extension power was assessed by hierarchical multiple regression analysis with adjustment for age, gender, weight, energy, energy-adjusted protein, carbohydrate, vitamin d intakes, serum albumin concentration, and physical activity. results: the mean serum 25(oh)d concentration of 100 participants was 88.3 ± 32.9 nmol/l. low serum 25(oh)d status (< 50nmol/l) was observed in 12.5% (8/100) of participants. the mean affm was 17.1 ± 3.7 kg, and handgrip strength was 29.3 ± 7.2 kg. serum 25(oh)d concentration was significantly associated with affm (β = 0.091, p = 0.033), but not with tffm (β = 0.071, p = 0.090), handgrip strength (β = 0.115, p = 0.081) and leg extension power (β = -0.022, p = 0.781). conclusion: serum 25(oh)d concentration is related to affm japanese healthy elderly people, even if confounders are comprehensively considered. background: muscle quality, often defined as force produced per area or mass of muscle, declines as people age. objectives: we hypothesized that dietary protein quality will better predict muscle quality than energy, carbohydrate, protein, fat, or leucine intakes when controlling for age, bmi, composition, and moderate to vigorous physical activity (mvpa). methods: strength was measured using isokinetic dynamometry at 60 degrees per second, leg composition (lc) was examined via dual-x-ray-absorptiometry, and mvpa was measured with accelerometry. dietary intake was estimated using three-day food logs and esha software. muscle quality was defined as right knee extensor peak torque relative to right leg lean mass. protein quality was the ratio of total leucine over total protein intake. multiple linear regression and stepwise linear regression models were used. results: ninety-four women (mean ± sd; age 40.6 ± 17.5 years; bmi 25.7 ± 5.18 kg/m2; lc 37.6 ± 6.63 % fat; mvpa 81.1 ± 31.7 min/day; energy 1,977 ± 528 kcal/day; carbohydrate 226.2 ± 73.3 g/ day; protein 86.3 ± 29.6 g/day; fat 79.3 ± 24.2 g/day; leucine 3.20 ± 2.52 g/day) completed the assessments. only protein quality (mean ± sem; beta = 45.131 ± 22.303; t = 2.023; p = 0.046) was significant to the full regression model containing all covariates (r = 0.495; adjusted r2 = 0.154; f (10, 83) = 2.688; p = 0.007). to verify the importance of protein quality, a stepwise regression analysis using the same variables was performed and resulted in a model (r = 0.422; adjusted r2 = 0.160; f (2, 91) = 9.869; p < 0.001) that included protein quality (mean ± sem; beta = 28.755 ± 8.720; t = 3.405; p = 0.001) and energy intake (mean ± sem; beta = 0.000730 ± 0.000269; t = 2.710; p = 0.008). conclusion: dietary protein quality is positively associated with muscle quality when controlling for bmi, lc, mvpa, and energy, protein, fat, carbohydrate, and leucine intakes. the most parsimonious model included protein quality and energy intake, suggesting that they are most related to muscle quality. background: it has been suggested that disruption of the apoptotic process may have an effect on the incidence of sarcopenia. on the other hand, one of the dietary recommendations for seniors is to increase their daily protein intake. however, the effect of protein intake on apoptosis is not well understood. objectives: the purpose of this study was to investigate the effect of eight weeks of protein whey supplementation on the expression of genes involved in the internal and external pathways of apoptosis of long extensor muscle of thumb of aged wistar rats. methods: this is an experimental studies. statistical sample of this study consisted of 14 male wistar rats (age: 20 months, weight: 200 ± 12 gr). they were randomly divided into supplement (n=7) and control (n=7) group. supplement group received 0.375 gr per body weigh protein whey daily for eight weeks. the left thumb extensor muscle of all subjects was carefully separated and after freezing in liquid nitrogen transferred to -80 ° c. quantitative real time-pcr was performed to measure bax, bcl-2, caspase 3, 8 and 9 gene expression levels. independent t-test and mann-whitney u test were used to compare the means and rankings. the hypotheses were tested at the significant level p<0.05. results: results showed that bax, caspase 3, caspase 8, and caspase 9 genes expression increased in all samples in training group compared to the control group but this increase was only significant for bax, caspase 9 and 3 gens (p < 0.05) and also bcl-2 gene expression significantly deceresed (p < 0.05) in comparison with control group. conclusion: it seems that protein supplementation lead to activation of the internal pathway of apoptosis by increasing mitochondria permeability. background: the presence of obesity alongside with impaired aging in general, and with impaired muscular performance in particular, may result in a unique and growing phenotype of obese frail/sarcopenic, which may be hardly diagnosed by simple observation. characterizing the nutritional intake of this phenotype is of a substantial relevance. objectives: to characterize the nutritional intake among frail prone (fp) and obese subjects in a sample of community dwelling older adults in israel. methods: in this cross sectional study we evaluate the nutritional intake of frail, frail prone and robust subjects (with and without the presence of obesity), as well as their adherence to the dietary reference intakes (dri). data were retrieved a series of national studies on the status of health and nutrition in different age groups in israel (mabat zahav) for [2005] [2006] . the frailty likelihood presented here is based on a previous study from our group suggesting a non-direct validated model estimating frailty based on 5 components. results: compared to the robust, fp subjects were more likely to have lower intake of several nutrients. among them are: iron (mg) (mean 8.47 vs. 10.43, p < 0.0001), vitamin c (mg) (mean 123.51 vs. 103.87, p < 0.0001), folate (μg) (mean 263.55 vs. 301.97, p < 0.0001), vitamin a (iu) (mean 1075.09 vs. 1474.29, p = 0.004). the average overall adherence score according to the dri (based on a sum of 8 nutritional components) was 1.62 among fp subjects, compared to 1.76 among robust subjects (p = 0.03). obesity either defined by bmi or by wc had a lower «effect» on the nutritional intake differences as compared to frailty status. this observation was seen when obese subject were compared to non-obese subjects and as fp subjects were more likely to show a poor nutritional status regardless of the presence of obesity. conclusion: our results show a clear association between frailty and poor nutritional intake, regardless of the presence of obesity. moreover, the functional status may better reflect nutritional gaps than obesity -challenging the concept of the frail -obese phenotype regarding to nutritional status. background: the loss of bone density during aging induces risks of falls, fractures and mobility decline. moreover, bone structure seems to be a better predictor of fractures than bone density. these phenomena are exacerbated in the presence of sarcopenia. however, dynapenia alone or in combination with obesity is more involved in falls and loss of mobility than sarcopenia. nevertheless, the impact of obesity on bone density and bone structure is still controversial. furthermore, protein intake appears to be associated with maintenance of muscle, bone density and bone structure. to our knowledges, the impact of protein intake on bone density and bone structure among dynapenic-obese older adults is not known even if this condition reached around 20% of elderly. objectives: to assess the influence of protein intake on bone density and bone structure among dynapenic-obese older adults. methods: twenty-six older adults (>= 60 years), obese (%fat: men >25 ; women: >35) and dynapenic (relative to body weight grip strength: men <0.61 ; women <0.44) were divided into 2 groups according to their initial protein intake : prot-: < 1g/kg/d (n=13; 53.8% of women; 66.5±3.3 years) and prot+: >1.2g/ kg/d (n=13; 61.5% of women; 67.2±2,7 years). the following measurements were performed: relative to body weight grip strength using lafayette dynamometer, body composition using dxa, femoral bone structure using ct-scan, nutritional intake using the 3-day food record method. results: excepted, by design, for initial protein intake, both groups were comparable at baseline. the prot-group had a higher (p<0.05) marrow area (139 ± 54) than the prot + group (91 ± 38). in addition, the compressive loading strength was greater (p<0.05) in the prot-group (3019 ± 465) than in the prot + group (2604 ± 560). finally, the total bone area was larger (p<0.05) in the prot-group (650 ± 69) compared to the prot + group (579 ± 91). conclusion: surprisingly, a lower protein intake but higher than rda seems to protect bone structure but not bone density among dynapenic-obese older people. these results should be confirmed in larger studies designed to address this question. background: unintentional weight loss occurs in 15% to 20% of older adults and has been associated with morbidity, functional incapacity, risk of hip fracture, and overall mortality. while the impact of this condition is well established in frailty, studies involving sarcopenia are still insipient. objectives: to investigate the association between unintentional weight loss and sarcopenia in community-dwelling older adults. methods: a cross-sectional study was conducted among older adults (>=60 years) assisted in primary care. the unintentional weight loss was assessed by questions contained in three frailty assessment tools and one nutrition screening and assessment tool, described below: (1) "have you recently lost weight such that your clothing has become more loose?" [edmonton frail scale (efs)]; (2) "have you lost a lot of weight recently without wishing to do so? ('a lot' is: 6 kg or more during the last six months, or 3 kg or more during the last month)" [tilburg frailty indicator (tfi)]; (3) "in the last year, have you lost weight unintentionally (i.e., not due to dieting or exercise)? (unintentional weight loss is: more than 4.5 kg or of at least 5% of previous year's body weight)" [phenotype for frailty (pf)]; (4) «weight loss greater than 3 kg during the last 3 months" [mini nutritional assessment (mna®)]. sarcopenia was identified by european working group on sarcopenia in older people (ewgsop2) criteria. the data were analyzed with use of pearson chi-square test (p< 0.05). results: a total of 375 older adults were evaluated (69.9% female). the mean age was 72.7±7.2 years (61-95 y). sarcopenia was identified in 7.7% of the sample (n= 29). the frequency of unintentional weight loss in sarcopenics was 38% in tfi (n= 11; p=0.012), 31% in efs (n= 09; p=0.037), 34.5% in pf (n= 10; p=0.072) and 17.2% in mna® (n= 05; p=0.210). conclusion: we observed that the unintentional weight loss evaluated by tfi and efs (frailty assessment tools) was associated with sarcopenia. so, different ways to evaluate weight loss (amount and time) seems to influence this association. funding: this study was financed by fapergs (process number 1183-2551/13-4) and capes (finance code 001). background: half of older adults admitted to hospital are malnourished. malnutrition often leads to weight-loss and may lead to a loss of muscle mass, muscle strength and physical performance. nutritional interventions should individualise nutritional requirements, particularly energy and protein. objectives: to assess if energy requirements, determined by indirect calorimetry compared to usual care (predictive equations), can lead to a reduction in weight loss (primary outcome) and improvements in muscle mass, muscle strength and physical performance (secondary outcomes) in geriatric rehabilitation patients at risk of malnutrition. methods: geriatric rehabilitation inpatients were derived from the resort cohort (royal melbourne hospital, australia) and allocated by wards to either the indirect calorimetry or usual care group for the need study. energy requirements were measured using indirect calorimetry; the results were utilised by dietitians in the indirect calorimetry group and concealed for the usual care group. weights were obtained weekly. food intake assessment, muscle mass (bioelectrical impedance analyser), handgrip strength (hgs) and physical performance (short physical performance battery (sppb)) were measured at admission and discharge. within-group and betweengroup differences were calculated for the changes in outcome measures during hospitalisation. results: twenty-one patients (indirect calorimetry n=12; usual care n=9) were included (mean age 81.7 ± 11 years; 12 males, 9 females). preliminary results showed that in the indirect calorimetry group, five patients gained weight, four patients maintained weight and one patient lost weight during hospitalisation; the usual care group had four patients with weight gain and five patients maintaining weight. there were no significant within-group differences or between-group differences for changes in weight ( background: many older people have difficulties in performing daily living activities such as preparing meals and food shopping, which could be partly due to cognitive and physical decline [1]. these factors may influence food choice and represent a potential barrier to achieving good nutrition [2] . nevertheless, the association between mealrelated difficulties and nutritional risk, as well as dietary intake, has been understudied. objectives: (1) to examine the prevalence of autonomy in food-related activities, as measured with instrumental activities of daily living scale (iadl), among frail and pre-frail older subjects with an objective cognitive impairment (2) to characterize the association of food autonomy with an insufficient dietary intake and nutritional risk of cognitive frail older people. methods: this is a secondary cross-sectional analysis using baseline data from the cogfrail study, which is a monocentric observational study of 345 cognitive frail and prefrail older participants, aged >=70 years, with an objective cognitive decline. dietary intake is evaluated with a dietitian, using a diet history method. autonomy in food-related activities is assessed using iadl scale. nutritional status was categorized according to the mini nutritional assessment (mna). results: ongoing analyses. preliminary results show a mean energy intake of less than 1600 kcal and 65 g of protein per day, we considered all nutritional needs cannot be covered under this threshold. conclusion: frail older people, with cognitive impairment, are particularly at nutritional risk and insufficient dietary intake. food autonomy has to be evaluated systematically to prevent nutritional risk in this population. elderly aged 65 years or over, and this number will continue to increase. in order to extend the healthy life expectancy, disease prevention and health management of the elderly are important. preventive intervention of sarcopenia is considered to be an important issue in promoting care prevention for the elderly. objectives: the purpose of this study was to clarify the relationship of muscle weakness and physical characteristics with nutritional intakes. methods: subjects were 390 men and women (63 to 89 years old) in the nagoya longitudinal study for healthy elderly (nls-he) in 2018, excluding those who had missing values of the examinations. nutritional intakes were assessed by the food frequency questionnaire (ffq). low grip strength (gs) was diagnosed by asian working group for sarcopenia (awgs) criteria. the cut-off value of gs was 26 kg for men and 18 kg for women. results: the number of the subjects diagnosed with low gs was 64, (34 men and 30 women). comparison was made between the low gs group and the normal group. there were no significant differences between the two groups in age, sex, number of teeth, chewing ability and occlusal force, whereas mini nutritional assessment (mna) score, walking speed at the normal and maximum speed, exercise habits, and percent of body fat were significantly lower in the low gs group than the normal group. also, the rate of polypharmacy was significantly higher. in nutritional intakes, vitamin d and b12 were significantly lower in the low gs group. in the intakes by food groups, fish and meat intakes were significantly lower, but the intakes of snack were significantly higher. furthermore, the protein ratio and the amount of animal protein intakes were significantly lower in the low grip strength group. conclusion: in this study, muscle weakness was related to lower intake of specific nutrients such as vitamin d, b12, and animal protein, independent of number of teeth, chewing ability, and occlusal force. background: the status of calcium intake, the main mineral of the bone has no suitable biomarker to assess it. its evaluation is relevant in clinical practice as in research. postmenopausal women should be evaluated for risk factors for osteoporosis, including poor calcium intake. objectives: to develop and validate a food frequency questionnaire (ffq) to assess the calcium intake of mexican postmenopausal women. methods: after obtaining approval from the institutional ethics committee, a pilot study was performed including 25 mexican women whose calcium intake was assessed trough a 3 day food diary (3dfd). the ffq was designed including the foods reported by the participants of the pilot study that provided more than 1.5% of the calcium requirement and that were reported by at least 2 participants. the ffq was tested through a validation study that included 86 postmenopausal whom also completed the 3dfd. the validity of the ffq was assessed with the interclass correlation coefficient (icc) alongside a bland-altman analysis. results: 84 postmenopausal women were assessed from june 21, 2019 to january 18, 2020. participant's characteristics are shown in the table 1 . the ffq underestimated mean calcium intake compared to 3 day food diary (-210 mg ± 141.28, p<0.60). the two methods were strongly correlated by the icc (icc= 0.8204, ci 0.72-0.88). the ffq could identify individuals who consumed >=1200 mg/ day with a high sensitivity, and a reasonable specificity (table 2 ). figure 1 shows the agreement between the 3dfd and the ffq were plotted against the average of the two measurements (figure 1 ), the mean (solid line) and the 95% ci (broken lines) of the difference are shown. conclusion: conclusions: the ffq´s good sensitivity in identifying low calcium intake in postmenopausal women makes it useful also as an educational tool in diet counselling and for identifying subjects in need of supplementation. the difference between methods limits its utility as an epidemiological tool. helen yl chan 1 , winnie kw so 1 , regina cheung 2 , kc choi 1 , brenda ho 2 , francis li 2 , ty lee 2 , janet wh sit 1 , martin mh wong 1 , sy chair 1 ( (1) background: nutritional status has been recognized as a predictor of the level of frailty. however, little is known about how the eating habits and dietary preferences associated with frailty, especially in the chinese elderly population. objectives: this study aims to identify dietary factors in predicting frailty among community-dwelling older adults. methods: a multicentre cross-sectional correlational study was conducted in hong kong in 2018. frailty was defined by using fried's phenotype model. the frail scale was used to classify level of frailty and the mini-nutritional assessment (mna) was used to evaluate the nutritional status, in addition to anthropometric parameters. association between nutritional status (at risk or malnourished vs normal) and frailty status was examined using ordinal regression in a hierarchical fashion for adjusting participant socio-demographics, health status, lifestyle characteristics, eating behaviours and dietary habits. all the statistical analyses were performed using ibm spss 25.0. all statistical tests were two-sided with level of significance set at 0.05. results: a total of 610 chinese older adults participated in the study. the prevalence of robust, pre-frail and frail were 30.9%, 48.1% and 20.8% respectively. one third of the participants were malnourished or at risk of malnutrition. malnutrition and at-risk of malnutrition significantly increased the likelihood of frailty (or 2.6, 95% ci 1.7 -4.0). however, the level of frailty was not associated with age, gender, anthropometric measurements, eating behaviours, and use of dietary supplements. other nutritional factors significantly increased the likelihood of frailty were chewing difficulties (or 2.0, 95% ci 1.4 -2.9) and inadequate consumption of vegetables (or 2.2, 95% ci 1.4 -3.7). however, good appetite significantly reduced the likelihood of frailty (or 0.6, 95% ci 0.4 -0.9). conclusion: the findings showed that chewing difficulties and inadequate consumption of vegetables were associated with frailty, whereas good appetite was a protective factor. hence, interventions for addressing chewing problem and promoting appetite and consumption of vegetables are imperative to counter frailty in the older population. lack of energy was associated with nutritional status in nursing-home (nh) residents. methods: we performed a cross-sectional analysis of the incur study cohort. lack of energy was measured at baseline as part of the 10-items geriatric depression scale. nutritional status was evaluated according to mini nutritional assessment short-form (mna-sf). a 36-items frailty index (fi) was computed. logistic regression models were performed to test the association of lack of energy with nutritional status. results: a total of 573 nh residents were available for analysis. the median age (iqr) was 88 (83-91) years, with 411 (71.7%) females. at baseline, median mna-sf (iqr) was 11 (9-12) with 71 (12.4%) patients that were malnourished. among the patients included 42.9% (246 patients) reported lack of energy. at univariate logistic regression analysis mna was inversely associated with lack of energy. at multivariate logistic regression analysis, adjusted for age, sex nursing home years and fi, we found that mna was independently inversely associated with lack of energy (or 0.88, 95% ci 0.81-0.96). being malnourished is independently associated with lack of energy (or 2.10, 95% ci 1.22-3.63). among mna components we found that item a (decrease in food intake), item c (reduced motricity) and item d (psychophysical stress) were inversely associated with lack of energy (or 0.54, 95% ci 0.37-0.80; or 0.69, 95% ci 0.53-0.89; or 0.48 95% ci 0.31-0.74; for each point respectively), independently each one and from the other confounders. conclusion: in a cohort of very old nh residents, we found that an impaired nutritional status is associated with lack of energy. in particular, being malnourished bring a 2-fold risk of reporting lack of energy. more precisely, decrease in food intake, reduced motricity and psychophysical stress, each one were independently associated with lack of energy. a g e . m a r g u e r i t a s a a d e h 1,2 , f e d e r i c a p r i n e l l i 1,3 , anna-karin welmer 1,4 , weili xu 1 , davide l vetrano 1,5 , serhiy dekhtyar 1 , laura fratiglioni 1,6 , amaia calderón-larrañaga 1 ( (1) background: while declines in physical function are a common feature of ageing, the rate of the loss varies substantially between individuals, and has been attributed to intrinsic but also extrinsic (modifiable) factors such as diet, physical activity, and psychosocial well-being. objectives: (1) to assess the role of food and nutrient intake in the speed of functional decline over 12 years of follow-up. (2) to explore whether such an association differs between levels of physical activity and psychosocial well-being. methods: we analysed data from 2004 individuals aged 60+ from the population-based swedish national study on aging and care in kungsholmen (snac-k). the mediterranean diet score, mds (trichopoulou et al.) and the healthy diet indicator, hdi (who recommendations for saturated fatty acids, monodisaccharides, cholesterol, pufas, protein and fibre) were calculated for each participant, based on baseline data from a validated food frequency questionnaire and the corresponding transformation into nutrient intake. physical activity levels were assessed with questions about type, frequency, and intensity, and categorised as inadequate vs health/fitness-enhancing. we created a psychosocial well-being index by integrating variables linked to life satisfaction, positive/negative affect, social network and social participation. a global score of physical function was obtained by combining data on walking speed, balance, and chair stand tests. linear mixed models were used and adjusted for age, sex, education, smoking, baseline number of chronic diseases and impaired activities of daily living, total energy intake and time to death/drop-out. results: one standard deviation (sd) increase in the mds was associated with a lower functional decline both crosssectionally (β=0.03; p=0.02) and over the 12-year follow-up (β*time=0.004; p=0.02). higher scores of the hdi were also significantly associated with a lower functional decline, but only cross-sectionally (β=0.03; p=0.02 for one sd increase). when stratifying the analyses by levels of physical activity and psychosocial well-being, the protective effect of high mds was limited to subjects with health/fitness-enhancing physical activity (β*time=0.004, p=0.016) and high levels of psychosocial well-being (β*time=0.006, p=0.04), respectively. conclusion: a high adherence to a mediterranean dietary pattern, especially in combination with higher physical activity and psychosocial well-being, may slow down the age-relate decline in physical function. background: this cross-sectional study describes the application and follow-up of the self-care actions applied in a white male, 60 years old,1.80 m tall, a former athlete, currently sedentary, who in january 2018 presented 6% of glycated hemoglobin in medical consultation -between 5.7 and 6.4%: pre-diabetes; fasting glycemia 107 (mg / dl); (mg /dl) and the postprandial dose between 113 and 164 mg / dl. blood pressure between 140-150 mmhg; characterizing hypertension in stage. objectives: the objective was applying and follow-up a food re-education program associated with a resistance training program to reduce non-communicable diseases. methods: during 2019, a program of dietary reeducation was carried out, with a few complex carbohydrates, an increase in proteins of high biological value, associated with a program of resistance exercises, which was adapted and individualized, obeying the individual's particularities. a short physical performance battery (sppb) was also applied to assess walking speed, strength and muscle balance. this program was performed three times a week, under the supervision of a physical education professional. capillary blood glucose was collected and analyzed 69 times and blood pressure 231 times, respectively. it was carried out a basic training for 4 weeks aiming to rescue the muscular memory of the elderly, after beginning the adaptive phase of the physical valence training (cardiovascular endurance, localized muscular resistance); for 6 weeks and the specified. the loads corresponded to 80% of 1rm for 8-10 repetitions with three series and 2 to 3 minutes intervals at each stage of the training. we used the ibm spss statistics 22 program to perform descriptive statistics. results: the mean glycemia was 107 (mg / dl), the 3 glycated hemoglobin analyzes showed 5.5; low risk of diabetes. systolic blood pressure and diastolic blood pressure presented a mean of 113.95 ± 6.99 mmhg, and 78.32 ± 3.51 mmhg, respectively. we observed a gradual gain every 2 months of resistance training. the sppb score changed from 3 to 4 points; performance between intermediate to high. conclusion: dietary re-education associated with a well-designed strength training program can result in the reduction of diabetes and hypertension, as well as strengthening the muscular system of the elderly. background: diet can be an important non-pharmacological aspect in order to prevent and/or attenuate brain and frailty outcomes in older adfults. objectives: to investigate, by a systematic review, studies associating the dietary inflammatory index (dii) with brain and frailty outcomes in older adults. methods: we searched the publications in pubmed and lilacs databases up to june 2019. inclusion and exclusion criteria were formulated based on pi(e)cos strategy (population= older adults, >= 60 years; intervention/ exposition= dietary inflammatory index; comparison= not applied; outcomes= brain and muscle outcomes; study type= randomized clinical trials, cohorts, cross-sectional, casecontrol studies). results: searches resulted in 206 publications, and after exclusion due to duplicity (n=26) and not compliance with exclusion and inclusion criteria (n=172), eight studies were selected. these studies were published from 2017 to 2019, all of them were cross-sectional, with participants above 60 years old, and the outcomes investigated were frailty and frailty risk, survival free of disabilities (by fried's frailty criteria, sppb test, lawton and broady scales); memory, cognitive decline and risk of dementia (by meem, cerad, gds, prime-md, dsst and animal fluency test). conclusion: the data extracted from the articles showed significant association between dii and the outcomes investigated, namely, the more inflammatory diet was associated with higher odds to be frail and pre-frail, and to have any type of cognitive impairment. therefore, the dii showed to be associated to brain and frailty outcomes in older adults, however, to understand causality, longitudinal studies are still necessary. background: it is well established that reactive oxygen species (ros) are increased in skeletal muscle with age. we have recently shown that increased ros with age is associated with increased expression of the senescence-associated microrna mir-34a-5p (mir-34a) in skeletal muscle as well as in muscle-derived extracellular vesicles. these vesicles enriched in mir-34a are elevated in aged mouse serum, and can induce senescence in bone stem cells. the histone deacetylase sirt1 is a validated target of mir-34a, and sirt1 plays important roles in cell survival as well as in muscle hypertrophy with functional overload. importantly, we previously found that mir-34a expression was much higher in muscle from aged female mice compared to male mice, a phenomenon others have observed in mouse cardiac muscle. objectives: here we tested the hypothesis that pharmacological ablation of senescent cells could modulate mir-34a and sirt1 bioavailability in skeletal muscle of aged mice. we utilized the senescent drug abt-263 (navitoclax) since previous studies have shown that oral administration of abt-263 removed senescent satellite (stem) cells in mouse skeletal muscle. methods: ten male and ten female c57bl6 mice, 24 months of age, received either abt-263 (50 mg/kg bw, 100 ul) or vehicle by oral gavage for ten days. tibialis anterior muscles were removed at the end of the study for examination of mir-34 and sirt1 levels using rt-pcr and elisa, respectively. results: abt-263 reduced mir-34a expression in both male and female mice, although the effect was more pronounced in male mice compared to females. abt-263 significantly increased sirt1 levels in male skeletal muscle but not in females. the changes in sirt1 and mir-34a levels were not associated with significant differences in muscle fiber size over the treatment period. conclusion: these findings suggest that certain senolytic compounds can modulate levels of senescence-associated mirnas and their targets in aging skeletal muscle. these data also underscore the importance of considering sex differences in the molecular mechanisms underlying age-related muscle atrophy. background: the growth of the elderly population is a worldwide phenomenon and is associated with profound changes in body composition. the purpose of this study was to describe the magnitude of the problem, to evaluate the associated factors and the relation with functional capacity in the study population. objectives: to estimate the association between demographic factors, comorbidities and muscle mass index over time until functional disability or death appears in non-obese elderly individuals. methods: longitudinal study of 335 elderly individuals aged 65 years or over, non-obese and absence of functional disability at the beginning of the cohort on the epidoso project database. the variables gender, age, ethnicity, medical history, functional capacity and death were investigated. the low or normal muscle mass index (mmi) was obtained through anthropometric data and a predictive equation. the functional capacity was measured using a structured and validated multidimensional questionnaire. the deaths occurred in the period were investigated with relatives through household surveys, in registries and registries of the state system of data analysis foundation. estimates of eventfree survival (functional disability or death) were calculated using kaplan-meier curves using the log-rank test in the gross comparisons. a multiple cox proportional hazards model was used to identify the independent effect of time predictors until onset of functional disability or death. results: the mean time found for the onset of functional disability or death was 7.1 years (95%ci=[6.8; 7.5]). in the crude analysis, there were statistically significant differences in the time to occurrence of functional disability or death, by age group (p<0.001), arterial hypertension (p= 0.046), diabetes mellitus (p=0.007) and marginal statistical difference muscle mass level (p=0.105 background: a consequence of the ageing population is the increasing number of older adults with physical limitations. these limitations are mainly caused by decreased muscle mass and strength (sarcopenia). treatment or rather prevention of sarcopenia is necessary, as it may lead to lowered quality of life, hospitalization, loss of independence and even mortality. since older ethnic minorities are more likely to have an unfavourable health status compared to the majority population, variations in the prevalence of sarcopenia for ethnic minority groups are expected. further investigation seems imperative to be able to target preventive interventions to those at high risk of sarcopenia within the population. objectives: to examine the sarcopenia prevalence and its association with protein intake in an older multi-ethnic population in the netherlands. methods: we used cross-sectional data from the helius (healthy life in an urban setting) study, comprising the largest ethnic populations living in amsterdam, the netherlands. in total 5161 individuals from dutch, south-asian surinamese, african surinamese, turkish and moroccan origin aged 55 years and over were included. sarcopenia was defined according to the ewgsop2. in a subsample (n=1371), protein intake was measured using ethnic-specific food frequency questionnaires. descriptive analyses were performed to study sarcopenia prevalence across ethnic groups in men and women, and logistic regression analysis were used to study associations between protein intake and sarcopenia. results: sarcopenia prevalence was found to be sex-and ethnic specific, varying from 29.8% in turkish to 61.3% in south-asian surinamese men and ranging from 2.4% in turkish up to 30.5% in south-asian surinamese women. higher protein intake was associated with a 4% lower odds of sarcopenia in the total population (or= 0.96, 95% ci 0.92-0.99) and across ethnic groups. conclusion: ethnic differences in the prevalence of sarcopenia and its association with protein intake suggest the need to target specific ethnic groups for prevention or treatment of sarcopenia. background: few studies have evaluated the relationship between frailty and acute respiratory illness (ari), despite of increasing heavy burden of ari in older people. objectives: we conducted a prospective cohort study in communitydwelling older people in hong kong, to evaluate the impact of frailty on the risk of acute respiratory infections in the community setting and the potential modifying role of outdoor activities. methods: we recruited and followed up participants who were chinese and aged from 65 to 95 years, from december 2016 to may 2018. frailty was measured by fried frailty index (ffi) twice during the study period. daily hours of outdoor activities were collected by a monthly activity journal (n=225) during the whole period, and by wearable gps device from some participants for one week in summer (n=173) and winter (n=185), respectively. the ari incidence was collected by monthly phone calls to the participants. we used a logistic regression model to estimate the odds ratio (or) of ari associated with frailty status (robust as reference group). results: the participants were classified into three groups according to the ffi criteria: 56 (24.9%) as robust, 152 (67.6%) as pre-frail and 17 (7.6%) as frail groups. of them, 68 reported ari during the study period. according to the activity journals, daily hours of staying outdoors in the ari participants were slightly less than those in without ari (4.37 vs 4.46 in whole study period, 4.03 vs 4.60 in summer, 4.45 vs 4.84 in winter). while, the gps data showed that the participants with ari had longer daily hours of outdoors activities in summer (3.27 vs 3.14) but shorter in winter (4.20 vs 5.30), although none were statistically significant (p > 0.05). after adjustment for age, age, living alone or with family and daily hours of outdoor activities, we found that the frailty and pre-frailty groups had a higher risk of ari incidence compared with the robust group, with or 3.67 (p = 0.047) and 2.58 (p = 0.017), respectively. conclusion: frailty might be associated with a higher risk of ari among older people, but the role of outdoor activities remains inconclusive. background: previous studies have investigated the association between impaired muscle health and mortality. however, muscle health is a dynamic entity which change with time. objectives: to assess the effect of a short-term decline of muscle health (i.e., over 1 year) and its association with long-term mortality (i.e., over 4 years). methods: the sarcophage cohort follows up 534 older belgian adults to assess consequences of sarcopenia. an assessment of muscle mass (dxa), muscle strength (handheld dynamometer) and physical performance (by means of sppb, including gait speed) are performed annually. all-causes deaths are collected annually. the association between short term (i.e. after one year) decline in muscle parameters and 4-year occurrence of deaths was tested using cox model. roc analyses were performed to assess performance of prediction of the different muscle components and to find optimal cut-points. missing data were handled using multiple imputations. results: from the 534 subjects recruited (73.5±6.2 years, 60.5 % women), 7 were discarded from our sample because they died during the first year. therefore, the muscle decline was available on a sample of 527 subjects. 40 deaths occurred within the 3 first years of follow-up. a 1-point decrease in performance at sppb test resulted in 15% higher risk of dealth (hradjusted = 1.15 [95%ci 1.07-1.25]). for each decrease of 0.1 m/s of gait speed, we observed an 8% higher risk of death (hradjusted = 1.08 [1.02-1.14]). a 1-kg decrease of muscle strength resulted in 15 % higher risk of death in men and 46% higher risk of death in women (hradjusted = 1.15 [1.07-1.24] and hradjusted = 1.46 [1.21-1.77], respectively). we did not found any association between short-term loss of muscle mass and the occurrence of death (p=0.16). then, we tried to find cutoffs optimizing the sensitivity-specificity ratio and we found following results : over 1 year, a decline of sppb superior or equal to 1, of gait speed superior or equal to 0.15 m/s and of muscle strength superior or equal to 1.8 kg in men and 2.8 kg in women. conclusion: a short-term decline in muscle function is predictive of premature deaths. background: sarcopenia, the age-related progressive loss of muscle mass and function, is associated with an increased likelihood of adverse outcomes like falls, fractures, physical disability, and mortality. international consensus groups continue providing new definitions and clinical cut-off points despite over a decade of work in this area. objectives: we examined the prevalence of sarcopenia using two of the most current operational definitions (foundation of nih sarcopenia project (fnih) and the european working group on sarcopenia in older persons 2 (ewgsop2)) in a cohort of older adults (n=345, >= 65 yrs) hospitalized for an acute disease at utmb hospital in galveston (jan 2014-may 2019). methods: testing included measures of: demographics (age, gender, race, education), body composition (dexa), physical function tests (sppb, tug, grip), psychological wellbeing and independence questionnaires, and chart review (comorbidity, length of stay). results: we found 70% had low physical performance, 36% had low muscle strength, and 33% low lean mass. we compared multiple tests and cutoffs for each of the three groupings under the fnih and ewgsop2 and found there to be differences depending on the test usedespecially for low performance which varied from 29%-75%. in our cohort, the prevalence of sarcopenia was 15.79% by ewgsop2 and 13.59% by fnih. the subgroupings were found to be near identical across almost all measures despite the definitions' discrepancies in cutoff points between fnih and ewgsop2. conclusion: in conclusion, recent updates to the new ewgsop2 make it almost indistinguishable to the older fnih standard, but the new ewgsop2 algorithm does provide a grading system to identify different levels of severity of sarcopenia. background: the population is experiencing a fast growth in the number of older adults, therefore determine the prevalence of frailty could help to inform future strategies to reduce its social and health burden. objectives: determine the prevalence of frailty in chilean older adults. methods: 233 participants, aged >60 years, from the chilean national health survey 2016-2016 were included in this study. frailty was assessed by fried criteria modified, therefore people classified as frail should meet at least 3 out of the 5 criteria (low strength, low physical activity, low body mass index, slow walking pace and tiredness). results: the prevalence of frailty was 10.9% (7.7% for men and 14.1% for women). the prevalence of prefrailty was 59.0% whereas 30.1% was classified as normal. the prevalence of frailty increased with markedly with age, 58.2% and 62.4% of men and women, respectively, were frail at the age of 80. this prevalence increased to 89.9% and 86.9% for men and women at the age of 90. the prevalence of pre-frailty increased from 43.0% to 92.1% for men and from 76.4% and 77.5% for women from the age of 60 to 90 years, respectively. conclusion: the prevalence of frailty increased markedly with age. with the chilean population expected to increase their life expectancy and number of older adults, it is important to implement prevention strategies that allow for early identification of high-risk individuals. a 10 year follow-up. jair licio ferreira santos 1 , yeda aparecida de oliveira duarte 2 , tiago da silva alexandre 3 background: sarcopenia has been increasingly recognized as leading to poor prognosis in health outcomes. likewise, falls -although important at older ages -have not been studied frequently and may lead to an increased risk of death. we evaluated survival of elderly people living in são paulo -brasil in a 10-year follow-up, considering the presence of sarcopenia at baseline and the occurrence of falls before the interview. objectives: to investigate whether sarcopenia and/or falls increase mortality among brazilian older adults. methods: data came from the second (2006) and fourth (2015) rounds of the health, welfare and aging study (sabe), which begun in 2000, with a sample of the population over 60 years old in the city of são paulo, brazil. after the first round, follow-up was performed every five years. sarcopenia was defined according to the consensus of the european working group on sarcopenia in the elderly (ewgsop), and the occurrence of falls was assessed by direct questions answered by the elder or his caregiver. a multivariate analysis with robust estimation and control for exposure time was done using the poisson regression model. results: mortality rates (per thousand person years) were: 19.6 (non sarcopenic, no falls) ; 35.6 (non sarcopenic with falls); 75.1 (sarcopenic no falls) ); and 68.6 (sarcopenic with falls. the poisson regression resulted in incidence rate ratios (when compared to sarcopenic, no falls) of 1.7 for non sarcopenic with falls; 2.5 for sarcopenic elders with no falls and 2.2 for sarcopenic with falls. conclusion: sarcopenia and the occurrence of falls are important risk factors for mortality. this finding highlights the importance of considering sarcopenia in health risk assessment and developing educational programs to prevent falls. ecosse l. lamoureux, 1,2 , alfred t.l. gan 1 , ryan e.k. man 1,2 , eva k. fenwick 1,2 , bao lin pauline soh 3 , angelique chan 2 , david ng 2 , chong foong-fong mary 4 , preeti gupta 1 ((1) singapore eye research institute and singapore national eye centre, singapore; (2) duke-nus medical school, singapore; (3) singapore institute of technology, health and social sciences, singapore; (4) saw swee hock school of public health, national university of singapore, singapore) background: individually, sarcopenia and frailty are known risk factors for cognitive impairment (ci) in older adults, but information on their conjoint presence on the increased risk of ci is unavailable in this same population. objectives: we examined the association of the combined presence of sarcopenia and frailty with ci in elderly singaporeans. health profile in elderly singaporeans study (pioneer), a nationally-representative, population-based study of singaporean chinese, malays, and indians aged >=60 years. participants underwent body composition (dual energy x-ray absorptiometry -dxa); grip strength (hand dynamometer) and habitual 4m-walking speed assessments. sarcopenia was defined using the asian consensus as low appendicular lean mass (lalm; men <7 kg/m2, women <5.4 kg/m2) and low muscle strength (lms; men <26 kg, women <18 kg) or slow walking speed (sws; <0.8 m/s); and frailty was defined as meeting three or more of the following components: 1) unintentional weight-loss >= 4.5 kg in the past 6-12 months and/or bmi <18.5 kg/m2, 2) lms, 3) self-reported exhaustion in the past one month, 4) sws, and 5) low physical activity level. ci was determined using the montreal cognitive assessment (moca) basic scale. logistic regressionb models were used to determine the cross-sectional sarcopenia-frailty and ci relationship. results: of the 487 included participants (mean age [sd]: 73.1 [8.3] years; 50.5% females), 248 (51%); 176 (36%); and 63 (13%) had neither sarcopenia nor frailty, either sarcopenia or frailty, and both sarcopenia and frailty, respectively. ci was present in 8 (3.2%) individuals without sarcopenia and frailty; 19 (10.8%) with either sarcopenia or frailty; and 16 (25.4%) individuals with both sarcopenia and frailty. in multivariable-adjusted analyses, presence of either sarcopenia or frailty was not significantly associated with higher odds of ci (odds ratio (or) [95% confidence interval]: 1.84 [0.71-4.73]), while having both sarcopenia and frailty significantly increased the odds of ci by nearly 3.5 times (3.48 [1.19-10.12]). conclusion: the co-presence of sarcopenia and frailty is independently associated with a higher risk of ci, compared to one condition alone, although longitudinal studies are needed to confirm this finding. strategies to prevent the concomitant onset of sarcopenia and frailty may be warranted to potentially reduce the risk of ci in older adults. background: car accidents related to older adults increased with aging, particularly in japan. safety driving required robust of physical function. however, the association between frailty and car accidents was still unclear. objectives: the aim of this study was to examine the association between frail status and car accidents. methods: participants were 12,013 older adults (45.4% women, mean age: 71.7 years) enrolled current drivers in the national center for geriatrics and gerontology -study of geriatric syndromes. the criterion of frailty used in this study was j-chs index modified according to fried's criteria (chs index). the components of frailty in j-chs index were based on the original chs index: shrinking (weight loss), weakness, poor endurance (exhaustion), low activity level, and slowness. based on the presence numbers of these five components, our study defined "frailty" as 1 and over, i.e., including pre frail and frail. the data of car accidents were collected from self-reported history of car accidents during 2 years. results: among 12,013 participants, 1,117 participants (9.3%) had a history of car accident. higher proportion of car accidents group was observed in shrinking (9.0% vs 11.1%, p = 0.006), exhaustion (9.1% vs 10.8%, p = 0.033), physical inactivity (9.0% vs 10.4%, p = 0.035) and slowness (9.0% vs 10.5%, p = 0.032), but not weakness (9.2 vs 9.9, p = 0.447). in a logistic regression analysis, frailty was independently associated with car accidents in an adjusted model (or 1.26 [95%ci 1.11-1.43], p < 0.001). conclusion: this population study reveals frailty associated with car accidents. the findings have contribution of enhancing utility of risk assessments among older drivers. further studies were required to clarify risk of car accidents.model. background: frailty, a state of vulnerability to stressors resulting from a loss of physiological reserve across multiple systems. frailty is associated with higher morbidity, mortality and healthcare utilization. the national prevalence of frailty among us older veterans was found to be as high a 45%. however, little is known about the incidence of frailty in older, community-dwelling veterans. objectives: determine the incidence over 5 years of frailty among robust or prefrail community-dwelling older veterans. methods: this is a retrospective cohort study of 16897 community-dwelling veterans 60 years and older who had determinations of frailty from july 2013-june 2014 and were followed until their last clinician visit before september 30, 2019. a 31-item va frailty index (va-fi) was generated at baseline and during each subsequent primary care encounter as a proportion of all potential variables (morbidity, function, sensory loss, cognition and mood and other) with data from electronic health records. the va-fi categorized veterans into robust (fi<.10), prefrail (fi=>.10, <.21) and frail (fi>=.21). using baseline and median duration of follow-up data based on event rates, incidence rates of frailty per 1000 person/years were calculated for robust, prefrail, combined (robust and prefrail) and gender groups. results: patients were 73.8% white, 90.6% non-hispanic, 97.1% male, mean age 72.11 (sd=9.32) years. the proportion of robust, pre-frail and frail patients at baseline was 42.4% (n=7158), 36.7% (n=6209) and 20.9% (n=3530) respectively. among robust veterans surviving a median follow-up of 4.85 (iqr 3.03) years, 14.87% (1065/7158) became frail with an incidence rate of 37.02 cases/per 1000 person-years. among prefrail veterans 47.02% (2920/6209) became frail and the incidence rate was 154.99 cases/per 1000 person-years. among the combined group, 30% became frail, with an incidence rate of 83.70 per 1000 person-years. the proportion of veterans becoming frail and the incidence rates were higher in women than men (32.64% vs. 29.73% and 106.20 vs 83.14 cases per 1000 person-years respectively). conclusion: this study shows a high incidence of frailty in community-dwelling older us veterans. identification of older veterans at high risk for frailty may assist in the development of interventions aimed at preventing frailty and its associated complications. background: anticholinergic drugs are prescribed to treat a variety of medical conditions through pharmacological actions opposing the actions of acetylcholine. anticholinergics and may contribute to frailty by causing cognitive, functional and physical impairment. frailty represents a state of vulnerability to stressors resulting from a loss of physiological reserve across multiple systems. frailty may potentially make patients more susceptible to the deleterious effects of anticholinergic medications on cognition. objectives: determine the crosssectional association of anticholinergics with cognitive impairment according to frailty status among communitydwelling older veterans. methods: this is a cross-sectional study of 17,211 community-dwelling veterans 60 years and older whose frailty status was assessed october 2018-october 2019. the use of medications (active/inactive) with high anticholinergic burden scale (acb3) and cognitive impairment diagnoses (icd codes for mild cognitive impairment/dementia) were obtained from electronic health records. a 30-item va frailty index (va-fi) was generated as a proportion of all potential variables at the time of the assessment. we compared robust (fi≤.10), prefrail (fi=>.10, <.21) and frail (fi>=.21) patients. after adjusting for age, gender, race, marital status, median household income, and bmi, odds ratios (ors) and 95% confidence intervals (cis) were calculated using binomial logistic regression with cognitive impairment as the outcome variable and anticholinergics (acb3) as independent variables. we repeated the analysis according to frailty status. results: patients were 68% white, 97.6% male, mean age 75.45 (sd=7.98) years, 9.3% (1593) had cognitive impairment, 11.5% (n=1976) were taking acb3 medications, 30.8% (5308) took them in the past and 57.5% (9927) never used them. the proportion of robust, pre-frail and frail patients was 32.1% (n=5524), 37.6% (n=6476) and 30.3% (n=5211) respectively. in binomial logistic regression, active and inactive acb3 medications were associated with higher risk for cognitive impairment, adjusted or=3. background: frailty, a state of vulnerability to stressors resulting from a loss of physiological reserve across multiple systems. the national prevalence of frailty among us older veterans was found to be as high a 45%. multiple studies have shown a higher prevalence of frailty and mortality in african americans. however, little is known about racial-differences in all-cause mortality in older veterans who had just transitioned to frailty. objectives: determine racial differences in allcause mortality over 5 years among community-dwelling older us veterans who transitioned to frailty. methods: this is a retrospective cohort study of 3,756 community-dwelling veterans 60 years and older who transitioned to frailty from july 2013-september 2019 and were followed until death or september 2019. a 31-item va frailty index (va-fi) was generated at baseline and during each subsequent primary care encounter as a proportion of all potential variables with data from electronic health records. the va-fi categorized veterans into robust (fi≤.10), prefrail (fi=>.10,<.21) and frail (fi>=.21). at the end of follow-up, we aggregated data on mortality only on those veterans who transitioned to frailty (robust/prefrail at baseline) and compared whites and african americans. after adjusting for age, gender, ethnicity, marital status and median household income, the association of race with mortality was determined using a multivariate cox regression model. results: patients were 81.5% white, 18.5% african-american, 89.6% non-hispanic, 96.8% male, mean age at frailty transition was 73.59 (sd=8.677) years. over a median follow-up period of 1038 days (iqr=1047) from the time they transitioned to frailty, 760 deaths occurred (n=635, in whites vs. n=125 in african americans). african american veterans had a lower risk for all-cause mortality than white veterans, unadjusted hazard ratio (hr) =.595 (95%ci: .491-.721), p<.0005. however, these mortality differences disappeared after adjustment for covariates, adjusted hr =.777 (95%ci: .545-1.108), p=.164. conclusion: our study suggests that in community dwelling older us veterans who had transitioned to frailty, race is not significantly related to overall survival when adjusting for other covariates. background: previous studies show that sarcopenic obesity (so) is associated with higher risk of mortality. however, a consensus definition of so is lacking, and more information is needed on the validity of simple measures applicable at a regular health care visit, such as anthropometric measurements and hand-grip strength or chair stand test. objectives: to examine the association between so and mortality, defining so based on body mass index, waist circumference, hand-grip strength and chair stand test, in a representative sample of finnish population. methods: this study was based on 2,550 participants aged 55 years or over with data on anthropometrics, hand-grip strength and chair stand test from the nationally representative health 2000 survey. baseline sarcopenic obesity was defined as having bmi >=30 kg/m2 or waist circumference >=102 cm (men)/ 88 cm (women), and hand-grip strength <27 kg in men, <16 kg in women, or chair stand >15 s for five rises. register-based follow-up data of the statistic finland containing 1,115 deaths during the 15 years of follow-up were individually linked with the baseline data. survival analyses were based on cox proportional hazards models using age as the time scale. results: mean age was 68.0 years (sd 9.4) and 58.3% were females. overall prevalence of sarcopenic obesity was 24.4% at baseline. sarcopenic obesity was associated with higher risk of mortality (hr 1.35, 95%ci 1.19-1.54) in an age and sex adjusted model. further adjustments for education, smoking, alcohol use, and physical activity did not notably change the results (hr 1.27, 95%ci 1.10-1.46). conclusion: sarcopenic obesity, as defined based on anthropometric measurements as well as hand-grip strength or chair stand test, predicted higher mortality over 15 years of follow-up. background: malnutrition and sarcopenia have a negative impact on mobility, risk of falls, fractures, physical disability and mortality. currently, limited information is available on nutritional status and nutritional interventions in geriatric rehabilitation (gr) patients. objectives: to characterize nutritional status and evidence of nutritional interventions with and without physical exercise in gr patients. methods: eight electronic databases were screened for nutritional status and interventions in patients >= 60years, admitted to gr, one search string was used for both topics. pooled estimates were calculated for mean bmi and prevalence of (risk of) malnutrition (mna). meta-analyses were performed to quantify intervention effects on albumin, muscle mass, barthel index (bi), and hand grip strength (hgs). results: 62 observational and 12 intervention studies were included out of 1717 references. pooled estimates (95% confidence interval (ci)) for prevalence of malnutrition and risk of malnutrition were 13 (5-20)% and 47 (40-54)%. pooled estimate (95%ci) for bmi was 23.8 (23.2-24.5) kg/m². low protein and energy intake and vitamin d deficiency were prevalent. intervention studies were heterogeneous in interventions and outcomes. meta-analyses showed no significant effects on albumin (standardized mean difference (smd) 0.34, 95% ci -0.13:0.80), muscle mass (mean difference (md) 2.14 kg, 95% ci -2.17:6.45), bi (md 2.85 points, 95% ci -7.59:13.29) and hgs (smd -0.04, 95% ci -0.61-0.53), based on 3-4 studies. eight interventions tested oral nutritional supplements (ons) with protein, with or without exercise, 6 reported protein intake and showed an increase, 3/4 studies showed increased albumin levels and 4/7 reported improved functional outcomes. conclusion: a high percentage of gr patients was affected by reduced nutritional status. intervention studies were limited and heterogeneous, but studies with ons improved nutritional outcomes, and functional outcomes in the majority of reporting studies. the results emphasize the need for malnutrition and sarcopenia screening and show benefits of protein supplementation in this population. future well-designed, well-powered trials are needed to clarify existing controversial aspects. therefore, feasibility of an intervention with a high-whey protein, leucine and vitamin d enriched ons (fortifit®), combined with resistance-type exercise in gr hip fracture patients will be investigated in a new intervention study (empower-gr). background: sarcopenia is a progressive and generalized skeletal muscle disorder associated with an increased likelihood of adverse outcomes such as falls, fractures, physical disability and mortality. the geographical region of residence (urban and rural area) may affect the prevalence of sarcopenia due to physical and environmental conditions. in 2018, the european working group on sarcopenia in older people (ewgsop) updated the definition of sarcopenia (ewgsop2). objectives: to describe the prevalence of sarcopenia related to ewgsop and ewgsop2 criteria and to analyze the association between sarcopenia and geographical regions of residence. methods: this is a cross-sectional study involving elderly women (60 years old or more) that were undergoing dxa in a radiology facility located in palmeira das missões (southern brazil). sociodemographic data were collected through a questionnaire. for the diagnosis of sarcopenia, we used the criteria recommended by the ewgsop (low muscle mass plus low grip strength and/or low gait speed), and ewgsop2 (low grip strength plus low muscle mass and/or low gait speed). the study was approved by the university ethics committee. results: out of the 288 participants, 60.1% was married, 44.1% had education between 4 and 8 years of schooling, 71.2% was caucasian, and 93.1% was retired. the mean age was 67.6±5.8 years old (60-88). the frequency of sarcopenia in the total sample assessed by the ewgsop and ewgsop2 was 5.2% and 2.1%, respectively. the prevalence of sarcopenia by the ewgsop was 73% in the urban area and 26.7% in the rural area (p= 0.007) and by the ewgsop2 was 66.7% in the urban area and 33.3% in the rural area (p= 0.177). conclusion: in a sample of elderly women from the southern brazil, the prevalence of sarcopenia was low through both consensus (ewgsop and ewgsop2), and was higher among urban area. funding: this study was financed in part by the coordenação de aperfeiçoamento de pessoal de nível superior -brazil (capes) -finance code 001. background: patients with disuse syndrome have gradually increased with aging of inpatients in saitama medical university hospital. because these patients have been inactive in the acute phase, sarcopenia is likely to occur. sarcopenia was graded by three criteria in ewgsop2 ; muscle strength, muscle quantity and physical performance. muscle volume can be measured only in limited medical centers. many of patients with disuse syndrome can not walk even after the acute phase. for these reasons, muscle strength is the only quantitative factor reflecting sarcopenia, especially in old patients with disuse syndrome after the acute phase. objectives: to show 1) muscle strength in old patients with disuse syndrome after the acute phase, 2) effect of muscle strength on activities of daily living (adl). methods: subjects were old patients with disuse syndrome admitted in the department of rehabilitation medicine (rm) in saitama medical university hospital from january 2011 to december 2018. inclusion criterion were as follows; 1) patient age was 65 or older 2) patients could not walk independently at admission in the department of rm exclusion criterion were as follows; 1) patients with motor paresis, contracture of fingers 2) patients in inactivity before the onset of the disease causing disuse syndrome. grip strength (gs) was measured by handheld dynamometer. cut-off point of gs set by awgs in 2019 was adopted; 28kg for men and 16kg for women, adl was evaluated using functional independence measure motor scale (mfim) one week after admission in the department of rehabilitation medicine . percentage of gs below cut-off point was shown in men and women respectively. effect of gs on mfim was investigated using regression analysis. results: ninety nine out of 186 patients were subjects in this study. median age was 77.0 years in men (n=51), 79.0 years in women (n=48). only two in men and one in women were below gs cut-off point. correlation coefficient between gs and mfim was 0.379(p=0.0052) in men, 0.415(p=0.0025) in women respectively. conclusion: gs was below cut-off point in most of the subjects. gp may affect adl after the acute phase in old patients with disuse syndrome. death, whereas measures of functional ability, physical strength and morbidity were stronger associated with time to death than with chronological age. from the age of 70 and forwards participants have a high life-satisfaction in general, however, a decline is seen as persons get older and with proximity to death. measures of functional ability (e.g. going shopping) and morbidity (e.g. self-related health) had a significantly increasing effect on life-satisfaction with increasing age. whereas social function (e.g. living alone, meeting friends) did not significantly modify the decrease in life satisfaction with increasing age. conclusion: physical strength, functional ability and morbidity were measures mostly linked to biological aging, while social functioning was strongly correlated with chronological age. functional ability and self-related health are important factors to prevent age-related decrease in life satisfaction. background: previous studies mostly conducted in western countries support that physical frailty predicts future cognitive decline in general older populations. however, longitudinal evidence on this association is limited, especially among older japanese women. objectives: this study has investigated the prospective associations of frailty status with cognitive decline over two years among community-dwelling older japanese women, including which individual frailty components (i.e., slowness, weakness, exhaustion, low activity, and unintentional weight loss) could predict cognitive decline. methods: this study was a two-year population-based cohort study conducted in a metropolitan area of tokyo, japan. data were collected in october 2017 (baseline) and september 2019 (follow-up) and analyzed between december 2019 and january 2020. participants were community-dwelling older japanese women, aged 65 to 80 years at the baseline, without any neurological diseases or cognitive impairment as measured by a mini-mental state examination (mmse) score of >= 24 points. cognitive decline was defined as a drop of two points or more in the mmse score over two years. the physical frailty phenotype was classified by the japanese version of cardiovascular health study criteria. multiple poisson regression analyses with a robust error variance were applied to assess risk ratios (rrs) of two-year cognitive decline across the baseline frailty statuses (robust [reference category], prefrail, or frail). results: of the 522 women analyzed, 219 (42.0%) were prefrail (1 or 2 components), and 17 (3.3%) were frail (≥3 components) at the baseline. at the follow-up, 17 (5.9%) robust, 29 (13.2%) prefrail, and 6 (35.3%) frail women experienced cognitive decline. after being adjusted for various confounding factors including age, educational attainment, and baseline mmse score, the rrs of cognitive decline were 2.05 (95% confidence interval [ci]: 1.11, 3.80) in the prefrail and 3.68 (95%ci: 1.64, 8.27) in the frail women. among the five frailty components, slowness (rr: 2.19, 95%ci: 1.04, 4.62), weakness (rr: 2.85, 95%ci: 1.64, 4.94), and unintentional weight loss (rr: 1.78, 95%ci: 1.01, 3.14) were significantly associated with cognitive decline. conclusion: over the two-year period, approximately 10% of women experienced cognitive decline. baseline physical frailty status, particularly slowness, weakness, and unintentional weight loss, predicted this decline. intervention strategies targeting physical frailty may help delay cognitive decline in older japanese women. background: menopause leads to estradiol (e2) deficiency that is associated with decreases in muscle mass and strength. yet the mechanistic role of e2 in the loss of muscle mass has not been established. programmed cell death termed apoptosis has been proposed a key signaling route in skeletal muscle homeostasis, including muscle aging and sarcopenia. to date several micrornas (mirs) have been found to regulate key steps in apoptotic pathways. objectives: here we studied the effect of e2 deficiency on mir-signaling in skeletal muscle apoptosis. our aim was to reveal whether e2-responsive mirs have mechanistic role in inducing skeletal muscle apoptosis. methods: we utilized c57bl6 mice with three study groups; sham (normal estrous cycle, n=8), ovx (e2 deficiency, n=7) and ovx+e2 (high e2 supplemented by pellet, n=4). in our setup, ovx and ovx+e2 groups represent the extremes of e2 level. six weeks following the sham or ovx surgery, mice were sacrificed, gastrocnemius muscles were harvested and rna isolated. mir-profile was studied with ngs and candidate mirs verified using qpcr. the target proteins of the mirs were found using in silico analysis (target scan) and target proteins measured at mrna (qpcr) and protein levels (western blot). results: of the apoptosis-linked mirs found, four (122-5p, 133a-3p, 483-3p and 491-5p) indicated differential expression patterns between ovx and ovx+e2 groups. in qpcr verification, ovx had lower expression in all of the studied mirs compared with ovx+e2 (p=0.050). accordingly, ovx had higher expression of cytochrome c and caspases 3, 6 and 9 compared with ovx+e2 at the mrna level (p<0.050). at protein level, ovx had greater cytochrome c and active caspase 9 compared with ovx+e2 (p<0.050). conclusion: in muscle from e2 deficient mice (ovx vs. ovx+e2 group), several apoptosis-linked mirs were down regulated concomitant with higher mrna expression of the target proteins. furthermore, e2 deficiency was associated with higher cytochrome c and active caspase 9 protein levels. to conclude, e2 deficiency down regulated several mirs related to apoptotic pathways that may lead to increased apoptosis and reduced skeletal muscle mass. background: although sarcopenia's pathogenesis is multifactorial, with its major phenotypes, muscle mass and muscle strength, being highly heritable, its genetic underpinning is not well studied. objectives: summarize evidence for use of zebrafish as a model system to decode the sarcopenia's gwas findings. methods: several genome-wide association studies (gwas) of muscle-related traits were published recently, providing dozens of candidate genes, many of them with unknown function. therefore, animal models are required not only to identify causal mechanisms, but also to clarify the underlying biology and to translate this knowledge into new interventions. over the past several decades, small teleost fishes had emerged as a powerful system for modeling the genetics of human diseases. due to their amenability to rapid genetic intervention and the large number of conserved genetic and physiological features, small teleosts, such as zebrafish (d. rerio), are indispensable for skeletal muscle genomic studies. results: we summarize the evidence supporting the utility of small fish model for accelerating our understanding of human skeletal muscle in norm and disease. the following stable mutants (mostly knockouts) exist for the «monogenic muscle» diseases (human gene, fish mutant, disease): for duchenne and becker muscular dystrophy (md), sapje/dmd (homology of human dmd gene); for limb-girdle md, popdc1s191f (bves); for bethlem myopathy and ullrich congenital md, col6a1ama605003 (col6a1); for nemaline myopathy, froto27c (myo18b), and tmod4trg (tmod4); for merosin deficient congenital md, lama2cl501/cl501; candyfloss/lama2 (lama2); for limb-girdle md, bvesicl1/icl1 (popdc1), heltg287 (ttn), and «foie gras» (trappc11); for native american myopathy, stac3mi34 (stac3), as well as fish homologues of the acvr1, cacnb1, cavin4, cms, dag1, fhl1, flnc, vcp and other human genes. these models provide evidence of muscle-related gene's conservancy and similarity of skeletal muscle morphology and physiological phenotypes. we will outline challenges in interpreting zebrafish mutant phenotypes and translating them to human disease. conclusion: we conclude with recommendations of future directions to leverage. centenarians exhibit extreme longevity and a compression of morbidity. we showed previously that centenarians display a unique genetic signature, in terms of mrna and mirna profile, which is similar to that found in young people and different from that found in octogenarians. centenarian offspring seem to inherit centenarians' compression of morbidity, as measured by lower rates of age-related pathologies such as hypertension, diabetes, strokes, and heart attacks. we therefore hypothesized that they will also display a lower incidence of frailty. in this study, we aimed to ascertain whether centenarian offspring are endowed which such "genetic footprint" and a lower incidence of frailty, when compared to their contemporaries. for this purpose, we collected plasma and peripheral blood mononuclear cells from 88 septuagenarians, 88, age-matched centenarian offspring (but not sons or daughters of the centenarians included in this study) and 63 centenarians. mirna expression and mrna profiles were performed by the genechip mirna 4.0 array (affimetrix) and genechip clariom s human array (affimetrix), respectively. frailty phenotype was determined by meeting three or more of the following criteria: unintentional weight loss, low grip strength, exhaustion, slow gait speed, and low physical activity. we found that mirna and mrna expression patterns in centenarians are similar to centenarian offspring and different to non-centenarian offspring (p<0.01). importantly, we found a lower incidence of frailty among centenarians' offspring (p<0.01), when compared to their contemporaries. taken together, our results indicate that centenarian offspring resemble centenarian characteristics and that they enjoy significantly less frailty than their less fortunate contemporaries that are not sons or daughters of centenarians. this lower incidence of frailty may be a key feature to achieve extraordinary ageing. background: hypoglycemic episodes increase in older patients and their consequences are more significant. objectives: the aim of this prospective observational study is to explore unknown hypoglycemic episodes diagnosed by continuous glucose monitoring in older type 2 diabetic patients and to describe the link between the occurrence of hypoglycemia and glycosylated hemoglobin (hba1c) level. methods: we included 36 patients with type 2 diabetes aged 75 years or over hospitalized during 19 consecutive months in a geriatric acute care unit in tours university hospital in france. demographic characteristics, type of diabetic treatment, mini mental state examination, hba1c levels, albumin and creatinin level were recorded. continuous glucose monitoring (cgm) was used to detect hypoglycemia for a maximum of 5 days, and capillary blood glucose measurements (cbgm) were also performed 4 to 8 times a day. patients with at least one blood glucose measure lower than 70 mg/dl were compared with others for demographic, clinical and biological parameters. results: seventeen patients experienced hypoglycemia. these groups did not differ in demographic characteristics and in diabetic drug class. among these patients, 5 had an episode of severe hypoglycemia (< 40 mg/dl) and 14 patients had nocturnal episodes, more often between 4 and 8 am. twelve patients had unrecognized hypoglycemia by cbgm. the average duration of hypoglycemic episodes was 4.1 hours. there was no difference in the hba1c levels between the two groups (mean 7.5%, p=0.86). conclusion: the prevalence of hypoglycemia is underestimated in the oldest diabetic population receiving hypoglycemic drugs. measurements of cbgm and hba1c level in the target may overlook nocturnal and prolonged hypoglycemic episodes. our study showed the benefit of cgm in older diabetic patients in order to detect unknown hypoglycemia. more prospective studies are needed to explore factors that predict hypoglycemia. catenacci, sophie le-gonidec, alizée dortignac, ophélie pereira, romain madeleine, jean-philippe pradère, philippe valet, cedric dray (umr1048 inserm,universitéfédéral de toulouse -universitépaul sabatier toulouse iii, france) background: healthy lifespan does not increase proportionally compared to global lifespan leading to an increased number of disabled aged persons. to increase healthy lifespan, locomotion could be considered in the future as the main targetable outcome to fight against the frailty to dependency transition. the so-called sarcopenia, characterized as the loss of muscle mass and function, affects 6 to 22% of the populations over 65. mechanistically, sarcopenia is associated with an imbalance between protein synthesis and degradation, an increase of muscle inflammatory processes, a reduction of mitochondria-driven metabolism and an exacerbated fibrosis. several therapeutic strategies have been proposed such as hormonal replacement but, regarding the adverse effects, these strategies have been abandoned. in this context, we hypothesize that, through a modified secretory profile, adipose tissue could play a crucial role in the muscle loss of function. we previously promoted an unbiased proteomic study and identified haptoglobin as an up-regulated cytokine overproduced by the adipose tissue during aging. objectives: in this context, our project proposes to better understand the role of adipocyte haptoglobin in age-related muscle weakness. methods: to do so, we used complementary in vitro and in vivo models of haptoglobin supplementation and strategies of adipocyte haptoglobin over-expression/deletion. impacts of such interventions have been monitored by measuring myogenesic processes as well as muscle aging. moreover, a human cohort in progress will help to constitute a new biobank by collecting blood, adipose and muscle from sarcopenic individuals in order to evaluate the role of hapatoglobin on sarcopenia (inspire cohort). results: the results obtained in vivo and in vitro suggest that haptoglobin treatments induced an age-dependent decrease in muscle mass. moreover, these protocols indicated a muscle-specific role of haptoglobin when we measured the fiber diameter. in addition, a direct effect of haptoglobin on differentiation alteration was also observed in in vitro human muscle cells. conclusion: these results suggest that haptoglobin induces effects according to the age, the muscle type and the dose on muscle physiology. thus, a better knowledge of adipocyte haptoglobin production could help to better apprehend the age-related muscular complications. background: sarcopenia contributes to loss of independence and is increases risk of mortality. mitochondrial dysfunction and loss of proteostasis are two interrelated hallmarks of aging with well-established roles in skeletal muscle function. mitochondrial dysfunction increases cellular oxidative stress and impairs atp-generating capacity. consequentially, oxidatively-damaged proteins accumulate; however, a dysfunctional mitochondrial reticulum cannot sufficiently provide energetic resources to repair the proteome. in skeletal muscle, this impaired proteostasis and mitochondrial dysfunction promote sarcopenia. thus, improving mitochondrial function by increasing endogenous antioxidants could attenuate age-related loss of muscle function. objectives: using a phytochemical nrf2 activator (nrf2a), we sought to determine if upregulation of cytoprotective genes would improve mitochondrial function and gait, an integrative metric of musculoskeletal function. methods: we utilized dunkin-hartley (dh) guinea pigs that develop primary osteoarthritis and experiences age-related skeletal muscle dysfunction by 9 months of age (~20% of their maximal predicted lifespan). we treated young (2mo) and older (5mo) dh guinea pigs for 3 and 10 months, respectively, daily with a nrf2a. we assessed metrics of gait monthly to measure the effect of nrf2a on agerelated musculoskeletal dysfunction. we evaluated the effect of nrf2a on skeletal muscle protein turnover using the stableisotope deuterium oxide. we also assessed soleus mitochondrial function using high resolution respirometry. results: while nrf2a did not affect gait in young guinea pigs, 10 months of nrf2a treatment maintained stride length (p=0.067) in older male and stance width (p<0.05) in older female guinea pigs compared to untreated controls. nrf2a improved (p=0.089) adp vmax in young females and old males compared to their respective controls. nrf2a also increased uncoupled electron transport system capacity in both male and female guinea pigs of both ages (p<0.05). nrf2a augmented contractile protein synthesis in the soleus of old male and female guinea pigs (p=0.071), but did not prevent the age-related declines in the gastrocnemius. conclusion: in summary, long-term nrf2a treatment improved skeletal muscle mitochondrial function, increased contractile protein synthesis, and maintained aspects of gait. together, our findings provide evidence that targeting the transcription factor nrf2 mitigates the decline in musculoskeletal function in a model of osteoarthritis and sarcopenia, with concomitant improvements in mitochondrial function and protein turnover. . j a n n e k e v a n w i j n g a a r d e n 1 , francina j dijk 1 , miriam van dijk 1 , lisette cpgm d e g r o o t 2 , y v e s b o i r i e 3 , 4 , y v e t t e c l u i k i n g 1 background: sarcopenia is a muscle disease rooted in adverse muscle changes that accumulate across the lifespan. multiple factors cause or worsen sarcopenia, with aging as the primary factor and malnutrition, inactivity and diseases as secondary factors. objectives: to design a nutritional strategy to manage sarcopenia. methods: our research program investigated 1) specific nutrient deficiencies in sarcopenic older adults, 2) muscle protein synthesis (mps) response in cells and rodent models, and 3) effect of a specific nutrient combination (whey protein, leucine and vitamin d -actisyn(tm), present in the medical nutrition supplement fortifit(r), on mps in older adults. results: cross-sectional studies indicated a significantly lower intake of protein (-6%) and vitamin d (-36%) in sarcopenic versus healthy older adults (p<0.05) [verlaan, clin nutr 2017], and higher prevalence of sarcopenia among those with lower blood levels of leucine, total essential amino acids ( the specific combination of whey protein, leucine and vitamin d (actisyn(tm)) provides the right environment for muscle building in sarcopenia, where these nutrients are often deficient. this combination acts through a proven anabolic mode of action with optimal nutrient bioavailability for the muscle to stimulate mps. fortifit and actisyn are trademarks of n.v. nutricia. background: age-related sarcopenia is a major responsible for premature death, poor quality of life and several adverse outcomes, which lead to higher health care costs. despite its recent incorporation as a muscle disease (icd-10-cm m62.84), early identification of this disease remains challenging. mostly, due to classification and diagnostic criteria, which are predominantly based on technically advanced assessment tools, which may not be available in all clinic settings. recently, a non-invasive technique to analyze variations in biological tissues considering the effect of physiological and biological properties on microwave signals is being studied for its potential to determine muscle mass, with possible applications in the early diagnosis of this disease. objectives: therefore, the principal objective of this study is to preliminarily test the potential of this technique as a new tool for early diagnosis of age-related sarcopenia in a clinical setting. methods: muscle surface area are going to be assessed by abdominal computational tomography (ct) on the third lumbar spine vertebra (l3) and bioimpedance measurements among 50 men and women, aged >=60 years in the maastricht university medical center, the netherlands. participants will also be subjected to measurements done with the device under test (dut) (the proposed technique) in the same location. the data collected from the three different measurements are analyzed looking for correlation. laboratory experiments made from synthetic materials emulating human tissues and from ex-vivo porcine tissues are used for optimization and interpretation of the clinical measurements. results: up-tonow, the campaign has just started and there is no enough data to give a preliminary result. initial laboratory experiments prove that the thickness of the fat and muscle tissues is correlated to the system response. conclusion: this prospective device will estimate the muscle mass locally using microwave electromagnetic principles. the results of this study can contribute to reveal the potential of this approach as a tissueanalysis tool for early diagnosis and management of age-related sarcopenia. the results might also provide useful evidence to consider in a future planned prospective cohort study, which aims to examine the impact of dietary biomarkers and genetic factors on the incidence of age-related sarcopenia in older adults. background: sarcopenia has become a serious problem in this aging society. at present diagnosis of sarcopenia consist of physical performance and muscle quantity. dexa has been widely applied to examine muscle quantity in clinical but it's radioactive, inconvenient and unaffordable in remote area. as a result, there are more studies in ultrasound in replace of dexa. objectives: based on others researches csa might be a suitable parameter to evaluate the muscle quantity. we develop a cheaper ultrasonic imaging system to evaluate the cross-sectional area (csa) of rectus femoris (rf)muscle. methods: we use a cmos image sensor combing with digital signal processor to detect the displacement of single element ultrasonic transducer. therefore, we combine us a-mode signal with displacement into b-mode image. by circling region of interest (roi), we can obtain the csa of rf muscle. then, we use siemens s3000 evaluating the csa in the same region to testify the reliability. results: we recruited 10 young college students undergoing the experiment. the result shows that the correlation coefficient is up to 0.96. conclusion: in conclusion, our device can successfully evaluate the csa of rf muscle. moreover, our system using single element ultrasonic transducer is much cheaper than linear transducer in practice .it can be affordable in remote village or somewhere lacking in medical resource. a case-control study. camille nicolay 1 , sandra higuet 2 , sandra de breucker 1 ((1) geriatric department, hôpital erasme, brussels, belgium; (2) geriatric department, hôpital isppc-charleroi, charleroi, belgium) background: ten percents of belgian population are considered to be informal caregivers. little is known about their frailty status and their physical health. objectives: we compared the frailty status, the clinical and psychosocial status of old caregivers with controls (>65). we analyzed the association of frailty status according to fried's criteria and rockwood frailty index (fi) with the characteristics of caregivers and controls in multiple regression analysis. methods: eighty six caregivers and 105 gender and agematched controls were included. frailty was assessed by the frailty phenotype (fried) and the 40-deficit frailty index (fi). social data, sf-12 health survey, basic and instrumental adl, geriatric depression scale, mini nutritional assessment, mini-cog, cumulative illness rating scale-geriatric, usual gait speed, handgrip strength, and burden scale (zarit) were collected. results: the prevalence of frailty was similar in caregivers and controls with the fi (p=0.479) but higher with the fried's criteria (p=0.001). compared with the control group, caregiving was associated with a lower mental quality of life (p<0.001), a higher risk of depression (p<0.001), a higher consumption of antidepressant (p=0.02), a lower nutritional status (p=0.019), a more frequent help from health care providers (p=0.005), and more problems to maintain physical contacts with a social network (p=0.008). in multiple regression, the fried's criteria adjusted for age, gender, marital status and incomes were associated with the age, the grip strength, the physical quality of life, the gait speed and the nutritional status (r2=0.79 -p<0.0001), while fi was associated with the risk of depression, the use of antidepressants, the physical quality of life, the cognitive status and basal & instrumental adl (r2=0.85 -p <0.0001) in caregivers. conclusion: the prevalence of frailty is similar in caregivers and controls when using fi, but higher in caregivers with fried's criteria. compared with controls, caregiving is associated with poorer health and psychological issues. while fried's criteria focus on physical frailty, the fi is more related with geriatric syndromes like depression, cognitive disorders, loss of autonomy, and quality of life. this study could help researchers to choose between frailty scales before starting a study about older caregivers. background: nursing home (nh) residents are often undernourished and physically inactive contributing to sarcopenia and frailty. mobility is identified by older nh residents as being key to their quality of life and well-being. the combination of protein supplementation and physical exercise has been shown to be most effective to maintain and increase muscle mass. objectives: the older persons exercise and nutrition (open) study aimed to investigate the effects of sit-to-stand exercises (sts) integrated into daily care combined with a protein-rich oral nutritional supplement (ons), on physical function, nutritional status, body composition, healthrelated quality of life and resource use. methods: residents in eight nh were randomized by nh units into an intervention group (ig) or a control group (cg) (n=60/group). the ig was offered a combination of sts (four times/day) and ons (2 bottles/day providing 600 kcal and 36 g protein) for 12 weeks. the participants resided in nh units (dementia and somatic care), were >=75 years and able to rise from a seated position. the 30 seconds chair stand test (30scst) was the primary outcome. secondary outcomes were balance, walking speed, dependence in adl, nutritional status and body composition, health-related quality of life and resource use. data was analyzed using descriptive and inferential statistics including regression models. results: altogether 102 residents (86±5 years, 62% females) completed the study. no improvement in the physical function assessments was observed in the ig, whereas body weight increased significantly (2.05±3.5 kg, p=0.013) vs the cg. twenty-one (of 52) participants with high adherence to the intervention, i.e. at least 40% compliance to the combined intervention, increased their fat free mass (2.12 kg (0.13, 4.26 iqr), p=0.007 vs cg. logistic regression analyses indicated that the odds ratio for maintained/improved 30scst was 3.5 (ci 1.1, 10.9, p=0.034) among the participants with high adherence compared to the cg. waly dioh 1 , cendrine tourette 1 , carole margalef 1 , amy chen 2 , rené lafont 1,3 , pierre dilda 1 , stanislas veillet 1 , samuel agus 2 ((1) biophytis, sorbonne université -bc9, paris, france; ( background: sarcopenia is a geriatric condition characterized by loss of muscle mass and functions and can contribute to risks of falls, fractures and hospitalization. sara-obs is a multicenter, observational trial designed to better characterize age-related sarcopenia in a community dwelling population at risk of mobility disability. this is part of a clinical program that strives to provide more understanding of the target population in order to further develop a potential sarcopenia medical intervention. sara-obs study rationale, design and main baseline characteristics are presented. objectives: the objective is to characterize sarcopenia and sarcopenic obesity in older adults through evaluation of their physical performance and body composition. changes in baseline characteristics after a 6-month period will be assessed and used for development of a phase 2 interventional study on the efficacy and safety of an investigational drug, bio101. methods: participant recruitment was based on age (>=65 years), sppb score =<8 and body mass based on the fnih criteria. physical functions were assessed by two walking tests (400m walk test and the 6-minute walk test), the sppb, the handgrip strength test and the stair climb power test. patient reported outcomes were also assessed with the sf-36 and the sarqol questionnaires. results: 218 subjects were included in this study and the main screen failures were sppb scores and body mass criteria. baseline characteristics indicated that the average bmi was high, ~61 % of the participants were women and that the alm/bmi in men was lower than the fnih threshold (0.69 vs 0.789) but was similar in women (0.52 vs 0.52). 400m gait speed was 0.83 m/s, the mean total sppb score was 6.12 with the gait speed component of <0.8m/s and the chair stand sub-score of 1.73. conclusion: this population has a similar 400m gait speed as the populations in life and sprint-t studies at baseline. however, the sppb total score and the chair stand sub-score correspond more closely with the sprint-t study. addressing the loss of physical function and preventing mobility disability is still an unmet need of older adults. sara-obs included a population representative of a suitable target for subsequent interventional studies aimed to fulfill this need. yen-lung chen, hui-hua chiang (department of biomedical engineering, national yang-ming university, taipei, taiwan) background: in whole world, the elderly formally entered the aging society , and the patients with sarcopenia were highrisk groups in the fall. more than 20% of the elderly suffered moderate injuries due to falls. the sarcopenia as defined by the eu's sarcopenia working group was refers to progressive reduction in muscle mass and decreased muscle function. objectives: it is expected to provide diagnostic tools and techniques for the rapid determination of sarcopenia and muscle strength. at the same time, it will also be developed toward portable devices to facilitate the diagnosis of the aging of muscle function in the elderly at home to take care of the health and well-being of the elderly. methods: at present, the clinical measurement part is assisted by the radiation department of the veterans general hospital to collect and measure the subjects. clinical testing methods are mainly for older people over 65 years of age. the walking speed test is firstly performed on the method. if it is normal, then the grip strength test is performed. if the grip strength is too small, the femoral rectus femoris muscle volume test should be performed. generally, dual energy is used. dual-energy x-ray absorptiometry (dxa) is used for testing. if the walking speed is too slow, the dxa test should be performed directly. the test value is less than 6.0 (kg/m2) in woman and less than 7.0 (kg/m2)in man. that is, it is determined as a sarcopenia patient. since dxa has a small amount of free radiation, high cost, and a large space occupation, we expect to obtain a wide range of data through ultrasonic scans. back-end development algorithms are calculated to determine if there is sarcopenia and how severe it is. results: at present, the rectus femoris muscle volume obtained by using ultrasound has a highly linear relationship with the appendicular muscle mass measured by dxa (r2=0.87,p<0.001), and has the ability to distinguish whether it is sarcopenia. conclusion: the use of muscle volume of rectus femoris can improve the accuracy of sarcopenia prediction. in the near future, this plan will be used to develop automated ultrasonic scanners. background: although sarcopenia has multifactorial causes, the decline in physical activity has been considered a very important aspect for its development. since the promotion of higher levels of physical activity can attenuate the progression of sarcopenia, it is possible that the participation in a programmed training increases the spontaneous physical activity of the participants. objectives: to investigate if the participation of sarcopenic older women in a resistance training program and supplementation with fish oil leads to changes in the level of spontaneous physical activity (sedentary time and number of steps). methods: randomized, double-blind, placebo-controlled clinical trial. thirty-two older women, aged >= 65 years, participated in the study. all participants were classified as sarcopenic based on the criteria of the european consensus on sarcopenia 2010 (ewgsop). the participants were divided into two experimental groups: (1) exercise group + placebo (ep) and (2) exercise group + fish oil (efo). both groups underwent a resistance exercise program over 14 weeks, consisting of three weekly supervised sessions. all volunteers were instructed to take two capsules of food supplement at each main meal, lunch and dinner (4g/day). the ep group used capsules composed of sunflower oil as placebo, and the efo group fish oil capsules, (epa 440mg and dha 220mg). measurements of the level of spontaneous physical activity were made before and after the intervention by using the actipal® physical activity monitor (glasgow, uk), for a period of seven consecutive days, during which the volunteers were instructed to maintain their normal routine. the volume of the quadriceps muscle in the pre and post intervention periods was calculated from the images obtained by magnetic resonance imaging. for statistical analysis, a linear regression model with mixed effects was used to compare longitudinal data on mean intra-group differences between groups and moments. for all analyzes, a significance level of 0.05 was adopted. results: both groups showed an increase in muscle volume after the intervention (47.4 cm3 (13.5%) and 15.1 cm3 (4.9%), respectively). regarding the level of spontaneous physical activity, both groups had a similar sedentary time and number of steps, at both times (average 8.9h and 8,608 steps in the pre-intervention period and 8.3h and 8,844 steps in the postintervention period for the ep group, and 9.6hrs and 9,869 steps in the pre-period and 9.0h and 7,045 steps in the postintervention period in the eop group). conclusion: although sarcopenic older women supplemented with fish oil showed a higher increase in muscle volume, the level of spontaneous physical activity remained unchanged both in the pre and post intervention periods and between groups, indicating that the increase in muscle volume was not associated with significant changes in the level of spontaneous physical activity. background: regardless of improvements in surgical and anesthetic practices, older surgical patients often experience postoperative complications. the purpose of this study was to investigate the association between physical frailty and cognitive function using a validated upper-extremity function (uef) test with in-hospital outcomes in aging adults undergoing abdominal surgery. objectives: to recognize frailty and cognitive function as a risk factor for in-hospital adverse outcomes. methods: we administered pre-operative uef tests, within 24-hours after admission, among patients aged 40 years and older undergoing emergent/urgent abdominal surgery. the uef involved two tests; 20-and 60-sec of respectively fast and consistent elbow flexion, while angular velocity was measured via two wearable motion sensors applied to the wrist and upper-arm of the dominant arm. uef physical score was calculated, based on slowness, weakness, flexibility, and exhaustion (range: resilient=0-frail=1). uef cognitive score was assessed based on motor function variability within a dual-task performance that involved uef motor task and a cognitive task of counting backwards by threes (range: cognitive normal=0-cognitive impairment=1). adverse outcomes included: length of stay, complications, and death during their hospital stay. a logistic regression model was used to assess the association between uef physical and cognitive scores (independent variables) and in-hospital outcomes (dependent variable). results: a total of 75 participants (mean age 60.7±11.6 years) completed the preoperative uef assessment. thirty-six participants with an average age of 63.7±10.3 years experienced at least one adverse outcome while in the hospital. while age independently predicted in-hospital outcomes with receiver operating characteristic area under the curve (roc-auc) of 62%, this prediction improved by adding either the uef physical or the cognitive score. the physical score predicted in-hospital outcomes with a roc-auc of 80%, and the cognitive scores predicted in-hospital outcomes with a roc-auc of 77%. conclusion: the proportion of emergency surgical procedures increases with age, and population trends indicate that this demand will increase significantly. results from the current study showed that sensor-based measures of physical and cognitive function can provide an objective tool for predicting adverse outcomes, with potential applications for other surgical procedures. risk stratification can help to establish targeted management strategies to improve the healthcare system and patient-centered outcomes. background: while sensor-based daily physical activity (dpa) gait performance has been demonstrated to be an effective measure of physical frailty, it is not clear how repeatable the dpa gait parameters are between different days of measurement, especially across frailty groups. objectives: to evaluate the test-retest reliability (repeatability) of dpa gait performance parameters (stride time, variability, and irregularity) and quantitative measures (number of steps and walking duration) between two separate days of assessment among older adults. methods: dpa was acquired for 48-hours from older adults (age>=65 years) using a tri-axial accelerometer motion-sensor attached to the trunk. purposeful continuous walking bouts (>=60s) without long pauses (>1.7s) were identified from acceleration data and used to extract gait performance parameters, including stride time, power spectral density (psd) slope (representing the variability of walking cycles), dominant frequency of walking, and gait irregularity (sample entropy, representing predictability of walking cycles). to assess repeatability, intraclass correlation coefficient (icc) was calculated using two-way mixed effects f-test models for day-1 vs. day-2 as the independent random effect. repeatability tests were performed once for all participants and once within each frailty group (non-frail and pre-frail/frail). results: data from 63 older adults, 29 non-frail (age: 74.97±7.10 years) and 34 pre-frail/frail (age: 81.26±8.94 years) were analyzed. within all 63 participants with purposeful walking bouts on both the days, gait performance parameters of stride-time and gait variability parameters (slope and dominant frequency of walking) showed excellent test-retest reliability values (icc>=75%) while quantitative parameters, including number of steps and walking duration showed poor test-retest reliability results (icc<30%). among gait performance parameters (stride time, dominant walking frequency and sample entropy), we observed higher repeatability among the pre-frail/frail group with icc>78% compared to icc<53% for non-frail individuals. conclusion: from our study, it is evident that gait performance parameters including average step-and stride-time and frequency-domain gait variability parameters provided higher test-retest reliability compared to quantitative measures. further, gait performance parameters showed higher repeatability among pre-frail/frail volunteers between the two days compared to non-frail volunteers, which may be attributed to a lack of functional capacity among frail individuals for performing more intense and more variable physical tasks. background: while evaluation methods for skeletal muscle characteristics which are necessary to know the pathogenesis of sarcopenia are being considered, ultrasonography is attracting attention as a method simultaneously evaluate quantitative and qualitative evaluation of skeletal muscle. although we have found many, the statements that examined the relation between muscle thickness, echo intensity, physical function, and sarcopenia by quadriceps muscle ultrasonography in the previous report, there are few reports for the lower leg muscles. objectives: we conducted a study to examine whether the lower leg muscle ultrasonography is useful for evaluating sarcopenia index and muscle quality (muscle strength per unit muscle mass) evaluation in comparison with the quadriceps ultrasonography. methods: the participants were 52 patients over 65 years old (27 males, 25 females). the muscle thickness of the quadriceps muscle, tibialis anterior muscle, gastrocnemius muscle, soleus, and echo intensity were measured by ultrasonography, and the relationship between lower extremity muscle mass, muscle strength, physical function, and muscle quality was examined. results: the muscle thickness of quadriceps muscle, tibialis anterior muscle, soleus muscle was related to lower extremity muscle mass, grip strength, leg muscle strength, and only quadriceps muscle was related to gait speed. the echo intensity of the quadriceps, tibialis anterior, gastrocnemius was related to, grip strength, leg muscle strength, and only the tibialis anterior muscle was related to gait speed. the muscle thickness and the echo intensity of tibialis anterior muscle and soleus muscle are highly correlated with the quadriceps. the echo intensity of the tibialis anterior muscle, as well as that of the quadriceps muscle, showed a high correlation with the muscle quality of lower extremity. conclusion: concerning the assessment of sarcopenia using ultrasonography, muscle thickness and echo intensity evaluation by tibialis anterior muscle showed the same utility as them by the quadriceps muscle, and echo intensity of the tibialis anterior muscle can be a marker of muscle quality. lucena germano 1 , cristiano dos santos gomes 1 , juliana fernandes de sousa barbosa 1,2 , raysa freitas 1,3 , alvaro campos c. maciel 1 , ricardo oliveira guerra 1 ( (1 background: phase angle (pha) is emerging as a measure of great clinical relevance provided through bioimpedance assessment and its related to health adverse outcomes such as osteoporosis and sarcopenia. on the other hand, poor physical performance as gait speed and grip strength in elderly is associated with poor health conditions. we hypothesized it is plausible that those two measures might be related and can be used as a tool in clinical practice. objectives: to investigate the relationship between pha and physical performance measures in community-dwelling older adults from brazil. methods: this cross-sectional study enrolled 253 older adults of both sexes who had a comprehensive health evaluation including physical performance tests (gait speed and handgrip strength) and electrical bioimpedance screening. linear regression models were used to estimate the associations between pha and physical performance measures. results: the mean age of 72.06 ± 3.49 and 72.88 ± 4.90 for men and women respectively. hand grip strength (n: 0,248; p-value < 0,05) and gait speed (n: 0,212; p-value < 0,05) were independently correlated with pha. conclusion: pha could help to easily identify elderly on the onset of present heath adverse outcome and guide specific interventions by clinicians. shosuke satake 1,2 , kaori kinoshita 1 , yasumoto matsui 3 , background: in japan, we have a simple yes/no questionnaire to assess multiple functions in daily living for older adults; the kihon checklist (kcl). in the questionnaire, 5 questions to assess mobile functions are included. objectives: we examined whether the 5-item questions in the physical domain of the kcl (kcl-phys) could be a surrogate of validated measurements of physical functions. methods: subjects were 465 independent and ambulatory seniors aged 65 years or older who had been consulted in our frailty clinic. all of them received grip strength test, dual energy x-ray absorptiometry, physical performance tests, cognitive examination, and the kcl questionnaire. among them, we excluded 2 subjects with missing data, and 8 with moderate cognitive impairments. we examined the relationships between scores of the kcl-phys and usual gait speed, short physical performance battery (sppb), and timed up and go (tug) with the spearman's rank correlation. the score of the kclphys were counted when the subject meets any criteria with each question as previously reported. also, we evaluated the cutoff point of the kcl-phys equivalent to slow gait speed (<0.8m/s), low sppb score (sppb < 8), and slow tug (tug >= 20 sec) with the receiver operating characteristic (roc) curve analysis. results: the mean values of age, body mass index, and prevalence of sarcopenia were 77.4 years old (women 67.9%), 23.7 (kg/m2), and 22.9 (%), which were no differences between sexes. on the other hand, physical functions of gait speed, sppb, and tug were all worse in women than in men. relationships between the scores of the kcl-phys and usual gait speed, sppb, and tug were moderate with the coefficients of -0.595, -0.589, and 0.544, respectively (p<0.0001 for all). the area under the roc curve of the kcl-phys score equivalent to slow gait speed, low sppb score, and slow tug were 0.791, 0.820, and 0.792, respectively. the cutoffs were thought to be the best at 3 points of the kcl-phys to identify low physical functions based on the youden index. conclusion: physical domain of the kcl could be a surrogate of assessments of physical functions in older people. yuji hirano 1 , izumi kondo 1 , tetuya nemoto 1 , naoki itoh 1 , hidenori arai 1 ((1) national center for geriatrics and gerontology, japan; (2) nihon fukushi university, japan) background: we have developed a new type of grip strength measurement that addresses the time axis in evaluating physical function. it can measure the dynamic force, response in gripping performance, and maximum grip strength. the "kihon checklist" (kcl) is used to screening the frail elderly, based on the japanese long-term care insurance system. however, the relationship between the gripping performance and kcl has not been well investigated. objectives: the purpose of this study was to introduce a novel automatic reading method for dynamic force parameters in gripping performance and to evaluate their relationship with the kcl. methods: the subjects comprised 248 patients (94 men, 154 women, average age 78.2 ± 6.0 years) who visited the integrated healthy aging clinic (locomo-frail outpatient clinic in japanese) of our hospital. the four indices of grip force response measured were: reaction start time (rst), time constant (tc), maximum value of force (mvf), and force rising slope (frs). we examined the relationship between these four indices and seven categories of the kcl; activities of daily living (adl), physical functions and fall, nutrition state, oral functions, outdoor activities, cognitive functions and mood, using spearman's correlation coefficient. results: in the female right hand, the mvf was only significantly correlated with adl and overall scores; whereas, in the female left hand, the mvf and the frs were significantly correlated with many items (adl, physical functions and fall, nutrition state, outdoor activities, and cognitive functions). the time-dependent items (rst and tc) were significantly correlated with outdoor activities in the female left hand and significantly correlated with adl and oral functions in the male left hand. however, in the right hand, the time-dependent items were not correlated with any of items in kcl in both sexes. conclusion: our newly developed grip strength measurement system could automatically calculate not only the maximum grip strength but also the time response of the grip force. moreover, their relationship with kcl was clearly indicated. the relationship between detailed grip strength response indicators and kcl items differed between men and women, and the left hand was correlated with more items than the right hand. ranyah almardawi, rao gullapalli, michael terrin (university of maryland school of maryland, baltimore, usa) background: rotator cuff (rc) tear and shoulder pain are both highly prevalent in older populations. routine medical screening for shoulder dysfunction is uncommon for community-dwelling older adults. the disabilities of the arm, shoulder and hand (dash) survey estimates self-reported dysfunction of both upper limbs in a composite score. dash offers a quick method to identify older adults with potential dysfunction in either shoulder, which otherwise may go unrecognized during routine medical visits. objectives: 1. to determine if dash, american shoulder and elbow surgeons (ases) and simple shoulder test (sst) surveys are related to one another in older adults. 2. to assess dash, ases and sst score relationships to the sf-36 physical functioning (pf) subcomponent score, shoulder forward flexion range of motion (ff-rom) and shoulder abduction range of motion (abd-rom) in older adults. methods: cross-sectional study: twenty-three community-dwelling-older-adult volunteers [mean age, 69.7 ± 6.8 years; range, 61 to 84 years; female, 65%] with no history of rc surgery and no history of shoulder injury or shoulder physical therapy in the prior 3 months completed shoulder magnetic resonance imaging (mri) and dash, sf-36, charlson co-morbidity index (cci), katz activities of daily living (adls) and lawton instrumental adls (iadls) surveys. for the shoulder ipsilateral to mri, participants completed ases, sst, visual analog scale for pain (vas) surveys; and shoulder ff-rom and abd-rom. descriptive statistics and spearman rank order correlation (rho) were performed. results: frequencies: rc tear (supraspinatus tendon) on mri: 47.8%; shoulder pain >= 2 on vas: 56.5%; no limitation (score=6) on katz adls: 91.3%; no limitation (score=8) on lawton iadls: 95.6%. means: cci, 3.0 ± 1.0; dash, 16.6 ± 7.5; ases, 81.4 ± 19.2; sst 70.2 ± 29.4; 81.7 ± 19.7; 144.1 ± 31.4; 133.3 ± 31.7 . range of correlation among dash-ases-sst surveys: (|rho|=0.92-0.95, p<0.001). range of correlation for dash-ases-sst with sf-36 pf(|rho|=0.61-0.69, p<0.002), p<0 .001), abd-rom (|rho|=0.74-0.82, p<0.001). conclusion: dash, ases and sst correlate well, and all three surveys show a consistent relationship with sf-36 physical functioning, ff-rom and abd-rom. next steps would be to evaluate the feasibility of dash to identify older adults with shoulder dysfunction during routine medical visits. background: physical performance is closely associated with chronic diseases and dysfunction of numerous organ systems. old persons with chronic renal failure have shown the apparent decline in physical performance, especially in the end-stage. however, it is unclear whether the subclinical kidney dysfunction is associated with skeletal muscle function deficit in the elderly population. objectives: the aim of this study is to determine the association between renal function and skeletal muscle function deficit in old persons without nephropathy. methods: eight hundred fifty-four korean elderlies (female, 75.3%) aged 65 to 89 years were included in the cross-sectional analysis. of the participants, 135 elderlies (female 57.0%) were available for the 1-year follow-up test session. all participants were interviewed face-to-face and received measures of anthropometry, body composition and serum biomarkers of metabolic diseases. estimated glomerular filtration rate (egfr) was calculated using the chronic kidney disease epidemiology collaboration (ckd-epi) equation based on serum creatinine concentration. skeletal muscle function deficit was defined as a combination of weakness and slowness based on the handgrip strength to body mass index ratio (hs/bmi, men < 1.0, women < 0.56) and converted timed up-and-go to walking speed (tugspeed < 0.8 m/s). results: the subjects with 30 <= egfr < 45 ml/min/1.73m2 showed significantly lower physical performance for muscular strength and functional mobility than those with 45 <= egfr < 60 and egfr > 60 ml/min/1.73m2, respectively (all for p < 0.05). logistic regression analysis indicated the significant association between egfr and skeletal muscle function status even after adjustment for potential confounders (p for trend < 0.01). moreover, the prospective observational analysis by ancova showed the significant effects of enhancement in hs/bmi [f(2, 122) = 4.89, p = 0.009] and tugspeed [f(2, 122) = 9.50, p < 0.001] on the improvement in egfr during 1-year followup. conclusion: taken together, skeletal muscle function status is associated with even moderately reduced egfr in an older population. these results suggest that maintenance of physical and functional fitness may be a contributory factor for preserving renal function in elderly persons. rn, brazil) background: sarc-f is a brief and useful test to identify older people at risk of sarcopenia-associated adverse outcomes. previous studies with older populations have suggested that it may be useful to screen those with severe sarcopenia. its ability to screen sarcopenia among low-income brazilian older adults is still unknown and its association with sarcopenia diagnostic criteria may be useful to understand its utility among this population. objectives: this study aims to evaluate the validity of sarc-f in screening low muscle strength and low physical performance among a low-income sample of older adults. methods: in a cross-sectional study, 62 community-dwelling older-adults (>=60 years old; men and women) from santa cruz (northeast brazil) answered the sarc-f questionnaire and were classified as sarcopenic (>=4) and non-sarcopenic (<4) according to sarc-f scores. they were also evaluated in relation to the sarcopenia criteria of muscle strength (handgrip strength) and physical performance (sppb). the cutoff of <16 kg for women and <27 kg for men were used to classify those with low muscle strength. a sppb score of <=8 was used to classify low physical performance. a chi-square test was used to assess the association between the sarc-f and the objective parameters of sarcopenia. sensitivity and specificity of the sarc-f according to the objective functional parameters were also assessed. results: the sample was composed by 71% of women, with mean age of 72.4 (±1.06) years old. according to sarc-f, 24.2% of the sample was sarcopenic. low muscle mass and low physical performance were identified in 37.1% and 46.8% of the sample respectively. sarcopenia was significantly associated to low muscle mass (p<0.01) and low physical performance (p<0.001). the sensitivity of sarc-f in identifying those with low muscle mass was of 67% and specificity of 59%. for low physical performance, sensitivity and specificity were of 45% and 94% respectively. conclusion: sarc-f has a moderate ability to identify the sarcopenia criteria of low muscle mass and low physical function among older adults from a low-income setting. since it is a simple measure, it can be advantageous for low-income and rural communities. background: menopause marks a critical transition towards older adulthood for women and studies suggest that it is associated to several sarcopenia parameters, such as muscle mass and physical functioning. understanding how the menopausal transition associates to sarcopenia diagnostic criteria may help to direct screening tests for middle-aged populations and to identify earlier those at higher risk of sarcopenia. objectives: to evaluate the association between menopausal status and sarcopenia diagnostic criteria (muscle strength, muscle quantity and physical performance). methods: in a cross-sectional study, 389 communitydwelling women from northeast brazil (40-65 yearsold) were evaluated in relation to menopausal status using the stages of reproductive aging workshop classification (premenopausal, perimenopausal or postmenopausal) , and in relation to sarcopenia diagnostic criteria according to european working group on sarcopenia in older people (ewgsop2): muscle strength (grip strength -handheld dynamometer), muscle quantity (appendicular muscle mass adjusted for height through bioelectrical impedance) and physical performance (gait speed). association between menopausal status and sarcopenia criteria was evaluated with multiple linear regression models adjusted for covariates (current age, education, family income, walking, bmi, reproductive history). results: among the participants, 26.7% were classified as premenopausal, 39.1% as perimenopausal, and 34.2% as postmenopausal. menopausal status was significantly associated to grip strength, since premenopausal women were significantly stronger than perimenopausal or postmenopausal women, even in the fully adjusted analyses (b= 2.26; 95% ci= 0.39: 4.12). muscle quantity and gait speed were not significant according to menopausal status. conclusion: perimenopausal and postmenopausal status are associated with less muscle strength among middle-aged women. muscle weakness may be the first sarcopenia parameter that is affected by women's aging and should be tracked among middle-aged to women for early identification of sarcopenia risk.. background: we speculate maintaining good postural stability is the key to good adl in elderly patients. this is a preliminary study to evaluate which factor relates to good postural stability. objectives: we evaluated 69 patients (22 males and 47 females) over 65 years old. the average age was 75.8 years old ranging 65 to 97. methods: we measured index of postural stability(ips) using gravicoder gw-5000 manufactured by anima. the ips was adovocated by mochizuki in 2000. it was defined following this equation; ips=log[(area of stability limit + area of postural sway)/area of postural sway). larger ips means better postural stability. the average ips in each age was already known. ips was calculated automatically through gravicoda. we devided these patients into two groups by the results of ips. group a with the patients whose ips was larger, group b with the patients whose ips was smaller than the average in their age. we compared the following items between the two groups. nutrition(albumin, calcium, magnesium, ferritin, vitamin b1,b12, 1,25-d3, zinc in blood test) , bone status(bone density, % of yam), spinopelvic parameters (pelvic incidence(pi), lumbar lordosis(ll), pelvic tilt(pt) using whole spine x-ray photograph. results: ten patients were classified into group a and 59 patients were into group b. the average age was 77.6±6.1years old in group a and 75.5±5.7 in group b. in group a , ll and pt were respectively 49.7, 17.1. in group b, 36.1, 23.7. ll and pt were significantly different between the two groups. pi minus ll is an important indicator to determine the spino-pelvic balance. it is known that pi-ll<10 means good spino-pelvic balance. in group a, pi minus ll was 1.7±16.9. in group b, it was 15.7±17.0. according to nutrition and bone status, albumin was significantly higher in group b. conclusion: our results showed spino-pelvic alignment related to the postural stability. this suggests good spino-pelvic alignment is likely the key to good postural stability. background: physical performance is of main relevance for quality of life and independence in the community. identification of deterioration of physical performance helps to start early interventions to stay independently in old age. objectives: to determine physical performance of communitydwelling older adults above 70 years by using a comprehensive geriatric assessment to find most sensitive tests for functional decline. methods: older community-dwelling adults aged 70+. analysis of baseline and 6 (t1) and 24 months (t2) of followup data of hand grip strength (hgs), stair climb power test (scpt), timed up and go test (tug), short physical performance battery (sppb), 4m gait speed (4mgs), 5-time chair rise test (5tcr), 6 minute walking test (6mwt) and frailty categories according to fried. results are shown in mean (± sd) in total numbers and percentage. results: 251 participants (75,4 y.± 3,89) were included, 148 (59%) female. overall physical performance was on high level, above geriatric cut-offs for physical disabilities at baseline: (hgs female: 22, 13 (±4, 76) (-16,95 (± 11,55 )%) followed by scpt (-9,15 (± 16,84)%). all tests showed a decline except 5tcr (+2,78 (±14,24)%). conclusion: physically active, communitydwelling older people show a high level of functional performance, far from geriatric cut-offs indicating physical disabilities. nevertheless, after two years a clinically relevant reduction of strength in upper (handgrip) and lower extremities (stair climb) was detected. these data may be relevant for the identification of older individuals who may benefit from early intervention exercise programs to keep them physically independent as long as possible. 5tcr showed divergent results and could be of special interest for continuous measurements to identify gradual decreases in functional performance. background: sarcopenia is characterized by loss of skeletal muscle mass and strength and it is a frequent finding in oncology, being associated with reduced quality of life, impairment in the response to antineoplastic therapy and increased toxicity, especially in older patients. objectives: the aim of the present study was to evaluate the association between low muscle mass (lmm) assessed by computed tomography (ct) analysis and sarcopenia considering the revised european consensus published by the european working group on sarcopenia in older people (ewgsop2) with the variables of the comprehensive geriatric assessment (cga) in older oncological patients. methods: for this purpose, 67 patients (50.7% female; mean age of 76.8±7.9 years) followed at the oncogeriatric outpatient clinic of a university hospital were enrolled. clinical data were obtained from electronic medical records and the skeletal muscle mass evaluation was performed using ct (in the height of the third lumbar vertebra). for lmm and sarcopenia classification, specific cutoff points were adopted. cga variables were compared between lmm and normal skeletal muscle mass (nsmm) and between sarcopenic and non-sarcopenic individuals. groups were compared by the independent t test (r core team®, p<0.05). results: the most frequent tumors were breast, intestine, stomach and lung, at different stages of the disease. the prevalence of lmm was 78.6% and the prevalence of sarcopenia was 50%. of all cga variables evaluated, hand grip strength (16,53±6,46) and katz scale (4,87±1,68) were associated with lmm and sarcopenia. conclusion: the results highlight the importance of early geriatric clinical assessment of older cancer patients, considering the association of cga variables with low muscle mass and most important, to sarcopenia, for the possible reversal of functional and nutritional impairments and for the indication or appropriate planning of cancer therapy. lygia paccini lustosa 1 , patricia parreira batista 1 , jéssica rodrigues de almeida 1 , andré gustavo pereira de andrade 2 , aimée de araújo cabral pelizari 1 , stephanie aguiar 1 , leani de souza máximo pereira 1 ((1) physical therapy department -universidade federal de minas gerais, ufmg, eeffto, belo horizonte, mg, brazil; (2) sports department -universidade federal de minas gerais, ufmg, eeffto, belo horizonte, mg, brazil) background: functional tests in the older person reflect the integrity of the interrelationship between muscle mass and function, vascular, endocrine and neurological aspects of central and peripheral command. the reduction in functionality, muscle mass and strength associated with advancing age is related to the increase of circulating proinflammatory cytokines in plasma, which in turn predisposes the individual to negative repercussions, such as the development of chronic diseases, falls and disability. they can identify changes in the intrinsic capacity of the older people. objectives: to compare older women who reported being active or sedentary regarding functional capacity and plasma indices of inflammatory mediators. methods: participated community older women (60 years or older), recruited for convenience. those unable to walk were excluded; acute musculoskeletal diseases; lower limb fractures in the last year; neurological diseases and sequelae; history of cancer in the last five years and cognitive impairment (mental state mini-exam). all responded to clinical and demographic information, performed the short physical performance battery (sppb), timed up and go (tug) and plasma tests of stnfr1 and il-6 (elisa method). correlation analysis by spearman test. 5% significance level. approval by the research ethics committee/ ufmg (caae: 14129513.7.1001.5149). results: 97 older women participated, with a mean age of 73.29 ± 6.3 y; number of comorbidities 2.55 ± 1.92 and medications in use of 3.06 ± 2.08. mean of body mass index were 27.18 ± 4.52 kg/m2. there was a significant negative relationship between the sppb test and stnfr1 (rho= 0.29; p= 0.003) and a significant positive relationship between tug and stnfr1 (rho= 0.57; p= 0.001). other relationships were not significant (p> 0.05). conclusion: older women with better functional capacity presented lower plasma dosage of stnfr1. the results suggest influence between these variables -functional capacity, mobility and inflammatory process -and no causal factor can be attributed. in these case, longitudinal studies are needed to verify functional performance vulnerability factors and their causal relationship with circulating inflammatory mediators in plasma. however, these results point to the importance of evaluating these variables in daily clinical practice. patricia parreira batista 1 , stephanie aguiar 1 , andré gustavo pereira de andrade 2 , jéssica rodrigues de almeida 1 , leani de souza máximo pereira 1 , lygia paccini lustosa 1 ((1) physical therapy department -universidade federal de minas gerais, ufmg, eeffto, belo horizonte, mg, brazil; (2) sports department -universidade federal de minas gerais, ufmg, eeffto, belo horizonte, mg, brazil) background: perceptions of health and well-being in the older people are identified as subjective aspects by the international classification of functioning (icf), with direct and indirect interference with overall performance, activities of daily living, social relationships and independence. subjective well-being is associated with the form of coping adopted with a health condition, adaptability and resilience. positive and negative physiological repercussions on functionality and interaction with the family and social network may be consequences of inadequate adaptation and perception of subjective well-being. objectives: to explore the relationship between subjective well-being, functionality and plasma indices of inflammatory mediators in community older wowen. methods: participated community older women (60 years or older), recruited for convenience. those unable to walk were excluded; acute musculoskeletal diseases; lower limb fractures in the last year; neurological diseases and sequelae; history of cancer in the last five years and cognitive changes (mini-mental state examination). all answered about clinical and demographic data and information about subjective well-being. they performed tests of functional capacity (short physical performance battery -sppb) and mobility (timed up and go -tug). plasma dosages of stnfr1 and il-6 were by elisa method. correlation analysis by spearman test. significance level of 5%. approval by the research ethics committee/ ufmg (caae: 14129513.7.1001.5149). results: 97 elderly women participated, with a mean age of 73.29 ± 6.3 years; number of comorbidities 2.55 ± 1.92, final sppb score 9.6 ± 1.98, tug of 11.26 ± 3.96 seconds; body mass index of 27.18 ± 4.52kg/m2. there was a significant positive relationship between subjective well-being and sppb (rho= 0.27; p= 0.007) and tug (rho= 0.23; p= 0.02). other associations were not significant (p> 0.05). conclusion: the results showed a significant association of subjective well-being with functional capacity in the older women. however, this condition was not associated with inflammatory markers, suggesting the need for further studies. on the other hand, it can be thought that the identification of personal strategies and perception of health and well-being act as barriers and/ or facilitators in a functional rehabilitation process, indicating the need for a multidisciplinary approach. background: the united states census bureau projects a rise in the population aged 65 and over from 43.1 million in 2012 to 83.7 million by 2050. the projected rise in the elderly population represents an accompanying increase in geriatric syndromes. frailty is a common geriatric syndrome defined as a clinically recognizable state of increased vulnerability to adverse outcomes related to a decline in physiologic reserve. this decline in reserve places the individual at increased risk for poor health outcomes including falls, disability, hospitalization, institutionalization and mortality. various effective interventions for frailty are established in the literature. the body of knowledge on the role of technology in reducing frailty is less abundant. objectives: to summarize available evidence on frailty and technology use for community dwelling older adults. methods: a comprehensive search of computerized databases was conducted in the following databases published between 2013-2018: cinahl, pubmed, and academic search complete. the prisma search strategy was utilized for this review. articles were included if they met the following criteria: 1) focused on community dwelling adults aged 65 and over; 2) peer-reviewed; 3) published in the english language; 4) featured randomized controlled trials (rcts), cohort studies or qualitative research; and 5) included an operationalized definition for frailty. results: the database searches yielded a total of 183 articles. 41 duplicates were removed. 114 results were excluded based on title and abstract. 32 relevant articles were retrieved for full text examination. 18 articles were excluded based on inclusion/exclusion criteria. references of 14 included articles were hand searched for relevant works. four additional relevant articles were identified. the final analysis included 18 articles. conclusion: current research focuses on assessment and diagnosis as opposed to intervention studies. methodological weaknesses limit generalizability and validity of findings. few studies utilize frailty as an outcome measure thus, limiting available research directly related to frailty. emerging technologies represent potentially effective, flexible and integrative solutions for frailty assessment, monitoring and intervention in the home environment. more research is needed on the potential for technological tools as interventions for frailty in community dwelling elderly specifically, for the purpose of detection and prevention of pre-frailty. a study protocol. inae c. gadotti 1 , raquel aparicio ugarriza 2,3 , fernanda civitella 1 , jorge g. ruiz 2,4 , edgar ramos vieira 1 ( (1) background: there are several studies on the association of balance and gait impairments with frailty and falls in older adults. however, little is known about the associations between postural alterations, frailty and falls in older adults in general and among older veterans. also, inter-relations among postural alterations, balance, strength, gait impairments, falls and frailty in older adults are not well known. objectives: the objective of this study is to evaluate if postural alterations, gait and balance impairments are associated with falls and frailty in older veterans. methods: sixty veterans, 60 years old or older, will participate on a voluntary basis. one-hour long assessments will be completed at baseline, 6, and 12 months. participants will fill out a questionnaire including information on demographics (age, sex, height, and weight), health conditions, falls (history, characteristics, and fear of falls), mobility impairments, physical activity level, medication history, medication changes and adherence, and health care utilization. frailty status will be assessed based on fried's frailty phenotype. the following physical health variables will be assessed: sagittal head and neck posture using photogrammetry, spinal curvatures using flexicurve, deep neck flexors activation by performing the craniocervical flexion test with a pressure biofeedback, grip strength using a dynamometer, usual and fast gait analysis using a gaitrite, balance using a force plate, and lower limb functional strength based on chair stands in 30s. differences among the variables by frailty status and falls history will be assessed using manovas. results: the results will be presented at conferences and published in scientific journals. conclusion: the results of this study may inform interventions to reduce frailty and falls in older veterans and possible among non-veterans as well. background: the number of deaths caused by pneumonia is increasing. the guidelines for pneumonia recommend optimal application of antibiotics based on a pathogenoriented strategy. despite wide distribution of these guidelines, pneumonia demonstrates high mortality in aged people. thus, for developing the next strategy for pneumonia management in aged people, new targets are required. with aging, the loss of skeletal muscle mass and strength occurs, which is named sarcopenia. the sarcopenia phenotype is associated with malnutrition. little is known about relationship between muscles and pneumonia, however, we reported that aspiration pneumonia induced respiratory muscle atrophy. impaired swallowing and/or cough functions often induce pneumonia in aged people. the swallowing muscle weakness is associated with impaired swallowing function. the strong respiratory muscles generate effective cough, which clears the airways and prevents pneumonia. objectives: to investigate presently unknown relationships between onset or recurrence of pneumonia in aged people and; respiratory muscle strength; swallowing muscle strength; and malnutrition. methods: a cross-sectional cohort study consisted of 47 patients aged 70-year-old and older admitted to the hospital by pneumonia, and 35 controls. the respiratory muscle strength was measured by a hand-held multi-functional spirometer with a pressure sensing transducer. the swallowing muscle strength was evaluated by measuring tongue pressure. a bioelectrical impedance analysis evaluated muscle and body fat masses. malnutrition was evaluated by serum albumin level and body fat mass. results: the respiratory (both the inspiratory and the expiratory) and the tongue muscle strengths, body trunk muscle mass, serum albumin level, and body fat mass divided by height2 were lower in aged pneumonia patients than in controls. body trunk muscles include the respiratory and swallowing muscles. the multivariate logistic regression model showed the low inspiratory and expiratory respiratory muscle strengths, the low body trunk muscle mass divided by height2, and the low serum albumin level as risk factors for onset of pneumonia. for recurrence of pneumonia within 6 months after the onset of pneumonia, low body fat mass divided by height2 was a risk factor. conclusion: above findings suggest that the respiratory muscles and malnutrition as new targets of the new management strategy for pneumonia in aged people. background: more than 50% of the people with hiv are older than fifty years. data about this population are still scarce and mainly focused on comorbidity instead of on physical function and frailty. hiv-funcfrail cohort is one of the four european cohorts of older hiv adults launched in 2018. objectives: our main objective in this work was to know the factors associated to physical impairment. methods: longitudinal prospective cohort study. patients from the "hiv-funcfrail: multicenter spanish cohort to study frailty and physical function in 50 years or older hiv-infected patients" were included. eleven centers participated. we recorded sociodemographic data, comorbidities and variables related to hiv infection. physical function was measured by gait speed and sppb and frailty according to frailty phenotype. other components of the comprehensive geriatric assessment such as depression and cognitive impairment were evaluated too. results: 563 were included. median age was 56.2 (53.7-60.6). 25.8% were women. at baseline median cd4 count was 672.5 (473.5 -904.5). viral load was undetectable in 91.2%. 30% of the patients had > 4 comorbidities and 21.8% had polypharmacy. 97.5% of the patients were able to walk independently and 97% were completely independent for the activities of daily living. more than half were prefrail, 5.8% prefrail and 42.6% were robust according to frailty phenotype. 17.7% of the patients had a sppb score < 9 and 5.4% had a gait speed < 0.8m/sg. in the univariate analysis we found association between physical impairment defined as sppb score < 9 with: diabetes, copd, osteoarthritis, comorbidities number, moca test < 20, gds-sf >9 and age. but in the multivariate analyses the factors associated were just: polypharmacy ) p= 0.001], gds-sf >9 [3.09 (1.63-5.84) p=0.001]. conclusion: functional impairment was prevalent among older adults with hiv in their middleage. polypharmacy doubles the risk of functional impairment and depression increases the risk three-fold. therefore, polypharmacy, depression and physical function should be assessed in all the older adults with hiv in order to implement early prevention intervention to avoid physical impairment. sophie bastijns, anne-marie de cock, maurits vandewoude, stany perkisas (university of antwerp, antwerp, belgium) background: acute sarcopenia is defined as a decline in muscle mass and muscle function within 28 days after hospitalization or acute illnesses, sufficiently to meet the sarcopenia criteria. muscle ultrasound is an objective and non-invasive technique that can measure muscle quantity and quality. muscle elastography can furthermore measure muscle stiffness, which is regarded as an important qualitative parameter. objectives: the primary aim of the study is to assess the effect of acute hospitalization on muscle stiffness. the secondary aim is to evaluate other influencing parameters. methods: this study is a prospective, observational study. patients admitted for at least 7 days to one of the geriatrics departments of the zna antwerp hospitals are included. rectus femoris (rf) and vastus lateralis (vl) muscle stiffness are measured through elastography on day 1 of admission, and then every 7 days until discharge. results: preliminary results show significant differences between rf and vl values in men, but not in women. in rf, a non-significant downwards trend is seen for elastography between day 1 and day 8. in vl, a non-significant downwards trend is seen in women, but also a non-significant upwards trend is seen in men between day 1 and day 8. in rf, a non-significant trend of decreasing stiffness is seen with increasing age in men, but an increase is seen in women. a significant negative correlation is seen between elastography of rf and vl on day 1 and hand grip strength on day 1. conclusion: this study seeks to gain insight in parameters affecting muscle stiffness and of the evolution of muscle stiffness after acute illness or hospitalization. a trend of decreasing muscle stiffness is seen after seven days of hospitalization and illness. this study showed no direct relation between age and muscle stiffness. a decrease in muscle stiffness results in higher hand grip strength and therefore better muscle performance. more data and longer follow-up periods are needed and are expected by march 2020. ainhoa indurain 1,2 , jennifer linge 3 , mikael petersson 3 , thobias romu 3 , fredrik uhlin 1,4 , anders fernström 1 , mårten segelmark 1,6 , olof dahlqvist leinhard ((1) departments of nephrology and medical and health sciences, linköping university, linköping, sweden; (2) departments of acute internal medicine and geriatrics and medical and health sciences, linköping university, linköping, sweden; (3) background: sarcopenia is a prevalent condition in hemodialysis patients and it´s associated with poor quality of life, hospitalization and mortality. recent research using magnetic resonance imaging (mri) has demonstrated the importance of proper body size-adjustment in the assessment of muscle mass, and that the addition of muscle fat infiltration reflecting muscle quality, improves functional correlations and prediction of hospitalization in sarcopenia. it is not yet demonstrated if this new mri method, combining body sizeadjusted muscle volume and muscle fat infiltration, improves the evaluation of sarcopenia in hemodialysis patients. objectives: to investigate if adverse muscle composition, defined using mri, predicts survival and comorbidity in hemodialysis patients. methods: in 2014, 11 patients on hemodialysis were scanned using rapid whole body fat and water separated mri. following 5 years, survival and comorbidity index (nci) were recorded using electronic health care records. thigh muscle fat infiltration (mfi) and fatfree muscle volume (ffmv) normalized with height2 was assessed using amra research (amra medical, linköping sweden). a z-score describing the deviation from expected ffmv/height2 was calculated using sex and bmi-matched virtual controls (ffmvvcg) and mfi adjusted (mfiadj) was calculated using the sex-specific population mean. for these calculations, normative data from 9615 subjects in uk biobank was used. to estimate a combined muscle score (musclecomb), mfiadj and ffmvvcg were projected on the linear regression line describing the normal population relationship between mfiadj and ffmvvcg in the uk biobank dataset. spearman rank correlation was estimated comparing mfiadj, ffmvvcg and musclecomb to nci. wilcoxon signed-rank test was used to estimate the association to survival. roc values and confidence interval were also calculated. results: musclecomb (combined muscle score) was significantly correlated to comorbidity (p<0.05) and predicted survival (p<0.05) while mfiadj (adjusted muscle fat infiltration) and ffmvvcg (deviation from an individual´s expected muscle volume) did not reach significant level on either test. the roc values for predicting survival were 0.86 (0.61-1.00) for ffmvvcg, 0.82 (0.55-1.00) for mfiadj, and 0.89 (0.69-1.00) for musclecomb. background: frailty is a risk factor for cardiovascular disease (cvd). as declines in bone metabolism and impaired inflammatory response are often associated with frailty, bone analytes and inflammation markers involved in these signaling pathways may act as biomarkers of frailty-related disease progression. objectives: this study sought to examine differences in systemic bone analyte and inflammation marker concentrations based on cvd risk profile and frailty status. methods: 1030 females with no prior cvd were stratified into low or high cvd risk groups based on their framingham risk scores. frailty was assessed using the fried phenotype of frailty. greedy matching with pre-frailty as the exposure variable was used to identify a set of 26 closely matched pairs in both the low and high cvd risk groups for a total of 104 females in a case-control design. factorial anova was used to compare differences in log transformed concentrations of 15 bone and inflammation analytes based on frailty status, cvd risk, and their potential interaction. results: differences for il-6 (5.25 ± 14.30 vs. 1.35 ± 1.74 pg/ml, p=0.001), leptin (12628.48 ± 10472.90 vs 7562.96 ± 4972.25 pg/ml, p=0.023) and tnfα (1.41 ± 1.83 vs 0.89 ± 0.40 pg/ml, p=0.06) systemic concentrations were found with high cvd risk status compared to low. no differences in bone or inflammation analyte concentration were found based on frailty status, nor were any interaction effects. conclusion: there was a difference in inflammatory marker concentrations based on cvd risk status indicating that higher cvd risk is associated with impaired inflammatory response in females. there was no difference in bone or inflammation analytes in the pre-frail group compared to their robust peers as these females may be too early in the progression of frailty to have these signs of impaired bone health and inflammation. (2) pancreato-biliary cancer center, gangnam severance hospital, yonsei university college of medicine, seoul, korea) background: biliary tract cancer (btc) is a highly lethal disease, and improved prognostication methods should be sought. sarcopenia (low muscle mass), poor muscle quality (low muscle attenuation) and excess adiposity (subcutaneous and visceral) can be surrogate markers of sarcopenia and related frailty. however this hypothesis has not been demonstrated conclusively in btc patients. objectives: to evaluate associations of all four body composition measures, derived from clinically acquired ct at the time of initial diagnosis, with overall survival in advanced btc patients. methods: we measured skeletal muscle index (smi), mean muscle attenuation (ma), visceral adipose tissue index, and subcutaneous adipose tissue index via computed tomography at the level of the l3 vertebra. clinical data were extracted from patients' charts. results: a total of 601 patients (58% males, median age 67 [range 30-91]) were included in this study, 65% were metastatic and 35% were recurrent disease. during the follow-up duration (median of 9.4 months; range 0.1 month to 128 months), 570 patients (95%) died. sarcopenia, defined as low l3smi (lower than 39 cm2/m2 for women and lower than 55 cm2/m2 for men) was noted in 463 patients (77%), and 162 patients (27%) had low muscle radiodensity. for adiposity, 31% and 29% of patients had low subcutaneous and visceral fat, respectively. when we combined this four factors and grouped the patients, no risk group (n =67) had the best overall survival (median 14.6 months, 95% ci, 11.7-17.5), while the patients who suffered all the risk factors (n=12) showed the poorest survival (median 2.5 months, 95% ci, 0-5.7) which was statistically significant (log-rank test <0.001). this classification was independent factor for survival in multi-variate analysis along with other clinical factors, carcinoembryonic antigen (cea), neutrophil-to-lymphocyte ratio, white blood count, platelet, and cholesterol (hr 1.271, 95% ci 1.126-1.435). conclusion: sarcopenia, ma, and adiposity independently predict mortality in patients with btc and can be utilized as surrogate markers for prognosis. background: frailty is a clinical syndrome of reduced systemic physiological reserve that phenotypically overlaps with heart failure. nt-probnp is a cardiac-specific marker that increases with ventricular stress, whereas growth differentiation factor 15 (gdf-15) is a non-tissue specific systemic marker that increases with inflammation, tissue injury and possibly inflammageing. objectives: this study aims to determine if combination of nt-probnp and gdf-15 organised in a 2x2 matrix can classify cardiac dysfunction with and without frailty, non-cardiac frailty, and non-frailty. methods: this is a cross-sectional analysis of a prospective cohort study (phase 1), undiagnosed heart failure in older adults (ufo), that recruited community-living older adults aged >/=60 years in a ratio of 1:1:1 for robust, pre-frail and frail status classified by the frail scale. participants without a history of heart failure and meeting the eligibility criteria were entered into the study. nt-probnp and gdf-15 levels were measured using the roche cobas elecsys platform. echocardiography and 6-minute walk distance (6mwd) were documented. informed consent was obtained from all participants. the study was approved by the local institutional review board. ) was ascertained by correlation with abnormal echocardiographic diastology represented most prominently by increased left atrial volume index (r=0.37, p=5.8x10e-11). conclusion: a 2x2 dual biomarker approach utilising nt-probnp and gdf-15 may assist in subclassification of cardiac (diastolic) dysfunction and frailty. background: frailty was occurred frequently in elderly and known as higher risk of mild cognitive impairment (mci) and dementia than healthy elderly. hippocampus, parahippocampus and entorhinal cortex as memory system is considered one of the key regions of dementia especially alzheimer's disease. in addition, atrophy of these regions presumably related to higher risk of alzheimer's disease. on the other hand, it is poor understood about neural substrates of relationships frailty and higher incident rates of mci and dementia. objectives: the purpose of this study, therefore, to clarify differences of atrophy level of hippocampus, parahippocampus and entorhinal cortex and total gray matter between healthy, pre-frail and frail in elderly. methods: a total 1,220 elderly were measured brain structure with 3t-mri, and 1,117 were fulfilled inclusion criteria in this study. structural brain images were preprocessed and total hippocampal volume was estimated using freesurfer v6.0.0 and ubuntu 16.04 lts. we classified participants into three groups as healthy, pre-frail and frail characterized by 0, 1 or 2 and 3 or more of the following 5 domains respectively: low activity, slowness, weight loss, exhaustion and weakness. we compared total gray matter or hippocampal volume between healthy, pre-frail and frail in elderly with one way analysis of covariance (ancova) adjusted for sex, age, educational years, drinking and smoking habit, geriatric depression scale points and estimated total intracranial volume (etiv) and multiple comparison using bonferroni correction. results: the prevalence of pre-frail and frail was 49.2% and 5.9% respectively. hippocampus, parahippocampus and entorhinal cortex volume were significantly decreased in elderly with frail compared healthy and pre-frail (hippocampus: p=0.002 and p=0.014; parahippocampus: p=0.002 and p<0.001; entorhinal cortex: p=0.024 and p=0.043 respectively). in contrast, total gray matter volume was not significantly difference between three groups. conclusion: hippocampus, parahippocampus and entorhinal cortex were atrophied in elderly with frailty compared healthy or pre-frail elderly. it might be neural substrates of higher risk of dementia in elderly with frailty. rasekh kashkosh 1 , irina gringauz 1 , jonathan weissmann 2 , gad segal 3,4 , michael swartzon 5 , abraham adunsky 1,4 , dan justo 1,4 ((1) geriatrics division, sheba medical center, israel; (2) biomedical engineering department, israel; ( background: low alanine aminotransferase (alt) blood levels prior to rehabilitation are associated with poor rehabilitation outcomes in terms of low mobility and function in older adults following hip fracture. objectives: we have hypothesized that low alt blood levels prior to rehabilitation are also associated with 1-year mortality in this population. methods: included were 456 older adults (age >=60 years, median age 83 years, 82.5% women) admitted for rehabilitation following hip fracture. alt blood levels were documented between one and six months prior to rehabilitation. excluded were patients with alt blood levels over 40 iu/l possibly consistent with liver injury. the study group included patients with low (10 iu/l or lower) alt blood levels, and the control group included patients with high-normal (11-40 iu/l) alt blood levels. the main outcome was all-cause mortality one year following rehabilitation admission. results: the study group included 142 (31.1%) patients with low alt blood levels, and the control group included 314 (68.9%) patients with high-normal alt blood levels. overall, 52 (11.4%) patients died within one year following rehabilitation admission. compared with the control group, patients with low alt blood levels had significantly higher 1-year mortality rates (17.6% vs. 8.6%, or 2.27, 95%ci 1.27-4.08). cox regression analysis showed that low alt blood levels prior to rehabilitation were associated with 1-year mortality (hr 1.61, 95%ci 0.91-2.84) together with peripheral vascular disease (hr 2.69, 95%ci 1.08-6.68) -independent of age, gender, albumin serum levels, length of rehabilitation, and rehabilitation outcomes. conclusion: low alt blood levels prior to rehabilitation are associated with 1-year mortality in older adults following hip fracture. fawaz azizieh 1 , dia shehab 2 , khaled al jarallah 2 , renu gupta 2 , raj raghupathy 2 ((1) gulf university for science & technology, mubarak al-abdullah area, kuwait; (2) faculty of medicine, kuwait university, jabriya, kuwait) background: in addition to some well-characterized bone turnover markers, cytokines and adipokines have also been suggested to be linked to osteoporosis seen in menopause. however, there is much controversy on the possible association between these markers and bone mineral density (bmd). objectives: this study was aimed at measuring circulatory levels of selected cytokines and adipokines in postmenopausal women with normal and low bmd. methods: the study population included 71 post-menopausal women, 25 of whom 25 had normal bmd, 31 had osteopenia and 13 had osteoporosis. circulatory levels of selected pro-resorptive (tnf-a, il-1b, il-6, il-8, il-12, il-17), anti-resorptive (ifng, il-4, il-10, il-13, tgf-b) and five adipokine markers (adiponectin, adipsin, lipocalin-2/ngal, pai-1 and resistin) were measured using the multiplex system and read on the magpix elisa platform. further, two bone turnover markers (p1np, ctx) as well as estradiol levels were assayed from the same samples. results: while circulatory levels of cytokines were comparable between groups, women with low bmd had statistically significantly higher median circulatory levels of adipokines as compared to those with normal bmd. further, while levels of ctx were not different between the two groups; p1np, p1np/ctx ratio and estradiol levels were significantly lower in women with low bmd. levels of adiponectin, p1np, p1np/ctx ratio and estradiol correlated significantly with bmd of the hip and spine. conclusion: while the associations between the studied markers and bmd may be complex and multivariate, our data provide insights into the possible use of circulatory levels of cytokines, adipokines and bone turnover markers on the pathogenesis of postmenopausal osteoporosis. background: with the application of diffusion tensor imaging (dti), a few studies have found that some white matter (wm) structures were closely related to impaired gait speed. however, the evidence is still sparse and the wm structural association with overall lower-body physical function, which can be evaluated by short-physical performance battery (sppb), has never been investigated among older adults. objectives: the aim of this study is to explore the associations between wm structures (evaluated by dti parameters) and sppb scores among older adults. methods: data of 209 participants (75 ± 4 years old), who were recruited in the multidomain alzheimer's preventive trial (mapt) study and with no dementia at baseline level, were analysed in this study. based on the functional magnetic resonance imaging data, dti parameters of fractional anisotropy (fa), mean (md), axial (ad) and radial diffusivity (rd) were calculated in 48 wm structures that were annotated by the john hopkins university white matter parcellation atlas. linear regression was used to analyse the association between sppb score and each dti parameter while controlling for age, gender, body mass index, physical activity level, total intracranial volume, cardiovascular risk and time interval between the dti and sppb measurement. results: three dti parameters (the md and rd of left corticospinal tract, and the md of right cerebral peduncle) were associated with the sppb score at a p-value < 0.05. conclusion: the findings indicate that wm structures of corticospinal tract and cerebral peduncle might be related to overall lower-body physical function of older adults. further studies on the changes of these wm structures with physical function alterations during ageing will be more informative. background: ct-derived skeletal muscle index and skeletal muscle density (smd) have been independently associated with mortality in older adults. although smd is a commonly used measure of myosteatosis on ct images, more novel muscle texture (i.e., radiomic) features may provide an alternative measure of muscle quality, independent of smd. there have been no prior studies on the association of ct-derived muscle texture features and mortality. objectives: to examine the association of skeletal muscle texture features with all-cause mortality in older adults from the national lung screening trial (nlst). methods: the relationship between ct-derived skeletal muscle texture and all-cause mortality over 6 years was determined in 13,279 participants (39% women, age range 60-74 years, mean age 64.8) in the nlst. using ct images at the level of t12 vertebra, paraspinous muscle was automatically segmented using machine learning algorithm, and muscle texture features determined using pyradiomics. 75 second order (and higher) texture features were grouped into 5 categories: gray level dependence matrix (gldm), gray level co-occurence matrix (glcm), gray level run length matrix (glrlm), gray level size zone matrix (glszm), and neighbouring gray tone difference matrix (ngtdm). muscle texture features often indicate greater or lower heterogeneity/complexity of an image. associations between standardized muscle texture variables and all-cause mortality were determined using cox proportional hazards models, adjusted for age, sex, race, body mass index, pack years of smoking, presence of type 2 diabetes, chronic lung disease, cardiovascular disease, cancer at enrollment, and smd. multiple comparisons were accounted for using false discovery rate testing. results: after a mean 6.41 ± 1.11 years of follow-up, 1188 (8.95%) participants died. in fully adjusted models, the following muscle texture features were associated with mortality: gldm-dependenceentropy (hazzard ratio (hr) per standard deviation (sd)=0.88, p<0.001), gldm-dependencenonuniformity (hr per sd=0.91, p=0.011), gldmsmalldependencelowgraylevelemphasis (hr per sd=1.15, p<0.001), glrlm-graylevelnonuniformity (hr per sd=0.89, p<0.001), glszm-small area low gray level emphasis (hr per sd=1.08, p=0.003), ngtdm-coarseness (hr per sd=1.06, p=0.005), ngtdm-strength (hr per sd=1.06, p=0.003). each of these associations were in the direction that suggested greater heterogeneity of the image was associated with increased mortality. conclusion: in a large multicenter cohort of community-dwelling older adults, ct-derived muscle texture features indicating greater heterogeneity were associated with mortality, independent of common covariates including skeletal muscle density. background: growth differentiation factor 15 (gdf15) has been related with disease progression, mitochondrial dysfunction, and mortality. elevated gdf-15 level was recently reported to be associated with poorer physical performance in very healthy community-dwelling adults. however, until now, the relationship of serum gdf-15 level with sarcopenia in community-dwelling older adults has not been well characterized. objectives: this study aimed to investigate the association between serum gdf-15 levels and sarcopenia in community-dwelling older adults. methods: we analyzed 929 participants (mean age, 75.9±8.9 years; 48.0% men) who underwent measurement of serum gdf-15 level and sarcopenia parameters, using their baseline data from the korean frailty and aging cohort study. participants with reduced kidney function, specifically an estimated glomerular filtration rate (egfr) from creatinine of <60 ml/min/1.73 m2, were excluded. serum gdf-15 level was quantified with an enzyme-linked immunosorbent assay kit. appendicular skeletal muscle mass was measured using dual-energy x-ray absorptiometry. sarcopenia status was determined in accordance with the asian working group for sarcopenia (awgs) 2019 guidelines. results: according to the awgs 2019 algorithm, 154 (16.6%) of the participants in the whole study population were classified as having sarcopenia. gdf-15 concentration had significant negative correlations with appendicular lean mass (men, r = -0.183, p < 0.001 and women, r = -0.118, p = 0.009), grip strength (men, r = -0.150, p = 0.001 and women, r =-0.113, p = 0.013), and gait speed (men, r = -0.148, p = 0.002 and women, r = -0.137, p = 0.002). in the multivariate analysis adjusted for potential confounders, the highest gdf-15 quartile (>=1245 pg/ml) was associated with a greater risk of sarcopenia (odds ratio [or] = 1.95; 95% confidence interval [ci], 1.15-3.31) than the lowest quartile (<885 pg/ml). these associations remained unchanged (or = 1.90; 95% ci, 1.14-3.23) after further adjustment for potential biomarkers (e.g., myostatin, dehydroepiandrosterone, and insulin-like growth factor-1). the or per unit increase in log-transformed gdf-15 level was 3.59 (95% ci, 1.21-10.70). conclusion: higher circulating gdf-15 levels were independently associated with a greater risk of sarcopenia in community-dwelling older adults. gdf-15 may be considerate a promising biomarker of sarcopenia. background: frailty has been recognized as an emerging public health problem in rapidly aging populations worldwide. use of biomarkers to identify frailty has been suggested for early frailty screening. among multiple risk factors of frailty, inadequate nutrition such as inadequate intake of protein and vitamin d has been shown to be associated with increased risk of frailty. therefore, nutritional biomarkers could be useful for early screening of frailty. objectives: to review the evidence of potential biomarkers, especially nutritional biomarkers for early screening of frailty in community-dwelling older adults. methods: a literature search was conducted using pubmed and scopus databases. studies evaluating blood biomarkers and frailty in community-dwelling older adults from 2000 to 2019 were included. information on the definition of frailty, study design, characteristics of the study populations, and the associations between biomarkers and frailty was summarized. results: in total, 95 studies were identified in which 60 observational studies were published since 2015. majority of studies used physical frailty. other definitions such as multidimensional, social and frailty were also used. 123 biomarkers were identified. cross-sectional and longitudinal studies consistently showed that low level of vitamin d was associated with frailty. emerging scientific evidence suggested that abnormal level of albumin, low levels of high-density lipoprotein (hdl), beta-hydroxy beta-methylbutyrate (hmb), vitamin b6 (measured by pyridoxal-5-phosphate), carotenoids, or a-tocopherol (vitamin e), and high level of dp-ucmgp (marker of vitamin k) could have the potential for frailty screening. besides nutritional biomarkers, the evidence showed that inflammatory markers such as c-reactive protein (crp), interleukin-6 (il-6), and fibrinogen, and endocrine-related markers such as hemoglobin, dehydroepiandrosterone sulfate (dheas), and hemoglobin a1c could be useful for screening frailty. additionally, there is evidence suggesting that some oxidative or immune-related markers were associated with frailty. conclusion: vitamin d could be a useful nutritional biomarker for early frailty screening in the community setting. other nutritional biomarkers, inflammatory markers and endocrine-related markers could be associated with frailty. further research is needed to validate and refine other potential biomarkers. jonathan quinlan 1,2,3 , amritpal dhaliwal 2,3 , felicity williams 2,3 , matthew armstrong 3,4 , leigh breen 1,3,5 , ahmed elsharkawy 3,4 , carolyn greig 1,3,5 , janet lord 2,3,5 ( (1) background: end stage liver disease (esld) is associated with reduced muscle mass with a reported incidence of sarcopenia of 40-60% (bhanji, 2017). loss of muscle mass in esld patients has a negative impact on clinical outcomes including mortality and recovery rates from liver transplantation (montano-loza, 2014) . previous research has investigated loss of muscle mass in esld via appendicular skeletal muscle mass and psoas muscle cross sectional area (csa) using dxa and magnetic resonance imaging (mri) respectively. however, the quadriceps muscle group has high functional significance and thus should be investigated in esld patients in whom function may be limited. ultrasound (us) offers a non-invasive, bedside imaging assessment of quadriceps muscle mass. however, esld may be associated with increased subcutaneous fat which can present an operational challenge for us and thus its application in esld patients requires validation. objectives: the aim of this research is to validate the accuracy of ultrasonographic measures of quadriceps muscle mass by comparison with the gold standard of mri. methods: 24 parallel mri and us were collected from patients with an esld diagnosis and awaiting liver transplant (12 patients, age 52±10yrs, bmi 28.4±6.4). participants underwent us scanning of both left and right quadriceps followed directly by an mri. specifically, measures of vastus lateralis (vl) muscle thickness (mt) and quadriceps csa were obtained at 50% femur length during longitudinal and extended field of view us respectively. to enable direct comparison with quadriceps csa obtained during mri, an oil capsule was placed upon the leg to mark the exact location of us image collection. all procedures received research ethics committee approval and written informed consent from the participants. results: a significant (p<0.001, n=24) positive correlation was found between vl mt and quadriceps csa obtained via mri (r2=0.42). similarly, there was a significant positive correlation (p<0.0001, n=22) between csa obtained via extended field of view us and mri (r2=0.97). bland-altman plots demonstrated a bias of -0.07 ± 1.4cm2, with 95% limits of agreement of -2.96cm2 and 2.83cm2. conclusion: our data demonstrate that the assessment of quadriceps csa and vl mt via us may offer a suitable bedside alternative to mri in patients with esld. background: sarcopenia is defined as the gradual ageassociated loss of both muscle quantity and strength in older adults, and severe sarcopenia affects subject performance (such as reduced gait speed). it is a devastating condition, predicting an increase in mortality, falls, fractures and hospitalizations. current clinical criteria diagnose sarcopenia through dual x-ray absorptiometry (dxa) measures of muscle mass, a test that cannot be performed at the bedside and is rarely used to find this condition. point-of care ultrasound (pocus) is rapidly becoming a standard part of the physical exam, and has the potential to become a quick, noninvasive marker for both muscle mass and function. objectives: we examined the relationship between ultrasound measures of muscle mass (vastus medialis thickness, mt) and other measures of muscle quantity (appendicular skeletal mass, asm; mid-arm biceps circumference, mabc). we also examined the association between mt and measures of muscle strength (grip strength) and muscle performance (gait speed) in an older adult population. methods: 150 older adults (age >= 65; mean age 80.0±0.5 years, 66 women, 84 men) were recruited sequentially from geriatric medicine clinics. each subject had appendicular skeletal muscle mass (asm, by bioimpedance assay), grip strength, mid-arm biceps circumference (mabc), gait speed, and an ultrasonic measure of muscle quantity (mt, vastus medialis muscle thickness) measured. our initial models contained age, sex, bmi, and mt as predictor variables, and our outcome variables were asm, grip strength, mabc and gait speed. results: in our final parsimonious models, mt showed a strong significant correlation with all measures of muscle mass, including asm(standardized ß=0.204±0.058, r2 = 0.58, p<0.001) and mabc(standardized ß = 0.141±0.067, r2 = 0.77, p=0.038). with respect to measures of muscle quality, there was a strong significant correlation with grip strength (standardized ß = 0.156±0.058, r2 =0.51, p=0.008) but not with subject performance (gait speed). conclusion: mt showed strong correlations with both measures of muscle mass (asm and mabc) and with muscle strength (grip strength). riki kosugi 1 , yung-li hung 2 , toshiharu natsume 3 , shuichi machida 4 ((1) faculty of health and sports science, juntendo university, inzai, chiba, japan; (2) institute of health and sports & medicine, juntendo university, inzai, chiba, japan; (3) coi project center, juntendo university, bunkyo-ku, tokyo, japan; (4) graduate school of health and sports science, juntendo university, inzai, chiba, japan) background: loquat (eriobotrya japonica) leaves are commonly used in teas and folk medicines. recently, loquat leaf extract (lle) has been reported to promote muscle protein synthesis in vitro. additionally, resistance exercise has been shown to promote muscle protein synthesis in vivo. it is considered that lle and resistance exercise might have a synergistic effect on activating muscle protein synthesis. however, this has never been investigated. objectives: the purpose of the present study was to investigate whether lle enhances the muscle contraction-induced activation of muscle protein synthesis signaling in rats. methods: male wistar rats (12 weeks old, n=6-7/group) were categorized into a control (con) group, an lle-administered (lle) group, an electrical muscle stimulation (ems) group , and an ems with lle (ems+lle) group. rats were administered lle (1.5 g/kg/ day) or distilled water once in a day by oral gavage for 7 days. on the seventh day, 3 h post-lle administration, the gastrocnemius muscle of the right legs of ems group and ems+lle group rats were stimulated by ems (100 hz, 30 v) through 5 sets of 10 isometric contractions (7 s contraction, 3 s rest) with 3 min inter-set intervals. rats were then sacrificed and their gastrocnemius muscles were rapidly excised 3 h post-ems. expression levels of muscle synthesis-related proteins [protein kinase b (akt), mammalian target of rapamycin (mtor), and ribosomal protein s6 kinase beta-1 (p70s6k)] were determined by western blotting. results: no significant differences were observed in body weight, water intake, and diet intake among the groups. akt phosphorylation at ser473 was found to be significantly increased in the ems+lle group compared to that in con group; mtor phosphorylation at ser2448 did not show a significant difference. p70s6k phosphorylation at thr389 was found to be significantly increased in the ems group compared to that in con group, while the ems+lle group was observed to have significantly higher p70s6k phosphorylation at thr389 than the ems group. conclusion: our study suggests that lle enhances the muscle contraction-induced activation of p70s6k phosphorylation. background: metabolic aging has emerged as a new sedentarity related syndrome combining metabolic diseases and sarcopenia, a degenerative loss of skeletal muscle mass, quality, and strength associated with aging. it has been recently shown that kynurenic acid (ka), a key metabolite of tryptophan/ kynurenine pathway, improved glycemic control and lipid profile in rodents. objectives: to show that ka has a key role in metabolic aging, we have evaluated its effect on muscle function and mass in vitro and in vivo in muscle cell line and in a model of hindlimb immobilization in mouse. methods: in vitro in c2c12 muscle cells we measured the ability of ka to inhibit myostatin gene expression (endogenous inhibitor of muscle growth), stimulate protein synthesis and enlarge muscle cell size. differentiated cells were exposed to ka for 2h30 for protein analysis, 6h for gene study and the 5 days of differentiation for cell enlargement examination. in vivo, muscle mass (tibialis and soleus) was measured after a 1 week-hindlimb immobilization in mice treated or not with ka (3mg/kg.day per os). results: in vitro, ka significantly and dose-dependently inhibited myostatin gene expression, stimulated protein synthesis and enlarged c2c12 muscle cells. in mice, ka treatment significantly reduced tibialis and soleus muscle wasting induced by immobilization. conclusion: we demonstrated for the first time the positive impact of ka on muscle function and mass preservation offering a promising therapy for patients affected by metabolic aging, who do not currently benefit from relevant therapeutic solutions. â n g e l a m a r i a p e r e i r a 1 , 2 , 3 , a n a f r e i t a s 1 , a n a p a c i f i c o 1 , c a t a r i n a c o s t a 1 , m a r g a r i d a a l m e i d a 1 ((1) physiotherapy departement, escola superior de saúde egas moniz, portugal; (2) centro de investigação interdisciplinar egas moniz, monte da caparica, portugal; (3)hospital garcia de orta, almada; portugal) background: as people age they are more likely to fall. although most fall-related injuries are minor, they can cause significant pain and discomfort, affect a person's confidence and lead to loss of independence. some falls can cause serious long-term health problems. one strategy to promote greater adherence and motivation to intervention in physical therapy is the use of virtual environment (ve) programs associated with a balance exercise programs as an effective method of preventing falls. objectives: the purpose of this study was to analyze the benefit of a virtual environment exercise program in non-institutionalized elderly at the end of six weeks. methods: in this randomized controlled trial 80 non-institutionalized elderly were included. 40 subjects, age 81.6±7.9 yrs constituted the experimental group (eg); and 40, age, 81.9±76.1 yrs constituted the control group (cg). the eg was submitted to 6 weeks of a ve exercise program performed on a nintendo wii, and to a set of recreational activities. the cg only performed the activities. the instruments used in the present study to evaluate performance were tinetti's index, which evaluates the static balance and the gait to quantify the risk of fall, and the fullerton's functional fitness tests to assess physical parameters such as strength, aerobic endurance, flexibility and agility/ balance. results: at the end of the 6 weeks of intervention in a virtual environment, significant improvements in upper limb strength, agility and static balance were observed. in the intragroup comparison, it was possible to verify improvements in all physical fitness battery tests. the values of functional fitness tests were significantly different (p<.05) between eg and cg groups for the following variables: 30-second chair stand 15.1±3.1 vs. 10.8±2.9 times; arm curl 16.8±3.5 vs. 13.8±4.6 times; 8-foot up-and-go 9.7±2.3 vs. 15.8±5.1 sec; two min. step 126.8±34.9 vs. 75.7±34.8 steps, respectively; as well as for the tinetti index. conclusion: this study, suggests that exercise in ve context applied to non-institutionalized elderly, promotes improvements in mobility, in lower limbs muscular strength, and may help to reduce the risk of falls by improving the static and dynamic balance. background: the small non-coding micrornas (mirs) are endogenous regulators of gene expression. they bind to complementary sequence on target messenger rna transcripts resulting in translational repression or target degradation. they are involved in the skeletal muscle response to training in animals and humans (kirby, 2015) . objectives: the aim of our study was to measure the effects of high intensity interval training (hiit) associated or not with l-citrulline on the expression of serum and muscle mirs in a group of men. methods: we selected 9 men (mean age: 66.6 ± 2.9 years, 6 men in the placebo group and 3 in the l-citrulline group, 10 gr/day) from a cohort of 56 men and women submitted for 12 weeks to hiit (buckinx, 2018) . we evaluated the expression of serum and muscle mirs before and after training. the quantification of mir expression was performed using the next generation sequencing (ngs) technique (exiqon). for statistical analysis, the measurements were normalized with the tmm method (trimmed mean of m-values). results: we identified 225 mirs from serum and 379 mirs from muscle above the detection limit (>= 1 tpm, tags per million). after benjamini-hochberg correction, 5 serum mirs from the l-citrulline group had a significantly different level of expression before and after training: 744-5p, 106b -5p, 484, 151a-3p and -6511a-3p (p <0.05, 5% fdr). no mir of the placebo group had a significantly altered expression. in muscle, our approach revealed 59 mirs with a significantly different level of expression before and after training in the placebo group and 8 in the l-citrulline group, 7 of which were common to both groups. these mirs were different from those highlighted at the serum level. the 5 most-expressed muscle mirs with the greatest difference in expression before and after training were 483-5p, 504-5p, 542-3p, 483-3p and 146b-5p (p <0.05, 5% fdr). conclusion: with the ngs approach, we identified 65 mirs differentially expressed before and after hiit. expression of circulating mirs appears to be influenced by l-citrulline. the next validation step will be to measure these specific mirs in the entire cohort to determine the clinical utility of these markers. background: recent interventional studies on frailty used multicomponent programs (physical exercise, cognitive stimulation, and nutritional supplementation) with some promising results. however, these emerging programs developed to counter the multidimensional concept of frailty still need methodological improvements to be completely effective. objectives: the objective of this innovative project is to develop personalized multicomponent interventions that could be easily used by frail older adults in order to reverse physical, cognitive and psychosocial symptoms associated with frailty. three original and specific action levers will be used to insure a better effectiveness: 1/to target a key population (hospitalized frail older adults who will be discharged to home), 2/to use a real multicomponent program (physical exercises simultaneously associated with cognitive and social components that mimic daily gestures), and 3/to encourage adherence through medical prescription. methods: one hundred and twenty frail older adults (>= 75) will be recruited from the geriatrics unit of the university hospital of tours (france), and randomly assigned to one of the two study arms: the intervention group (ig), who will receive a medical prescription of an adapted multicomponent intervention, vs the control group (cg; no intervention). twelve-week programs will be adapted according to observed intrinsic capacities of the frail older adults. including exercises will be based on effective international physical programs, with original cognitive and social components added to the physical exercises. all participants will perform pre-and post-tests to compare their physical health (gait speed, balance, and strength), cognitive health (global cognition and executive functions), and psychosocial health (self-efficacy and quality of life) before and after the three-month program. results: a pilot study to this rct has already started in tours. the international conference on frailty and sarcopenia research would be the perfect opportunity to share preliminary results. the intervention will be considered as feasible if ig participants adhere to > 75% of the prescribed exercise and as effective if we observe significant improvements in all clinical outcomes for ig participants, compared to the cg. conclusion: final objective will be to disseminate to a large number of individuals the idea that several concrete ways exist to age well. amanika kumar, clarissa polen-de, gladys asiedu carrie langstraat, aminah jatoi (mayo clinic, rochester, minnesota, usa) background: frailty in patients with advanced stage ovarian cancer (oc) is common and associated with increased oncologic and surgical morbidity and mortality. prehabilitation is one option to reverse frailty in this subset of patients. objectives: our aim was to investigate potential barriers and facilitators of prehabilitation during neoadjuvant chemotherapy (nact) in oc patients. methods: we identified 16 patients who underwent nact from 2016-2018 at a large volume single institution. patients underwent a semi-structured one-on-one phone interview. transcripts from interviews were read by 4 independent reviewers to identify emerging themes related to patients' experience, functioning and exercise during chemotherapy. results: five primary themes emerged following analysis of the participants transcripts. participants were overall willing to participate in exercise during chemotherapy, with 12/16 patients stating they would walk or did walk at least 30 minutes daily during treatment; this was linked to a strong motivation to improve surgical and survival outcomes. only 1/16 patients stated they were not interested in exercise during treatment. most notable, patients' motivations were tied closely to physician recommendation. patients prominently identified a shift in health as a priority following their ovarian cancer diagnosis, which subsequently lead to an increase in daily activities and exercise. surgery and improvement in mental well-being were strong motivators for patients to start or continue an exercise program. participants also identified barriers to exercise during treatment including a variety of treatment related and nontreatment related concerns, including neuropathy, nausea, pain, program availability, time and most significantly fatigue. despite this, most retrospectively thought they would have been willing to exercise with modifications. almost all participants voiced the importance of a supportive treatment community, including their medical care team, family, friends and the local community. conclusion: patients with advanced ovarian cancer demonstrated high motivation and willingness to exercise during chemotherapy when there was a perceived benefit to overall survival. prehabilitation may be a helpful to improve outcomes, but a prehabilitation strategy should be designed specifically for the patients with the most need and designed with barriers and motivators in mind. randomized control trial. kosuke fujita 1,2 , hiroki umegaki 2 , aiko inoue 1 , huang chi hsien 1,2 , hiroyuki shimada 3 , masahumi kuzuya 1,2 ((1) institute of innovation for future society, nagoya university nagoya, japan; (2) department of community healthcare and geriatrics, nagoya university graduate school of medicine nagoya, japan; (3) department of preventive gerontology, center for gerontology and social science, national center for geriatrics and gerontology obu, japan) background: gait disorder in older adults could lead fatal consequence following falling or reducing physical activity, especially in individual with pre-clinical / clinical cognitive decline. effectiveness of exercise intervention for the gait characteristics has been examined in previous studies, however, evidence about differences between exercise modality such as aerobic training (at) and resistance training (rt) for the acute and long phase is unclear. objectives: the aim of the present study was to compare the effect of different exercise modality on the gait characteristics of older adults with preclinical cognitive decline. methods: 415 individuals (mean age, 72.3 years) with self-reported cognitive decline were enrolled in randomized controlled trial. subjects assigned to at group (n = 104), rt group (n = 102) and at+rt group (n = 104) underwent exercise intervention 2 days a week for 26 weeks. subjects assigned to control group (n =105) were provided information about healthy aging. gait characteristics were examined before, just after the intervention and after the 26 weeks of follow-up period using an electronical walkway system. results: in the analyses about the change between pre and just after the intervention period, all of three exercise groups significantly improved gait velocity (at, p < 0.01; rt, p < 0.01; at+rt, p < 0.01), stride time (at, p < 0.01; rt, p = 0.03; at+rt, p < 0.01), cadence (at, p < 0.01; rt, p = 0.02; at+rt, p < 0.01), stride length (at, p < 0.01; rt, p = 0.04; at+rt, p < 0.01) and double support time (at, p < 0.01; rt, p < 0.05; at+rt, p < 0.01), and at+rt group improved significantly with cv of step width (p < 0.05). in the analyses about the change between pre and follow-up period, rt group only had improvements with gait velocity (p < 0.05), stride length (p = 0.03) and double support time (p = 0.04). conclusion: all exercise interventions could improve gait characteristics of older adults with pre-clinical cognitive decline. for the purpose of maintain improved gait characteristics for a long phase, rt is likely to be recommended. activity and a broader array of physical and psychological outcomes among nursing home residents. however, some limitation of this game should be acknowledged (e.g. too long, too bulky, exercises too simple). taking into account these weaknesses, we decided to develop and validate a new version of a giant exercising board game: the gamotion. objectives: to evaluate the impact of gamotion on physical capacity, motivation and quality of life among nursing home residents. methods: a one-month randomized controlled trial was performed in two comparable nursing homes. eleven participants (71.63±8.15 years; 7 men) meeting the inclusion criteria took part in the intervention in one nursing home, whereas 10 participants (84±7.57 years; 4 men) were assigned to the control group in the other institution. the gamotion required participants to perform strength, flexibility, balance and endurance activities. the assistance provided by an exercising specialist decreased gradually during the intervention in an autonomy-oriented approach based on the selfdetermination theory (ryan & deci, 2002) . physical capacity (i.e. quantitative evaluation of walking using locometrix; grip strength using jamar dynamometer; knee extensor isometric strength using microfet2; fall risk using tinetti test; dynamic balance using timed up and go test (tug) and physical abilities using sppb test), motivation (i.e. using behavioral regulation in exercise questionnaire-2) and quality of life (i.e. using eq-5d questionnaire) were assessed at baseline and at the end of the intervention. a two-way repeatedmeasure analysis of covariance (ancova) was used to assess time*group (intervention vs. control group) effects. results: globally, during the intervention period, the experimental group displayed a greater improvement in symmetry of steps (p=0.04), tinetti score (p<0.0001), tug (p=0.02), sppb (p<0.0001), knee extensor isometric strength (p=0.04), grip strength (p=0.02), 3 domains of the eq-5d (i.e. mobility, self-care, usual activities : p<0.0001) and intrinsic motivation (p=0.02) compared to the control group. conclusion: the effects of gamotion on physical capacity, motivation and quality of life of nursing home residents confirm the results obtained with the previous version of the giant exercising board game. in-hospital stay, even in short stays, is associated with functional impairment in older patients. objectives: the agecar plus study aims to evaluate the effectiveness of a program of physical exercise and health education to prevent the functional deterioration during the in-hospital stay. methods: randomized clinical trial. patients older than 74 years admitted to the ace of the general university hospital gregorio marañón were included and randomized at admission in control group (cg) or intervention group (ig). exclusion criteria were baseline barthel (15 days before admission) less than 20 points, severe cognitive impairment or unable to walk. both groups received usual care, and patients in intervention group also performed simple supervised exercises (strengthening of lower limbs, walking, and inspiratory muscle training). in the preliminary analysis, we analyzed the effect of the intervention on changes in short physical performance battery (sppb) and alusti test, at admission and discharge, by t-test of repeated measures in the 2 study periods. results: from may 2018 to february 2019, 55 patients were included: 28 gc and 27 ig. the cg and ig were homogeneous in sex (women 47.3%), age (86.5±5.1 vs. 87.6±4.5), comorbidities (charlson: 2.3±1.8 vs. 2.9±2.1), cognitive impairment (pfeiffer: 6.8 ± 2.7 vs. 7.5±1.6), fragility (fried >=3: 69% p=0.297), and functional-physical capacity (sppb: 3.6± 06 vs 3.9±3.4; alusti, 61.4±14.1 vs 60.2±13.0). p <0.05 for all variables. a significant effect of the intervention was found, with a higher mean score in the alusti test in the ig (cg: 63.5±12.4 vs 67.3±12.5; f(1,50)=4.6; p=0.038), not finding such differences with the sppb (4.0±2.3 vs 4.5±3.4; f(1,48) =0.47; p=0.496). conclusion: the preliminary analysis shows that the alusti test could be used as an evaluation test for functional capacity in hospitalized elderly patients. a physical exercise program during hospitalization in an acute unit improves the functional capacity assessed by the alusti test at discharge significantly. funding: instituto de la salud carlos iii (pi17/02021), ciberfes, fondo europeo de desarrollo regional (feder). the authors declare no conflicts of interest. a. sampaio 1 , i. marques-aleixo 1,2 , j. carvalho 2 ((1) ciafel -research center in physical activity, health and leisure, faculty of sport, university of porto, portugal; (2) faculty of psychology, education and sports, lusófona university of porto, portugal) background: cognitive impairment is a highly prevalent, poorly managed, and disabling consequence of dementia. exercise training that improves physical fitness can represent a promising approach for managing cognitive impairment in persons with dementia. objectives: the aim of this crosssectional study investigated the association of physical fitness and balance with cognitive function. methods: sixty-four institutionalized older adults, aged 78.0±8.4 years, with dementia, predominately female (70%) and with dementia due to alzheimer's disease (53.1%). regression analyses were used to examine associations between physical fitness components (senior fitness test), balance (tinetti index) and cognitive function (mini-mental state examination). results: univariate regression indicates a significant association between the strength of the upper body (p=0,047) and aerobic endurance (p=0,037) with the cognitive function in older people with dementia. conclusion: these results suggest an association between the specific dimensions of physical fitness and cognitive function. consequently, multicomponent exercisebased therapeutic strategies aiming to improve physical fitness could be an important nonpharmacological strategy for dementia management. satoshi kurita, takehiko doi, kota tsutsumimoto, sho nakakubo, hideaki ishii, hiroyuki shimada (section for health promotion, department of preventive gerontology, center for gerontology and social science, national center for geriatrics and gerontology, aichi, japan) background: women had higher risk of cognitive impairment or dementia compared to men. although studies reported physical activity (pa) and/or cognitive activity (ca) had protective association with cognitive impairment among older adults, it is unknown whether the association is depended on sex or not. objectives: the purpose of the present study was to examine the sex differences in the association of pa and/or ca with cognitive impairment in community-dwelling older adults. methods: a community-based cohort survey was conducted in a total of 2726 participants (mean age 75.5 ± 3.9 years; 51.8% female) who met the study criteria. time of moderate-to-vigorous intensity pa was measured using an accelerometer. ca was assessed by the frequency of engaging in 6 activities using a ca scale including reading, doing crossword puzzles, and playing board games or cards. participants were categorized into four groups based on quartile 1 (low) and 2 to 4 (high) values of pa and ca. cognitive impairment was defined by at least 1 out of 4 neuropsychological tests having a result at least 1.5 standard deviation below the reference threshold. results: in both sex, the prevalence of cognitive impairments showed significant differences among 4 groups; that of low pa/low ca group, low pa/high ca group, high pa/low ca group, and high pa/high ca group were respectively 30.6%, 18.0%, 20.4%, and 14.1% for male (p <0.001) and 28.1%, 18.8%, 21.8%, and 15.4% for female (p <0.01). in binomial logistic regression models for male, all groups showed a low odds ratios of cognitive impairment compared to the low pa/low ca group (odds ratio = 0.50 to 0.66, all p <0.05), while for female, only high pa/high ca group had significant association with cognitive impairment (odds ratio = 0.53, 95% confidence interval = 0.32 to 0.88, p = 0.015). conclusion: in male, pa and ca are associated with cognitive impairment even in the case of low engagement in either pa or ca. in female, higher engaging in both activities are associated with cognitive impairment. female older adults may need to engage in more activities than male to acquire benefit on preventing cognitive impairment. (139 interventions) were included in the systematic review and 64 in the meta-analyses (86 interventions). there was considerable heterogeneity in the number for interventions that detected significant increases in muscle mass (50/139, 36%) and muscle strength (61/86, 71%). of those muscle strength interventions 9/24(38%), 52/74(70%), 20/26(77%) and 4/4 (100%) interventions reported a significant increase in handgrip strength, lower body muscle strength, upper body muscle strength and whole body muscle strength respectively. ret factors associated with the greatest gains in muscle mass and muscle strength were: use of combination of equipment, seven to eight exercises per session with three lower body exercises, a volume of three to four sets and 12 to 15 repetitions per exercise, a frequency of two-three days per week, intervention length of greater than six weeks, progressive intensity, intervention duration of 15-45 minutes, and in a supervised individually training structure. these results align with current guidelines provided by american, australian, japanese, british, canadian and japanese societies. conclusion: not all ret interventions are effective for improving muscle mass and strength, but our meta-analysis suggests that adhering to the current ret guidelines for older adults are likely to be most effective. duarte barros, andreia pizarro, arnaldina sampaio, joana carvalho (research center in physical activity, health and leisure, faculty of sports, university of porto, portugal) background: sedentary time (sed) and low physical activity (i.e. low levels of moderate-to-vigorous physical activity [mvpa] ) are different behaviours associated with negative health outcomes, but how synergetic combinations of these behaviours impact the risk of frailty are still unexplored. objectives: to examine the relationship between different combinations of sedentary time and mvpa in the risk of being frail. methods: a cross-sectional study including 152 community dwelling elders (74.37±6.29 years; 66.4% female) accessed frailty through the phenotype of frailty. daily sed and mvpa were objectively measured using accelerometry. sed and mvpa were ranked by the median and then participants were categorized into one of four groups: lowsed+lowmvpa, l o w s e d + h i g h m v p a , h i g h s e d + l o w m v p a a n d highsed+highmvpa. results: overall, 13.2% of the participants were frail. mvpa was associated with reduced odds of being frail (or 0.958 ic: 0.938-0.979, p < 0.001). moreover, compared to the highsed+lowmvpa, the groups lowsed+highmvpa (or 0.34 ic: 0.127-0.825, p = 0.018) and highsed+highmvpa (or 0.086 ic: 0.027-271, p < 0.001) were associated with reduced odds of being frail. conclusion: mvpa seems associated with reduced odds of being frail, irrespective of sedentary time. background: sarcopenia is central to frailty and the strongest evidence for reversal lies in the combination of resistance exercise and protein supplementation. unfortunately, uptake amongst older adults remains low, partly due to a lack of suitable exercise programs. delivery by health professionals alone will not achieve widespread participation. objectives: defrail aims to develop a novel exercise program (focused on resistance training), feasible for delivery to frail older adults in a group setting without the input of health professionals, and to examine its effect when combined with commercially-available protein-supplemented milk. methods: a multi-component exercise program was designed by expert consensus using a modified delphi process. participants were recruited from geriatric medicine clinics and primary care, with assessments at baseline, after eight weeks of regular activity and then after the eight-week intervention. the primary outcome measure was the change in the fried frailty criteria (ffc) during the intervention compared with the period of regular activity. secondary outcome measures included the timed up & go (tug) and 30-second sit-to-stand (30sts) tests. results: the first 12 participants to complete the program (7 females, 5 males, mean age 84, range 78-91) had a median ffc score of 3 (interquartile range (iqr) 3,3), i.e. frail, both at baseline and after the period of regular activity period, but had improved to 2 (iqr 1,2), i.e. pre-frail, following the intervention. similarly, the median tug was 17.5 (iqr 14.6, 19) at baseline, increasing to 18.8 (iqr 15,22.2) after the period of regular activity, improving to 15.5 (iqr 13.2,18.7) following the intervention. the median 30sts was 6 (iqr 3,8) at baseline, 6 (iqr 5,7) after the period of regular activity, improving to 8 (iqr 6,9) following the intervention. conclusion: median frailty improved from frail to pre-frail for the first 12 defrail participants. this program could allow increased community-based participation in resistance exercise for frail older adults. further work now includes completion of the intervention and analysis of data on a range of secondary outcome measures (assessments of cognition, mood, pain, body mass composition and biochemical markers of frailty). background: exercise interventions have been shown to improve functional status and quality of life of frail older people, and in some cases to reverse frailty status. it is important that such interventions are targeted to those people who would benefit the most. objectives: the objective of this pilot study was to assess the effectiveness of a physical activity intervention given to mildly frail older people, who were identified using electronic health records (ehr). methods: the electronic frailty index (efi) was used to identify mildly frail older people and offer them a physical activity intervention of their choice. the pilot study was offered in one area of luton (uk), with invitation letters sent by the participants gp. participants were tested before and after a 12-week programme of strength, balance and mobility, delivered in a weekly session lasting one hour. participants were assessed at baseline for motivation using the patient activation measure (pam), physical function using the short physical performance battery (sppb), and fear of falling using the falls efficacy scale international (fes-i). each test was carried out in a follow-up test after the programme had concluded. bootstrapped paired t-tests were used to assess the effect of the intervention. results: twenty-seven people aged 74.6 ± 5.4 years took part in the intervention. the pam scores improved from 74.5% to 83.6% (9.1, 95% ci: 2.9, 14.7), which is twice the minimal clinically important difference (mcid) of 4. for sppb, there was an improvement from 8.5 to 9.8 (1.27, 95% ci: 0.71, 1.86). the average increase was greater than the mcid for a substantial improvement of 1.0. when fes-i was assessed, only three people (11%) had high concern about falling. there was no significant improvement in fes-i after the intervention (-2.5, 95% ci: -5.3, -0.2). after the intervention, 62% of participants choose to pay for the continuation of the programme. conclusion: the findings of this study suggest that a targeted exercise programme including strength and balance training can significantly improve motivation and functional status among mildly frail older people identified using the efi, with the majority choosing to continue exercising. background: despite frailty has traditionally been examined from a physical standpoint, recent studies advocate for the existence of cognitive frailty (1), and suggest that both physical and cognitive frailty are interrelated. thus, interventions should aim to prevent or attenuate the effects of frailty from a multidimensional perspective. objectives: to evaluate the effects of three different exercise programs on frailty among older adults living in long-term nursing homes (ltnh). methods: 128 participants (67.3% female) met the following criteria: aged 70 years, scored 50 on the barthel index, scored 20 on mec test (an adapted version of mmse in spanish) and capacity to stand up and walk 10m independently. participants were randomly assigned to a progressive multicomponent group (mcg; n=43), a multicomponent dual-task group (dtg; n=42), or to a walking group (wg; n=43). the mcg underwent a 3-month moderate intensity strength and balance exercise program twice a week. the dtg performed simultaneous cognitive training (attention, inhibitory control, calculations and semantic memory) to the mc program. the wg walked up to 20 minutes per day for 7 days a week. frailty was measured though the following tests: fried frailty index (ffi), the tilburg frailty index (tfi) and the study of osteoporotic fractures (sof). results: the ffi revealed reductions in frailty in all groups, although only the mcg and the wg reached statistical significance (p<0.05). as for the tfi and sof tests, no statically significant differences were found in any of the groups. however, there was a positive trend in tfi in the dtg (p=0.07). no group-by-time interactions were found in any of the frailty tests used (p>0.05). conclusion: our study showed no differences between interventions regarding frailty. however, the mcg and the wg showed significant reductions in phenotypic frailty, whereas the dtg showed a positive trend in the tfi, which takes into account physical, psychological and social domains. therefore, further studies should explore the effects of different exercise modalities on frailty from a broad perspective in older adults living in ltnhs. references: kelaiditi et al 2013 . j nutr health aging. 2013 17(9) :726-34. noirez 1,2 , iraj hashemi 1 , deborah kopoin 1 , pierrette g a u d r e a u 3 , m a r c b é l a n g e r 2 , g i l l e s g o u s p i l l o u 2 , josé a morais 4 , aubertin-leheudre 1 ( (1) background: aging leads to a loss of muscle strength and functional capacity. these phenomena can be slow down by daily exercise practice or resistance training intervention. objectives: the aim of this study was to investigate in elderly men muscle fiber size and type after resistance training. methods: among sedentary older men who completed a 12-week mixed power training program, 8 were biopsied in the vastus lateralis before and after the program. cross sections were performed on these muscles, followed by triple immunohistochemical staining with antibodies directed against laminin, myosin heavy chain (myhc)-1 and myhc-2a coupled with staining with secondary fluorescent antibodies. immunostaining analysis of laminin allowed us to determine fiber size and these of myhcs to determine fiber type. results: the size of the muscle fibers remained the same between before and after the mixed power training (p=0.71).there was no significant difference in the percentage of expression of myhc-1, 2a, 2x (p= 0.67, p = 0.34, p = 0.5286) between before and after intervention. in addition, there was no difference in the size of fiber expressing myhc-1 between before and after the training (p = 0.97). however, significant increase in the sizes of fiber expressing myhc-2a and myhc-2x (respectively p = 2e-04, p <.0001) after the mixed power training was observed. conclusion: in elderly men, an increase of the size in fibers both expressing myhc-2a and myhc-2x in vastus lateralis muscle could explained the improvement on muscle mass observed previously (carvalho et al. acer 2019) . to confirm the mechanism explanation of this promising exercise modality, mitochondrial parameters should be also analyzed. background: muscle (in)activation related with sedentary behavior (sb) and physical (in)activity (pa) is a risk for sarcopenia in older adults. although age is not yet a risk factor for sarcopenia in adulthood, other factors such as lifestyle may significantly contribute to its progression. objectives: considering the primary and secondary prevention of sarcopenia, the aim of this study was to analyze associations of sb and pa with markers of muscle strength (lower limb muscle power) and muscle mass (fat mass (fm) to fat free mass ratio (ffm) in adult women and men with and without deficits in these markers. methods: participants were 225 apparently healthy adults (147 women) with a mean age 45.2±9.4yrs, employed in activities requiring office work. fm and ffm were evaluated by bioelectrical impedance analysis (bia, 50 khz bia 101 rjl, akern bioresearch, florence, italy akern). muscle power relative to body mass (pmax/mass) was assessed during a single two-legged jump on a force platform (leonardo mechanograph, novotec medical, pforzheim, germany) . sb and pa were assessed by accelerometry (actigraph, gt3x model, fort walton beach, fl, usa) during four consecutive days (2-week+2-weekend days). the variables analyzed were time spent per day in sb, in light-, moderate-, vigorous-, moderate to vigorous-intensity pa, total pa and breaks per day of sb. multiple linear regressions were performed by stepwise to examine associations of sb and pa with muscle power and fm/ffm, separately for men and women with and without muscular deficits. for the identification of deficits (<-0.5 sd), muscle power and fm/ffm were standardized separately for men and women having as reference their respective mean. results: linear regressions by stepwise evidenced an association of sb with muscle power in women with muscular deficit (β = -0.360, p = 0.017, adjr2 = 11,9%%) and an association of vigorous pa with fm/ffm in men without muscular deficit (β = 0.501, p < 0.001, adjr2 = 23,5%). no associations were observed between sb or pa with muscle power or fm/ffm in other groups. conclusion: sb was negatively evidenced in women with muscle power deficit while vigorous pa revealed to be associated with fm/ffm in men without ffm deficit. funded by portuguese science and technology foundation; project c mup-eri/hc i/0046/2013 patricia parreira batista 1 , andré gustavo pereira de andrade 2 , jéssica rodrigues de almeida 1 , aimée de araújo cabral pelizari 1 , leani de souza máximo pereira 1 , lygia paccini lustosa 1 ((1) physical therapy department, ufmg -eeffto, belo horizonte, brazil; (2) sports department ufmg -eeffto, belo horizonte, brazil) background: the practice of regular physical activity in the older people leads to the decreased of the loss of muscle mass and function with advancing age, and enhances the functionality in activities of daily living and social interaction. in addition, exercise promotes gains in the quantity and quality of muscle fibers and improves muscle strength and power, acting as a protective factor for negative health-related outcomes such as falls, frailty, and hospitalizations. regular practice of physical activity is known to modify the chronic proinflammatory condition common in the older people. probably, exercise reduces the drive of catabolic stimuli from this proinflammatory cascade, modifies the metabolism and production of cytones in tissues and organs, promoting protective and anti-inflammatory effect in the body. objectives: to compare older women who reported being active or sedentary regarding functional capacity and plasma indices of inflammatory mediators. methods: participated women (60 years or older), recruited for convenience. those unable to walk were excluded; acute musculoskeletal diseases; lower limb fractures in the last year; neurological diseases and sequelae; history of cancer in the last five years and cognitive impairment (mental state mini-exam). all informed clinical and demographic data and performed the tests short physical performance battery (sppb) and timed up and go (tug). plasma dosages of stnfr and il-6 were by elisa method. comparison was by independent student t test. approval by the research ethics committee / ufmg (caae: 14129513.7.1001.5149). results: fiftytwo sedentary older women participated (74.35 ± 6.97 ys.); number of comorbidities of 2.83 ± 2.07; body mass index of 26.81 ± 4.25 kg/m2. from the active group were 45 elderly women (72.07 ± 5.23 ys.); comorbidity number of 2.22 ± 1.67; body mass index of 27.6 ± 4.81 kg/m2. there was significant difference between groups in sppb (p = 0.017), tug (p = 0.001) and stnfr1 (p = 0.01). conclusion: the results showed that the active older women had better functional and mobility performance and worse plasma stnfr levels. in this case, one can think about the possible influence of body mass index in these older women, which should be explored in future studies. background: our research group designed a comprehensive geriatric intervention program (cgip) consisting of resistance exercise, physical activity increments, oral functional care, and a nutritional guide. we conducted a 12-week intervention and investigated the effects. after the short-term intervention, we followed up the all participants. we hypothesized that the follow-up could mitigate the loss of short-term intervention effects. objectives: the aim of this study was to compare physical functions before and after the 12-week intervention, and the end of the follow-up. methods: a total of 526 were willing to participate in the 12-week cgip. we encouraged them to increase their daily steps and to carry out the program by using daily self-monitoring logs. the participants were randomly assigned to two groups [class-styled session (cs) group 251; home-based (hb) group 275] based on their residential districts. while cs group attended 90-minute weekly sessions and independently executed the program on other days, hb group did not attend the weekly sessions but received instructions on program execution. after the shortterm intervention, all participants were instructed to carry out the gcip habitually. also, three optional sessions for all participants were held in order to recommend implementation of the program. physical functions, such as knee extension strength (kes), maximum walking speed (mws), and anterior thigh muscle thickness (mt) were measured before and after the short-term intervention, and the end of the follow-up. results: of the 526 participants identified, 312 (cs 153; hb 159) took part in the measurements after the follow-up. thus, we analyzed their data. a significant interaction were observed in mws (p=0.033). the 12-week cs intervention significantly improved mws (p<0.001). but, mws in cs group significantly decreased after the follow-up (p=0.003). there was no significant difference between before the intervention and after the follow-up in mws in cs group. on the other hand, no significant change was observed in hb group. significant time effects were observed in kes and mt (p<0.001). both 12-wk interventions significantly improved kes and mt. while kes was maintained even after the follow-up, mt was significantly decreased. conclusion: the results suggested that appropriate follow-up helps to preserve short-term intervention effects. background: with the increasing prevalence of alzheimer disease and the current absence of drugs therapeutic, nonpharmacological strategies are definitively necessary. physical intervention is often proposed to aid in preventing or slowing cognitive decline. recent studies suggest that combining physical exercise with cognitive stimulation may have more global effect. objectives: we aimed at assessing effect of aerobic exercise alone or combined to intellectual exercises on major cognitive functions: attention (stroop), problem solving (hanoi tower) and working memory (digit span). subjects were trained twice a week for eight weeks. cognitive functions were assessed before training (base line), at the fourth and at the eighth weeks. to evaluate persistency of the effect, subjects were assessed one month after the end of training. methods: two groups were randomly constituted mild cognitive impairment subjects (mci) and alzheimer disease moderate patients (adm). each group was subdivided into three sub groups according to the task to be performed. aerobic exercise (pedaling) alone or combined to cognitive games presented on screen. control groups performed a reading task. results: an effect of training on cognitive functions was observed in adm as well as in mci subjects. however, only adm patient's performances were further improved by adding cognitive games. after four weeks, the observed effects were still maintained in both groups. mci results were obviously better than those of adm. there was no significant change in performances for control groups. conclusion: aerobic exercise induce cognitive improvement in adm and mci patients. combined physical exercise and cognitive games potentiated this effect mainly in adm group. this procedure has long lasting beneficial effect. this supports the necessity of regular aerobic exercise to prevent cognitive deficits in aging cognitive deficits. background: increasing physical activity represent a key therapeutic intervention to prevent the loss of mobility disability for enhancing health related quality of life. hence, we have set up a primary and secondary prevention care path through exercise training and nutrition to improve mobility and physical performances. objectives: our primary goal is to integrate a prevention care path into daily life of elders who may present a mobility disability risk. we aim to improve quality of life and mobility. methods: our program includes 70 years or more who present a risk of developing a mobility disability. initially, we identify and screen a risk of mobility disability in wide elders communities. we diagnose mobility disability risk factors, sarcopenia and frailty, in day hospital (dietician, geriatrician and a kinesiologist). we use the ewgsop2 algorithm to diagnose sarcopenia. the patient then attend a 3-months training program, including 2 sessions per week. sessions combine resistance exercises and balance training during 60 minutes. we support the patient for his own project of long-term maintenance quality of life between physical activity and nutrition. results: 152 patients have been seen after 20 sessions. physical performance was significantly improved after 3 months of intervention (sppb p<0,001, gait speed p<0,001 and time-up-and-go p<0,001) likewise grip strength (p<0,001). the "sarqol" score was also significantly higher (p<0.001). sub-group sppb ≤8 with severe sarcopenia improve significantly more its score (+1.6±1.9 p<0,001) comparing to the overall population (+0.6±1.7). moreover, there was a significant difference (p<0,001) for sppb at baseline between responders (7.6±2.3) and nonresponders (9.8±2.0). conclusion: our intervention enhances mobility through physical performance benefits. we can make the assumption that adverse events will be occurring less and physical dependence will be delayed, regarding gait speed improvement. patients with lower physical performance are responding better than the overall population meaning that our intervention is more specially indicated for patients with severe sarcopenia. furthermore, our program sustains motivation for physical activity and exercise after 3 months. we were able to show that it was possible to set up a comprehensive and effective care path for frail and sarcopenic elderly people. background: middle-aged adults who are pre-sarcopenic are at the highest risk of developing sarcopenia due to the progressive nature of the syndrome. objectives: to determine whether high intensity interval training (hiit) results in greater improvements in body composition, compared to a control group, in middle-aged adults with pre-sarcopenia. methods: eighty-two sedentary adults (40-50 yrs) with a low appendicular skeletal muscle mass index (asmi) were randomized into control (n=41) or intervention group (n=41) using stratified randomization based on age, sex and bmi. low asmi (asm/ht2) was determined by dxa (lunar prodigy, ge healthcare) using age-and sex-specific cut-scores as proposed by prado. the control group received one education session on general physical activity recommendations. the intervention was supervised, group-based, high-intensity aerobic and resistance interval training (hitt), 3 times weekly for 20-weeks. an intention-to-treat mixed model linear regression, with a random effect, was used to analyse group differences for body composition. results: 85.4% of the sample were female, the mean age was 45.1 yrs (3.1) and the mean bmi at baseline was 25.8 kg/m2 (3.5). 71 people (87%) completed the intervention, 39 people in the hitt group and 32 in the control group. no adverse events were reported. significant group differences were observed for total muscle mass (0.73 kg, 95%ci: 0.065-1.398), leg muscle mass (0.40 kg, 95%ci 0.121-0.681), asmi (0.21 kg/m2, 95%ci 0.087-0.331) and visceral fat mass our study indicated that group-based hiit is an effective, tolerable and safe exercise modality to increase total body and appendicular muscle mass, and to decrease visceral fat, in middle-aged adults with pre-sarcopenia. background: aging is related to body composition modifications and functional capacities declines. it is recognized than being active can prevent these changes and improve quality of life. however, it is unclear if gender or age influence this relationship and if a sub-type of voluntary physical activity is more efficient to maintain these physical parameters. objectives: to assess the association between current physical activity level or type and functional capacities and body composition among elderly people and to examine if age (< or >= 65 yrs old) or sex modulate the relationship. methods: functional capacities using different validated tests (i.e. grip strength, timed up and go, sit-to-stand, muscle power, alternate step test, leg extension, vo2 max), body composition (fat & fat-free masses) using dxa were assessed. current global (total) and specific (aerobic, resistance or body and mind) physical activity levels (duration) were obtained through a questionnaire. multiple regressions, adjusted on age, sex and bmi, were performed to assess the relationship between current physical activity level and functional capacities or body composition. sub-group analysis, according to the sex and age (<65y vs. >= 65y) were also performed by means of pearson correlations. results: a total of 525 subjects (61.7±8.1years; women: 68.9%; bmi=26.4±4.8kg/ m²) were enrolled. after adjustment on confounding factors, total current physical activity level has positive impact on total fat mass (%; β=-2.09, p=0004) and balance (β=0.10; p=0.05). moreover, current body & mind activities influence total fat-free mass (kg; β=-0.22, p=0.02) and balance (β=0.17; p=0.001) whereas resistance activities influence fat-free mass (kg; β=0.17; p=0.05), fat mass (%; β=-0.16; p=0.04) and sitto-stand test (β=-0.10; p=0.05). sub-analysis shows that total physical activity level was significantly associated with fat mass, sit-to-stand test, balance and vo2 max in women but not in men. moreover, among people under 65 y, the time spent on cardio activities does not affect functional capacities and body composition. nonetheless, among people aged 65 y and over, the time spent on resistance activities is associated with functional capacities and body composition. conclusion: being active is associated with body composition and functional capacities, especially among women aged 65 years and over. itxaso mugica-errazquin 1 , nagore arizaga 3 , janire virgala 3 , julen gomez 1 , garbiñe lozano 1 , yune aranburu 4 , udane elordi 1 , maider kortajarena 1 , ana rodriguez-larrad 2 , jon irazusta 2 ( (1) background: low physical fitness, frailty and dependency are highly prevalent in people living in long term nursing homes (ltnh). multicomponent physical exercise, including strength, balance and endurance, has demonstrated to be effective for improving physical fitness and reducing frailty in ltnh. however, there is no evidence that this type of programs are capable to improve or even maintain the levels of autonomy in activities of daily living (adl) of this population. objectives: the major aim is to ascertain whether a new approach of 6 months, individualized and progressive multicomponent program focused on functioning maintains autonomy in older adults living in ltnhs; the secondary aim is to assess the effects on frailty and physical fitness. methods: 77 people living in ltnh, between 70 and 103 years, participated in this single group interventional study. inclusion criteria were: >=70years, >=50 barthel index, >=20 mec-35 and be able to stand up from a chair and walk 10 meters with or without one person/technical assistance. the intervention consisted of 3 months of a progressive multicomponent physical exercise program (ep) aiming to improve the physical condition, followed by 3 months of physical exercises focused on functional adl with the objective of maintaining/improving autonomy of the participants. barthel index was used to assess autonomy level in adl, frailty was measured by fried frailty index and short physical performance battery (sppb) was used to assess physical fitness. the study is registered in u.s clinical trial (nct04221724) and approved by the committee on ethics in research of the university of the basque country (m10/2018/171). results: during the 3 first months of ep participants lowered the score in the barthel index (p<0,001). however, participants showed significant improvements in frailty (fried frailty index p<0,01) and in physical fitness (sppb p<0, 001) . from the 3rd to 6th months, while physical fitness of participants did not change, they improved autonomy in adl, and decreased frailty non-significantly. when comparing the effects of the entire intervention, barthel index did not change significantly and physical fitness and frailty improved (sppb p< 0,001; fried p<0,005). conclusion: this new approach of 6 months of individualized and progressive multicomponent program focused on daily functioning maintains autonomy in activities of daily living, improves physical fitness and reduces frailty in older adults living in ltnhs. shuji sawada 1 , hayao ozaki 1,2 , toshiharu natsume 1 , daiki nakano 1 , pengyu deng 1 , toshinori yoshihara 1 , takuya osawa 3 , shuichi machida 1 , hisashi naito 1 ((1) juntendo university, chiba, japan; (2) tokai gakuen university, aichi, japan; (3) japan women 's college of physical education, tokyo, japan) background: in previous study, we found that low-load resistance training using own body weight and elastic band even only biweekly could induce muscle hypertrophy in older adults after 12 weeks of training. however, it is unclear whether levels of different blood parameters before training associated with the effects of training. objectives: this study aimed to clarify whether levels of different blood parameters before training influenced the effect of low-load resistance training on lower limb muscle thickness (mt). methods: sixty-nine communitydwelling japanese subjects aged 69.4±6.5 years (49 women and 20 men) volunteered for this study and participated in a lowload resistance training program using their own body weight and elastic band. the training was performed biweekly for 12 weeks. each participant's mt at the anterior aspects of the thigh (at) was measured using a b-mode ultrasound device. further, the levels of the following blood parameters were assessed before and after the training program: serum albumin (alb), hemoglobin (hb), total cholesterol (tc), and hemoglobin a1c (hba1c). we checked the first quartile value of each blood parameter to establish the cutoff criteria for reduced levelsserum alb = 4.1 g/dl, hb = 12.6 g/dl, tc = 181 mg/dl, and hba1c = 5.3%. participants were divided into low or normal groups in each blood parameter, and their data were analyzed using two-way analysis of variance. results: when using the abovementioned criteria, biweekly low-load resistance training increased mt at the at in every group after training. the interaction between time and groups was only detected with low (<4.1 g/dl) versus normal (>=4.1 g/dl) serum alb levels. in this case, there was no difference in mt at the at before training, but participants in the normal serum alb level group had greater mt after training than those in the low serum alb level group. conclusion: the effect of low-load resistance training on lower limb mt appears to be limited in participants with low pre-training serum alb level. objectives: it was to estimate the affect of complex 3-week treatment with 4 kinesiotherapy methods on body weight loss and muscle function in patients with obesity. methods: 80 men and women aged 21-69 years old with alimentary obesity were enrolled in the study (mean age 52.4±11 years, weight 111.3±24.5 kg, bmi 40.3±8.1 kg/m2, waist circumstance wc 113.4±16 cm, hip circumstance hc 124.2±16 cm). the complex kinesiotherapy administered daily for 3 week and included interactive sensorimotor trainings on double unstable platform, kinesiohydrotherapy in a pool, special complex of physical exercises in a gym and ergocycle trainings. weight, wc, hc, fall number for last 3 weeks were measured at baseline and after the treatment was completed. muscle strength and walking speed functional tests results assessment (10-meters-walk test, up-and-go test, 4 special tests for back and abdomen muscle endurance to static and dynamic loading) were performed at baseline and in 3 weeks. results: there was a significant reduction in body weight (111.3±24.4 kg at baseline vs 107.9±23.1 kg in 3 weeks; p=0,000), in bmi (40.3±8.1 vs 39.1±7.7 kg/m2; p=0.000), in wc (113.4±15.9 vs 109.2±15.1 cm; p=0.000) and in hc (124.1±15.5 vs 119.7±14.1 cm; p=0.000) in treated obese patients. 10-meters-walk speed increased from 0.84±0.15 m/sec at baseline to 0.88±0.17 m/ sec in 3 weeks (p=0.000). up-and-go test results improved from 8.4±2.1 to 7.9±2.09 sec (p=0.000). we registered statistically significant elevation of the endurance to static loading in abdomen muscles from 13.1±9.7 to 16.49±12.8 sec (p=0.000) and in back muscles from 14.8±11.9 sec to 18.6±14.9 sec (p=0.000). the endurance to dynamic loading increased in abdomen muscles from 29.9±11.2 to 34.84±11.93 times (p=0.000) and also in back muscles from 9.1±7.4 to 12.2±9.2 times (p=0.000). fall namber markably decreased from 0.14 ±0.34 at baseline to 0.0 (95%ci: 0.02; 0.25) after completion of treatment. conclusion: investigated complex treatment with 4 kinesiotherapy methods promotes body weight loss, wc and hc reduction in obesity. 3-week special training of obese patients is associated with increasing in gate speed and lower extremities muscle strength, and it also causes improvement in static and dynamic loading endurance of back and abdomen muscles. those changes may probably improve balance function and decrease risk of falling in obese patients. thaiana pacheco, candice medeiros, rummenigge dantas, inae c. gadotti, edgar r vieira, fabrícia costa cavalcanti (department of physical therapy, florida international university, miami, usa) background: integrating technological advances into clinical practice can be challenging. physical therapists have been developing serious games/exergames for a variety of rehabilitation purposes, but uptake has been slow. games with virtual scenarios are an engaging and affordable way to encourage and increase physical activity levels. serious games have been developed to adapt virtual gaming environments to patients' needs and evolving capabilities. games can improve adherence and therapy effectiveness. the sensory and motor stimulation while playing serious games can help geriatric rehabilitation to improve mobility and balance. objectives: this study analyzed the effects of a new serious game on the balance of older adults. methods: this was a pilot quasiexperimental design study in which older adults completed six sessions of dynamic balance training using the virtualter serious game that uses the kinect sensor for motion capture. this game was developed by researchers from the federal university of rio grande do norte in brazil. the game consists of static and dynamic tasks for training balance. it involves stationary walk, lateral reaching and climbing steps up and down. it has 3 phases with increasing the level of difficulty. the participants were evaluated before and after the program using the berg balance scale (bbs) and the short physical performance battery (sppb). t-test for dependent samples was used to analyze the pre vs. post data. results: twenty three participants participated in the study (age = 72±8; sex = 65% women). the results indicate improvement in bbs scores (pre: 50±6; post: 51.4±6; p = 0.006) and sppb scores (pre: 10±2; post: 11±2; p = 0.01). conclusion: playing the virtualter serious game improved balance in older adults. helen chan 1 , duncan wong 2 , cindy fan 2 ((1) the nethersole school of nursing, the chinese university of hong kong, hk; (2) silver yoga lab, hk) background: evidence showed that both frail and prefrail significantly increase the risk of developing or worsening disability in activities of daily living, poor quality of life and institutionalisation. yoga has been consistently reported as effective intervention in improving physical functioning in terms of balance, lower limb strength, mobility and body flexibility. objectives: to assess the feasibility of silver yoga in older adults and to examine the preliminary effects of silver yoga on their physical health. methods: this was a one group pre-test post-test study conducted in a community centre. people who aged 60 and above, were mentally competent, home-living, and classified as prefrail based on physical phenotypes using fried criteria, were eligible to the study. the silver yoga class included eight 1.5-hour weekly sessions delivered by two experienced yoga instructors with specialized training in silver yoga. senior fitness test (sft) was conducted to assess changes in physical health. paired t-test was used to compare the within-subject differences across 2-month time. results: a total of 25 older adults were recruited. there were significant improvement in six dimensions of the sft, including upper extremity muscle strength, lower extremity muscle strength, upper body flexibility, lower body flexibility, agility and dynamic balance, and aerobic endurance (ps < 0.001). all participants except one completed the yoga programme, with high level of satisfaction. in addition to the effects of physical conditions, the participants also appreciated it as mind-soothing and relaxing. conclusion: the findings showed that silver yoga is well-received by older adults generally, with significant effects in improving their physical fitness. more rigorous study is needed to examine its effects in a longer term and also in a more holistic manner. ku leuven, leuven, belgium; (2) physical activity, sports and health research group, department of movement sciences, ku leuven, leuven, belgium) background: with aging skeletal muscle tissue becomes less responsive to anabolic stimuli, eventually contributing to muscle wasting. inflammation is considered an important player in this age-related anabolic insensitivity. recent reports provide a promising role for omega-3 polyunsaturated fatty acids (ω-3) in (muscle) health, as they possess systemic anti-inflammatory properties and stimulate muscle anabolic signaling. objectives: we investigated whether ω-3 supplementation improves the systemic inflammation and muscular adaptations (i.e. strength, mass, molecular signaling) to resistance exercise in an elderly population. methods: twenty-three elderly (65-84y; 8♀) were randomized to receive either ω-3 (~3g/d) or an isocaloric amount of corn oil (plac) during 14 weeks. after two weeks of supplementation, participants engaged in resistance exercise (re; 3x/week) for 12 weeks. prior to and after completion of the intervention, muscle and blood tissue, parameters of body composition, muscle strength and functionality were assessed. results: upon re, 1-rm significantly improved in plac (+23.5%) and in ω-3 (+ 30.4%), irrespective of condition. isometric strength significantly improved in ω-3 (+12.2%), but not in plac (-0.3%). muscle volume did not change following re. plasma crp levels decreased, though not non-significantly, in ω-3 (-28.9%), whereas only a small increase was observed in plac (+6.9%). ω-3 supplementation nor re affected the muscle anabolic sensitivity (akt phosphorylation) in response to a protein bolus. conclusion: this study confirms that ω-3 pufas improve the gains in isometric but not in dynamic muscle strength upon re in elderly. however, this was not associated with changes in anabolic sensitivity or systemic inflammation. further analyses will investigate whether the ω-3 induced gains in strength can be related to systemic hormones or muscle molecular signaling (mtor signaling, inflammation). meera suresh, clarence chikusu, caroline goodger (nutrition and dietetics, st. peter's hospital, chertsey, uk) background: deconditioning is a common phenomenon in patients over 75 years old in acute settings. it is well known that poor nutritional status has a major impact on adverse outcomes in frailty and can exacerbate sarcopenia (1). currently, there is limited research exploring the impact of dietitians on optimising nutritional status in acute settings in older populations for frailty and sarcopenia. objectives: compare the impact of dietetic intervention on the change in frailty scores between a patient group (n=125; mean age 87.07 years) who received dietetic intervention (di) and a patient group (n=254; mean age 86.79 years) who did not receive dietetic intervention (ndi). methods: a 5-month retrospective study (august-december 2018) was undertaken at the older persons short stay unit at a district hospital in england. frailty scores were calculated based on the rockwood model of clinical frailty. dietary intake was recorded and analysed using a standardised nutritional profile of hospital meals. the di group was given standardised dietetic care including oral nutrition support and build up dietary advice. descriptive statistics were used to determine frequencies. results: the di had higher frailty scores (mean of 5.6; range: 3-8) and a higher mortality rate (35%).the ndi had a mean score of 4.73 (range: 1-8) and mortality rate of 18%. the average oral intake for energy and protein for patients in the di group prior to dietetic intervention was 40% lower than the espen recommendations. despite the higher frailty scores and mortality rates in the di group, progression in their frailty score was slower compared to the ndi group (24% vs 38%). conclusion: the results highlight the importance of a timely referral for early dietetic intervention which is crucial for optimisation of better clinical outcomes in these patients. a dietitian is a key member of the mdt and can prevent further deterioration in muscle mass and the impact on patients' frailty and independence and also slow down the progression of sarcopenia and frailty. this has long term impact on health and social services by reducing length of stay, hospital re-admissions and the increasing burden on social care. uz leuven, leuven, belgium) background: while the protein recommended dietary allowance (rda) for healthy adults is 0.8g protein/kg bodyweight (bw)/day (d), expert groups recommend a protein intake up to 1.5g protein/kg bw/d for older people with chronic diseases. in addition, at least 25-30g protein (whereof at least 2.5g of leucine) is recommended per meal. objectives: we aim to assess in (pre)sarcopenic older people the daily energy and protein quantity and quality intake, and their change due to supplementation. methods: dietary protein quantity, and quality (plant/animal source, amount of amino acids, amount of leucine and leucine distribution over a day) and dietary energy intake were calculated from four day estimated dietary records of (pre)sarcopenic participants of the enhance study (clinicaltrials.gov nct03649698) before and after a 12-week supplementation period. participants received an individualized protein supplement (resource® instant protein, nestlé) , to achieve a total (dietary + supplemental) intake of 1.5g protein/kg bw/d. results: 51 (pre)sarcopenic adults (73.61 ±6.47 years, 53% female) had an average dietary protein intake of 1.06 ±0.26 g/kg bw/d, which is higher than the rda, but below the 1.5g/kg bw/d recommended by experts. 20 (pre)sarcopenic adults were supplemented with protein powder, which improved the total protein intake to 1.55 ±0.26g/kg bw/d without affecting dietary protein or energy intake. moreover, supplementation increased the protein intake to at least 29 g protein/meal without affecting dietary intake. more than 60% of dietary protein intake was of animal origin. leucine intake at baseline was insufficient at all meals, but increased to at least 2.81 g at lunch and dinner by supplementation without affecting dietary leucine intake. conclusion: community-dwelling (pre)sarcopenic older people do not reach the recommended protein intake proposed by expert groups. individualized protein supplementation results in adequate intake of protein without substantial change in dietary intake. nutrition and dietetics, internal medicine, amsterdam university medical centers, amsterdam, the netherlands) background: weight loss is a main treatment goal in obese older adults with dm2. combined lifestyle interventions (cli) may be more effective in preserving muscle mass during weight loss. whether severe obese benefit similar to less obese is unknown. objectives: our probe-study showed an increase in muscle mass during cli in obese older adults (55+) with dm2. do severe obese (bmi > 35 kg/m2) benefit similarly to less obese. methods: in a post-hoc analysis, 97 out of 123 enrolled older adults had both body weight and protein intake data before and after a 3-month cli consisting of dietary advice (-600 kcal/day) and resistance exercise. a selection of assessments were appendicular skeletal muscle mass (asmm, by dxa), physical performance (wmax; by cycle ergometer steep ramp test), quality of life (rand-36 physical component summary score (pcs), visceral adipose tissue (vat, by dxa), crp, insulin sensitivity and resistance (matsuda, homa-ir; by ogtt), blood pressure (sbp, dbp). linear regression analysis was used with protein intake (g/kg, except for asmm being included in kg) as independent and assessments after 3-months as dependent (with assessment before intervention as confounder) for both groups bmi>35 (severe obese n=28) and bmi<=35 (n=69). results: mean age was 67, mean bmi was 33.3, sex 62m/35f and protein intake during intervention was 93+30 gram/day. mean weight loss was -2.6+2.9kg and fat loss -2.8+2.3kg. per 20g protein intake increase 175+62g muscle was preserved (p=0.006). however, this appeared 68+168 (p=0.686) vs 204+67g (p=0.003) for severe obese vs not severe obese. severe obese showed higher response for wmax (+60.9+26.3 (p=0.033) vs -4.3+8.3) and pcs (+10.5+5.3 (p=0.058) vs -1.7+1.7), for vat (-58.9+32.1 (p=0.079) vs +2.5+6.6) and crp (-2.5+1.4 (p=0.081) vs +0.3+1.3), for insulin sensitivity (matsuda +1.2+0.6 (p=0.044) vs +0.4+0.4) and insulin resistance (homa-ir -5.3+2.4 (p=0.034) vs +0.2+0.6), sbp (-19.1+9.4 (p=0.055) vs -1.3+4.2) and dbp (-16.7+6 .7 (p=0.022) vs +1.2+2.4). while whole group and not severe obese group showed no significant effect. conclusion: these results suggest that severe obese might benefit even more from combined lifestyle intervention compared to less obese older adults with dm2. further investigation is needed to confirm these findings and identify potential mechanisms. background: nutritional interventions have been shown to stimulate muscle protein synthesis. to optimize muscle mass preservation and gains, several factors, including type, dosage, frequency, timing, duration and compliance have to be considered. objectives: this systematic review and meta-analysis aimed to summarize these factors influencing the efficacy of nutritional interventions on muscle mass in older adults. methods: data sources: a systematic search was performed using the electronic databases medline, embase, cinahl, cochrane central register of controlled trials and sportdiscus, from inception date to 22nd november 2017, in accordance with the prisma guidelines. inclusion criteria included randomized controlled trials, mean/median age >=65 years and reporting muscle mass at baseline and post-intervention; exclusion criteria included genetically inherited diseases, anabolic drugs/hormone therapies, neuromuscular electrical stimulation, chronic kidney disease, kidney failure, neuromuscular disorders and cancer. data extraction: extracted data included study characteristics (population, sample size, age, sex), muscle mass measurements (method, measure, unit) , effect of the intervention versus the control group, and nutritional intervention factors i.e. type, composition, dose, duration, frequency, timing and compliance. data analysis: standardized mean differences and 95% confidence intervals were calculated from baseline to post-intervention for the intervention and control group. a meta-analysis was performed using a random-effects model and grouped by the type of intervention. results: twentyeight articles were included encompassing 2190 participants (mean age 75.7 years, sd 2.22). amino acids, creatine, betahydroxy-beta-methylbutyrate, and protein with amino acids supplementation significantly improved muscle mass. no effect was found for protein supplementation alone, protein and other components, and poly-unsaturated fatty acids. high inter-study variability was observed regarding the dose, duration and frequency, coupled with inconsistency in reporting timing and compliance. conclusion: overall, nutrition alone is an effective intervention to improve muscle mass in older adults. due to the substantial variability of the intervention factors among studies, the optimum profile is yet to be established. background: physical and functional capacities decline with age. one new potential intervention is oral citrulline supplementation (cit) since cit seems to increase muscle protein synthesis, mass, size and strength, improve mobility but also decrease adipose tissue mass, particularly visceral depot in old rats. furthermore, exercise is known to be another efficient intervention. however, studies assessing cit supplementation combined or not with exercise on muscle function and mobility in older human adults are emerging and literature conclusions are needed to help health professionals. objectives: establish the potential effectiveness of citrulline supplementation combined or not with exercise on muscle function and physical performance via a systematic review of randomized controlled trials (rcts) in human aged 50 years and older. methods: the preferred reporting items for systematic reviews and meta-analysis (prisma) statement has been followed. medline, cochrane central register for rcts and scopus databases have been searched. studies selection and data extraction have been performed by two researchers independently. methodological quality of each included studies was assessed using the quality assessment of diagnostic accuracy studies-2 (quadas-2) tool. results: based on prisma guideline, 103 references have been identified. among this number, only 6 rcts (250 participants) matched the inclusion criteria (e.g rcts, age>50yrs, human, cit supplementation, muscle or physical parameters) and were included in the systematic review. among these studies, 5/6 reported beneficial effects of cit on muscle mass. effects on muscle strength is reported on 4/6 studies but when cit is combined to exercise better improvements in upper muscle strength are observed. finally, 3/6 studies reported beneficial effect of cit on physical performance but suggested that cit with exercise displayed greater improvements in walking speed than exercise or cit alone. the overall quality of studies was rather high. conclusion: cit supplementation seems able to improve muscular and physical factors in specific elderly people (malnourished, women, hypertensive, obese, dynapenic-obese) compared to placebo. more importantly, cit with exercise is more efficient than exercise or cit alone. however, due to the small number (6) and heterogeneity (dose, duration, population) of the studies, further investigations are needed to confirm its promising intervention for health professionals. background: the medical nutrition supplement fortifit (r), containing the specific nutrient combination actisyn™, is designed to support muscle building in sarcopenia (muscle loss). actisyn (whey protein, leucine and vitamin d) provides high bioavailability of leucine and essential amino acids for the muscle; the nutrients in actisyn act together to optimize the muscle protein synthesis response in a state of sarcopenia where these nutrients are often deficient. preclinical and acute human studies confirmed this mode of action. objectives: to demonstrate the longer-term effects of fortifit supplementation on muscle building in healthy and sarcopenic older adults and on muscle preservation in obese (diabetic) older adults during a weight-loss lifestyle intervention. methods: our clinical research program investigated the effects on muscle mass, strength and function in healthy and sarcopenic older adults and in obese and type 2 diabetic patients. muscle mass was measured by dexa; strength and function by handgrip strength, 5-times chairstand test and short physical performance battery (sppb). all studies were randomized-controlled trials with an intervention duration of 6 to 13 weeks. results: a significant increase in appendicular lean mass and leg lean mass was observed in healthy older adults after 6 weeks supplementation (p<0.05 vs non-caloric control) [chanet, jnutr 2017]. in sarcopenic older adults, 13-week intervention increased appendicular lean mass (0.17kg, 95%ci 0.004-0.338kg; p=0.045 vs iso-caloric control) [bauer, jamda 2015] . moreover, during a 13-week lifestyle intervention of energy restriction and resistance exercise training in obese older adults with or without type 2 diabetes, fortifit preserved appendicular lean mass (p<0.05 vs iso-caloric control) [verreijen, ajcn 2015; memelink, clin nutr 2018] . a significant improvement was observed in chairstand time after 13-week intervention in sarcopenic older adults (-1.01s, 95%ci -1.77 to -0.19s; p=0.018 vs isocaloric control), but improvements in handgrip strength and sppb (primary outcomes) were only significant versus baseline (p<0.05) and not versus control [bauer, jamda 2015] . conclusion: the medical nutrition supplement fortifit effectively supports muscle building in healthy, sarcopenic and obese older adults. moreover, the improvement in chair-stand time observed in sarcopenic older adults is clinically relevant. background: chronic kidney disease (ckd) is commonly found in older persons and it affects the quality of life and economic burden. knowledge and health literacy have been reported as fundamental factors for persons with chronic illness to perform health behavior. however, from a literature review, relationships among knowledge, health literacy, and health behavior in older persons with non-dialysis ckd have rarely been reported. objectives: to examine relationships among knowledge, health literacy, and health behavior in older persons with chronic kidney disease. methods: nutbeam's conceptual framework of health literacy was used to guide the study. the sample recruited by purposive sampling consisted of 98 older persons with non-dialysis stage 4 to 5 ckd, who sought healthcare services at a ckd clinic in a university hospital, thailand. data were collected by interviews using the questionnaires about the demographic data, knowledge about care of ckd, health literacy, and health behavior of older persons with ckd and then were analyzed using descriptive statistics and spearman's rho correlation coefficients. results: the sample consisted of 52 men and 46 women with their age ranging from 60 to 88 years (m = 73.02, sd = 7.26). the analysis revealed that the sample had the mean scores of total knowledge about care of ckd, health literacy, and health behavior at a high level. health literacy was positively associated with health behavior (r = .30, p = .001), but knowledge about care of ckd was not significantly associated with health literacy (r = .13, p = .092), nor health behavior (r = .16, p = .057). conclusion: only health literacy was significantly positively related to health behavior. although knowledge is fundamental of health literacy, it was not significantly related to health literacy nor health behavior in this study. it is explained that health literacy is the ability and skills that might link knowledge of individuals to perform behaviors. thus, healthcare providers should find strategies for enhancing health literacy of older persons with ckd to promote appropriate health behavior, thereby delaying complications. background: handgrip strength (gs) is linked to the vitality domain of the intrinsic capacity (ic) construct and is a marker of sarcopenia and frailty. low gs is a predictor of adverse health outcomes like disability onset and mortality. small increases in gs have been reported after exercise interventions, suggesting that life-course determinants rather than short-term determinants influence gs. objectives: to assess social inequality in the distribution of gs and the association of gs levels with a proxy of social determinants of health (sdh) among adults and older adults. methods: secondary analysis from wave 1 (2007-2010) of the world health organization (who) study on global ageing and adult health (sage), which is nationally-representative of six countries, including 16,903 participants aged >=60 years and 20,168 <59y. gs was computed in kg. wealth quintiles were assigned according to ownership of household assets. the last level of education of the participant and his/her mother was self-reported (the latter was used as a marker of early life sdh). social inequality was estimated using pairwise comparisons among the average of gs of the extreme social groups; and gradient inequality by the slope index of inequality (multivariate linear regression to adjust for age, sex, body mass index). estimations were weighted to consider the complex design of the sample. results: average gs was 22.2 kg for participants >=60y and 29.8kg for <59y. participants >=60y who reported a postgraduate level of education or higher showed 51% (9.3kg) higher gs than their illiterate counterparts (34%, 8.0kg, for participants <59y). gs was on average 12% higher in participants >=60y in the most top wealth quintile compared to those in the lowest quintile (11% in <59y). in the multivariate models, gs was 2.5kg higher in urban than rural participants and 5.1kg higher among participants whose mothers had completed >=9 years of education compared to those whose mothers were illiterate. slope coefficients were significant after controlling for confounders. conclusion: grip strength displayed an unequal distribution among social groups and also among groups of early life exposures, which suggests that vitality as a domain of ic is shaped by the sdh and built through the life course. background: intrinsic capacity (ic) is the composite of the physical and mental abilities of an individual. the distribution and correlates of ic in older adults (oa) have not been reported using an integrative score with routinely-collected clinical data. it is not clear how ic is associated with multi-systemic biochemical age-related processes captured by alterations in standard clinical laboratory tests. objectives: to describe the distribution and correlates of ic in a population of older adults from the frailty day hospital of toulouse and to test its cross-sectional association with low or high haemoglobin or high crp, accounting for frailty status. methods: using routinely collected cross-sectional data of 2,324 first visits of oa aged 60+ to the frailty day clinic of toulouse (2011-2016), we calculated an index of ic (biomarkers and validated scales for five who domains). low/high haemoglobin levels or high crp levels served as indicators of acute and middleterm multisystem disruption. we used descriptive statistics to learn the distribution of ic across sex, age, education and fried frailty categories. multivariate linear models were used to test the hypothesis that higher ic holds a negative association with the multi-system deficits depicted by altered laboratory tests. results: 63% of the population was female, and 50% was frail. our ic score has theoretical limits (0-1). overall, the ic was: mean=0.65,sd=0.11,min=0.28, max=0.91. on average ic men scored 0.68 (ic95% 0.67, 0.69) and women 0.63 (ic95% 0.63, 0.64). the relationship found between ic and age was not linear. frail older adults displayed 25% less ic than their robust counterparts and 17% less ic than their pre-frail counterparts. if frail oa would return to robust in this population, the average ic would potentially* rise 19%. disruption in haemoglobin or crp was inversely and significantly associated with the ic score after adjusting for age2, sex, level of education and fried frailty status. conclusion: the population attending the toulouse frailty clinic displayed highly-heterogeneous ic levels, with frail oa showing significantly lower levels than robust oa. the association between ic and age is not linear. sex, age, education, frailty status and disruption in haemoglobin or crp levels were all significantly associated with ic in a multivariate model. background: older persons tend to be hospitalized increasingly because of the complex interaction among acute problems, age-related changed, and chronic diseases. qualified nursing care needs knowledge, understanding, and a positive attitude towards the care of older persons. however, little is known factors predict the caring behavior of nurses to care for hospitalized older persons. objectives: to examine the predictability of selected factors to explain intention to care and caring behavior for older persons of professional nurses. methods: the theory of reasoned action was used to guide the study. the proportionate stratified random sampling was used to recruit a sample of 150 professional nurses from clinical wards providing care for older patients in a university hospital. data were collected using 6 questionnaires and then, analyzed with descriptive statistics, pearson's product-moment correlation, and multiple regression analysis with the enter method. results: almost all of the sample were female, with their age ranged from 23 to 54 years (m = 30.4). factors related to professional nurses' intention to care were perceived caring climate in organization and attitude toward caring for older persons. also, factors related to caring behavior for older persons were perceived caring climate in an organization, intention to care, and attitude toward caring for older persons. through multiple regression analysis, perceived caring climate in an organization, attitude toward caring older persons, and basic knowledge about older persons jointly predicted 8.7% of the variance in intention to care. together, perceived caring climate in an organization, intention to care, attitude toward caring for older persons, and basic knowledge about older persons accounted for 32.3% of the variance in caring behavior for older persons of professional nurses. the perceived caring climate in an organization was the strongest predictor of caring behavior, whereas basic knowledge about older persons was not a significant predictor. conclusion: the findings support the notion of the theory of reasoned action. it is suggested that strategies to promote perceived caring climate in an organization, attitude toward caring for older persons, and intention to care should be established and maintained to promote caring behavior for older persons of professional nurses. background: environmental and social conditions play a major influence in the development and progression of negative health-related outcomes. they represent crucial elements when taking clinical decisions and planning the care plans of frail patients. nevertheless, they still often remain overlooked because priority is given to the clinical manifestations. objectives: the aim of this study is to explore the importance of social support in the definition of major health-related outcomes among hospitalized patients compared to other critical factors of older persons (i.e., frailty, age). methods: data were retrospectively collected from the medical records of patients aged 70 years and older admitted to the geriatric unit of the fondazione irccs ca' granda ospedale maggiore policlinico (milan, italy). a 42-items frailty index (fi) was computed from clinical variables recorded during the first days of hospitalization (i.e., medical history, cognitive, functional and social assessment, physical examination, laboratory tests). mortality, length of hospital stay above the median, and risk of institutionalization were the outcomes of interest. results: we included 87 patients (mean age 87.5, sd 6.3 years, women 75.9%). six patients died during the hospital stay (6.9%). the median duration of hospital stay was 12 (iqr 7-20) days. twenty-seven patients were discharged to other institutions (31%). the mean fi was 0.39 (sd 0.12). the fi showed a statistically borderline association with mortality (or 1.07, 95% c.i. 0.99-1.15, p=0.09), and was predictive of longer length of stay (or 1.05, 95% c.i. 1.00-1.09, p=0.05), even after adjustment for confounders. the presence of a caregiver was the only factor significantly associated with the discharge at home of patients (or 0.23, 95% c.i. 0.08-0.68, p=0.01) at the multivariate analysis. age had no significant association with the three studied outcomes. conclusion: health systems should be organized according to an integrated model of care in order to adequately address the complex health needs of older people. social and environmental context plays a critical role in determining the person's health trajectory. social factors (as the presence of a caregiver) may play a stronger role in clinical decisions than biological or clinical aspects. background: the acute therapy team was formulated after the integration of an older persons assessment and liaison team (opal) with medical ward therapists. the team was spread across all acute areas. this team worked closely with the acute geriatric and frailty clinical team and it was recognised that length of stay, and improved patient experience and overall outcomes would be improved with earlier assessment and cga planning at the front door allowing closer collaborative working between the clinicians and therapists. objectives: to enhance service improvement and prevent the impact of sarcopenia and frailty syndromes leading to greater hospital stay and disability as a consequence of a delay to assessment by clinicians and therapists in the acute setting. through the screening of frailty syndrome risk and sarcopenia risk patients by the ed geriatrician and junior doctor, there would be a speedier response to therapy led interventions thereby reducing the conversion rate from ed and also therefore improving overall outcomes in length of stay and reduced disability through prolonged hospital stay. methods: consultant geriatrician and junior doctor (opssu team) to go to the emergency department in the mornings and see up to 6 patients in cdu/a&e beds; the use of a the rockwood frailty score template identified those patients at risk of frailty syndrome and likely to benefit from early therapy intervention. these patients would have been highlighted as having the potential to be discharged within 24 hours. a 3 month data collection period from was chosen with data collected monday to friday only. data examined was categorised as follows: new patients, follow-ups; how many patients were seen on day of ed attendance vs after day of attendance?; number of patients seen by therapists same day of ed attendance number of patients not seen by therapists day of attendance; which team was looking after the patient from a clinically; how much time spent with patients; therapy led plan after initial assessment; an integrated assessment too was instrumental in the cga component of the therapy and clinical assessments. results: 88% of patients seen by therapists in ed are new patients referred. 28% of patients referred are seen on the actual date of ed attendance. the rest are seen later admission episode. 53% of therapy time is spent doing non-face to face tasks such as documentation. but up to 65% of patients have a discharge plan put in place after being seen by therapists in the ed. conclusion: a great deal of time is spent by therapists on documentation during assessment. this has a negative impact on the amount of time dedicated to clinical assessments and physiological and functional assessments required in the cga. there is a large number of patients referred by the clinical team to the therapists for review but a majority of patients are seen elsewhere during an admission episode and not in the ed. streamlined assessments and screening tools are recommended & planned for the future model of care. yi-chun cheng 1 , li-ning peng 1,2 ((1) center for geriatrics and gerontology, taipei veterans general hospital, taipei, taiwan; (2) aging and health research center, national yang ming university, taipei, taiwan) background: older people with frailty are at risk of adverse outcomes, such as falls, disability, hospital admission, long term care placement, poorer quality of life, and mortality, which denotes the importance of sarcopenia in the health care for older people, and integrated intervention program may prevent those. objectives: to evaluate the effectiveness of an integrated intervention program among those communitydwelling frail older people in north taiwan. methods: a total of 435 participants over 65 years old mild to moderate disability and mild cognitive impairment persons were recruited from a community-dwelling frail older people in north taiwan during august 2017 and july 2019, frail older people were invited for the study. a 12 weeks integrated intervention program was provided for all participants. they attended the 2 hours program once per two weeks and physical activity, high protein diet education, and cognitive stimulation activity were included in the integrated intervention program. comprehensive geriatric assessments were performed before and after the intervention program, including basic demographic data, risk for malnutrition (by mna-sf), mood condition (by gds-5), cognitive condition (by mmse), weakness (by handgrip strength), exhaustion (by self-report in chs) slowness (by gait speed) and time-up-go test. pretest on the 1st week before intervention and post-test on the 12th week to compare the difference between twice evaluate consequence. results: overall, 435 participants were identified as having pre-frailty (55.6%) and frailty ( background: low appendicular skeletal muscle mass (asm), an integral component of current sarcopenia definitions, is commonly measured using bioimpedance analysis (bia). bia equations for estimation of asm are not generalizable across population groups and instrument types, potentially giving rise to inaccurate results when applied inappropriately. there is a lack of bia prediction equations for asian populations, none of which have been developed or validated for singaporean older adults. objectives: to develop a bia prediction equation for estimation of asm in communitydwelling older singaporean adults. methods: we studied 230 healthy community-dwelling subjects (mean age 67.2 years) from the gerilabs-2 cohort. bia was performed using a single-frequency instrument. the reference method used for asm measurement was dual-energy x-ray absorptiometry (dxa). we first identified independent asm predictors by assessing the correlation of demographic, anthropometric and bia variables with dxa-measured asm. the best-fitting prediction equation was derived from these variables using stepwise (backward elimination and forward selection) linear regression with bootstrap validation. using asian working group for sarcopenia (awgs) cutoffs, we then compared anthropometric, strength and physical performance parameters between normal and low bia-derived asm groups. results: the derived bia equation incorporated 4 predictorsimpedance index, weight, gender and body mass index (bmi), i.e. asm(kg) = 2.098 + (0.155 x impedance index) + (0.202 x weight) + (-1.397 x gender) + (-0.252 x bmi), where males = 0, females = 1 and impedance index = height(cm2)/resistance. the r2 and standard error of the estimate of this regression model were 0.93 and 0.91kg respectively, with impedance index accounting for 87.3% of its variability. individuals with low bia-derived asm have significantly smaller mid-arm and calf circumference and weaker grip strength, compared to individuals with normal bia-derived asm (p<0.001). physical performance was similar in both groups. conclusion: we have developed a valid single-frequency bia prediction equation which can provide good estimates of asm in communitydwelling older singaporean adults. validation of this prediction equation in an independent sample of population is required to establish its accuracy and precision. (2) faculty of sport sciences, waseda university, tokorozawa, japan) background: it has been well known that appendicular lean mass (alm) and skeletal muscle mass index (smi), which is the ratio of alm to height 2 (m), is positively proportional to regional bone mineral density (bmd) in elderly men. however, there is limited information about these relationships in middleaged men. objectives: the purposes of this study were to investigate the difference in bmds (arms, lumbar spine, pelvis, legs, and subtotal: total body without head area) in middleaged men with low and normal smi (alm/height 2 ≤7.0 kg/ m 2 from asian working group for sarcopenia: awgs), and to determine the associations between alm, smi, and bmds. methods: three hundred and two middle-aged japanese men between 40 and 65 years of age participated in this study. alm and bmd measurements were taken using dual-energy x-ray absorptiometry (dxa, delphi a-qdr, hologic). results: based on the definition from awgs, the prevalence of low smi was approximately 7% in middle-aged men. the subjects with low smi (low smi group, n = 22, 6.6 kg/m 2 ) had significantly lower body weight (58.2 vs. 70.4 kg), bmi (19.9 vs. 23.9 kg/m 2 ), and fat mass (12.2 vs. 14.9 kg) compared to the normal group (n = 280, 8.2 kg/m 2 ), although there were no differences in age (51 vs. 52 years), standing height (170.9 vs. 171.4 cm), and body fat percentage (20.6 vs. 20.8 %) between the two groups. bmds were significantly lower in low smi group than normal group for regional body parts (arms 0.729 vs. 0.765 g/cm 2 ; lumbar spine 0.925 vs. 0.991 g/cm 2 ; pelvis 1.043 vs. 1.138 g/cm 2 ; legs 1.144 vs. 1.205 g/cm 2 ) and subtotal (0.916 vs. 0.972 g/cm 2 ). moreover, body weight, fat mass, alm, and smi were positively correlated with bmds using partial regression analysis controlling for age in all subjects, except for fat mass vs. lumbar spine bmd. in a stepwise multivariable model, alm was more closely related to bmds, except in the case of pelvis. conclusion: these results suggest that in order to maintain the regional bmd in middle-aged men, a key factor is to maintain or increase both alm and smi. background: the societies on sarcopenia have recently accepted the use of bioelectrical impedance analysis (bia) in the assessment of appendicular skeletal muscle mass (asm). several bia equations and devices have been introduced, which analyze the whole body composition, including the trunk and excluding the left arm and left leg at 50khz. it is necessary to measure the appendicular body segments of impedance parameters with a specific frequency (hz) that optimally analyze the muscle for valid assessment of asm. prior our study, literature-based bia equations and the two devices estimated asm at >75% of r2 (coefficient of determination) with the significant constant-errors rated as «poor». objectives: thus, the aims of this study were (1) externally cross-validate the equations and devices of bia on the appendicular skeletal muscle mass and (2) develop valid equations based on appendicular bioimpedance parameters at the specific frequency (khz) that reflects the muscle for estimating asm; methods: 201 community dwelling koreans over 70-year-old (77+4.4yrs, 107 females and 94 males) participated. asm was predicted using bia-based equations available in literature and bia devices and compared to dxa outcomes which is the gold standard. we conduct internal cross-validation and stepwise multiple linear regression to develop asmformulas with segmental multi-frequency bias. results: our new prediction formulas were developed by the appendicular impedance(z) index = height2 / (z of right arm + z of left arm + z of right leg + z of left leg)) at higher than 50khz and the appendicular reactance(xc) = xc of right arm + xc of left arm + xc of right leg + xc of left leg at 5khz. r2s were over 93%, see wes under 0.90kg of asm with the subject rating as «excellent» for men and «good» for women. conclusion: we found that our new protocol resulted in higher agreement with dxa and improved bia accuracy for this specific age group. clinicians can use this lower cost protocol and equations to better diagnose sarcopenia in larger cohorts with comparable to measurement of dxa. background: greater protein intake throughout the lifespan may be related to better body composition through the preservation of lean body mass during aging. objectives: we sought to determine whether an association between dietary protein intake (pi) and body fat percentage (bf) exists among women when controlling for dietary and lifestyle factors. methods: body composition and lean body mass were examined via dual-energy x-ray absorptiometry, grip strength (gs) was assessed using a hand grip dynamometer, and moderate-to-vigorous physical activity (mvpa) was measured by accelerometry. dietary intakes were estimated via threeday food logs and esha software. multiple linear regression and stepwise linear regression models were used. results: a total of 94 women (mean ± sd; age 40.6 ± 17.5 years) finished all assessments. a full regression model (i.e., containing all covariates; r = 0.863; adjusted r2 = 0.710; f(11,82) = 21.662; p < 0.001) was created using fat, carbohydrate, protein and leucine intake (g/day), protein quality (g/day of leucine over g/day of protein), energy intake (kcal/day), age (years), lean body mass (kg), bmi (kg/m2), gs (kg), and mvpa (min/day). only bmi (mean ± sem; beta = 1.244 ± 0.119; p < 0.001), gs (mean ± sem; beta = -0.401 ± 0.099; p < 0.001), and pi (mean ± sem; beta = -0.113 ± 0.048; p = 0.021) were significant to the full regression model. to verify their importance, a stepwise regression using the same variables was performed and resulted in a model (f(3,90) = 74.994; p < 0.001; r = 0.845; adjusted r2 = 0.714) that included bmi (mean ± sem; beta = 1.330 ± 0.093; p < 0.001), gs (mean ± sem; beta = -0.347 ± 0.079; p < 0.001), and pi (mean ± sem; beta = -0.048 ± 0.016; p = 0.003). conclusion: greater protein intakes are associated with lower bf in women when controlling for various covariates. we theorize that greater protein intakes preserve lean body mass which results in improved body composition. more specifically, a one gram per day increase in dietary protein is predicted to decrease bf by 0.113% when controlling for all other variables. background: muscle aging and the increased prevalence of obesity in the geriatric population create a new area of research: sarcopenic obesity. in prospective cohorts of nonhospitalized subjects, it is associated with an increased risk of developing physical limitation. hospitalization is an event with high risk of loss of independence. the impact of sarcopenic obesity during this episode isn't known yet. objectives: analyze the evolution of functional independence during a hospitalization in an acute geriatric ward, looking for a link between the presence of sarcopenic obesity and a decline of independence. early readmission, length of stay and changes in body composition during hospitalization were also examined. methods: prospective descriptive monocentric cohort study carried out in an acute geriatric ward of the pau hospital. sarcopenia was diagnosed using the european working group on sarcopenia in older people algorithm by an impedancemeter. a bmi over 30 was used to report obesity. functional independence was rated on the adl katz scale. results: 92 patients were included. sarcopenic obesity was diagnosed in 5.43% of cases, sarcopenia and obesity in 59% and 21% of patients, respectively. the greatest variation in functional independence during hospitalization was observed in sarcopenic obese patients (mean variation of 2 out of 6 points, p=0.046). a total of 15 early readmission at 1 month were counted, with the highest rate for sarcopenic obese (60%, but 16% at the sample level) (p=0.045). the average length of stay was 17.4 days. conclusion: sarcopenia is common in patients hospitalized in geriatrics, and when associated with obesity, there is greater variation in functional independence and more readmissions. background: known that is sarcopenic obesity, excessive accumulation of adipose tissue is detected, with a decrease in muscle mass and strength, which is already over the age of 30 years. modern diagnostic methods have their drawbacks for the diagnosis of sarcopenic obesity. bodpod quality and timeliness of diagnosis of signs of sarcopenia in obese patients is improved, which ultimately will contribute to an earlier targeted treatment of sarcopenia and an improvement in its prognosis. bodpod methodology can be recommended for use in complexes for the diagnosis of sarcopenic obesity. objectives: to compare the effectiveness of three methods of body composition assessment such as bioimpedans analysis (bia), air-replacement bodyplatismography (bodpod) and dual x-ray absorptiometry total body program (dxa total body) in the verification of reducing of skeletal muscle mass as sign of sarcopenic obesity in obese patients. methods: the study group included 95 patients aged 21-69 y.o. (average age 53,9±11,05 years) with bmi>=30.0 kg/m2. the control group included 37 patients aged 37-69 y.o (average age 50,73±10,6 years) of the same age without obesity with bmi 20.0-29.9 kg/m2. body composition was tested using bia, bodpod and dxa with calculating fat, lean and skeletal muscles mass (kg) and % in all the patients. (bodpod) is the most sensitive in the verification of skeletal muscle mass reduction in obese patients. this method shows that patients with obesity have a significantly reduced muscle mass compared with normal weight or overweight subjects. background: in overweight and obesity excess energy and changes in body composition may favor the onset of metabolic derangements. combined with excess adiposity, the age-related decline in lean body mass can accelerate the development of insulin resistance and the consequences in terms of cardiovascular risk. objectives: the aim of our study was to investigate the association between the phenotype of sarcopenic obesity and cardio-metabolic risk in postmenopausal women. methods: postmenopausal women were recruited among subjects admitted to the high specialization centre for the care of obesity (casco), at the sapienza university, rome, italy. fat mass (fm) and fat-free mass (ffm) were assessed by dxa. obesity was defined as body fat >= 35%. appendicular skeletal muscle mass (asmm) was calculated. sarcopenia was defined as asmm/weight < 2sd than the sex-specific mean of a young population. the cut-point was asmm/weight< 0.2347. the lipid accumulation product was calculated: lap = (waist circumference cm -58) × triglycerides mmol/l]. the estimated glucose disposal rate (egdr) was calculated. high-sensitivity c-reactive protein (hs-crp) was measured. results: 335 women were included (age: 58.7 ± 7.2 years, bmi: 37.1 ± 6.3 kg/m2). sarcopenia was diagnosed in 57.6% of study participants. sarcopenic obese women were older than nonsarcopenic women (59.4 ± 6.7 vs. 57.7 ± 7.7 years, p=0.04). lap was higher in sarcopenic obese women compared to their nonsarcopenic counterparts (96.8 ± 51.3 vs. 87.7 ± 55.8, p=0.03) after adjustment for age, body fat, and hs-crp levels. estimated gdr was significantly lower in sarcopenic obese women (4.02 ± 2.28 vs. 5.55 ± 2.36, p=0.03) after adjustment for age and body fat. an inverse association emerged between the index of sarcopenia, asm/weight, and lap (beta: -3.9*10-5, se: 1.9*10-5, p=0.03), independent of age, body fat, and hs-crp levels. a positive association was observed between asm/weight and egdr (beta: 1.4*10-3, se:4.7*10-4, p=0.004) adjusting for age, body fat, and hs-crp levels. conclusion: postmenopausal sarcopenic obese women exibithed a high lap and a low egdr, indicating increased cardiometabolic risk and decreased insulin sensitivity, respectively. l e a t h a a . c l a r k 1 , 4 , 5 , todd m. manini 2 , nathan p. wages 1,5 , janet e. s i m o n 1,3 , d a v i d w . r u s s 1,3 , b r i a n c . c l a r k 1,4,5,6 ( (1) background: muscle weakness strongly contributes to mobility limitations and physical disability. the role of neural mechanisms contributing to age-related weakness have not been fully delineated to sufficiently target interventions that enhance strength and physical function in older adults. objectives: we sought to compare differences in voluntary inactivation and measures of motor corticospinal excitability in older adults with clinically meaningful muscle weakness compared to young adults and stronger adults without muscle weakness. methods: maximal voluntary isokinetic and isometric leg extensor strength, electrical stimulation of the leg extensors, and transcranial magnetic stimulation (tms) of the motor cortex were performed in older adults and young adults. outcome measures of leg extensor strength relative to body weight, voluntary inactivation (via), motor evoked potential (mep) amplitude and silent period (sp) duration during isometric leg extension contractions at 5%, 20%, and 40% of maximum voluntary contraction (mvc) were obtained. older adults were classified into three weakness groups based on previously established isokinetic leg strength/ body weight cut points (severely weak, moderately weak, or not weak). group differences were examined after controlling for sex. results: the older adults had 63% lower isokinetic strength/body weight when compared to the young adults. the severely weak older adults were 33% and 84% weaker than the moderately weak and older adults who were not weak, respectively. severely weak older adults exhibited higher levels of leg extensor via than older adults who were not weak (14.2+1.7% vs. 6.1+1.8%). severely weak older adults exhibited 24% longer sp's compared to the older adults who were not weak, but this difference was not statistically significant (p=0.06). the severely weak older adults' mep's were approximately half the amplitude of the older adults who were not weak. regression analyses demonstrated that mep amplitude and sp duration -indices of hypoexcitability-were associated with relative strength. conclusion: weak older adults have significant deficits in their nervous systems' ability to fully activate their leg extensor muscles. additionally, motor corticospinal hypoexcitability is associated with age-related weakness, suggesting that interventions targeting the nervous system could be used to enhance muscle strength and prevent future health risks in older adults with muscle weakness. model. results: we evidenced oxidative stress in a mouse model of the pathology at different ages (4, 10 and 15 months) and aimed to identify the consequences of opa1 inactivation on redox homeostasis. increased ros levels were observed in cortices of the murine model opa1+/-as well as in opa1 down-regulated cortical neurons. this increase is associated to a decline in mitochondrial respiration and an increase of antioxidant enzyme levels. upon exogenous oxidative stress opa1-depleted neurons did not further up-regulated antioxidant defenses. finally, low levels of antioxidant enzymes were observed in fibroblasts from patients supporting their role as modifier factors. moreover, the simulations obtained with our mathematical model of complex i are able to reproduce biological experiments of quantification of ros production by complex i. conclusion: our study shows: (i) the prooxidative state induced by opa1 loss can be considered as a pathological mechanism (ii) differences in antioxidant defenses can contribute to the variability in expressivity and (iii) antioxidant defenses can be used as prognostic tools to gauge the severity and the evolution of the disease. (iv) furthermore, our mathematical model model of ros porduction by complex i will help to understand the dysfunctions of oxidative metabolism in opa1 gene related disorders. we will present the last results of our algorithm and wet laboratories experiments. amanika kumar, deepa m narasimhulu, michaela e. mcgree, amy l.weaver, aminah jatoi, nathan k lebrasseur (mayo clinic, rochester, mn, usa) background: patients with advanced ovarian cancer (eoc) are often frail and require multi-agent chemotherapy. objective: to evaluate the relationship between frailty and adjuvant chemotherapy tolerance and toxicity among women with advanced epithelial ovarian cancer. methods: women who underwent primary debulking surgery for stage iiic or iv eoc and received adjuvant chemotherapy at the same institution were identified. a frailty deficit index (fi) was derived from 30 items representing comorbidities and activities of daily living. frailty was defined as a fi ≥0.15. if data were unavailable for frailty index calculation, patients were excluded. relative dose intensity (rdi) for carboplatin and paclitaxel was calculated as the percentage of the standard dose that was actually administered and compared between frail and non-frail using the wilcoxon rank sum test. results: of the 169 women who met inclusion criteria, 17.2% (29/169) were frail. frail women were older (67.9 vs 62.3 years, p=0.01), had a higher bmi (29.6 vs 25.7 kg/m2, p=0.003), and were more likely to have american society of anesthesiologists (asa) score ≥3 (65.5 vs 35.0%, p=0.002) compared to nonfrail women. frail patients were less likely to complete 6 cycles of adjuvant chemotherapy, (76% versus 94%, p<0.008). despite the decrease in total cycles of chemotherapy, we did not observe significant differences in dose delays (34.5 vs. 42.1%), dose reductions (65.5 vs 68.6%), and severe neutropenia (44.8 vs. 39.3%) between frail and non-frail women. we analyzed a subset of 96 patients (19 frail and 77 non-frail) women received both intravenous carboplatin and paclitaxel. we observed that frail women were less likely to have a carboplatin rdi of 85% or higher (15.8% vs. 66.2%, p<0.001) and less likely to have a paclitaxel rdi of 85% or higher (57.9% vs. 80.5%, p=0.07). conclusion: frail women with advanced eoc undergoing adjuvant chemotherapy receive reduced rdi and are less likely to complete 6 cycles of chemotherapy despite no increase in dose reduction, delays, and neutropenia. physician bias and patient choice may influence chemotherapy intensity decisions. further studies are needed to explore the association between frailty, chemotherapy, and survival. background: gait speed is a core component of physical frailty (pf) and, as a single measure, is correlated with important health outcomes, including mortality. immune dysregulation has been previously associated with pf -including increased il-6 production in peripheral blood mononuclear cell (pbmc) lipopolysaccharide (lps) stimulation assays. it is not known whether gait speed is associated with lps-stimulated cytokine production. objectives: this pilot study evaluated whether gait speed is correlated with dysregulated immune response in two populations of older adults undergoing procedures -knee osteoarthritis (oa) scheduled for knee replacement, and chronic kidney disease (ckd) approaching hemodialysis initiation. methods: 10 older adults with ckd and 11 older adults with knee oa underwent preoperative evaluation including gait speed (usual pace, 4-meter walk, best of two trials) and immune stimulation testing (in vitro, thawed pbmcs stimulated with lps at doses 0, 0.1, and 10 ug/ml, with il-6 quantified by elisa at 2, 18, 24, and 48 hours; reported as area under the curve (auc)). correlation coefficient and p-value were calculated. results: for ckd, the il-6 auc of lps stimulated pbmcs was negatively associated with gait speed (lps 0.1 ug/ml r = -0.286, p=0.423; lps 10ug/ml r= -0.515, p=0.128). for oa, the correlation between il6 auc and gait speed was positively correlated for lps dose 0.1 ug/ml (lps 0.1 ug/ml r = 0.228, p=0.501; lps 10ug/ml r= 0.062, p=0.857). none of these associations were statistically significant. similar results were obtained when age was included as a covariate. conclusion: in people with ckd, increased cytokine production was correlated with decreased gait speed. in people with knee oa, results do not support this hypothesis. further studies with larger sample size are warranted. for participants with knee oa, future studies should account for severity of knee pain at time of gait speed assessment. background: skeletal muscle drives fuel utilization, and carbohydrate (cho) is a major fuel source. metabolic flexibility describes the ability to balance cho and fat oxidation efficiently in response to changes in metabolic demands or conditions. despite its role in long-term metabolic health, little is known about cho oxidation or metabolic flexibility in sarcopenic older adults. objectives: to examine resting metabolism and metabolic flexibility from a fasted to fed state after a cho-rich meal in sarcopenic versus nonsarcopenic older adults. methods: twenty-two men and women (age ± sd=77±9 y) were enrolled into this pilot study with either normal (non-sarcopenic, n=11) or low (sarcopenic, n=11) handgrip strength, gait speed and relative skeletal muscle index. resting metabolism was assessed in a fasted state at baseline, and metabolic flexibility was assessed after (180 min, post-prandial) consuming a meal containing 9 g of fat, 6 g of protein, and 51 g of a rapidly-digestible cho. respiratory quotient (rq), cho, and fat oxidation were measured with open-circuit spirometry, indirect calorimetry. fat and fat-free mass were measured with dual x-ray absorptiometry. blood glucose was assessed from venous samples using glucose oxidase methodology. results: rq was 5-9% higher (p=0.02-0.04) in sarcopenic participants throughout the experiment. after adjusting for fat-free mass, fat oxidation was 18% lower (p=0.02), while cho oxidation was 18% higher (p=0.04) at baseline for sarcopenic men and women. sarcopenic participants also exhibited delayed and limited (p<0.05) postprandial increases in cho oxidation, despite greater (p<0.05) increases in blood glucose. conclusion: sarcopenic individuals are more reliant on cho and less reliant on fat oxidation than non-sarcopenic adults, which is generally consistent with poorer metabolic health. when compared to non-sarcopenic adults, sarcopenia delayed and truncated cho utilization after a meal, indicating impaired metabolic flexibility in this population. impaired metabolic flexibility could be a mechanism underlying the losses of strength and physical function accompanying sarcopenia. anton de spiegeleer 1,2,3 , hasan kahya 1,2 , nele van den noortgate 2 , evelien wynendaele 3 , tine decruy 1 , srinath govindarajan 1 , dirk elewaut 1 ((1) unit for molecular immunology and inflammation, vib-center for inflammation research, ghent, belgium; (2) department of geriatrics, faculty of medicine and health sciences, ghent university hospital, ghent, belgium; (3) drug quality and registration (druquar) group, faculty of pharmaceutical sciences, ghent university, ghent, belgium) background: acute and chronic muscle wasting represent an important unmet clinical health problem. most pathophysiological studies suggest an effect of the immune system, primarily through catabolic cytokine productions such as il-6. also endoplasmic reticulum (er) stress is considered to be an important pathway favouring muscle wasting. er stress in turn plays an important role in innate-like t cells, particularly invariant natural killer t cells (inkt cells), by controlling their cytokine production [govindarajan et al., nat. commun. 2018 ]. as such we reasoned that inkt cells may play a pivotal role in muscle homeostasis through their excessive cytokine production. previous studies have already highlighted the importance of these cells in a wide range of diseases such as cancer and metabolic disorders such as obesity. objectives: the aim of this study was to investigate the in vivo role of inkt cells in muscle homeostasis. methods: we compared wild-type (wt) versus inkt cell depleted mice (jα18 ko) for clinical, histological and gene expression differences in lower limb skeletal muscle. results: interestingly, we found that inkt cell depleted mice (jα18 ko) had a lower relative muscle weight, i.e. a muscle wasting phenotype, compared to wt mice. this clinical muscle wasting was associated with a decrease in oxidative enzymatic activity (succinate dehydrogenase histology). moreover jα18 ko mice showed a decreased transcription of genes involved in skeletal muscle growth and differentiation (follistatin and myogenin), sarcomere assembly (myosin-3) and neuromuscular junction function (neuronal acetylcholine receptor subunit alpha-1). conclusion: taken together, our results suggest a role for inkt cells in muscle wasting diseases and put innate-like t cells at the centre stage of immune cells controlling skeletal muscle biology. a r m a n d a t e i x e i r a -g o m e s 1 , 2 , s o l a n g e costa 1,2 , bruna lage 1,2 , dietmar fuchs 3 , vanessa valdiglesias 1,4 , blanca laffon 4 , joão paulo teixeira 1,2 ( (1) background: frailty is a multidimensional geriatric syndrome characterised by increased vulnerability and functional decline that may be reversed if addressed early. it has been identified to be the most common condition leading to disability, institutionalisation and death in older adults. despite its known biological basis, no particular biological trait has been consistently associated with frailty syndrome so far. objectives: on this basis, the main objective of the present work was to evaluate the possible association between immunological: biomarkers and the frailty status in a group of community dwellers. methods: a group of older adults (>=65 years old) was engaged in this study. frailty status was assessed via fried's frailty model. the levels of several immune activation molecules -neopterin, tryptophan, kynurenine -were analysed. results: the classification of the study population was 47.5% robust, 49.2% pre-frail and 3.3% frail. no significant differences were found between robust and pre-frail groups regarding serum concentrations of neopterin. although, the kynurenine/tryptophan ratio was significantly higher in pre-frail individuals as compared with robust subjects. conclusion: the preliminary data obtained suggest the activation of immunobiochemical pathways and are in agreement with previous studies that report alterations of the immune response in frail older adults. nevertheless, further investigation is encouraged and required to consistently demonstrate these findings. in future studies physical activity, nutritional, psychological, sociological and clinical features should also be considered when evaluating changes in immune biomarkers and frailty. the work developed by armanda teixeira-gomes and solange costa is supported by fct under the grants sfrh/bd/121802/2016 and sfrh/ bpd/100948/2014, respectively. vanessa valdiglesias was supported by beatriz galindo research fellowship beagal18/00142. background: frailty and hemoglobin count, above what would be considered clinical anemia, are two common findings in older patients and lead to an increased risk of negative health outcomes. objectives: evaluate whether hemoglobin concentration is an independent predictor of frailty and investigate possibe causal pathways in particuliar the relationship between inflammation and nutrition with hemoglobin concentration. methods: 1829 communitydwelling participants aged 65 years or older who visited the toulouse frailty clinic between 2011 and 2016 were included in this analysis. patients underwent a comprehensive geriatric assessment and had a blood sample. a series of multivariate logistic regression models were perfomed after minimizing potential influence from age, gender, kidney function, inflammation, cognition, nutritionnal status and certain socioeconomic factors. results: hemoglobin count and frailty are significantly associated after minimizing potential influence from other covariates (p<0.005). an increase in one point of hemoglobin concentration is associated with a 14% risk decrease of being frail (or=0.79, 95%ic=0.71-0.89). there were no evidences of significant impact of inflammation and nutritional status in the relationship between hemoglobin concentration and frailty status (p>0.005). conclusion: hemoglobin concentration is strongly associated with frailty in older adults. these results can have potentially important implications for prevention policies targeting frailty, by identifying potential patients with high risk of adverse outcomes and functional outcomes. juliette tavenier 1 , line jee hartmann rasmussen 1 , jan nehlin 1 , morten baltzer houlind 1 , aino leegaard andersen 1 , ove andersen 1 , janne petersen 1,2 , anne langkilde 1 ( (1) background: chronic inflammation is thought to be involved in the development of frailty. we hypothesized that increased monocyte inflammatory activity plays a role in chronic inflammation and thereby in frailty. objectives: to study the potential role of chronic monocyte inflammatory activity in frailty. methods: two groups of elderly adults (>=65 years) were included: 52 patients with a recent admission to the emergency department (ed) and 52 age-and sex-matched controls, without recent ed admission. data was collected at baseline and after 1 year. participants were considered frail if they had 2 or more of the following: hand grip strength ≤26 kg for men or ≤16 kg for women, gait speed ≤0.76 m/s, unintentional weight loss of >1kg within the last 3 months. frailty was also assessed using the frailty index (fi)-outref. we measured cognitive function (mini mental state examination -mmse) and chronic inflammation (soluble urokinase plasminogen activator receptor -supar). monocyte inflammatory activity was assessed by nf-κb phosphorylation (pnf-κb) using flow cytometry. results: participants had a mean age of 76.6 years (range: 65.8-92.2) and 48% were women. preliminary results show that at baseline, the patient group had a greater proportion of frail individuals compared to the control group (21 vs. 1, p<0.0001). fi-outref was on average 1.5 points higher (p<0.0001) and supar levels 35% higher (p<0.0001) in the patient group, however, there was no difference in mmse score between the groups (p=0.17). at 1 year, although the proportion of frail individuals decreased in the patient group, it was still greater than in the control group (9 vs. 3, p=0.04). fi-outref remained elevated in the patient group (p=0.004), but there was no difference in supar levels (p=0.70). pnf-κb was positively associated with age in the control group (p=0.002), but not in the patient group (p=0.45). pnf-κb was 53% higher in the patient group compared to the control group (p<0.0001), and this was unchanged when adjusting for frailty, supar, and mmse. conclusion: the patient group was more frail and had elevated monocyte inflammatory activity compared to the control group. however, none of the frailty measures were confounders for the difference in monocyte inflammatory activity between groups. background: aging is most often accompanied by a loss of body weight: a decrease of fat deposits and muscle body weight. body mass index (bmi) in adults is considered normal if it is in the range of 18.5 to 24.9 kg / m2 (according to the who classification). bmi is widely used in the diagnosis of obesity. the association of bmi and cardiovascular and cerebrovascular diseases is known. objectives: the purpose of research is to identify the relationship of bmi with physical abilities and cognitive functions in long-livers. methods: 75 long-living subjects aged 93.7 ± 2.8 years were examined. in long-livers, height, body weight were measured, calculated bmi. the level and direction of cognitive disturbances was determined by the mmse test (mini mental state examination). physical abilities were determined by the questionnaire and physical tests (tests the muscular strength in forearms and of the hands, chair stand test). results: bmi in long-livers had a normal distribution. the median bmi was 24.7 kg / m2, the minimum value was 11.4 kg / m2, and the maximum value was 42.4 kg / m2. 37.9% of long-livers had a bmi ranging from 18.5 to 24.9 kg / m2. 34.8% of long-livers have lost weight during the past year, including 37.5% by 10 kg or more. 84.1% of long-livers could stand up of the chair. however, only 39.4% of long-livers were able to complete the test correctly. amongst them, 42.3% had a normal bmi. indicators of muscular strength in forearms and of the hand in long-livers who completed the chair stand test were significantly higher compared to long-livers who did not completed the chair stand test (r = 0.31, p <0.01). bmi had a positive correlation with the ability of a long-lived to wash without anyone's help (r = 0.24, p <0.05), go up and down the stairs (r = 0.30, p <0.05), do light housework (r = 0.44, p <0.001). mmse indicators also positively correlated with bmi (r = 0.54, p <0.001). the average mmse 27.8 ± 1.5 was observed with average bmi 26.1 ± 2.7. conclusion: against the background of a decrease in the bmi indicator in long-livers, a decrease in physical abilities and cognitive functions is observed. however, there is a problem in determining the boundaries of the ratio of height and body weight for elderly people. in all likelihood, there are not linear, but more complex dependencies between bmi and functional abilities of long-livers. suparb aree-ue 1 , inthira roopsawang 1 , jansudaphan boontham 2 , surinrat baurangtheinthong 2 , yuwadee phiboonleetrakun 2 ((1) ramathibodi school of nursing, faculty of medicine ramathibodi hospital, mahidol university, bkk, thailand; (2) faculty of graduate studies, mahidol university, bkk, thailand) background: depressive symptom results in increasing poor outcomes and care dependency in older adults. the prevalence of depressive symptoms is common with its associated multiple factors. however, this conundrum problem is underestimated, particularly in older people living in rural areas. to promote healthy aging, understanding of the conundrum problem is essential in strengthening care quality and enhancing the quality of life in this population. objectives: to determine the relationships of the number of medication use, pain, frailty, and locomotive syndrome and their effects on depressive symptoms among community-dwelling thai older adults. methods: a cross-sectional study was employed. the sample consisted of 310 community-dwelling thai older adults who met the inclusion criteria. data were assessed by using demographics questionnaire, thai version 25-question geriatric locomotive function scale: glfs-25; numeric rating scale; the reported edmonton frailty scale: refs-thai version; and the 15-item geriatric depression scale, tgds-15. a path analysis was employed to determine the pathways linking the number of medication use, pain, locomotive syndrome, frailty to influence depressive symptoms. results: there were significant positive direct paths from pain (beta = 2.78, p <.001) to locomotive syndrome and from locomotive syndrome to the number of medication use (beta = -.03, p <.01). an inversely, the locomotive syndrome was a negative significant direct to depressive symptoms (beta = -.06, p <.01). pain had an indirect effect on depressive symptoms (beta = -.17, p <.01). additionally, the model explained 30.8% of the variability in depressive symptoms. conclusion: the locomotive syndrome is a major factor influencing depressive symptoms. the complex relationship among pain, number of medication use, locomotive syndrome, and depressive symptoms should be taken into account for designing an appropriate intervention to reduce depressive symptoms among community-dwelling thai older adults. background: total knee arthroplasty (tka) is a clinical curative treatment for severe knee osteoarthritis. however, the outcomes are differences in each patient's perception. preoperative patients' expectations to functional abilities are one of important factors influencing on postoperative outcomes and satisfaction. objectives: to investigate the association among preoperative patients' expectations, postoperative functional abilities, and satisfaction to functional abilities among older adults undergoing tka at 6-week after surgery. methods: participants were 97 older adults who were diagnosed with knee osteoarthritis and required to receive tka at a university hospital in bangkok, thailand. the sample was purposely selected based on the following criteria: were aged 60 years or over, received tka for the first time, and had no cognitive impairment. the data were collected at preoperative and postoperative tka by using the demographic data questionnaire, the hospital for special surgery knee replacement expectations survey, and the knee and osteoarthritis outcome score in the part of function in daily living (koos adl) thai version. the data analysis was performed by using descriptive statistics, paired t-test, and pearson product moment correlation coefficient. results: before surgery, patients' expectations to postoperative functional abilities had a high level with the total mean score of 70.21 (sd =13.86), and the item of improving ability to walk in a short distance was rated as the highest expectation. at 6-week after surgery, the overall functional ability had a significant improvement (t = -9.229, p = .000). satisfaction to functional ability also had a high level (mean ± sd = 71.15 ± 14.73), and the improving ability to walk in a short distance item had the highest. patients' expectations to functional abilities had a significantly low positive correlation to postoperative functional ability and satisfaction (r = .273, p < .05; r = .292, p < .01, respectively). moreover, there was a significant moderate positive correlation between functional abilities and satisfaction to functional abilities (r = .603, p < .01). conclusion: a better understanding of expectations may be beneficial in gaining knowledge, paving expectations on possible outcomes, and developing trust resulting in enhancing quality of care for thai older adults undergoing tka. background: identifying low muscle strength is a key step in many operational definitions of sarcopenia including the one recently proposed by the european working group on sarcopenia in older people-2 (ewgsop2). grip strength is widely used to identify people with low muscle strength. however, it is unclear what impact variation in the type of hand-held dynamometer used to measure grip strength has on the prevalence of low muscle strength. objectives: we aimed to assess the impact of estimated differences of between 4 and 5kg in the measurement of grip strength when using different types of hand-held dynamometer on the case-finding of low muscle strength. methods: study participants were 118 men and women aged 45-74 from a randomised, repeated measurements cross-over trial. maximum grip strength was assessed using four hand-held dynamometers (jamar hydraulic; jamar plus+ digital; nottingham electronic; smedley) in a randomly allocated order. ewgsop2 recommended cutpoints (<27kg men; <16kg women) were applied to estimate prevalence of low muscle strength for each device. agreement between devices was assessed using kappa statistics. results: prevalence of low muscle strength varied by dynamometer type ranging between 3% and 22% for men and, 3% and 15% for women. of the 13 men identified as having low muscle strength by at least one of the four dynamometers, only 8% were identified by all four and 54% by just one. of the 15 women classified as having low muscle strength by at least one of the four dynamometers, only 7% were identified by all four and 67% by only one. when comparing pairs of devices, kappa statistics ranged from 0.13 to 0.55 suggesting poor to moderate agreement. conclusion: case-finding of low muscle strength is influenced by the type of hand-held dynamometer used. it is important to identify the sources of variation in the measurement of grip strength and consider the implications of these for sarcopenia. further research is required to understand how best to standardise the assessment of each of the different components of commonly used operational definitions of sarcopenia and take account of sources of variation in these measures where standardisation cannot be achieved. background: sarcopenia is characterized by a progressive loss of skeletal muscle mass and strength associated with mortality and severe adverse events on health. for a healthy aging, the quality of life (qol) is essential and it is associated to autonomy of persons, social relations, and socioeconomic factors. objectives: to compare the qol of chilean older people with sarcopenia living in santiago de chile, according to an adapted version of the european working group on sarcopenia. methods: 562 community-dwelling older people (mean ± sd: 69.8 ± 6.2 years; 72.1% females) were interviewed, registering self-reported chronic diseases and the questions of short-form-12 health survey (sf-12). anthropometry, dynamometry and physical performance were measured. qol was measured using sf-12, validated in chilean older adults. norm-based score of 8 subscales and two summaries components -mental and physical (mcs and pcs; respectively)-were calculated using the chilean-specificscoring for older people. low score was defined as having a score ≤ 25th percentile of mcs and pcs. logistic regressions were estimated. results: sarcopenia was identified in 20.5% of the sample (20.5% women; 20.4% men; p=0.966). the average score of the 8 subscales were significantly higher in non-sarcopenic adults than sarcopenic. the average of mcs and pcs were also significantly higher in non-sarcopenic adults than sarcopenic (mcs: 48.2 vs 46.1; p=0.006; respectively; pcs: 47.2 vs 44.8; p<0.0001; respectively), and were significantly higher in men than women non-sarcopenic (mcs: 49.7 vs 47.7; p=0.006; respectively; pcs: 47.7 vs 47.1, p=0.0287; respectively). there were non-significant differences in sarcopenic adults by sex. logistic regressions demonstrated an association between sarcopenia and low mcs and pcs (or = 3.27; 95%ci: 1.77 -6.04; or = 2.70; 95%ci: 1.48 -4.93; respectively), adjusted by age, sex, multimorbidity, body mass index and lean/fat mass ratio. conclusion: sarcopenia was associated with a worse quality of life, which shows the impact of this pathology and the importance of developing programs for its prevention, delay or reversal. funded by fondef15i10053 p271-munich sarcopenia registry (idsar): first results. uta ferrari 1,3 , marina schraml 1 , ralf schmidmaier 1,3 , navina röcker 1,3 , sigrid adler-reichel 1,3 , christian lottspeich 1,3 , martin bidlingmaier 1,3 , benedikt schoser 1,3 , sabine krause 1,3 , martin reincke 1,3 , michael drey 1,3 ((1) department of medicine iv, university hospital, lmu munich, germany; (2) friedrich baur institute at the department of neurology, university hospital, lmu munich, germany; (3) preventive geriatrics study group, germany) background: since 2018 sarcopenia can be coded as disease in germany (icd-gm 62.50). in the same year we established the first sarcopenia registry linked with a biobank to identify modifiable, crucial risk factors for sarcopenia and its adverse outcomes. objectives: objectives of the registry are (i) how to optimize and standardize the diagnosis over in-and outpatient settings for musculoskeletal health, (ii) identification of clinical and molecular modifiable risk factors (iii) improvement of interdisciplinary treatment and prevention of sarcopenia as a new icd-code-based geriatric syndrome here we present the design as a practical approach for diagnosis in out-and inpatient care and a first descriptive analysis of influencing factors and comparison between in-and outpatients data. methods: patients older than 70 years of age from outpatient clinic and acute geriatric ward at munich university hospital were consecutively screened by the sarc-f questionnaire. patients with high risk (sarc-f score >= 4) were further assessed for sarcopenia in line with the european consensus definition 2 (ewgsop2). among further factors assessed in the registry, we retrieved presence of further comorbidities, daily medication, nutritional status, sppb, frailty, and quality of life. results: at time of analysis, 282 patients have been screened and within the first 50 patients with high risk (82% women) 16% had sarcopenia. patients screened positive for sarcopenia have lower quality of life, even in a subclinical condition (mean euroqol (eq5d-vas) = 47.4±16.5). lower bmi (22.1±2.8, p=0.010) and sex (p=0.029) were statistically significant different for sarcopenia status, but not age (mean 78.5±5.2 years, p=0.326) or number of medication (p=0.691) and comorbidities (p=0.691). but the latter two were the most significant factors for inpatient status (both p<0.001). the results underline the need for an early screening for sarcopenia in all patients older than 70 years of age, suggested by hand grip strength in inpatients and sarc-f for outpatients. sex differences and further laboratory factors are necessary to add in sarcopenia diagnosis for precision medicine approaches. hospitalised older adults. we consider acute sarcopenia to be the last remaining acute organ insufficiency, with potentially devastating impact on function. characterising this condition will enable development of targeted interventions to ameliorate these changes. mobility disability, and incident mobility disability over 2.2 + 0.3 years. factor 1 was associated with incident and prevalent mobility disability only, and factor 2 was associated with only prevalent mobility disability. conclusion: muscle mass by d3cr co-segregated with strength and physical performance measures, and together was associated with mobility and disability outcomes in older men. body composition measures (including dxa alm) did not co-segregate with strength and physical performance measures and together was associated with only mobility disability. background: currently, there are no registered drug treatments for the loss of skeletal muscle mass, strength and function that occurs during sarcopenia and cachexia. moreover, they are only limited relevant pharmacological screening options available. objectives: to improve in vitro pharmacological screening options, we developed a model of muscle wasting using donor primary muscle cells and our myoscreen™ platform that generates standardized myotubes for high-throughput phenotypic screening (young et al., slas discov. 2018 23(8) :790-806). methods: myoblasts from four donors aged 4, 20, 37 and 68 years were compared in terms of proliferation, differentiation, size of formed myotubes and achr cluster formation using imaging and high content analysis. we then established an assay for muscle wasting: in each of the four donors various molecular pathways implicated in the pathogenesis of sarcopenia were activated using tnfa, tgfb or dexamethasone. results: myotubes formed from elderly patient's myoblasts displayed a reduced capacity to proliferate and differentiate, thinner myotubes and fewer acetylcholine receptor clusters. therefore, myotubes cultured using the myoscreen system continue to reflect age-related properties of donor muscle. interestingly, we also found that myotube sensitivity to atrophy stimulation increased with increasing age. myotubes were then co-incubated with growth/ repair factor igf-1 or hdac inhibitor, trichostatin a (tsa). both agents attenuated tnfa-induced myotube atrophy and differentiation inhibition in a dose-dependent manner. the extent of fusion index and myotube size increase was highest in myotubes from elderly subjects while myotubes from young subjects were more resistant to the protective effects of igf-1 and tsa. conclusion: myoscreen can be exploited to quantify age-dependent modifications in skeletal muscle fibers in vitro and identify candidate compounds that counteract the muscle wasting phenotype. andreas friedberger 1 , alexandra grimm 1 , wolfgang kemmler 1 , klaus engelke 1,2 ((1) institute of medical physics, friedrich-alexander-universität erlangen-nürnberg, erlangen, germany; (2) department of internal medicine; (3) friedrich-alexander-universität erlangen-nürnberg and university hospital erlangen, erlangen, germany) background: sarcopenia is characterized by a progressive loss of skeletal muscle mass, which is infiltrated by adipose tissue. dual energy x-ray absorptiometry can only differentiate overall lean and fat mass. a local muscle analysis requires 3d imaging like magnetic resonance imaging (mri). usually, t1 weighted images are used for a visual grading of the amount of intermuscular adipose tissue (imat). however, a quantitative analysis requires segmentation of the fascia lata (fl, deep fascia of the thigh). objectives: our aim was to develop a highly reproducible 3d segmentation method in oder to quantify imat and the fat fraction of the thigh muscles using a combination of t1 weighted turbo spin echo (t1wtse) and corresponding 6pt turbo spin echo (tse) dixon fat fraction (ff) images. methods: mri scans were acquired on a 3t scanner (magnetom skyrafit siemens) at the midthigh (length 10 cm, 34 slices, voxel size t1w 0.5x0.5x3.0 mm³, dixon 0.8x0.8x3.0 mm³). since the fl is difficult to detect in the ff images, the t1wtse images were used for segmentation. this process involved several steps, starting with a fuzzy c-mean clustering followed by several filtering steps to enhance 3d surface like structures representing the fl. finally, a level set algorithm was applied to obtain a closed 3d surface. if necessary, results were corrected manually. segmented masks were transferred from the t1w to the ff images by rigid registration. imat was then segmented using a threshold determined from the histogram of the ff values within the intra-fascia region. 15 sarcopenic (80±5 y) and 5 healthy (28±4 y) male subjects were analyzed by three operators once (interoperator reproducibility) and three times by one operator (intraoperator reproducibility). results: inter-and intra-operator variability results of imat are shown in the table as mean / root mean square of the standard deviation (rms-sd) in units of the measured variable / coefficient of variation (rms-cv) in %. overall precision was excellent with errors below 0.5 %. conclusion: a semi-automatic 3d segmentation for the fascia of the thigh was developed. the operator impact on imat was almost negligible. background: sarcopenia a muscle disease that causes muscle mass loss and weakness. the calf circumference is a good screening test for sarcopenia in older adults in primary care. the most commonly used cutoff point is 31 cm, but it is derived from north american studies and it may not be adequate for screening different populations that have lower height, weight and bmi. objectives: the objective of this study was to determine the ideal cutoff point for calf circumference for sarcopenia in community-dwelling older people in northeastern brazil. methods: this was a cross-sectional study of 538 community-dwelling older people with a mean age of 70±7 years (63% women). data on sociodemographics, anthropometrics, grip strength, gait speed, and skeletal muscle mass (bioimpedance) were collected. sarcopenia was assessed based on the diagnostic criteria suggested by european working group on sarcopenia in older people 2 (ewgsop2). the area under the roc curve (auc) was calculated for different calf circumferences to identify the best cutoff point to determine sarcopenia among the participants. results: the prevalence of sarcopenia was 15%. the most appropriate calf circumference cutoff point was 30 cm, with an auc of 0.68, 79% sensitivity and 45% specificity. conclusion: it was found that the most appropriate calf circumference cutoff point to diagnose sarcopenia in older northeastern brazilians was 30 cm. this is a more accurate cutoff point and will reduce the number of false positives and optimize health services in brazil. background: osteosarcopenia is a new geriatric syndrome defined as the presence of both sarcopenia and osteopenia or osteoporosis. this musculoskeletal disorder is related to higher prevalence of disabilities, falls and fractures and higher risk of mortality among community-dwelling older adults. therefore, the early diagnosis of this condition must be considered in order to reduce costs and negative impact on function. objectives: to explore the use of the infrared spectroscopy as a potential screening tool for osteosarcopenic older women (>=65 years old). methods: sarcopenia was identified by observing the presence of both reduction of muscle strength (grip strength) and mass (appendicular skeletal muscle mass) as suggested by the revised algorithm of the european working group on sarcopenia in older people (2019). reduction on bone mineral density was identified through bone densitometry and a t-score of <-1,0 was adopted to classify the older women as osteopenic/osteoporotic. infrared spectroscopy through attenuated total reflection-fourier transform infrared spectroscopy (atr-ftir) was used to collect the sample information and to perform a multivariate analysis model. vibrational spectrum was obtained from serum. six samples of each group (osteosarcopenic and non-osteosarcopenic) were used to test the model and thirteen ostesarcopenic samples and fifteen non-osteosarcopenic samples were used for training. results: the most suitable model was the ga-svm with an accuracy of 91.7%, 100% of sensibility and 83.3% of specificity to differ osteopenic to non-osteopenic women. the more important selected variables found in the model were at the spectral regions: ~900 cm-1 for carbs, ~1000 to 1150 cm-1 for nuclei acids and ~1500 to 1650 cm-1 for proteins. conclusion: infrared spectroscopy may be a promisor future method to early and easily diagnosis osteosarocopenia and prevent the harms this health condition may cause to the elderly population and minimizing costs to treat them. background: the modified european working group on sarcopenia in older people (ewgsop-2) algorithm to identify older people with sarcopenia contains three steps after initial clinical suspicion. the chair stand test, also known as the fivetimes sit-to-stand test (5sts), is one of two tests that can be used to assess muscle strength. the 5sts is also a component of the short physical performance battery (sppb), which is used as a measure of severity in the ewgsop-2 algorithm. objectives: the objective of this study was to determine whether the 5sts could be used to assess both muscle strength and physical performance in the ewgsop-2 algorithm to detect sarcopenia. methods: one hundred and ten older people aged 70.2 ± 5.4 years participated in the study. all participants were evaluated using the sppb score, as well as the timed-upand-go (tug). the ewgsop-2 algorithm specifies cut-off points of ≤8 points on the sppb, ≤ 0.8 m/s for gait speed, and ≥ 20 s for the tug. each participant was classified for tug and gait speed using the ewgsop-2 cut-offs, with stepwise discriminant function analysis used to predict the classification of 90 participants. the remaining 20 participants were used for cross-validation. prediction of sppb classification used the 5sts score in combination with predicted balance and sppb gait scores from stepwise linear regression. the total sppb score obtained using this method was used to predict sppb classification for the ewgsop-2 cut-off for sppb. results: the 5sts scores were able to predict tug and gait speed classification with 89% and 79% accuracy, respectively for the learning set of 90 participants. the predicted sppb score had a classification accuracy of 95%, with 100% sensitivity and 93% specificity. when the remaining 20 participants were evaluated, the sppb classification was correctly predicted for 19 participants (95%), with 100% sensitivity and 92% specificity. conclusion: the 5sts can be used to accurately predict sppb classification in the ewgsop-2 algorithm to detect sarcopenia, meaning that the 5sts test could be used as a standalone test in an initial screening for sarcopenia. barrientos-calvo (nutritional support department and geriatric department, geriatric national hospital , san josé, costa rica) background: obesity is a disease characterized by increased adiposity with negative impact on patient health. aging process is associated with a progressive loss in muscle function, that may lead to functional decline and frailty. there are only few studies that have compared the prevalence of sarcopenia and dynapenia in obesity. objectives: the aims of this study were to determine the prevalence of sarcopenic and dynapenic obesity in elderly using the european working group on sarcopenia in older people 2 criteria. methods: we conducted a cross-sectional study that included elderly patients with obesity from the obesity clinic since january 2018 to june 2018. sarcopenia was defined according to the european working group on sarcopenia in older people 2 (ewgsop2) criteria, and obesity with body mass index (bmi) > 28 kg/m2. handgrip strength was assess using a hydraulic dynamometer (jamar). bioimpedance analysis (bia) was performed. results: we evaluated 130 persons, but only 90 had bia data (70%). a total of 90 older (72.9 ± 6 years), 88% were women. mean body mass index, waist circumference, weight and calf circumference were 37.1±5.1 kg/m2, 119.4±11.6 cm, 89.2±15.5 kg and 39.4±4.2 cm respectively. all patients had elevated body fat (mean 51%) and 100% had abdominal obesity. patients showed higher frequency of hypertension (91%), diabetes (60%), dyslipidemia (56%). sedentary was present in 80% and falls in 5%. mean handgrip strength and muscle mass for men and women were 26.18±8.3 kg; 17.29±6.3kg and 29.7±4.5 kg; 22.5±5.5 kg respectively. there were 3 (3.3%) individuals fulfilling criteria for sarcopenic obesity, all women. but, dynapenic obesity was present in 4.4% men and 38% women. conclusion: although the loss of muscle mass is associated with the decline in strength during aging, the decline in strength is more prevalent than the loss in muscle mass in our obeses. a large difference in prevalence of the two conditions was observed, sarcopenia obesity 3.3% and dynapenic obesity 42%, respectively. barrientos-calvo (nutritional support department and geriatric department, geriatric national hospital, san josé, costa rica) background: sarcopenia is a geriatric syndrome characterized by progressive and generalized loss of skeletal muscle mass, strength, and function. several operative definitions for sarcopenia have been proposed over the past two decades. objectives: the aim of this study was to determine the prevalence of sarcopenia in costa rican longevity and health aging study (creles) using the ewgsop and ewgsop2 criteria. methods: to carry out the analysis, all the available cases of the creles study database in 2005 which belong to the cohort that follows in the period 2005-2009 were used. we analyzed 2142 community-dwelling older adults. low muscle mass was assessed using calf circumference <31 cm and low strength if <30 kg in men or <20 kg in women (ewgsop) vs <27 kg in men or <16 kg in women (ewgsop2). results: according to the ewgsop 17.8% of the participants had sarcopenia, while according to the ewgsop2 sarcopenia was present in 9,7% of participants. there was an increasing trend of sarcopenia by age group, it was more prevalent in women. mean handgrip strength was 21,95 kg in men and 13,65 kg in women with sarcopenia. mean calf circumference was 28,4 cm. sarcopenia was positively associated with age (or=1.10; ci:1.06-1.15), incomplete primary education (or 4, 264; ic 1, 753) , perceived as unhealthy (or 1,691; ic 1,133-2,525), antecedent of ischemic vascular event (or 3,221; ic 1,566-6,628), arthritis (or 1,648; ic 1,044-2,601), and falls (0r 1,676; ic 1,143-2,458). conclusion: the overall prevalence sarcopenia were significantly lower in ewgsop2. prevalence of sarcopenia varies widely depending on the grip strength cut-off points applied. based on a 24-hour dietary recall, and poorer nutritional status as determined using must compared to their non-sarcopenia counterparts (all p<=0.0063). conclusion: the high prevalence of sarcopenia in community-dwelling older people who are at risk of malnutrition highlights the importance to devise targeted exercise and nutrition interventions to improve muscle health, physical performance and nutritional status. these interventions are essential to reduce the risk of progression to frailty and disability in this population group. v i n c e n z o m a l a f a r i n a 1 , l e t i z i a s u e s c u n p u e r t a 2 , a r a n t z a z u b i a i n u g a r t e 3 , i ñ a k i a r t a z a a r t a b e 4 , virtudes niño martín 5 ( (1) s o p h i e g u y o n n e t 1 , c a t h e r i n e t a k e d a 2 , philipe de souto barreto 3 , yves rolland 1 , sandrine andrieu 4 , bruno vellas 1 and the inspire study group ( (1) background: the new geroscience field should not only be focusing on preventing age-related diseases, but should investigate the optimal maintenance of intrinsic capacity (ic): mobility, cognition, psychological, vitality and sensorial (hearing and vision) capacities as defined by the w.h.o. a better understanding about how to measure biological aging is an indispensable step that may lead to the definition of the best putative markers of aging capable of predicting healthspan. objectives: the main objective of inspire bioresource research platform for healthy aging is to build a comprehensive research platform gathering biological, clinical (including imaging) and digital resources that will be explored to identify robust (set of) markers of aging, age-related diseases and ic evolution. methods: the inspire platform will gather clinical data and biospecimens from 1000 subjects in the occitania region of different ages (from 30 years or over -no upper limit for age) and functional capacity levels (from robust to frail to disabled) over 10 years (inspire human translational research cohort). data are collected annually. between two annual visits, ic domains are monitored (with or without the help of a caregiver) each 4-month. once ic declines are confirmed, participants have a thorough clinical assessment and blood sampling to investigate the response of markers of aging at the time declines are detected. biospecimens includes blood, urine, saliva, and dental plaque that are collected from all subjects at baseline and then, annually. nasopharyngeal swabs and cutaneous surface samples are collected from all subjects at 6 time-points (baseline visit and follow-up visits at m24, m48, m72, m96 and m120). feces, hair bulb and skin biopsy are collected optionally at the baseline visit. results: recruitment started in october 2019 for a two years period. the identification of markers of aging will take advantage of three complimentary approaches to look for the best markers of aging: without a priori approach (transcriptomics, proteomics, lipidomics); semi a priori approach (metabolism, inflammation, cell cycle, mitochondrial network…); and targeted approach (pre-identified targets). the inspire platform will also aim to develop an integrative approach to promote novel new technologies for the assessment and monitoring of functional capacities. *acknowledgments: the inspire plateform is supported by grants from the occitania region and the european regional development fund (erdf), and co-funding by the apoc, the ctad, and the edenis, korian, pfizer, and pierre fabre groups. the promotion of this study is supported by the university hospital center of toulouse. background: energy balance is usually regulated by silent information regulator 2 related enzyme 1 (sirt1) and adenosine monophosphate-activated protein kinase (ampk). caloric restriction (cr) can postpone the pathological process of aging-related diseases and has a neuroprotective effect on nervous system degenerative diseases, but the mechanism is complex and not yet fully elucidated, although some of the cr effects may be mediated by sirt1 and ampk. objectives: to evaluate the beneficial effects of a cr diet on learning and memory ability. methods: six-week-old male c57/bl mice were fed ad libitum for 1 week before the experiment began. animals were weight-matched and randomly divided into three different groups: normal control group (nc group, n = 30), high-energy group (he group, n = 30), and cr group (n = 30). the energy of nc diet, he diet and cr diet caloric ratio was 1:1.3:0.7. the total experimental duration was 10 months. results: cr improved spatial learning and memory ability and decreased body weight and serum glucose. nissle staining showed the cell density was significantly decreased in the he group and increased in the cr group. cr decreased the expression of insulin signal pathway-related proteins such as igf-1, ir, irs-1, pi3k, akt/pkb, and p-creb. more sirt1-immunoreactive cells and fewer mtor-and s6k1immunoreactive cells were observed in the hippocampal in the cr group than in the nc group. cr decreased hippocampal mtor and s6k1 protein activation and mrna expression. the expression of beclin1, lc3 and cat b was increased and p62 was decreased in the cr group. the number of gfap-positive and iba-1-positive cells in the cr group was significantly reduced compared to the nc group. conclusion: cr may prevent age-related learning and memory impairment via suppression of pi3k/akt pathway and activation sirt1/ ampk/ mtor pathway in brain. background: head-down (6°) bed rest (hdbr) is a wellaccepted model to understand the pathophysiology of disuseinduced sarcopenia. human centrifugation as a measure to counteract muscle wasting during spaceflight is discussed. previous studies have observed decreases in maximal voluntary contraction force of the knee and hip-extensors of up to 22% following 5 weeks of hdbr. muscle force is regulated by the recruitment of motor units (mus) and the modulation of mu firing rate. objectives: the aim of this study was to assess whether long-duration hdbr alters motor unit properties as one cause for disuse induced sarcopenia and whether human centrifugation can attenuate this decrement. methods: twelve healthy participants (35.9±9.7yr; 174±7cm & 76.8±6.7kg) were confined to 60-days 6° hdbr in the frame of the first campaign of the agbresa bedrest study. eight received 30mins of artificial gravity (ag) daily via human centrifugation whereas four belonged to a control group. estimations of mu number (munix) and size (musix) in the abductor digiti minimi (adm) and tibialis anterior (ta) muscles were made using the motor unit number index method from on day 5 preceding bed rest (bdc5) and on days 4 (hdt4) and 59 (hdt59). mean compound muscle action potential (cmap), munix and musix as a percent change from bdc5 were compared using repeated-measures anova, where muscle and time were ascribed as within-group factors and intervention a between-group factor. significance was denoted by p<0.05. results: both cmap and munix were unaltered over time in both muscles, irrespective of the intervention. although musix was also indifferent over time for both muscles, a significant muscle*time interaction was observed, indicating that the changes over time differed between the two muscles. conclusion: the preliminary data from the ongoing study indicate that neurodegeneration due to bedrest might affect muscles differently. there does not seem to be an effect of ag on mu number. analyses have to be repeated when the study is completed with a larger number of participants. additional histological and biochemical data will give further insight in the pathophysiology. living. soumaya msaad 1 , geoffroy cormier 2 , guy carrault 1 ((1) univ rennes, inserm, ltsi -umr 1099, f-35000 rennes, france; (2) neotec vision , rennes , france) background: several models have been proposed for elderly frailty detection. there is a consensus on two of them: the fried model, and the rockwood model. however, daily monitoring of the elderly is impossible with these models, whereas it is very important to detect any change as soon as possible to prevent dependency, since frailty is reversible only if early detected. objectives: the objective of this study is to propose a non-intrusive and low-cost method that anticipates frailty using depth images. crucial hypotheses are that regularity of daily activities is important for the elderly and that any prolonged change is considered as an indicator of frailty. methods: the proposed method consists in three steps: 1) extraction of parameters from depth images: lying and sitting time percentage during the day, walking speed, and number of falls, visits, and exits. 2) classification of the daily state using logistic regression and the extracted parameters. the daily state is considered as normal if the daily routine is maintained and abnormal if it is broken. 3) computation of the weekly percentage of maintaining routine based on the classification of the nature of the day. results: tracking frailty is a difficult task that requires recording data over several months. as real data has not been collected yet, the feasibility of our approach was assessed on simulated data. in the latter, we reproduced variations of the parameters we would have extracted from real images of a patient after investigating his or her daily life. the classification of the days (normal/abnormal) led to an accuracy of 99% (training dataset: 135 days, test dataset: 45 days). a patient is considered frail when the weekly percentage of maintaining routine decreases steadily. conclusion: the preliminary results prove that in addition to being non-intrusive, a depth-imaging based approach can be a promising tool for frailty detection. anna franke 2 , ellen freiberger 2 , robert kob 2 simon moskowitz 1 , david w. russ 1,2 , leatha a clark 1,3,4 , nathan p. wages 1,3 , dustin r. grooms 1,5 , brian c. clark 1,3,6 ( (1) background: one putative mechanism explaining mobility limitations (mls) in older adults (oas) is a reduction in the central nervous system's (cns) ability to rapidly drive muscle force/torque production. rapid movements can be mathematically expressed as the time derivative of force/ torque, also termed 'yank' (y). muscles are ultimately responsible for generating y, but cns input (ni) to the muscles clearly influences y. the time derivative of the voluntary electromyogram during maximal efforts is associated with gait speed (gs) and chair rise time (crt). however, since the electromyogram is influenced by non-physiological factors (e.g., subcutaneous adipose tissue acting as a low pass filter), it is difficult to fully ascribe this finding to cns deficits. theoretically, normalizing y to the time derivative of electrically evoked force/torque controls for musculoskeletal factors contributing to y (ymsk), which yields a value representing the cns's ability to rapidly produce force/torque (yni=y/ymsk). objectives: to better understand the role of the cns in mls in oas we 1) compared leg extensor yni between young and oas, and 2) examined the association between leg extensor yni and measures of mobility. methods: twenty-one young and fifty-nine oas (21.95 +/-1.8 and 75.07 +/-6.8yrs) were instructed to "kick out as fast and hard as possible" against a fixed lever arm attached to a torque motor, and we quantified y between onset and 100-msec. next, we quantified ymsk from a supramaximal electrically evoked torque-time recording (potentiated 100-hz doublet) and calculated yni as described. on a separate visit six-minute walk (6mw) gs, stair climb power (scp), and 5x crt were measured. results: oas had higher yni vs. young adults reflecting a 22% reduction in central neural activation during rapid torque development (0.503 +/-0.141 vs. 0.393 +/-0.148; p<0.001). significant associations were observed between yni and 6mwgs (r=0.30), scp (r=0.43), and 5x crt (r=-0.48). conclusion: oas have a slower rate of volitional neural activation during rapid leg extensor torque production relative to young adults. in addition, yni explained ~10-25% of the variability in measures of mobility, thereby supporting the notion that age-related reductions in the ability of the cns to rapidly activate muscles contribute to mls. background: opa1 mutations cause dominant optic atrophy (doa), an incurable retinopathy with variable severity and which mechanisms are still unknown. more than 20% of patients will endure a doa plus syndrome with ataxia, deafness or parkinsonism. the hypothesis of an oxidative stress has been proposed to explain the variability of these symptoms. objectives: that's why our goal is to improve understanding of the physiopathological mechanisms involved in this disease by developing mathematical models of the production of reactive oxygen species (ros) by the mitochondrial respiratory chain. methods: we monitored the levels of mitochondrial respiration, reactive oxygen species (ros), anti-oxidant defenses and cell death by biochemical and in situ approaches using in vitro and in vivo models of opa1related disorders and model the complex i functioning with a detailed stochastic background: the sarc-f is a 5-question screening tool for sarcopenia. we present results for reliability and validity of the german version of the sarc-f. objectives: translation, adaptation and validation of the german version of the sarc-f for community-dwelling older adults in germany. methods: design: cross-sectional. setting and participants: 117 community-dwelling outpatients with a mean age of 79.1 ± 5.2 years were included in the study, 94 (80.4%) of them were female. 63 (53.8%) had a positive sarc-f score of >= 4 points. according to the definition for sarcopenia from the european working group on sarcopenia in older people (ewgsop2), eight patients (6.8%) were identified as sarcopenic and 57 (48.7%) as probable sarcopenic. methods: translation and cultural adaption was composed of seven different steps that were in general based on the guidelines put forward by the world health organization. validation include test-retest and the inter-rater reliability (intra-class correlation coefficient) as well as internal consistency (cronbach's alpha). further, sensitivity, specificity, positive predictive value, and negative predictive value of the sarc-f were calculated. receiver operating characteristics (roc) analysis was performed to calculate the area under the curve. results: the translated and culturally adopted version of the sarc-f for the german language has shown excellent interrater reliability and good test-retest reliability. the internal consistency is acceptable. sensitivity (63%) and specificity (47%) for sarcopenia is low. for detecting patients with probable sarcopenia, the sarc-f in the german version has shown 75% sensitivity and 67% specificity. conclusion: due to a low sensitivity for detecting sarcopenia but an acceptable sensitivity for identifying probable sarcopenia, the german version of the sarc-f is a suitable tool for case finding of probable sarcopenia. background: skeletal muscle is a vital component of the locomotor system necessary for physical function. however, there is increasing evidence that skeletal muscle acts as a secretory organ in itself, communicating with other organ systems. acute sarcopenia is an emerging condition affecting adults following hospitalisation, which should be considered akin to organ insufficiency elsewhere. however, acute sarcopenia remains poorly characterised to date. objectives: • to characterise changes in muscle quantity, strength, physical performance, and patient-reported physical function in hospitalised older adults at one week and three months. • to determine what biological and clinical factors are predictive of changes to enable further research towards targeted interventions. methods: planned recruitment will include hospitalised patients aged 70 years and older; 56 elective colorectal surgery patients, 56 emergency surgery patients, and 56 general medical patients with acute bacterial infections. patients will be recruited to the elective cohort in pre-operative assessment clinic with repeat measures within 48 hours of surgery, at one week, and at three months. emergency surgery patients will be recruited pre-or post-operatively with repeat measures at one week, and at three months. medical patients will be recruited within 48 hours of admission, with repeat measures at one week, and at three months. muscle quantity will be measured by bilateral anterior thigh thickness using ultrasound and bioelectrical impedance. muscle function will be measured by handgrip strength and short physical performance battery. serum and plasma samples will be obtained prior to admission in the elective cohort, within 48 hours of surgery in both surgical cohorts, and within 48 hours of admission in the medical cohort. background: sarcopenia is common in old age and is associated with various diseases. as human life expectancy is projected to increase, this will pose a challenge for the global healthcare industry. since sarcopenia is highly heritable, study of its genetic underpinning can help its etiology. in the past decade genome wide association studies (gwas) have allowed the identification of new genetic markers for various conditions. identification of new genetic markers through gwas requires functional validation using cellular models in order to both prioritize and validate the potential loci/genes. objectives: demonstrate that a locus identified in gwas may affect muscle health, which is approximated by lean mass and hand grip strength. methods: gwas results are screened using a two-step scoring system which utilizes publicly available databases such as genecards, ensembl and coxpresdb to assess the relevance of a certain locus. relevant genes are then knocked out using crispr-cas9 in c2c12 mouse myotube cells which are induced to differentiate. after cell harvest rt-qpcr and western blot are performed to assess mrna and protein expression, respectively. knocked out cells are also examined against wild type cells for morphological phenotype. results: slc8a1 is a promising candidate based on: (a) muscle gwas results, (b) the expression of the gene in smooth and striated muscle tissue, (c) the lack of co-expression with other genes that have an effect on muscle; (d) mouse phenotypes associated with a mutation in the mouse ortholog slc8a1, (e) cell epigenetic data and (f) the topologically associated domain (tad) at chr. 2:40,097,270-40,611,053. rt-qpcr of wild type c2c12 cells showed a fast increase in the expression of slc8a1's mrna which remains constant during the entire differentiation process. conclusion: preliminary results indicate that slc8a1 might be a promising candidate to investigate for involvement in muscle health. there is a fast and stable increase of the gene's expression during myotube formation. positive results may suggest that slc8a1 is of importance to muscle health. to farther assess slc8a1 role, wild type cells will be compared to knocked-out cells. this might lead to a new genetic marker for muscle health, thus extending personalized medicine in the field of sarcopenia and muscle health. jesse zanker 1 , terri blackwell 2 , sheena patel 2 , kate d u c h o w n y 2,3 , s h a r o n b r e n n a n -o l s e n 1 , s t e v e n r . cummings 2,3 , william j. evans 4,5 , eric s. orwoll 6 , david scott 1,7 , sara vogrin 1 , gustavo duque 1 , peggy m. cawthon 2,3 ( (1) background: muscle mass, strength and physical performance are independent risk factors for disability and mobility disability in older adults. it is not known how measures of body composition (muscle, lean and fat mass), strength and physical performance are interrelated or how empirical groupings of these measures relate to disability and mobility disability. objectives: to determine the relationship between measures of body composition, strength and physical performance in older men and to examine how empirical groupings of these measures relate to adverse mobility and disability outcomes. methods: muscle mass was assessed by d3-creatine dilution (d3cr muscle mass) in 1345 men (84.1 + 4.1 years) enrolled in the osteoporotic fractures in men (mros) study. participants completed anthropomorphic measures, walk speed (6m), grip strength (kg), chair stands (s), and dual x-ray absorptiometry (dxa) appendicular lean mass (alm) (adjusted for weight, body mass index or height2) and body fat percentage. factor analysis was conducted to reduce variables into smaller components. men self-reported limitations in mobility (walking 2-3 blocks, climbing 10 steps, or carrying 10 pounds); activities of daily living (adls); and instrumental adls at initial and follow-up visits. negative binomial models adjusted for participant characteristics were used to determine the relative risk of factors with mobility and disability outcomes. results: factor analysis reduced 10 variables into four factors: factor 1, body composition, with strong loading by alm, body fat percentage, weight and muscle mass; factor 2, body size and lean mass, with strong loading by height, weight and alm; factor 3, muscle mass, strength and performance, with strong loading by walk speed, chair stands, grip strength, and muscle mass; and factor 4, lean mass and weight, with strong loading by alm and weight. only factor 3 was associated with prevalent disability and background: urinary incontinence(ui) is a prevalent and costly condition that affects ~40% of older communitydwelling women.one of the contributors of ui is decreased pelvic muscle strength. objectives: to determine the effect of additional oral glutamine supplementation to kegel-exercise on pelvic floor strength and clinical parameters of ui in females. methods: it is a randomized, double-blind study. females with ui were included. digital test and a vaginal manometer were used for measuring the strength of the pelvic floor muscles. 24 hours pad weight test was examined. participants were randomized into 2 groups as oral glutamine 30 gr/day and placebo. it was asked to use the supplementation and kegel-exercises to all participants for 3 months. basic and 3th month measurements were compared by paired sample t -test and wilcoxon tests in each group. the progression between measurements at basic and 3th months was compared between the groups by using mann-whitney-u test. (clinical trials protocol id: 2014 /1203 background: it is important to identify if middle-aged people are at risk for sarcopenia. a screening-tool identifying predictors of pre-sarcopenia early in the lifespan may inform prevention focused interventions. objectives: develop and validate a practical screening-tool to identify middle-aged adults at risk for pre-sarcopenia using data from the dunedin multidisciplinary health and development study (dmhds). methods: the dmhds is an ongoing longitudinal birth cohort study from the greater dunedin (nz) metropolitan area. the primary outcome of the screening-tool was low appendicular lean muscle index (almi) in middle-aged adults, at age 45. low almi was classified using prado's age-specific median cut-scores. the models were developed in 80% (n=720) of the cohort and cross-validated in the remaining 20% (n=179). possible predictors at age 38, were examined for associations with low almi, using univariate logistic regression. significant predictors were selected in a multivariate logistic regression to derive sex-specific prediction models. each individual in the cohort was allocated a risk-score and classified as low, medium and high risk, based on the quartile risk score. overall performance of the final models was estimated with nagelkerke r2 score, discrimination of the models with the area under the roc curve and calibration of the final models with hosmer-lemeshow tests. results: 49% of the development set and 51% of the validation set were female. the final models for both sexes included body mass index (b=-0.704, p=0.000; b=-0.746, p=0.000), vo2max (b=-0.137, p=0.000, b=-0.187, p=0.004) and grip strength (b=-0.067, p=0.000, b=-0.118, p=0.001). the final model for females also included creatinine (b=-0.187, p=0.016). nagelkerke's r2 showed that 56.7% and 67.6%, of the variance in low almi, is explained by the variables in the screening-tool for males and females, respectively. the area under the roc curve demonstrated good discrimination (0.827). sensitivity in the lowest quartile was 93.8%, specificity in the highest quartile was 97.8%. the hosmer-lemeshow p-values were respectively 0.539 and 0.617, showing goodness of fit. conclusion: this screening-tool was able to predict the sex-specific risk of pre-sarcopenia in a large birth cohort of early middle-aged adults. clinical utility and application of this screening-tool require further investigation. background: aging-associated changes in body composition include a decrease in skeletal muscle mass, which may predispose women to physical limitations and disabilities. in women, these changes may already be accelerated during menopause, when ovarian estradiol (e2) production ceases. e2, the main female sex hormone, is known to have beneficial effects on female skeletal muscle mass. objectives: the aim of this study was to investigate the effects of menopausal transition on lean body mass, lower limb muscle mass, muscle area and muscle fiber cross-sectional area in middle-aged women. methods: middle-aged women (n=199) were followed from perimenopause to postmenopause. menopausal state was defined based on repeated follicle-stimulating hormone (fsh) measurements and menstrual bleeding diaries. serum hormone levels (e2 and fsh; immulite2000), lean body mass (lbm), right leg lean mass (dxa, n=190), and thigh muscle cross-sectional area (computed tomography (ct), n=37) were measured in peri-and postmenopause. muscle biopsies for immunohistochemistry were obtained from 7 participants at peri-and postmenopausal phases, and muscle fiber crosssectional areas were measured. the level of physical activity (pa) from the previous 12 months was assessed with a questionnaire (met-hours/day, n=183). statistical differences were analyzed with paired t-test and wilcoxon signed rank test. gee-modeling was used to analyze the effects of covariates during follow-up. results: the average followup time was 1.2 years (range 0.4-3.6 years) and there was a significant difference in e2 and fsh levels during the transition (p<0.001 for both). lbm decreased 0.5% (p=0.027) and leg lean mass 1.2% (p=0.003) during the menopausal transition. no changes were found in the cross-sectional area of thigh muscles or muscle fibers. the level of pa declined during the transition (p=0.037). when individual menopausal transition time and pa were controlled, only systemic e2 levels were positively associated with lbm (b=0.675, p=0.031). conclusion: despite the relatively short follow-up time, significant declines were observed in lbm and leg lean mass during the menopausal transition. the decrease in lbm was associated with lower systemic e2 level. therefore, it seems that although pa might slow the decrease in muscle mass, estradiol loss is one key factor in whole body muscle loss during menopausal transition. hiroyuki shimada 1 , takehiko doi 1 , sangyoon lee 1 , kota tsutsumimoto 1 , seongryu bae 1 , sho nakakubo 1 , keitaro makino 1 , hidenori arai 2 ((1) department of preventive gerontology, center for gerontology and social science, national center for geriatrics and gerontology, aichi, japan;(2) national center for geriatrics and gerontology, aichi, japan)background: in 2018, the european working group on sarcopenia in older people met again (ewgsop2) to update the original definition of sarcopenia. ewgsop2 uses detection of low muscle quantity and quality to confirm the sarcopenia diagnosis, and identifies poor physical performance as indicative of severe sarcopenia. however, it is not clear that the relationships between the revised definition of the sarcopenia and disability incidence in japanese older adults. objectives: to examine the associations between sarcopenia for ewgsop2 criteria and disability incidence among community-dwelling older japanese individuals. methods: a total of 4561 older adults participated in the study (2301 women; average age, 71.9 ± 5.4 years) form a japanese national cohort study called the ncgg-sgs. skeletal muscle mass was assessed using a bioimpedance analysis device and handgrip strength and walking speed were measured as physical performance. we used the cut-points of the asian working group for sarcopenia to determine the low muscle mass and low physical performances. the participants were divided into non-sarcopenia, sarcopenia, and severe sarcopenia groups. the incidence of disability was determined using data collected by the japanese longterm care insurance system over 49 months. results: the prevalence rates of sarcopenia and severe sarcopenia were 2.6% and 1.4%, respectively. the participants with sarcopenia, included sarcopenia and sever sarcopenia, showed higher risk of disability incidence than those with non-sarcopenia (hazard ratio [hr]: 1.78, 95% confidence interval [95% ci]: 1.27-2.49). in analysis between non-sarcopenia and sarcopenia or severe sarcopenia, although the association between disability incidence and severe sarcopenia remained significant (hr: 2.00, 95% ci: 1.32-3.02), there was no significant association in sarcopenia (hr: 1.54, 95% ci: 0.97-2.46). conclusion: severe sarcopenia combined low muscle mass and low physical performance could have a higher risk of disability than healthy older adults or older adults with low muscle mass alone. further studies are needed to determine whether sarcopenia without poor physical performance is associated with disability incidence.background: sarcopenia is one of the biological hallmarks of frailty that has been associated with adverse events in older adults undergoing cardiac surgery. dual x-ray absorptiometry (dxa) is a recommended modality to measure muscle mass, however, dxa may be less accurate in acute cardiac patients due to the confounding effects of peripheral edema and fluid shifts. objectives: the study aims to determine if sarcopenia as measured by a combination of dxa and timed chair rises is associated with mortality in older adults referred for cardiac surgery. methods: a convenience sample of hospitalized older adults being evaluated for cardiac surgery was prospectively enrolled at the jewish general hospital. after a questionnaire and physical performance battery, patients underwent a dxa scan (ge lunar) to measure their appendicular muscle mass (amm). patients were categorized as sarcopenic based on the european working group guidelines if they had low amm defined as <7 kg/m2 in men or <6 kg/m2 in women and low muscle strength defined as 5 chair rises >15 seconds. multivariable logistic regression was used to test the ageand sex-adjusted association between sarcopenia and allcause mortality. results: the cohort consisted of 146 patients with a mean age of 70.1 ± 10.3 years and 22% females. the interventions were isolated coronary bypass in 60%, valve surgery in 30%, and decision not to proceed with surgery in 10%. the mean amm was 24.1 ± 5.2 kg in men and 21.1 ± 5.2 kg in women. the prevalence of sarcopenia was 15% (n=22), similar in men and women. sarcopenia was not associated with 1-year mortality (or 0.87, 95% ci 0.21-3.57) and, in a separate model, neither was low amm (or 1.00, 95% ci 0.28-3.61). slow chair rise time was associated with higher 1-year mortality (or 6.10, 95% ci 1.21-30.89). when patients with heart failure and reduced ejection fraction were excluded, sarcopenia appeared to be more prognostic (or 1.96, 95% ci 0.39-9.82) although it did not reach statistical significance. conclusion: lower-extremity muscle strength, but not dxa-based measures of muscle mass or sarcopenia, is predictive of survival in hospitalized older adults referred for cardiac surgery. background: the "blue zone" are limited areas with a high prevalence of centenarians, with rather homogeneous characteristics, life styles and environment." this blue zone, located in the nicoya peninsula, is in the province of guanacaste. even though costa rica has this blue zone, there are no studies that characterize the prevalence sarcopenia in the centenarians of the region. objectives: the aim of this study was to determine the prevalence of sarcopenia on centenarians from nicoya, costa rica, using the ewgsop2 criteria. methods: this is a cross-sectional study using a population base of 43 community-dwelling centenarians from guanacaste. antropometric measures, weight, height and strength were assessed. to assess the nutritional state, the mini nutritional assessment (mna) was used and activities of daily living (adl) scores. low muscle mass was assessed by calf circumference <31 cm and low strength if <27 kg in men or <16 kg in women. results: the mean age of the patients were 101.93±1.7 years. from this group, 18 (41.9%) were men and 25 (58.1%) were women. patients showed comorbilities: hypertension (55.5%), diabetes (11.6%), copd (20.9%), cancer (7%), osteoarthritis (25%) and depression (25%). mean body mass index, weight, brachial and calf circumference were 20.8±4.3 kg/m2, 44.3±10.5 kg, 22.6±3.3 cm and 27.2±4.6 cm. mean handgrip strength was 9.9±5.3 kg. the mean score for the mna test was 19.9±4.9 and adl score 54.65±33.9. with respect to sarcopenia prevalence, a total number of 20 (46.5%) subjects were detected, 8 (18.6%) men and 12 (27.9%) women fulfilled the criteria. according to the nutritional status, 3 patients with sarcopenia had malnourishment, 15 were on nutritional risk and 5 had a good nutritional state. from the sarcopenic centenarians, at least 55% of the subjects had dependency with adl. conclusion: we had high prevalence sarcopenia in centenarians from the "blue zone". there are few studies in centenarians, but using the ewgsop2 criteria, it is the first in latin america. background: sarcopenia is a geriatric syndrome characterized by low muscle mass and low muscle function and/or reduced physical performance. malnutrition is a major risk factor for sarcopenia. there is limited data on the prevalence of sarcopenia in community-dwelling older people who are at risk of malnutrition in singapore. objectives: the objectives were (i) to determine the prevalence of sarcopenia and its components i.e. low handgrip strength, low appendicular skeletal muscle mass index (asmi) and low gait speed based on the asian working group for sarcopenia consensus (chen et al., 2014) , (ii) to describe the characteristics and dietary intake of older adults with sarcopenia to those without sarcopenia. methods: a total of 811 community-dwelling older adults (>=65 years) who were at risk of malnutrition (malnutrition universal screening tool; must score >=1) took part in this study. sarcopenia was diagnosed by low muscle mass (asmi using bioelectrical impedance analysis) plus low muscle strength (handgrip strength) and/or low physical performance (4-meter usual gait speed). anthropometric measurements, dietary intake, and short physical performance battery (sppb) were also collected. results: over 90% of participants had a charlson comorbidity score of 0. the overall prevalence of sarcopenia was 70%; 81.3% had low asmi, 81.7% had low handgrip strength and 44.2% had low gait speed. participants with sarcopenia were significantly older, shorter, and with lower body weight and bmi, mid-upper arm circumference, calf circumference and bone mass compared to those without sarcopenia (all p<0.0001). they also had lower physical functions as measured using handgrip strength and endurance, leg strength, and sppb score than those without sarcopenia (all p<=0.0021). additionally, older adults with sarcopenia had lower total energy intake and energy-adjusted protein intake background: the prevalence of sarcopenia varies according to the diagnostic criteria used, however it is an important geriatric syndrome related to a worse functional state in the elderly. very older adults are often excluded from clinical trials. objectives: the aim of this observational prospective study is to describe the prevalence of sarcopenia in community very older adults with high comorbidity. methods: we included patients who enter the geriatric day hospital of the hospital of navarra, spain, aged more than 75 y, underwent bioelectrical impendance analisys (bia), measurement of hand grip strength (hgs), gait speed (gs), short physical performance battery (sppb), mini-nutritional assessment (mna-sf), barthel index and cumulative illness rating scale-geriatric (cirs-g). sarcopenia were defined according to ewgsop2 (2019). the study begining in 2017 and it is actually ongoing. we registered variables at baseline, and at the time 6, 12 and 24 months. all-cause mortality were registered. results: we present the preliminary results of baseline value. we icluded 302 patients (52.3% men, 87.4±4.6 y). sarcopenia were present in 173 participts, vithout sex differences. sarcopenic vs no-sarcopenic patiets were older (88.2±4.4 vs 86.2±4.4 y) (p<0.001) and they presented worse nutritional status (bmi 23.3±2.9 vs 28.7±4.7 kg/m2) (p<0.001), mna-sf 9 (95%ci 8-11) vs 11 (10-13) (p<0.001). sarcopenic patients presented lower barthel index (75, 95%ci 60-90 vs 85, 70-95) (p=0.022), but we have no observed differnces nor in the sppb 5, 95%ci 3-7 in sacropenic, vs 5, 4-8 in no-sarcopenic participats (p=0.139), neither in comorbididy index (cirs-g 16, 13-20 vs 17, 15-20 respectivelly) (p=0.552). sarcopenia is significantly associated with higher mortality (hr 0.623, 95%ci 0.388-0.999) (p=0.045). at the present time the mean follow-up is 15.7±8.6 months. at 6 months in 18 patients (17%) the sarcopenia reverted, and we have observed 20 new sarcopenic cases (22%) (incident sarcopenia). conclusion: sarcopenia is highly prevalent in very older adults with high comorbidity. sarcopenia is associated with malnutrition and with higher mortality. background: disability is a multifactorial trait that contributes substantially to decline of health/wellbeing and increases steeply with age after midlife. progress in genomewide sequencing has created the potential for discovering genes influencing various health-related traits. the vast majority of such studies focus on the genetic bases of different traits assuming that they have independent mechanisms. as conceptualized by geroscience age/aging are major risk factors of geriatric traits of distinct etiologies. accordingly, the same mechanisms can predispose not to just one, but to a large fraction of geriatric conditions. objectives: identify the common genetic architecture of various traits by discovering the genetic architecture of complex multifactorial trait such as disability. methods: genome-wide association study of disability in a sample of 24,068 subjects from five studies with 12,550 disabled individuals from the women's health initiative (whi) genomics and randomized trials network, whi memory study, cardiovascular health study, framingham heart study, and health and retirement study. disability was defined as having at least one of four basic activities of daily living impairments (bathing, dressing, getting out of bed, and walking). results: we identified 30 promising disability-associated single nucleotide polymorphisms (snps) in 19 loci at p<10-4. four of them attained suggestive level of significance, p<10-5. in contrast, polygenic risk scores (prs) aggregating effects of minor alleles of independent snps that were adversely or beneficially associated with disability showed highly significant associations in meta-analysis, p=3.13×10-45 and p=5.60×10-23, respectively, and were replicated in each study. the analysis of genetic pathways, related diseases, and biological functions supported the connections of genes for the identified snps with disabling and age-related conditions primarily through oxidative/nitrosative stress, inflammatory response, and ciliary signaling. we identified musculoskeletal system development, maintenance, and regeneration as important components of gene functions. conclusion: the discovery of adverse and beneficial prs for a multifactorial trait of distinct etiologies such as late life disability supports the concept of geroscience. the beneficial and adverse gene sets may be differently implicated in the development of musculoskeletal-related disability with the beneficial set characterized, e.g., by regulation of chondrocyte proliferation and bone formation, and the adverse set by inflammation and bone loss. key: cord-004894-75w35fkd authors: nan title: abstract date: 2006-06-14 journal: eur j epidemiol doi: 10.1007/s10654-006-9021-1 sha: doc_id: 4894 cord_uid: 75w35fkd nan the organisers of the european congress of epidemiology 2006, the board of the netherlands epidemiological society, and the board of the european epidemiology federation of the international epidemiological association (iea-eef) welcome you to utrecht, the netherlands, for this iea-eef congress. epidemiology is a medical discipline that is focussed on principles and methods of research on causes, diagnosis and prognosis of disease, and establishing the benefits and risks of treatment and prevention. epidemiological research has proven its importance by contributions to the understanding the origins and consequences of diseases, and has made major contributions to the management diseases and improvement of health in-patients and populations. this meeting provides a major opportunity to affirm the scientific and societal contributions of epidemiological research in health care practice, both in clinical medicine and in public health. during this meeting major current health care problems are addressed alongside methodological issues, and the opportunities and challenges in approaching them are explored. the exchange of ideas will foster existing co-operation and stimulate new collaborations across countries and cultures. the goal of this meeting is to promote the highest scientific quality of the presentations and display advanced achievements in epidemiological research. our aim is to offer a comprehensive and educational programme in the field of epidemiological research in health care and public health, and create room for discussions on contemporary methods and innovations from the perspective of policy makers, professionals and patients. above all, we want to stimulate open interaction among the congress participants. your presence in utrecht is key to an outstanding scientific meeting. the european congress of epidemiology 2006 is organised by epidemiologists of utrecht university, under the auspices of the iea-eef, and in collaboration with the netherlands epidemiological society. utrecht university, founded in 1634, is the largest university in the netherlands and harbours the largest academic teaching hospital in the netherlands. the epidemiologists from utrecht university work in the faculties of medicine, veterinary medicine, pharmacy and biology. the current meeting was announced through national societies, taking advantage of their newsletters and of the iea-eef newsletter. in addition, avoiding the costs and disadvantages of the traditional journal advertisements and leaflets, information about the congress was disseminated via an internet mailing list of epidemiologists, which was compiled from, among other, the meeting in porto in 2004, the european young epidemiologist network (http://higiene.med.up.pt/eye/) and several institutions and departments. many of the procedures followed this year were based on or directly borrowed from the stimulating iea-eef congress in porto in 2004. publication in an international journal of large circulation of the congress programme and abstracts selected for oral and poster presentation, signifies the commitment of the organisers towards all colleagues that decided to present their original work at our meeting, and is intended to promote our discipline and to further stimulate the quality of the scientific work of european epidemiologists. and methods to the objectives and quality of its description; presentation of results; importance of the topic; and originality. a final rating was given on a 0-10 point scale. the two junior epidemiologists independently evaluated each abstract. based on ratings of the juniors, the senior epidemiologist gave a final abstract rating. the senior reviewer decided when juniors disagreed, and harnessed against untoward extreme judgements of the juniors. based on the judgement by the seniors abstracts with a final rating of 6 or higher were accepted for presentation. next, in order to shape the scientific programme according to scientific and professional topics and issues of interest for epidemiologists, members of the scientific programme committee grouped the accepted abstracts in major thematic clusters. for these, topics, keywords and title words were used. within each cluster, abstracts with a final rating of 8 or higher, as well as abstracts featuring innovative epidemiological approaches were prioritised to be programmed as an oral presentation. the 642 submitted abstracts had an average final rating of 6 (sd=1). in total 148 abstracts (23%) with a final rating of 5 or lower were rejected. because of the thematic programming some abstracts with a final rating of 8 or higher will be presented as posters, while few with a final rating of 7 are programmed as oral presentation. there were 345 abstracts (54%) accepted and programmed for poster presentation; each poster will be displayed for a full day. in total 149 abstracts (23%) are accepted for oral presentation. these are programmed in 29 parallel sessions. based on the topics of their abstracts the oral sessions were arranged into 7 themes, notably epidemiology of diseases, methods clinical & population research, burden of disease, high risk populations, growth and development, public health strategies, translational epidemiology. sessions from one theme never are programmed parallel. in table 1 we present the submitted and accepted abstracts (oral or poster) according to the distribution of country of origin. in table 2 submitted abstracts are displayed according to their topic, as classified by the authors using the topic long list of the submission form. the scientific programme committee convened in a telephone meeting by the end of the summer of 2005 and decided on the above programming process. the scientific programme committee was informed on the result of the programming process by the end of april 2006. fifteen abstracts were submitted for the eye session work in progress. of these 3 abstracts were selected for oral presentation and thereby nominated for the eye award. in total, 10 abstracts were submitted in relation to the student award, of which 6 were programmed for oral presentation and thus nominated. during the congress authors of poster presentations may name themselves as candidate for the poster award. during the closing ceremony the winners of the student award 2006 and the poster award 2006 will be announced. these awards are an initiative of the netherlands epidemiological society that will fund them in 2006. according to the iea rules expenses of congress participation for applicants from low-income countries will be covered. the board of the iea-eef will select a maximum of 10 candidates; their travel and registration expenses will be (partly) covered from the congress budget. in order to stimulate participation form as many as possible junior researchers and young epidemiologists the congress budget covers registration fee reduction for undergraduate (msc) participants and eye members. this also holds for the registration fee reduction of iea-eef members and nes members. it is 11 years ago (1995) that the iea regional european meeting was held in the hague, the marcon 348 wei 352 leray 353 gehring 354 leray 356 spallek 362 greving 367 laan 372 brussee 379 brussee 383 mayde groot 385 hoefman 386 goettsch 387 posters ordered by abstract number 11 olawuyi 19 de vries 21 uotinen 22 smits 26 gimeno 28 houben 29 de vries 30 de vries 31 ten berg 34 diaconu 36 diaconu 46 streppel 47 belo 48 sauvaget 51 koopman 71 kilsztajn 76 pembrey 81 schmidt 85 kretzschmar 102 scholtens 109 defraye 116 medronho 117 eljedi 124 van de garde 127 mello 128 hosper 129 feleus 134 bayingana 135 de wit 139 stolk 169 teixeira 171 teixeira 175 verhoef 180 capon 185 de boer 186 lazarevska 198 terschu¨ren 201 khosravi boroujeni 202 molag 208 mikolajczyk 209 luijsterburg 216 stolk 219 mirabelli 236 barreto 242 curzio 262 pereira 268 van gageldonk-lafeber 284 van nispen 287 roobol 294 mokkink 295 rava 303 haukka 304 jansen 307 de kraker 313 bogers 322 donalisio 325 behrens 329 borders 332 melis 347 pac 364 muller 365 van den hooven 369 van der sande 373 van den berg 395 novoa 410 van den boogaard 411 vannoord 412 koedijk 414 kuczerowska 420 giorgi rossi 432 vannoord 433 baussano 434 agabiti 457 bierma-zeinstra 460 van wier 464 faustini 465 jarrin 477 juhl 484 miguel 485 maira 497 lindert 508 van den berg 509 mierzejewska 520 fonseca cardoso 525 martens 536 cotton 539 corte 542 ursoniu 544 vernic 545 boer 563 ruskamp 568 szurkowska 572 bijkerk 574 fonseca cardoso 576 mazur 595 ahrens 598 dijkstra 600 ajdacic-gross 603 ajdacic-gross 604 lucas 607 santos 634 gielkens-sijstermans 639 tobi 643 de kraker proteomics and genomics are supposed to be related to epidemiology and clinical medicine, among other because of the putative diagnostic usefulness of proteomics and genomics tests. hence, clinical and sometimes even public health applications are promised by basic sciences. it is debated whether such promises and subsequent expectation are fulfilled. what are at meaningful and consequential examples of current findings in proteomics, genomics and similar approaches in biomedical research? are they different from the ''classic'' tools and frameworks of clinical epidemiology? in the context of proteomics and genomics, etiologic studies, primary prevention, epidemiological surveillance and public health are concerned with the influence of environmental exposures on gene expression and on the accumulation of genetic alterations. proponents and advocates of proteomics and genomics have suggested that their products can yield clinically useful findings, e.g., for early diagnosis, for prognosis, for therapeutic monitoring, without always needing to identify the proteins, peptides or other 'biomarkers' at stake. do we feel comfortable with this ''black-box'' reasoning, i.e. do we question the role of pathophysiological and mechanistic reasoning in clinical medicine? how much sense does it make for epidemiology to play with and scrutinize proteomics and genomics approaches in epidemiology and clinical medicine? what are at present (and in the near future) the main biological, clinical and public health implications of current findings in these research fields? in this plenary session these and other questions regarding the place and role of proteomics and genomics in clinical epidemiological research are discussed from different perspectives. infection diseases: beneficial or disaster for man? infectious diseases pose an increasing risk to human and animal health. they lead to increasing mortality, in contrast to the situation fifty years ago when new control measures still provided hope of overcoming many problems in the future. improved hygiene, better socio-economic circumstances, vaccination and use of antibiotics has led to a gradual decline of tuberculosis, rheumatic fever, measles and mumps in western societies over the last five decades. paradoxically, absence of exposure to infectious agents has a major impact as well. the decline in infectious disease risk is accompanied by a gradual increase of allergic and autoimmune diseases and this association is believed to be causal. exposure to infectious agents from early on in life can markedly boost an individual's natural resistance and hence influence the individual's reaction to future exposure to both biological and non-biological antigens. in this plenary session we want to emphasise both aspects of the effect of infectious agents on human and animal health. evidence based medicine in health care practice and epidemiological research p. glasziou & l. bonneux evidence-based medicine is defined as the conscientious, explicit and judicious use of current best evidence in making decisions about the care of individual patients. proponents of evidence-based medicine maintain that coming form a tradition of pathophysiological rationale and rather unsystematic clinical experience, clinical disciplines should summarize and use evidence concerning their practices, by using principles of critical appraisal and quantitative clinical reasoning. for this they should convert clinical information needs into answerable questions, locate the available evidence, critically appraise that evidence for its validity and usefulness, and apply the results of the best available evidence in practice. applying the principles of evidence-based medicine implies improvement of the effectiveness and efficiency of health care. therefore, evidence-based medicine has commonalties with clinical medical and epidemiological research. for integration of evidence-based medicine into health care practice the challenge is to translate knowledge from clinical medical and epidemiological research, for example in up to date practice guidelines. the limitations of using evidence alone to make decisions are evident. the importance of the values and preference judgments that are implicit in every clinical management decision are also evident. critics of evidence based medicine argue that applying best available research evidence in practice in order to improve the effectiveness and efficiency of health care contradicts with the importance of the values and preference judgments in clinical management decisions. in this plenary session we want to contrast these and other viewpoints on evidence based medicine in health care practice. statistical topics i: missing data prof. dr. t. stijnen this workshop will be an educational lecture on missing data by professor stijnen from the department of epidemiology and biostatistics of the erasmus mc rotterdam, the netherlands. every clinical or epidemiological study suffers from the problem of missing data. in practice mostly simple solutions are chosen, such as restricting the analysis to individuals without missing data or imputing missing values by the mean value of the individuals with observed data. it is not always realised that these simple approaches can lead to considerable bias in the estimates and standard errors of the parameters of interest. in the last 10 to 15 years much research has been done to better methods for dealing with missing values. in this workshop first an overview will be given of the methods that are available and their advantages and disadvantages will be discussed. most attention will be given to multiple imputation, to date generally considered as the best method for dealing with missing values. also the available software in important statistical packages such as spss and sas will be shortly discussed. prof. dr. b. van hout suppose that one wants to know how often individuals have a certain characteristic, and suppose that one doesn't have any knowledge -any knowledge at all -how often this is the case. now, suppose that one starts by checking 10 individuals and only finds 1 individual with this characteristic. than the probability that the 11' th individual has the characteristic is 1/6. the fact that this is not 1/10 (although it will be close to that if the numbers of observations increase) may be counter-intuitive. it will become less so, when realising how it is obtained from the formal integration of the new information with the complete uncertainty beforehand. this formal integration, with a prior indicating that it is as likely to be 1/100 as it is to be 50/100 as it is 99/100, and with 9 negative and 1 positive observation -is by way of bayes rule. the italian mathematician, actuary, and bayesian, bruno de finetti (1906 -1985 , estimated that it would take until the year 2020 for the bayesian view of statistics to completely prevail. the purpose of this workshop is to not only convince the attendants that this is appealing outlook but also to aid the workshop participants in realising this prediction. after a first introduction of the work of reverend bayes, a number of practical examples are presented and the attendant is introduced in the use of win-bugs. a first example -introducing the notion of noninformative priors -concerns a random effects logistic regression analysis. second, the use of informative priors, is illustrated (in contrast with non-informative priors) using an analysis of differences in quality of life as observed in a randomised clinical trial. it will be shown how taking account of such prior information changes the results as well as showing how such information may increase the power of the study. in a third example, it will be shown how winbugs offers a powerful and flexible tool to estimate rather complex multi-level models in a relatively easy way and how to discriminate between various models. within this presentation some survival techniques (or stress control techniques) will be presented for when winbugs starts to spit out obscure error-codes without giving the researcher any clue where to search for the reason behind these errors. communicating research to the public h. van maanen, prof. dr. ir. d. kromhout, a. aarts most researchers will at some point in their career face difficulties in communicating research results to the public. whereas most scientific publications will pass by the larger public in silence, now and then a publication provokes profound interest of popular press. interest from the general public should be regarded as positive. after all, public money is put into research and a researcher has a societal responsibility of spreading new knowledge. however, often, general press interest is regarded upon as negative by the researcher. the messages get shortened, distorted or ridiculed. whose responsibility is this misunderstanding between press and researchers? should a researcher foresee press reaction and what can be done to prevent negative consequences? is the press responsible background and relevance: patients with a carotid artery stenosis, including those with an asymptomatic or moderate stenosis, have a considerable risk of ischemic stroke. identification of risk factors for cerebrovascular disease in these patients may improve risk profiling and guide new treatment strategies. objectives and question: we cross-sectionally investigated whether carotid stiffness is associated with previous ischemic stroke or tia in patients with a carotid artery stenosis of at least 50%. design and methods: patients were selected from the second manifestations of arterial disease (smart) study, a cohort study among patients with manifest vascular disease or vascular risk factors. arterial stiffness, measured as change in lumen diameter of the common carotid arteries during the cardiac cycle, forms part of the vascular screening performed at baseline. the first 420 participants with a stenosis of minimally 50% in at least one of the internal carotid arteries measured by duplex scanning were included in this study. logistic regression analysis was used to determine the relation between arterial stiffness and previous ischemic stroke or tia. results: the risk of ischemic stroke or tia in the highest quartile (stiffest arteries) relative to the lowest quartile was 2.1 (95% ci 1.1-4.1). these findings were adjusted for age, sex, systolic blood pressure, minimal diameter of the carotid artery and degree of carotid artery stenosis. conclusion and discussion: in-patients with a ‡50% carotid artery stenosis, increased common carotid stiffness is associated with previous ischemic stroke and tia. measurement of carotid stiffness may improve selection of high-risk patients eligible for carotid endarterectomy and may guide new treatment strategies. background (and relevance): patients with advanced renal insufficiency are at increased risk for adverse cardiovascular disease (cvd) outcomes. objectives and question: the aim was to establish whether impaired renal function is an independent predictor of cvd and death in an unselected high-risk population with cvd. design and methods: the study was performed in 2784 patients with cvd. primary outcomes were all vascular events and all cause death. during a median follow-up of 39 months, 291 patients had a vascular event (10%) and 266 patients died (9.5%). results: the adjusted hazard ratio (hr) of an estimated glomerular filtration rate <60 vs >90 ml/min per 1.73 m2 was 1.8 (95% ci 1. 2-2.7) for vascular events and 1.4 (95% ci 0.9-2.2) for all cause death. for stroke as a separate outcome it was 2.7 (95% ci 1. 2-5.8) . subgroup analysis according to vascular disease at presentation or the risk factors hypertension, diabetes and albuminuria had no influence on the hr's. conclusion and discussion: renal insufficiency is an independent risk factor for adverse cvd events in patients with a history of vascular disease. renal function was a particularly important factor in predicting stroke. the presence of other risk factors hypertension, diabetes or albuminuria had no influence on the impact of renal function alone. background and relevance: patients with hypertension have an increased case-fatality during acute mi. coronary collateral (cc) circulation has been proposed to reduce the risk of death during acute ischemia. objectives and question: we determined whether and to which degree high blood pressure (bp) affects the presence and extent of cc-circulation. design and methods: cross-sectional study in 237 patients (84% males), admitted for elective coronary angioplasty between january 1998 and july 2002. collaterals were graded with rentrop's classification (grade 0 -3). ccpresence was defined as rentrop-grade ‡1. bp was measured twice with an inflatable cuff-manometer in seated position. pulse pressure was calculated by systolic blood pressure (sbp) )diastolic blood pressure (dbp). mean arterial pressure was calculated by dbp + 1/3*(sbp-dbp). systolic hypertension was defined by a reading ‡140 mmhg. we used logistic regression with adjustment for putative confounders. results: sbp (odds ratio (or) 0.86 per 10 mmhg; 95% confidence-interval (ci) 0.73-1.00), dbp (or 0.67 per 10 mmhg; 95% ci 0.49-0.93), mean arterial pressure (or 0.73 per 10 mmhg; 95% ci 0.56-0.94), systolic hypertension (or 0.49; 95% ci 0.26-0.94), and antihypertensive treatment (or 0.53; 95% ci 0.27-1.02), each were inversely associated with the presence of cc's. also, among patients with cc's, there was a graded, significant inverse relation between levels of sbp, levels of pulse pressure, and collateral extent. conclusion and discussion: there is an inverse relationship between bp and the presence and extent of cc-circulation in patients with ischemic heart disease. background and relevance: silent brain infarcts are associated with decreased cognitive function in the general population. objectives and question: we examined whether this relation also exists in patients with symptomatic arterial disease. furthermore, we compared cognitive function of patients with stroke or tia, with cognitive function of patients with symptomatic arterial disease at other sites in the arterial tree. design and methods: an extensive screening was done in 336 consecutive patients participating in the second manifestations of arterial disease (smart) study, including a neuropsychological test. inclusion diagnoses were cerebrovascular disease, symptomatic coronary artery disease, peripheral arterial disease, or abdominal aortic aneurysm. mri examination was performed to assess the presence of silent infarcts in patients without symptomatic cerebrovascular disease. the patients were assigned to one of three categories according to their patient history and inclusion diagnosis: no stroke or tia, no silent infarcts (n = 220; mean age 57 years); no stroke or tia, but silent infarcts present (n = 33; mean age 65 years); stroke or tia at background and relevance: patients with manifest vascular disease are at high risk of a new vascular event or death. modification of classical risk factors is often not successful. objectives and question: we determined whether the extra care of a nurse practitioner (np) could be beneficial to the cardiovascular risk profile of high-risk patients. design and methods: randomised controlled trial based on the zelen design. 236 patients with manifestations of a vascular disease and who had ‡2 modifiable vascular risk factors were prerandomised to receive treatment by a np plus usual care or usual care alone. after 1 year, risk factors were re-measured. primary endpoint was achievement of treatment goals for risk factors. results: of the pre-randomised patients, 95 of 119 (80%) in the intervention group and 80 of 117 (68%) in the control group participated in the study. after a mean follow-up of 14 months, the patients in the intervention group achieved significantly more treatment goals than did the patients in the control group (systolic blood pressure 63% versus 37%, total cholesterol 79% vs 61%, ldl-cholesterol 88% vs 67%, and bmi 38% vs 24%). medication use was increased in both groups and no differences were found in patients' quality of life (sf-36) at followup. conclusion and discussion: treatment delivered by nps, in addition to a vascular risk factor screening and prevention program, resulted in a better management of vascular risk factors compared to usual care alone in vascular patients after 1 year follow-up. were used as non-invasive markers of vascular damage and adjusted for age and sex if appropriate. results: the prevalence of the metabolic syndrome in the study population was 45%. in pad patients this was 57%; in chd patients 40%, in stroke patients 43% and in aaa patients 45%. patients with the metabolic syndrome had an increased mean imt (0.98 vs. 0.92 mm, p-value <0.01), more often a decreased abpi (14% vs. 10%, p-value 0.06) and increased prevalence of albuminuria (20% vs. 15%, p-value 0.03) compared to patients without this syndrome. an increase in the number of components of the metabolic syndrome was associated with an increase in mean imt (p-value for trend <0.001), lower abpi (p-value for trend < 0.01) and higher prevalence albuminuria (p-value for trend < 0.01). conclusion and discussion: in patients with manifest vascular disease the presence of the metabolic syndrome is associated with advanced vascular damage. background (and relevance): in patients with type 2 diabetes the progression of atherosclerosis is accelerated, as observed by the high incidence of cardiovascular events. objectives (and question): to estimate the influence of location and extent of vascular disease on new cardiovascular events in type 2 diabetes patients. design and methods: diabetes patients (n = 669), mean age 59 years, with and without prior vascular disease were followed through 1996-2004 (mean follow-up 3 years). patients with vascular disease (n = 399) were classified according to symptomatic vascular location, and number (extent) of locations. we analyzed occurrence of new (non)-fatal cardiovascular events using cox proportional hazards models and kaplan-meier analysis. results: multivariate-adjusted hazard ratios (hrs) were comparable in diabetes patients with cerebrovascular disease (hr 3.2; 95% ci 1.3-7.4), coronary heart disease (hr 3.3; 1.5-7.1) and peripheral arterial disease (hr 2.6; 1.1-6.3), compared to those without vascular disease. multivariate-adjusted hr was 2.7; (1. 3-5.9 ) in patients with one vascular location and 4.8; (2.1-10.9) in those with ‡2 locations. the 3-year risks were respectively 11.6% (7.4-15.7) and 26.7% (16. 8-36.7) . conclusion and discussion: diabetes patients with prior vascular disease have an increased risk of cardiovascular events, irrespective of symptomatic vascular location. cardiovascular risk increased with the number of locations. data emphasize the necessity of early and aggressive treatment of cardiovascular risk factors in diabetes patients. background (and relevance): despite recent advances in medical treatment, cardiovascular disease (cvd) is still health problem number one in western societies. a multifactorial approach with the aid of nurse practitioners (nps) is beneficial for achieving treatment goals and reducing events in patients with manifest cvd. objectives (and question): in the self-management of vascular patients activated by internet and nurses (spain) pilot study, we want to implement and test a secure personalized website with additional treatment and coaching of a np for hypertension, hyperlipidemia, diabetes mellitus, smoking and obesity in patients with clinical manifestations of cvd. design and methods: 50 interesting patients are going to use the secure patient-specific website. before the use of the web-application, risk factors are measured. realistic treatment goal(s) for elevated risk factors based on current guidelines are made and appointments how to achieve the treatment goal(s) are determined between the patients and the np in a face to face contact. patients can enter his/ her own weight or a new blood pressure measurement for instance, besides the regular exchange information with the responding np through e-mail messages. the np personally replies as quick as possible and gives regular but protocol driven feedback and support to the patient. the risk factors are remeasured after six months. conclusion and discussion: the spain study is aimed to implement and test a patient specific website. secondary outcome is the change in cardiovascular risk profile. the pre-post measurements of risk factors and the amount of corresponding e-mail messages between the patient and the np enhances the feasibility of this innovative way of risk factor management. background (and relevance): modification of vascular risk factors has been shown to be effective in reducing mortality and morbidity in patients with symptomatic atherosclerosis. nevertheless, reduction of risk factors in clinical practice is difficult to achieve and maintain. objectives (and question): in the risk management in utrecht and leiden evaluation (rule) study, a prospective, comparative study, we assess the effects of a multidisciplinary vascular screening program on improvement of the cardiovascular risk profile and to compare this to a setting without such a program that provides current standard practice in patients referred for cardiovascular disorders. design and methods: patients with diabetes mellitus, coronary artery disease, cerebrovascular disease, or peripheral arterial disease (150 per disease category in each hospital) referred by the general practitioner will be enrolled, started january 2005. at the umcu, patients need to be enrolled in the vascular screening program or will be identified through the hospital registration system. at the lumc patients will be identified through the hospital registration system. risk factors will be measured in the two hospitals at baseline and one year after their initial visit. a risk function will be developed for this population based on data of the whole cohort. analysis will be performed on the two comparison groups as a whole, and on subgroups per disease category. changes in risk factors will be assessed with linear or logistic regression procedures, adjusting for differences in baseline characteristics between groups. conclusion and discussion: the rule study is aimed to evaluate the added value of a systematic hospital based vascular screening program on risk factor management in patients at high risk for vascular diseases. background: signs of early cerebral damage are frequently seen on mri scans in elderly people. they are related to future manifest cerebrovascular disease and cognitive deterioration. cardiovascular risk factors can only partially explain their presence and progression. evidence that inflammation is involved in atherogenesis continues to accumulate. chronic infections can act as an inflammatory stimulus. it is possible that subclinical inflammation and chronic infections play a role in the pathogenesis of early cerebral damage. objectives (and question): to unravel the role of inflammation and chronic infection in the occurrence and progression of early cerebral damage in patients with manifest vascular disease. design and methods: 1200 participants of the smart study with manifest vascular disease underwent an mr investigation of the brain between may 2001 and december 2005. starting in january of 2006 all patients are invited for a second mr of the brain after an average follow-up period of four years. both at baseline and after follow-up all cardiovascular risk factors are measured and blood samples are stored to assess levels of inflammatory biomarkers and antibodies against several pathogens. occurrence and progression of early cerebral damage is assessed by measuring the volume of white matter lesions, the number of silent brain infarctions, cerebral atrophy, aberrant metabolic ratios measured with mr spectroscopy and cognitive function at baseline and after follow-up. the relation between inflammation, chronic infection and the occurrence and progression of early cerebral damage will be investigated using both crosssectional and longitudinal analysis. abstract 13 monocyte chemoattractant protein 1 (mcp-1) polymorphism and susceptibility for coro-nary collaterals j.j. regieli 1,2 , j. koerselman 2 , ng sunanto 1,2 , m. entius 1 , p.p. de jaegere 1 , y. van der graaf 2 , d.e. grobbee 2 , p.a. doevendans 1 1 heart lung institute, dept of cardiology 2 clinical epidemiology, julius center for health sciences and primary care, utrecht, netherlands background (and relevance): collateral formation is an important beneficial condition during an acute ischemic event. a marked interindividual variability in high risk patients is seen, but at present the basis for this variability is unclear and can not be explained solely by environmental factors. a genetic factor might be present that could influence coronary collateral formation. objectives (and question): we have analyzed the association between a single nucleotide polymorphism in mcp-1 and the formation of coronary collaterals in patients admitted for angioplasty. mcp-1 has been suggested to play an important role in collateral development. design and methods: this study involved 226 caucasian patients who were admitted for coronary angioplasty. coronary collateral development was defined angiographically as rentropgrade ‡1. polymorphisms in the promoter region of mcp-1 ()2518) were identified by pcr and allele specific restriction digestion. this method allows identification of individuals with either aa, ag or gg at mcp-1 position )2518. statistical analysis was performed using a x2-test, unconditional logistic regression, likelihood ration and a wald's test. results: we could genotype 224 of the 226 patients. coronary collaterals (rentropgrade >1) were found in 84 patients. the allele frequency for aa, ag and gg was 53.1%, 40.2% and 6.7%, respectively. the dis-tribution of mcp-1 genotypes in subjects without collaterals was in hardy weinberg equilibrium. we found that individuals with g allele (24%) were more likely to have collaterals than those with homozygous aa (or 1.66, 95% ci 0.96 to 2.87) adjusted for potential confounders. linear regression shows that the allele g increased the likelihood for collateral presence with a factor 1.41. conclusion and discussion: this study provides evidence for a role for genetic variation of mcp-1 gene in the occurrence of coronary collaterals in high risk patients. 2001 until september 2003 patients with recently established clinically manifest atherosclerotic disease with >2 modifiable vascular risk factors were selected for the study. the mean self-efficacy scores were calculated for vascular risk factors (age, sex, vascular disease, weight, diabetes mellitus, smoking behavior, hypercholesterolemia, hypertension, and hyperhomocysteinemia). results: diabetes, overweight, and smoking, but none of the other risk factors, were significantly associated with the level of self-efficacy in these patients. patients with diabetes had lower self-efficacy scores (3.0) for exercise and controlling weight (3.7) than patients without diabetes (4.2 p = 0.05) and (4.1 p = 0.01) respectively. overweight patients scored low on controlling weight (3.8 and 3.5 p<0.001) and choosing healthy food (3.7 and 3.3 p = 0.01) than patients who were on a healthy weight (4.3 and 4.0). conclusion and discussion: patients with vascular diseases appear to have high levels of self-efficacy regarding medication use (4.8), exercise (4.1), and controlling weight (4.0). in patients with diabetes, overweight and in smokers, self efficacy levels were lower. practice implications: in nursing care and research on developing self-efficacy based interventions, lower self-efficacy levels can be taken into account for specific vascular patient groups. background (and relevance): little is known about the role of serum uric acid in the metabolic syndrome and increased risk of cardiovascular disease. we investigated the association between uric acid levels and the metabolic syndrome in a population of patients with manifest vascular diseases and whether serum uric acid levels conveyed an increased risk for cardiovascular disease in patients with the metabolic syndrome. design and methods: this is a nested case-cohort study of 431 patients originating from the second manifestations of arterial disease (smart) study. all patients had manifest vascular diseases, constituting peripheral artery disease, cerebral ischemia, coronary artery disease and abdominal aortic aneurysm. analyzing the relationship of serum uric acid with the metabolic syndrome, age, sex, creatinine clearance, alcohol and diuretics were considered as confounders. investigating the relationship of serum uric acid levels with the risk for cardiovascular disease, values were adjusted for age and sex. results: the metabolic syndrome was present in 50% of the patients. serum uric acid levels in 214 patients with metabolic syndrome were higher compared to 217 patients without (0.36 ± 0.08 mmol/l vs. 0.32 ± 0.09 mmol/l). serum uric acid concentrations increased with the number of components of the metabolic syndrome (0.30 mmol/l to 0.38 mmol/l) adjusted for age, sex, creatinine clearance, alcohol and use of diuretics. increased serum uric acid concentrations showed to be independently associated with the occurrence of cardiovascular events in patients without the metabolic syndrome (age en sex adjusted hr: 1.9, 95% ci 0. 9-3.9) , contrary to patients with the metabolic syndrome (adjusted hr: 1.3, 95% ci 0.6 -2.7). conclusion: elevated serum uric acid levels are strongly associated with the metabolic syndrome, yet are not linked to an increased risk for cardiovascular disease in patients with the metabolic syndrome. however, in patients without the metabolic syndrome elevated serum uric acid levels are associated with increased risk for cardiovascular disease. the objective of this study is to investigate the overall and combined role of late-life depression, prolonged psychosocial stress exposure, and stress hormones in the etiology of hippocampal atrophy and cognitive decline. design and methods: as part of the smart study, 1200 participants with manifest vascular disease underwent an mri of the brain between may 2001 and december 2005. in a subsample of 800 subjects, cognitive function and depressed mood were assessed. starting in january 2006, all patients are invited for a follow-up mri of the brain. at this follow-up measurement, minor and major depression, hypothalamic-pituitary-adrenal (hpa) axis function indicated by salivary cortisol, psychosocial stress exposure indicated by stressful life events early and later in life, and cognitive functioning will also be assessed. the independent and combined effects of late-life depression, (change in) hpa-axis activity, and psychosocial stress exposure on risk of hippocampal atrophy and cognitive decline will be estimated with regression analysis techniques adjusting for potential confounders. introduction the netherlands epidemiological society advocates according to good epidemiological practice, that research with sound research questions and good methodology should be adequately published independent of the research outcomes. although reporting bias in clinical trials is fully acknowledged, failure to report outcomes or selective reporting of outcomes in non-clinical trial epidemiological studies is less well known, but most likely occurs as well. in this mini-symposium the netherlands epidemiological society wants to give attention to this phenomenon of not publishing research outcomes, to encourage publication of all outcomes of adequate research. different scopes to this subject will be addressed: the background, an example of occurrence, initiatives to possibly avoid it and an editor's point of view. selective reporting of outcomes in clinical studies (reporting bias) has been described to occur frequently. therefore a registration of clinical trials is started which enables to address this problem in the future since occurrence of not publishing negative or adverse outcomes can be investigated with this registration. in non-clinical epidemiological studies the failure to report outcomes or selective reporting of outcomes most likely occurs as well, but is less studied and reported. again studies with negative outcomes or no associations are the ones most likely not to be reported. the most important obstacles for not publishing no or negative associations are tradition and priorities of researchers and journals. the reviewers might play a role in this as well. the netherlands epidemiological society advocates according to good epidemiological practice, that research with sound research questions and good methodology should be adequately published independent of the research outcomes. however, reality occurs not to be accordingly. therefore we would like to give attention to this phenomenon of not publishing research outcomes in non-trial-based epidemiological studies, to encourage publication of all outcomes of adequate research. in this mini-symposium, firstly the effects of failure or selective publishing of outcomes on subsequent meta-analysis in a non-clinical research setting will be demonstrated. afterwards, initiatives to promote and improve publication of observational epidemiological research will be addressed, the editor's point of view on this phenomenon will be given and finally concluding remarks will be given. background: there are several reasons for suspecting reporting bias in time-series studies of air pollution. such bias could lead to false conclusions concerning causal associations or inflate estimates of health impact. objectives: to examine time-series results for evidence of publication and lag selection bias. design and methods: all published time-series studies were identified and relevant data extracted into a relational database. effect estimates were adjusted to an increment of 10lg/m 3 . publication bias was investigated using funnel plots and two statistical methods (begg, egger). adjusted summary estimates were calculated using the ''trim and fill'' method. the effect of lag selection was investigated using data on mortality from 90 us cities and from a european multi-centre panel study of children. results: there was evidence of publication bias in a number of pollutant-outcome analyses. adjustment reduced the summary estimates by up to 20%. selection of the most significant lag increased estimates by over 100% compared with a fixed lag. conclusion and discussion: publication and lag selection bias occurs in these studies but significant associations remain. presentation and publication of time-series results should be standardised. background: selective non-publication of study outcomes hampers the critical appraisal and appropriate interpretation of available evidence. its existence could be shown empirically in clinical trials. observational research often uses an exploratory approach rather than testing specific hypotheses. results of multiple data analyses may be selected based on their direction and significance. objectives: to improve the quality of reporting of observational studies. to help avoid selective non-publication of study outcomes. methods: ''strengthening the reporting of observational studies in epidemiology (strobe)'' is an international multidisciplinary initiative that currently develops a checklist of items recommended for the reporting of observational studies (http:// www.strobe-statement.org). results: strobe recommends to avoid selective reporting of 'positive' or 'significant' study results and to base the interpretation on main results rather than on results of secondary analyses. discussion: strobe cannot prevent data dredging, but it promotes transparency at the publication stage. for instance, if multiple statistical analyses were performed in a large dataset to identify new exposure-outcome associations, authors should give details and not only report significant associations. strobe could have a ''feedback effect'' on study quality since, ideally, researchers think ahead when a study is planned and consider points that are essential for later publication. good publishing practice begins with researchers considering (1) whether an intended study can bring added value, irrespective its result, (2) and whether its methodology is valid to pick up positive and negative outcomes equally well. when reporting (3) they should adequately discuss the significance of a negative result (4) and be as eager to publish negative results as positive ones. as to editors, intentional bias in relation to study results is considered editorial malpractice, whatever its motivation. unintentional bias may be more frequent but will not easily be noticed, also by editors. editorial responsibility implies several levels (accepting for review, choice of reviewers, assess their reviews, decision making, and a repeated process in case of resubmission). various designs for process evaluation can be considered. evaluation will be more difficult for journals with few professional support. collaboration between journals can help, and may also avoid 'self evaluation bias'. in line with registering of randomized trials, registers for observational study protocols could facilitate monitoring for bias and searching unpublished results. but practicalities, methodological requirements, and bureaucratic burden should not be underestimated. in principle, in an era of electronic publishing every study can be made widely accessible widely also if not 'accepted', by editors or authors themselves. however, this would need huge changes in culture of authoring and reading, editorial practice, publishing business, and scientific openness. background: high circulating levels of insulin-like growth factor-i (igf-i), a mitogenic and anti-apoptotic peptide, have been associated with increased risk of several cancer types. objective: to study circulating levels of igf-i and igf binding protein-3 (igfbp-3) in relation to ovarian cancer risk. design and methods: within the european prospective investigation into cancer and nutrition (epic), we compared levels of igf-i and igfbp-3 measured in blood samples collected at baseline in 214 women who subsequently developed ovarian cancer (37 women diagnosed before age 50) and 388 controls. results: the risk of developing ovarian cancer before age 50 ('premenopausal' was increased among women in the middle or top tertiles of igf-i, compared to the lowest tertile: or = 2.69 [95% ci: 0.87 8.35 ], and or = 3.20 [95% ci: 1.01 -10.2], respectively (p trend = 0.06). results were adjusted for bmi, previous hormone use, fertility problems and parity. adjustment for igfbp-3 levels slightly attenuated relative risks. in older women we observed no association between igf-i, igfbp-3 and ovarian cancer risk. discussion and conclusion: in agreement with the only other prospective study in this field (lukanova et al, int j cancer, 2002) , our results indicate that high circulating igf-i levels may increase the risk of premenopausal ovarian cancer. background: the proportion of glandular and stromal tissue in the breast (percent breast density) is a strong breast cancer risk factor. insulin-like growth factor 1 (igf-1) is hypothesized to influence breast cancer risk by increasing breast density. objectives: we studied the relation between premenopausal circulating igf-1 levels and changes in breast density over menopause. design and methods: mammograms and blood samples of 684 premenopausal participants of the prospect-epic cohort were collected at baseline. a second mammogram was collected after these women became postmenopausal. we determined serum igf-1 levels. mammographic density was assessed using a computer-assisted method. changes in percent density over menopause were calculated for quartiles of igf-1, using linear regression, adjusted for age and bmi. results: premenopausal percent density was not associated with igf-1 levels (mean percent density 0.43 in all quartiles). however, women in the highest igf-1 quartile showed less decrease in percent density over menopause (1st quartile: )0.094 vs 4th quartile: )0.059, p-trend = 0.02). this was mostly explained by a stronger decrease of total breast size in women with high igf-1 levels. conclusion and discussion: women with high igf-1 levels show a lower decrease of percent density over menopause than those with low igf-1 levels. background: body mass index (bmi) has been found to be associated with risk of colon cancer in men, whereas weaker associations have been reported for women. reasons for this discrepancy are unclear but may be related to fat distribution or use of hormone replacement therapy (hrt) in women. objective: to examine the association between anthropometry and risk of colon cancer in men and women. design and methods: during 6.1 years of followup, we identified 984 cases of colon cancer among 368,277 subjects free of cancer at baseline from 9 european countries. results: bmi was significantly related to colon cancer risk in men (rr per kg/ m2, 1.05; 95%-ci 1.02-1.08) but not in women (rr 1.02; 1.00-1.04; p interaction = 0.04), whereas waist-hip-ratio (whr) was equally strong related to risk in both genders (rr per 0.1, men, 1.24; 95%-ci 1.05-1.46; women, 1.24; 1.10-1.39; p interaction = 0.92). the positive association for whr was not apparent among postmenopausal women who used hrt. conclusions: abdominal obesity is an equally strong risk factor for colon cancer in both sexes and whr is a disease predictor superior to bmi in women. the association may vary depending on hrt use in postmenopausal women; however, these findings require confirmation in future studies. background: fruits and vegetables are thought to protect against colorectal cancer. recent cohort studies, however, have not been able to show a protective effect. patients & methods: the relationship between consumption of vegetables and fruit and the incidence of colorectal cancer within epic was examined among 453,158 subjects of whom 1808 developed colorectal cancer. a multivariate cox proportional hazard model was used to determine adjusted cancer risk estimates. a calibration method based on standardized 24-hour dietary recalls was used to correct for measurement errors. results: after adjustment for potential confounding and exclusion of the first two years of follow-up, the results suggest that consumption of vegetables and fruits is weakly, inversely associated with risk of colorectal cancer (hr 1.00, 0.85, 0.85, 0.86, 0.79, for quintiles of intake, 95% ci upper quintile 0.65-0.97, p-trend 0.06), with each 100 gram daily increase in vegetables and fruit associated with a statistically borderline significant 3% reduction in colorectal cancer risk (hr 0.97; 0.94-1.00). linear calibration strengthened this effect. further subgroup analyses will be presented. conclusion: findings within epic support the hypothesis that increased consumption of fruits and vegetables may protect against colorectal cancer risk. a diverse consumption of vegetables and fruit may influence the risk of gastric and oesophageal cancer. diet diversity scores (dds) were calculated within the epic cohort data from >520,000 subjects in 10 european countries. four scores, counting the number of ffq-based food-items usually eaten at least once in two weeks, were calculated to represent the diversity in the overall vegetable and/or fruit consumption. after an average follow-up of 6.1 years, 400 incident cases of gastric and oesophageal cancer were observed. cox proportional hazard models were used to compute tertile specific risks, stratified by follow-up duration, gender and centre and adjusted for total consumption of vegetables and fruit and potential confounders.preliminary findings suggest that, compared to individuals who eat from only 5 or less vegetable sub-groups, individuals who usually eat from eight different subgroups, have a reduced gastric cancer risk (hr 0.68; 95% ci 0.45-1.05). in comparison to all others, individuals who usually eat only the same fruit may experience an elevated risk (hr 1.34; 95% ci 0.95-1.89). these findings from the epic study suggest that a diverse consumption of vegetables may reduce gastric and oesophageal cancer risk. subjects with a very low diversity in fruit consumption may experience higher risk. g. steindorf 1 , l. friedenreich 2 , j. linseisen 1 , p. vineis 3 , e. riboli 3 for the epic group 1 german cancer research center, heidelberg, germany 2 alberta cancer board, alberta, canada 3 imperial college london, great-britain background: previous research on physical activity and lung cancer risk, conducted predominantly in males, has yielded inconsistent results. objectives: we examined this relationship among 416,277 men and women from the epic-cohort. design and methods: during 6.3 years of follow-up we identified 607 men and 476 women with incident primary lung cancer. detailed information on recreational, household and occupational physical activity, smoking habits, and diet was assessed. relative risks (rr) were estimated using cox regression. results: we did not observe an inverse association between occupational, recreational or household physical activity and lung cancer risk either in males or in females. we found a modest reduction in lung cancer risk associated with sports in males and cycling in females. for occupational physical activity, lung cancer risk was increased for unemployed men (rr = 1.55; 95% confidence interval 1.18-2.03) and men with standing occupations (rr = 1.34; 1.01-1.78) compared with sitting professions. conclusion: our study shows no convincing protective associations of physical activity with lung cancer risk. discussion: it may be speculated that the elevated risks for occupational physical activity could reflect the higher probability that manual workers are exposed to industrial carcinogens compared to workers having sitting/office jobs. purposes: epidemiological research almost always means using data and, increasingly, human tissue as well. the use of these resources is not free but is subject to various regulations, which differ in the european countries on several important aspects. usually these regulations have been determined without involvement of active epidemiological researchers or patient organisations. this workshop will address the issues involved in these regulations in the european context. it will serve the following purposes: -to provide arguments and tools and to exchange best practices for a way out of the regulatory labyrinths especially in cross european research projects; -to provide a platform for epidemiologists and patient groups to discuss their concerns about impediments for epidemiological research with other parties, like data protection authorities. targeted audience: the mini symposium is primarily meant for epidemiologists, but provides an excellent opportunity to meet and discuss with other stakeholders, like from patient groups, data protection authorities, the european commission etc. as well. therefore program allows for extra time for discussion. the other stakeholders will be explicitly invited. a special 'day ticket' is available to satellite symposium epidemiology and the seventh eu research framework over the last few years the seventh eu research framework has been drafted. it is now rapidly moving towards the first calls for proposals. previous eu research programmes and frameworks have been criticised because they are considered to include too few possibilities for epidemiological research and public health research. this satellite-symposium will provide an outline of the research framework and inform researchers about the current state of affairs of the seventh eu research framework. special focus will be on the possibilities for epidemiology and public health research. 30-14.35 welcome by our host prof. jan willem coebergh, rotterdam, introduction, international and national regulations on the use of data and tissue or research in europe, different approaches to: evert-ben van veen l.l.m. (medlawconsult, the netherlands) -'identifiability' of data -consent for using data and tissue for research the tubafrost code of conduct to exchange data and tissue across europe. 14. 50-15.05 data and tissuebanking for research in denmark: a liberal approach the danish approach to use patient data for epidemiological research, cooperation of the danish data protection authority, the danish act of 2004 to use anonymous but coded tissue for research based on an opt-out system, first experiences hans storm ph.d. (copenhagen, denmark) 15. 05-15.20 estonian data protection act: a disaster for epidemiology the story of the birth of the act, implementing the european data protection directive and of its consequences reveal political and administrative incapability resulting in gradual vanishing of register-based epidemiological research. background: non-invasive assessment of atherosclerosis is important. most of the evidence of coronary calcium has been based on images obtained by electron beam ct (ebct). current data suggest that ebct and multi-slice ct (msct) give comparable results. since msct is more widely available than ebct, information on its reproducibility is relevant. objective: to assess inter-scan reproducibility of msct and to evaluate whether reproducibility is affected by different measurement protocols, slice thickness, cardiovascular risk factors and technical variables. design: cross-sectional study. materials and methods: the study population comprised 76 healthy postmenopausal women. coronary calcium was assessed in these women twice at two separate visits using msct (philips mx 8000 idt 16). images were made using 1.5 and 3.0 mm slice thickness. the agatston, volume and mass scores were assessed. reproducibility was determined by mean differences, absolute mean differences and intra-class correlation coefficients (iccc). results: the reproducibility of coronary calcium measurements between scans was excellent with iccc of > 0.98, and small mean and absolute mean differences. reproducibilility was similar for 1.5 as for 3.0 mm slices, and equal for agatston, volume and mass measurements. conclusion: inter-scan reproducibilility of msct is excellent, irrespective of slice thickness and type of calcium parameter. background: it has been suggested that the incidence of colorectal cancer is associated with socioeconomic status (ses). the major part of this association may be explained by known lifestyle risk factors such as dietary habits. objective: to explore the association between diet and ses measured at area-based level. methods: the data for this analysis were taken from a multi-centre case-control study conducted to investigate the association between some environmental, genetic factors and colorectal cancer incidence. the townsend scores (as deprivation index) were categorized into fifths. a linear regression analysis was used to estimate difference in mean of each continuous variable of diet by deprivation fifth. results: the mean of processed meat consumption in the most deprived area was higher compared to the mean of that in the most affluent areas (mean difference = 5.5, 95% ci: 3.94, 7.05). by contrast, the mean of vegetables and fruits consumption in the most deprived areas was lower than that in the affluent areas. conclusion: our findings suggest that lifestyle factors are likely to be related to ses. thus any relation between ses and colorectal cancer may direct us to seek for the role of different life style factors in aetiology of this cancer. background: the reason for the apparent decline in semen quality during the past 50 years is still unexplained. objective: to investigate the effect of exposure to cigarette smoke in utero on the semen quality in the male offspring. design and methods: in this prospective follow-up study, 350 adult sons of mothers, who during pregnancy provided information about smoking and other lifestyle factors, are sampled in six strata according to prenatal tobacco smoke exposure. each man provides a semen sample, a blood sample, and answers a questionnaire, which is collected in a mobile laboratory. external quality assessment of semen analysis is performed twice a year. results: until now, a total of 265 men have been included. the participation rate is 52%. the percentage of men with decreased sperm concentration (<20 mill/ml) is 23%. the unadjusted median (25-75% percentile) sperm concentration in the non-exposed group (n = 90) is 49 (23-86) mill/ml compared to 33 (12-63) mill/ml among men exposed to >19 cigarettes per day in fetal life (n = 26 aim: to estimate the prevalence of overweight and obesity, and their effects in physical activity (pa) levels of portuguese children and adolescents aged 10-18 years. methods: the sample comprises 12669 subjects (6489 females-6180 males) attending basic/secondary schools. the prevalence of overweight and obesity was calculated using body mass index (bmi), and the cut-off points suggested by cole et al. (2000) . pa was assessed with the baecke et al. (1982) questionnaire. proportions were compared using chi-square tests and means by anova. results and conclusions: overall, 17.1% were overweight (females = 16.4%; males = 17.8%) and 3.3% were obese (females = 3.0%; males = 3.6%). prevalence was similar across age and gender. bmi changed with age (p<0.001), and a significant interaction between age and gender was found (p = 0.001): whereas bmi in males increased with aging, in females increased up to 16 years and stabilized onwards. males showed significantly higher values of pa (p<0.001). both genders had a tendency to increase their pa until 16-17 years. a significant interaction between age and gender (p = 0.006) points out different gender patterns across age: pa increased with aging in males but in females started to decline after 16 years. no significant differences in pa were found between normal weight, overweight and obese subjects (p = 0.352). background: atherosclerosis is an inflammatory process. however, the relation between inflammatory markers and extent and progression of atherosclerosis remains unclear. objectives: we studied the association between c-reactive protein (crp) and 5 established measures of atherosclerosis. design and methods: within the rotterdam study, a population-based cohort of 7,983 persons over age 55, we measured crp, carotid plaque and intima-media thickness (imt), abdominal artery calcification, ankle-brachial index (abi) and coronary calcification. using ancova, we investigated the relation between crp and extent of atherosclerosis. we studied the association between progression of extra coronary atherosclerosis (mean follow-up period: 6.4 years) and crp using multinomial regression analysis. results: crp levels were positively related to all measures of atherosclerosis, but the relation was weaker for measures based on detection of calcification only. crp levels were associated with severe progression of carotid plaque (multivariable adjusted odds ratio: 1.5, 95% ci: 0.9-2.5), imt (1.7, 1.0-2.8) and abi (1.7, 1.1-2.6). no relation was observed with progression of abdominal artery calcification. conclusion and discussion: crp is related to extent and progression of atherosclerosis. the relation seems weaker for measures based on detection of calcification only, indicating that calcification of plaques might attenuate the inflammatory process. background: maternal stress during pregnancy has been reported to have an adverse influence on fetal growth. the terrorist attacks of september 11, 2001 on the united states have provoked feelings of insecurity and stress worldwide. objective: our aim was to test the hypothesis that maternal exposure to these acts of terrorism via the media had an unfavourable influence on mean birth weight in the netherlands. design and methods: in a prospective cohort study, we compared birth weights of 1885 dutch neonates who were in utero during the attacks with those of 1258 neonates who were in utero exactly 1 year later. results: in the exposed group, birth weight was lower than in the non-exposed group (difference, 48 g, 95%ci 13.6, 82.9, p = 0.006). the difference in birth weight could not be explained by tobacco use, maternal age, parity or other potential confounders, nor by shorter pregnancy durations. conclusion: these results provide evidence supporting the hypothesis that exposure of dutch pregnant women to the september 11 events via the media has had an adverse effect on the birth weight of their offspring. objective: asian studies suggested potential reduction in the risk of pneumonia among patients with stroke on ace-inhibitor therapy. because of the high risk of pneumonia in patients with diabetes we aimed to assess the effects of ace-inhibitors on the occurrence of pneumonia in a general, ambulatory population of diabetic patients. methods: a case-control study was performed nested in 142,175 patients with diabetes. cases were defined as patients with a first diagnosis of pneumonia. for each case, up to 4 controls were matched by age, gender, practice, and index date. current ace-inhibitor use was defined within a time-window encompassing the index date. results: ace-inhibitors were used in 12.7% of 4,719 cases and in 13,7% of 15,322 matched controls (crude or: 0.92, 95% ci 0.82 to 1.01). after adjusting for potential confounders, ace-inhibitor therapy was associated with a reduction in pneumonia risk (adjusted or: 0.72, 95% ci 0.64 to 0.80). the association was consistent among different relevant subgroups (stroke, heart failure, and pulmonary diseases) and showed a strong dose-effect relationship (p<0.001). conclusions: use of ace-inhibitors was significantly associated with reduced pneumonia risk and may apart from blood pressure lowering properties be useful in prevention of respiratory infections in patients with diabetes. background: progressive decline in serum levels of testosterone occurs with normal aging in both men and women. this is paralleled by a decrease in physical performance and muscle strength, which may lead to disability, institutionalization and mortality. objective. we examined whether low levels of testosterone were associated with three-year decline in physical performance and muscle strength in two population-based samples of older men and women. methods: data were available for 623 men in the longitudinal aging study amsterdam (lasa) and 1172 men and 1278 women in the health, aging, and body composition (health abc) study. levels of total testosterone and free testosterone were determined at baseline. physical performance and grip strength were measured at baseline and after three years. results: total and free testosterone were not associated with change in physical performance or muscle strength in men. in women, low levels of total testosterone (<=20 ng/dl) increased the risk of decline in physical performance (p = 0.03), and low levels of free testosterone (<2 pg/ ml) of decline in muscle strength (p = 0.03). conclusion: low levels of total and free testosterone were associated with decline in physical performance and muscle strength in older women, but not in older men. background: obesity and physical inactivity are key determinants of insulin resistance, and chronic hyperinsulinemia may mediate their effects on endometrial cancer (ec) risk. aim: to examine the relationships between prediagnostic serum concentrations of cpeptide, igf binding protein (igfbp)-1 and igfbp-2, and ec risk. methods: we conducted a case-control study nested within the epic prospective cohort study, including 286 incident cases of ec, in pre-and post-menopausal women, and 555 matched control subjects. odds ratios (or) and 95% confidence intervals (ci) were calculated using conditional logistic regression models. results: in fasting women (>6 h since last meal), serum levels of c-peptide, igfbp-1 and igfbp-2 were not related to risk. however, in nonfasting women (6 h or less since last meal), ec risk increased with increasing serum levels of c-peptide ( background: tobacco is the single most preventable cause of death in the world today. tobacco use primarily begins in early adolescent. objective: to estimate the prevalence and evaluate factors associated with smoking among high school going adolescents in karachi, pakistan. methods: a school based cross sectional survey was conducted in three towns of karachi from january through may 2003. two-stage cluster sampling stratified on school types was employed to select schools and students. self-reported smoking status of school going adolescents was our main outcome in analysis. results: prevalence of smoking (30 days) among adolescents was 13.7%. multiple logistic regression model showed that after adjustment for age, ethnicity and place of residence, being student of a government school (or=1.6; 95% ci: 1.0-2.7), parental smoking (or = 1.7; 95% ci: 1.1 -2.8), uncle (or = 1.7; 95% ci: 1. 2-2.8) , peer smoking (or = 6.2; 95% ci: 3.9 -9.9) and spending leisure time outside home (or = 3.9; 95% ci 1. 2-13.2) were significantly associated with adolescents smoking. conclusion: a 13.7% prevalence of smoking among school going adolescents and influence of parents and peers in initiating smoking in this age group warrant the need for effective tobacco control in the country especially among the adolescents. background: individual patient data meta-analyses (ipd-ma) have been proposed to improve subgroup analyses that may provide clinically relevant information. nevertheles, comparison of the effect estimates of ipd-ma and meta-analyses of published data (map) are lacking. objective: to compare main and subgroup effect estimates of ipd-ma and map. methods: an extended literature search was performed to identify all ipd-ma of randomized controlled trials, followed by a related article search to identify maps with a similar domain, objective, and outcome. data were extracted regarding number of trials, number of subgroups, effect measure, effect estimate and their confidence intervals. results: in total 16 ipd-ma and 18 map could be included in the analysis. twentyfive main effect estimates could be compared; of which 22 were in the same direction. although over 100 subgroups were studied in both ipd-ma and map, only 18 effect estimates could be compared; 17 were in the same direction. subgroup analyses in map most often related to trial characteristics, whereas subgroup analyses in ipd-ma were related to patient characteristics. conclusion: comparable ipd-ma and map report similar main and subgroup effect estimates. however, ipd-ma more often study subgroups based on patient characteristics, and thus provide more clinically relevant information. patients with diabetes have an increased risk of a complicated course of community-acquired lower respiratory tract infections. although influenza vaccination is recommended for these persons, vaccination levels remain too low because of conflicting evidence regarding potential benefits. as part of the prisma nested casecontrol study among 75,000 persons recommended for vaccination, we studied the effectiveness of single and repeat influenza vaccination in the subgroup of adult diabetic population (9, 238) during the 1999-2000 influenza a epidemic. case patients were hospitalized for diabetes, acute respiratory or cardiovascular events, or died and controls were sampled from the baseline cohort. after control for age, gender, health insurance, prior health care, medication use and co-morbid conditions logistic regression analysis showed that the occurrence of any complication (131 hospitalizations, 61 deaths) was reduced by 56% (95% confidence interval 36% to 70%). vaccine effectiveness was similar for those who received the vaccine for the first time and for those who received an earlier influenza vaccination. although we did not perform virological analysis or distinguish type i from type ii diabetes we conclude that patients with diabetes benefit substantially from influenza vaccination independent of whether they received the vaccine for the first time or received earlier influenza vaccinations. background: construction workers are at risk of developing silicosis. regular medical evaluations to detect silicosis preferably in the pre-clinical phase are needed. objectives: to identify the presence or absence of silicosis by developing an easy to use diagnostic model for pneumoconiosis from simple questionnaires and spirometry. design and methods: multiple logistic regression analysis was done in 1291 dutch construction workers, using chest x-ray indicative for pneumoconiosis (ilo profusion category > 1/1) as the reference standard (prevalence 2.9%). model calibration was assessed with graph and the hoshmer-lemeshow goodness of fit test; discriminative ability using area under receiver operating characteristic curve (auc); and internal validity using bootstrapping procedure. results: age > 40 years, current smoking, high exposure job title, working > 15 years in the construction industry, 'feeling unhealthy', and standardized residual fev1 below )1.0 were selected as predictors. the diagnostic model showed a good calibration (p = 0.5) and discriminative ability (auc 0.81; 95% ci 0.74 to 0.85). internal validity was reasonable (correction factor of 0.82 and optimism corrected auc of 0.76). conclusions: and discussion: our diagnostic model for silicosis showed reasonable performance and internal validity. to apply the model with confidence, external validation before application in a new working population is recommended. background: artemisinin based combination therapy (act) reduces microscopic gametocytaemia, the malaria parasite stage responsible for transmission from man to mosquito. as a result, act is expected to reduce the burden of disease in african populations. however, molecular techniques recently revealed high prevalences of gametocytaemia below the microscopic threshold. our objective was to determine the importance of sub-microscopic gametocytaemia after act treatment. methods: kenyan children (n=528) aged 6 months -10 years were randomised to four treatment regimens. gametocytaemia was determined by microscopy and pfs25 real-time nucleic acid sequence-based amplification (qt-nasba). transmission was determined by membrane feedings. findings: gametocyte prevalence at enrolment was 89.4% (219/245) as determined by pfs25 qt-nasba and decreased after treatment with act. membrane feedings in randomly selected children revealed that the proportion of infectious children was up to fourfold higher than expected when based on microscopy. act did not significantly reduce the proportion of infectious children but merely the proportion of infected mosquitoes. interpretation: sub-microscopic gametocyte densities are common after treatment and contribute considerably to mosquito infection. our novel approach indicates that the effect of act on malaria transmission is much smaller than previously suggested. these findings are sobering for future interventions aiming to reduce malaria transmission. background: adequate folate intake may be important in the prevention of breast cancer. factors linked to folate metabolism may be relevant to its protective role. objectives: to investigate the association between folate intake and breast cancer risk among postmenopausal women and evaluate the interaction with alcohol and vitamin b12 intake. methods: a prospective cohort analysis of folate intake among 62,739 postmenopausal women from the e3n french cohort who completed a validated food frequency questionnaire in 1993 was conducted. during 9 years follow-up 1,814 cases of pathology-confirmed breast cancer were documented through followup questionnaires. nutrient intakes were categorized in quintiles and energy-adjusted using the regression-residual method. cox modelderived relative risks (rr) were adjusted for known risk factors for breast cancer. results: the multivariate rr comparing the extreme quintiles of folate intake was 0.76 (95% ci 0.65-0.88; p-trend=0.005). after stratification, the association was observed only among women whose alcohol consumption was above the median (=6.2 g/day) and among women who consumed =6.5lg/day of vitamin b12. however, tests for interaction were not significant. conclusions: in this population, high intakes of folate were associated with decreased breast cancer risk; alcohol and vitamin b12 intake may modify the observed inverse association. background: the simultaneous rise in the prevalence of obesity and atopy in children has prompted suggestions that obesity might be a causal factor in the inception of atopic diseases. objective: we investigated the possible role of ponderal index (kg/m 3 ) as marker for fatness at birth in early childhood atopic dermatitis (ad) in a prospective birth cohort study. methods: between november 2000 and november 2001, mothers and their newborns were recruited after delivery at the university of ulm, germany. active follow-up was performed at the age of 12 months. results: for 872 (82%) of the 1066 children included at baseline, information on physician reported diagnosis of ad was obtained during follow-up. incidence of ad was 12.4% at the age of one year. mean ponderal index at birth was 24.7 kg/m 3 . risk for ad was higher among children with high ponderal index at birth (adjusted or for children within the third and fourth compared to children within the second quartile of ponderal index: 2.14; 95% ci 1. respectively) background: the relationship between duration of breastfeeding and risk of childhood overweight remains inconclusive, possibly in part caused by using never breastfeeding mothers as the reference category. objectives: we assessed the association between duration of breastfeeding and childhood overweight among ever breastfed children within a prospective birth cohort study. methods: between november 2000 and november 2001 all mothers and their newborns were recruited after delivery at the university of ulm, germany. active follow-up was performed at age 24 months. results: among 855 children (80% of 1066 children included at baseline) with available body mass index at age two 72 (8.4%) were overweight. whereas 76 children (8.9%) were never breastfed, 533 (62.3%) were breastfed for at least six months, and 322 (37.7%) were exclusively breastfed for at least six months. compared to children who were exclusively breastfed less than three months, the adjusted or for overweight was 0.8 (95% ci 0.4; 1.5) in children who were exclusively breastfed for at least three but less than six months and 0.4 (95% ci 0.2; 0.9) in children who were exclusively breastfed for at least six months. conclusion: these results highlight the importance of prolonged breastfeeding in the prevention of overweight in children. background: in africa, hiv and feeding practices influence child mortality. exclusive breastfeeding for 6 months (bf6) and formula feeding (ff) when affordable are two who recommendations for safe feeding. objective: we estimated the proportion and the number of children saved with each recommendation at population level. design and methods: data on 31 sub-saharan countries were analysed. we considered saved a child remaining hiv-free and alive after two years of life. a spreadsheet model based on a decision tree for risk assessment was used to calculate this number according to six scenarios that combine the two recommendations without and with promotion then with promotion and group education. results: whatever the country, the number of children saved with bf6 would be higher than with ff. overall, without promotion, 52 315 ( background: farming has been associated with respiratory symptoms as well as protection against atopy. effects of different farming practices on respiratory health in adults have rarely been studied. objectives: we studied associations between farming practices and hay fever and current asthma in organic and conventional farmers. design and methods this cross-sectional study evaluated questionnaire data of 1205 conventional and 593 organic farmers. associations between health effects and farm exposures were assessed by logistic regression. results: organic farmers reported slightly more hay fever than conventional farmers (9.3% versus 6.9%, p = 0.07). however, organic farming was no independent determinant for hay fever in multivariate models including farming practices and potential confounders. livestock farmers who grew up on a farm had a five-fold lower prevalence of hay fever than crop farmers without farm childhood (or 0.2, 95% ci 0.1-0.5). use of disinfectants containing quaternary ammonium compounds was positively related to hay fever (or 2.4, 95% ci 1.1-5.1). no effects of farming practices were found for asthma. conclusion and discussion: our study adds to the evidence that a farm childhood in combination with current livestock farming protects against allergic disorders. this effect was found for both organic and conventional farmers. background: although a body mass index (bmi) above 25 kg/m 2 is clearly associated with an increase in mortality in the general population, the meaning of high levels of bmi among physically heavily working men is less clear. methods: we assessed the association between bmi and mortality in a cohort of 19513 male construction workers, aged 25-64 years, who underwent an occupational health examination in wu¨rttemberg (germany) during 1986-1992 and who were followed over a 10 years period. covariates considered in the proportional hazard regression analysis included age, nationality, smoking status, alcohol consumption, and comorbidity. results: during the follow-up 802 deaths occurred. there was a strong u-shaped association between bmi and all-cause mortality, which was lowest for bmi levels between 25 and 35 kg/m 2 . this pattern persisted after exclusion of the first years of follow-up and control for multiple covariates. compared with men with a bmi < 25.0 kg/m 2 , the relative mortality was 0.76 (95% confidence interval: 0,64-0,91), 0.75 (0.59-0.97) and 1.00 (0.62-1.62) for bmi ranges 25-29.9, 30-34.9 and = 35.0 kg/m 2 . conclusion and discussion: bmi levels commonly considered to reflect overweight or moderate obesity in the general population may be associated with reduced mortality in physically heavily working men. background: colonoscopy with removal of polyps may strongly reduce colorectal cancer (crc) incidence and mortality. empirical evidence for optimal schedules for surveillance is limited. objective. to assess risk of proximal and distal crc after colonoscopy with polypectomy. design and methods: history and results of colonoscopies were obtained from 540 cases and 614 controls in a population-based case-control study in germany. risk of proximal and distal crc according to time since colonoscopy was compared to risk of subjects without previous colonoscopy. results: subjects with previous detection and removal of polyps had a much lower risk of crc within four years after colonoscopy (adjusted odds ratio 0.38, 95% confidence interval 0.18-0.78), and a similar risk as those without colonoscopy in the long run. within four years after colonoscopy, risk was particularly low if only single or small adenomas were detected. most cancers occurring after polypectomy were located in the proximal colon, even if polyps were found in the sigma or rectum only. conclusion and discussion: our results support suggestions that surveillance colonoscopy after removal of single and small adenomas may be deferred to five years and that surveillance should include the entire colorectum even if only distal polyps are detected. background: a population-based early detection programme for breast cancer has been in progress in finland since 1987. recently, detailed information about actual screening invitation schemes in 1987 -2001 has become available in electronic form, which enables more specific modeling of breast cancer incidence. objectives: to present a methodology for taking into account historical municipality-specific schemes of mass screening when constructing predictions for breast cancer incidence. to provide predictions for numbers of new cancer cases and incidence rates according to alternative future screening policies. methods: observed municipality-specific screening invitation schemes in finland during 1987-2001 were linked together with breast cancer data. the incidence rate during the observation period was analyzed using poisson regression, and this was done separately for localized and nonlocalized cancers. for modeling, the screening programme was divided into seven different phases. alternative screening scenarios for future mass-screening practices in finland were created and an appropriate model for incidence prediction was defined. results and conclusion: expanding the screening programme would increase the incidence of localized breast cancers; the biggest increase would be obtained by expanding from women aged 50-59 to 50-69. the impacts of changes in the screening practices on predictions for non-localized cancers would be minor. background: new screening technologies are implemented to routine screening in increasing numbers, with limited evidence on their effectiveness. randomised evaluation of new technologies is encouraged but rarely done. objective: to evaluate in a randomised design whether the effectiveness of an organised cervical screening programme can be improved by means of new technologies. methods: since 1999 150,000-170,000 women have been invited annually to a randomised multi-arm trial ran within the finnish organised cervical screening programme. the invited women are randomly allocated to three study arms of different primary screening tests: conventional cytology, automation-assisted cytology and, since 2003, human papillomavirus (hpv) testing. up to 2005, we have gathered information on 185,000 screening visits in the automation-assisted arm and 4,653 in the hpv arm, and we have compared the results to conventional screening. results: automation-assistance resulted in a slightly increased detection of precancers, but the efficacy based on interval cancers is not known. results on hpv screening suggest higher detection of precancers and cancers compared to conventional screening. conclusion: evidence of higher effectiveness of new screening technologies is needed, especially when changing the existing screening programmes. the multi-arm trial shows how these technologies can be implemented to routine in a controlled manner. introduction: nodules and goitres are important risk factors for thyroid cancer. as the number of diagnosed cases of thyroid cancer is increasing, the incidence of such risk factors has been assessed in a french cohort of adults. methods: the su.vi.max (supple´mentation en vitamines et mine´raux antioxydants) cohort study included 12741 middle-aged adults followed-up during eight years. incident cases of goitres and nodules have been identified retrospectively by scheduled clinical examinations and spontaneous consultations by the participants. cox proportional hazards modeling was used to identify factors associated to thyroid diseases. results: finally, 160 incident cases of nodules and goitres were identified among 4,002 subjects free of thyroid diseases at inclusion. after an average follow-up of 7 years, the incidence of goitres and nodules was 2.2% in 45-60 year old men, 4.9% in 35-44 year old women and 7.4% in 45-60 year old women. identified associated factors were age, low urinary thiocyanate level and oral contraceptive use in women, and high urinary thiocyanate level and low urinary iodine level in men. conclusion: estimated incidences are consistent with those observed in other countries. the protective role of urinary thiocyanate in both men and women and, in women, oral contraceptives deserve further investigation. background: various statistical methods for outbreak detection in hospital settings have been proposed in the literature. usually validation of those methods is difficult, because the long time series of data needed for testing the methods are not available. modeling is a tool to overcome that difficulty. objectives: to use model generated data for testing sensitivity and specificity of different outbreak detection methods. methods: we developed a simple stochastic model for a process of importation and transmission of infection in small populations (hospital wards). we applied different statistical outbreak detection methods described in the literature to the generated time series of diagnosis data and calculated and the sensitivity and specificity of different methods. results: we present roc curves for the different methods and show how they depend on the underlying model parameters. we discuss how sensitivity and specificity measures depend on the degree of underdiagnosis, on the ratio of admitted colonised patients to colonisation resulting from transmission in the hospital, and on the frequency of testing patients for colonisation. conclusions: modeling can be a useful tool for evaluating statistical methods of outbreak detection especially in situation where real data is scarce or its quality questionable. associated with higher mammographic density and breast pain, has been increased which has bearing on screening performance. objective: we compared the screening performance for women aged 49-69 years with dense and lucent breast patterns in two time periods and studied the possible interaction with use of hrt. methods: data were collected from a dutch regional screening programme for women referred in 1994-1995 (n = 642) and 2001-2002 (n = 107) . in addition, we sampled controls for both periods that were not referred (n = 1927 and n = 212 resp.) and women diagnosed with an interval cancer. mammograms were digitised and computer-assisted methods used to measure mammographic density. among other parameters, sensitivity was calculated to describe screening performance. results: screening performance has improved slightly, but the difference between dense and lucent breast patterns still exists (e.g. sensitivity 62% vs. 78%). hrt use has increased; sensitivity was particularly low (38%) in the group of women with dense breast patterns on hrt. discussion: in conclusion, the detrimental effect of breast density and the interaction with hrt on screening performance warrants further research with enlargement of the catchment area, more referred women, interval cancers and controls. background: population based association studies might lead to false-positive results if possibly underlying population structure is not adequately accounted for. to assess the nature of the population structure some kind of cluster analysis has to be carried out. we investigated the use of self-organizing maps (soms) for this purpose. objectives: the two main questions concern identification of an either discrete or an admixed population structure and identification of the number of subpopulations involved in forming the structured population under investigation. design and methods: we simulated data sets with different population models and included varying informative marker and map sizes. sample sizes ranged from 200 to 2400 individuals. results: we found that a discrete structure can easily be accessed by soms. a near to perfect assignment of individuals to their population of origin can be obtained. for an admixed population structure though, soms do not lead to reasonable results. here, even the correct number of subpopulations involved can not be identified. conclusion: in conclusion, soms can be an alternative to a model-based cluster analysis if the researcher assumes a discrete structure but should not be applied if an admixed structure is likely. background: little is known about the combined effect of duration of breastfeeding, sucking habits and malocclusion in the primary dentition. objectives: we studied the association of breastfeeding and non-nutritive sucking habits on malocclusion on the primary dentition. design and methods: a cross-sectional study nested in a birth cohort was carried out in pelotas, brazil. a random sample of 359 children aged 6 was examined and their mothers interviewed. the foster and hamilton criteria were used to define anterior open bite (aob) and posterior cross bite (pcb). information regarding breastfeeding and non-nutritive sucking habits was collected from birth to 6 years-old. poisson's regression analysis was used. results: non-nutritive sucking habits between 12 months and 4 years of age (pr3.5 [2.3;5.4] ) and digital sucking at 6 years of age (pr1.5[1.1;2.1]) were risk factors for aob. breastfeeding for less than 9 months (pr7.6[1.5; 39.5] ) and the regular use of a pacifier between 12 months and 4 years of age (pr7.5[1.3;44.3]) were the risk factors for pcb. for pcb an interaction was identified between lack of breastfeeding and the use of a pacifier. conclusion: lack of breastfeeding and longer non-nutritive sucking habits during early childhood were the main risk factors for malocclusion in primary dentition. background: recent, dramatic coronary heart disease (chd) mortality increases in beijing, can be mostly explained by adverse changes in risk factors, particularly total cholesterol and diabetes. it is important for policy making to predict the impact of future changes in risk factors on chd mortality trends. objective: to assess the potential impact of changes in risk factors on numbers of chd deaths in beijing from 1999 to 2010, to provide evidence for future chd strategies. design: the previously validated impact model was used to estimate the chd deaths expected in 2010 a) if recent risk factor trends continue or b) if levels of risk factors reduce. results: continuation of current risk factor trends will result in a 48% increase in chd deaths by 2010, (almost half being attributable to increases in total cholesterol levels). even optimistically assuming a 1% annual decrease in risk factors, chd deaths would still rise by 21% because of population ageing. conclusion: a substantial increase in chd deaths in beijing may be expected by 2010. this will reflect worsening risk factors compounded by demographic trends. population ageing in china will play an important role in the future, irrespective of any improvements in risk factor profiles. background: since smoking cessation is more likely during pregnancy than at other times, interventions to maintain quitting postpartum may give the best opportunity for a long-time abstinence. it is still not clear what kind of advice or counseling should be given to help prevent the relapse postpartum. objectives: to identify the factors, which predispose women to smoking relapse after delivery. design and methods: the cohort study was conducted in 2004 and 2005 in public maternity units in lodz, poland. the study population consisted of pregnant women between 32-36 weeks of pregnancy who have quit smoking no later than three months prior to participation in the study. smoking status was verified using saliva cotinine level. women were interviewed twice: during pregnancy and three months after delivery. results: within three months after delivery about half of women relapsed into smoking. the final model identified the following risk factors for smoking relapse: having partner and friends who smoke, quitting smoking in late pregnancy, and negative experiences after quitting smoking such as dissatisfaction with weight, nervousness, irritation, loosing pleasure. conclusion. this study advanced the knowledge of the factors that determine smoking relapse after delivery and provided preliminary data for future interventions. introduction: it remains difficult to predict the effect of an particular antihypertensive drug in an individual patient and pharmacogenetics might optimise this. objective: to investigate whether the association between use of angiotensin converting enzyme (ace)-inhibitors or ß-blockers and the risk of stroke or myocardial infarction (mi) is modified by the t-allele of the angiotensinogen m235t polymorphism. methods: data were used from the rotterdam study, a population-based prospective cohort study. in total, 4093 subjects with hypertension were included from july 1st, 1991 onwards. follow-up ended at the diagnosis of mi or stroke, death, or the end of study period (january 1st, 2002) . the drug-gene interaction and the risk of mi/stroke was determined with a cox proportional hazard model (adjusted for each drug class as time-dependent covariates). results: the interaction between current use of ace-inhibitors and the angiotensinogen m235t polymorphism increased the risk of mi (synergy index (si) = 4.00; 95% ci:1.32-12.11) and non-significant increased risk of stroke (si = 1.83; 95% ci:0.95-3.54). no interaction was found between current use of ß-blockers and the agt m235t polymorphism on the risk of mi or stroke. conclusion: subjects with at least one copy of the 235t allele of the agt gene might have less benefit from ace-inhibitor therapy. [2.4-6.9 ] to 1.5 [1.1-2.1] in those without ms-idf and 1.9 [1.5-2.6] with ms-idf. ms-ncep had no effect. conclusion and discussion: although cardiovascular disease was self-reported, we conclude that the higher prevalence of cardiovascular disease is partly accounted for by marked differences in the prevalence of metabolic syndrome. the ms-idf criteria seem better for defining metabolic syndrome in ethnic groups than the ms-ncep criteria. background: selenium is an essential trace mineral with antioxidant properties. objective: to perform meta-analyses of the association of selenium levels with coronary heart disease (chd) endpoints in observational studies and the efficacy of selenium supplements in preventing chd in randomized controlled trials. methods: we searched medline and the cochrane library from 1966 through 2005. relative risk (rr) estimates were pooled using an inversevariance weighted random-effects model. for observational studies reporting three or more categories of exposure we conducted a dose-response meta-analysis. results: twenty-five observational studies and 6 clinical trials met our inclusion criteria. the pooled rr comparing the highest to the lowest categories of selenium levels was 0.85 (95% confidence interval 0.74-0.99) in cohort studies and 0.43 (0.29-0.66) in case-control studies. in dose-response models, a 50% increase in selenium levels was associated with a 24% (7-38%) reduced risk of coronary events. in randomized trials, the rr comparing participants taking selenium supplements to those taking placebo was 0.90 (0.75-1.09). conclusion: selenium levels were inversely associated with the risk of chd in observational studies. the randomized trials findings are still inconclusive. these results require confirmation in randomised controlled trials. currently, selenium supplements should not be recommended for cardiovascular prevention. 140 background propensity score analysis (psa) can be used to reduce confounding bias in pharmacoepidemiologic studies of the effectiveness and safety of drugs. however, confidence intervals may be falsely precise because psa ignores uncertainty in the estimated propensity scores. objectives: we propose a new statistical analysis technique called bayesian propensity score analysis (bpsa). the method uses bayesian modelling with the propensity score as a latent variable. our question is: does bpsa yield improved interval estimation of treatment effects compared to psa? our objective is: to implement bpsa using computer programs and investigate the performance of bpsa compared to psa. design and methods: we investigated bpsa using monte carlo simulations. synthetic datasets, of sample size n = 250, 1000, 4000, were simulated by computer. the datasets were analyzed using bpsa and psa and we estimated the coverage probability of 80% credible intervals. results the estimated coverage probabilities ranged from 78% to 84% for bpsa, and from 42% to 82% for psa, with simulation standard errors less than 2%. background: several factors associated with low birth weight, such as smoking and body mass index (bmi) do not explain all ethnic differences. this study investigates the effects of working conditions on birth weight among different ethnic groups. methods: questionnaire data, filled in 2 weeks after prenatal screening, was used from the amsterdam born children and their development (abcd) study (all pregnant women in amsterdam [7/1/03-7/3/04 (n = 12.381), response 8267 (67%)]. ethnicity (country of birth). was dichotomised into dutch and non-dutch. working conditions were: weekly working hours, weekly hours standing/walking, physical load and job-strain (karasek-model). only singleton deliveries with pregnancy duration = 37 weeks were included. results: although only 39.4% of the non-dutch women worked during first trimester (79.6% of the dutch women), they reported significantly more physical load (15.1% vs 9.0%), more hours standing/walking (10.6% vs 6.3%) and more high job-strain (10.2 vs 5.7). linear regression revealed that only high job-strain lowered significantly birth weight (non-dutch: 159 gram and dutch: 75 gram). after adjusting for confounders (gender, parity, smoking, maternal length, maternal bmi and education), this was only significant in the non-dutch group (112 vs. 30 gram). conclusion: job-strain has more effect on birth weight in non-dutch compared to dutch women. background: in 2004 panama population was estimated in 3.2 million habitants, from which three millions lived in malaria endemic areas. until january 26 1998 malaria control activities were accomplished under a vertical structure. objective: to evaluate the evolution of malaria control in panama, before and after the decentralization of the malaria program. design and methods: average (standard deviation) of the program indexes are described for the last decades. the correlation between positive smears index and per capita cost of the program is analyze. results: in the 1960's the average (standard deviation) positive smears index per 100 habitants was 3.3% (1.8); in the 1970's: 0.4% (0.5); in the 1980's: 0.13% (0.1); in the 1990's: 0.32% (0.2); and in the first five years of 2000: 1.7% (1.1). after the decentralization of the program was accomplished in 1998, the positive smears index increased 5.3 fold. the average per capita cost involved in malaria control activities per decade ranged between 0.19 y 1.25 us dollars and presented a determination coefficient of 0.42 in the reduction of the positive smears index. discussion: the decentralization had significant detrimental implications in the control program capabilities. background: notification rates of new smear-positive tuberculosis in the central mountainous provinces (26/100,000 population) are considerably lower than in vietnam in general (69/100,000 population). this study assessed whether this is explained by low case detection. objective: to assess the prevalence and case detection of new smear-positive pulmonary tuberculosis among adults with a prolonged cough in central mountainous vietnam. design and methods: a house-to-house survey of adults 15 years or older was carried out in 12 randomly selected districts in three mountainous provinces in central vietnam in 2003. three sputum specimens were microscopically examined of persons reporting a cough of 3 weeks or longer. results: the survey included 68,946 persons with a response of 95%. a cough of 3 weeks or longer was reported by 1,298 (1.9% 95% ci 1. 8-2.2) persons. of these, 18 were sputum smear-positive of whom 2 had had anti-tuberculosis treatment. the prevalence of new smear-positive tuberculosis was 27/100,000 population (95% ci 11-44/100,000 population). the patient diagnostic rate was 1.6 per person-year, suggesting that the case notification rate as defined by who was 76%. conclusion: low tuberculosis notification rates in mountainous vietnam are probably due to low tuberculosis incidence. explanations for low incidence at high altitude need to be studied. background: although patients with type 2 diabetes (dm2) have an increased risk of urinary tract infections (utis), not much is known about predictors of a complicated course. objective: this study aims to develop a prediction rule for complicated utis in dm2 patients in primary care. design and methods: we conducted a 12-month prospective cohort study, including dm2 patients aged 45 years or older from the second dutch national survey of general practice. the combined outcome measure was defined as the occurrence of recurrent cystitis, or an episode of acute pyelonephritis or prostatitis. results: of the 6,343 dm2 patients 46% was male and mean age was 67 years (sd 11). incidence of the outcome was 3 per 100 patient years (n = 179). predictors were age, male sex, number of physician contacts, incontinence of urine, cerebro vascular disease or dementia and renal disease. the area under the receiver-operating curve (auc) was 0.77 (95% ci 0.73 to 0.80). subgroup analyses for gender showed no differences. there is an increased early postoperative mortality (operation risk) after elective surgery. this mortality is normally associated with cardiovascular events, such as deep venous thrombosis, pulmonary embolism, and ischemic heart diseases. our objective was to quantify the magnitude of the increased mortality and how long the mortality after an operation persists. we focused on the early postoperative mortality after surgery for total knee and total hip replacements from the national registries in australia and norway, which cover more than 95% of all operations in the two nations. only osteoarthritis patients between 50 and 80 years of age were included. a total of 244.275 patients remained for analyses. smoothed intensity curves were calculated for the early postoperative period. effects of risk factors were studied using a nonparametric proportional hazards model. the mortality was highest immediately after the operation ($1 deaths per 10.000 patients per day), and it decreased until the 3rd postoperative week. the mortality was virtually the same for both nations and both joints. mortality increased with age and was higher for males than for females. a possible reduction of early postoperative mortality is plausible for the immediate postoperative period, and no longer than the 3rd postoperative week. background/objectives: single, modifiable risk factors for stroke have been extensively studied before, but their combined effects were rarely investigated. aim of the present study was to assess single and joint effects of risk factors on stroke and transitoric ischemic attack (tia) incidence in the european prospective investigation into cancer and nutrition (epic)-potsdam study. methods: among 25538 participants aged 35-65 years at baseline 100 total stroke cases and 112 tia cases occurred during 4.3 years of follow-up. relative risks (rr) for stroke and tia related to risk factors were estimated using cox proportional hazard models. results: after adjustment for potential confounders rr for ischemic stroke associated with hypertension was 2.32 (95% ci, 1.35-3.99) and for tia 1.14 (95% ci 0.76-1.71). the highest rr for ischemic stroke (rr 5.12, 95% ci 1.49-17.6, p trend<0.0001) and tia (rr 3.08, 95% ci 1.00-9.44, p trend=0.024) were observed among participants with 4 or 5 modifiable risk factors. 58.5 % of ischemic strokes and 26.2% of tia cases were attributable to hypertension, diabetes mellitus, high alcohol consumption, hyperlipidemia, and smoking. conclusion: almost 60% of ischemic stroke cases could be explained by classical modifiable risk factors. however, only one in four tia cases was attributable to those risk factors. background: the investigation of genetic factors is gaining importance in epidemi-ology. most relevant from a public health perspective are complex diseases that are characterised by complex pathways involving gene-gene-and gene-environment-interactions. the identification of such pathways requires sophisticated statistical methods that are still in their infancy. due to their ability in describing complex association structures, directed graphs may represent a suitable means for modelling complex causal pathways. objectives: we present a study plan to investigate the appropriateness for using directed graphs for modelling complex pathways in association stud-ies. design and methods: graphical models and artificial neural networks will be investigated using simulation studies and real data and their advantages and disadvantages of the respective ap-proaches summed up. furthermore, it is planned to construct a hybrid model exploiting the strengths of either model type. results and conclusions: the part of the project that concerns graphical models is being funded and ongoing. first results of a simulation study have been obtained and will be presented and discussed. a second project is currently being applied for. this shall cover the investigation of neural networks and the construction of the hybrid model. this study investigates variations in mortality from 'avoidable' causes among migrants in the netherlands in comparison with the native dutch population. data were obtained from population and mortality registries in the period 1995-2000. we compared mortality rates for selected 'avoidable' conditions for turkish, moroccan, surinamese and antillean/aruban groups to native dutch. we found slightly elevated risk in total 'avoidable' mortality for migrant populations (rr = 1.13). higher risks of death among migrants were observed from almost all infectious diseases (most rr>3.00) and several chronic conditions including asthma, diabetes and cerebro-vascular disorders (most rr>1.70). migrant women experienced a higher risk of death from maternity-related conditions (rr = 3.37). surinamese and antillean/ aruban population had a higher mortality risk (rr = 1.65 and 1.31 respectively), while turkish and moroccans experienced a lower risk of death (rr = 0.93 and 0.77 respectively) from all 'avoidable' conditions compared to native dutch. control for demographic and socioeconomic factors explained a substantial part of ethnic differences in 'avoidable' mortality. conclusion: compared to native dutch, total 'avoidable' mortality was slightly elevated for all migrants combined. mortality risks varied greatly by cause of death and ethnicity. the substantial differences in mortality for a few 'avoidable' conditions suggest opportunities for improvement within specific areas of the healthcare system. warmblood horses scored by the jury as having uneven feet will never pass yearly selection sales of the royal dutch warmblood studbook (kwpn).to evaluate whether the undesired trait 'uneven feet' influences performance, databases of kwpn (n = 62234 horses) and knhs (n = 16015 show jumpers, n = 24269 dressage horses) were linked through the unique number of each registered horse. using a proc glm model of sas was investigated whether uneven feet had effects on age at first start and highest performance level. elite show jumpers with uneven feet start at 7.2 years and dressage horses 9.4 years of age, which is a significant difference (p<0.05) with elite even feet horses (8.0 respectively 9.0 years). at their maximum level of performance horses with even feet linearly scored in show jumping 31.1 at regular and 116.8 at elite level (29.0 resp. 105.7 with uneven feet), while in dressage horses scores were 38.0 at regular and 139.7 at elite level (35.5 resp. 136.7 with uneven feet).the conformational trait 'uneven feet' appears to have a significant effect on age at first start, while horses with even feet demonstrate a higher maximal performance than horses with uneven feet. objectives: to identify children with acute otitis media (aom) who might benefit more from treatment with antibiotics. methods: an individual patient data meta-analysis (ipdma) on six randomized trials (n = 1643 children). to preclude multiple testing, we first performed a prognostic study in which predictors of poor outcome were identified. subsequently, interactions between these predictors and treatment were studied by fixed effect logistic regression analyses. only if a significant interaction term was found, stratified analyses were performed to quantify the effect in each subgroup. results: interactions were found for: age and bilateral aom, and otorrhea. in children less than 2 years with bilateral aom, a rate difference (rd) of )25% (95% ci )30; )20%) was found, whereas in children aged 2 years or older with unilateral aom the rd was )4% (95% ci )6; )2%). in children with and without otorrhea the rd were )36% (95% ci )45; )27%), and )14% (95% ci )17%; )11%). conclusion: although there still are many areas in which ipdma can be improved, using individual patient data appear to have many advantages especially in identifying subgroups. in our example, antibiotics are beneficial in children aged less than 2 years with bilateral aom, and in children with otorrhea. major injuries, such as fractures, are known to increase the risk of venous thrombosis (vt). however, little is known of the risk caused by minor injuries, such as ankle sprains. we studied the risk of vt after minor injury in a population-based case-control study of risk factors for vt, the mega-study. consecutive patients, enrolled via anticoagulation clinics, and control subjects, consisting both of partners of patients and randomly selected control subjects, were asked to participate and filled in a questionnaire. participants with cancer, recent plastercasts, surgery or bedrest were excluded from the current analyses. 270 out of 2207 patients (12.2%) and 200 out of 4467 controls (4.5%) had suffered from a minor injury resulting in a three-fold increased risk of vt (odds ratio adjusted for age and sex 3.2; 95% confidence interval 2.7-3.9) compared to those without injury. the risk was highest in the first month after injury and was no longer increased after 3 months. injuries located in the leg increased the risk five-fold, while those located in other body parts did not increase the risk. these results show that minor injuries in the leg increase the risk of vt. this effect appears to be temporary and mainly local. introduction: in southeast asia, dengue was considered a childhood disease. in the americas, this disease occurs predominantly in older age groups, indicating the need for studies to investigate the immune status of the child population, since the presence of antibodies against a serotype of this virus is a risk factor for dengue hemorrhagic fever (dhf). objective: to evaluate the seroprevalence and seroincidence of dengue in children living in salvador, bahia, brazil. methods: a prospective study was carried out in a sample of children of 0-3 years by performing sequential serological surveys (igg/ dengue). results: seroprevalence in 625 children was 26.6%. a second survey (n = 289 seronegative children) detected an incidence of 33.2% and no difference was found between males and females or according to factors socioeconomic analyzed. conclusion and discussion: these results show that, in brazil, the dengue virus circulates actively in the initial years of life, indicating that children are also at great risk of developing dhf. it is possible that in this age group, dengue infections are mistaken for other febrile conditions, and that there are more inapparent infections in this age group. therefore, epidemiological surveillance and medical care services should be aware of the risk of dhf in children. since 1996, in the comprehensive cancer centre limburg (cccl) region, all women aged 30-60 years are invited to participate in the cervical cancer screening programme once every five years. we had the unique opportunity to link data from the cervical screening programme and the cancer registry. we studied individual pap smear testing and participation in the screening programme preceding the diagnosis of cervical cancer. all invasive cases of cervical cancer of women aged 30-60 years in the period 1996-2003 were selected. subgroups were based on results of the pap smear and invitation and participation in the screening programme. time interval between screening and detection of tumours was calculated. in 1996-2003, the non-response rate was 18%. in total, 211 invasive cervical cancer cases were detected of which 54 were screening and 32 interval carcinomas. in the group of women who were invited but did not participate and women who were not invited, respectively 64 and 61 tumours were detected. these tumours had a higher stage compared to screening carcinomas. in the cccl region, more and higher stage tumours were found in women who did not participate in the screening compared to women with screening tumours. background: pcr for mycobacterium tuberculosis (mtb) has already proved to be a useful tool for the diagnosis and investigation of molecular epidemiology. objectives: evaluation of pcr assay for detection of mycobacterium tuberculosis dna as a diagnostic aid in cutaneous tuberculosis. design and methods: thirty paraffinembedded samples belonging to 28 patients were analyzed for acid fast bacilli. dna was extracted from tissue sections and pcr was performed using specific primers based on is 6110 repeated gene sequence of mtb. results: two of the tissue samples were positive for acid fast bacilli (afb). pcr was positive in eight samples from six patients. amongst them, two were suspected of having lupus vulgaris confirmed histopathologically, whom their entire tests were positive. accounting histopathology as gold standard, the sensitivity of pcr in this study was determined as 75%. conclusion: from 8 cases of skin tuberculosis diagnosed by histopathology, 6 were positive by pcr technique, which shows the priority of previous method to molecular technique. discussion: pcr assay can be used for rapid detection of mtb from cutaneous tuberculosis cases, particularly when staining for afb is negative and there is a lack of growth on culture or when fresh material has not been collected for culture. background: recent epidemiological studies used automated oscillometric blood pressure (aod) devices that systematically measure higher blood pressure values than random zero sphygmomanometer devices (rzs) hampering the comparability of the blood pressure values between these studies. we applied both a random zero and an automated oscillometric blood pressure device in a randomized order in an ongoing cohort study. objectives: the aim of this analysis was to compare the blood pressure values by device and to develop a conversion algorithm for the estimation of blood pressure values from one device to the other. methods: within a randomized subset of 2365 subjects aged 45-75 years, each subject was measured three times by each device (hawskley random zero and omron hem-705cp) in a randomized order. results: the mean difference (aod-rzs) between the devices was 3.9 mmhg and 2.6 mmhg for the systolic and diastolic blood pressure respectively. linear regression models including age, sex, and blood pressure level can be used to convert rzs blood pressure values to aod blood pressure values and vice versa. conclusions: the results may help to better compare blood pressure values of epidemiological studies that used different blood pressure devices. a form was used to collect relevant perinatal clinical data, as part of a european (mosaic) and italian (action) project. the main outcomes were mortality and a variable combining mortality and severe morbidity at discharge. the cox proportional hazards and logistic regression models were used, respectively, for the two outcomes. results: twenty-two of percent of vpbs were among fbms. comparing to control group, the percentage of babies below 28 weeks and plurality was statistically significant higher among babies of fbms: 52% vs. 41.7 and 28.3% vs. 16.0%. adjusting for potential confounders, no association for mortality among immigrant group was found, whereas a slightly excess of morbidity-mortality was observed (odd ratio, 1.36; 95% cis 0.99-1.88). conclusions: the high proportion of vpbs among fbms and the slight excess observed in morbidity and mortality indicate the need to improve the health care delivery for the immigrant population. background: high-risk newborns have excess mortality, morbidity and use of health services. objectives: to describe re-hospitalizations after discharge from an italian region. design and methods: the population study consisted of all births with <32 weeks' gestation discharged alive from the twelve neonatal intensive care units in lazio region during 2003. the perinatal clinical data was collected as part of a european project (mosaic). we used the regional hospital discharge database to find hospital admissions within 12 months, using tax code for record linkage. data were analyzed through logistic regression for re-hospitalization. results: the study group included 361 children; among these, 111 (30.7%) were re-hospitalized; overall, 206 readmission were observed. the median total length of stay for re-admissions was 5 d. the two most common reasons for re-hospitalization were respiratory (37.8%) and gastrointestinal (16.5%) disorders. the presence of a severe morbidity at discharge (odd ratio 2.03: 95% cis 1.20-3.42) and male sex (odd ratio 1.97; 95% cis 1.24-3.15) predicted re-hospitalization in multivariate model. conclusions: almost one out three preterm infants was re-hospitalized in the first 12 months. readmissions after initial hospitalization for a very preterm birth could be a sensitive indicator of quality of follow-up strategies in high risk newborns. background: self-medication with antibiotics may lead to inappropriate use and increase the risk of selection of resistant bacteria. in europe the prevalence varies from 1/1000 to 210/1000 respondents. self-medication may be triggered by experience with prescribed antibiotics. we investigated whether in european countries prescribed use was associated with self-medication with antibiotics. methods: a population survey was conducted in 19 european countries with 15548 respondents completing the questionnaire. multivariate logistic regression analysis was used to study the relationship between prescribed use and self-medication (both actual and intended) in general, for a specific symptom/disease or a specific antibiotic. results: prescribed use was associated with selfmedication, with stronger effect in northern/western europe (odds ratio 7.6, 95% ci 4.2-13.6) than in southern (2.1, 1.2-3.6) and eastern europe (1.9, 1.3-2.7). prescribing of a specific antibiotic increased the probability of self-medication with the same antibiotic. prescribing for a specific symptom/disease increased the likelihood of self-medication for the same symptom/disease. the use of prescribed antibiotics and actual self-medication were both determinants of intended self-medication in general and for specific symptoms/diseases. conclusions: routine prescribing of antibiotics increases the risk of self-medication with antibiotics for similar ailments, both through the use of leftovers and buying antibiotics directly from pharmacies. background: in 2003 the american national kidney foundation published a guideline based on opinion and observational studies which recommends tight control of serum calcium, phosphorus and calcium-phosphorus product levels in dialysis patients. objectives: within the context of this guideline, we explored associations of these plasma concentrations with cardiovascular mortality risk in incident dialysis patients. design and methods: in necosad, a prospective multi-centre cohort study in the netherlands, we included 1629 consecutive patients new on haemodialysis or peritoneal dialysis between 1997 and 2004. risks were estimated using adjusted time-dependent cox regression models. results: mean age was 60±15 years, 61% was male, and 64% was treated with haemodialysis. cardiovascular mortality risk was significantly higher in haemodialysis patients (hr: 1.5; 95% ci: 1.1 to 2.1) and in peritoneal dialysis patients (hr: 2.4; 1.3 to 4.2) with elevated plasma phosphorus levels when compared to patients who met the target. in addition, having elevated plasma calcium-phosphorus product concentrations increased cardiovascular mortality risk in haemodialysis (hr: 1.5; 1.1 to 2.1) and in peritoneal dialysis patients (hr: 2.2; 1.3 to 3.8). conclusion: application of the current guideline in clinical practice is warranted since it reduces cardiovascular mortality risk in haemodialysis and peritoneal dialysis patients in the netherlands. background: urologists are increasingly confronted with requests for early detection of prostate cancer in men from hereditary prostate cancer (hpc) families. however, little is known about the benefit of early detection among men at increased risk. objectives: we studied the effect of biennial screening with psa in unaffected men from hpc families, aged 50-70 years, on surrogate endpoints (test and tumour characteristics). methods: the netherlands foundation for the detection of hereditary tumours holds information on approximately 140 hpc families. here, 172 nonaffected men from these families were included and invited for psa testing every 2 years. we collected data on screening history and complications related to screening. results: in the first round, serum psa was elevated (3 ng/ml or greater) in 39 of 172 men screened (23%). further diagnostic assessment revealed 14 patients with prostate cancer (8.1%). compared to population-based prostate cancer screening trials, the referral rate is equal but the detection rate is twice as high. discussion: in conclusion, the results of prostate cancer screening trials will not be directly applicable to screening in hpc families. the balance between costs, side-effects and potential benefits of screening when applied to a high-risk population will have to be assessed separately. background: in industrialized countries occupational tuberculosis among health care workers (hcws) is re-emerging as a public health priority. to prevent and control tuberculosis transmission in nosocomial settings, public health agencies have issued specific guidelines. turin, the capital of the piedmont region in italy, is experiencing a worrying rise of tuberculosis incidence. here, hcws are increasingly exposed to the risk of nosocomial tuberculosis transmission. objectives: a) to estimate the sex-and age-adjusted annual rate of tuberculosis infection (arti) (per 100 person-years [%py]) among the hcws, as indicated by tuberculin skin test conversion (tst) conversion, b) to identify occupational factors associated with significant variations in the arti, c) to investigate the efficacy of the regional preventive guidelines. design and methods: multivariate survival analysis on tst conversion data from a dynamic cohort of 2185 hcws in turin, between 1998 and 2004. results: the overall estimated arti was 2.4 (95% ci: 1.9-3.0) %py. the risk of tst conversion significantly differed among workplaces, occupations, and age of hcws. the guidelines implementation was associated with an arti reductions of 1.35 (95% ci: 1.33-1.27) %py. conclusions: we identify occupational risk categories for targeting surveillance and prevention measures and assessed the efficacy of the local guidelines. background: a positive family history (fh) of breast cancer is an established risk factor for the disease. screening for breast cancer in israel is recommended annually for positive-fh women aged = 40 y and biennially for average-risk women aged 50-74 y. objective: to assess the effect of having a positive breast cancer fh on performing screening mammography in israeli women. methods: a cross-sectional survey based on a random sample of the israeli population. the study population consists of 1,605 women aged 40-74 y and telephone interviews were used. logistic regression models identified variables associated with mammography performance. results: a positive fh for breast cancer was reported by 153 (9.5%) participants. performing a mammogram in the previous year was reported by 43.1% and 24.7% of the positive and negative fh subgroups, respectively (p<0.0001). rates increased with age. among positive fh participants, being married was the only significant correlate for a mammogram in the previous year. conclusions: over 60% and around 55% of high-risk women aged 40-49 y and = 50 y, respectively, are inadequately screened for breast cancer. screening rates are suboptimal in average-risk women too. discussion: national efforts should concentrate on increasing awareness and breast cancer screening rates. to evaluate the association between infertility, infertility treatments and breast cancer risk. methods: a historical prospective cohort with 5,788 women who attended 5 israeli infertility centers between 1964 and 1984. their medical charts were abstracted. breast cancer incidence was determined through linkage with the national cancer registry. standardized incidence ratios (sirs) and 95% confidence intervals were computed by comparing observed cancer rates to those expected in the general population. additionally, in order to control for known risk factors, a casecontrol study nested within the cohort was carried out as well based on telephone interviews with breast cancer cases and controls matched by 1:2 ratio. results: compared to 115.2 expected breast cancer cases, 131 were observed (sir = 1.1;non-significant). risk for breast cancer was higher for women treated with clomiphene citrate (sir = 1.4; 95% ci 1.0-1.8). similar results were noted when treated and untreated women were compared, and when multivariate models were applied. in the nested case-control study, higher cycle index and treatment with clomiphene citrate were associated with significantly higher risk for breast cancer. conclusions: clomiphene citrate may be associated with higher breast cancer risk. smoking is a strong risk factor for arterial disease. some consider smoking also as a risk factor for venous thrombosis, while the results of studies investigating the relationship are inconsistent. therefore, we evaluated smoking as a risk factor for venous thrombosis in the multiple environmental and genetic assessment of risk factors for venous thrombosis (mega) study, a large population-based case-control study. consecutive patients with a first venous thrombosis were included from six anticoagulation clinics. using a random-digit-dialing method a control group was recruited in the same geographical area. all participants completed a questionnaire including questions on smoking habits. persons with known malignancies were excluded from the analyses, leading to a total of 4086 patients and 2567 controls. current and former smoking resulted in a small increased risk of venous thrombosis (ors adjusted for age, sex and bmi) (or-current:1.5 ci95:1.3-1.7, or-former:1.2 ci95:1.0-1.4). an increasing amount and duration of smoking was associated with an increase in risk. the highest risk was found among young (lowest tertile:18 to 41 yrs) current smokers; twenty or more pack-years resulted in a 3.3-fold increased risk (ci95:2.2-5.0). in conclusion, smoking results in a small increased risk of venous thrombosis, with the greatest relative effect among young heavy smokers. objective: to explore whether the observed association between silica exposure and lung cancer was confounded by exposure to other occupational carcinogens, we conducted a nested case-control-study among a cohort of male workers in 29 chinese mines and potteries. methods: 511 lung cancer cases and 1879 matched controls were selected. exposure to respirable silica as well as relevant occupational confounders were evaluated quantitatively based on historical industrial hygiene data. the relationship between silica exposure and lung cancer mortality was analyzed by conditional logistic regression analysis adjusted for exposure to arsenic, polycyclic aromatic hydrocarbons (pahs), radon, and smoking habit. results: in a crude analysis adjusted for smoking only, a significant trend of increasing risk of lung cancer with exposure to silica was found for tin, copper/iron miners, and pottery workers. however, after the relevant occupational confounders were adjusted, no association can be observed between silica exposure and lung cancer mortality (pro mg/m3-year increase of silica exposure: or = 1.01, 95% ci: 0.99 -1.02). conclusion: our results suggest that, the observed excess risk of lung cancer among silica exposed chinese workers is more likely due to exposure to other occupational carcinogens such as arsenic and pahs rather than due to exposure to respirable silica. background: modelling studies have shown that lifestyle interventions for adults with a high risk of developing diabetes are costeffective. objective: to explore the cost-effectiveness of lifestyle interventions for adults with low or moderate risk of developing diabetes. design and methods: the short-term effects of both a community-based lifestyle program for the general population and a lifestyle intervention for obese adults on diabetes risk factors were estimated from international literature. intervention costs were based on dutch projects. the rivm chronic diseases model was used to estimate long-term health effects and disease costs. costeffectiveness was evaluated from a health care perspective with a time horizon of 70 years. results: intervention costs needed to prevent one case of diabetes in 20 years range from 1,000 to 5,000 euro for the community program and from 5,000 to 21,000 euro for the intervention for obese adults. cost-effectiveness was 3,000 to 3,500 euro per quality adjusted life-year for the community program and 3,500 to 5,500 for the lifestyle intervention. conclusion: a lifestyle intervention for obese adults produces larger individual health benefits then a community program but, on a population level, health gains are more expensively achieved. both lifestyle interventions are cost-effective. background: in barcelona, the proportion of foreign-born patients with tuberculosis (tb) raised from 12.8% in 1999 to 35,2% in 2004. objective: to determine differences in infection by country of origin among contacts investigated by the tb programme in barcelona from 2000-2004. design and methods: data were collected on 1198 cases and their 4638 contacts. generalized estimating equations were used to obtain the risk of infection (or and 95% ci) to account for potential correlation among contacts. results: contacts of foreign born cases were more infected than contacts of natives patients (41% vs 20%, p<0.001) factors related to infection among contacts of foreign cases were inner city residency (or:1.8,95% ci: 1.2-2.8) and sputum smear positivity of the case (or:1.9,95% ci: 1. 2-2.8) and male contact (or:1.4,95% ci: 1.0-1.9), but not daily contact (or:1.1,95% ci:0.8-1.6) among natives cases, inner city residency (or:2.0,95% ci: 1.2-3.2), sputum smear positivity (or:2.2,95% ci: 1.5-3.1) and daily exposure (or:2.3,95% ci: 1.7-2.9) increased risk of infection. conclusion: contacts immigrant tb cases have a higher risk of infection than contacts of natives cases, however daily exposure to an immigrant case was not associated with a greater risk of infection. this could be explained by the higher prevalence of tb infection in their country of origin. background: an inverse association between birthweight and subsequent coronary heart disease (chd) has been widely reported but has not been formally quantified. we therefore conducted a systematic review of the association between birthweight and chd. design and methods: seventeen studies including a total of 144,794 singletons that had reported quantitative or qualitative estimates of the association between birthweight and chd by october 2005 were identified. additional data from two unpublished studies of 3801 individuals were also included. in total, the analyses included data on 4210 non-fatal and 3308 fatal coronary heart disease events in 147,009 individuals. results: the mean weighted estimate for the association between birthweight and chd incidence was 0.84 (95% ci 0.81-0.88) per kg of birthweight. overall, there was no significant heterogeneity between studies (p = 0.09) or evidence of publication bias (begg test p = 0.3). fifteen studies were able to adjust for some measure of socioeconomic position, but such adjustment did not materially influence the association: 0.85 (95% ci 0.81-0.90). discussion: these findings are consistent with one kilogram higher birthweight being associated with 10-20% lower risk of subsequent chd, but the causal nature of this association remains uncertain and its direct relevance to public health is likely to be small. objective: diabetes has been reported to be associated with a greater coronary hazard among women compared with men with diabetes. we quantified the coronary risk associated with diabetes by sex by conducting a meta-analysis of prospective cohort studies. methods: studies reporting estimates of the relative risk for fatal coronary heart disease (chd) comparing those with and without diabetes, for both men and women were included. results: 37 studies of type-2 diabetes and chd among 447,064 individuals were identified. the summary relative risk for fatal chd, diabetes versus not, was significantly greater among women than men: 3.50 (95% ci 2.70 to 4.53) versus 2.06 (95% ci 1.81 to 2.34), p<0.0001. after excluding eight studies that had only adjusted for age, the sex risk difference was substantially reduced, but still highly significant (p = 0.003). the pooled ratio of the relative risks (female: male) from the 29 multiple-adjusted studies was 1.46 (95% ci 1.14 to 1.88). conclusions: the relative risk for fatal chd associated with diabetes is 50% higher in women than in men. more adverse cardiovascular risk profiles among women with diabetes, combined with possible treatment disparities that favour men, may explain the greater excess coronary risk associated with diabetes in women. background: malaria in sri lanka is strongly seasonal and often of epidemic nature. the incidence has lowered in recent years which increased the relevance of epidemic forecasting for better targeting control resources. objectives: to establish the spatio/temporal correlation of precipitation and malaria incidence for use in forecasting. design and methods: de-trended long term (1972 de-trended long term ( -2001 monthly time series of malaria incidence at district level were regressed in a poisson regression against rainfall and temperature at several lags. results: in the north and east of sri lanka, malaria seasonality is strongly positively correlated to rainfall seasonality (malaria lagging one or two months behind rainfall). however, in the south west, no significant (negative) correlation was found. also in the hill country, no significant correlation was observed. conclusion and discussion: despite high correlations, it still remains to be explored to what extent rainfall can be a used as a predictor (in time) of malaria. observed correlation could simply be due to two cyclical seasonal patterns running in parallel, without causal relationship. e.g. similarly, strong correlations were found between temperature and malaria seasonality at 9 months time lag in northern districts, but causality is biologically implausible. background: few studies assessed the excess burden of acute respiratory tract infections (rti) among preschool children in primary care during viral seasons. objective: to determine the excess of rti in preschool children in primary care attributable to influenza and respiratory syncytial virus (rsv). methods: we performed a retrospective cohort study including all children aged 0-5 years registered in the database of the utrecht general practitioner (gp) network. during 1998 during -2002 , gps recorded episodes of acute rti. surveillance data of influenza and rsv were obtained from the weekly sentinel system of the dutch working group on clinical virology. viral seasons and base-line period were defined as the weeks with respectively more than 5% and less than 1% of the yearly number of isolates of influenza or rsv. results: on average 329 episodes of rti were recorded per 1,000 child years (95% ci:321-337). notably more consults for rti occurred during influenza-season (rr 1.74, 95% ci:1.63-1.86) and rsv-season (rr 2.27, 95% ci:2.14-2.42) as compared to base-line period, especially in children younger than two years of age. conclusion: substantial excess rates of rti were demonstrated among preschool children in primary care during influenza-season and particularly during rsvseason, notably in the younger age group. background: many cancer patients who have already survived some time want to know about their prognosis, given the precondition that they are still alive. objective: we described and interpreted population-based conditional 5-year relative survival rates for cancer patients. methods: the longstanding eindhoven cancer registry collects data on all patients with newly diagnosed cancer in the southeastern part of the netherlands (2.4 million inhabitants). patients aged 25-74 years, diagnosed between 1985 and 2002 and followed up until january 1, 2005 were included. conditional 5-year relative survival was computed for every additional year survived. results: for many tumours conditional 5-year relative survival approached 90-100% after having survived 5-10 years. however, for stomach cancer and hodgkin's lymphoma conditional 5-year relative survival increased to only 80-90% and for lung cancer and non-hodgkin's lymphoma it did not exceed 70-80%. initial differences in survival at diagnosis between age and stage groups disappeared after having survived for 5-10 years. conclusion: prognosis for patients with cancer changes with each year survived and for most tumours patients can considered to be cured after a certain period of time. however, for stomach cancer, lymphoma's and lung cancer the odds for death remains elevated compared to the general population. background: systematic review with meta-analysis, now regarded as 'best evidence', depends on availability of primary trials and on completeness of review. whilst reviewers have attempted to assess publication bias, relatively little attention has been given to selection bias by reviewers. method: systematic reviews of three cardiology treatments, that used common search terms, were compared for inclusion/exclusion of primary trials, pooled measures of principal outcomes and conclusions. results: in one treatment, reviews included 18, 11, 19, 28, 27 and 35 trials. there was little overlap: of 35 trials in the last review only 5, 4, 6, 13 and 3 were included by others. reported summary effects ranged from (most effective to least significant); mortality relative risk 0.29 (0.12, 0.70) in 4 trials to 0.96 (0.85, 1.09) in 23, and in one morbidity measure; standardised mean difference from 0.28 (0.10, 0.47) in 11 trials (822 patients) to 0.01 ()0.02, 0.04) in 10 (3960 patients). reviewers' conclusions ranged from 'highly effective' to 'no evidence of effect'. conclusions: these examples illustrate strong selection bias in published meta-analyses. post hoc review contravenes one important principal of science 'first the hypothesis, then the test'. selection bias by reviewers may affect 'evidence' more than does publication bias. in the context of a large population based german case control study examining the effects of hormone therapy (ht) on breast cancer risk, we conducted a validation study comparing ht prescription data with participants' self-reports for data quality assurance. included were 224 cases and 225 controls aged 50-74 years, stratified by age and hormone use. study participants provided detailed information on ht use to trained interviewers, while gynecologists provided prescription data via telephone or fax. data were compared using proportion of agreement, kappa, intraclass correlation coefficient (icc), and descriptive statistics. overall agreement for ever/never use was 88.2%, while agreement for ever/never use by type of ht was 80.6%, 80.3%, and 90.5% for mono-estrogen, cyclical, and continuous combined therapy, respectively. icc for duration was high (0.82 (95% ci: 0.77-0.85)), as were the iccs for age at first and last use (0.88(95% ci: 0.85-0.91) and 0.98 (95% ci: 0.97-0.98), respectively). comparison of exact brand name resulted in perfect agreement for 50.2% of participants, partial agreement for 29.3%, and no agreement for 20.7%. higher education and shorter length of recall were associated with better agreement. agreement was not differential by disease status. in conclusion, these self-reported ht data corresponded well with gynecologists' reports. background: legionnaires' disease (ld) is a pneumonia of low incidence. however, the impact of an outbreak can be substantial. objective: to stop a possible outbreak at an early stage, an outbreak detection programme was installed in the netherlands and evaluated after two years. design: the programme was installed nationally and consisted of sampling and controlling of potential sources to which ld patients had been exposed during their incubation period. potential sources were considered to be true sources of infection if two or more ld patients (cluster) had visited them, or if available patients' and environmental strains were indistinguishable by amplified fragment length polymorphism genotyping. all 39 municipal health services of the netherlands participated in the study. the regional public health laboratory kennemerland sampled potential sources and cultured samples for legionella spp. results: rapid sampling and genotyping as well as cluster recognition helped to target control measures. despite these measures, two small outbreaks were only stopped after renewal of the water system. the combination of genotyping and cluster recognition lead to 29 of 190 (15%) patient-source associations. conclusion and discussion: systematic sampling and cluster recognition can contribute to ld outbreak detection and control. this programme can cost-effectively lead to secondary prevention. -up (1990-2002) , 1896 primary invasive breast cancers occurred. results: compared with hrt never-use, use of estrogen alone was associated with a significant 1.4-fold increased risk. the association of estrogen-progestagen combinations with breast cancer risk varied significantly according to the type of progestagen: while there was no increase in risk with estrogen-progesterone (rr 1.0 [0.8-1.3]), estrogen-dydrogesterone was associated with a significant 1.3-fold increase, and estrogen combined with other synthetic progestins with a significant 1.8-fold increase. although the latter type of hrt involves a variety of different progestins, their associations with breast cancer risk did not differ significantly from one another. rrs did not vary significantly according to the route of estrogen administration (oral or transdermal/percutaneous). conclusion and discussion: progesterone rather than synthetic progestins may be preferred when an opposed estrogen therapy is to be prescribed. additional results on estrogen-progesterone are needed. background: although survival of hodgkin's lymphoma (hl) is high (>85%), treatment may cause long-term side-effects like premature menopause. objectives: to assess therapy-related risk factors for premature menopause (age <40) following hl. design and methods: we conducted a cohort-study among 387 female 5year hl-survivors, aged <31 at diagnose and treated between 1965 and 1995. patients were followed from first treatment until june 2001, menopause, death, or age 40. cumulative dose of various chemotherapeutic agents as well as radiation fields were studied as risk factors for premature menopause. cox-regression was used to adjust for age, year of treatment, smoking, bmi, and oral contraceptive-use. results: after a median follow-up of 11.4 years, 130 (34%) women reached premature menopause. overall 20 women (5%) were treated with chemotherapy only, 115 (30%) with radiotherapy only and 252 (65%) with both radio-and chemotherapy. exposure to procarbazine ), cyclophosphamide (hr 3.6 [2.1-5.9] ) and irradiation of the ovaries ]) were associated with significant increased risks for premature menopause. for procarbazine a dose-response relation was observed. procarbazine-use has decreased over time. conclusion: to decrease the risk for premature menopause after hl, procarbazine and cyclophosphamide exposure should be minimized and ovarian irradiation should be avoided. background: casale is an italian town where a large asbestos cement plant was active for decades. previous studies found increased risk for mesothelioma in residents, suggesting a decreasing spatial trend with distance from the plant. objective: to analyse the spatial variation of risk in casale and the surrounding area ($100,000 inhabitants) focussing on non-occupationally exposed individuals. design/methods: population-based case-control study including pleural mesotheliomas diagnosed between 1987 and 1993. information on the 97 cases and 250 controls comprised lifelong residential and occupational history of subjects and their relatives. nonparametric tests of clustering were used to evaluate spatial aggregation. parametric spatial models based on distance between the longest-lasting subject residence (excluding the last 20 years before diagnosis) and the source enabled estimation of risk gradient. results: mesothelioma risk appeared higher in an area of roughly 9-11 km radius from the source. spatial clustering was statistically significant (p = 0.003) and several clusters of cases were identified within casale. risk was highly related to the distance from the source; the best fitting model was the exponential decay with threshold. conclusion/discussion: asbestos pollution has increased dramatically the risk of mesothelioma in the area around casale. risk decreases slowly with the square of distance from the plant. malaria control programmes targeting malaria transmission from man to mosquito can have a large impact of malaria morbidity and mortality. to successfully interrupt transmission, a thorough understanding of disease and transmission parameters is essential. our objective was to map malaria transmission and analyse microenvironmental factors influencing this transmission in order to select high risk areas where transmission reducing interventions can be introduced. each house in the village msitu-wa-tembo was mapped and censused. transmission intensity was estimated from weekly mosquito catches. malaria cases identified through passive case detection were mapped by residence using gis software and the incidence of cases by season and distance to river were calculated. the distribution of malaria cases showed a clear seasonal pattern with the majority of cases during the rainy season (chisquare = 62.3, p<0.001). living further away from the river (p = 0.04) was the most notable independent protective factor for malaria infection. transmission intensity was estimated at 3.4 (95% ci 0.7 -9.9) infectious bites per person per year. we show that malaria in the study area is restricted to a short transmission season. spatial clustering of cases indicates that interventions should be planned in the area closest to the river, prior and during the rainy season. background: the effectiveness of influenza vaccination of elders has been subject of some dispute. its impact on health inequalities also demands epidemiological assessments, as health interventions may affect early and most intensely better-off social strata. objectives: to compare pneumonia and influenza (p&i) mortality of elders (aged 65 or more years old) before and after the onset of a largescale scheme of vaccination in sao paulo, brazil. methods: official information on deaths and population allowed the study of p&i mortality at the inner-city area level. rates related to the period 1998 to 2002, during which vaccination coverage ranked higher than 60% of elders were compared with figures related to the precedent period (1993) (1994) (1995) (1996) (1997) . the appraisal of mortality decrease used a geo-referred model for regression analysis. results: overall p&i mortality reduced 26.3% after vaccination. also the number of outbreaks, the excess of deaths during epidemic weeks, and the proportional p&i mortality ratio reduced significantly after vaccination. besides having higher prior levels of p&i deaths, deprived areas of the city presented a higher proportional decrease of mortality. conclusion: influenza vaccination contributed for an overall reduction of p&i mortality, while reducing the gap in the experience of disease among social strata. background: alcohol's first metabolite, acetaldehyde, may trigger aberrations in dna which predispose to developing colorectal cancer (crc) through several distinct pathways. our objective was to study associations between alcohol consumption and the risk of crc, according to two pathways characterized by mutations in apc and k-ras genes, and absence of hmlh1 expression. methods: in the netherlands cohort study, 120,852 men and women, aged 55-69 years, completed a questionnaire on risk factors for cancer in 1986. case-cohort analyses were conducted using 575 crc cases with complete data after 7.3 years of follow-up, excluding the first 2.3 years. gender-specific adjusted incidence rate ratios (rr) and 95% confidence intervals (ci) were estimated. results: neither total alcohol, nor beer, wine or liquor consumption was clearly associated with the risk of colorectal tumors lacking hmlh1 expression or harboring a truncating apc mutation and/or an activating k-ras mutation. in men and women, total alcohol consumption above 30 g/day was associated with an increased risk of crc harboring a truncating apc and/or activating k-ras mutation, though not statistically significant. (rr:1.37 (95% ci: 0.8-2.5) in men, rr: 1.88 (95% ci: 0.8-4.6) in women). in conclusion, alcohol consumption is not involved in the studied pathways leading to crc. background: educational level is commonly used to identify social groups with increased prevalence of smoking. other indicators of socioeconomic status (ses) might however be more discriminatory. objective: this study examines to what extent smoking behaviour is related to other ses indicators, such as labour market position and financial situation. methods: data derived from the european household panel, which includes data on smoking for 11 european countries. we selected data for 101,312 respondents aged 25-60 years. the association between ses indicators and smoking prevalence was examined through logistic regression analyses. results: preliminary results show that, in univariate analysis, all selected ses indicators were associated with smoking. higher rates of smoking in lower social groups were observed in all countries, except for women in some mediterranean countries. in multivariate analyses, education retained an independent effect on smoking. no strong effect was observed for labour market position (occupational class, employment status) or for income. however, smoking prevalence was strongly related to economic deprivation and housing tenure. conclusion: these results suggest that different aspects of people's ses affect their smoking behaviour. interventions that aim to tackle smoking among high-risk groups should identify risk groups in terms of both education and material deprivation. objective: we investigated time trends in overweight and leisure time physical activities (ltpa) in the netherlands since 1980. intra-national differences were examined stratified for sex, age and urbanisation degree. design and methods: we used a random sample from the health interview survey of about 140 000 respondents, aged 20-to-69 years. self-reported data on weight, height and demographic characteristics were gathered through interviews (yearly) and data on ltpa were collected by selfadministered questionnaires . linear regression was performed for trend analyses. results: during 1981-2004, mean body mass index (bmi) increased by 1.0 kg/m2 (p = 0.001). trends were similar across sex and urbanisation degrees. in 20-to-39 year old women, mean bmi increased more (1.7 kg/m2; p = 0.05) than in older women. concerning ltpa, no clear trend was observed during 1990 observed during -97 and 2001 observed during -04. however, in 2001 year old women spent $ 150 min/wk less on ltpa compared to older women, while this difference was smaller during 1990-97. conclusions: mean bmi increased more in younger women, which is consistent with the observation that this group spent less time on ltpa during recent years. although the overall increase in overweight could no´t be explained by trends in ltpa, physical activity interventions should target the younger women. background: prediction rules combine patient characteristics and test results to predict the presence of an outcome (diagnosis) or the occurrence of an outcome (prognosis) for individual patients. when prediction rules show poor performance in new patients, investigators often develop a new rule, ignoring the prior information available in the original rule. recently, several updating methods have been proposed that consider both prior information and information of the new patients. objectives: to compare five updating methods (that vary in extensiveness) for an existing prediction rule that preoperatively predicts the risk of severe postoperative pain (spp). design and methods: the rule was tested and updated on a validation set of 752 new surgical patients (274 (36%) with spp). we estimated the discrimination (the ability to discriminate between patients with and without spp) and calibration (the agreement between the predicted risks and observed frequencies of spp) of the five updated rules in 283 other patients (100 (35%) with spp). results: simple updating methods showed similar effects on calibration and discrimination as the more complex methods. discussion and conclusion: when the performance of a prediction rule in new patients is poor, a simple updating method can be applied to improve the predictive accuracy. about two million ethnic germans (aussiedler) have resettled in germany since 1990. analyses with a yet incomplete follow-up of a cohort of aussiedler showed a different mortality compared to russia and germany. objectives: we investigated whether the mortality pattern changed after a complete follow-up and whether residential mobility after resettlement has an effect on mortality. we established a cohort of 34393 aussiedler who moved to germany between 1990 and 2001. we calculated smr for all causes, external causes, cardiovascular deaths and cancer in comparison to german rates. results: with a complete follow-up, the cohort accumulated 248798 person years. overall, 1726 deaths were observed (smr 0.85, 95% ci: 0.81-0.89). smr for all external causes, all cancer and cardiovascular deaths were 0.84, 0.85 and 0.79, respectively. increased number of moves within germany was associated with increased mortality. conclusion and discussion: the mortality in the cohort is surprisingly low, in particular for cardiovascular deaths. there is a mortality disadvantage from external causes and for some selected cancers. this disadvantage is however not as large as would be expected if aussiedler were representative of the general population in fsu countries. mobility as an indicator for a lesser integration will be discussed. background: breast cancer screening (bcs) provides an opportunity to analyze the relationship between lymph node involvement (ln), the most important prognostic factor, and biological and time dependent characteristics. objective: our aim was to assess those characteristics that are associated with ln in a cohort of screen-detected breast cancers. methods: observational population study of all invasive cancers within stage i-iiia detected from 1996 to 2002 through a bcs program in catalonia (spain). age, tumor size, histological grade, ln status and screening episode (prevalent or incident) were analyzed. pearson chi-square or fisher's exact test, mann-whitney test and stratified analyses were applied, as well as multiple logistic regression techniques. results: twenty nine percent (95% ci 21.7-35.4%) out of 168 invasive cancers had ln and 37.5% were prevalent cancers. in the bivariate analysis, tumor size and age were strongly associated to ln (p< 0.010) while grade was related to ln only in incident cancers (p = 0.027). grade was associated with tumor size (p = 0.005) and with screening episode (p = 0.013). adjusting for screening episode and grade, age and tumor size were independent predictors of ln. conclusion: in conclusion, age and tumor size are independent predictors of ln. grade emerges as an important biological factor in incident cancers. background: the evidence regarding the association between smoking and cognitive function in the elderly is inconsistent. objectives: to examine the association between smoking and cognitive function in the elderly. design and methods: in 2003, all 740 participants of a population-based cohort study aged 70 years or older were eligible for a telephone interview on cognitive function using validated instruments, such as the telephone interview of cognitive status (tics). information on smoking history was available from questionnaires administered in 2002. we estimated the odds ratios (or) of cognitive impairment (below 25th percentile) and the corresponding 95% confidence intervals (ci) by means of logistic regression adjusting for age, sex, alcohol consumption, body mass index, physical exercise, educational level, depressive symptoms and co-morbidity. results: in total, 465 participants were interviewed and had complete information on smoking history. former smokers had a lower prevalence of cognitive impairment (oradjusted = 0.61;95% ci:0.33-1.13) compared with never smokers, but not current smokers (oradjusted = 0.96;95% ci:0.34-2.70). conclusion: there is no association between current smoking and cognitive impairment in the elderly. discussion: the lack of association between current smoking and cognitive impairment is in line with previous non-prospective studies. the inverse association with former smoking might be due to smoking cessation associated with co-morbidities. background: many studies have reported late effects of treatment in childhood cancer survivors. most studies, however, focused on only one late effect or suffered from incomplete follow-up. objectives: we assessed the total burden of adverse events (ae), and determined treatment-related risk factors for the development of various aes. methods: the study cohort included 1362 5-year survivors, treated in the emma childrens hospital amc in the netherlands between 1966-1996. aes were graded for severity by one reviewer according to the common terminology criteria adverse events version 3.0. results: medical follow-up data were complete for 94.3% 5-year survivors. median follow-up time was 18 years. almost 75% of survivors had one or more aes, and 24.6% had even 5 or more aes. of patients treated with rt alone, 55% had a high or severe burden of aes, while this was only 15% in patients treated with ct alone. radiotherapy (rt) was associated with the highest risk to develop an ae of at least grade 2, and was also associated with a greater risk to develop a medium to severe ae burden. conclusions: survivors are at increased risk for many health problems that may adversely affect their quality of life and long-term survival. background: studies in the past demonstrated that multifaceted interventions could enhance the quality of diabetes care. however many of these studies showed methodological flaws as no corrections were made for patient case-mix and clustering or a nonrandomised design was used. objective: to assess the efficacy of a multifaceted intervention to implement diabetes shared care guidelines. methods: a cluster randomised controlled trial of 2097 patients with type 2 diabetes was conducted at 40 general practises (n = 1714) and one outpatient clinic (n = 383). in primary care, facilitators analysed barriers to change, introduced structured care, gave feedback and trained practice staff. at the outpatient clinic, an abstract of the guidelines was distributed. case-mix differences such as duration of diabetes, education, co-morbidity and quality of life were taken into account. results: in primary care, more patients in the intervention group were seen on a three monthly basis (85.7% versus 69.4%, p<0.001) and their hba1c was statistically significant lower (6.9±0.9 versus 7.0±0.1, p<0.01). however, significance was lost after correction for case-mix (p = 0.6). change in blood pressure and total cholesterol was not significant. we were unable to demonstrate any change in secondary care. conclusion: multifaceted implementation did improve the process of care but left cardiovascular risk unchanged. background: we have performed a meta-analysis including 43 studies on the diagnostic accuracy of mr-mammography in patients referred for further characterization of suspicious breast lesions. using the bivariate diagnostic meta-analysis approach we found an overall sensitivity and specificity of 0.90 and 0.73, respectively. the aim of the present analysis was to detect heterogeneity between studies. materials and methods: seventeen study and population characteristics were separately included in the bivariate model to compare sensitivity and specificity between strata of the characteristics. results: both sensitivity and specificity were higher in studies performed in the united states compared to non-united states studies. both estimates were also higher if two criteria for malignancy were used instead of one or three. only specificity was affected by the prevalence of cancer: specificity was highest in studies with the lowest prevalence of cancer in the study population. furthermore, specificity was affected by whether the radiologist was blinded for clinical information: specificity was higher if there was no blinding. conclusions: variation between studies was notably present across studies in country of publication, the number of criteria for malignancy, the prevalence of cancer and whether the observers were blinded for clinical information. objective: the aim of this project is to explore variation in three candidate genes involved in cholesterol metabolism in relation to risk of acute coronary syndrome (acs), and to investigate whether dietary fat intake modifies inherent genetic risks. study population: a case-cohort study is designed within the danish 'diet, cancer and health' study population. a total of 1500 cases of acs have been identified among 57,053 men and women who participated in a baseline examination between 1993-1997 when they were aged 50-64 years. a random sample of 1500 participants will serve as 'control' population. exposures: all participants have filled out a detailed 192-item food frequency questionnaire and a questionnaire concerning lifestyle factors. participants were asked to provide a blood sample. candidate genes for acs have been selected among those involved in cholesterol transport (atp-binding cassette transporter a1, cholesterol-ester transfer protein, and acyl-coa:cholesterol acyltransferase 2). five single nucleotide polymorphisms (snps) will be genotyped within each gene. snps will be selected among those with demonstrated functional importance, as assessed in public databases. methods: statistical analyses of association between genetic variation in the three chosen genes and risk of acs. explorations of methods to evaluate biological interaction will be of particular focus. background: c-reactive protein (crp) has been shown to be associated with type 2 diabetes mellitus. it is unclear whether the association is completely explained by obesity. objective: to examine whether crp is associated with diabetes independent of obesity. design and methods: we measured baseline characteristics and serum crp in 5954 non-diabetic participants of the rotterdam study and followed them for a mean of 9.8 years. cox regression was used to estimate the hazard ratio. in addition, we performed a meta-analysis on 10 published studies. results: during follow-up, 658 participants developed diabetes. serum crp was significantly and positively associated with the risk to develop diabetes. the risk estimates attenuated but remained statistically significant after adjustment for obesity indexes. age, sex and body mass index (bmi) adjusted hazard ratios (95% ci) were 1.90(1.43-2.52) for the fourth quartile, 1.66(1.25-2.20) for the third quartile, and 1.51(1.16-2.01) for the second quartile of serum crp compared to the first quartile. in the meta-analysis, weighed age, sex, and bmi adjusted risk ratio was 1.44(1.16-1.78), for the highest crp category (>2.6 mg/l) compared to the reference category (<0.5 mg/l). conclusion: our findings shows that the association of serum crp with diabetes is independent of obesity. background: effectiveness of screening can be predicted by episode sensitivity, which is estimated by interval cancers following a screen. full-field digital or cr plate mammography are increasingly introduced into mammography screening. objectives: to develop a design to compare performance and validity between screen-film and digital mammography in a breast cancer screening program. methods: interval cancer incidence was estimated by linking 721 000 screening visits from 1991-2001 at an individual level to the files of the cancer registry in finland. these data was used to estimate the study size requirements for analyzing differences in episode sensitivity between screen-film and digital mammography in a randomized setting. results: the two-year cumulative incidence of interval cancers per 100 000 screening visits was estimated to be 300. to allow the maximum acceptable difference in the episode sensitivity between screenfilm and digital arm to be 20% (80% power, 0.05 significance level, 1:1 randomization ratio, 85% attendance rate), approximately 240 000 women need to be invited. conclusion: only fairly large differences in the episode sensitivity can be explored within a single randomized study. in order to reduce the degree of non-inferiority between the screen-film and digital mammography, meta-analyses or pooled analyses with other randomized data are needed. session: socio-economic status and migrants presentation: oral. background: tackling urban/rural inequalities in health has been identified as a substantial challenge in reforming health system in lithuania. objectives: to assess mortality trends from major causes of death of the lithuanian urban and rural populations throughout the period of 1994-2004. methods: information on major causes of death (cardiovascular diseases, cancers, external causes, and respiratory diseases) of lithuanian urban and rural populations from 1994 to 2004 was obtained from lithuanian department of statistics. mortality rates were age-standardized, using european standard. mortality trends were explored using the logarithmic regression analysis. results: overall mortality of lithuanian urban and rural populations was decreasing statistically significantly during 1994-2004. more considerable decrease was observed in urban areas where mortality declined by 1.7% per year in males and 2.2% in females, compare to the decline by 1.2% in males and 1.7% in females in rural areas. the most notable urban/rural differences in mortality trends with unfavourable situation in rural areas were estimated in mortality from stoke, breast cancer in females, and external causes of death (traffic accidents and suicides). background: recent studies indicate that depression plays an important role in the occurrence of cardiovascular diseases (cvd). underlying mechanisms are not well understood. objectives: we investigated whether low intake of omega-3 fatty acids (fas) is a common cause for depression and cvd. methods: the zutphen elderly study is a prospective cohort study conducted in the netherlands. depressive symptoms were measured with the zung scale in 332 men, aged 70-90 years, and free from cvd and diabetes in 1990. dietary factors were assessed with a cross-check dietary history method. results: compared to high intake (= 156.2 mg/d), low intake (<58.9 mg/d) of omega-3 fas, adjusted for demographics and cvd risk factors, was associated with an increased risk of depressive symptoms (or 2.20; 95% ci 1.06-4.58) at baseline, and non-significantly with 10-year cvd mortality (hr 1.14; 95% ci 0.67-1.95). the adjusted hr for a 5-point increase in depressive symptoms for cvd mortality was 1.13 (95% ci 1.01-1.26), and did not change after additional adjustment for omega-3 fas. conclusion: low intake of omega-3 fas may increase the risk of depression. our results, however, do not support the hypothesis that low intake of omega-3 fas explains the relation between depression and increased risk of cvd. background: during the last decades the incidence of metabolic syndrome has risen dramatically. several studies have shown beneficial effects of nut and seed intake on components of this syndrome. the relationship with prevalence of metabolic syndrome has not yet been examined. objectives: we studied the relation between nut and seed intake and metabolic syndrome in coronary patients. design and methods: presence of metabolic syndrome (according to international diabetes federation definition) was assessed in 904 stable myocardial infarction patients (77% men) aged 60-80 years, as part of the alpha omega trial. dietary data were collected by food-frequency questionnaire. results: the prevalence of metabolic syndrome was 42%. median nut and seed intake was 3.82 g/day (interquartile range, 1.53-8.33 g/day). intake of nuts and seeds was inversely associated with the metabolic syndrome (prevalence ratio: 0.84; 95% confidence interval: 0.59-1.19, for >10 g/day versus <1 g/day), after adjustment for age, gender, dietary and lifestyle factors. the prevalence of metabolic syndrome was 31% lower (p = 0.050) in men with a high nut and seed intake compared to men with a low intake, after adjustment for confounders. conclusion and discussion: intake of nuts and seeds may reduce the risk of metabolic syndrome in stable coronary patients. background: in epidemiology, interaction is often assessed by adding a product term to the regression model. in linear regression the regression coefficient of the product term refers to additive interaction. however, in logistic regression it refers to multiplicative interaction. rothman has argued that interaction as departure from additivity better reflects biological interaction. hosmer and lemeshow presented a method to quantify additive interaction and its confidence interval (ci) between two dichotomous determinants using logistic regression. objective: our objective was to provide an estimation method for additive interaction between continuous determinants. methods and results: from the abovementioned literature we derived the formulas to quantify additive interaction and its ci between one continuous and one dichotomous determinant and between two continuous determinants using logistic regression. to illustrate the theory, data of the utrecht health project were used, with age and body mass index as risk factors for diastolic blood pressure. conclusions: this paper will help epidemiologists to estimate interaction as departure from additivity. to facilitate its use, we developed a spreadsheet, which will become freely available at our website. background: the incidences of acute myocardial infarction (ami) and ischemic stroke (is) in finland have been among highest in the world. accurate geo-referenced epidemiological data in finland provides unique possibilities for ecological studies using bayesian spatial models. objectives: examine sex-specific geographical patterns and temporal variation of ami and is. design and methods: ami (n = 205,213) and is (n = 115,383) cases in 1991-2003 in finland, localized at the time of diagnosis according to the place of residence address using map coordinates. cases and population were aggregated to 10 km x10 km grids. full bayesian conditional autoregressive models (car) were used for studying the geographic incidence patterns. results: the incidence patterns of ami and is showed on average 70% (95% ci 50-85%) common geographic variation and significantly the rest of the variation was disease specific. there was no significant difference between sexes. the patterns of high-risk areas have persisted over the years and the pattern of is showed more annual random fluctuations. conclusions: although ami and is showed rather similar and temporally stable patterns, significant part of the spatial variation was disease specific. further studies are needed for finding the reasons for disease specific geographical variation. most studies addressing socio-economic inequalities in health services use fail to take into account the disease the patient is suffering from. the objective of this study is to compare possible socioeconomic differences in the use of ambulatory care between 2 distinct patient groups: diabetics and patients with migraine. data was obtained from the belgian health interview surveys 1997, 2001 and 2004. in total 4381 patients with self reported diabetes or migraine were identified. in a multilevel analysis the probability of a contact and the volume of contacts with the general practitioner and/or the specialist were studied for both groups in relation to educational attainment and income. adjustment was made for age, sex, subjective health and comorbidity at the individual level, and doctors' density and region at district level. no socio-economic differences were observed among diabetic patients. among patients with migraine we observed a higher probability of specialist contacts in higher income groups (or 1,6;95% ci 1,1-2,4) and higher educated persons (or 1,6;95% ci 1,2-2,2), while lower educated persons tend to report more visits with the general practitioner. to correctly interpret socio-economic differences in the use of health services there is need to take into account information on the patient's type of disease. background: the suitability of non-randomised studies to assess effects of interventions has been debated for a long time, mainly because of the risk of confounding by indication. choices in the design and analytical phase of non-randomised studies determine the ability to control for such confounding, but have not been systematically compared yet. objective: the aim of the study will be to quantify the role of design and analytical factors on confounding in non-randomised studies. design and methods: a meta-regression analysis will be conducted, based on 41 cohort and 8 case-control studies analysed in a recent cochrane review on influenza vaccine effectiveness against hospitalisation or death in the elderly. primary outcome will be the degree of confounding as measured by the difference between the reported effect estimate (odds ratios or relative risks) and the best available estimate (nichol, unpublished data) . design factors that will be considered include study design, matching, restriction and availability of confounders. statistical techniques that will be evaluated include multivariate regression analysis with adjustment for confounders, stratification and, if available, propensity scores. results the rsults will be used to develop a generic guideline with recommendations how to prevent confounding by indication in non-randomised effect studies. the wreckage of the oil tanker prestige in november 2002 produced a heavy contamination of the coast of galicia (spain). we studied relationships between participation in clean-up work and respiratory symptoms in local fishermen. questionnaires including details of clean-up activities and respiratory symptoms were distributed among associates of 38 fishermen's cooperatives, with postal and telephone follow-up. statistical associations were evaluated using multiple logistic regression analyses, adjusted for sex, age, and smoking status. between january 2004 and february 2005, information was obtained from 6,780 fishermen (response rate 76%). sixty-three percent had participated in clean-up operations. lower respiratory tract symptoms were more prevalent in clean-up workers (odds ratio (or) 1.73; 95% confidence interval 1.54-1.94). the risk increased when the number of exposed days, number of hours per day, or number of activities increased (p for linear trend <0.0001). the excess risk decreased when more time had elapsed since last exposure (or 1.45 (1.28-1.64) and 2.16 (1.91-2.45) for more and less than 17 months, respectively; p for interaction <0.05). in conclusion, fishermen who participated in the clean-up work of the prestige oil spill show a prolonged dosedependent increased prevalence of respiratory symptoms one to two years after the beginning of the spill. background. hpv testing has been proposed for cervical cancer screening. objectives: evaluating the protection provided by hpv testing at long intervals vs. cytology every third year. methods: randomised controlled trial conventional arm: conventional cytology. experimental arm: in phase 1 hpv and liquid-based cytology. hpv-positive cytology-negatives referred for colposcopy if age 35-60, for repeat after one year if age 25-34. in phase 2 hpv alone. positives referred for colposcopy independently of age. endpoint: histologically confirmed cervical intraepithelial neoplasia (cin) grade 2 or more. results: overall 94,323 women were randomised. preliminary data at recruitment are presented. overall, among women aged 35-60 years relative sensitivity of hpv versus conventional cytology was 1.43 (95% c.i. 1.09-1.88) and relative positive predictive (ppv) value was 0.59 (95% c.i. 0.45-0.76). among women aged 25-34 relative sensitivity of hpv vs. conventional cytology was 1.58 (95% c.i. 1.03-2.44) during phase 1 but 3.79 (95% c.i. 2.26-6.35) during phase 2. conclusions: hpv testing increased cross-sectional sensitivity, but reduced ppv. in younger women data suggest that direct referral of hpv-positives to colposcopy results in relevant overdiagnosis of regressive lesions. measuring detection rate of cin at the following screening round will allow studying overdiagnosis and the possibility of longer screening intervals. background: plant lignans are present in foods such as whole grains, seeds, fruits and vegetables, and beverages. they are converted by intestinal bacteria into the enterolignans, enterodiol and enterolactone. enterolignans possess several biological activities whereby they may influence carcinogenesis. objective: to study the association between plasma enterolignans and the risk of colorectal adenomas. colorectal adenomas are considered to be precursors of colorectal cancer. design and method: the case-control study included 532 cases with at least one histologically confirmed colorectal adenoma and 503 controls with no history of any type of adenoma. associations between plasma enterolignans and colorectal adenomas were analyzed by logistic regression. results: associations were stronger for incident than for prevalent cases. when only incident cases (n = 262) were included, high compared to low enterodiol plasma concentrations were associated with a reduction in colorectal adenoma risk after adjustment for confounding variables. enterodiol odds ratios (95% ci) were 1.00, 0.69 (0.42-1.13), 0.60 (0.37-0.99), 0.53 (0.32-0.88) with a significant trend (p = 0.01) through the quartiles. although enterolactone plasma concentrations were 10fold higher, enterolactone's reduction in risk was not statistically significant (p for trend = 0.09). conclusion: we observed a substantial reduction in colorectal adenoma risk among subjects with high plasma concentrations of enterolignans, in particular enterodiol. background: smoking is a risk factor for tuberculosis diseases. recently the question was raised if smoking also increases the risk of tuberculosis infection. objective: to assess the influence of environmental tobacco smoke (ets) exposure in the household on tuberculosis infection in children. design and methods: a crosssectional community survey was done and information on 1373 children was obtained. tuberculosis infection was determined with a tuberculin skin test (tst) (cut-off 10 mm) and information on smoking habits was obtained from all adult household members. univariate and multivariate analyses were performed, and odds ratio (or) was adjusted for the presence of a tb contact in the household, crowding and age of the child. results: ets was a risk factor for tuberculosis infection (or: 1.92, 95% ci: 1.27 -2.92) when all children with a tst read between two and five days were included. the adjusted or was 1.64 (95% ci: 1.03 -2.61). in dwellings were a tuberculosis case had lived the association was strongest (adjusted or 5.67, 95% ci: 1.26 -25.65). conclusion and discussion: ets exposure seems to be a risk factor for tuberculosis infection in children. this is of great concern considering the high prevalence of smoking and tuberculosis in developing countries. background and objective: to implement a simulation model to analyze demand and waiting time (wt) for knee arthroplasty and to compare a waiting list prioritization system (ps) with the usual first-in, first-out (fifo) system. methods: parameters for the conceptual model were estimated using administrative data and specific studies. a discrete-event simulation model was implemented to perform 5-year simulations. the benefit of applying the ps was calculated as the difference in wt weighted by priority score between disciplines, for all cases who entered the waiting list. results: wt for patients operated under the fifo discipline was homogeneous (standard deviation (sd) between 1.3-1.7 months) with mean 18.7. wt under the ps had higher variability (sd between 10.6-11.6) and was positively skewed, with mean 7.6 months and 10% of cases over 24 months. when wt was weighted by priority score, the ps saved 6.6 months (95% ci 6.4-6.9) on average. the ps was favorable for patients with priority scores over 50, but penalized those with lower priority scores. conclusions: management of the waiting list for knee arthroplasty through a ps was globally more effective than through fifo, although patients with low priority scores were penalized with higher waiting times. background: we developed a probabilistic linkage procedure for the linking of readmissions of newborns from the dutch paediatrician registry (lnr). 15% of all newborns (30.000) are admitted to a neonatal ward. the main problems were the unknown number of readmissions per child and the identification of admissions of twins. objective: to validate our linking procedure in a double blinded study. design and methods: a random sample of admissions from 200 children from the linked file has been validated by the caregivers, using the original medical records. results: response was 97%. for admissions of singletons the linkage contained no errors except for the small uncertain area of the linkage. for admissions of multiple births a high error rate was found. conclusion and discussion: we successfully linked the admissions of singleton newborns with the developed probabilistic linking algorithm. for multiple births we did not succeed in constructing valid admission histories due to too low data quality of twin membership variables. validation showed alternative solutions for linking twin admissions. we strongly recommend that linkage results should always be externally validated. background: salmonella typhimurium definitive phage type (dt) 104 has emerged as an important pathogen in the last two decades. a 10-fold increase in cases in the netherlands during september-november 2005 prompted an outbreak investigation. objective: the objective was to identify the source of infection to enable preventive measures. methods: a subset of outbreak isolates was typed by molecular means. in a case-control study, cases (n = 109) and matched population controls (n = 411) were invited to complete self-administered questionnaires. results: the molecular typing corroborated the clonality of the isolates. the molecular type was similar to that of a recent s. typhimurium dt104 outbreak in denmark associated with imported beef. the incriminated shipment was traced after having been distributed sequentially through several eu member states. sampling of the beef identified s. typhimurium dt104 of the same molecular type as the outbreak isolates. cases were more likely than controls to have eaten a particular raw beef product. conclusions: our preliminary results are consistent with this s. typhimurium dt104 outbreak being caused by contaminated beef. our findings underline the importance of european collaboration, traceability of consumer products and a need for timely intervention into distribution chains. background: heavy-metals may affect newborns. some of them are presenting tobacco smoke. objectives: to estimate cord-blood levels of mercury, arsenic, lead and cadmium in newborns in 2 areas in madrid, and to assess the relationship with maternal tobacco exposure. design and methods: bio-madrid study obtained 115 cord-blood samples from recruited trios (mother/father/ newborn). cold-vapor atomic absorption spectrophotometry (aas) was used to measure mercury and graphite-furnace aas for the other metals. mothers answered a questionnaire including tobacco exposure. median, means and standard errors were calculated and logistic regression used to estimate or. results: median levels for mercury and lead were 7.5 mg/l and 13.7 mg/l. arsenic and cadmium were undetectable in 82% and 47 % of samples. preliminar analysis showed a significant association of maternal tobacco exposure and levels of arsenic (or:3.59;95% ci:1. 11-11.55 ), cadmium (or:2.24;95% ci:1.04-4.79), and lead (or:3.83;95% ci:1.41-10.36). smoking in pregnancy was associated to arsenic (or:3.90;95% ci:1.17-12.96), while passive exposure was more related to lead (or:3.61;95% ci:1.26-4.79) and cadmium (or:2.06;95% ci:0.91-4.97). conclusion: madrid newborns have high cord-blood levels of mercury. tobacco exposure in pregnancy might increase levels of arsenic, cadmium and lead. background: road traffic accidents (rta) are the leading cause of death for young. rta police reports provide no health information other then the number of deaths and injured, while health databases have no information on the accident dynamics. the integration of the two databases would allows to better describe the phenomenon. nevertheless, the absence of common identification variables through the lists makes the deterministic record linkage (rl) impossible. objective: to test feasibility of a probabilistic rl between rta and health information when personal identifiers are lacking. methods: health information came from the rta integrated surveillance for the year 2000. it integrates data from ed visits, hospital discharges and deaths certificates. a deterministic rl was performed with 149 police reports, where the name and age of deceased were present. results of the deterministic rl was then used as gold standard to evaluate the performance of the probabilistic one. results: the deterministic rl resulted in 141 (94.6%) linked records. the probabilistic rl, where the name was omitted, was capable to correctly identify 130 (87.2%). conclusions: performance of the probabilistic rl was good. further work is needed to develop strategies for the use of this approach in the complete datasets. background: overweight constitutes a major public health problem. the prevalence of overweight is unequally distributed between socioeconomic groups. risk group identification, therefore, may enhance the efficiency of interventions. objectives: to identify which socioeconomic variable best predicts overweight in european populations: education, occupation or income. design: european community household panel data were obtained for 9 countries (n = 52,855). overweight was defined as a body mass index >= 25 kg/m2. uni-and multivariate logistic regression analyses were employed to predict overweight in relationship to socioeconomic indicators. results: major socioeconomic differences in overweight were observed, especially for women. for both sexes, a low educational attainment was the strongest predictor of overweight. after control for confounders and the other socioeconomic predictors, the income gradient was either absent or positive (men) or negative (women) in most countries. similar patterns were found for occupational level. for women, inequalities in overweight were generally greater in southern european countries. conversely, for men, differences were generally greater in other european countries. conclusion: across europe, educational attainment most strongly predicts overweight. therefore, obesity interventions should target adults and children with lower levels of education. background: because incidence and prevalence of most chronic diseases rise with age, their burden will increase in ageing populations. we report the increase in prevalence of myocardial infarction (mi), stroke (cva), diabetes type ii (dm) and copd based on the demographic changes in the netherlands. in addition, for mi and dm the effect of a rise in overweight was calculated. methods: calculations were made for the period 2005-2025 with a dynamic multi-state transition model and demographic projections of the cbs. results: based on ageing alone, between 2005 and 2025 prevalence of dm will rise from 550.000 to 870.000 (+58%), prevalence of mi from 310.000 to 365.000 (+18%), stroke prevalence from 185.000 to 290.000 (+57%) and copd prevalence from 55 455.000 to 540.000 (+19%). a continuation of the dutch (rising) trend in overweight prevalence would in 2025 lead to about 940.000 diabetics (+70%). a trend resulting in american levels would lead to over 1 million diabetics (+90%), while the impact on mi was much smaller: about 375.000 (+20%) in 2025. conclusion: the burden of chronic disease will substantially increase in the near future. a rising prevalence of overweight has an impact especially on the future prevalence of diabetes background: there has been increasing concern about the effects of environmental endocrine disruptors (eeds) on human reproductive health. eeds include various industrial chemicals, as well as dietary phyto-estrogens. intra-uterine exposures to eeds are hypothesized to disturb normal foetal development of male reproductive organs and specifically, to increase the risk of cryptorchidism, hypospadias, testicular cancer, and a reduced sperm quality in offspring. objective: to study the associations between maternal and paternal exposures to eeds and the risks of cryptorchidism, hypospadias, testicular cancer and reduced sperm quality. design and methods: these associations are studied using a case-referent design. in the first phase of the study, we collected questionnaire data of the parents of 231 cases with cryptorchidism, 329 cases with hypospadias and 742 referent children. in the second phase, we will focus on the health effects at adult age: testicular cancer and reduced sperm quality. in both phases, we will attempt to estimate the total eed exposure of parents of cases and referents at time of pregnancy through an exposure-assessment model in which various sources of exposure, e.g. environment, occupation, leisure time activities and nutrition, are combined. in addition, we will measure hormone receptor activity in blood. background: eleven percent of the pharmacotherapeutic budget is spent on acid-suppressive drugs (asd); 3% of patients are chronic user. most of these indications are not conform to dyspepsia guidelines. objectives: we evaluated the implementation of an asd rationalisation protocol among chronic users, and analysed effects on volume and costs. method: in a cohort study 2871 patients from 158 gp's with protocol were compared to a control group of 8120 patients from 267 gp's without. prescription data of 2002-2004 were extracted from agis health database. a log-linear regression model compared standardised outcomes of number of patients that stopped or reduced asd (>50%) and of prescription volume and costs. results: gp's and patients in both groups were comparable. 7% in the intervention group had stopped; 6% in the control group (p<0.01). the volume had decreased in another 11% of patients; 8% in control group (p<0.001). compared to the baseline data in the control group (100%) the adjusted or of volume in the intervention group was 98.2%. the total costs adjusted or was 97.5%. the implementation significantly reduced the number of chronic users, and substantially dropped volume and costs. active intervention from insurance companies can stimulate rationalisation of prescription. background/objective: today, 20% of lung cancers are resectable (stage i/ii). 5-year survival is therefore low (15%). spiral computed tomography (ct) screening detects more lung cancers than chest x-ray. it is unknown if this will translate into a lung cancer mortality reduction. the nelson trial investigates whether 16detector multi-slice ct reduces lung cancer mortality with at least 25% compared to no screening. we present baseline screening results. methods: a questionnaire was sent to 550,000 men and women. of the 150,000 respondents, 30,500 high-risk current and former smokers were invited. until december 22, 2005, 15,530 of them gave informed consent and were randomised (1:1) in a screen arm (ct in year 1, 2 and 4) and control arm (no screening). data will be linked with the cancer registry and statistics netherlands to determine cancer mortality and incidence. results: of the first 5,700 baseline ct examinations 82% was negative (ct after one year), 16% indeterminate (ct after 3 months) and 2% positive (referral pulmonologist). seventy percent of detected tumours were resectable. conclusion/discussion: ct screening detects a high percentage of early stage lung cancers. it is estimated that the nelson trial is sufficiently large to demonstrate a 25% lung cancer mortality reduction or more. background: due to diagnostic dilemmas in childhood asthma, drug treatment of young children with asthmatic complaints often serves as a trial treatment. objective: to obtain more insight into patterns and continuation of asthma medication in children during the first 4 years of life. design: prospective birth cohort study methods: within the prevention and incidence of asthma and mite allergy (piama) study (n = 3,291 children) we identified 125 children using asthma medication in their first year of life. results: about 80% of children receiving asthma medication before the age of one, discontinued use during follow-up. continuation of therapy was associated with male gender (adjusted odds ratio [aor] 3.6, 95% confidence interval [ci]: 1.6-8.2), a diagnosis of asthma (aor 2.9, 95% ci: 1.3-6.3) and receiving combination or controller therapy (aor 2,6, 95% ci: 1.1-6.1). conclusion: patterns of medication use in preschool children support the notion that both beta2-agonist and inhaled corticosteroids are often used as trial medication, since 80% discontinues. the observed association between continuation of therapy and both an early diagnosis of asthma and a prescription for controller therapy suggests that, despite of diagnostic dilemmas, children in apparent need of prolonged asthma therapy are identified at this very early age. background: this study explored the differences in birthweight between infants of first and second generation immigrants and infants of dutch women, and to what extent maternal, fetal and environmental characteristics could explain these differences. method: during 15 months all pregnant women in amsterdam attending their first prenatel screening were asked to fill out a questionnaire (sociodemographic status, lifestyle) as part of the amsterdam born children and their development (abcd)-study; 8267 women (67%) responded. only singleton deliveries with pregnancy duration = 37 weeks were included (n = 7209). results: infants of all first and second generation immigrant groups (surinam, the antilles, turkey, morocco, ghana, other countries) had lower birthweights (range: 3227-3529 gram) than dutch infants (3548 gram). linear regression revealed that, adjusted for maternal height, weight, age, parity, smoking, marital status, gestational age and gender, infants of surinamese women (1st and 2nd generation), antillean and ghanaian women (both 1st generation) were still lighter than dutch infants (93.7, 166.7, 113.1, and 128.0 grams respectively; p<0.05). conclusion: adjusted for maternal, fetal and environmental characteristics infants of some immigrant groups had substantial lower birthweights than infants of dutch women. other factors (like genetics, culture) can possibly explain these differences. introduction: missing data is frequently seen in cost-effectiveness analyses (ceas). we applied multiple imputation (mi) combined with bootstrapping in a cea. objective: to examine the effect of two new methodological procedures of combining mi and bootstrapping in a cea with missing data. methods: from a trial we used direct health and non-health care costs and indirect costs, kinesiophobia and work absence data assessed over 12 months. mi was applied by multivariate imputation by chained equations (mice) and non-parametric bootstrapping was used. observed case analyses (oca), where analyses were conducted on the data without missings, were compared with complete case analysis (cca) and with analyses when mi and bootstrapping were combined after 10 to 30% of cost and effect data were omitted. results: by the cca effect and cost estimates shifted from negative to positive and cost-effectiveness planes and acceptability curves were biased compared to the oca. the methods of combining mi and bootstrapping generated good cost and effect estimates and the cost-effectiveness planes and acceptability curves were almost identical to the oca. conclusion: on basis of our study results we recommend to use the combined application of mi and bootstrapping in data sets with missingness in costs and effects. background: since the 1980s, coronary heart disease (chd) mortality rates have halved with approximately 50% of this decrease being attributable to medical and surgical treatments. objective: this study examined the cost-effectiveness of specific chd treatments. design and methods: the impact chd model was used to calculate the number of life-years-gained (lyg) by specific cardiology interventions given in 2000, and followed over ten years. this previously validated model integrates data on patient numbers, median survival in specific groups, treatment uptake, effectiveness and costs of specific interventions. cost-effectiveness ratios were generated as costs per lyg for each specific intervention. results: in 2000, medical and surgical treatments together prevented or postponed approximately 1,635 chd deaths in patients aged 25-84 years; this generated approximately 13,645 extra life years. aspirin and beta-blockers for secondary prevention of myocardial infarction and heart failure, and spironolactone for heart failure all appeared highly cost-effective (<e1,500 per lyg). less cost effective, however, were revascularisation for chronic angina (cabg surgery e12,970 and angioplasty e14,865 per lyg), or statins for primary prevention (e11,475 per lyg) or for community patients with angina (e11,220 per lyg). conclusions: cost effectiveness ratios generally favoured simple medical treatments for myocardial infarction, secondary prevention, and heart failure. objective: is population-based primary prevention more favourable than secondary prevention (risk factor reduction in coronary heart disease (chd) patients)? methods: the previously validated im-pact model was used to integrate data describing chd patient numbers, specific treatment uptake levels, trends in major risk factors, and the mortality benefits of these risk factor changes in healthy people and in chd patients. results: approximately 2,530 fewer deaths were attributable to reductions in the three major risk factors between 1985 and 2000. declining smoking prevalence resulted in approximately 685 fewer deaths: 395 in healthy people and 290 in known chd patients. decreasing population total cholesterol concentrations resulted in approximately 1,340 fewer deaths attributable to dietary changes (1,250 in healthy people and 90 in chd patients) plus 265 fewer deaths attributable to statin treatment (45 in people without chd and 220 in chd patients). decreasing mean population blood pressure resulted in approximately 170 fewer deaths attributable to secular falls in blood pressure (150 in healthy people and 20 in chd patients) plus approximately 70 fewer deaths attributable to antihypertensive treatments in people without chd. conclusions: compared with secondary prevention (620 fewer deaths), primary prevention (1,910 fewer deaths) achieved a three-fold larger reduction in chd deaths. background: carotenoid intake has been positively associated with plasma concentrations in different populations. however, the influence of body mass index (bmi) on this association is mostly unknown. objectives: we explored the relationship between intake of carotenoids and vitamin c, and their plasma concentrations by bmi categories in spanish elderly people. desgin/methods: a dietary interview using a 135-item food-frequency questionnaire was conducted with 240 men and 293 women, 65 and older, participating in the eureye study in spain. blood samples were collected for measurement of carotenoids and vitamin c. correlation coefficients (r) between energy adjusted nutrient intakes and plasma concentrations were calculated by categories of bmi, adjusting for sex, age and smoking. results: significant correlations between acarotene, ß-carotene, lycopene, ß-cryptoxanthin and vitamin c intakes, and plasma concentrations were observed, r=0.21;0.19;0.17;0.20,0.41, respectively (p<0.05). correlations for carotenoids changed substantially by bmi categories, with the highest correlations for a-carotene, ß-carotene, and, to a lesser extension, ß-cryptoxanthin and lycopene, in subjects with bmi<25 (0.39;0.34;0.25;0.22 respectively), and the lowest, in subjects with bmi=30 (0.08;0.19;0.18;0.19 respectively). correlations for vitamin c remained unchanged by bmi. conclusions: our data suggest that carotenoids in plasma may be good markers of dietary intake in elderly subjects with lower bmi. background: reduced heart rate variability (hrv) is associated with an increased mortality, morbidity and worse prognosis of cardiovascular diseases (cvd). there is a lack of population-based data to examine the distribution of hrv, its association with cardiovascular risk factors (cvrf), and its role as a potential mediator of the effect of established risk factors on cvd. objective: to study the distribution of hrv and its association with cvrf in an elderly eastern german population. design and methods: this analysis is based on data of 1336 participants (45-83 years) of an ongoing cross-sectional study. time-and frequency-domain measures of hrv were computed. their association with cvrf was determined by linear regression modelling. results: age-and heart rate-adjusted standard deviation of the durations of nn intervals and high frequency power was significantly higher in women. significant inverse associations of timeand frequency-domain hrv with anthropometric parameters, triglycerides, blood pressure, prevalent diabetes and age were observed in both sexes. there was a graded inverse association of hrv with age except for the oldest age-group. discussion/conclusion: established cvrf are associated with a reduced hrv. therefore reduced hrv could be a mediator between cvrf and cvd, which will be examined in a follow-up study. background: aalen's model and cox's proportional hazard model postulate different relationship between hazard and covariates and the subject matter seldom suggests which of the models are to be preferred. actually the assumption of constant effects, either additive or multiplicative, may be incorrect especially in cancer survival analysis. objectives: the aim of the study is to analyse survival for a breast cancer cohort where typical prognostic factors lack of proportionality. design and methods: the cohort consists of 2700 invasive breast cancer cases from turin cancer registry within a high resolution study in co-operation with the breast cancer screening program, diagnosed from 1997 through 2000, aged 40-79. an additive-multiplicative cox-aalen model with age at diagnosis, categorized tumour size (t) and nodal status (n) is fitted. results: the prognostic role of age at diagnosis, t and n are confirmed. proportionality assumption holds only for age (hazard ratio = 1.03, p-value<0.0001). t, particularly the category referring to 'extended to chest wall or skin' versus 'less than 2 cm', has a significant time-varying effect (p-value = 0.02) after 12 months since diagnosis. discussion: more flexible regression tools than cox model which is routinely used for analyzing cancer survival are needed. cox-aalen proves to be an appealing alternative. background: the major software packages for meta-analysis of causal -notably intervention -research are generally too expensive for developing countries. moreover, interactive educational software for students and teachers is largely unavailable. we recently developed the 'mix' program, an easy-to-maintain, interactive, and educational meta-analysis add-in for excel, available as free download at http://www.mix-for-meta-analysis.info. objectives: to formally establish whether the program's numerical and graphical output is comprehensive and accurate enough for scientific standards. design and methods: the study was designed as a software validation. data sets, primarily intervention studies, with substantially different features were analyzed by three investigators with mix and stata, using the latter program as golden standard. additionally, a feature (software options) comparison was made with modern programs for meta-analysis, such as cma 2.0, metawin 2.1, weasyma 2.2, and revman 4.2. results: the results of the validation project will be fully reported at the congress. preliminary results indicate that the mix program's output is comparable to stata output. it distinguishes itself from other software by the variety of graphical output, the excel-based interface, and free availability. conclusion and discussion: the mix program appears to provide valid output and may be an attractive, feature-rich alternative to existing meta-analysis software. background: an ankle-arm index (aai) <0.9 of systolic blood pressure (sbp) as marker of peripheral arterial disease is a predictor of coronary and carotid artery disease. the present gold standard examination with doppler-ultrasound and sphygmomanometric cuff is subject to observer bias and requires intensive training. for epidemiologic studies, valid and easy-to-use examination methods are needed. objective: to validate the easy-to-use omron hem-705cp for sbp measurements in the ankle and for aai determination in epidemiologic studies. design/methods: in a population-based sample of 112 subjects (45-80 years), arm and ankle sbp measurements by the omron hem-705cp and corresponding aai were compared with those using a hand-held doppler and sphygmomanometric cuff. bland-altman plots of sbp and aai differences, validation criteria for use in clinical practice and diagnostic values for the detection of an aai<0.9 were employed. results: omron measured higher sbp than doppler. sbp and aai differences increasing towards higher sbp levels. specificity, sensitivity and negative predictive value for the detection of aai<0.9 were >99% (positive predictive value was 67%). conclusion: omron fails the validation criteria for ankle sbp measurement. however, the ease of use of the device could outweigh the inaccuracy if used as a screening tool for aai<0,9 in epidemiologic studies. background: associations exist between: 1) parental birth weight and child birth weight; 2) birth weight and adult psychopathology; and 3) maternal psychopathology during pregnancy and birth weight of the child. this study is the first to combine those associations. objective: to investigate the different pathways from parental birth weight and parental psychopathology to child birth weight in one model. design and methods: depression and anxiety scores on 6,507 mothers and 4,764 fathers during 20 weeks pregnancy and birth weights from 6,116 children were available. path analyses with standardized regression coefficients were used to evaluate the different effects. results: in the unadjusted path analyses significant effects existed between: maternal (r = .17) and paternal birth weight (r = .13) and child birth weight; maternal birth weight and maternal depression (r=).05) and anxiety (r=).06); and maternal depression (r = .06) and anxiety (r = .06) and child birth weight. after adjustment for confounders, only maternal (r = .10) and paternal (r = .08) birth weight and maternal depression (r=).02) remained significantly related to child birth weight. conclusion after adjustment maternal depression, and not anxiety, remained significantly related to child birth weight. discussion future research should focus on the different mechanisms of maternal anxiety and depression on child birth weight. background: most patients with peripheral arterial disease (pad) die from coronary artery disease (cad). non-invasive cardiac imaging can assess the presence of coronary atherosclerosis and/or cardiac ischemia. screening in combination with more aggressive treatment may improve prognosis. objective: to evaluate whether a non-invasive cardiac imaging algorithm, followed by treatment will reduce the 5-year-risk of cardiovascular events in pad patients free from cardiac symptoms. design and methods: this is a multicenter randomized controlled clinical trial. patients with intermittent claudication and no history of cad are eligible. one group will undergo computed tomography (ct) calcium scoring. the other group will undergo ct calcium scoring and ct angiography (cta) of the coronary arteries. patients in the latter group will be scheduled for a dobutamine stress magnetic resonance imaging (dsmr) test to assess cardiac ischemia, unless a stenosis of the left main (lm) coronary artery (or its equivalent) was found on cta. patients with cardiac ischemia or a lm/lm-equivalent stenosis will be referred to a cardiologist, who will decide on further (interventional) treatment. patients are followed for 5 years. conclusion: this study assesses the value of non-invasive cardiac imaging to reduce the risk of cardiovascular events in patients with pad free from cardiac symptoms. background: hpv is the main risk factor for cervical cancer and also a necessary cause for it. participation rates in cervical cancer screening are low in some countries and soon hpv vaccination will be available. objectives: aim of this systematic review was to collect and analyze published data on knowledge about hpv. design and methods: a medline search was performed for publications on knowledge about hpv as a risk factor for cervical cancer and other issues of hpv infection. results: of individual studies were stratified by age of study population, country of origin, study size, publication year and response proportion. heterogeneity was described. results: knowledge between 27 included studies varied substantially. thirteen to 57% (closed question) and 0.6 to 1.9% (open question) of the participants knew about hpv as a risk factor for cervical cancer. women had consistently better knowledge on hpv than men. there was confusion of hpv with other sexually transmitted diseases. conclusion and discussion: studies were very heterogeneous, thus making comparison difficult. knowledge about hpv infections depended on the type of question used, gender of the participants and their professional background. education of the general public on hpv infections needs improvement, specially men should also be addressed. background: influenza outbreaks in hospitals and nursing homes are characterized by high attack rates and severe complications. knowledge of the virus' specific transmission dynamics in healthcare institutions is scarce but essential to develop cost-effective strategies. objective: to follow and model the spread of influenza in two hospital departments and to quantify the contributions of the several possible transmission pathways. methods: an observational prospective cohort study is performed on the departments of internal medicine & infectious diseases and pulmonary diseases of the umc utrecht during the 2006 influenza season. all patients and regular medical staff are checked daily on the presence of fever and cough, the most accurate symptoms of influenza infection. nose-throat swabs are taken for pcr analysis for both symptomatic individuals and a sample of asymptomatic individuals. to determine transmission, contact patterns are observed between patients and visitors and patients and medical staff. results/discussion: spatial and temporal data of influenza cases will be combined with contact data in a mathematical model to quantify the main transmission pathways. among others the model can be used to predict the effect of vaccination of the medical staff which is not yet common practice in the studied hospital. background: the long term maternal sequelae of stillbirths is unknown. objectives: to assess whether women who experienced stillbirths have an excess risk of long term mortality. study design: cohort study. methods: we traced jewish women from the jerusalem perinatal study, a population-based database of all births to west jerusalem residents (1964 -1976 who gave birth at least twice during the study period, using unique identity numbers. we compared the survival to 31-12-2004 of women who had at least one stillbirth (n = 569) to that of women who had only live births (n = 24108) using cox proportional hazards models. results: during a median follow up of 36.2 years, 77 (13.5%) mothers with stillbirths died compared to 1,483 (6.2%) unexposed women; crude hazard ratio (hr) 2.15 (95% ci: 1.71-2.70). the mortality risk remained significantly increased after adjustments for sociodemo-graphic variables, maternal diseases, placental abruption and preeclampsia (hr: 1.42, 95% ci: 1.12-1.80). stillbirth was associated with increased risk of death from cardiovascular (adjusted hr:1.95, 0.99-3.84), circulatory (1.77, 1.07-2.92) and genitourinary (4.59, 1.41-14.91) causes. conclusions: the finding of increased mortality among mothers of stillbirths joins the growing body of evidence demonstrating long term sequelae of obstetric events. future studies should elucidate the mechanisms underlying these associations. resilience is one of the essential characteristics of successful ageing. however, very little is known about the determinants of resilience in old age. our objectives were to identify resilience in the english longitudinal study of ageing (elsa) and to investigate social and psychological factors determining it. the study design was a crosssectional analysis of wave 1 of elsa. using structural equation modelling, we identified resilience as a latent variable indicated by high quality of life in the face of six adversities: ageing, limiting long-standing illness, disability, depression, perceived poverty and social isolation and we regressed it on social and psychological factors. the latent variable model for resilience showed a highly significant degree of fit (weighted root mean square resid-ual=0.035). determinants of resilience included good quality of relationships with spouse (p = 0.002), family (p = 0.028), and friends (p< 0.001), good neighbourhood (p<0.001), high level of social participation (p<0.001), involvement in leisure activities (p = 0.003); perception of not being old (p<0.001); optimism (p = 0.041), and high subjective probability of survival to an older age (p<0.001). we concluded that resilience in old age was as much a matter of social engagement, networks and context as of individual disposition. implications of this on health policy are discussed. background: there is extensive literature concluding that ses is inversely related to obesity in developed countries. several studies in developing populations however reported curvilinear or positive association between ses and obesity. objectives: to assess the social distribution of obesity in men and women in 3 middle-income countries of eastern and central europe with different level of economic development. methods: random population samples aged 45-69 years from poland, russia and czech republic were examined between 2002-2005 as baseline for prospective cohort study. we used body-mass index (bmi) and waist/hip ratio (whr) as obesity measures. we compared age-adjusted bmi and whr for men and women by educational levels in all 3 countries. results: the data collection was concluded in summer 2005. we collected data from about 29,000 subjects. lower ses increased obesity risk in women in all 3 countries (the strongest gradient in the czech republic and the lowest in russia), and in czech men. there was no ses gradient in bmi in polish men and positive association between education and bmi in russian men. conclusions: our findings strongly agree with previous literature showing that the association between ses status and obesity is strongly influenced by overall level of country economic development. background: inaccurate measurements of body weight, height and waist circumference will lead to an inaccurate assessment of body composition, and thus of the general health of a population. objectives: to assess the accuracy of self-reported body weight, height and waist-circumference in a dutch overweight working population. design and methods: bland and altman methods were used to examine the individual agreement between self-reported and measured body weight and height in 1298 overweight workers (67% male; mean age 43.9 +/) 8.6 years; mean body mass index [bmi] 29.5 +/) 3.4 kg/m2). the accuracy of self-reported waistcircumference was assessed in a subgroup of 250 persons (70% male; mean age 44.1 +/) 9.2 years; mean bmi 29.6 +/) 3.0 kg/ m2), for whom both measured and self-reported waist circumference was available. results: body weight was underreported by a mean (standard deviation) of 1.4 (1.9) kg, body height was on average over-reported by 0.7 (1.5) cm. bmi was on average underreported by 0.68 (0.8) kg/m2. waist-circumference was overreported by 1.1 (4.0) cm. the overall degree of error from selfreporting was between 0.4 and 2.3%. conclusion and discussion: self-reported anthropometrics seem satisfactorily accurate for the assessment of general health in a middle-aged overweight working population. the incidence of breast cancer and the prevalence of metabolic syndrome are increasing rapidly in chile, but this relationship is still debated. the goal of this study is to assess the association between metabolic syndrome and breast cancer before and after menopause. a hospital based case-control study was conducted in chile during 2005. 170 cases with histologically confirmed breast cancer and 170 age matched controls with normal mammography were identified. metabolic syndrome was defined by atpiii and serum lipids, glucose, blood pressure and waist circumference were measured by trained nurses. data of potential confounders such as, obesity, socioeconomic status, exercise and diet were obtained by anthropometric measures and a questionnaire. odds ratios (ors) and 95% confidence intervals (cis) were estimated by conditional logistic regression stratified by menopause. in postmenopausal women, a significant increase risk of breast cancer was observed in women with metabolic syndrome (or = 1.90, 95% ci = 1.00-3.60). the elements of metabolic syndrome strongly associated were high levels of glucose and hypertension. in conclusion, postmenopausal women with metabolic syndrome had 90% of excess risk of breast cancer. these findings support the theory that there is a different risk profile of breast cancer after and before menopause. background: physical exercise during pregnancy has numerous beneficial effects on maternal and foetal health. it may, however, affect early foetal survival negatively. objectives: to examine the association between physical exercise and spontaneous abortion in a cohort study. design and methods: in total, 92,721 women recruited to the danish national birth cohort in early pregnancy, provided information on amount and type of exercise during pregnancy and on possible confounding factors. 3,187 women experienced foetal death before 23 gestational weeks. hazard ratios for spontaneous abortion in four periods of pregnancy ()10, 11-14, 15-18, and 19-22 weeks) according to amount (min/week) and type of exercise, respectively, were estimated using cox regression. various sensitivity analyses to reveal distortion of the results from selection forces and information bias were made. results: the hazard ratios of spontaneous abortion increased stepwise with amount of physical exercise and were largest in the earlier periods of pregnancy (hrweek11-14 = 3.4 (ci 2.7-4.3) for 420 min/week, compared to no exercise). weight bearing types of exercise were strongest associated with abortion, while swimming showed no association. these results remained stable, although attenuated, in the sensitivity analyses. discussion: handling of unexpected findings that furthermore challenge official public health messages will be discussed. hemodialysis (hd) patients with a low body mass index (bmi) have an increased mortality risk, but bmi changes over time on dialysis treatment. we studied the association between changes in bmi and all-cause mortality in a cohort of incident hd patients. patients were followed until death or censoring for a maximum follow-up of 7 years. bmi was measured every 6 months and changes in bmi were calculated over each 6-mo period. with a time-dependent cox regression analysis, hazard ratios (hr) were calculated for these 6-mo changes on subsequent mortality from all causes, adjusted for the mean bmi of each 6-mo period, age, sex and comorbidity. 712 men and 494 women were included (age: 64?14 years, bmi: 25.1?4.6 kg/m2, 7-y mortality: 75%). a loss of bmi>5% was independently associated with an increased mortality risk (hr: 1.83, 95%-ci: 1.41-2.37), while a loss of 1-5% showed no difference (hr: 0.89, 0.69-1.14) compared to no change in bmi ()1% to +1% change). a gain in bmi of 1-5% showed beneficial (hr: 0.67, 0.51-0.88), while a gain of bmi>5% was not associated with a survival advantage (hr: 1.02, 0.69-1.50). in conclusion, hd patients with a decreasing bmi have an increased risk of all-cause mortality. background: within the tripss-2 project, impact of clinical guidelines (gl) on venous thromboembolism (vte) prophylaxis was evaluated in a large italian hospital. gl were effective in increasing the appropriateness of prophylaxis and in reducing vte. objectives: we performed a cost-effectiveness analysis by using a decision-tree model to estimate the impact of the adopted gl on costs and benefits. design and methods: a decision-tree model compared prophylaxis cost and effects before and after gl implementation. four risk profiles were identified (low, medium, high, very high). possible outcomes were: no event, major bleeding, asymptomatic vte, symptomatic vte and fatal pulmonary embolism. vte patients risk and probability of receiving prophylaxis were defined using data from the previous survey. outcome probabilities were assumed from literature. tariffs and hospital figures were used for costing the events. results: gl introduction reduced the average cost per patient from e 190 to 165 ()13%) with an increase in terms of event free patients (+4%). results are particularly relevant in the very high risk group. conclusion: the implementation of locally adapted gl may lead to a gain in terms of costs and effects, in particular for patients at highest vte risk. background: assisted reproductive techniques are used to overcome infertility. one reason of success is the use of ovarian stimulation. objectives: compare two ovarian stimulation protocols, gonadotropin-releasing hormone agonists/antagonists, assessing laboratorial and clinical outcomes, to provide proper therapy option. identify significant predictors of clinical pregnancy and ovarian response. design and methods: retrospective study (agonist cycles, 203; antagonist cycles, 177) including ivf/intracytoplasmic sperm injection cycles. multiple logistic and regression models, with fractional polynomial method were used. results: antagonist group exhibited lower length of stimulation and dose of recombinant follicle stimulating hormone (rfsh), higher number of retrieved and fertilized oocytes, and embryos. agonist group presented thicker endometrium, better fertilization, implantation and clinical pregnancy rates. clinical pregnancy has shown positive correlation with endometrial thickness and use of agonist; negative correlation with age and number of previous attempts. retrieved oocytes shown positive correlation with estradiol on day of human chorionic gonadotrophin (hcg) and use of antagonist; negative correlation with rfsh dose. conclusion: patients from antagonist group are more likely to get more oocytes and quality embryos, despite those from agonist group are more likely to get pregnant. background: prevalence studies of the metabolic syndrome require fasting blood samples and are therefore lacking in many countries including germany. objectives: to narrow the incertitude resulting from extrapolation of international prevalence estimates, with a sensitivity analysis of the prevalence of the metabolic syndrome in germany using a nationally representative but partially non-fasting sample. methods: stepwise analysis of the german health examination survey 1998, using the national cholesterol education program (ncep) criteria, hemoglobin a1c (hba1c), non-fasting triglycerides and fasting time. results: among 6666 participants aged 18-79 years, the metabolic syndrome prevalence was (i) 13.6% with 13.3% inconclusive cases using the unmodified ncep criteria, (ii) 17.6% with 9.4% inconclusive cases using hba1c > 6.1% if fasting glucose was missing, (iii) 23.8% with 0.6% inconclusive cases when additionally using non-fasting triglycerides = 75th percentile stratified by fasting time, and (iv) 21.2% to 23.8% with <1% inconclusive cases using different cutoffs (hba1c 6.1%, non-fasting triglycerides 200 and 250 mg/dl). discussion: despite a lower prevalence of obesity in germany compared to the us, the prevalence of the metabolic syndrome is likely to be in the same order of magnitude. this analysis may help promote healthy life styles by stressing the high prevalence of interrelated cardiovascular risk factors. background: epidemiologic studies that directly examine fruits and vegetables (f&v) consumption and other lifestyle factors in relation to weight gain are sparse. objective: we examined the associations between the f&v intake and 10-y weight gain among spanish adult people. design/methods: the study was conducted with a sub-sample of 214 healthy people aged 15 y and over at baseline in 1994, who participated in a population-based nutrition survey in valencia-spain. data on diet, lifestyle factors and body weight (direct measurement) were obtained in 1994 and 2004. information on weight gain was available for 187 participants in 2004. results: during the 10-y period, participants tended to gain on average 4.61 kg (median = 3.6 kg). in multivariate analyses, participants with the highest tertile of f&v intake at baseline had a 65% of lower risk of gaining =3.6 kg compared with those who had the lowest intake tertile after adjustment for sex, age, education, smoking, tv-viewing, bmi, and energy intake (or = 0.35;95% ci:0.15 0.84;p-fortrend = 0.02). for every 100 g/d increase in f&v intake, the or was reduced by 14% (or = 0.86;0.75-0.99;p-trend=0.036). tvviewing at baseline was positively associated with weight gain, or for-1 h-increase=1.32 (1.01-1.71;p-trend=0.04). conclusions: our findings suggest that a high f&v intake and low tv-viewing may reduce weight gain among adults. background: diabetic patients develop more readily atherosclerosis thus showing greatly increased risk for cardiovascular disease. objective: the heinz nixdorf recall-study is a prospective cohort-study designed to assess the prognostic value of new risk stratification methods. here we examined the association between diabetes, previously unknown hyperglycemia and the degree of coronary calcification (cac). methods: a population-based sample of 4,814 men and women aged 45-74 years was recruited from three german cities between 2000-2003. baseline examination included amongst others a detailed medical history, blood analyses and electron-beam tomography. we calculated adjusted prevalence ratios (pr), adjusting for age, smoking, bmi and 95%-confidence intervals (95% ci) with log-linear binomial regression. results: the prevalence of diabetes is 8.4% (men: 9.8%, women: 6.7%), for hyperglycemia 5.7% (men: 8.1%, women: 3.4%). prevalence ratio for cac in male diabetics without overt coronary heart disease is 1.87 (95% ci: 1.28-2.72), for those with hyperglycemia 1.62 (1.09-2.46). in women the association is even stronger: 2.62 (1.78-3.87) with diabetes, 1.92 (1.11-3.31) with hyperglycemia. conclusion: the data support the concept of regarding diabetic patients as being in a high risk category meaning >20% hard events in 10 years. furthermore, even persons with elevated blood glucose levels already show higher levels of coronary calcification. background: birth weight is associated with health in infancy and later in life. socioeconomic inequality in birth weight is an important marker of current and future population health inequality. objective: to examine the effect of maternal education on birth weight, low birth weight (lbw, birth weight<2,500 g), and small for gestational age (sga) background: in clinical practice patient data are obtained gradually and health care practitioners tune prognostic information according to available data. prognostic research does not always reproduce this sequential acquisition of data: instead, 'worst', discharge or aggregate data are often used. objective: to estimate prognostic performance of sequentially updated models. methods: cohortstudy of all very-low-birth-weight-babies (<1500 g) admitted to the study neonatal icu <2 days after birth (984 eligible from 1991 to 2002) and followed-up until 2 years old (7.8% lost-to-follow-up). main outcomes: disabling cerebral palsy at 2 years (37, 3.8%) or death (194, 19 .7% )95% in the first 4 weeks). main prognostic determinants: neonatal cerebral lesions identified with cranial ultrasound (us) exams performed per protocol on days 2, 7, 28 and at discharge. logistic regression models were updated with data available at these different moments in time during admission. results: at days 2, 7 and 28 respectively, main predictor (severe parenchymal lesion) adjusted odds ratio: 18, 31 and 37; us model c-statistic: 0.69, 0.75 and 0.80. discussion: prognostic models performance in neonatal patients improved from inception to discharge, particularly for identification of the high risk category. time of data acquisition should be considered when comparing prognostic instruments. in epidemiological longitudinal studies one is often interested in the analysis of time patterns of censored history data. for example, how regular a medication is used or how often someone is depressed. our goal is to develop a method to analyse time patterns of censored data. one of the tools in longitudinal studies is a nonhomogeneous markov chain model with discrete time moments and categorical state space (for example, use of various medications). suppose we are interested only in the time pattern of appearance of a particular state which is in fact a certain epidemiological event under study. for this purpose we construct a new homogeneous markov chain associated with this event. the states of this markov chain are the time moments of the original nonhomogeneous markov chain. using the new transition matrix and standard tools from markov chain theory we can derive the probabilities of occurence of that epidemiological event during various time periods (including ones with gaps). for example, probabilities of cumulative use of medication during any time period. in conclusion, the proposed approach based on markov chain model provides a new way of data representation and analysis which is easy to interpret in practical applications. background: tuberculosis (tb) cases that belong to a cluster of the same mycobacterium tuberculosis dna fingerprint are assumed to be consequence of recent transmission. targeting interventions to fast growing clusters may be an efficient way of interrupting transmission in outbreaks. objective: to assess predictors for large growing clusters compared to clusters that remain small within a 2 years period. design and method out of the 10567 culture confirmed tb patients diagnosed between 1993 and 2004, 4783 (45%) had unique fingerprints while 5784 were part of a cluster. of the clustered cases 673 were in a small (2 to 4 cases within the first 2 years) and 83 in a large cluster (more than 4 cases within the first 2 years). results independent risk factors for being a case within the first 2 years of a large cluster were non-dutch nationality (or = 6.38 95% ci [1. 38-29.55 background: passive smoking causes adverse health outcomes such as lung cancer or coronary heart disease (chd). the burden of passive smoking on a population level is currently unclear and depends on several assumptions. we investigated the public health impact of passive smoking in germany. methods: we computed attributable mortality risks due to environmental tobacco smoke (ets). we considered lung cancer, chd, stroke, copd and sudden infant death. frequency of passive smoking was derived from the national german health survey. sensitivity analyses were performed using different definitions of exposure to passive smoking. results: in total, 3301 deaths every year in germany are estimated to be caused by exposure to passive smoking at home (women 2293, men 1008). most of these deaths are due to chd (2148) and stroke (774). additional consideration of passive smoking at workplace increased the number of deaths to 3864. considering any exposure to passive smoking and also active smokers who report exposure to passive smoking increased the number of deaths further. conclusions: passive smoking has an important impact on mortality in germany. even the most conservative estimate using exposure to ets at home led to a substantial number of deaths related to passive smoking. des daughters have a strongly increased risk of clear-cell adenocarcinoma of the vagina and cervix (ccac) at a young age. longterm health problems, however, are still unknown. we studied incidence of cancer, other than ccac, in a prospective cohort of des daughters (desnet project). in 2000 13,674 questionnaires were sent to des daughters registered at the des center in utrecht. also, informed consent was asked for linkage with disease registries. for this analysis, data of 12,219 responders and nonresponders were linked to palga, the dutch nationwide network and registry of histo-and cytopathology. mean age at the end of follow-up was 41.7 years. a total of 244 incident cancers occurred. increased standardized incidence rates (sir) were found for vaginal/vulvar cancers (sir = 4.1, 95% confidence interval (95% ci) 1.4-9.7), melanoma (sir = 1.9, 95% ci 1.4-2.6)) and breast cancer (sir=1.2, 95% ci 1.0-1.4) as compared to the general population. no increased risk was found for invasive cervical cancer, possibly due to effective screening. results for breast and cervical cancer are consistent with the sparse literature. the risk of melanoma might be due to surveillance bias. future analyses will include non-invasive cervical cancer, stage specific sirs for melanoma and adjustment for confounding (sister control group) for breast cancer. background: contact tracing plays an important role in the control of emerging infectious diseases in both human and farm animal populations, but little is known yet about its effectiveness. here we investigate in a generic setting for well-mixed populations the dependence of tracing effectiveness on the probability that a contact is traced, the possibility of iteratively tracing yet asymptomatic infectives, and delays in the tracing process. methods and findings: we investigate contact tracing in a mathematical model of an emerging epidemic, incorporating a flexible infectivity function and incubation period distribution. we consider isolation of symptomatic infected as the basic scenario, and determine the critical tracing probability (needed for effective control) in relation to two infectious disease parameters: the reproduction ratio under isolation and the duration of latent period relative to the incubation period. the effect of tracing delays is considered, as is the possibility of single-step tracing vs. iterative tracing of quarantined invectives. finally, the model is used to assess the likely success of tracing for influenza, smallpox, sars, and foot-and-mouth disease epidemics. conclusions: we conclude that single-step contact tracing can be effective for infections with a relatively long latent period or a large variation in incubation period, thus enabling backwards tracing of super spreading individuals. the sensitivity to changes in the tracing delay varies greatly, but small increases may have major consequences for effectiveness. if single-step tracing is on the brink of being effective, iterative tracing can help, but otherwise it will not improve much. we conclude that contact tracing will not be effective for influenza pandemics, only partially for fmd epidemics, and very effective for smallpox and sars epidemics. abstract: infections of highly pathogenic h5n1 avian influenza in humans underline the need for tracking of the ability of these viruses to spread among humans. here we propose a method of analysing outbreak data that allows determination of whether and to what extent transmission in a household has occurred after an introduction from the animal reservoir. in particular, it distinguishes between onward transmission from humans that were infected from the animal reservoir (primary human-to-human transmission) and onward transmission from humans who were themselves infected by humans (secondary human-to-human transmission). the method is applied to data from an epidemiological study of an outbreak of highly pathogenic avian influenza (h7n7) in the netherlands in 2003. we contrast a number of models that differ with respect to the assumptions on primary versus secondary human-to-human transmission. session: mathematical modelling of infectious diseases presentation: oral. usually models for the spread of an infection in a population are based on the assumption of a randomly mixing population, where every individual may contact every other individual. however, the assumption of random mixing seems to be unrealistic, therefore one may also want to consider epidemics on (social) networks. connections in the network are possible contacts, e.g. if we consider sexually transmitted diseases and ignore all spread by other than sexual ways, the connections are only between people that may have intercourse with each other. in this talk i will compare the basic reproduction ratio, r0 and the probability of a major outbreak of network models and for randomly mixing populations. furthermore, i will discuss which properties of the network are important and how they can be incorporated in the model. in this talk a reproductive power model is proposed that incorporates the following points met when an epidemic disease outbreak is modeled statistically: 1) the dependence of the data is handled with a non-homogeneous birth process. 2) the first stage of the outbreak is described with an epidemic sir model. soon control measures will start to influence the process. these measures are in addition to the natural epidemic removal process. the prevalence is related to the censored infection times in such a way that the distribution function, and therefore the survival function, satisfies approximately the first equation of the sir model. this leads in a natural way to the burr-family of distributions. 3) the non-homogeneous birth process handles the fact that in practice, with some delay, it is the infected that are registered and not the susceptibles. 4) finally the ending of the epidemic caused by the measures taken is incorporated by modifying the survival function with a finalsize parameter in the same way as is done in long-term survival models. this method is applied to the dutch classical swine individual and area (municipality) measures of income, marital and employment status were obtained. there were 9,011 suicides and 180,220 controls. after controlling for compositional effects, ecological associations of increased suicide risk with declining area levels of employment and income and increasing levels of people living alone were much attenuated. individual-level associations with these risk factors were little changed when controlling for contextual effects. we found no consistent evidence that associations with individual level risk factors differed depending on the areas characteristics (cross-level interactions). this analysis suggests the ecological associations reported in previous studies are likely to be due in greater part to the characteristics of the residents in those areas than area-influences on risk, rather than to contextual effects. were found to be at higher risk. risk was significantly greater in women whose first full-term pregnancy was at age 30 or more (or 7.79, ). in addition, more than 5 full-term pregnancies would be expected to correlate with an increase in the risk (x2 111.12, p<0.05). in multivariate analysis, history of breast feeding is a significant factor in decreasing risk (or 0.68, 95% ci 0. 12-0.97 the euregion meuse-rhine (emr) is an area with different regions, regarding language, culture and law. organisations and institutions received frequently signals about an increasing and region-related consumption of addictive drugs and risky behaviour of adolescents. as a reaction 11 institutions from 4 regions of the emr started a cross-border cooperation project 'risky behaviour adolescents in the emr'. the partners intend to improve the efficiency of prevention programmes by investigating the prevalence and pre-conditional aspects related to risky behaviour, and creating conditions for best-practice-public-health. the project included two phases: study. two cross-border (epidemiological) studies where realized: a quantitative study of the prevalence of risky behaviour (46000 pupils) and a qualitative study mapped preconditional aspects of risky behaviour and possibilities to preventive programmes. implementation. this served bringing about recommendations on policy level as well as on prevention level. during this phase the planning and realisation of cross-border preventionprogrammes and activities started. there is region-related variance of prevalence in risky-behaviour of adolescents in de emr. also there are essential differences in legislation and regulation, (tolerated) policy, prevention structures, political and organizational priorities and social acceptance toward stimulants. cross-border studies and cooperation between institutions have resulted in best-practice-projects in (border) areas of the emr. abstract background: beta-blockers increase bone strenght in mice and may reduce fracture risk in humans. therefore, we hypothesized that inhaled beta-2 agonists may increase risk of hip fracture. objective: to determine the association between daily dose of beta-2 agonist use and risk of hip fractures. methods: a case-control study was conducted among adults who were enrolled in the dutch phar-mo database (n = 950,000). cases (n = 6,763) were patients with a first hip fracture. the date of the fracture was the index date. four controls were matched by age, gender and region. we adjusted our analyses for 10 indicators of asthma/copd severity, and for disease and drug history. results: low daily doses (dds) (<400 ug albuterol eq.) of beta2-agonists (crude or 1.2, 95% ci 0.8-1.8) did not increase risk of hip fracture, in contrast to high dds (>1600 ug albuterol eq., crude or 2.0, 95% ci 0.1.5-2.7). after extensive adjustment for indicators of the severity of the underlying disease, (including corticosteroid intake), fracture risk in the high dd group decreased to 1.5 (95% ci 1.1-2.1). conclusions: high dds of beta-2 agonists are linked to increased risk of hip fracture. extensive adjustments for the severity of the underlying disease is important when evaluating this association. abstract salivary nitrate arises from ingested nitrate and is the main source of gastric nitrite, a precursor of carcinogenic n-nitroso compounds. we examinated the nitrate and nitrite levels in saliva of children who used private wells for their drinking water supply. saliva was collected in the morning, from 150 children aged 7-16 years. control group (n = 50) drank water containing 0.03-15.5 mg/l (milligrams/litre) nitrate. exposure groups consisting of subjects (n = 50) who used private wells with nitrate levels in drinking water below 50 mg/l (mean ± standard deviation 20.05 ± 11.42 mg/l) and above 50 mg/l (n = 50) (141.32±80.56 mg/l) respectively. the nitrate and nitrite of saliva samples was determined by high performance liquid chromatographs method. the values of nitrate in saliva samples from exposed groups ranged between 4.57 to 25.94 mg/l (15.33±8.88 mg/l). for control groups, the levels of 0.89 to 14.57 mg/l (7.18±4.54 mg/l) were registered. no differences between levels of salivary nitrite from control and exposed groups were found. regression analysis on water nitrate concentrations and salivary nitrate showed significant correlations. in conclusion, we estimate that salivary nitrate may be used as biomarkers of human exposure to nitrate. abstract disinfection of public drinking water supplies produces trihalomethanes. epidemiological studies have associated chlorinated disinfection by-products with cancer, reproductive and developmental effects. we studied the levels of trihalomethanes (chloroform, dibromochloromethane, bromodichloromethane, bromoform) in drinking water delivered to the population living in some urban areas (n=20). the water samples (n=150) were analysed using gas chromatographic method. assessment of exposure to trihalomethanes in tap water has been on monitoring data collected over 2-12 months periods and that we averaged over entire water system. analytical data revealed that total trihalomethanes levels were higher in the summer: mean ± standard deviation 72.07±42.88lg/l (micrograms/litre). these organic compounds were present in the end of distribution networks (9.87±5.87lg/l). it is noted that, sometimes, we found high concentrations of chloroform exceeding the sanitary norm (100lg/l) in tap water (maximum value 41.65lg/l). results of sampling programs showed stronger correlations between chlorine and trihalomethanes value (correlation coefficient r = 0.821 to 0.952, credible 95%interval). in conclusion, the population drank water with the law concentration of trihalomethanes, especially chloroform. abstract objective: to determine the validity of a performance-based assessment of knee function, dynaport[rsymbol] kneetest (dpkt), in first-time consulters with non-traumatic knee complaints in general practice. methods: patients consulting for nontraumatic knee pain in general practice aged 18 years and older were enrolled in the study. at baseline and 6-months follow-up knee function was assessed by questionnaires and the dpkt; a physical examination was also performed at baseline. hypothesis testing assessed cross-sectional and longitudinal validity of the dpkt. results: a total of 87 patients were included for dpkt of which 86 were available for analysis. the studied population included 44 women (51.2%), median age was 54 (range 18-81) years. at follow-up, 77 patients (89.5%) were available for dpkt. only 3 out of 11 (27%) predetermined hypotheses concerning cross-sectional and longitudinal validity were confirmed. comparison of the general practice and secondary care population showed a major difference in baseline characteristics, dynaport knee score, internal consistency and hypotheses confirmation concerning the construct validity. conclusion: the validity of the dpkt could not be demonstrated for first-time consulters with non-traumatic knee complaints in general practice. measurement instruments developed and validated in secondary care are not automatically also valid in primary care setting. abstract although animal studies have described the protective effects of dietary factors supplemented before radiation exposure, little is known about the lifestyle effects after radiation exposure on radiation damage and cancer risks in human. the purpose of this study is to clarify whether lifestyle can modify the effects of radiation exposure on cancer risk. a cohort of 40,000 japanese atomic-bomb survivors, for whom radiation dose estimates were currently available, had their lifestyle assessed in 1980. they were followed during 20 years for cancer incidence. the combined effect of smoking, drinking, diet and radiation exposure on cancer risk was examined in additive and multiplicative models. combined effects of a diet rich in fruit and vegetables and ionizing radiation exposure resulted in a lower cancer risk as compared to those with a diet poor in fruit and vegetables and exposed to radiation. similarly, those exposed to radiation and who never drink alcohol or never smoke tobacco presented a lower oesophagus cancer risk than those exposed to radiation and who currently drink alcohol or smoke tobacco. there was no evidence to reject either the additive or the multiplicative model. a healthy lifestyle seems beneficial to persons exposed to radiation in reducing their cancer risks. abstract background: clinical trials have shown significant reduction in major adverse cardiac events (mace) following implantation of sirolimus-eluting (ses) vs. bare-metal stents (bms) for coronary artery disease (cad). objective: to evaluate long-term clinical outcomes and economic implications of ses vs. bms in usual care. methods: in this prospective intervention study, cad patients were treated with bms or ses (sequential control design). standardized patient and physician questionnaires 3, 6, and 12 months following implantation documented mace, disease-related costs and patient quality of life (qol). results: 602 patients treated with ses (mean age 63±9, 87% male), 295 with bms (mean age 65±10, 79% male). there were no significant baseline differences in cardiovascular risk factors and severity of cad. after 12 months, 18% ses vs. 30% bms patients had suffered mace (p<0.05). initial hospital costs were higher with ses than with bms, but respective 12month follow-up direct and indirect costs were lower (5,052±642 vs. 6,052±590 euro and 753±459 vs. 2,013±422 euro, p = ns). overall, disease-related costs were similar in both groups (ses 11, 765±827, bms 11, 826±760, p = ns) . differences in qol were not significant. conclusions: as in clinical trials, ses patients experienced significantly fewer mace than bms patients during 12-month follow-up with similar overall costs and qol. abstract background: meta-analyses that use individual patient data (ipd-ma) rather than published data have been proposed as an improvement in subgroup-analyses. objective: to study 1) whether and how often ipd-ma are used to perform subgroup-analyses 2) whether the methodology used for subgroup-analyses differs between ipd-ma and meta-analyses of published data (map) methods: ipd-ma were identified in pubmed. related article search was used to identify map on the same objective. metaanalyses not performing subgroup-analysis were excluded from further analyses. differences between ipd-ma and map were analysed, reasons for discrepancies were described. we recently developed a simple diagnostic rule (including 7 history and physical findings plus d-dimer assay results) to safely exclude the presence of deep vein thrombosis (dvt) without the need for referral in primary care patients suspected of dvt. when applied to new patients, the performance of any (diagnostic or prognostic) prediction rule tends to be lower than expected based on the original study results. therefore, rules need to be tested on their generalizability. the aim was to determine the generalizability of the rule. in this cross-sectional study, 532 primary care patients with suspicion of dvt were prospectively identified. the 8 rule items were obtained from each patient plus ultrasonography as reference standard. the accuracy of the rule was quantified on its discriminative performance, sensitivity, specificity, negative predictive value, and negative likelihood ratio, with accompanying 95% confidence interval. dvt could be safely excluded in 21% (23% in the original study) of the patients, without referral. none of these patients had dvt (0.7% in the derivation population). in conclusion, the rule appears to be a safe diagnostic tool for excluding dvt in patients suspected of dvt in primary care. abstract background: long-term exposure to very low concentrations of asbestos in the environment and relation to incidence of mesothelioma contributes to insight into the dose-response relationship and public health policy. aim: to describe regional differences in the occurrence mesothelioma in the netherlands in relation to the occurrence in the asbestos polluted area around goor and to determine whether the increased incidence of pleural mesothelioma among women in this area could be attributed to environmental exposure to asbestos. methods: mesothelioma cases were selected in the period 1989-2002 from the netherlands cancer register (n = 4781). for the women in the region goor (n = 30) exposure to asbestos due to occupation, household or environment was verified from the medical files, the general practitioner and next-of-kin for cases. results: in goor the incidence of pleural mesothelioma among women was 5-fold increased compared with the netherlands and among men 2fold. of the additional 19 cases among women, 11 cases were attributed to the environmental asbestos pollution and in 4 cases this was the most likely cause. the average cumulative asbestos exposure was estimated at 0.1 fiber-years. . temporal trends and gender differences were investigated by random slope analysis. variance was expressed using median odds ratio (mor). results: ohcs appeared to be more relevant than administrative areas for understanding physicians' propensity to follow prescription guidelines (mor_ohc = 2.7 and mor_aa = 1.5). conclusion and discussion: as expected, the intervention increased prevalence and decreased variance, but at the end of the observation period practice variation remained high. these results may reflect inefficient therapeutic traditions, and suggest that more intensive interventions may be necessary to promote rational statin prescription. abstract background: mortality rates in ska˚ne, sweden have decreased in recent years. if this decline has been similar for different geographical areas have not been examined closely. objectives: we wanted to illustrate trends and geographical inequities in all cause mortality between the 33 municipalities in ska˚ne, sweden from 1970 to 2000. we also aimed to explore the application of multilevel regression analysis (mlra) in our study, since it is a relatively new methodology when describing mortality rates. design and methods: we used linear mlra with years at the first level and municipalities at the second to model direct age-standardized rates. temporal trends were examined by random slope analysis. variance across time was expressed using intra-class correlation (icc). results: the municipality level was very relevant for understanding temporal differences in mortality rates (icc = 26 %). in average, mortality decreased by 34/10 ù 4 along the study period but this trend varied considerably between municipalities, geographical inequalities along the years were u-shaped with lowest variance in the 80s (var = 26). conclusion: mortality has decreased in ska˚ne but municipality differences are increasing again. mlra is a useful technique for modelling mortality trends and variation among geographical areas. abstract background: ozone has adverse health effects but it is not clear who is most susceptible. objective: identification of individuals with increased ozone susceptibility. methods: daily visits for lower respiratory symptoms (lrs) in 6 general practitioner (gp) offices in the north of the netherlands (1989-2000, 38000 patients) were related to daily ozone levels in summer. ozone effects were estimated for patients with asthma, copd, atopic dermatitis, and cardiovascular diseases (cvd) and compared to effects in patients without these diseases. generalized additive models adjusting for trend, weekday, temperature, and pollen counts were used. results: the mean daily number of lrs-visits in summer in the gp-offices varied from 1.3 to 8.5. mean (sd) 8-hour maximum ozone level was 62.6 (30.5) lg/m3. rrs (95% ci) for a 90lg/m3 increase (from 5th to 95th percentile) in the mean of lag 0 to 4 of ozone for patients with/ without disease are: abstract asthma is a costly health condition, its economic effect is greater than that estimated for aids and tuberculosis together. following global initiative for asthma recommendations that require more data about the burden of asthma, we have determined the cost of this illness from 1998-2002. an epidemiological approach based on population studies was made to estimate global as well as direct and indirect costs. data were obtained mainly from the national health ministry database, the national statistics institute of spain and the national health survey. the costs were averaged and adjusted to 2002 e. we have found a global burden (including private medicine) of 920 million e. indirect and direct costs account for 35,4 and 64,6%.the largest components within direct costs were pharmaceutical (29.6%), primary health care systems (8,4%), hospital admissions (5.2%) and hospital non-emergency ambulatory visits (3.2%). within indirect costs, total cessation of work days (19.4%), permanent labour incapacity (8.5%) and early mortality (3.1%) costs were the main components. pharmaceutical cost is the first component as in most studies from developed countries, followed by primary health care systems unlike some reports that consider hospital admissions in second place. finally, direct costs represent 1.3% of the total health care expenditure. abstract background: it is well known that fair phenotypical characteristics are a risk factor for cutaneous melanoma. the aim of our study was to investigate the analogous associations between phenotypical characteristics and uveal melanoma. design/methods: in our casecontrol study we compared incident uveal melamom patients with population controls to evaluate the role of phenotypical characteristics like iris-, hair-and skin color and other risk factors in the pathogenesis of this tumor. a total of 455 patients and 827 controls matched on sex, age and region were interviewed. conditional logistic regression was used to calculate odds ratio (or) and 95% confidence intervals (95% ci). results: risk of uveal melanoma was increased among people with light iris color (or = 1.9 95% ci 1.4-2.7) and light skin color was slightly associated with an increased risk of uveal melanoma (or 1.4 95% 1.1-1.4). hair color, tanning ability, burning tendency and freckles as a child showed no increased risk. results of the combined analysis of eye-and hair color, burning tendency and freckles showed that only light iris color was clearly associated with uveal melanoma risk. conclusion: among potential phenotypical risk factors only light iris-and skin color were identified as risk factor for uveal melanoma. abstract background: between-study variation in estimates of the risk of hcv mother-to-child transmission (mtct) and associated risk factors may be due to methodological differences or changes in population characteristics over time. objective: to investigate the effect of sample size and time on risk factors for mtct of hcv. design and methods: heterogeneity was assessed before pooling data. logistic regression estimated odds ratios for risk factors. results: the three studies included 1633 mother-child pairs born between 1992 and 1998, 346 born between 1986 and 2000, and 1758 between 1999 and 2003 . there was no evidence of heterogeneity of the estimates for maternal hcv/hiv co-infection and mode of delivery (q = 2.16, p = 0.34 and q = 1.42, p = 0.49, respectively). in pooled analysis the proportion of hcv/hiv co-infected mothers significantly decreased from 54% before 1994 to 10% since 2002 (p<0.00001). the pooled adjusted odds ratios for maternal hcv/hiv co-infection and elective caesarean section delivery were 2.80 (95%ci 1.99-3.95), p<0.001 and 1.11 (95%ci 0.79-1.57), p = 0.53 respectively. there was no evidence that the effect of risk factors for mtct changed over time. conclusion: although certain risk factors have become less common, their effect on mtct of hcv has not changed substantially over time. abstract background: the need to gain insight into prevailing eating pattrerns and their health effects is evident. objective: to identify dietary patterns and their relationship with total mortality in dutch older women. methods: principal components analysis on 22 food groups was used to identify dietary patterns among 5,427 women (60-69 y) included in the dutch epic-elderly cohort (follow-up $8.2 y). mortality ratios for three major principle components were assessed using cox proportional hazard analysis. results: the most relevant principal components were a 'mediterranean-like' pattern (high in vegetable oils, pasta/rice, sauces, fish, and wine), a 'traditional dutch dinner' pattern (high in meat, potatoes, vegetables, and alcoholic beverages) and a 'healthy traditional' pattern (high in vegetables, fruit, non-alcoholic drinks, dairy products, and potatoes). in 44,667 person years 277 deaths occurred. independent of age, education, and other life style factors only the 'healthy traditional' pattern score was associated with a lower mortality rate, women in the highest tertile experienced a 30 percent reduced mortality risk. conclusion: from this study a healthy traditional dutch diet, rather than a mediterranean diet, appears beneficial for longevity and feasible for health promotion. this diet is comparable to other reported 'healthy' or 'prudent' diets that have been shown to be protective. parents of 413 (aged 0-4) and 294 (aged 5-15) children were sent a questionnaire, as were 113 adolescents (aged 10-15). to assess validity, generic outcome instruments were included (infant toddler quality of life questionnaire (itqol) or the child health questionnaire (chq) and the euroqol-5d). response rate was 48-53%. internal consistency of hobq and boq-scales was good (cronbach's alpha's >0.7 in all but two scales). test-retest results showed no differences in 70-92% of scales. high correlations between hobq-and boq-scales and conceptually equivalent generic outcome instruments were found. the majority of hobq (7/10) and boq scales (11/12) showed significant differences between children with a long versus short length of stay. the dutch hobq and boq can be used to evaluate functional outcome after burns in children. the study estimated caesarean section rates and odds ratios for caesarean section in association with maternal characteristics in both public and private sectors; and maternal mortality associated with mode of delivery in the public sector, adjusted for hypertension, other disorders, problems and complications, as well as maternal age. results: the caesarean section rate was 32.9% in the public sector, and 80.4% in the private sector. the odd ratio for caesarean section was 2.6 (95%ci: 2.6-2.7) for women with 12 or more years of education. the odd ratio for maternal mortality associated with caesarean section in the public sector was 3.3 (95%ci:2.6-4.3). conclusion and discussion: sao paulo presented high caesarean section rates. caesarean section compared to vaginal delivery in the public sector presented higher risk for mortality even when adjusted for hypertension, other disorders, problems and complications, as well as maternal age. we show that serious bias in questionnaires can be revealed by bland-altman methods but may remain undetected by correlation coefficients. we refute the argument that correlation coefficients properly investigate whether questionnaires rank subjects sufficiently well. conclusions: the commonly used correlation approach can yield misleading conclusions in validation studies. a more frequent and proper use of the bland-altman methods would be desirable to improve epidemiological data quality. abstract screening performance relies on quality and efficiency of protocols and guidelines for screening and follow-up. evidence of low attendance rates, over-screening of young women and low smear specificity gathered by the early 1990's in the dutch cervical cancer screening program called for an improvement. several protocols and guidelines were redefined in 1996, with emphasis on assuring that these would be adhered to. we assessed improvement since 1996 by changes in various indicators: coverage rates, follow-up compliance and number of smears. information on all cervix uteri tests in the netherlands registered until 31st march 2004 was retrieved from the nationwide registry of histo-and cytopathology (palga). five-year coverage rate in the age group 30-60 years rose to 77%. the percentage of screened women in follow-up decreased from 19% to 3%. fourteen percent more women with abnormal smears were followed-up, and the time spent in follow-up decreased. a 20% decrease in the annual number of smears made was observed, especially among young women. in conclusion, the 1996 changes in protocols and guidelines, and their implementation have increased coverage and efficiency of screening, and decreased the screening-induced negative side effects. similar measures can be used to improve other mass screening programmes. abstract background: it is common knowledge that in low endemic countries the main transmission route of hepatitis b infection is sexual contact, while in high endemic regions it is perinatal transmission and horizontal household transmission in early childhood. objectives: to get insight into what determines the main transmission route in different regions. design and methods: we used a formula for the basic reproduction number r0 for hepatitis b in a population stratified by age and sexual activity to investigate under which conditions r0 > 1. using data extracted from the literature we investigated how r0 depends on fertility rates, rates of horizontal childhood transmission and sexual partner change rates. results: we identified conditions on the mean offspring number and the transmission probabilities for which perinatal and horizontal childhood transmission alone ensures that r0 > 1. those transmission routes are then dominant, because of the high probability for children to become chronic carriers. sexual transmission dominates if fertility is too low to be the driving force of transmission. conclusion: in regions with high fertility rates hepatitis b can establish itself on a high level of prevalence driven by perinatal and horizontal childhood transmission. therefore, demographic changes can influence hepatitis b transmission routes. abstract background: the artificial oestrogen diethylstilboestrol is known to be fetotoxic. thus, intrauterine exposure to other artificial sex hormones may increase the risk of fetal death. objective: to study if use of oral contraceptive 4 months prior to or during pregnancy is associated to an increased risk of fetal death. design and methods: a cohort study of 92 719 pregnant women who were recruited into the danish national birth cohort during the years 1996-2002 and interviewed about exposures during pregnancy, either during the first part of their pregnancy (n = 90 167) or following a fetal loss (n = 2552). cox regression analyses with delayed entry were used to estimate the risk of fetal death. results: in total 1102 (1.2%) women took oral contraceptives during pregnancy. use of combined oestrogen and progesterone oral contraceptives (coc) or progesterone only oral contraceptives (poc) during pregnancy were not associated with increased hazard ratios of fetal death compared to non-users, hr 1.01 (95% ci 0.71-1.45) and hr 1.37 (95% ci 0.65-2.89) respectively. neither use of coc nor poc prior to pregnancy was associated with fetal death. conclusion: use of oral contraceptive 4 months prior to conception or during pregnancy is not related to an increased risk of fetal death. abstract background: few studies have been performed to assess if water fluoridation reduces social inequalities among groups of different socioeconomic status, and none of them was conducted in developing countries. objectives: to assess socioeconomic differences between brazilians towns with and without water fluoridation, and to compare dental caries indices among socioeconomic strata in fluoridated and non-fluoridated areas. design and methods: a countrywide survey of oral health performed in 2002-3 and comprising 34,550 children aged 12 years provided information about dental caries indices in 249 brazilian towns. socioeconomic indices, the coverage and the fluoride status of the water supply network of participating towns were also appraised. multivariate regression models were performed. inequalities in dental outcomes were compared in towns with and without fluoridated tap water. results: better-off towns tended to present a higher coverage by the water supply network, and were more inclined to add fluoride. fluoridated tap water was associated with an overall improved profile of caries, concurrent with an expressively larger inequality in the distribution of dental disease. conclusion: suppressing inequalities in the distribution of dental caries requires an expanded access to fluoridated tap water; a strategy that can be effective to foster further reductions in caries indices. objective: to investigate the role of family socioeconomic trajectories from childhood to adolescence on dental caries and associated behavioural factors. design and methods: a population-based birth cohort was carried out in pelotas, brazil. a sample (n=888) of the population of subjects born in 1982 were dentally examined and interviewed at aged 15. dental caries index, care index, toothbrushing, flossing, and pattern of utilization of dental services were the outcomes. these measures were compared among four different family income trajectories. results: adolescents who were always poor showed, in general, a worse dental caries profile, whilst adolescents who never were poor had a better dental caries profile. adolescents who had moved from poverty in childhood to nonpoverty in adolescence and those who had moved from non-poverty in childhood to poverty in adolescence had similar dental profiles to those who were always poor except for pattern of utilization of dental services which was higher in the first group. conclusion: poverty in at least one stage of the lifespan has a harmful effect on dental caries, oral behaviours and utilization of dental services. we assessed contextual and individual determinants of dental caries in the brazilian context. a country-wide survey of oral health informed the dental status of 34,550 twelve-year-old schoolchildren living in 250 towns in 2003. a multilevel model fitted the adjustment of untreated caries prevalence to individual (socio-demographic characteristics of examined children) and contextual (geographic characteristics of participating towns) covariates. being black (or = 1.6; 95% ci: 1.5-1.7), living in rural areas (or = 1.9; 1.7-2.0) and studying in public schools (or = 1.7; 1.6-1.9) increased the odds of having untreated decayed teeth. the multilevel model identified the fluoride status of water supplies (ß=)0.3), the proportion of households linked to the water network (ß=)0.3) and the human development index (ß=)0.2) as town-level covariates of caries experience. better-off brazilian regions presented an improved profile of dental health, besides having a less unequal distribution of dental treatment needs between blacks and whites, rural and urban areas, and public and private schools. dental caries experience is prone to socio-demographic and geographic inequalities. monitoring contrasts in dental health outcomes is relevant for programming socially appropriate interventions aimed both at overall improvements and at the targeting of resources for groups of population presenting higher levels of needs. abstract background: ultraviolet radiation (uvr) is the main cause of nonmelanoma skin cancer but has been hypothesised to protect against development of prostate cancer (pc). if this is true, skin cancer patients should have lower pc incidence than the general population. objectives: to study the incidence of pc after a diagnosis of skin cancer. design methods: using the eindhoven cancer registry, a cohort of male skin cancer patients diagnosed since 1970 (2565 squamous cell carcinoma (scc), 9295 basal cell carcinoma (bcc) and 1419 melanoma (cm)) was followed up for incidence of invasive pc. observed incidence rates of pc amongst skin cancer patients were compared to those in the reference population, resulting in standardised incidence ratios (sir). results: scc (sir 0.88 (95%ci: 0.64; 1.2)) and bcc (sir 0.79 (95%ci: 0.65;0.94)) showed a decreased incidence of pc, cm did not. patients with bccs occurring in the chronically sun-exposed head and neck area (sir 0.79 (95%ci: 0.64; 0.97) had significantly lower pc incidence rates. conclusion discussion: although numbers of scc and cm were too small to obtain unequivocal results, this study partly supports the hypothesis that uvr protects against pc and also illustrate that cm patients are different from nmsc patients in several aspects. abstract introduction: hypo-and hyperthyroidism have been associated to various symptoms and metabolic dysfunctions in men and women. incidences of these diseases have been estimated in a cohort of middle-aged adults in france. methods: the su.vi.max (sup-ple´mentation en vitamines et mine´raux antioxydants) cohort study included 12741 volunteers followed-up for eight years since 1994-1995. the incidence of hypo-and hyperthyroidism was estimated retrospectively from scheduled questionnaires and the data transmitted by the subjects during their follow-up. factors associated to incident cases have been identified by cox proportional hazards models. results: among the 5166 subjects free of thyroid dysfunction at inclusion, 95 incident cases were identified. after an average follow-up of 7.5 years, the incidence of hyper-and hypothyroidism was 0.5% in men, 2.3% in 35-44 year old women, and 3.6% in 45-60 year old women. no associated factor was identified in men. in women, age and alcohol consumption (>15 grams/day) increased the risk of hypo-or hyperthyroidism, while a high urinary thiocyanate level in 1994-1995 would be a protective factor. conclusion: the incidences of hypo and hyperthyroidism observed in our study as well as the associated risk factors found are in agreement with the data of studies performed in other countries. abstract background: lung cancer is the most frequent malignant neoplasm world-wide. in 2000, the number of new lung cancer cases was estimated at 1.2 million, which makes over 12% of all new cases of neoplasm registered all round the globe. it is also the leading cause of cancer deaths. objective: the objective of this paper is to provide a systematic review of life-related factors for lung cancer risk. methods: data sources were medline from january 1950 to december 2005, title in the field. search terms included: lung cancer, tobacco smoke, education, diet, alcohol consumption or physical activity terms. book chapters, monographs, relevant news reports, and web material were also reviewed to find articles. results: the results of the literature review suggest that smoking is a major, unquestionable factor of lung cancer risk. exposure to environmental tobacco smoke (ets) and education could also play a role in the occurrence of the disease. diet, alcohol consumption and physical activity level are other important but less extended determinants of lung cancer. conclusions: effective prevention programs against some of the life style-related factors for lung cancer, especially against smoking must be developed to minimize potential health risks and prevent the future cost of health. stedendriehoek twente and south (n = 179), additional data (co-morbidity, complications after surgery and follow-up) were gathered. cox-regression analyses were used. results: the proportion resections declined from 80% of patients <60 to 30% of patients aged > = 80 years, whereas primary radiotherapy increased from 7% to 36%. in the two regions 25 patients (14%) underwent resection. co-morbid conditions did not influence the choice of the therapy. 75% had complications. postoperative mortality was 20%. in multivariate analysis, only treatment had an independent effect.two year survival was 58% for patients undergoing surgical resection and 27% for those receiving radiotherapy (p<0.05). conclusion: number of co-morbid conditions did not influence choice of treatment, postoperative complications, and survival in patients with nsclc > = 80 years. the epidemiology of oesophageal cancer has changed in recent decades. the incidence has increased sharply, mainly comprising men, adenocarcinoma and tumours of the lower third of the oesophagus. the eurocare study suggested large variation in survival between european countries, primarily related to early mortality. to study potential explanations, we compared data from the rotterdam and thames cancer registry. computer records from 18,320 patients diagnosed with oesophageal cancer in the period 1993-2003 were analysed by age, gender, histological type, tumour subsite, period and region. there was a large variation in resection rates between the two regions, 31% for rotterdam versus 14% for thames (p<0.001). resection rates were higher for men, younger patients, adenocarcinoma and distal tumours. postoperative mortality (pom) was defined as death within 30 days of surgery and was 7.4% on average. pom increased with age from 3.3% for patients younger than 60 years to 12.6% for patients older than 70 years. pom was significantly lower in high-volume hospitals (>20 operations per year), 8.7% versus 2.4% (p<0.001). this study shows a large variation in treatment practice between the netherlands and the united kingdom. potential explanations will need to be studied in detail. abstract russia has experienced tremendous decline in life expectancy after break up of the ussr. surprisingly, im has also been decreasing. less is known on the structure of im in different regions of russia. the official im data may be underestimated partly due to misreporting early neonatal deaths (end) as stillbirths (sb). end/sb ratio considerably exceeding 1:1 indicates misreporting. we present the trends and structure of im in arkhangelsk oblast (ao), north-west russia from 1980 to 2004 as obtained from the regional statistical committee. im decreased from 22.3 to 10.1 per 1000 live births. cause-specific death rates (per 100,000) decreased from 251 to 7.0 for infectious diseases, from 745 to 56 for respiratory causes, from 141 to 56 for traumas, from 384 to 285 for inborn abnormalities but did not change for conditions of the perinatal period (501 in both 1980 and 2004) . the end/sb ratio increased from 1 to 1.5. in 2004, im from infections and respiratory causes in the ao are much lower than in russia in general. the degree of misreporting end as sb in the ao is lower than in russia in general. other potential sources of underestimation of im in russia will be discussed. abstract background: epidemiological studies that investigated malocclusion and different physical aspects in adolescents are rare in the literature. objective: we studied the impact of malocclusion on adolescents' self-image regardless of other physical aspects. design and methods: a cross-sectional study nested in a cohort study was carried out, in pelotas, brazil. a random sample of 900 15 yearsold adolescents was selected. the world health organization (1987) criteria were used to define malocclusion. interviews about self-reported skin colour and appearance satisfaction were administered. the body mass index was calculated. gender, birth weight and socioeconomic characteristics were obtained from the birth phase of the cohort study. poisson regression models were performed. results: the prevalence of moderate or severe malocclusion was 31.6% [95%ci 28.5; 34.7] in the whole sample without significant difference between boys and girls. a higher statistically significant difference of appearance dissatisfaction was identified in girls (46.5%) than in boys (29.8%). a positive association between malocclusion and appearance dissatisfaction was observed only in girls, after adjusting for other physical and socioeconomic characteristics. conclusions: malocclusion influenced appearance dissatisfaction only in young women. abstract background: factors for healthy aging with good functional capacity and those which increase the risk of death and disability need to be identified. objectives: we studied the prevalence of low functional capacity and its associations in a small city in southern brazil. design and methods: a population based cross sectional study was carried out with a random sample size of 345 elderly people. a home-applied questionnaire including socioeconomic, demographic, house conditions, socioeconomic self-perception characteristics was applied. the low functional capacity was defined as the difficulty in the performance of 6 or more activities or inability to carry out 3 of those activities according to scale proposed by rikli and jones. descriptive statistics, association using chi-square test as well as the multiple logistic regression analysis were performed. abstract introduction: assessment of trichiuriasis spatial distribution is important to evaluate sanitation conditions. our objective was to identify risk areas for the trichuris trichiura infection. methods: cross sectional study was held in 19 census tracts of duque de caxias county, rio de janeiro, brazil. collection and analysis of fecal specimens and a standardize questionnaire were carry out in order to evaluate socio-economic and sanitation conditions in a sample of 1,546 children between 1 and 9 years old. geoestatistics techniques were used to identify risk areas for trichiuriasis. results: the mean age of the studied population was 4.4 years old, which 52% were females and 48% were males. the prevalence of trichuris trichiura in the sample was 17%. children whose mothers studied for 4 years or less had odds ratio (or) = 1.9 than children whose mothers studied for more than 4 years old. children who were living in houses without water supply had or = 2.6 comparing to children living in houses with water supply. the spatial analysis identified risk areas for infection. conclusion: the results show association between socio-economic conditions and the proliferation of trichuris trichiura infection. the identification of risk areas can guide efficient actions to combat the disease. abstract background: refuge life and diabetes mellitus can affect the healthrelated quality of life (hrqol). objective: to assess how both aspects influence hrqol of the diabetic refugees in gaza strip. methods: overall 591 subjects filled a self-administered questionnaire including world health organization quality of life questionnaire (whoqol-bref) and some socio-demographic information. the sample consisted of three frequency matched groups for gender and sex, 197 each. first group were refugees with diabetes mellitus, second refugees without diabetes and third diabetes patients with no refugee history. the response rate was 87% on average. global score consisting of all four domains of who-qol-bref was dichotomized by the value of 50 and logistic regression was used for the analysis. results: crude odds ratios (or) for lower quality of life were 17.2 (95% ci 10.4-28.3) for diabetes refugees compared to diabetes non-refugees and 19.4 (11.7-32. 2) compared to non-diabetes refugees. after adjusting for age, gender, education, employment, income status and number of persons depending on the respondents or was 11.2 (6.1-20.5) and 35.3 (17.7-70.4), respectively. additionally, adjusting for length of diabetes and complications reduced the or to 5.6 (2.4-13.4) for diabetes refugees compared to diabetes non-refugees. conclusion: quality of life is highly reduced in refugees with diabetes. abstract background: pesticides have a significant public health benefit by increasing food production productivity and decreasing diseases. on the other hand, public concern has been raised about the potential health effects of the exposure to pesticides on the developing fetus and child. objectives: to review the available literature to find an epidemiological studies dealing with the exposure to pesticides and children health. design and methods: epidemiological studies were identified during search of the literature basis. following health effects were taking into account: adverse reproductive and developmental disorders, childhood cancer, neurodevelopmental effects and the role of pesticides as endocrine disrupters. results: pesticides were associated with wide range of reproductive disorders. the association between exposure to pesticides and the risk of childhood cancer and neurodevelopmental effects was found in several studies. epidemiological studies have been limited by luck of specific pesticide exposure, exposure based on job title, small size of examined groups. conclusions: in the light of existing although still limited evidence of adverse effects of pesticide exposure it is necessary to reduce the exposure. the literature review suggests a great need to increase awareness of people who are occupationally or environmentally exposed to pesticides about its potential negative influence on their children. in order to match local health policy more with the needs of citizens, the municipal health service utrecht started the project 'demand-orientated prevention policy'. one of the aims was to explore the needs of the utrecht citizens. the local health survey from 2003 contained questions about needs of information and support with regard to disorders and lifestyle. do these questions about needs give other results compared to questions about prevalence of health problems? in total 2284 utrecht citizens aged 16 to 54 years returned the health questionnaire (response rate 55%). most needs were observed on subjects concerning overweight and mental problems, and were higher among women, moroccans, turks, low educated people and citizens of deprived areas. the prevalence of disorders and unhealthy lifestyles did not correlate well to the needs (majority correlation coefficients: <0,30). most striking, of the utrecht population 30% were smokers and 20% excessive alcohol drinkers, while needs related to these topics were low. furthermore, higher needs among specific groups did not always correspond to higher prevalences of related health problems in these groups. these results show the importance of including questions about needs in a health survey, because they add additional information to questions about prevalences. abstract background: recent studies associated statin therapy with better outcome in patients with pneumonia. because of an increased risk of pneumonia in patients with diabetes we aimed to assess the effects of statin use on pneumonia occurrence in diabetic patients managed in primary care. methods: we performed a case-control study nested in 142,174 patients with diabetes. cases were defined as patients with a diagnosis of pneumonia. for each case, up to 4 controls were matched by age, gender, practice, and index date. patients were classified as current statin user when the index date was between the start and end date of statin therapy. results: statins were currently used in 1.1 % of 4,719 cases and in 2.1% of 15,322 controls (crude or: 0.51, 95% ci 0.37-0.68). after adjusting for potential confounders, statin therapy was associated with a 51% reduction in pneumonia risk (adjusted or: 0.49, 95% ci 0.35-0.68). the association was consistent among relevant subgroups (stroke, heart failure, and pulmonary diseases) and independent of age or use of other prescription drugs. conclusions: use of statins was significantly associated with reduced pneumonia risk in diabetic patients and may apart from lipid lowering properties be useful in prevention of respiratory infections. abstract introduction: cigarette smoking is the most important risk factor for copd development. therefore, smoking cessation is the best preventive measure. aim: to determine the beneficial effect of smoking cessation on copd development. methods: incidence of copd (gold stage > = 1) was studied in smokers without copd who quitted or continued smoking during 25 yr of followup. we performed logistic regression analyses on pairs of observations. correlations within a subject and time, and time between 2 successive surveys were taken into account. abstract objectives: to describe the prevalence and severity of dental caries in adolescents of the city of porto, portugal, and to assess socioeconomic and behavioral covariates of dental caries experience. methods: a sample of 700 thirteen-year-old schoolchildren underwent dental examination. results from the dental examination were linked to anthropometric information and to data supplied by two structured questionnaires assessing nutritional factors, sociodemographic characteristics and behaviors related to health promotion. dental caries was appraised in terms of the dmft index, and two dichotomous outcomes, one assessing the prevalence of dental caries (dmft = 1); the other assessing the prevalence of a high level of dental caries (dmft = 4). results: consuming soft drinks derived from cola two or more times per week, attending a public school, being girl and having parents with low educational attainment were identified as risk factors both for having dental caries and for having a high level of dental caries. conclusion: the improvement of oral health status in the portuguese context demands the implementation of polices to reduce the frequency of sugar intake, and could benefit from an overall and longstanding expansion of education in society. abstract background: migrant mortality does not conform to a single pattern of convergence towards rates in the host population. to better understand how migrant mortality will develop, there is a need to further investigate how the underlying behavioural determinants change following migration. objective: we studied whether behavioural risk factors among two generations of migrants converge towards the behaviour in the host population. design and methods: cross-sectional interview-data were used including 299 moroccan and 476 turkish migrants, aged 15-30. questions were asked about smoking, alcohol consumption, physical inactivity and weight/height. age-adjusted prevalence rates among first and second generation migrants were compared with prevalence rates in the host population. results: converging trends were found for smoking, physical inactivity and overweight. for example, we found a higher prevalence of physical inactivity in first generation turkish women as compared to ethnic dutch (or = 1.78(1.22-2.62)), whereas among second generation no differences were found (or = 0.82(0.57-1.17)). however, this trend was not found in all subgroups. additionally, alcohol consumption remained low in all subgroups and did not converge. conclusion and discussion: behavioural risk factors in two generations of migrants seem to converge towards the prevalence rates in the host population. although, some groups and risk factors showed a deviant pattern. abstract background/relevance: arm-neck-shoulder complaints are common in general practice. for referral in these complaints, only guidelines exist for shoulder complaints and epicondylitis. besides, other factors can be important. objective: what factors are associated with referral to physiotherapy or specialist in non-traumatic armneck-shoulder complaints in general practice, during the first consultation? design/methods: 31 general practitioners (gps) recruited consulters with new arm, neck or shoulder complaints. data on complaint-, patient-, gp-characteristics and management were collected. the diagnosis was categorised into: shoulder specific, epicondylitis, other specific or non-specific. multilevel analyses (adjustment for treating gp) were executed in procgenmod to assess associated variables (p<0.05). results: during the first consultation, 23% was referred for physiotherapy and 5% for specialist care. indicators of reference to physiotherapy were: long duration of complaint, recurrent complaint and gp located in a little/not urbanised area. while having shoulder specific or other specific diagnoses was negatively associated. indicators of reference to specialist care were: having other specific diagnosis, long duration of complaint, musculoskeletal co-morbidity, functional limitations and consulting a less experienced gp. conclusion/discussion: most referrals were to physiotherapy and only a minority to specialist care. mainly diagnosis and other complaint variables indicate on 'who goes where'. besides gp-characteristics can play a role. abstract background: the ruhr area has for 170 years been a synonym for a me´gapolis of heavy industry with a high population density. presently, 40% of the population of the state of north rhine-westphalia live there, i.e. more than five million people. objectives: for the first time, social and health indicators of nrw's health indicator set were brought together for this me´gapolis area. design and methods: new standard tables were constructed for the central area of 'ruhr-city' including seven cities with more than 2000 inhabitants/km2 and the peripheral zone with eight districts and cities. for the pilot phase, four socio-demographic and four health indicators were recalculated. comparability of the figures was achieved by age standardization. the results obtained were submitted to a significance test by identifying 95% confidence intervals. results: the centre of 'ruhr-city' is characterised by elderly, unemployed, foreign, low-income citizens living closely together. infant mortality lies above nrw's average, male life expectancy is 1.34 years lower and female life expectancy 0.90 years lower than life expectancy in nrw (without 'ruhr-city'). several avoidable deaths' rate in the ruhr area are significantly higher than the average in nrw. specific intervention strategies are required to improve the health status in 'ruhr-city'. abstract background: general practitioners (gps) have a fundamental role to play in tobacco control, since they reach a high percentage of the target population. objectives: to evaluate specific strategies to enhance promotion of smoking cessation in general practice. design and methods in a cluster-randomized trial, 82 medical practices were randomized following a 2·2 factorial design. 577 patients aged 36-75 years who smoked at least 10 cigarettes per day (irrespective of their intention to stop smoking) were recruited. the intervention included (ti) the provision of a two-hour physician group training in smoking cessation methods plus direct physician payments for every participant not smoking 12 months after recruitment; and (tm) provision of the same training plus direct participant reimbursements for pharmacy costs associated with nicotine replacement therapy or bupropion treatment. results: in the mixed logistic regression model, no effect was identified for intervention ti (odds ratio (or) = 1.26, 95% confidence interval (ci) 0.65-2.43), but intervention tm strongly increased the odds of cessation (or = 4.77, 95% ci 2.03-11.22). conclusion and discussion: the cost-free provision of effective medication along with improved training opportunities for gps may be an effective measure to enhance smoking cessation promotion in general practice. in europe, little research on international comparison of health surveys has been accomplished, despite a growing interest in this field. smoking prevalence is chosen to explore data comparability. we aim to illustrate methodological problems encountered when comparing data from health surveys and investigate international variations in smoking behaviour. we examined a sample 89.754 individuals aged 16 and more, from six european health surveys performed in 2000-2002. problems met during the comparisons are described. we took the example of current smoking as an indicator allowing a valid comparison of the prevalences. the differences in age and sex distribution between countries were adjusted through direct standardisation. additionally, multivariate analysis will assess variations in current smoking between countries, when controlling for sex, age, and educational level. methodological problems concern comparability of socioeconomic variables. the percentage of current smokers varies from 29% to 43%. smoking patterns observed by age groups, sexes and educational level are similar, although rates per country differ. further results will determine if the variations in smoking related to socioeconomic status are alike. this international comparison of health surveys highlights methodological problems encountered when comparing data of several countries. furthermore, variations in smoking may call for adaptations in public health programs. from research it appears that adolescent alcohol use in the achterhoek is much higher than in the rest of the netherlands and rapidly increasing. excessive alcohol use has consequences for health and society. parents play an important role in preventing excessive adolescent alcohol use, but are not aware of the problem and consequences. for this reasons the municipalities in the achterhoek launch an alcohol moderation programme, starting with a regional media campaign to increase problem awareness among parents. the objective of this study is to assess the impact of this media campaign in the achterhoek. three successive independent cross-sectional telephone surveys, interviewing approximately 350 respondents each, will be conducted before, during and after the campaign. respondents will be questioned on knowledge and awareness of excessive adolescent alcohol use, its consequences and the role child raising can play. also the reach and appreciation of the different activities of the campaign will be investigated. results: of the surveys before and during the implementation will be known by may 2006. with these first findings the unawareness of the problem among parents and partly the reach and appreciation of the campaign can be assessed. abstract background: obesity is a growing problem, increasingly so in children and adolescents. overweight is partly 'programmed' during pregnancy, but few comprehensive studies looked prospectively into the changes of body composition and metabolic factors from birth. objectives: the aim of the population-based birth-cohort study within gecko is to study the etiology and prognosis of overweight and the metabolic syndrome during childhood. design and methods: the gecko drenthe will be a population based observational birth-cohort study, which includes all children born from april 2006 to april 2007 in drenthe, one of the northern provinces of the netherlands. during the first year of life, the study includes repeated questionnaires, extensive anthropometric measurements and blood measurements at birth (cord blood) and at the age of eleven months. results: the number of babies born in the drenthe province is about 5.500 per year. the results from a feasibility study conducted in february 2006 will be presented. conclusion: gecko drenthe is a unique project that will contribute to the understanding of the development of obesity in childhood and its tracking into adulthood. this will enable early identification of children at risk and opens the way for timely and tailored preventive interventions. abstract background: tunisia is facing an epidemiologic transition with the extension of chronic diseases that share common risk factors. obesity is a leading risk factor and happens to occur frequently in early life. objective: to study the prevalence and the risk factors of obesity and overweight among urban schoolchildren in sousse, tunisia. methods: cross sectional study of a tunisian sample of schoolchildren aged between 13 and 17 years living in the urban area of sousse, tunisia. a representative sample of 1600 school children selected by multistage cluster sampling procedure. measurements: weight and height, blood pressure measured by electronic system, fasting blood lipids. questionnaire assessment was used for family history of cardiovascular disease, smoking habits, physical activity and diet. abstract background: quality of life (qol) measurements are acknowledged as very important in the evaluation of health care. objectives: we studied the validity and the reliability of the hungarian version of the whoqol-bref among people living in small settlements. method: a questionnaire-based cross-sectional study was conducted in a representative sample (n = 814) of persons aged 35 years and over in south-east-hungary, in 2004. data were analysed by the spss 13.0. the internal consistency was evaluated using cronbach's alpha; for comparison of the qol scores amongst the various groups the two-tailed t-tests were used; convergent validity was assessed by spearman coefficients. results: the male:female ratio was 48.3 to 51.7%, and the average age 59.68 (sd:14.37) years. the domain scores were 14.14 (sd:3.08) for the physical, 14.19 (sd:2.42) for psychological, 14.15 (sd:3.03) for the social, and 14.01 (sd:2.08) for the environment domains. the cronbach's alpha values ranged from 0.73 to 0.87 across domains. the whoqol-bref seemed to be suitable to distinguish healthy and unhealthy people. the scores for all domains correlated with the self-evaluated health, and overall quality of life (p<0.01). conclusion: our study supported that the whoqol-bref provided a valid, reasonable and useful determination of the qol of people living in hungarian villages. abstract background: further than a cardiovascular disease, arterial hypertension (aht) is the main cardiovascular risk factor. in spain, the aht prevalence reaches 47%, placed in the third position after germany and finland in affecters percentage. although its high morbi-mortality, the aht is a forecast factor. the treatment's objective (pharmacological and life style modifications) of hypertensive patients is not only to reduce blood pressure levels to optimum levels but also to treat all modifiable vascular risk factors. objective: economic impact evaluation of direct costs due to aht pathology (cie9-mc 401-405) in spain in 2003, according to autonomous region. design and methods: descriptive and transversal study of costs estimation in the period between january to december 2003 in spain according to autonomous region. the study is based on data available from the national health ministry database and the national statistics institute of spain. results: the national health service assigned 2000 million e to aht treatment. 73,4% of the total cost is owe to pharmaceutical service expenses, 23,2% to primary health care and a 3,4% to hospital admissions. conclusion and discussion: the costs generated by aht are mainly due to the pharmaceutical service. the costs distribution is modified according to the geographical region. abstract background: over the last decades, for low-stage cervical cancer less surgical treatment and for high-stage cervical cancer chemoradiotherapy was recommended in the national guidelines. objectives: to describe changes and variation in treatment and survival in cervical cancer in the regions of the comprehensive cancer centre stedendriehoek twente (cccst) and south (cccs) in the netherlands. design and methods. 1736 newly diagnosed cervical cancer cases were selected from both cancer registries in the period 1989-2002. patient characteristics, tumour characteristics, treatment and follow-up data were collected from the medical records. results: in figo stages ia2-ib2 the percentage hysterectomy decreased from 90% in 1989 -1993 to 77% in 1999 -2002 (p<.05) and survival improved comparing 1989 -1993 with 1999 -2002 . figo stages iii-ivb had mostly received radiotherapy only (60%). no differences in survival between years of diagnosis were found. in the cccs-region more chemoradiotherapy was given in these stages (11% versus 5% in the cccst-region in the whole period). conclusion and discussion:. abstract background: the reason for the increased prevalence of depression in type 2 diabetes (dm2) is unknown. objective: we investigated whether depression is associated with metabolic dysregulation or that depression is rather a consequence of having dm2. methods: baseline data of the utrecht health project were used. subjects with cardiovascular disease were excluded. 4,203 subjects (age: 38.0 +/) 12) were classified into four mutually exclusive categories: normal fasting plasma glucose (fpg < 5.6 mmol/l), impaired fpg (> = 5.6 and < 7.0 mmol/l), undiagnosed dm2 (fpg > = 7.0 mmol/l), and diagnosed dm2. depression was defined as either a score of 25 or more on the depression subscale of the symptom check list-90 or use of antidepressants. results: subjects with impaired fasting glucose and undiagnosed dm2 had no increased prevalence of depression. diagnosed dm2 patients had an increased prevalence of depression (or = 2.11 (1.08-4.11)) after adjustment for gender, age, body mass index, smoking, alcohol consumption, physical activity, education level and number of chronic diseases. conclusions: our findings suggest that depression is not related to disturbed glucose homeostasis. the increased risk of depression in diagnosed dm2 only, suggests that depression is rather a consequence of the psychosocial burden of diabetes. abstract background: breast-conserving surgery (bcs) followed by radiotherapy (bcs-rt) is a safe treatment option for the large majority of patients with tumours less than 5 cm. aim: the use of bcs and bcs-rt in pt1 (?2 cm) and pt2-tumours (2-5 cm) was investigated in the netherlands in the period 1990 and 2001. methods: from the netherlands cancer registry patients were selected with invasive pt1 (?2.0 cm) or pt2 (2.1-5.0 cm) tumours, without metastasis at time of diagnosis. trends in the use of bcs and rt after bcs were determined for different age groups and regions. results: in the period 1990-2001 52,937 pt1-tumours and 36,285 pt2-tumours were diagnosed. the %bcs in pt1-tumours increased in all age groups. it remained lowest in patients 80 years and older (32% in 2001). in pt2-tumours a decrease was observed in patients 80 years and older (from 23% to 17% in 2001). in both pt1 and pt2tumours the %bcs-rt increased in patients 80 years and older to respectively 59% and 44%. between regions and hospitals large differences were seen in %bcs and %bcs-rt. conclusion: multidisciplinary treatment planning, based on specific guidelines, and patient education could increase the use of bcs combined with rt in all age groups. abstract this is a follow-up study on the adverse health effects associated with pesticide exposure among cut-flower farmers. survey questionnaires and detailed physical and laboratory examinations were administered to 114 and 102 respondents, respectively, to determine pesticide exposure, work and safety practices, and cholinesterase levels. results showed that pesticide application was the most frequent activity associated with pesticide exposure, and entry was mostly ocular and dermal. majority of those exposed were symptomatic. on physical examination, 90 or 88.2 % of those examined were found to have abnormal peak expiratory flow rate (pefr). eighty-two percent had abnormal temperature, followed by abnormal general survey findings (e.g. cardiorespiratory distress). 51% had cholinesterase levels below the mean value of 0.7 ? ph/hour, and 25.5% exhibited a more than 10% depression in the level of rbc cholinesterase. certain hematological parameters were also abnormal, namely hemoglobin, hematocrit, and eosinophil count. using pearson's r, factors strongly associated with illness due to pesticides include using a contaminated piece of fabric to wipe sweat off (p.=0.01) and reusing pesticide containers to store water (p.=0.01). the greatest adverse effect of those exposed is an abnormal cholinesterase level which confirms earlier studies on the effect of pesticides on the body. objectives: this pair-study was performed to find out the rate of spontaneous abortions in female workers exposed to organic solvents from the wood-processing industry. methods: the level of organic solvents was assessed within the workplaces during a 10year period. 366 exposed female workers from the wood-processing industry were examined. the occupational and non-occupational data associated with their fertility were obtained by applying a standard epidemiological computed questionnaire. the reference group consisted of female workers non-exposed to hypo-fertilizing agents, residing in the same locality. the rate of spontaneous abortions was evaluated in both groups as an epidemiological fertility indicator. results: within the studied period, the organic solvents levels exceeded several time the maximal admissible concentrations in all workplaces. the long-term exposure to organic solvents caused a significant increase in rate of spontaneous abortions compared to the reference group (p<0.05). the majority of abortions (85%) have happened in the first trimester of pregnancy. conclusions: the long-term exposure to organic solvents may cause low fertility on female workers because of the spontaneous abortions. it is advised to reduce the organic solvents level in the air of all workplaces, as well as to stop working the pregnant women in exposure to organic solvents. abstract introduction: rio de janeiro city (rj) presents a fast aging of the population with changes in morbi-mortality. cardiovascular diseases are the first cause of death in elderly population. more than a half of ischemic heart diseases (ihd) cases occur in aged people (> 60 years old). objective: describe the spatial distribution of ihd mortality in the elderly population in rj and associations with socio-demographics variables. methods: data were gathered from information on mortality system of the ministry of health and the 2000 demographic census of the foundation of the brazilian institute for geography and statistics. the geographic distributions of the standardized coefficient of mortality due to ihd and socio-demographics variables, by districts, in 2000 were analyzed in arcgis 8.0. spatial autocorrelation of ihd was assessed by the moran and geary indices. a conditional autoregressive model was used to evaluate the association between idh and socio-demographics variables. results: association between idh mortality and income, educational level, family type and to possess computer, videocassette and microwave was found. conclusion: spatial analysis of the idh mortality and socio-demographics factors influence are fundamental to subsidize more efficient public policies in sense to prevention and control of this important injury of health. abstract purpose: to evaluate the prognostic impact of isolated loco-regional recurrences on metastatic progression among women treated for invasive stage i or ii breast cancer (within phase iii trials concerning the optimal management of breast cancer). patients and methods: the study population consisted of 3,602 women primary surgically treated for early stage breast cancer, enrolled in eortc trials 10801, 10854, or 10902, by breast conservation (55%) and mastectomy (45%) with long time of follow-up (median: 10.2 range: 0. 2-17.4 ). data were analysed in a multi-state model by using multivariate cox regression models, including a state-dependent covariate. results: after the incidence of the loco-regional recurrence, a positive nodal status at baseline is a significant prognostic risk factor for distant metastases. the effects of the young ages at diagnosis and larger tumour size, become less significant after the incidence of loco-regional recurrences. the presence of a locoregional recurrence in itself is a significant prognostic risk factor for distant metastases after loco-regional recurrences. the effect of the time to the loco-regional recurrence is not a significant prognostic factor. conclusion: the presence of local recurrence is an important risk factor for outcome in patients with early breast cancer. abstract background: the relationship between the antral follicles and ovarian reserve tests (ort) to determine ovarian response in ivf is extensively studied. we studied the role of follicle size distribution in the response on the various orts in a large group of subfertile patients. methods: in a prospective cohort study, female patients were included if they had regular ovulatory cycles, subfertility for >12 months, > = 1 ovary and > = 1 patent ovarian tube. antral follicles were counted by ultrasound and blood was collected for fsh, including a clomiphene challenge test (ccct), inhibin b, and estradiol before and after administration of puregon [rsymbol] . (efort test). statistical analysis was performed using spss 12.0 for windows. results: of 740 eligible patients, 489 participated. mean age was 32.6 years and mean duration of subfertility was 21.7 months. age, baseline fsh, ccct and efort correlated with the number of small follicles (2-5 mm) but not with large follicles (6-10 mm). regression analysis confirmed that the number of small follicles and average follicle size contributed to ovarian response after correction for age, while large follicles did not. conclusion: small antral follicles are responsible for the hormonal response in ort and may be suitable to predict ovarian response in ivf. abstract background: dengue epidemics account annually for several million cases and deaths worldwide. the high endemic level of dengue fever and its hemorrhagic form (dhf) correlates to extensive house infestation by aedes aegypti and multiple viral serotype human infection. objective: to describe dengue incidence evolutionary patterns and spatial distribution in brazil. methods: it is a review study that analyzed serial case reports registered since 1981 until 2003. results: it was shown that defined epidemic waves followed the introduction of every serotype (den 1 to 3) , and reduction in susceptible people possibly responded for downward case frequency. conclusions and discussion: an incremental expansion of affected areas and increasing occurrence of dhf with high lethality were noted in recent years. in contrast, efforts based solely on chemical vectorial combat have been insufficient. moreover, some evidence demonstrated that educational action do not permanently modify population habits. in this regard it was stated that while vaccine is not available, further dengue control would depend on potential results gathered from basic interdisciplinary research and intervention evaluation studies, integrating environmental changes, community participation and education, epidemiological and virological surveillance, and strategic technological innovations aimed to stop transmission. abstract background: patient participation in treatment decisions can have positive effects on patient satisfaction, compliance and health outcomes. objectives: study objectives were to examine attitudes regarding participation in decision-making among psoriasis patients and to evaluate the effect of a decision-aid for discussing treatment options. methods: a 'quasi experiment' was conducted in a large dermatological hospital in italy: a questionnaire evaluating the decision-making process and knowledge on treatments was selfcompleted by a consecutive sample of 231 psoriasis patients after routine clinical practice and by a second sample of 171 patients exposed to a decision-board. results: in routine clinical practice 67.9% of patients wanted to be involved in treatment decisions, 28.4% wanted to leave decisions entirely to the doctor and 3.7% preferred making decisions alone. 17.9% and 25.3% of the control and decision-board group had good knowledge level. at multivariate analysis good knowledge on treatments increased the likelihood of preferring an active role (or = 2.21; 95%ci 1.3-3.9; p = 0.006). the decision-board only marginally improved patient knowledge and doctor-patient communication. conclusion and discussion: in conclusion, large proportions of patients want to participate in decision-making, but insufficient knowledge can represent a barrier. further research is needed for developing effective instruments for improving patient knowledge and participation. abstract background: the only available means of controlling infections caused by the dengue virus is the elimination of its principal urban vector (aedes aegypti). brazil has been implementing programs to fight the mosquito; however, since the 1980's the geographic range of infestation has been expanding steadily, resulting in increased circulation of the virus. objective: to evaluate the effectiveness of the dengue control actions that have been implemented in the city of salvador. methods: prospective design, serologic inquiries were made in a sample population of residents of 30 urban 'sentinel areas'.the seroprevalence and one year seroincidence of dengue are estimated and the relationship between intensity of viral circulation and the standards of living and vector density is analysed. results: there were high overall seroprevalence (67.7%) and seroincidence (70.6%) for the circulating serotypes (denv-1 and denv-2). the effectiveness of control measures appears to be low, and although a preventable fraction of 29.7% was found, the incidence of infections in these areas was still very high (55.4%). conclusions and discussions: it is necessary to revise the technical and operational strategies of the infection control program in order to attain infestation levels that are low enough to interrupt the circulation of the dengue virus. this study investigates the difference in cancer mortality risks between migrant groups and the native dutch population, and determines the extent of convergence of cancer mortality risks according to migrants' generation, age at migration and duration of residence. data were obtained from the national population & mortality registries in the period 1995-2000 (75860 person years, 173461 cancer deaths). we used poisson regression to compare the cancer mortality rates of migrants originating from turkey, morocco, surinam, netherlands antilles/aruba to the rates for the native dutch. results: all-cancer mortality among all migrant groups combined was significantly lower compared to the native dutch population (rr=0.55 ci: 0.52-0.58). mortality rates for all cancers combined were higher among 2nd generation migrants, among those with younger age at migration, and those with longer duration of residence. this effect was particularly pronounced in lung cancer and colorectal cancer. for most cancers, mortality among 2nd generation migrants remained lower compared to the native dutch population. surinamese migrants showed the most consistent pattern of convergence of cancer mortality. conclusions: the generally low risk of cancer mortality for migrants showed some degree of convergence but the cancer mortality rates did not yet reach the levels of the native dutch population. abstract background: legionnaires' disease (ld) is a notifiable disease in the netherlands. ld cases are reported to authorities for national surveillance. supplementary, a national ld outbreak detection program (odp) is installed in the netherlands. these two registration systems have their own information exchange process and databases. objectives: surveillance systems are known to suffer from incompleteness of reported data. co-existence of two databases creates the opportunity to investigate accuracy and reliability in a national surveillance system. design and methods: comparison was made between the outcome 'diagnosis by culture' in both databases and physical presence of legionella strains in laboratories for 174 patients. accuracy is described using the parameters sensitivity and correctness. for reliability, cohen's kappa coefficient (?) was applied. results: accuracy and reliability were significantly higher in the odp database, but not optimal in both databases when compared to data in laboratories. the odp database was moderately reliable (? = 0.56; 95%ci 0.43-0.69), the surveillance database slightly (? = 0.14; 95%ci 0.02-0.27). conclusion: our findings suggest that diagnostic notification data concerning ld patients are most accurate and reliable when derived directly from diagnostic laboratories. discussion: involvement of data-entry persons in outbreak detection results in higher reliability. unreliable data may have considerable consequences during outbreaks of ld. the aim of the study was to investigate the medical students' plans to emigrate, quantify the scale of migration in the near future and to build a profile of the possible emigrants. data were collected based on anonymous questionnaire delivered to random group of 367 medical students (katowice). we used the binary logistic regression and multivariate analysis to identify the differences between groups preferring to go abroad or stay in poland. 85% respondents confirmed that considerate the emigration; 35.3% of them declared they are very likely to move and further 10.7% is certain. 23,9% of those considering emigration confirmed having taken practical steps towards moving. binary logistic regression showed no difference between people who were certain or almost certain to go and those who were not considering going for most baseline characteristics: hometown size, socio economic background and having family tradition of the medical profession (p = 0.19). only marks' mean differentiates between the two groups: 4.01 for those who will definitely stay vs 3.7 for students who will definitely move (p = 0.02). the multivariate analysis gave similar results. conclusions: most of the students consider the emigration, but the declarations of will to departure are more frequent among those with the worse marks. abstract background: falls incidence in home resident elderly people varies from 30% to 40%. falls induce loss of self-sufficiency and increase mortality and morbidity. objectives: to evaluate falls incidence and risk factors in a group of general practice elderly patients. design : prospective cohort study with 1 year follow-up methods: eight hundreds elderly (>75 years) were visited by 18 practitioners for a baseline assessment. information on current pathologies and previous falls in the last six months was collected. functional status was evaluated using: short portable mental state questionnaire, geriatric depression scale, activities of daily living (adl), instrumental activities of daily living, total mobility tinetti score. falls were monitored through 2 phone-interviews at 6 and 12 months. data were analyzed through logistic regression. results: twenty-eight percent of the elderly fell in the whole period. sixty percent of falls were not reported to the practitioner. independent predictors for falls were adl score (adl<5: or = 1.88; 95% ci 1.04-3.38) and previous falls (or = 1.60; 95% ci 1.02-1.52). tinetti score was significantly associated to falls only in univariate analysis. conclusions: practitioners can play a key-role in identifying at-risk subjects and managing prevention interventions. falls monitoring and a continuous practice of comprehensive geriatric assessment should be encouraged. abstract background: oral health represents an important indicator of health status. socio-economic barriers to oral care among elderly are considerable. in the lazio region, a public health program for oral rehabilitation was implemented to offer dentures to elderly people with social security. objectives: to compare hospitalisation between elderly enrolled in the program and a control group. design and methods: for each elderly enrolled in the program living in rome, three controls, matched for sex and age, were selected from rome municipality register. hospital admissions in the two-year period before enrollment were traced by record-linkage with the hospital discharge register. results: totally, 2,935 admissions occurred. the annual admissions rate was 218 per 1000 elderly among controls and 329 in the program group (incidence rate ratio: irr = 1.50; 95% ci 1.40-1.63). when comparing diagnosis-specific rates, significant excesses were observed in the program group for respiratory diseases ( abstract background: herpes simplex virus (hsv) type 1 and 2 are important viral sexually transmitted diseases (sti) and can cause significant morbidity. in the netherlands, data about prevalences in the general population are hampered. objective: description of the seroprevalences of hsv-1 and hsv-2 and associated factors in the netherlands. design and methods: a population based serum bank survey in the netherlands with an age-stratified sample was used (1995) (1996) . antibodies against hsv-1 and hsv-2 were determined using elisa. a questionnaire was used to get information on demographics and risk factors. a logistic regression adjusting for age and full multiple regression were done to establish risk factors. results: questionnaires and sera were available for 7166 persons. both hsv-1 and hsv-2 seroprevalence increased with age. seroprevalence of hsv-1 was 59.5% and was amongst others associated with female sex and being divorced. seroprevalence of hsv-2 was 8.4% and was amongst others associated with being divorced and a history of sti. conclusion: seroprevalence is higher in certain groups like teenagers, women, divorced people and those with a history of sti. prevention should be focused on those groups. more research is needed on prevention methods, which can be used in the netherlands, like screening or vaccination. abstract background: frequently, statistically significant prognostic factors are reported with suggestions that patient management should be modified. however, the clinical relevance of such factors is rarely quantified. objectives: we evaluated the accuracy of predicting the need for invasive treatment among bph patients managed conservatively with alpha1-blockers. methods: information on eight prognostic factors was collected from 280 patients treated with alpha1-blockers. with phm regression coefficients a risk score for retreatment was calculated for each patient. the analyses were repeated on 1000 groups of 280 patients sampled from the original case series. these bootstrap results were compared to the original results. results: three significant predictors of retreatment were identified. the 20% of patients with the highest risk score had an 18-month risk of retreatment of only 20%. analyses of less than half of all the bootstrap samples resulted in the same three significant prognostic factors. the 20% of patients with the highest risk score in each of the 1000 samples experienced a highly variable risk of retreatment of 0% to 42%. conclusions: four of the five high risk patients would be overtreated with a modified policy. internal validation procedures may warn against the invalid translation of statistical significance into clinical relevance. background: e-cadherin expression is frequently lost in human epithelium derived cancers, including bladder cancer. for two genetic polymorphisms in the region of the e-cadherin gene (cdh1) promoter, a reduced transcription has been reported: a c/a single nucleotide polymorphism (snp) and a g/ga snp at 160 bp and 347 bp, respectively, upstream of the transcriptional start site. objective: we studied the association between both polymorphisms and the risk of bladder cancer. methods: 174 patients with bladder cancer and 326 population controls were genotyped for the )160 c/ a and the )347 g/ga promoter polymorphisms using pcr-rflp. results: a significantly increased risk for bladder cancer was found for a allele carriers compared to the homozygous c allele carriers (or 1.58; 95% ci: 1.06-2.35). the risk for the heterozygous and homozygous a allele carriers, was increased approximately 1.5 and 2-fold, respectively. the association was stronger for more aggressive tumors. we did not find any association between the )347 g/ga snp and bladder cancer. conclusion: this study indicates that the )160 c/a snp in the e-cadherin gene promoter is a low-penetrance susceptibility factor for bladder cancer. background: health problems, whether somatic, psychiatric or accident-related cluster within persons. the study of allostatic load as a unifying theme (salut) aims to identify risk factors that are shared by different pathologies and that could explain this clustering. studying patients with repetitive injuries might be helpful to identify risk factors that are shared by accident-related and other health problems. objectives: to study injury characteristics in repetitive injury (ri) patients as compared to single injury (si) patients. methods: the presented study included 196 ri patients and 558 si patients. medical records provided information about injury characteristics and patients were asked for possible causes and context. results: ri patients suffered significantly more from contusions than si patients (25% vs 16%). regarding the context, si patients were significantly more injured in traffic (28% vs 23%). in both groups most injuries were attributed to 'mere bad luck' (ri 44%, si 49%), closely followed by 'clumsiness or inattention' (ri 39%, si 44%). ri patients pointed out aggression or substance misuse significantly more often than si patients (17% vs 7%). conclusion: ri patients seem to have more 'at risk' behavior (i.e. aggression, impulsivity), which will increase their risk for psychiatric health problems. abstract background: breastfeeding may have a protective effect on infant eczema. bias as a result of methodological problems may explain the controversial scientific evidence. objective: we studied the association between duration of breastfeeding and eczema when taking into account the possible influence of reverse causation. design and methods: information on breastfeeding, determinants and outcomes at age one year was collected by repeated questionnaires in 2834 mother infant-pairs participating in the koala study (535 cases of eczema). to avoid reverse causation, a periodspecific-analysis was performed in which only 'at risk' infants were considered. results: no statistically significant association between the duration of breastfeeding (>12 weeks versus formula feeding) and the risk of eczema in the first year was found (or 2.07 95%ci 0.69-6.22). after excluding from the analysis all breastfed infants with symptoms of eczema reported in the same period as breastfeeding, also no statistical significant association was found for the duration of breastfeeding and eczema between 4 and 12 months (or 1.45 95%ci 0.34-6.25). conclusion and discussion: in conclusion, no evidence was found for a protective effect of breastfeeding duration on eczema. this conclusion was strengthened by risk period-specific-analysis which made the influence of reverse causation unlikely. abstract background: the internet can be used to meet health information needs, provide social support, and deliver health services. the anonymity of the internet offers benefits for people with mental health problems, who often feel stigmatized when seeking help from traditional sources. objectives: to identify the prevalence of internet use for physical and mental health information among the uk population. to investigate the relationship of internet use with current psychological status. to identify the relative importance of the internet as a source of mental health information. design and methods: self-completion questionnaire survey of a random sample of the uk population (n = 1800). questions included demographic characteristics, health status (general health questionnaire), and use of the internet and other information sources. results: 59% of internet users had sought health information online, and 18% had sought mental health information. use was higher among those with current psychological problems. only 12% of respondents identified the internet as one of the most accurate sources of mental health information, compared with 24% who identified it as one of the sources they would use. conclusions: health service providers must recognise the increasing use of the internet in healthcare, even though it is not always regarded as being accurate. abstract old age is a significant risk factor for falls. approximately 45% of people older than 80 are falling at least once a year, mostly in the own homes. resulting hip fractures cause at least partial immobility in 40-50% of the affected persons. almost 20% are sent to nursing homes afterwards. in mecklenburg-west pomerania, ageing of the population proceeds particularly fast. to prevent falls and the loss of independent living a falls prevention module was integrated in a community-bbased study conducted in cooperation with a general practitioner (gp). in the patients homes' a trained nurse performed a test to estimate the falls risk of each patient and a consultation how to reduce risk, e.g. eye sight check, gymnastic exercise. in the feasibility study 11 (55%) out of 20 patients (average age 74 years), agreed to a visiting of each room of their homes in search for tripping dangers. the evaluation was assisted by a standardized, computer-based documentation. the prevention module received a considerable acceptance despite the extensive home visiting. within one month the patients started to transfer advice into practice. during the first follow up visits of the nurse three patients reported e.g. to have started gymnastics and/or wear stable shoes. abstract background: the emergence of drug resistant m. tuberculosis (mtb) is an increasing problem in both developed and developing countries. objectives: investigation of isoniazid (inh) and rifampin (rif) susceptibility patterns among mtb isolates from patients. design and methods: in total 80 sputum samples were collected. smears were prepared for acid fast staining and all the isolates were identified as m. tuberculosis by preliminary cultural and biochemical tests. the isolates were examined for inh and rifampin resistance using conventional mic method and pcr technique by using specific inh (kat g) and rifampin (rpo b) resistant primers. results: seven isolates were resistant to both inh and rifampin by mic method. in pcr technique, 5 and 6 out of 7 above mentioned strains showed resistant to inh and rifampin respectively. coclusion: the epidemiology of drug resistance is 8.7% in region of study which is significant. discussion: conventional mic method despite being time consuming is more sensitive for evaluation of drug resistance, however, pcr as a rapid and sensitive technique is recommended additionally to conventional method for having quicker results to start treatment and disease control management. abstract background and objectives: we studied in literature which design characteristics of food frequency questionnaires (ffqs) influence their validity to assess both absolute and relative levels of energy intake in adults with western food habits, and to rank them according to these intakes. this information is required in harmonizing ffqs for multi centre studies. design and methods: we performed a review of studies investigating the validity or reproducibility of ffqs, published since 1980. the included studies validated ffqs against doubly labeled water (for energy expenditure) as a gold standard, or against food records or 24 hour recalls for assessing relative validity (for energy intake). the design characteristics we studied were the number of food items, the reference period, the administration mode, and inclusion of portion size questions. results: and conclusion: for this review we included 35 articles representing the validation of 37 questionnaires. three questionnaires were validated against dlw, ten against urinary n and 25 against 24-hour recalls or food records. in conclusion a positive linear relationship (r = 0.57, p<0.0001) was observed between the number of items on the ffq and the reported mean energy intake. details about the influence of other design characteristics on validity will be discussed at the conference. abstract background: high ethanol intake may increase the risk of lung cancer. objectives: to examine the association of ethanol intake with lung cancer in epic. design and methods: information on baseline and past alcohol consumption, lifetime tobacco smoking, diet, and anthropometrics of 478,590 participants was collected between 1992 and 2000. cox proportional hazard regression was used to examine the association of ethanol intake at recruitment (1119 cases) and mean lifelong ethanol intake (878 cases) with lung cancer. results: non-consumers at recruitment had a higher lung cancer risk than low consumers (0.1-4.9 g/day) [hr = 1.22, 95% ci 0.99-1.50]. lung cancer risk was lower for moderate ethanol intake at recruitment (5.0-14.9 g/day) compared with low intake (hr = 0.76, 95% ci 0.63-0.90); no association was seen for higher intake. compared with lifelong low consumers, lifelong non-consumers did not have a higher lung cancer risk (hr = 1.01, 95% ci 0.67, 1.50) but lifelong moderate consumers had a lower risk (hr = 0.80, 95% ci: 0.66-0.97). lung cancer risk tended to increase with increasing lifelong ethanol intake (=60 vs. 0.1-4.9 g/ day hr = 1.29, 95% ci: 0.93-1.74). conclusion: while lung cancer risk was lower for moderate compared with low ethanol intake in this study, high lifelong ethanol intake might increase the risk. abstract background: one of the hypotheses to explain the increasing prevalence of atopic diseases (eczema, allergy and asthma) is imbalance between dietary intake of omega-6 and omega-3 fatty acids. objectives: we evaluated the role of perinatal fatty acid (fa) supply from mother to child in the early development of atopy. design and methods: fa composition of breast milk was used as a marker of maternal fa intake and placental and lactational fa supply. breast milk was sampled 1 months postpartum from 312 mother-infant pairs in the koala birth cohort study, the netherlands. the infants were followed for atopic symptoms (repeated questionnaires on eczema and wheezing) and sensitisation at age 2 (specific serum ige against major allergens). multivariate logistic regression analysis was used to adjust for confounding factors. results: high levels of omega-3 long chain polyunsaturated fas were associated with lower incidence of eczema in the first year (odds ratio for the highest vs lowest quintile 0.31, 95% confidence interval 0.12-0.81; trend over quintiles p = 0.007). wheeze and sensitisation were not associated with breast milk fa composition. conclusion and discussion: the results support the omega-6/3 hypothesis. we suggest that anti-inflammatory activity of omega-3 eicosanoid mediators is involved but not allergic sensitisation. abstract background: acute myocardial infarction (ami) is among the main causes of death in italy and is characterized by high fatality associated with a fast course of the disease. consequently timeliness and appropriateness of the first treatment are paramount for a positive recovery. objectives: investigate the differences among italian regions of ami first treatment and in-hospital deaths. design and methods: following the theoretical care pathway (from onset of ami to hospitalization and recovery or death), regional in-hospital deaths are decomposed into the contributions of attack rate, hospitalization and in-hospital fatality. hospital discharges, death and population data are provided by the official statistics. results: generally in northern and central regions there is an excess of observed in-hospital deaths, while the opposite occurs in southern regions. conclusion: in northern and central regions the decomposition method suggests a more frequent and severe illness, generally accompanied by a higher availability of hospitals; exceptions are lombardia and lazio, where some inefficiencies in the hospital system are highlighted. in most southern regions the decomposition confirms a less frequent and less severe illness; exceptions are campania and sicilia, where only the less severe patients reach the hospital and then recover, while the others die before reaching the hospital. abstract background: atherosclerotic lesions have typical histological and histochemical compositions at different stages of their natural history. the more advanced atherosclerotic lesions contain calcification. objective: we examined the prevalence of and associations between calcification in the coronary arteries, aortic arch and carotid arteries assessed by multislice computed tomography (msct). methods: this study was part of the rotterdam study,a population-based study of subjects aged 55 years and over. calcification was measured and quantified in 600 subjects. correlation coefficients were computed using spearman's correlation coefficients. results: the prevalence of calcification increased with age throughout the vascular bed. in subjects aged 80 and over, up to 100% of men had calcification in the coronary arteries and up to 100% of women had calcification in the aortic arch. in men, the strongest correlation was found between calcification in the aortic arch and the carotid arteries (r=0.60, p<0.001). in women, the relations were somewhat lower, the strongest correlation was found between calcification in the coronary arteries and the carotid arteries (r = 0.47, p<0.001). conclusion and discussion: in conclusion, the prevalence of calcification was generally high and increased with increasing age. the study confirms the presence of strong correlations between atherosclerosis in different vessel beds. abstract background: health status deteriorates with age and can be affected by transition from active work to retirement. objective: to assess the effect of retirement on age related deterioration of health. methods: secondary analysis of the german health survey (bundesgesundheitssurvey 1998) and california health interview survey (chis 2003) . subjective health was assessed by a single question regarding respondent's health status from 1 = excellent to 5 = poor. locally weighted regression was used for exploratory analysis and b-splines for the effect estimation in regression models. results: subjective health decreased in an obviously non-linear manner with age. in both cases the decrease could be reasonably approximated by two linear segments, however the pattern was different in the german and california sample. in germany, the change point of the slope describing deterioration of health was located at 59. abstract objective: to assess the effectiveness of physiotherapy compared to general practitioners' care alone, in patients with acute sciatica. design, setting and patients: a randomised clinical trial in primary care with a 12-months follow-up period. 135 patients with acute sciatica (recruited 2003 -2004) were randomised in two groups: 1) intervention group received physiotherapy (active exercises), and 2) control group received general practitioners' care only. main outcome measures the primary outcome was patients' global perceived effect. secondary outcomes were severity of leg and back pain, severity of disability, general health and absence from work. the outcomes were measured at 3, 6, 12 and 52 weeks after randomisation. results: at 3 months follow-up, 70% of the intervention group and 62% of the control group reported improvement (rr 1.1; 95% ci 0.9 to 1.5). at 12 months follow-up, 79% of the intervention group and 56% of the control group reported improvement (rr 1.4; 95% ci 1.1; 1.8). no significant differences in secondary outcomes were found at short-term or long-term follow-up. conclusion: at 12 months follow-up, evidence was found that physiotherapy added to general practitioners' care is more effective in the treatment of patients with acute sciatica than general practitioners' care alone. abstract background: only little is known about the epidemiology of skin melanoma in the baltic states. objectives: the aim of this study was to provide insights into the epidemiology of skin melanoma in lithuania by analyzing population-based incidence and mortality (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) time trends and relative survival based on 3485 skin melanoma. methods: we calculated age-standardized incidence and mortality rates (cases per 100,000) using the european standard population and calculated period estimates of relative survival. for the period 1993-2002, 76% of all registered cases were checked by reviews of the medical charts. results: about 97% of the 2013 cases of the period 1993-2002 were reported to the cancer registry indicating a high quality of cancer registration of skin melanoma in lithuania. the incidence rates increased from 1978 (men: 1.7, women: 2.3) to 2002 (men: 5.0, women: 7.0). mortality rates increased from 1990 (men: 1.2, women: 1.7) to 2002 (men: 2.3, women: 2.2). relative 5-year relative survival rates among men were 10% lower than among women. the overall difference in survival is mainly due to a more favorable survival among women aged 60-74 years. conclusions: overall prognosis is less favorable among men most likely due to diagnoses at later stages. abstract background: only little is known about the epidemiology of skin melanoma in the baltic states. objectives: the aim of this study was to provide insights into the epidemiology of skin melanoma in lithuania by analyzing population-based incidence and mortality (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) (2001) (2002) time trends and relative survival based on 3485 skin melanoma. methods: we calculated age-standardized incidence and mortality rates (cases per 100,000) using the european standard population and calculated period estimates of relative survival. for the period 1993-2002, 76% of all registered cases were checked by reviews of the medical charts. results: about 97% of the 2013 cases of the period 1993-2002 were reported to the cancer registry indicating a high quality of cancer registration of skin melanoma in lithuania. the incidence rates increased from 1978 (men: 1.7, women: 2.3) to 2002 (men: 5.0, women: 7.0). mortality rates increased from 1990 (men: 1.2, women: 1.7) to 2002 (men: 2.3, women: 2.2). relative 5-year relative survival rates among men were 10% lower than among women. the overall difference in survival is mainly due to a more favorable survival among women aged 60-74 years. conclusions: overall prognosis is less favorable among men most likely due to diagnoses at later stages. abstract background: multifactorial diseases share many risk factors, genetic as well as environmental. to investigate the unresolved issues on etiology of and individual susceptibility to multifactorial diseases, the research focus must move from single determinantoutcome relations to modification of universal risk factors. objectives: the aim of the lifelines project is to study universal risk factors and their modifiers for multifactorial diseases. modifiers can be categorized into factors that determine the effect of the studied risk factor (eg gen-expression), those that determine the expression of the studied outcome (eg previous disease), and generic factors that determine the baseline risk for multifactorial diseases (eg age). design and methods: lifelines is carried out in a representative sample of 165.000 participants from the northern provinces of the netherlands. apart from questionnaires and clinical measurements, a biobank is constructed (blood, urine, dna). lifelines will employ a three-generation family design (proband design with relatives), which has statistical advantages, enables unique possibilities to study social characteristics, and offers practical benefits. conclusion: lifelines will contribute to the understanding of how disease-overriding risk factors are modified to influence the individual susceptibility to multifactorial diseases, not only at one stage of life but cumulatively over time: the lifeline. abstract background: obesity-related mortality is a major public health problem, but few studies have been conducted on severely obese individuals. objectives: we assessed long-term mortality in treatment-seeking, severely obese persons. design and methods: we enrolled 4837 persons in six centres for obesity treatment in four italian regions, with body mass index (bmi) at first visit => 40 kg/m2 and age => 18. after exclusion of duplicate registrations and persons with missing personal or clinical data, 4662 persons were followed up; as 164 (3.5%) could not be traced, 4498 persons (972 men, 3526 women) were retained for analysis. results: there were 484 (153 men, 331 women) deaths; the standardized mortality ratios (smrs) and 95% confidence intervals were 278 (236-326) among men and 210 (188-234) among women. mortality increased with increasing bmi, but the trend was not monotonic in men. lower smrs were observed among persons recruited more recently. excess mortality was inversely related to age attained at follow-up. conclusions and discussion: the harmful, long-term potential of severe obesity we documented confirms observations from studies carried out in different nutritional contexts. the decrease in mortality among most recently recruited persons may reflect better treatment of obesity and of its complications. abstract background: in finland, every cancer patient should have equal access to high quality care provided by the public sector. therefore no regional differences in survival should be observed. objectives: the aim of the study was to find any regional differences in survival, and to elaborate whether possible differences could be explained, e.g., by differences in distributions of prognostic factors. design and methods: the study material consisted of 159,000 patients diagnosed in 1993 to 2000 with cancer at one of the 15 major primary sites. the common closing date was 31 dec. 2001. finland was divided into five university hospital regions. stage, age at diagnosis and sex were used as prognostic factors. the relative survival rates for calendar period window, 1998-2001, were tabulated using period method and modelled. results: survival differences between the regions were not significant for most primary sites. for some sites, the differences disappeared in the modelling phase after adjusting for the prognostic factors. for a few of the primary sites (e.g., carcinoma of the ovary), regional differences remained after modelling. conclusion: we were able to highlight certain regional survival differences. ways to improve the equity of cancer care will be considered in collaboration with the oncological community. abstract background: the prevalence of cardiovascular disease (cvd) is extremely high in dialysis patients. disordered mineral metabolism, including hyperphosphatemia and hypercalcaemia, contributes to the development of cvd in these patients. objectives: to assess associations between plasma calcium, phosphorus and calciumphosphorus product levels and risk of cvd-related hospitalization in incident dialysis patients. design and methods: in necosad, a prospective multi-centre cohort study in the netherlands, we included 1629 consecutive patients new on haemodialysis or peritoneal dialysis between 1997 and 2004. risks were estimated using adjusted time-dependent cox regression modeling. results: mean age was 60±15 years, 61% was male, and 64% was treated with haemodialysis. cvd was the cause of hospitalization in 159 haemodialysis patients (26% of hospitalizations) and in 60 peritoneal dialysis patients (22%). most common cardiovascular morbidities were peripheral vascular disease and coronary artery disease in both patient groups. in haemodialysis patients risk of cvd-related hospitalization increased with elevated plasma calcium (hazard ratio: 1.8; 95% ci: 1.1 to 2.9) and calcium-phosphorus product levels (1.8; 95% ci: 1.2 to 2.7). in peritoneal dialysis patients, we observed similar effects that were not statistically significant. conclusion: tight control of plasma calcium and calcium-phosphorus product levels might prevent cvd-related hospitalizations in dialysis patients. abstract background: nurses are at health risk due to the nature of their work. analysis of morbidity among nurses was conducted to provide insight concerning the relationship between their occupational exposure and health response. methods: self reported medical history, was collected from an israeli female-nurses cohort (n = 395, 50+ years old) and their siblings (n = 180, age matched +/)7 years) using a structured questionnaire. to compare disease occurrence between the two groups we used chi-square tests and hazard ratio (hr) was calculated by cox-regression to account for age of onset. results: cardiovascular diseases were more frequent among the nurses compared to the controls: heart diseases 14.2% vs. 6.1, p = .0052 (hr=2.02, p = .0329); hypertension 43.8% vs. 23.3%, p<.0001 (hr=1.78, p = .0008). the frequency of hyperlipidemia was 40.3% among the nurses, and only 12.2% among the controls. (hr=3.31,p = .0001). for the following chronic diseases the occurrence were significantly higher among the nurses and the hrs were significantly higher than 1: thyroid, hr=2.21; liver, hr=10.37. total cancer and diabetes rates were similar in the groups (hr$1). conclusions: the results suggest an association between working as a nurse and the existence of risk factors for cardiovascular diseases. the specific related determinants of their work should be further evaluated. abstract background: early referral (er) to a nephrologist and arteriovenous fistulae as first vascular access (va) reduce negative outcomes in chronic dialysis patients (cdp). objectives: to evaluate the effect of nephrologist referral timing and type of the first va on mortality. design and methods: prospective cohort study of 2260 incident cdp notified to lazio dialysis registry (italy) in 2002-2004. late referral (lr) was a patient not referred to nephrologists within 6 months before starting dialysis. we dichotomized va as fistulae versus catheters. to estimate mortality hazard ratios (hr) a multivariate cox model was performed. results: we observed 22.3% lr subjects and 24.8% catheters as first va; proportion of catheters was 41.2% vs. 20.1% (p<0.001) for lr and er, respectively. we found a higher mortality hr for patient with a catheter as first va both for er (hr = 1.58; 95%c.i. = 1.22-2.06) and lr (hr = 2.56; 95%c.i. = 1.92-3.43); the interaction between referral and va was slight significant (p = 0.13). conclusions: the originality of our study was to investigate the influence of nephrologist referral timing and va on cdp mortality using a population registry, area-based: we found that a catheter as first va has an independent effect for mortality and modifies the effect of referral timing on this outcome. abstract patients with idiopathic venous thrombosis (vt) without known genetic risk factors but with a positive family history might carry yet unknown genetic defects. to determine the role of unknown hereditary factors in unexplained vt we calculated the risk associated with family history. in the multiple environmental and genetic assessment of risk factors for vt (mega) study, a large population-based case-control study, we collected blood samples and questionnaires on acquired risk factors (surgery, immobilisation, malignancy, pregnancy and hormone use) and family history of 2463 patients and 2926 control subjects. overall, positive family history was associated with an increased risk of vt (or (95% ci): 2.4 (2.0-2.9)), especially in the absence of acquired risk factors (or (95% ci): 2.8 (2.2-3.6) ). among participants without acquired factors but with a positive family history, prothrombotic defects (factor v leiden, prothrombin 20210a, protein c or protein s deficiency) were identified in 80 out of 236 (34%) patients compared to 22 out of 143 (15%) control subjects. after excluding participants with acquired or prothrombotic defects, family history persisted as a risk factor (or (95% ci): 2.4 (1.7-3.3)). in conclusion, a substantial fraction of thrombotic events is unexplained. family history remains an important predictor of vt. abstract background: alcohol may have a beneficial effect on coronary heart disease (chd) through elevation of high-density lipoprotein cholesterol (hdlc) or other alterations in blood lipids. data on alcohol consumption and blood lipids in coronary patients are scarce. objectives: to assess whether alcohol consumption and intake of specific types of beverages are associated with blood lipids in older subjects with chd. design and methods: blood lipids (total cholesterol, hdlc, ldl cholesterol, triglycerides) were measured in 1052 myocardial infarction patients aged 60-80 years (78% male), as part of the alpha omega trial. intake of alcoholic beverages, total ethanol and macro and micronutrients were assessed by food-frequency questionnaire. results: seventy percent of the subjects used lipidlowering medication. mean total cholesterol was 5.14 mmol/l and hdlc was 1.28 mmol/l. in men but not in women, ethanol intake was positively associated with hdlc (difference of 0.095 mmol/l for =15 g/d vs. 0 g/d, p = 0.022) after adjustment for diet, lifestyle, and chd risk factors. also, liquor consumption was weakly positively associated with hdlc in men (p = 0.042). conclusion and discussion: moderate alcohol consumption may elevate hdlc in (treated) myocardial infarction patients. this is probably due to ethanol and not to other beneficial substances in alcoholic beverages. session: posters session 3: july 1 2006 presentation: poster. abstract objective: early detection and diagnosis of silicosis among dust exposed workers is based mainly on the presence of rounded opacities on radiographs. it is thus important to examine how reliable the radiographic findings are in comparison to pathological findings. methods: a systematic literature search via medline was conducted. validity of silicosis detection and its influence on risk estimation in epidemiology was evaluated in a sensitivity analysis. results: 4 studies on comparison between radiographic and pathological findings of silicosis were identified. the sensitivity of radiographic diagnosis of silicosis (ilo 1/1) varied between 39% and 71%, and specifity between 60% and 99%. under the realistic assumption of silicosis prevalence between 2% and 8% in dust exposed workers, 23% to 56% of silicosis identified may be falsely diagnosed. the sensitivity analysis indicates that invalid diagnostics alone may lead to the finding of an increased risk of lung cancer among patients with silicosis. it may also lead to findings of 1% to 4% of radiographic silicosis even when there is no case of silicosis. however, the risk of silicosis could also be underestimated if the prevalence of silicosis exceeds 10%. conclusion: epidemiological studies based on patients with silicosis should be interpreted with caution. abstract introduction: epidemics of dengue occurring in various countries have stimulated investigators to seek innovative ways of improving current knowledge on the issue. objective: to identify the characteristics of spatial-temporal diffusion of the first dengue epidemic in a major brazilian city (salvador, bahia). methods: notified cases of dengue in salvador in 1995 were georeferenced according to census sector (cs) and by epidemiological week. kernel density estimation was used to identify the spatial diffusion pattern. results: of the 2006 cs in the city, cases of dengue were registered in 1400 (70%). spatial distribution showed that in 1995 practically the entire city had been affected by the virus, with a greater concentration of cases in the western region, comprising cs of high population density and predominantly horizontal dwellings. conclusion and discussion: the pattern found showed characteristics of a contagious diffusion process. it was possible to identify the epicenter of the epidemic from which propagation initiated. the speed of progression suggested that even if a rapid intervention was initiated to reduce the vector population, it would probably have little effect in reducing the incidence of the disease. this finding confirms the need for new studies to develop novel technology for prevention of this disease. abstract background: knowing the size of drug user hidden populations in a community is important to plan and evaluate public health interventions. objectives: the aim of this study was to estimate the prevalence of opiate and cocaine users in liguria region by using the covariate capture-recapture method applied to four data sources. methods: we performed a cross-sectional study in the resident population aged 15-54 years (780.995 people at 2001 census). during 2002 individual cases identified as opiate or cocaine primary users were flagged by four sources (drug dependence services, social service at prefectures, therapeutic communities, hospital discharges). poisson regression models were fitted, adjusting for dependence among sources and for heterogeneity in catchability among categories of the two examined covariates: age (15-29 and 30-54 years) and gender. results: the prevalence of opiate or cocaine users was 2,0% (95% c.i., 1,5 -2,8%) and 2,1% (95% c.i.= 0,6 -8,5%) respectively. conclusions: the estimated prevalence of opiate and cocaine users is consistent with that found in inner london: 1.6% and 1.9% respectively (hickman m.,2004; hope v.d., 2005) . the covariate capture-recapture method applied to four data sources allowed identifying a large cocaine-using population and resulted appropriate to determine drug user hidden populations. abstract background: in 2002-2004 we performed a population based diabetes screening programme. objectives: to investigate whether the yield of screening is influenced by gp and practice characteristics. methods: a questionnaire containing items on the gp (age, gender, employment, specialty in diabetes, applying insulin therapy) and the practice (setting, location, number of patients from ethnic minority groups, specific diabetes clinic, involvement of practice assistant and practice nurse in diabetes care, cooperation with a diabetes nurse) was sent to 106 general practitioners (gps) in 79 practices in the southwestern region of the netherlands. multiple linear regression analysis was performed. outcome measure was the ratio screen detected diabetic patients/known diabetic patients per practice (sdm/kdm). results: sdm/kdm was independently associated with higher age of the gp (regression coefficient 0.20; 95% confidence interval 0.07 to 0.34), urban location ()4.60; )6.41 to )2.78) and involvement of the practice assistant in diabetes care (2.27; 0.49 to 4.06) . conclusion: a lower yield of screening, assumably reflecting a lower prevalence of undiagnosed diabetes, was found in practices of younger gps and in urban practices. a lower yield was not associated with an appropriate practice organization nor with a specialty of the gp in diabetes. session: posters session 3: july 1 2006 presentation: poster. background: since few years increased incidence rates for childhood cancer were reported from industrialized countries. these findings were discussed controversial, because increases could be caused by changing of potential risk factors. objectives: the question is: are observed increasing rates due to actual changes in incidence rates or mainly caused by changes in registration practice or artefacts? methods: for europe, data from the accis project (pooled data from 32 european population-based cancer registries, performed at iarc, lyon; responsible: e. steliarova-foucher) (1978) (1979) (1980) (1981) (1982) (1983) (1984) (1985) (1986) (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) (1995) (1996) (1997) , and for germany, data of the german childhood cancer registry available from1980 onwards were used. results: accis data (based on 75,000 cases) show significantly increased data with an overall average annual percentage change of about 1 % and it is seen for mainly all diagnostic subgroups. for germany, increases are seen for neuroblastoma (due to screening programmes) and brain tumours (due to improved registration). for acute leukaemia the observed increase is explained by changes in classification. conclusion and discussion: the increased incidence for europe can only partly be explained by registration artefacts or improved diagnostic methods. the observed patterns suggest that an actual change exists. in germany, from 1980 till now the observed increased rates could be explained by artefacts. abstract suicide is the fourth most common cause of death among working age finns. among men socioeconomic status is strongly and inversely associated with suicide mortality, but little is known about socioeconomic differences in female suicide. we studied the direct and indirect effects of different socioeconomic indicators -education, occupation-based social class and income -on suicide among finnish women aged 25-64. also the effect of main economic activity was studied. we used individual level data from the 1990 census linked to the death register for the years 1991-2001. altogether over 14 million person-years were included and 2137 suicides were committed. age-adjusted rii conducted using poissonregression model was 1.72 (95% ci 1.47-2.03) for education, 1.97 (1.68-2.30) for social class and 2.13 (1.82-2.49) for income. however, almost all of the effect of education was mediated by social class. fifteen per cent of social class was explained by education and 40 per cent was mediated by income. the effect of income on suicide was mainly explained by economic activity. in conclusion, net of other indicators occupation-based social class is a strong determinant of socioeconomic differences in female suicide mortality, and actions aimed at preventing female suicide should target this group. abstract c-reactive protein levels (crp) in the range between 1 and 5 mg/ l independently predict the risk of future cardiovascular events. besides being a marker of atherosclerotic processes, high-normal crp levels may also be a sign of a more pronounced response to everyday inflammatory stimuli. the aim of our study is to assess the association between response to everyday stimuli and the risk of myocardial infarction. we will perform a population based case-control study including a total of 600 persons. cases (n = 100) are first myocardial infarction (mi) patients. controls (n = 100) are partners of the patients. offspring of the mi patients (n = 200) are included because disease activity and the use of medication by the mi patients may influence the inflammatory response. in order to assess the inflammatory response in mi patients the mean genetically determined inflammatory response in the offspring will be assessed and used as a measure for the inflammatory response in the mi patients. the offspring is free of disease and medication use. partners of the offspring (n = 200) are the controls for the offspring. influvac vaccine will be given to assess crp concentration, i.e. inflammatory response, before and after the vaccination. abstract background:. ischemic heart disease risk may be influenced by long-term exposure to electromagnetic fields (emf) in vulnerable subjects, but epidemiological data is inconsistent. objectives: we studied whether the long-term occupational exposure to emf is related to an increased myocardial infarction (mi) risk. design and methods: we conducted a prospective case-control study, which involved 1042 mi cases and 2341 controls. emf exposure in 48 cases and 63 controls was assessed subjectively. the effect of emf exposure on mi risk was estimated using multivariate logistic regression. results: after adjustment for age, smoking, blood pressure, body mass index and psychological stress the odds ratios for emf exposure <10 years was 2.74; 95 % ci 0.62-12.07, for emf exposure 10-20 years -2.08; 95 % ci 0.91-4.76 and for emf exposure >20 years -2.05; 95 % ci 1.24-3.39. conclusion: longterm occupational exposure to emf may increase the risk of mi. our crude estimates of emf exposure might have impact on excess risk because of nondifferential misclassification in assigning exposure. abstract background: it has been suggested that noise exposure is associated with ischemic heart disease risk, but epidemiological evidence is still limited. objectives: we studied whether road traffic noise exposure increases the risk of myocardial infarction (mi). design and methods: we conducted population-based prospective casecontrol study, which involved 1042 mi cases and 2341 controls. we measured traffic-related noise levels at the 117 electoral districts and linked these levels to residential addresses. we used multiple logistic regression to assess effect of noise exposure on mi risk. results: after adjustment for age, smoking, blood pressure, body mass index, and psychological stress the risk of mi was higher for the men exposed to 70-75 dba ( background: some studies have suggested that patients, depressed following acute myocardial infarction (mi), experience poorer survival. however, i) other studies show no significant association, when adjusted for recognized prognostic indicators and ii) some 'natural' responses to mi may be recorded in questionnaires as indicators of depression. method: depression was assessed in mi patients, by interview on two measures (gwb and sf36) 1-2 weeks after discharge, clinical data were abstracted from patients' medical records and vital status was assessed at 2-4 years. survivals of depressed, marginally depressed and normal patients were calculated by kaplan meier method and comparisons made by log rank and cox proportional hazard modelling. results: crude survival at 3 years in 2137 patients was higher for depressed and marginally depressed (13%) than for normals (10%), although not significantly. in multivariate analysis, four patient characteristics contributed significantly to survival: age (p<0.001), previous mi (<0.001), diabetes (<0.001) and sex (<0.05): other potential explanatory variables, including hypertension, infarct severity and depression were excluded by the model. abstract background: the low coronary heart disease (chd) incidence in southern europe could result in lower low density lipoprotein cholesterol oxidation (oxldl). objective. the aim of this study was to compare oxldl levels in chd patients from several european countries. methods: a cross-sectional multicenter study included 796 stable chd male subjects aged 25 to 74 years from northen (finland and sweden), central (germany), and southern europe (greece and spain). lipid peroxidation was determined by plasma oxldl. results: the score of adherence to mediterranean diet, antioxidant intake, alcohol intake, and lipid profile were significantly associated with oxldl. oxldl levels were higher in northern (60.9 u/l) than in centre (54.4 u/l) and southern populations (53.8 u/l), p = 0.01, in the adjusted models. the probability of northern europe to have the highest oxldl levels was 95.5%, and 98.9, % in logarithm of triglyceride-adjusted and fully adjusted models, respectively. the probability of this order to hold after adjustment for country was 78.4%. conclusion: a gradient on lipoperoxidation from north to central and southern europe is very likely to exist, and parallels that observed in the chd mortality, and incidence rates. southern populations may have more favourable environmental factors against oxidation than northern europe. abstract background: whereas socioeconomic status (ses) has been established as a risk factor for a range of adverse health outcomes, little literature exists examining socio-economic inequalities in the prevalence of congenital anomalies. objectives: to investigate the relationship between the ses and the risk of specific congenital anomalies, such as neural tube defects (ntd), oral clefts (oc) and down's syndrome (ds). design and methods: a total of 485 cases of congenital anomaly and 970 non-malformed control births were collected between 2002 and 2003 from the italian archive of the certificates of delivery care. as a measure of ses, cases and controls were given a value for a 4 level deprivation index. data were analysed using a logistic regression model. results: we found 31 cases of dtn, 287 cases of sof and 167 cases of ds. the risk of having a baby with ntd was significantly higher for women of low ses (or = 2.7;c.i.: 1.1-7. 3), as well as for oc (or = 1.7; c.i.:1.3-2.3). no significant evidence for ses variation was found for ds. conclusion and discussion: our data suggest risk factors linked to ses, such as nutritional factors, lifestyle, and access to health services, may play a role in the occurrence of some malformations. abstract background: general practitioners (gp) are well-regarded by their patients and have the opportunity to play an active role in providing cessation advice. objectives: this study was run to examine whether a public health programme based on a carefully adapted programme of continuing education can increase gps' use of cessation advice and increase the success rates of such advice. methods: the particular context due to a randomization of gp leads us to consider a cluster randomization trial. marginal models, estimated by gee and mixed generalized linear models are used for this type of design. results: the cessation rate is relatively high for all smokers enrolled in the trial (n = 1075): a total of 313 smokers were ex-smokers at one year (29.1%). patients who were seen by trained gps were more likely to successfully stop smoking than those seen by the control gps (31.3% vs 24.4%). motivated subjects, aged over 40, lower had anxiety scores, and confidence in their ability to stop smoking, were predictive of successful cessation at one year follow-up. conclusions: cluster analysis indicated that factors important to successful cessation in this population of smokers are factors commonly found to influence cessation. abstract background: and purpose conventional meta-analysis showed no difference in primary outcome for coronary bypass surgery without (offpump) or with (onpump) the heart-lung machine. secondary outcome parameters such as transfusion requirements or hospitalization days favored offpump surgery. combined individual data analysis improves precision of effect estimates and allows accurate subgroup analyses. objective: our objective is to obtain accurate effect estimates for stroke, myocardial infarction, or death, after offpump versus onpump surgery, by meta-analysis on pooled individual patient data. method and results: bibliographic database search identified eleven large trials (>100 patients). the obtained data for 9 trials data included 1933 patients. primary endpoint was composite (n = 117), secondary endpoints were death (n = 34), stroke (n = 24) and myocardial infarction (n = 75). hazard ratio for event-free survival after offpump vs onpump (95% ci) was: composite endpoint 0.94(0.66;1.36), death 1.12(0.57;2.20) myocardial infarction 1.07(0.68;1.69), stroke 0.84(0.38;1.88). after stratification for diabetes, gender and age the results slightly favored offpump for high-risk groups. hazard ratios remained not statistically significant. conclusion: no clinical or statistical significant differences were found for any endpoint or subgroup. offpump coronary bypass surgery is at least equal to conventional coronary bypass surgery. offpump surgery therefore is a justifiable option for cardiac surgeons for cardiac bypass surgery. in 1996-1997 an outbreak of pertussis occurred, mostly among vaccinated children. since then the incidence has remained high. therefore, a fifth dose with acellular booster vaccine for 4-yearolds was introduced in october 2001. the impact of this vaccination on the age-specific pertussis incidence was assessed. mandatory notifications and hospitalisations were analysed for 2002-2004 and compared with previous years. surveillance data show 'epidemic' increases of pertussis in 1996, 1999, 2001 and 2004 . the total incidence/100,000 in 2004 (59.8) was higher than in the previous epidemic year 2001 (50.0). nevertheless, the incidence of notifications and hospitalisations in the age-groups targeted for the booster-vaccination had decreased with respectively 72% and 86% compared to 2001. in contrast, the incidence in adolescents and adults almost doubled. unlike other countries that introduced a pre-school booster, the incidence of hospitalised infants <6 months also decreased (31% compared with 2001). as expected, the booster-vaccination for 4-year-olds has decreased the incidence among the target-population itself. more importantly, the decreased incidence among infants <6 months suggests that transmission from siblings to infants has also decreased. in further exploration of the impact of additional vaccination strategies (such as boostering of adolescents and/or adults) this effect should not be ignored. abstract acute respiratory infections (ari) are responsible for considerable morbidity in the community, but little is known about the presence of respiratory pathogens in asymptomatic individuals. we hypothesized that asymptomatic persons could have a sub clinical infection and so act as a source of transmission. between 2000 and 2003 all patients with ari who visited their sentinel general practitioner were reported to estimate the incidence of ari in dutch general practices. a random selection of them (cases) and an equal number of asymptomatic persons visiting for other complaints (controls) were included in a case-control study. nose/ throat swabs of participants were tested for a broad range of pathogens. the overall incidence of ari was 545 per 10,000 person years, suggesting that in the dutch population an estimated 900,000 persons annually consult their general practitioner for respiratory complaints. viruses were detected in 58% of the cases, ?-haemolytic streptococci group a in 11% and mixed infections in 3%. besides, pathogens were detected in approximately 30% of controls, particularly in the youngest age groups. this study confirms that most ari are viral and supports the reserved policy of prescribing antibiotics. furthermore, we demonstrated that asymptomatic persons might be a neglected source of transmission. abstract background: the baking and flour producing industries in the netherlands agreed on developing a health surveillance system to reduce the burden of and improve prognosis of occupational allergic diseases. objectives: to develop and validate a diagnostic model for sensitization to wheat and fungal amylase allergens, as triage instrument to detect occupational allergic diseases. design and methods: a diagnostic regression model was developed in 391 bakers from a cross-sectional study with ige serology to wheat and or amylase allergens as the reference standard. model calibration was assessed with hoshmer-lemeshow goodness of fit test; discriminative ability using area under receiver operating characteristic curve (auc); and internal validity using bootstrapping procedure. external validation was conducted in 200 other bakers. results: the diagnostic model consisted of four questionnaire items (history of asthma, rhinitis, conjunctivitis, and work-related allergic symptom) showed good calibration (p = 0.7) and discriminative ability (auc 0.73; 95% ci 0.67 to 0.79). internal validity was reasonable (correction factor of 0.85 and optimism corrected auc of 0.70). external validation showed good calibration (p = 0.9) and discriminative ability (auc 0.73; 95% ci 0.63 to 0.83). conclusions and discussion: this easily applicable diagnostic model for sensitization to flour and enzymes shows reasonable diagnostic accuracy and external validation. abstract background: in the netherlands the baking and flour producing industries (3,000 small bakeries, 80 industrial bakeries, and 50 flour manufactures) agreed to reduce the high rate (up to 30%) of occupational related allergic diseases. objectives: to conduct health surveillance for early detection of occupational allergic diseases by implementing a diagnostic model as triage instrument. design and methods: in the preparation phase, a validated diagnostic regression model for sensitization to wheat and or a-amylase allergens was converted into score chart for use in occupational health practice. two cut off points of the sum scores were selected based on diagnostic accuracy properties. in the first phase, a questionnaire including the diagnostic predictors from the model was applied in 10.000 bakers. surveillance simulation was done in 4194 bakers recently enrolled in the surveillance. workers with high questionnaire scores were referred for advanced medical examination. results: implementing the diagnostic questionnaire model yielded 59%, 23%, and 18% bakers in the low, intermediate, and high score groups. workers with high scores showed the highest percentage of occupational allergic diseases. conclusions and discussion: with proper cut off points for referral, the diagnostic model could serve as triage instrument in health surveillance to early detect occupational allergic diseases. abstract background: the prevalence of cardiovascular risk factors in spain is high but myocardial infarction incidence is lower than in other countries. objective: to determine the role of basic lipid profile on coronary heart disease (chd) incidence in spain. methods: a cohort of 5,732 healthy spanish individuals aged 35 to 74 years was followed for 5 years. the end-points were fatal and non-fatal myocardial infarction, and angina. results: the 180 participants who developed a coronary end-point were significantly older (62 vs 56), more often diabetic (30% vs 16%), smoker (39% vs 24%) and hypertensive (65% vs 44%) than the rest, and their average total and hdl-cholesterols (mg/dl) were: 233 vs 232 (ns) and 47 vs 54, (p<0.001), respectively. chd incidence among individuals with low hdl levels (<40 in men/<46 in women) was higher than in the rest: 11.7&aeyear-1 vs 7.3&aeyear-1 (p<0.05) in men, and 8.8&aeyear-1 vs 3.2&aeyear-1 (p<0.001) in women. hdl-cholesterol was the only lipid related variable significantly associated with chd: hazard ratio for 1 mg/dl increase was 0.98 (95% ci:0.96-0.99) in men, and 0.96 (95% ci:0.93-0.98) in women, after adjusting for classical risk factors. conclusion: hdl-cholesterol is the only classical lipid variable associated with chd incidence in spain. abstract background: it is widely recognized that health service interventions may reduce infant mortality/imr rate which usually occurs alongside with economic growth. however, there are reports showing that imr decrease under adverse economic and social conditions, indicating the presence of other unknown determinants. objective: this study aims to analyze temporal tendency of infant mortality in brazil during a recent period (1980 to 1998) of economic crisis. methods: temporal series study using data from the mortality information system, censuses (ibge) and epidemiological information (funasa). applying arima -autoregressive integrated moving average, it was described series parameters and, spearman correlation coefficients were used to evaluate the association between infant mortality coefficient and some determinants. results: the infant mortality showed a declining tendency ()59.3%) and strong correlation to the majority of the indicators analyzed. however, only correlation between infant mortality coefficient and total fecundity and birth rates differed significantly within decades. conclusions/discussion: fecundity variation was responsible to the persistence of mortality decline during the eighties. in the next period those indicators of life conditions, mostly health care, could be more important. abstract background: across european union (eu) member states, considerable variation exists in the structure and performance of surveillance systems for communicable disease prevention and control. objectives: the study aims to support the improvement of surveillance systems of communicable diseases in europe while using benchmarking for the comparison of national surveillance systems. design and methods: surveillance systems from england & wales, finland, france, germany, hungary and the netherlands were described and analysed. benchmarking processes were performed with selected criteria (e.g. case definitions, early warning systems). after the description of benchmarks, best practices were identified and described. results: the six countries have in general wellfunctioning communicable disease control and prevention systems. nevertheless, different strengths and weaknesses in could be identified. practical examples for best practice from various surveillance systems demonstrated fields for improvement. conclusion and discussion: benchmarking national surveillance systems is applicable as a new tool for the comparison of communicable disease control in europe. a gold standard of surveillance systems in various countries is very difficult to achieve because of heterogeneity (e.g. in disease burden, personal and financial resources). however, to improve the quality of surveillance systems across europe, it will be useful to benchmark surveillance systems of all eu member states. abstract background: therapeutic decisions in osteoarthritis (oa) often involve trade-offs between accepting risks of side effects and gaining pain relief. data about the risk levels patients are willing to accept are limited. objectives: to determine patients' maximum acceptable risk levels (marls) for different adverse effects from typical oa medications and to identify the predictors of these risk attitudes. design and methods: marls were measured with a probabilistic threshold technique for different levels of pain relief. baseline pain and risk levels were controlled for in a 2x2 factorial design. clinical and sociodemographic characteristics were assessed using a selfadministered questionnaire. results: for 196 subjects, marls distributions were skewed, and varied by level of pain relief, type of adverse effect, and baseline risk level. given a 0% baseline risk, for a 2-point (0-10 scale) pain benefit the mean (median) marls were 3.0% (0%) for heart attack/stroke; 5.7% (0%) for stomach bleed; 13.4% (4.5%) for hypertension; and 23.4% (10.5%) for dyspepsia. most clinical and sociodemographic factors were not associated with marls. conclusion: subjects were willing to trade substantial risks of side effects for pain benefits. this study provides new data on risk acceptability in oa patients that could be incorporated into practice guidelines for physicians. background: several independent studies have shown that single genetic determinants of platelet aggregation are associated with increased ihd risk. objectives: to study the effects of clustering prothombotic (genetic) determinants on the prediction of ihd risk. design and methods: the study is based on a cohort of 17,357 women, aged 49 to 70 years, who were followed from 1993 to 1999. during this period, there were 200 women with registered ihd (icd9 410-414) . a nested case cohort analysis was performed to study the relation of plasma levels vwf and fibrinogen, blood group genotype and prothrombotic mutations in the gene of a2b1, gpvi, gpib and aiibb3 to ihd. results: blood group ab, high vwf concentrations and high fibrinogen concentrations were associated with increased incidence of acute ihd. when the effects of blood group ab/o genotype, plasma levels fibrinogen and vwf were clustered with a score, there was a convincing relationship between a high prothrombotic score and increased incidence of acute ihd: the full-adjusted hr (95% confidence interval) was 3.2 (1.4-6.7) for women with the highest score when the lowest score was taken as reference. conclusions: clustering of prothrombotic markers is a major determinant of increased incidence of acute ihd. abstract background: studies have revealed heart rate variability (hrv) was a predictor of hypertension; however its 24h-recording has not been analysed with the 24-hour ambulatory blood pressure. objective: we studied the relationship between hrv and blood pressure. methods: hrv and blood pressure were measured by 24-hour ambulatory recordings, in randomly selected population without evidence of heart disease. cross-sectional analyses were conducted in 571 women and 372 men (mean age: 65.64±0.79). hrv values, measured by the standard deviation of rr intervals (sdnn), were compared after logarithmic transformation between the blood pressure levels (135/85 mmhg), using analysis of variance. stepwise multiple-regression was performed to assess on sdnn the cumulative effects of systolic and diastolic blood pressure, clinical obesity, fasting glycaemia, c-reative protein, treatments, smoking and alcohol consumption. results: sdnn was lower in hypertensive men and women (p<0.05), independently of drug treatments. after adjustment for factors associated with hypertension, sdnn was no more associated with hypertension, but with obesity, glycaemia and c-reative protein in both genders. sdnn was negatively associated with diastolic blood pressure in men (p = 0.03) in the multivariate approach. conclusion: whereas blood pressure levels were not related to the sdnn in the multivariate analysis, diastolic blood pressure contributed to sdnn in men. it has been proposed that n-3 fatty acids may protect against the development of allergic disease, while n-6 fatty acids may promote its development. in the piama (prevention and incidence of asthma and mite allergy) study we investigated associations between breast milk fatty acid composition of 158 allergic and 107 non allergic mothers and allergic disease (doctor diagnosed asthma, eczema or hay fever) in their children at the age of 1 year and at the age of 4 years. in children of allergic mothers prevalences of allergic disease at age 1 and at age 4 were relatively high if the breast milk they consumed had a low content (wt%) of n-3 fatty acids and particularly of n-3 long chain polyunsaturates (lcps), a low content of trans fatty acids, or a low ratio of n-3lcps/n-6lcps. the strongest predictor of allergic disease was a low breast milk n-3lcps/n-6lcps ratio (odds ratios (95% ci) of lowest vs highest tertile, adjusted for maternal age, parity and education: 2.80 (1.07 to 7.28) for allergic disease at age 1 and 2.86 (1.09 to 7.52) for allergic disease at age 4). in children of non allergic mothers no statistically significant associations were observed. abstract background/relevance: to find out about the appropriateness of using two vision related quality of life instruments to measure outcome of visually impaired elderly in a mono-and multidisciplinary rehabilitation centre. objective/design: to evaluate sensitivity of the vision quality of life core measure (vcm1) and the low vision quality of life questionnaire (lvqol) to measure changes in vision related quality of life in a non-randomised followup study. methods: visually impaired patients (n=319) recruited from 4 ophthalmology departments administered questionnaires at baseline (2000) (2001) (2002) (2003) , 3 months and 1 year after rehabilitation. person measures were analysed using rasch analyses for polytomous rating scales. results: paired sample t-tests for the vcm1 showed improvement at 3 months (p = 0.02; effect size = 0.12 and p = 0.003; effect size=0.15) for the monodisciplinary and the multidisciplinary groups respectively. at 1 year only the multidisciplinary group showed improvement on the vcm1 (p = 0.03; effect size = 0.12). on the lvqol, no significant improvement or deterioration was found for both groups. discussion: although, vcm1 showed improvement in vision related quality of life over time, the effect sizes appeared to be quite small. we conclude that both instruments lack sensitivity to measure changes. another explanation is that rehabilitation did not contribute to quality of life improvements. abstract background: the natural history of asthma severity is poorly known. objective: to investigate prognostic factors of asthma severity. methods: all current asthmatics identified in 1991/93 in the european community respiratory health survey were followed up and their severity was assessed in 2002 by using the global initiative for asthma categorization (n = 856). asthma severity was related to baseline/follow-up potential determinants by a multinomial logistic model, using intermittent asthmatics as reference category for relative risk ratios (rrr). results: patients in the lowest/highest levels of severity at baseline had an 80% likelihood of remaining in a similar level. severe persistent had a poorer fev1%predicted at baseline, higher ige levels (rrr=2.06;95% ci:1.38-3.06), higher prevalence of chronic cough/phlegm (4.90;2.18-11.02) than intermittent asthmatics. moderate persistent showed similar associations. mild persistent were similar to intermittent asthmatics, although the former showed a poorer control of symptoms than the latter. subjects in remission had a lower probability of an increase in bmi than current asthmatics (0.86;0.75-0.97). allergic rhinitis, smoking, respiratory infections in childhood were not associated with severity. conclusion: asthma severity is a relatively stable condition, at least for patients at the two extremes of the severity spectrum. high ige levels and persistent cough/phlegm are strong markers of moderate/severe asthma. abstract background: thyroid cancer (tc) has a low, yet growing, incidence in spain. ionizing radiation is the only well established risk factor. objectives: this study sought to depict the municipal distribution of tc mortality in spain and to argue about possible risk factors. design and methods: posterior distribution of relative risk for tc was computed using a single bayesian spatial model covering all municipal areas of spain (8, 077) . maps were plotted depicting standardised mortality ratios, smoothed municipal relative risk (rr) using the besag, york and mollie`model, and the distribution of the posterior probability that rr>1. results: from 1989 to 1998 a total of 2,538 tc deaths were registered in 1,041 municipalities. there was a higher risk of death in some areas of canary islands, galicia and asturias. abstract igf-i is an important growth factor associated with increased breast cancer risk in epidemiological and experimental studies. lycopene intake has been associated with decreased cancer risk. although some data indicate that lycopene can influence the igfsystem, this has never been extensively tested in humans. the purpose of this study is to evaluate the effects of a lycopene intervention on the circulating igf-system in women with an increased risk of breast cancer. we conducted a randomized, placebo-controlled cross-over intervention study on the effects of lycopene supplementation (30 mg/day, 2 months) in pre-menopausal women with 1) history of breast cancer (n = 29) and 2) high familial breast cancer risk (n = 47). drop-out rate was 21%. mean igf-i and igfbp-3 concentrations after placebo were 175.8±51.2 ng/ml and 2.54±0.42 mg/ml respectively. lycopene supplementation did not significantly alter serum total igf-i (mean lycopene effect: )1.4 ng/ml; 95% ci: )8. 2-5.4 ) and igfbp-3 ()0.002 mg/ml; )0.052-0.056) concentrations. dietary energy and macronutrient intake, physical activity, body weight, and serum lycopene concentrations were assessed, and are currently under evaluation. in conclusion, this study shows that 2 months lycopene supplementation has no effect on serum igf-system components in a high risk population for breast cancer. abstract introduction: patients who experience burden during diagnostic tests may disrupt these tests. the aim was to describe the perception of melanoma patients with lymph node metastases of the diagnostic tests. methods: patients were requested to complete a self-administrated questionnaire. experienced levels of embarrassment, discomfort and anxiety were calculated, as well as (total) scores for each burden. the non-parametric friedman test for related samples was used to see if there was a difference in burden. results: the questionnaire was completed by 34 patients; response rate was 87%. overall satisfaction was high. in total 26% felt embarrassment, 27% discomfort and 39% anxiety. overall, 31% felt some kind of burden. there was no difference in anxiety between the three tests. however, patients experienced more embarrassment and discomfort during the pet (positron emission tomography) scan (p = 0.027 and p = 0.002). conclusion: overall levels of burden were low. however, patients experienced more embarrassment and discomfort during the pet scan, possibly as a result of lying immobile for a long time. the accuracy, costs and patients upstaged will probably be the most important to determine the additional value of fdg-pet and ct, but it is reassuring to know that only few patients experience severe or extreme burden. abstract gastric cancer (gc) is the second most frequent cause of cancer death in lithuania. some intercultural aspects of diet that is related to the outcome could be the risk factors of the disease. the objective of the study was to assess an associations between risk of gc and dietary factors. a case-control study included 379 cases with diagnose of gc and 1137 controls that were cancer and gastric diseases free. a questionnaire used to collect information on possible risk factors. the odds ratios (or) and 95% confidence intervals (ci) estimated by the conditional logistic regression model. after controlling for possible confounders that were associated with gc, use of salted meat (or = 2.21; 95% ci = 1.43-3.42; >1-2 times/week vs. almost never) smoked meat (or = 1.79; 95% ci = 1.23-2.60; >1-4 times/week vs. less), smoked fish (or = 1.70; 95% ci = 1.13-2.53; >1-2 times/week vs. less) was associated with increased risk of gc. higher risk of gc was associated with frequent use of butter, eggs and noodles. while frequent consumption of carrots, cabbages, broccolis, tomatoes, garlic, beans decreased the risk significantly. the data support a role of salt processed food and some animal foods in increasing the risk of gc and plant foods in reducing the risk of the disease. abstract background: standards for the evaluation of measurement properties of health status measurement instruments (hsmi), including explicit criteria for what constitutes good measurement properties, are lacking. nevertheless, many systematic reviews have been performed to compare and select hsmi, using different criteria to judge the measurement properties. objectives: (1) to determine which measurement properties are reported in systematic reviews of hsmi and how these properties are defined, (2) which standards are used to define how measurement properties should be assessed, and (3) which criteria are defined for good measurement properties. methods: a systematic literature search was performed in pubmed, embase and psychlit. articles were included if they met the following inclusion criteria: (1) systematic review, (2) hsmi were reviewed, and (3) the purpose of the review is to identify all measurement instruments assessing (an aspect of) health status and to report on the clinimetric properties of these hsmi. two independent reviewers selected the articles. a standardised data-extraction form was used. preliminary results: 103 systematic reviews were included. conclusions: large variability in standards and criteria used for evaluating measurement properties was found. this review can serve as basis for reaching consensus on standards and criteria for evaluating measurement properties of hsmi. abstract residential exposure to nitrogen dioxide is an air quality indicator and could be very useful to assess the effects of air pollution on respiratory diseases. the present study aims at developing a model to predict residential exposure to no2, combining data from questionnaires and from local monitoring stations (ms). in the italian centres of verona, torino and pavia, participating in ecrhs-ii, no2 concentrations were measured using passive samplers (ps-no2) placed outside the kitchen of 340 subjects for 14 days. simultaneously, average no2 concentrations were collected from all the mss of the three centres (ms-no2). a multiple regression model was set up with ps-no2 concentrations as response variable and questionnaire information and ms-no2 concentrations as predictors. the model minimizing the root mean square error (rmse), obtained from a ten fold cross validation, was selected. the model with the best predictive ability (rmse=12.20), had as predictors: ms-no2 concentrations, season of the survey, centre, type of building, self-reported intensity of heavy vehicle traffic. the correlation coefficient between predictive and observed values was 0.79 (95% ci: 0.75-0.83). in conclusion, this preliminary analysis suggests that the combination of questionnaire information and routine data from the mss could be useful to predict the residential exposure to no2. abstract background: currently only 18% of dutch mothers comply with the who recommendation to give exclusive breastfeeding for at least six months. therefore, the dutch authorities consider policies on breastfeeding. objectives: quantification of the health effect of several breastfeeding policies. methods: a systematic literature search of published epidemiological studies conducted in the general 'western' population. based on this overview a model is developed. the model simulates incidences of 11 diseases of mother and child depending on the duration that mothers breastfeed. each policy corresponds to a distribution in the duration of breastfeeding. the health effects of each policy are compared to the present situation. results: breastfeeding has beneficial health effects on both the short and the long term for mother and child. the longer the duration of breastfeeding, the larger is the effect. most public health gain is achieved by introducing breastfeeding to all newborns rather than through a policy focusing just on extending the lactation period of women already breastfeeding. conclusion: breastfeeding has positive health effects. policy should focus preferentially on encouraging all mothers to start with breastfeeding. abstract background: constant increase of international trade and travel activities has risen the significance of pandemic infectious diseases worldwide. the 2002/2003 sars outbreak rapidly spread from china to 28 countries, from which 9 were located in europe. in order to control and prevent pandemic infections in europe, systematic and effective public health preparation by every member state is essential. method: supported by the european commission, surveys focusing on national sars (september 2003) and influenza (october 2005) preparedness were accomplished. a descriptive analysis was undertaken to identify differences in european infectious disease policies. results: guidelines and guidance for disease management were well established in most european countries. however, the application of control measures, like e.g. measures for mass gatherings or public information policies, had varied among member states. discussion: the results show that european countries are aware of preparing for pandemic infections. yet, the effectiveness of certain control measures is analysed insufficiently. further research and detailed knowledge about factors influencing international spread of diseases is required. 'hazard analysis of critical control points' (haccp) will be applied to evaluate national health response in order to provide comprehensive data for recommendations to european pandemic preparedness. abstract background: influenza is still an important problem for public health. knowing its space-time evolution is of special interest in order to carry out prevention plans. objectives: to analyze the geographical diffusion of the epidemic wave in extremadura. methods: the influenza incidence absolute rates in every town have been calculated, according to the registered cases per week in the compulsory disease declaration system. continuous maps have been represented using a geographical interpolation method (inverse distance weighting (idw) was applied with weighting exponents of 2). results: the 2004/05 season began in the 40th week of 2004, with a small influenza incidence. there have been concrete cases in those towns until the 46th week. punctual areas diffusion in the north and southwest of the region between the 46th and the 51st weeks. the highest incidence appeared between the 52nd week of 2004 and the 3rd of 2005. influenza cases started to decrease in the northwest and north of the region from the 3rd week of 2005, till the 10th week, when most of the cases were found in the southwest. conclusion: there is a space-time diffusion of influenza, due to the higher population density. we propose to analyze these data combining temperature information. abstract background: acute lower respiratory tract infection (lrti) can cause various complications leading to morbidity and mortality notably among elderly patients. antibiotics are often given to prevent complications. to minimise costs and bacterial resistance, antibiotics are only recommended in case of pneumonia or in patients at serious risk for serious complications. objective: we assessed the course of illness of lrtis among dutch elderly primary care patients and assessed whether gps were inclined to prescribe antibiotics more readily to patients at risk for complications. methods: we retrospectively analysed medical data from 3,166 episodes of lrti among patients? 65 years of age presenting in primary care to describe the course of illness. the relation between prescriptions of antibiotics and patients with risk factors for a complicated course was assessed by means of multivariate logistic regression. results: in episodes of acute bronchitis antibiotics were more readily prescribed to patients aged 90 years or older. in exacerbations of copd or asthma gps favoured antibiotics in male patients and when diabetes, neurological disease or dementia was present. conclusion: gp's do not take all high risk conditions into account when prescribing antibiotics to patients with lrti despite recommendations of national guidelines. abstract background: the putative association between antidepressant treatment and increased suicidal behaviour has been under debate. objectives: to estimate the risk of suicide, attempted suicide, and overall mortality during antidepressant treatments. design and methods: study cohort consisted all subjects without non-affective psychosis, hospitalized due to a suicide attempt during the years 1997 -2003 , followed up by using nationwide registers. main outcome were completed suicides, attempted suicides, and mortality. main explanatory variable was antidepressant usage. results: 470 suicides, 4411 suicide attempts and 1263 deaths were observed. when the effect of background variables was taken into account, the risk of suicide attempts was increased markedly during antidepressant treatment (rr for selective serotonin reuptake inhibitors or ssri 1.34, 1.19-1.50) compared with no antidepressants. however, the risk of completed suicides was not increased. a lower mortality was observed during ssri use (rr 0.67, 0.54-0.84), which was mainly attributable to decrease in cardiovascular deaths. conclusion and discussion: in this suicidal high risk cohort the use of any antidepressant is associated with an increased risk of suicide attempts, but not with the increased risk of completed suicide. antidepressants and, especially, ssri use is associated with a substantial decrease in cardiovascular deaths and overall mortality. abstract background: the quattro study is a rct on the effectiveness of intensified preventive care in primary health care centres in deprived neighbourhoods. additional qualitative research on the execution of interventions in primary care was considered necessary for the explanation of differences in effectiveness. objectives: our question was: can we understand rct outcomes better with qualitative research? design and methods: an ethnographic design was used. in their daily work we observed 2 researchers for 8 months 2 days a week, and 4 practice nurses for 5 days each. two other practice nurses were interviewed. all transcribed observations were analysed thematically. results: from the rct showed differences in effectiveness among the centres and that intensified preventive care provided no additional effect compared to structural physical measurements. ethnographic results show that these differences are due to variations in execution of the intervention among the centres. conclusion: in conclusion ethnographic analysis showed that differences in execution of intervention lead to differences in rct outcomes. the rct conclusion 'no additional effect' is problematic. discussion as variations in primary care influence a rcts' execution they create methodological problems for research. to what extent can additional qualitative research improve rct research. abstract background: acute myocardial infarction is the most important cause of morbidity from ischemic heart disease (ihd) and is the leading cause of death in the western world. objectives: to assess the benefits and harms of 'dan shen' compound for acute myocardial infarction. methods: we searched the cochrane controlled trials register on the cochrane library, medline, embase, chinese biomedical database and the chinese cochrane centre controlled trials register. we included randomized controlled studies lasting at least 7 days. main results: eleven studies with 1196 participants in total were included. seven studies compared the mortality in routine treatment plus 'dan shen' compound and single routine treatment. one trial compared the arrhythmia in routine treatment plus 'dan shen' compound injection and single routine treatment. two trials compared the revascularization in routine treatment plus 'dan shen' compound injection and single routine treatment. conclusions: evidence is insufficient to recommend the routine use of 'dan shen' compound because of the small number of included studies and their low quality. no well designed randomized controlled trials with adequate power to provide a more definitive answer have been conducted. in addition, the safety of 'dan shen' compound is unproven, though adverse events were rarely reported. abstract antimicrobial resistance is emerging. to identify the scope of this threat and to be able to take proper actions and evaluate these, monitoring is essential. the remit of earss is to maintain a comprehensive surveillance system that provides comparable and validated data on the prevalence and spread of major invasive bacteria with clinically and epidemiologically relevant antimicrobial resistance in europe. since 2000, earss collects routine antimicrobial susceptibility test (ast) results of invasive isolates of five indicator bacteria, tested according to standard protocols. in 2004, ast results for 80,000 isolates were provided by 800 laboratories, serving 1200 hospitals, covering 100 million inhabitants in 30 countries. through a biannual questionnaire denominator information was collected. the quality of ast results of laboratories was evaluated by the yearly external quality assessment. currently, earss includes all member and candidate states (29) of the european union, plus israel, bosnia, bulgaria and turkey. participating hospitals treat a wide range of patients and laboratory results are of sufficient validity. earss identified antimicrobial resistance time trends and found a steady increase for most pathogen-compound combinations. in conclusion, earss is a comprehensive system with sufficient quality to show that antimicrobial resistance is increasing in europe and threatens health-care outcomes. abstract introduction: since chloroform has been detected in drinking waters, the number of studies has increased to identify the presence of trihalomethanes (thms) in drinking waters, as well as to establish the possible effects they may have population health. objectives: to determine thms levels in the water distributing network in the city of valencia. design and methods: over a one-year period, 16 points of the drinking water distributing netowrk have undergone sampling at 1 week intervals. the concentration of these pollutants was determined by gas chromatography. results: our results showed greater concentrations of the species substituted by chlorine and bromine atoms (dichlorobromomethane and dibromochloromethane) in the range of 10-20z lg/l for both, 0-10 lg/l for trichloromethane and between 0-5 lg/l for tribromomethane. an increase in thms concentration was observed in those points near the sea, although they did not exceed the legal limit of 100lg/l. conclusion: we established two areas of concentration of these species in water: high and average, according to their proximity to the sea. abstract background: childhood cancer survivors are known to be at increased risk for second malignancies. objectives: we studied longterm risk of second malignancy in 5-year survivors, according to therapy and follow-up interval. methods: the risk of second malignancies was assessed in 1368 5-year survivors of childhood cancer treated in the emma children's hospital amc in amsterdam and compared with incidence in the general population of the netherlands. complete follow-up till at least january 2001 was obtained for 91.9% of the patients. the median follow-up time was 16.8. results: sixty second malignancies were observed against 5.4 expected, yielding a standardized incidence ratio (sir) of ). the absolute excess risk (aer) was 3.2 per 1,000 persons per year. the sir appeared to stabilize after 15 years of follow-up, but the absolute excess risk increased with longer follow-up (aer follow-up > = 25 years of 8.24). patients who were treated with radiotherapy experienced the greatest increase of risk. conclusions: in view of the quickly increasing background rate of cancer with ageing of the cohort, it is concerning that even after more than 20 years of follow-up the sir is still increased, as is the absolute excess risk. the chek2*1100delc germline variant has been shown to increase susceptibility for breast cancer and could have an impact on breast cancer survival. this study aimed to determine the proportion of chek2*1100delc germline mutation carriers, and breast cancer survival and tumor characteristics, compared to non-carriers in an unselected (for family history) breast cancer cohort. women with invasive mammary carcinoma, aged <50 years and diagnosed in several dutch hospitals between 1973 and 1995, were included. for all patients, paraffin embedded tissue blocks were collected for dna isolation (normal tissue), and subsequent mutation analyses, and tumor revision. in 1479 breast cancer patients, 54 (3.7%) chek2*1100delc carriers were detected. chek2*1100delc tumors characteristics, treatment and patient stage did not differ from those of non-carriers. chek2*1100delc carriers had 2 times increased risk of developing a second breast cancer compared to non-carriers. with a mean follow up of 10 years, chek2*1100delc carriers had worse recurrence free and breast cancer specific survival than non-carriers. in conclusion, this study indicates a worse breast cancer outcome in chek2*1100-delc carriers compared to non-carriers. the extension of the presence of the chek2*1100delc germline mutation warrants research into therapy interaction and possibly into screening of premenopausal breast cancer patients. abstract background: for primary or secondary prevention (e.g. myocardial infarction) hormone therapy (ht) is no longer recommended in postmenopausal women. however, physicians commonly prescribe ht to climacteric women as a treatment of hot flashes/night sweats. objective: to assess efficacy and adverse reactions of ht in climacteric women with hot flashes (including night sweats). methods: for our systematic review (sr), we searched databases (medline, embase, cochrane) for randomized controlled trials, other srs and meta-analyses, published 1999 to 2004. the quality of the studies was assessed using checklists corresponding to the study type. results: we identified 18 studies of good/excellent quality. they included predominantly caucasian women and lasted 3-12 months. in all studies, ht showed a reduction of 75-95% in the number of hot flashes, which was significantly better than placebo. most common adverse events of ht were uterine bleeding and breast pain/tenderness. cardiovascular diseases and neoplasms were reported only sporadically. conclusions: ht is highly effective in treating hot flashes in climacteric women. however, to assess serious adverse events longer studies (including also non-caucasian women) are needed, as there are only sparse data available. abstract igf-i is an important growth factor, and has been associated with increased colorectal cancer risk in both prospective epidemiological and experimental studies. however, it is largely unknown which lifestyle factors are related to circulating levels of the igf-system. studies investigating the effect of isoflavones on the igf-system have thus far been conflicting. the purpose of this study was to evaluate the effects of isoflavones on the circulating igf-system in men with high colorectal cancer risk. we conducted a randomized, placebo-controlled, cross-over study on the effect of a 2-month isoflavone supplementation (80 mg/day) on igf levels in 40 men with a family history of colorectal cancer or a personal history of colorectal adenomas. dropout rate was 5%, and all but 3 men were more than 80% compliant. isoflavones supplementation did not significantly alter serum total igf-i ()1.6%; 95%ci: )9.3 -6.1) and igf binding protein 3 (+0.7%, 95%ci: )3.5 -4.8) concentrations. other covariables, e.g. dietary energy and macronutrient intake, physical activity, and body weight, are currently under evaluation. in conclusion, this study shows that a 2-month isoflavone supplementation has no effect on serum igf-system components in men with high colorectal cancer risk. abstract background/objective: eurociss-european cardiovascular indicators surveillance set project, funded under the health monitoring programme of european commission, aims developing health indicators and recommendations for monitoring cardiovascular diseases (cvd). methods: prioritise cvd according to their importance in public health; identify morbidity and mortality indicators; develop data collection and harmonizing recommendations; describe data collection, validation procedures and discuss their comparability. population (geographical area, age, gender), methods (case definition, icd codes), procedures (record linkage, validation), morbidity indicators (attack rate, incidence, case fatality) collected by questionnaire. results: the main outcome was the inventory of acute myocardial infarction (ami) populationbased registers in the 18 european partner countries: 8 countries have no register, 10 regional, 4 of which also national. registers differ for: icd codes (only ami or also acute and subacute ischemic forms), ages (35-64, 35-74, all) , record linkage (probabilistic, personal identification number), calendar years, validation (monica, esc/acc diagnostic criteria). differences make morbidity indicators difficult to compare. conclusion: new diagnostic criteria led to a more exhaustive definition of myocardial necrosis as acute coronary syndrome (acs). given the high burden of ami/acs, efforts are needed to implement population-based registers in all countries. application of recommended indicators, validated through standardized methodology, will provide reliable, valid and comparable data. abstract objective: the objective of this paper was to compare and discuss the use of odd ratios and prevalence ratios using real data with complex sampling design. method: we carried out a cross-sectional study using data obtained from a two-stage stratified cluster sample from a study conducted in 2001-2002 (n = 1,958) . odds ratios and prevalence ratios were obtained by unconditional logistic regression and poisson regression, respectively, for later comparison using the stata statistical package (v. 7.0). confidence intervals and design effects were considered in the evaluation of the precision of estimates. two outcomes of a cross-sectional study with different prevalence were evaluates: vaccination against influenza (66.1%) and self-referred lung disease (6.9%). results: in the high-prevalence scenario, using prevalence ratios the estimates were more conservative and we found narrower confidence intervals. in the low-prevalence scenario, we found no important differences between the estimates and standard errors obtained using the two techniques. discussion: however, it is the researcher's task to choose which technique and measure to use for each set of data, since this choice must remain within the scope of epidemiology. abstract background: in italy coronary heart disease chd mortality has been falling since the 1970s. objective: to examine how much of the fall between 1980 and 2000 could be attributed to trends in risk factors, medical and surgical treatments. methods: a validated model was used to combine and analyse data on uptake and effectiveness of cardiological treatments and risk factor trends. published trials, meta-analyses, official statistics, longitudinal studies, surveys are main data sources. results: chd mortality fell by 41% in men and 43% in women aged 25-84; 42,930 fewer deaths in 2000. approximately half mortality fall was attributed to treatments in patients and half to population changes in risk factors: in men, mainly improvements in cholesterol (39%) and smoking (33%) rather than blood pressure (6%). in women 1/3 mortality fall attributable to improvements in cholesterol (31%) and blood pressure (5%); adverse trends in smoking ()14%). adverse trends also in bmi ()2% in both genders) and diabetes ()4% in men; )0.5% in women). conclusion: half chd mortality fall was attributable to risk factors reductions, principally cholesterol in men and women and smoking in men; in women rising smoking rates generated substantial additional deaths. a comprehensive strategy promoting primary prevention is needed. objective: to investigate the efficacy of ni in the post exposure prophylaxis (pep), i.e. in persons who had contact with an influenza case. design and methods: we conducted a systematic electronic data base review for the period between 1999 and 2004. studies were selected and graded by two independent reviewers. the proportion of influenza-positive patients was chosen as primary outcome. for all analyses fixed effect models were used. weighted relative risks (rr) and 95% confidence intervals (ci) were calculated on an intention-to-treat basis. results: 5 randomized controlled trials (n=3,663) were included in the analysis. zanamivir and oseltamivir were effective against an infection with influenza (rr=0.23, 95% ci 0.15-0.36 and rr=0.20, 95% ci 0.11-0.34, respectively). prophylactic efficacy was comparable in the subgroup of persons who had contact with an index case with lab-confirmed influenza (4 studies, all ni, rr=0.18, 95% ci 0.12-0.28). conclusions: the available evidence suggests that ni are effective in the pep of influenza. discussion: results have to be interpreted with caution when transferred into general medical practice because study populations mainly included young and healthy adults without chronic diseases. abstract an important risk factor of breast cancer, mammographic breast density (mbd) is inversely associated with reproductive factors (age at first childbirth, and lactating). as pregnancy and lactating are highly correlated, whether this decline is induced by pregnancy or lactating is still unclear. we hypothesize that lactation reduces mbd independent of age at first pregnancy and parity. a study was done on 4051 women in the third sub-cohort of the dom project who had complete data regarding lactating, dy, had a child but varied by duration of lactating. multiple logistic regression analysis was done using dy (yes/ no) as outcome variable. explanatory variables added into the model were age, bmi, parity and age at first childbirth. a significant univariate relation was seen between lactating of the first child and dy. or 0.83 (ci 95% 0.73; 0.94). adjusted for explanatory variables, the or changed to 0.89 (ci 95% 0.73; 1.08). lactating seems to contribute independently to the reduction of mbd over and above pregnancy itself. given the limitations of the dichotomous dy ratio scores, additional studies will address which part; either glandular mass or fat tissue is responsible for the observed relation which will be measured from mammograms to be digitized. abstract background: alcohol consumption is common, but little is known about whether drinking patterns vary across geographic regions. objectives: to examine potential disparities in alcohol consumption across census regions and urban, suburban, and rural areas of the united states. design and methods: the data source was the national epidemiologic survey on alcohol and related conditions, an in-person interview of approximately 43,000 adults. the prevalence of abstinence and, among drinkers, the prevalences of heavy and daily drinking were calculated by census region and metropolitan status. multivariate logistic regression analyses were conducted to test for differences in abstinence and per drinker consumption after controlling for confounders. results: the odds of abstinence, heavy, and daily drinking varied widely across geographic areas. additional analyses stratified by census region revealed that rural residents in the south and northeast as well as urban residents in the northeast had higher odds of abstinence. rural residents in the midwest had higher odds of heavy drinking. conclusion and discussion: heavy alcohol consumption is of particular concern among drinkers living in the rural areas of the united states, particularly the rural midwest. other nations should consider testing for similar differences as they implement policies to promote safe alcohol consumption. abstract background: long-term exposure to particulate air pollution (pm) has been suggested to accelerate atherogenesis. objective: we examined the relationship between long-term exposure to traffic emissions and the degree of coronary artery calcification (cac), a measure of atherosclerosis. methods: in a population based, crosssectional study, distances between participants' home addresses and major roads were calculated with a geographic information system. annual mean pm2.5-exposure at the residence was derived from a small scale geostatistical model. cac, assessed by electronbeam computer tomography, was modelled with linear regression by proximity to major roads, controlling for background pm2.5air pollution and individual level risk factors. results: of 4424 participants 499 lived within 150 m of a major road. background-pm2.5 ranged from 16.1 to 26.8 lg/m3 (mean 22.8). mean cacvalues were strongly dependent on age, sex and smoking status. reducing the distance to major roads by 50% leads to increases in cac by 10.1% (95%ci 0.6-20.5%) in the unadjusted model and 5,5% (95%ci )2. 2-13.8 ) in the adjusted model. stronger effects (adjusted model) were seen in men (7,4%, 95%ci )3.9-20.1) and male non-smokers (10,5%, 95%ci )3.2-13.0). conclusions: this study provides epidemiologic evidence that long-term exposure to traffic emissions is an important risk factor for coronary calcification. abstract background: this polymorphism has been associated risk factor levels and in one study with a reduced risk of acute myocardial infarction (ami). yet, the risk relation has not been confirmed. objectives: we investigated the role of this polymorphism on occurrence of ami, coronary heart disease (chd) and stroke in healthy dutch women. design and methods: a case-cohort study in a prospective cohort of 15236 initially healthy dutch from1993 until january 1st 2000. results: we applied a cox proportional hazards model with an estimation procedure adapted for case-cohort designs. a lower ami (n=71) risk was found among carriers of the ala allele (n=364) compared with those with the more common pro12pro genotype (hazard ratio=0.51; 95% ci, 0.26 to 1.00). no relation was found for chd (n=211;hr 0.82; 95% ci, 0.58-1.17) and for stroke (n=74;hr 1.41; 95% ci, 0.85-2.33). in our data little evidence was found for a relation between pparg2 and risk factors. conclusion and discussion: this study shows the pro12ala polymorphism in pparg2 gene is modestly related to a reduced risk of ami in our study. no statistically significant relation was found for chd and stroke. abstract background: pseudo cluster randomization was used in a services evaluation trial because individual randomization risked contamination and cluster randomization risked selection bias due to expected treatment arm preferences of recruiting general practitioners (gps). gps were randomized in two groups. depending on this randomization, participants were randomized in majority to one study arm: intervention:control/80:20 or intervention:control/ 20:80. objectives: to evaluate internal validity of pseudo cluster randomization. have gps treatment arm preferences? what is the effect on allocation concealment and selection bias? design and methods: we compared the baseline characteristics of participants to study selection bias. using a questionnaire, gps indicated their treatment arm preferences on a visual analogue scale (vas) and the allocation proportions they believed were used to allocate their patients over treatment arms. results: gps preferred allocation to the intervention (vas 14.5 (sd 15.6); 0-100: 0 indicates strongly favoring the intervention arm). after recruitment 67% of gps estimated a randomization ratio of 50:50 was used. the participants showed no relevant differences at baseline. conclusion and discussion: gps profoundly preferred allocation to the intervention group. few indications of allocation disclosure or selection bias were found in the dutch easycare trial. pseudo cluster randomization proofs to be a valid randomization method. abstract background: epidemiological studies rely on self-reporting to acquire data on participants, although such data are often limited in reliability. the aim here is to assess nuclear magnetic resonance (nmr) based metabonomics for evaluation of self-reported data on paracetamol use. method: four in-depth 24-hour dietary recalls and two timed 24-hour urine collections were obtained for each participant in the intermap study. a 600 mhz 1h nmr spectrum was acquired for each urine specimen (n = 9,943). training and test sets involved two strata, i.e., paracetamol metabolites yes or no in the urine spectra, selected from all 17 population samples by a principal component analysis model. the partial least squares-discriminant analysis (pls-da) model based on a training set of 110 samples was validated by test set (n = 620). the model correctly predicted stratum for 575 of 587 samples (98%) after removal of 33 outliers not fitting the model, sensitivity 95.4%, specificity 100%. this model was used to predict paracetamol status in all intermap specimens. it identified 384 participants (8.2%) who underreported analgesic use, of whom 63 underreported analgesic use in both clinical visits. conclusion: nmr-based metabonomics can be used as a tool to enhance reliability of self-reported data. abstract background: in patients with asthma, the decline in forced expiratory volume in one second (fev1) is accelerated compared with non-asthmatics. objective: to investigate long-term prognostic factors of fev1 change in asthmatics from the general population. methods: a cohort of 667 asthmatics (20-44 years-old) was identified in the frame of the european community respiratory health survey (1991/93), and followed up in 1998/2002. spirometry was performed on both occasions. the annual fev1 decrease (?fev1) was analysed by multi-level regression models, according to age, sex, height, bmi, occupation, familiarity of asthma, hospitalization for asthma (baseline factors); cumulative time of inhaled corticosteroid (ics) use and annual weight gain during the follow-up; lifetime pack-years smoked. results: when adjusting for all covariates, ics use for >2 years significantly reduced ?fev1, with respect to non-users, of 10.4(95%ci: 1.6-19.2) ml/year. ?fev1 was 9.9(0.5-19.4) ml/year lower in women than in men. it increased by 0.7(0.2-1.2) ml/year for every additional year in patient age and by 7.2(3.3-11.0) ml/year for every additional kg/year in the rate of weight gain. conclusion: long-term ics use (>2 years) seems to be associated with a reduced ?fev1 over a 9-year followup. body weight gain seems a crucial factor in determining lung function decrease in asthmatics. abstract background: effectiveness of screening can be predicted by episode sensitivity, which is estimated by interval cancers following a screen. full-field digital or cr plate mammography are increasingly introduced into mammography screening. objectives: to develop a design to compare performance and validity between screen-film and digital mammography in a breast cancer screening program. methods: interval cancer incidence was estimated by linking 721 000 screening visits from 1991-2001 at an individual level to the files of the cancer registry in finland. these data were used to estimate the study size requirements for analyzing differences in episode sensitivity between screen-film and digital mammography in a randomized setting. results: the two-year cumulative incidence of interval cancers per 100 000 screening visits was estimated to be 300. to allow the maximum acceptable difference in the episode sensitivity between screen-film and digital arm to be 20% (80% power, 0.05 significance level, 1:1 randomization ratio, 85% attendance rate), approximately 240 000 women need to be invited. conclusion: only fairly large differences in the episode sensitivity can be explored within a single randomized study. in order to reduce the degree of non-inferiority between the screen-film and digital mammography, meta-analyses or pooled analyses with other randomized data are needed. according to the literature up to 70% of colorectal cancers worldwide is preventable by dietary change. however the results of the epidemiologic studies are not consistent across the countries. the objective of the study is to evaluate the role of dietary nutrients on colorectal cancer risk in poland. the hospital-based case-control study was carried out in 2000-2003. in total, 239 histologically confirmed cancer cases and 548 controls were recruited. adjustment for age, sex, education, marital status, multivitamin use, alcohol consumption, cigarette smoking, family history and energy consumption was done by logistic regression model. low tertile of daily intake in the control group was defined as a reference level. the lower colorectal cancer risk was found in cases with high daily intake of dietary fiber (or = 0,62; 95%ci: 0,42-0,91) and vitamin e (or = 0,67; 95%ci: 0,46-0,99). on the other hand, an increased risk for high monosaccharides consumption was observed. the risk pattern wasn't changed after additional adjustment for physical activity and body mass index. the results of the present study support the protective role of dietary fiber and some antyoxidative vitamins in the etiology of colorectal cancer. additionally they suggest that high consumption of monosaccharides may lead to elevated risk of investigated cancers. abstract assessment of nutrition is very difficult in every population, but in children there's additional question if child can properly recognize and recall foods that have been eaten. the aim of this study was to assess if dietary recall administered to adolescents can be used in epidemiological studies on nutrition. subjects were 100 children, 9-15 years old, and they caretakers. 24-h recall was used to evaluate children's nutrition. both, child and caretaker were asked to recall all products, drinks and dishes eaten by child during the day before recall. the statistical analyses were done separately for each meal. we have noticed statistically significant differenced for intake of energy and almost all nutrients from the lunch. the observed spearman rank correlation coefficients between child and his caretaker ranged from 0.39 for vitamin c up to 0.71 for intake of carbohydrates. only calcium intake (146.16 vs. 123.52 mg/day) differentiated groups for the breakfast and b-carotene for the supper. the study showed that the recall with adolescents could be helpful source of data for the research in the population aspect. however, one shouldn't use such data for the examination of the individual nutritional habit of children, especially information about dinner can be biased. abstract background: acute bronchitis is one of the most common diagnoses made by primary care physicians. in addition to antibiotics, chinese medicinal herbs may be a potential medicine of choice. objectives: this review aims to summarize the existing evidence of comparative effectiveness and safety of chinese medicinal herbs for treating uncomplicated acute bronchitis. methods: we searched the cochrane central register of controlled trials, medline, embase, chinese biomedical database and etc. we included randomised controlled trials comparing chinese medicinal herbs with placebo, antibiotics or other western medicine for treating uncomplicated acute bronchitis. at least two authors extracted data and assessed trial quality. main results: four trials reported the time to improvement of cough, fever, and rales; two trials reported the proportion of patients with improved signs and symptoms; thirteen trials analyzed the data of global assessments of improvement. one trial reported the adverse effect during treatment. conclusions: there is insufficient quality data to recommend the routine use of chinese herbs for acute bronchitis. the benefit found in individual studies and this systematic review could be due to publication bias and study design limitations. in addition, the safety of chinese herbs is unknown, though adverse events are rarely reported. design and methods: patients with a definite ms and classified as dead or alive at 1st january 2004 were included in this retrospective observational study. influence of demographic and clinical variables was assessed with kaplan meier and cox methods. standardised mortality ratios were computed to compare patients' mortality with the french general population. results: a total of 1935 patients were included (623 men, 1322 women). the mean age at ms onset was 31 +/) 10 years and the mean follow-up duration was 15 +/) 9 years (29260 patients-years). by 2004, 85 deaths occurred (3 per 1000 patients-years). male gender, progressive course, polysymptomatic onset and high relapse rate were related to a worse prognosis. ms did not increase the number of deaths in our cohort compared to the general french population (75 expected), except for highly disabled patients (58 observed, 18 expected). conclusion: this study gave precise insights on mortality in multiple sclerosis in west france. mattress dust. methods: we performed nested case-control studies within ongoing birth cohort studies in germany, the netherlands, and sweden and selected approximately 180 sensitised and 180 non-sensitised children per country. we measured levels of bacterial endotoxin, ß(1->3)-glucans, and fungal extracellular polysaccharides (eps) in dust samples collected on the children's mattresses. results: combined across countries, higher amounts of dust and higher endotoxin, ß(1->3)-glucans, and eps loads of mattress dust were associated with a significantly decreased risk of sensitization to inhalant allergens, but not food allergens. after mutual adjustment, only the protective effect of the amount of mattress dust remained significant [odds ratio (95% confidence interval) 0.57 (0.39-0.84)]. conclusion: higher amounts of mattress dust might decrease the risk of allergic sensitization to inhalant allergens. the effect might be partly attributable to endotoxin, ß(1->3)-glucans, and eps. it is not possible to distinguish with certainty, which component relates to the effect, since microbial agents loads are highly correlated with amount of dust and with each other. abstract background: postmenopausal hormone therapy (ht) increases mammographic density, a strong breast cancer risk factor, but effects vary across women. objective: to investigate whether the effect of ht use on changes in mammographic density is modified by polymorphisms in the estrogen (esr1) and progesterone receptor (pgr) genes. design and methods: information on ht use, dna and two consecutive mammograms were obtained from 795 ht users and 781 never ht users of the dutch prospect-epic and the english epic-norfolk cohorts. mammographic density was assessed using a computer-assisted method. changes in density between mammograms before and during ht use were analyzed using linear regression. results: a difference in percent density change between ht users and never users was seen in women with the esr1 pvuii pp or pp genotype (2.24%; p<0.01), but not in those with the pp genotype (0.90%; p = 0.47). similar effects were observed for the esr1 xbai and the pgr +331 g/a polymorphisms. the pgr progins polymorphism did not appear to make women more susceptible to the effects of ht use. discussion and conclusion: our results suggest that specific polymorphisms in the esr1 and pgr genes may make women more susceptible to the effects of ht use on mammographic density. abstract background: there is a paucity of data on the cancer risk of turkish migrant children in germany. objectives: to identify cancer cases of turkish origin in the german childhood cancer registry (gccr) and to compare the relative incidence of individual cancers among turkish and non-turkish children. design and methods: we used a name algorithm to identify children of turkish origin among the 37,259 cancer cases below 15 years of age registered since 1980. we calculated proportional cancer incidence ratios (pcir) stratified for sex and time period. results: the name algorithm performed well (high sensitivity and specificity), and 1774 turkish childhood cancers were identified. overall, the relative frequency of tumours among turkish and non-turkish children is similar. there are specific sites and cancers for which pcirs are different; these will be reported during the conference. conclusion: our study is the first to show differences in the relative frequency of cancers among turkish and non-turkish children in germany. discussion: case control studies could help to explain whether observed differences in the relative frequency of cancers are due to differences in genetic disposition, lifestyle or socio-economic status. mutations in the netherlands cohort study on diet and cancer. data from 120,852 participants, 528 cases and 4,176 subcohort members were analysed from a follow-up period between 2.3 to 7.3 years after baseline. adjusted gender-specific incidence rate ratios (rr) and 95% confidence intervals (ci) were calculated over tertiles of folate intake in case-cohort analyses. high folate intake did not reduce overall colon cancer risk. however, in men only, it was inversely associated with apc[csymbol] colon tumours (rr 0.58, 95% ci 0.32-1.05 for the highest versus the lowest tertile of folate intake), but positively associated with apc+ colon tumours (highest vs. lowest tertile: rr 2.77, ci 1.29-5.95). folate intake was neither associated with overall rectum cancer risk, nor with rectum cancer when apc mutation status was accounted for. we observed opposite associations between folate intake and colon cancer risk with or without apc mutations in men, which may implicate a distinct mutated apc pathway mediated by folate intake in men. abstract background and objectives: ten years after completion of the first serum bank of the general population to evaluate the long-term effects of the national immunisation programme (nip) a new serum collection is desirable. the objective is to provide insight into age-specific estimates of the immunity to childhood diseases and estimates of the incidence of infectious diseases with a frequent sub clinical course. design and methods: a two-stage cluster sampling technique was used to draw a nationwide sample. in each of five geographic regions, eight municipalities were randomly selected proportionally to their size. within each municipality, an age-stratified sample of 380 individuals (0-79 yr) will be drawn from the population register. in addition eight municipalities will be selected with lower immunization coverage to obtain insight into the immune status of persons who often refuse vaccination on religious grounds. furthermore over sampling of migrants will be performed to study whether their immune status is satisfactory. participants will be asked to fill in a questionnaire and to allow blood to be taken. extra blood will be taken for a genetic study. results and conclusion: the design of a population-based serum collection aimed at the establishment of a representative serum bank will be presented. abstract background: during the last decade, the standard of diabetes care evolved to require more intensive management focussing on multiple cardiovascular risk factors. treatment decisions for lipidlowering drugs should be based on cholesterol and blood pressure levels. objectives: to investigate the influence of hba1c, blood pressure and cholesterol levels on subsequent intensification of lipid-lowering therapy between 1998-2004. design and methods: we conducted a prospective cohort study including 2,373 type 2 diabetes patients who had at least two consecutive annual visits to a diabetes nurse. treatment intensification was measured by comparing drug regimes per year, and defined as initiation of a new drug class or dose increase of an existing drug. results: between 1998-2004, the prevalence of lipid-lowering drug use increased from 12% to 39%. rates of intensification of lipid-lowering therapy remained low in poorly controlled patients (12% to 28%;tc/hdl ratio>6). intensification of lipid-lowering therapy was only associated with tc/hdl ratio (age-adjusted or = 1.6;95%ci 1.5-1.7) and this association became slightly stronger over time. blood pressure was not found to be a predictor of the intensification of lipid-lowering therapy (or = 1.0). conclusion: hypercholesterolemia management intensified between 1998-2004, but therapy intensification was only triggered by elevated cholesterol levels. more attention for multifactorial risk assessment is needed. abstract background: there are no standard severity measures that can classify the range of illness and disease seen in general practice. objectives: to validate new scales of morbidity severity against age, gender, deprivation and poor physical function. design and methods: in a cross-sectional design, morbidity data for consulters in a 12-month period was linked to their physical function status . there were 9003 english older consulters (50 years +) and 7753 dutch consulters (18 years +). consulters for 116 morbidities classified on four gp-defined ordinal scales of severity ('chronicity', 'time course', 'health care use' and 'patient impact on activities of daily living') were compared to consulters for morbidity other than the 116, by age-groups, gender, and dichotomised deprivation and physical function scores. results: for both countries, on all scales, there was an increasing association between morbidity severity and older ages, female gender, more deprivation (minimum p<0.05) and poor physical function (all trends p<0.001). the estimates for categories, for example, within the 'chronicity' scale was ordered as follows: 'acute' (unadjusted odds ratio 1.4), 'acute-on-chronic' (1.8), 'chronic' (2.2) and 'life-threatening' (5.4). conclusions: new validated measures of morbidity severity indicate physical health status and offer the potential to optimise general practice care. hospitalization or death. calibration and discriminative capacity were estimated. results: among 445 episodes of lrti in elderly patients with dm, 68 endpoints occurred (attack rate 15%). reliability of the model was good (goodness-of-fit test p = 0.54). the discriminative properties of the original rule was acceptable (area under the receiver-operating curve (auc): 0.79, 95% ci: 0.72 to 0.86). conclusion: the prediction rule for the probability of hospitalization or death derived from an unselected elderly population with lrti appeared to have acceptable discriminative properties in diabetes patients and can be used to target management of these common diseases. confounding by indication is a major threat to the validity of nonrandomized studies on treatment effects. we quantified such confounding in a cohort study on the effect of statin therapy on acute respiratory disease (ard) during influenza epidemics in the umc utrecht general practitioner research database among persons aged > = 50 years. the primary endpoint was a composite of pneumonia or prednisolone-treated ard during epidemic, non-epidemic and summer seasons. to quantify confounding, we obtained unadjusted and adjusted estimates of associations for outcome and control events. in all, 22,638 persons provided 130,558 persons-periods, statin therapy was used in 5.3% and in 3,333 person-periods an outcome event occurred. without adjustments, statin therapy was not associated with the primary endpoint during influenza epidemics (relative risk [rr] 1.02; 95% confidence interval [95%ci]: 0.83-1.25). after applying multivariable generalized estimating equations (gee) and propensity score analysis the rrs were 0.72 (95% ci: 0.57-0.90) and 0.69 (95% ci: 0.59-0.89). the findings were consistent across relevant strata. in non-epidemic influenza and summer seasons the rr approached 1.0 while statin therapy was not associated with control event rates. observed confounding in the association between statin therapy and acute respiratory outcomes during influenza epidemics masked a potential benefit of more than 30%. abstract background: despite several advances in the treatment of schizophrenia, the currently available pharmacotherapy does not change the course of illness or prevent functional deterioration in a substantial number of patients. therefore, research efforts into alternative or adjuvant treatment options are needed. in this project, called the 'aspirine trial', we investigate the effect of the antiinflammatory drug acetylsalicylic acid as an add-on to regular antipsychotic therapy on the symptoms of schizophrenia. objectives: to objective is to study the efficacy of acetylsalicylic acid in schizophrenia on positive and negative psychotic symptoms, immune parameters and cognitive functions. design and methods: a randomized placebo controlled double-blind add-on trial of 80 inpatients and outpatients with schizophrenia, schizophreniform or schizoaffective disorder is performed. patients are 1:1 randomized to either 3 months 1000 mg acetylsalicylic acid per day or 3 months placebo, in addition to their regular antipsychotic treatment. all patients receive pantoprazole treatment for gastroprotection. participants are recruited from various major psychiatric hospitals in the netherlands. the outcomes of this study are 3-month change in psychotic and negative symptom severity, cognitive function, and several immunological parameters. status around 45 participants have been randomized. no interim analysis was planned. abstract background: congenital cmv infection is the most prevalent congenital infection worldwide. epidemiology and outcome are known to vary with socio-economic background, but few data are available on epidemiology and outcome in a developing country, where the overall burden of infectious diseases is high. objective: to determine prevalence, riskfactors and outcome of congenital cmv infection in an environment with high infectious disease burden methods: as part of an ongoing birth cohort study, baby and maternal samples were collected at birth, and tested with an inhouse pcr for the presence of cmv. standardised clinical assessment were performed by a paediatrician. placental malaria was also assessed. follow-up is ongoing till the age of 5 years. preliminary results: the prevalence of congenital cmv infection was 36/700 (5.1%). the infected children were more often first born babies (47.4% vs 21.5%, p<0.001). while no seasonality was observed, placental malaria was more prevalent among congenitally infected children (25.0% vs 11.3%,p = 0.04). there were no symptomatic babies detected. conclusion: this prevalence of congenital cmv is much higher than reported in industrialised countries, in the absence of obvious clinical pathology. further follow up is needed to assess impact on response to vaccinations, growth, and morbidities. of wheeze or cough at night in the first 3 years. data on respiratory symptoms and dda were collected by yearly questionnaires. in total, 193 symptomatic children with and 916 without an early dda were included in the study population. results: fifty-one percent of the children with and 29% of the children without an early dda had persistent respiratory symptoms at age 6. persistence of symptoms was associated with parental atopy, eczema, nose symptoms without a cold, or a combination of wheeze and cough in the first 3 years. conclusions: monitoring the course of symptoms in children with risk factors for persistent symptoms, irrespective of a diagnosis of asthma, may contribute to early recognition and treatment of asthma. little is known about the response mechanisms of survivors of disasters. objective: to examine selective non-response and to investigate whether attrition has biased the prevalence estimates among survivors of a disaster. design and methods: a longitudinal study was performed after the explosion of a fireworks depot in enschede, the netherlands. survivors completed a questionnaire 3 weeks (t1), 18 months (t2) and 4 years post-disaster (t3). prevalence estimates resulting from multiple imputation were compared with estimates resulting from complete case analysis. results: non-response differed between native dutch and nonwestern immigrant survivors. for example, native dutch survivors who participate at t1 only were more likely to have health problems at t1 such as depression than native dutch who participated at all three waves (or = 1.9, 95% ci: 1. 2-2.9) . in contrast, immigrants who participated at t1 only were less likely to have depression at t1 (or = 0.2, 95% ci: 0.1-0.6). conclusion and discussion: among native dutch survivors, the imputed estimates of t3 health problems tended to underestimated than the complete case estimates. the imputed t3 estimates among immigrants were unaffected or somewhat overestimated than the complete case estimates. multiple imputation is a useful statistical technique to examine whether selective non-response has biased the prevalence estimates. session: posters session 3: july 1 2006 presentation: poster. background: several epidemiologic studies have shown decreased colon cancer risk in physically active individuals. objectives: this review provides an update of the epidemiologic evidence for the association between physical activity and colon cancer risk. we also explored whether study quality explains discrepancies in results between different studies. methods: we included cohort (male n = 16; female n = 10) and case-control studies (male n = 13; female n = 12) that assessed total or leisure time activities in relation to colon cancer risk. we developed a specific methodological quality scoring system for this review. due to the large heterogeneity between studies, we refrained from statistical pooling. results: in males, the cohort and case-control studies lead to different conclusions: the case-control studies provide strong evidence for a decreased colon cancer risk in the physically active while the evidence in the cohort studies is inconclusive. these discrepant findings can be attributed to either misclassification bias in cohort or selection bias in case-control studies. in females, the small number of high quality cohort studies precludes a conclusion and the case-control studies indicate an inverse association. conclusion: this review indicates a possible association of physical activity and reduction of colon cancer risk in both sexes but the evidence is not yet convincing. abstract background/objectives: radiotherapy after lumpectomy is commonly applied to reduce recurrence of breast cancer but may cause acute and late side effects. we determined predictive factors for the development of late toxicity in a prospective study of breast cancer patients. methods: late toxicity was assessed using the rtog/ eortc classification among 418 women receiving radiotherapy following lumpectomy after a mean follow-up time of 51 months. predictors of late toxicity were modelled using cox regression in relation to observation time, adjusting for age, bmi and biologically effective dose in the maximum at the skin. results: 133 (31.8%) patients presented with telangiectasia and 28 (6.7%) patients with fibrosis. we observed a strong association between development of telangiectasia and fibrosis (p<0.01). increasing patient age was a risk factor for telangiectasia and fibrosis (p for trend 0.02 and 0.04, respectively). boost therapy (hazard ratio (hr) 4.2, 95% ci 1.7-10.7) and acute skin toxicity (hr 1.6, 95% ci 1.0-2.6) significantly increased risk of telangiectasia. risk of fibrosis was elevated among patients with atopic diseases (hr 2.2, 95% ci 1.0-4.7). discussion: our study revealed several risk factors for late complications of radiotherapy. further understanding of differences in response to irradiation may enable individualized treatment and improve cosmetic outcome. doctor-diagnosed asthma and respiratory symptoms (age 6) were available for 311 (rint) and 125 (no) children. results: the discriminative capacities of rint and exhaled no were statistically significant for the prediction of doctor-diagnosed asthma, wheeze (rint only) and shortness of breath (rint only). due to the low prevalence of disease in this general population sample, the positive predictive values of both individual tests were low. however, the positive predictive value of the combination of increased rint (cutoff 1.05 kpa.l-1.second) and exhaled no (cut-off 10 ppb) was 38% for the prediction of doctor-diagnosed asthma, with a negative predictive value of 97%. combinations of rint or exhaled no with atopy of the child showed similar results. conclusions: the combination of rint, exhaled no and atopy may be useful to identify high-risk children, for monitoring the course of their symptoms and to facilitate early detection of asthma. abstract background: in 1992 a cargo aircraft crashed into apartment buildings in amsterdam, killing 43 people, and destroying 266 apartments. an extensive, troublesome aftermath followed with rumours on toxic exposures and health consequences. objectives: we studied the long-term physical health effects of occupational exposure to this disaster among professional assistance workers. design and methods: in this historical cohort study we compared the 334 firefighters and 834 police officers who were occupationally exposed to this disaster (i.e. who reported one or more disasterrelated tasks) with their nonexposed colleagues (n = 194, and n = 634, respectively), using regression models adjusted for background characteristics. data collection took place from january 2000 to march 2002, and included various clinical blood and urine parameters (including blood count and kidney function), and questionnaire data on occupational exposure, physical symptoms, and background characteristics. the overall response rate was 71%. results: exposed workers reported various physical symptoms (including fatigue, skin and musculoskeletal symptoms) significantly more often than their nonexposed colleagues. in contrast, no consistent significant differences between exposed and nonexposed workers were found regarding clinical blood and urine parameters. discussion and conclusion: this epidemiological study demonstrates that professional assistance workers involved in a disaster are at risk for long-term unexplained physical symptoms. abstract background and objectives: recent studies indicate that women with cosmetic breast implants have significantly increased risk of suicide. reasons for elevated risk are not known. it is suggested that women with cosmetic breast implants differ in their characteristics and have more mental problems than women of general population. aim of this study was to find out possible associations between physical or mental health and postoperative quality of life among finnish women with cosmetic breast implants. design and methods: information was collected from patient records of 685 women and structured questionnaires mailed to 470 women of the same cohort. data was analysed by using pearson chi square testing and logistic regression modelling. results: although effects of implantation on postoperative quality of life in different areas were mainly reported as positive or neutral, 12 % of the women reported decreased state of health. postoperative dissatisfaction and decreased quality of life were significantly associated with diagnoses of depression (p = 0.01) and local complication called capsular contracture (p<0.001). conclusion: our results are consistent with previous results finding most of the cosmetic breast surgery patients satisfied after implantation. however, this study brings new information on associations between depression, capsular contracture and decreased quality of life. abstract cancer and its treatments often produce significant persistent morbidities that reduce quality of life (qol) in cancer survivors. research indicates that both, physical exercise and psycho-education might enhance qol. therefore, we developed a 12-week multidisciplinary rehabilitation program that combines physical training with psycho-education. the aim of the present multicenter study is to determine the effect of multidisciplinary rehabilitation on qol as compared to no treatment and, additionally, to physical training alone. furthermore, we will explore which variables are related to successful outcome (socio-demographic, disease related, physiological, psychological and environmental characteristics). 225 participants are needed to detect a medium effect. at present, 170 cancer survivors are randomised to either the multidisciplinary or physical rehabilitation program or a 6-month waiting list control group. outcome assessment will take place before, halfway, directly after, 3 and 9 months following the intervention by means of questionnaires. physical activity will be measured before, halfway and directly after rehabilitation using maximal and submaximal cycle ergometer testing and muscle strength measurement. effectiveness of multidisciplinary rehabilitation will be determined by analysing changes between groups from baseline to post-intervention using multiple linear and logistic regression. positive evaluation of multidisciplinary rehabilitation may lead to implementation in usual care. continuous event recorders (cer) have proven to be successful in diagnosing causes of palpitations but may affect patient qol and increase anxiety. objectives: determine qol and anxiety in patients presenting with palpitations, and to evaluate the burden of the cer on qol and anxiety in patients presenting to the general practitioner. methods: randomized clinical trial in general practice. the short form-36 (sf-36) and state-trait anxiety inventory (stai) were administered at study inclusion, 6-weeks and 6months. results: at baseline, patients with palpitations (n = 226) reported lower qol and more anxiety than a healthy population for both males and females. there were no differences between the cer arm and usual gp care at 6-weeks. at 6-months the usual care group (n = 92) showed minimal qol improvement and less anxiety compared to the cer group (n = 103). type of diagnosis did not account for any of these reported differences. conclusion: anxiety decreases and qol increases in both groups at 6-weeks and 6-month follow-up. hence it is a safe and effective diagnostic tool, which is applicable for all patients with palpitations in the general practice. abstract background: clinical benefits of statin therapy are accepted, but their safety profiles have been under scrutiny, particularly for the most recently introduced statin, rosuvastatin, relating to serious adverse events involving muscle, kidney and liver. objective: to study the association between statin use and the incidence of hospitalizations for rhabdomyolysis, myopathy, acute renal failure and hepatic impairment (outcome events) in real life. methods: in 2003 and 2004, 10,147 incident rosuvastatin users, 37,396 incident other statin users and 99,935 patients without statin prescriptions from the pharmo database of >2 million dutch residents were included in a retrospective cohort study. potential cases of hospitalization for myopathy, rhabdomyolysis, acute renal failure or hepatic impairment were identified using icd-9-cm codes and validated using hospital records. results: there were 26 validated outcome events in the three cohorts including one case each of myopathy (other statin group) and rhabdomyolysis (non-treated group). there were no significant differences in the incidence of outcome events between rosuvastatin and other statin users. discussion: this study indicated that the number of outcome events is less than 1 per 3000 person years. rosuvastatin does not lead to an increased incidence of rhabdomyolysis, myopathy, acute renal failure and hepatic impairment compared to other statins. the aim: the aim of the study was to assess the influence of insulin resistance (ir) on the coronary artery disease (cad) occurrence in middle aged women with normal glucose tolerance (ngt) material and methods: in 1998-2000 year 986 women aged 35-55, participants of the polish multicenter study on diabetes epidemiology were examined. anthropometric, biochemical (fasting lipids, fasting and after glucose load plasma glucose and insulin) and blood pressure determinations were performed . ir was defined as the matsuda index (irmatsuda) below the lower quartile of the irmatsuda distribution in ngt population the questionnaire examination of the lifestyle, present and past diseases was performed. results: ir was observed in 31 % of all examined women and in 17.9% with ngt. cad was diagnosed in 10, 3% of all examined women and in 6,9% of those with ngt. the relative risk of cad related to ir in ngt and normotensive women was 2,90 (95% ci:1,07-7,88) (p<0.05). regular menstruation was observed in 41,1% of cad women. irmatsuda was not different for cad menstruating and non menstruating women (respectively 9,31±1,01 and 9,70±1,68). conclusion: in middle aged, normotensive and normal glucose tolerant women ir seems to be an important risk factor of cad abstract background: in germany, primary prevention at population level is provided by general practitioners (gp). little is known about gps' strategies to identify patients at high risk for vascular diseases using standardised risk scores. objectives: we studied gp attitudes and current practice in using risk scores. methods-a cross-sectional survey was conducted among 744 gps in north rhine-westphalia, germany, using mailed self-administered questionnaires on attitudes and current practice in identification of patients at high risk for vascular diseases. results: in 2005, 350 gps participated in the study. 69.0% of gps stated to know the framingham-score, 81.3% the procam-score and 29.4% the score-score. 47.4% of gps reported regular use of standardised risk scores to identify patients at high risk for vascular diseases, most frequently procam-score (79.7%), followed by score-score (6.8%) and framingham-score (6.8%). main reasons for not using standardised risk scores were assumed rigid assessment of individual patients' risk profile (51.9%), time-consuming appliance (35.2%) and higher confidence in own work experience (17.3%). conclusion: use of standardised risk scores to identify patients at high risk for vascular diseases is common among gps in germany. however, more educational work might be useful to strengthen gps' belief in the flexible appliance of standardised risk scores in medical practice. among epilepsy patients than in general population, but effects of specific antiepileptic drugs on birth rate are not well known. objectives: to estimate birth rate in epilepsy patients on aed treatment or without aeds and in a population-based reference cohort without epilepsy. design and methods: patients (n = 20, 101) with reimbursement for aeds for the first time between 1985 and 1994 and information on their aed use, were identified from the databases of social insurance institution of finland. reference cohort without epilepsy (n = 29,828) and information on live births were identified from the finnish population register centre. the analyses were performed using poisson regression modelling. results:birth rate was decreased in epilepsy patients in relation to reference cohort without epilepsy in both genders regardless of aed use. in relation to untreated patients, women on any of the aeds had non-significantly lower birth rates. among men, birth rate was decreased in men on oxcarbazepine (rr = 0.52, 95% ci = 0.32,0.84), but was not clearly lower among those on carbamazepine (rr = 0.86,95% ci = 0.66,1.13) or valproate (rr = 0.78,95% ci = 0.55,1.11) when compared to untreated patients. conclusion: our results suggest that birth rate is decreased among epilepsy patients on aeds, more so in men. abstract background: hereditary hemochromatosis (hh), characterised by excessive iron absorption, subsequent iron storage and progressive clinical features, can when diagnosed at an early stage be successfully treated. high prevalence of the c282y-mutation on the hfe-gene in the hh patient population may motivate genetic screening. objectives: in first-degree relatives of c282y-homozygotes we studied the gender and age -related biochemical penetrance of hfe-genotype to define a high-risk population eligible for screening. design and methods: one-thousand-six first-degree family members of 280 probands with clinically overt hfe-related hh from five medical centres in the netherlands were approached. data on levels of serum iron parameters and hfe-genotype were collected. elevation of serum ferritin was defined using the centre-specific normal-values by age and gender. results: among the 610 participating relatives, highest serum iron parameters were found in male c282y-homozygous siblings aged >55 years: 97% had elevated levels of serum ferritin. generally, male gender and increased age are related with higher iron values. discussion and conclusion: genetic screening for hh is most relevant in male and elderly first-degree relatives of patients with clinically overt hfe-related hh, enabling regular investigations of iron parameters in homozygous individuals. abstract background: nosocomial infection causes increased hospital morbidity and mortality rates. although handwashing is known to be the most important action in its prevention, adherence of health care workers to recommended hand hygiene procedures is extremely poor. objective: evaluation of compliance of hand hygiene recommendations in health care workers of a tertiary hospital in barcelona after a course on hand hygiene was given to all nurses in the hospital during the previous year. methods: by means of nondeclared observation, compliance (handwashing or disinfecting, not solely glove exchange) of recommendations given by the center for disease control related to opportunities for hand hygiene was registered, in procedures of diverse risk level for infection, both in physicians and nurses. results: in 1288 opportunities for hand hygiene carried out by 254 health care workers compliance of recommendations was 19.9%. adherence differed between wards (68.9% in intensive care units, 17.8% in medical wards and 4.3% in surgical wards) and slightly between health care workers (21.4% in physicians, 19.2% in nurses). discussion: in conclusion, after one year of an intervention on education, adherence to hand hygiene recommendations is very low. these results enhance the need of reconsidering the type of interventions implemented. type of comorbidity affects qol most. objectives: we studied whether qol differed in subjects with dm with and without comorbidities. in addition, we determined differences in type of comorbidity. design and methods: cross-sectional data of 193 dm patients, participants of a population-based dutch monitoring project on risk factors for chronic disease (morgen) were analyzed. qol was measured by the short form 36. we compared the means of 8 subdimensions for dm patients with one comorbidity (cardiovascular diseases (cvd), musculoskeletal diseases (msd) and asthma/copd) to dm patients without this comorbidity, by regression analyses adjusted for age and sex. results: the prevalences of cvd, msd and asthma/copd were 17.1%, 26.4%, and 46.6%. all comorbidities were associated with lower qol, especially for physical functioning. the mean difference (95% ci) was 13. abstract background: the extent or increase of ueds is suggested repeatedly, but never before the scientific literature was systematic studied. objectives: a systematic appraisal of the worldwide incidence and prevalence rates of upper extremity disorders (ueds) available in scientific literature was executed to gauge the range of these estimates in various countries and to determine whether the rates are increasing in time. design and methods: studies that recruited at least 500 people, collected data by using questionnaires, interviews and/or physical examinations, and reported incidence or prevalence rates of the whole upper-extremity including neck, were included. results: no studies were found with regard to the incidence of ueds and 13 studies that reported prevalence rates of ueds were included. the point prevalence ranged from 1.6-53%; the 12months prevalence ranged from 2.3-41%. one study reported on the lifetime prevalence (29%). we did not find evidence of a clear increasing or decreasing pattern over time. it was not possible to pool the date, because the definitions used for ueds differed enormously. conclusions: there are substantial differences in reported prevalence rates on ueds. main reason for this is the absence of a universally accepted way of labelling or defining ueds. abstract background: the absolute number of women diagnosed with breast cancer increased from 7,899 in 1989 to 11,687 in 2003 in the netherlands. likewise, the age standardized rate increased from 100.1 to 120.7 per 100,000 women. besides the current screening programme, changes in risk profile could be a reason for the increased incidence. objective: we studied the changes in breast cancer risk factors for women in nijmegen. methods: in the regional screening programme in nijmegen, almost 20,000 women aged 35-64 years filled in a questionnaire about risk factors in [1975] [1976] . similar questions were applied in the nijmegen biomedical study in 2002, where 2345 women of 35-64 year participated. the median age in both studies was 50 years. results: the frequency of a first-degree relative with breast cancer was 9.9% and 11.1% in 1975 and 2002, respectively . none of the other risk factors, as the age of women at 1st birth (26.3% respectively 27.1%), nulliparity (19.2% resp. 20.6%), age at menarche (13.1% resp. 13.2%), age at menopause (47.2% resp. 49.2%) and obesity (11.9% resp. 11 .4%), changed in time. conclusion: the distribution of risk factors hardly changed, and is unlikely to explain the rise in breast cancer incidence from 1989 onwards. abstract background: a single electronic clinical history system has been developed in the bac (basque autonomous community) for general use for all health centres, thus making it possible to collect information online on acute health problems as well as chronic ailments. method: the prevalence of diabetes, high blood pressure and copd (chronic obstructive pulmonary disease) was estimated using icd-9-cm diagnosis performed by primary care physicians. an estimate was also made of the prevalence of cholesterolemia based on the results of analyses requested by physicians. results: in 2004, 441,097 patients (out of a total population of 2,082,587) were assessed for serum cholesterol levels. based on this highly representative sample, it was estimated that 13.3% had serum cholesterol levels above 250 mg/dl. the prevalence of diabetes mellitus in people over the age of 29 was 6.4%. the prevalence of high blood pressure in people over 13 was 25%. discussion: the primary care database makes it possible to access information on problems related to chronic illnesses. knowing the prevalence of diabetes patients enables doctors to analyse all aspects related to services used by the diabetic population. it also makes it possible to monitor analytical data in real time and evaluate health service outcomes. examinations were used to asses risk factors for diabetes. cases (n = 101) were matched on age and sex to controls (n = 709) who were not treated with antidiabetic drugs. logistic regression was used to calculate odds ratios (or). results: the or of incident diabetes for acei-use versus non-acei use was 3.63 (95%ci :1.93-6.88). for ace dd homozygotes the or was 0.57 (95%ci:0.07-4.47) and for ace-i allele carriers 5.72 (95%ci:2.77-11.81). the interaction or was 10.05 (95%ci:1.13-89.38). the agt and at1r genotypes did not modify the association between acei use and diabetes. abstract background: lignans have antioxidant and estrogen-like activity, and may therefore lower cardiovascular and cancer risk. objective: we have investigated whether intake of four plant lignans (lariciresinol, pinoresinol, secoisolariciresinol, matairesinol) was inversely associated with coronary heart disease (chd), cardiovascular diseases (cvd), cancer, and all-cause mortality. design: the zutphen elderly study is a prospective cohort study in which 570 men aged 64-84y were followed for 15 years. lignan intake was estimated using a recently developed database, and related to mortality using cox proportional hazards analysis. results: median total lignan intake in 1985 was 977lg/d. beverages such as tea and wine, vegetables, bread, and fruits were the major lignan sources. total lignan intake was not related to mortality. however, matairesinol was inversely associated with chd, cvd, cancer, and all-cause mortality. multivariate adjusted rrs (95% ci) per sd increase in intake were 0.72 (0.53-0.98) for chd, 0.83 (0.69-1.00) for cvd, 0.81 (0.65-1.00) for cancer, and 0.86 (0.76-0.97) for allcause mortality. conclusions: total lignan intake was not associated with mortality. the intake of matairesinol was inversely associated with mortality from chd, cvd, cancer, and all-causes. we can not rule out that this is due to an associated factor, such as wine consumption. abstract despite the drastic increase in the amount of research into neighbourhood-level contextual effects on health, studies contrasting these effects between different domains of health within one contextual setting are strikingly sparse. in this study we use multilevel logistic regression models to estimate the existence of neighbourhood-level variations of physical health functioning (pcs) and mental well-being (ghq) in the helsinki metropolitan area and assess the causes of these differences. the individual-level data are based on a health-survey of 40-60 year old employees of the city of helsinki (n = 4313, response rate 68%). the metropolitan area is divided into 53 neighbourhoods, which are characterised using a number of area-level indicators (e.g. unemployment rate). our results show moderate but systematic negative effect of indicators of neighbourhood deprivation on physical functioning, whereas for mental health the effect is absent. these effects were strongest for proportion of manual workers; odds ratio for poor physical functioning was 0.8 for respondents living in areas with low proportion of manual workers. part of this effect was mediated by differences in health behaviour. analyses on cross-level interactions show that individual-level socioeconomic differences in physical health are smallest in most deprived areas, somewhat contradicting the results of earlier studies. abstract background: the second-eye cataract surgery is beneficial, nevertheless, there is a considerable proportion of unmet needs. objective: to estimate the proportion of second-eye cataract surgery in the public health system of catalonia, and explore differences in utilisation by patients' gender, age, and region of residence. methods: a total of 154,215 senile cataract surgeries performed between 1999 and 2002 were included. proportions observed were adjusted through independent logarithmic regression models for each study factor. results: the proportion of second-eye surgery showed an increasing trend (r2 59.4%) from 23.8% (95% ci 21.6; 26.1) in november 2000 to 32.5% (95% ci 31.4; 33.6) in december 2002, and its projection to 5 years was 35,7% (95% ci 33.6; 37.7). the proportion of second-eye surgery was 2% (95% ci 0.9; 3.1) greater in women than in men. patients 80 years or older had a lowest proportion (20.7%; 95% ic 20.2; 21.3), which nevertheless increased during the period, unlike that of patients aged less than 60 years. differences among regions were moderate and decreased throughout the period. conclusions: if the observed trends persist, there will be a substantial proportion of unmet need for bilateral surgery. we predict greater use of second-eye surgery by older patients. abstract background: persistence with bisphosphonates is suboptimal which could limit prevention of fractures in daily practice. objectives: to investigate the effect of long term persistent bisphosphonate usage on the risk of osteoporotic fractures. methods: the pharmo database, including drug-dispensing and hospital discharge records for > two million subjects in the netherlands, was used to identify new female bisphosphonate users >50 years from jan '96 -jun '03. persistence with bisphosphonates was determined using the method of catalan. a nested matched case-control study was performed. cases had a first hospitalization for an osteoporotic fracture (index-date). controls were matched 10:1 to cases on year of inclusion and received a random index-date. the association with fracturerisk was assessed for one and two year persistent bisphosphonate use prior to the index-date. analyses were adjusted for di fferences in patient characteristics. results: 14,760 bisphosphonate users were identified and 541 had a hospitalization for osteoporotic fracture during follow-up. one year persistent bisphosphonate use resulted in a 26% lower fracture rate (or 0.74; 95% ci 0.57-0.95) whereas two year persistent use resulted in a 32% lower rate (or 0.68; 95% ci 0.47-0.96). conclusion and discussion: these results emphasize the importance of persistent bisphosphonate usage to obtain maximal protective effect of treatment. abstract background: in 1997 the who recommended all countries to add hepatitis b (hbv) vaccination to their national immunization programs. the netherlands is a low hbv endemic country and therefore adopted a vaccination policy targeted towards high-risk groups. methods: during 2004, epidemiological data and blood samples were collected from all reported patients with an acute hbv infection. a fragment of the s-gene was sequenced and phylogenetically analysed to clarify transmission patterns between risk groups. results: of 295 hbv cases reported, 60% was infected through sexual contact (34% homo-/bisexual, 23% heterosexual). for 158 patients samples were available for genotyping. phylogenetic analysis identified 6 genotypes: a(64%), b(3%), c(3%), d(21%), e(5%) and f(4%). of men who have sex with men (msm), 86% were infected with genotype a. among heterosexuals, all genotypes were found. in many cases, genotypes b-f were direct or indirect related to countries abroad. only 1 injecting drug user was found (genotype a). conclusion: genotype a is predominant in the netherlands, including most of the msm. migrant hbv carriers play an important role in the dutch hbv epidemic. genotyping provides insight into the spread of hbv among highrisk groups. this information will be used to evaluate the vaccination policy in the netherlands. abstract background: excess weight might affect the perception of both physical and mental health in women. objective: to examine the relationship between body mass index (bmi) and hrqol in women aged 18-to 60-year-old in a rural zone of galicia. design and methods: population-based cross-sectional study covering 1321 women, personally interviewed, from 14 villages. hrqol was assessed with sf-36 questionnaire, through personal interviews. each scale of sf-36 was dichotomised in suboptimal or optimal hrqol using previously defined cut-offs. odds ratios (or) obtained from logistic regression summarize the relationship of bmi with each scale, adjusting for sociodemographic variables, sedentary leisuretime, number of chronic diseases and sleeping hours. results: a 14.7% of women were obese (bmi = 30 kg/m2) and 31.2% overweight 9 kg/m2) . frequency of suboptimal physical function was higher among overweight women (adjusted or:1.76; 95% ci:1.27-2.45) and obesity (adjusted or:2.10;95% ci:1.40-3.16). furthermore, obese women had higher frequency of suboptimal scores on the general health scale (adjusted or:1.64; 95% ci:1.10-2.44). no differences were observed regarding mental health scores among women with different bmi categories. conclusion: in women from rural villages, overweight is associated with worse hrqol in physical function and general health. abstract background: pneumococcal vaccination among elderly is recommended in several western countries. objectives: we estimate the cost-effectiveness of a hypothetical vaccination campaign among the 65+ general population in lazio region (italy). methods: a cohort was followed during a 5 years timeframe. we estimated the incidence of invasive pneumococcal disease, in absence of vaccine, based on actual surveillance and hospital data. the avoided deaths and cases have been estimated from literature according to trial results. health expenditures included: costs of vaccine program, inpatient and some outpatient costs. cost-effectiveness was expressed as net healthcare costs per episode averted and life-year gained (lyg) and was estimated at baseline and in deterministic and stochastic sensitivity analyses. all parameters were age-specific and varied according to literature data. results: at baseline net costs per event averted and lyg at 2001 prices were, respectively, e34,681 (95% ci: e28,699-e42,929) and 23,361 (95% ci: e16,419-e38,297). in the sensitivity analysis, bacteraemic pneumonia incidence and vaccine effectiveness increased the net cost per lyg by 131% and 218% in the worst-case scenario, and decreased it to e4,249 in the best-case. conclusions: the intervention was not cost saving. the uncertainties concerning invasive pneumococcal disease incidence and vaccine effectiveness make the cost-effectiveness estimates instable. spain 1989 -1998 abstract background: spatial data analysis can detect possible sources of heterogeneity in spatial distribution of incidence and mortality of diseases. moreover small area studies have greater capacity to detect local effects linked to environmental exposures. objective: to estimate the patterns of cancer mortality at municipal level in spain using smoothing techniques in a single spatial model. design and methods: cases were deaths due to cancer, registered at a municipal level nation-wide for the period 1989-1998. expected cases for each town were calculated using overall spanish mortality rates and standard mortality ratios were computed. to plot the maps, smoothed municipal relative risks were calculated using besag york and mollie`model and markov chain monte carlo simulation methods. as an example maps for stomach and lung cancer neoplasms are shown. results: it was possible to obtain the posterior distribution of relative risk by a single spatial model including 8077 towns and the 46398 adjacencies. maps showed the singular patterns for both cancer locations. conclusion: the municipal atlas allows to avoid edge local effects, improving the detection of spatial patterns. discussion: bayesian modelling is a very efficient way to detect spatial heterogeneity by cancer and other causes of death. abstract background: little is known about the impact of socioeconomic status (ses) on outcomes of surgical care. objectives: we estimated the association between ses and outcomes of selected complex elective surgical procedures. methods: using hospital discharge registries (icd-ix-cm codes) of milan, bologna, turin and rome we identified patients undergoing cardiovascular operations (coronary artery bypass grafting, valve replacement, carotid endarterectomy, repair of unruptured thoracic aorta aneurysm) (n = 20,194) and cancer resections (pancreatectomy, oesophagectomy, liver resection, pneumonectomy, pelvic evisceration) (n = 2,300) in four italian cities, 1997-2000. an area-based income index was calculated. post-operative mortality (in-hospital or within 30 days) was the outcome. logistic regression adjusted for gender, age, residence, comorbidities, concurrent and previous surgeries. results: high income patients were older and had fewer comorbidities. mortality varied by surgery type (cabg 4,1%, valve 7,5%, endartectomy 1,2%, aorta aneurysm 10,2%, cancer 6.7%). low income patients were more likely to die after cabg (or = 1. abstract background: an important medical problem of renal transplant patients who receive immunosuppression therapy, is the development of a malignancy during the long term follow-up. however, existing studies are not in agreement over whether patients who undergo renal transplantation have an increased risk of melanoma. objective: the aim of this study was to determine the incidence of melanoma in renal transplantation patients in the northern part of the netherlands. methods: we linked a cohort of 1125 patients who received a renal transplantation in the university medical centre groningen between 1989 and 2003 with the cancer registry of the comprehensive cancer centre north-netherlands, to identify all melanoma patients in this cohort. results: only 1 patient developed a melanoma following the renal transplantation; no significant increase in the risk of melanoma was found. conclusion: although several epidemiologic studies have shown that the risk of melanoma is increased in renal transplantation patients who receive immunosuppression therapy to prevent allograft rejection, this increased risk was not found in the present study. the lower level of immunosuppressive agents given in the netherlands might be responsible for this low incidence. abstract background: socio-economic health inequalities are usually studied for self-reported income, although the validity of self-reports is uncertain. objectives: to compare self-reports of income by respondents to health surveys with their income according to tax registries, and determine to what extent choice of income measure influences the health-income relation. methods: around 22.000 respondents from the dutch permanent survey on living conditions were linked to data from dutch tax and housing registries of 2001. both self-reported and registry-based measures of household equivalent income were calculated and divided into deciles. the association with less than good self-assessed health was studied using prevalence rates and odds ratios. results: around 18% of the respondents did not report their income. around 27% reported an income 3 deciles lower or higher than the actual income value. the relation between income and health was influenced by choice of income measure. larger health inequalities were observed with selfreports compared to registry-based measures. while a linear healthincome relation was found using self-reported income, a curvilinear relation (with the worst health in the second lowest deciles) was observed for registry-based income. conclusion: choice of the income source has a major influence on the health-income relation that is found in inequality research. abstract background: while many health problems are known to affect immigrant groups more than the native dutch population, little is known about health differences within immigrant groups. objectives: to determine the association between self assessed health and socioeconomic status (ses) among people of turkish, moroccan, surinamese and antillean origin. methods: data were obtained from a social survey held among immigrants 20-59 years in the netherlands, with almost 2000 respondents per immigrant group. ses differences in the prevalence of 'poor' self-assessed health were measured using prevalence rate ratios estimated with regression techniques. results: within each immigrant group, poor health was much more common among those with low ses. the health of women was related to their educational level, occupational position, household income, financial situation and (to a lesser extent) their parents' education. similar relationships were observed for men, except that income was the strongest predictor of poor health. the health differences were about as large as those known for the native dutch population. conclusion and discussion: migrant groups are not homogenous. also within these groups, low ses is related to poor general health. in order to identify subgroups where most health problems occur, different socioeconomic indictors should be used. abstract background: genetic damage quantification can be considered as biomarker of exposure to genotoxic agents and as early-effect biomarker regarding cancer risk. objectives: to assess genetic damage in newborns and its relationship with anthropometrical, sociodemographic variables, maternal tobacco consumption and pollution perception. design and methods: the bio-madrid study recruited 150 trios (mother/father/newborn) from 2 areas in madrid to assess the impact of pollutants in humans. parents answered a questionnaire about socio-economic characteristics, pregnancy, life-style and perception of pollution. genetic damage in newborns were measured with the micronucleus(mn) test in peripheral lymphocytes poisson regression models were fitted using mn frequency per 1000 binucleated cells as dependent variable. explanatory variables included sex, parents age, tobacco, area and reported pollution level. results: the mean frequency of mn was 3.94 per 1000 (range:2-10). no differences were found regarding area, sex and maternal tobacco consumption. mn frequency was higher in underweighted newborns and in those residing near heavy traffic roads. in recent years minimally invasive surgery procedures underwent rapid diffusion and laparoscopic cholecystectomy has been among the first to be introduced. after its advent, increasing rates of overall and laparoscopic cholecystectomy have been observed in many countries. we evaluated the effect of the introduction of laparoscopic procedure on the rates of cholecystectomy in friuli venezia giulia region, performing a retrospective study. from regional hospitals discharge data we selected all records with procedure code of laparoscopic (icd 9 cm: 5123) or open (5122) cholecystectomy and diagnosis of uncomplicated cholelithiasis (icd 9 cm: 574.0; 574.1; 574, 2) or cholecystitis (575,0; 575,1), in any field, from 1993 to 2004. in the 12 year study period, the number of overall cholecystectomies increased from 1546 to 2039 (+31,9%), mainly for the relevant increase of laparoscopic interventions from 3 procedures, (0,2% of overall cholecystectomies), to 1697 (83,2%). rates of laparoscopic cholecystectomies increased from 0,1 to 46,8 per 100 admitted patients with diagnosis of cholelithiasis or cholecystitis. the introduction of laparoscopic cholecystectomies was followed not only by a shift towards laparoscopically performed interventions but also by an increase in overall cholecystectomies in friuli venezia giulia region. abstract background: although a diminished doses scheme of 7-valent pneumococcal conjugate vaccination (pcv7) may offer protection against invasive pneumococcal disease, it might affect pneumococcal carriage and herd immunity. long term memory has to be evaluated. objective: to compare the influence of a 3 and 2-doses pcv7-vaccination scheme on pneumococcal carriage, transmission, herd immunity and anti-pneumococcal antibody levels. methods: in a prospective, randomized, controlled trial infants are randomly allocated to receive pcv7 at ages 2 and 4 months; ages 2, 4 and 11 months and the age of 24 months only. nasopharyngeal (np) swabs are regularly obtained from infants and family members. the np swabs are cultured by conventional methods and pneumococcal serotypes are determined by quellung reaction. antibody levels are obtained at 12 and 24 months from 80 infants in group i and ii and from 30 infants in group iii. one thousand infants are needed to detect a 10% difference in pneumococcal carriage (a = 0.05, ß = 0.80) between the three groups. results: so far, 852 infants have been included. preliminary results show that prior to vaccination pneumococcal carriage was 16%. conclusion: this trial will provide insight into the effects of a diminished dose scheme on herd immunity and long-term antipneumococcal antibody development. abstract background: oil-spills cause important environmental damages and acute health problems on affected populations. objectives: to assess the impact of the prestige oil-spill in the hrqol of the exposed population. design and methods: we selected 1350 residents in coastal areas heavily affected by the oil-spill and 1350 residents in unaffected inland villages through random sampling, stratified by age and sex. hrqol was measured with the sf-36 questionnaire in personal interviews. individual exposure was also explored. mean differences in sf-36 scores >3 points were considered 'clinically relevant'. odds ratios (or) summarized the association between area of residence (coast vs inland) and suboptimum hrqol (lower than percentile 25th), adjusting for possible confounders. results: neither clinically relevant nor statistically significant differences were observed in most of the sf-36 scales regarding place of residence or individual exposure. worse scores (inland = 79,2; coast = 75,9; p<0,001) abstract background: patient comorbidities are usually measured and controlled in health care outcome research. hypertension is one of the most commonly used comorbidity measures. objectives: this study aims to assess underreporting of hypertension in ami patients, and to analyze the impact of coding practices among italian regions or hospitals' type. methods: a cohort of ami hospitalisations in italy from november 2002 to october 2003 was selected. 4820 patients with a previous hospital admission reporting a diagnosis of complicated hypertension within the preceding 22 months were studied. a logistic model was constructed. both crude and adjusted probability of reporting a hypertension in ami admissions, depending from the number of diagnosis fields compiled in discharge abstracts, and presence of other diseases were estimated. results: in 57.9% of patients hypertension was not reported. probability of reporting hypertension increased with the number of compiled diagnosis fields (adjusted ors range: 1.50-2.17). there were no significant differences among italian regions, while private hospitals' reporting was less accurate. disorders of lipoid metabolism were more probably coded with hypertension (adjusted or: 4.37). conclusions: information from both ami and previous hospitali-sations would be needed to include hypertension in a comorbidity measure. abstract background: the angiotensin converting enzyme inhibitors (acei) should be considered the standard initial treatment of the systolic heart failure. this treatment is not recommended in patients with hypotension, although figures of systolic blood pressure around 85-90 mmhg during the treatment are allowed if the patient remains asymptomatic. objectives: to know the proportion of patients with systolic heart failure receiving treatment with acei, and the proportion of these patients with signs oh hypotension. design and methods: the electronic clinical records of all the patients diagnosed of systolic heart failure were reviewed. the electronic information system covers a 60% of the population of the basque country, approximately. diagnosis of heart failure was defined as the presence of any of the following cie-9 codes: 428 or 402.11 or 402.91. to evaluate the blood pressure, the last available determination was considered. results: out of 9464 patients with left heart failure, 4108 (43.4%) have been prescribed acei. among the 328 patients with blood pressure lower than 85mmhg (systolic) or than 60mmhg (diastolic), 163 (49.7%) were also receiving this treatment. conclusions: acei are clearly underprescribed in the basque country for the treatment of heart failure. attention should be given to the group at risk of hypotension. abstract background: epidemiologic studies have shown an association between c-reactive protein (crp) and cardiovascular endpoints in population samples. methods: in a longitudinal study of 1006 myocardial infarction (mi) survivors, crp was measured repeatedly (up to 8 times) within a period of 13 months. data on disease history and life style were collected at baseline. we examined the association between different variables and the level of crp using a random effects model. results: in total 5835 crp samples were collected in athens, augsburg, barcelona, helsinki, rome and stockholm. mean levels of crp were 2.6, 2.4, 3.4, 2.0, 2.5, 2.8 [mg/l] respectively. body mass index (bmi) and chronic bronchitis (ever diagnosed) had the largest effect on crp (38% (for 5 kg/m 2 ) and 32% change from the mean level, respectively, p<0.05). age classes showed a cubic function with a minimum at ages 50 to 60. glycosylated hemoglobin (hba1c) <6.5% as a measure of long-term blood glucose control and being male were found to be protective ()21% and )17% respectively, p<0.05). conclusion: it was shown that bmi and history of bronchitis are important in predicting the level of crp. other variables, like alcohol intake, play a minor role in this large sample of mi patients. abstract background: during the last decades a remarkable increase in incidence rates of malignant lymphoma was seen. although some reasons are known or suspect underlying risk factors are not well understood. objectives: we studied the influence of medical radiation (x-ray, radiotherapy and szintigraphy) on the risk of malignant lymphoma. methods: we analysed data from a population-based case-control study with 710 incident lymphoma cases in germany from 1999-2003. after informed consent cases were pair-matched with controls recruited from registration office by age, gender and study region. data was collected in a personal interview. we analysed data using conditional logistic regression. results: the linear model shows an or = 0.99/msv due to x-ray exposure and or = 0.63 (95%-ci = 0.5-0.79) comparing higher with lower exposure. radiotherapy shows an or = 0.76 (n = 31 cases). there is no association between all lymphomas and szintigraphies but in the subgroup containing multiple myeloma, cll, malt-and marginalcell lymphoma we found an or = 1.86 (95%-ci = 1.02-3.40) in the multivariate model. discussion: no excess risk was observed for x-ray examinations. ionising radiation may increase risk for specific lymphoma subgroups. however, it should be noted that numbers in the subgroups are small and that radiation dose may be somehow inaccurate as no measures were available. abstract background: varus-alignment (bow-leggedness) is assumed to correlate with knee osteoarthritis (oa), but it is unknown whether varus-alignment precedes the oa or whether varus-alignment is a result of oa. objective: to assess the relationship between varusalignment and the development, as well as progression, of knee oa. methods: 1,501 participants in the rotterdam study were selected. knee oa at baseline and at follow-up (mean follow-up 6.6 years) was defined as kellgren & lawrence (k&l) grade 3 2, and progression of oa as an increase of 3 1 k&l degree. alignment was measured by the femoro-tibial angle on baseline radiographs. multivariable logistic regression for repeated measurements was used. results: of 2,664 knees, 35.2% showed normal alignment, 64.3% varus-alignment, and 0.5% valgus-alignment. comparison of high varus-alignment versus normal, low and mediate varus-alignment together, showed a two-fold increase in the development of knee oa. (or = 1.83; 95%ci = 1.17-2.85). the risk of progression was higher in the high varus group compared to the normal, low and mediate varus group (or = 2.53; 95%ci = 1.04-6.19). stratification for overweight gave similar odds ratio's in the overweight group, but weaker odds ratio's in the non-overweight group. conclusion: a higher value of varus-alignment is associated with the onset and progression of knee oa. abstract background: echocardiographic image quality in copd patients can be hampered by hyperinflated lungs. cardiovascular magnetic resonance imaging (cmr) may overcome this problem and provides accurate and reproducible information about the heart without geometric assumptions. objective: to determine the value of easily assessable cmr parameters compared to other diagnostic tests in identifying heart failure (hf) in copd patients. design and methods: participants were recruited from a cohort of 405 copd patients = 65 years. a panel established the diagnosis of hf during consensus meetings using all diagnostic information, including echocardiography. in a nested case-control study design, 37 copd patients with hf (cases) and a random sample of 41 copd patients without hf (controls) received cmr. the diagnostic value of cmr for diagnosing hf was quantified using univariate and multivariate logistic modelling and roc-area analyses. results: four easily assessable cmr measurements had significantly more added diagnostic value beyond clinical items (roc-area 0.91) than amino-terminal pro b-type natriuretic peptide (roc-area 0.80) or electrocardiography (roc-area 0.77). a 'cmr model' without clinical items had an roc-area of 0.88. conclusion: cmr has excellent capacities to establish a diagnosis of heart failure in copd patients and could be an alternative for echocardiography in this group of patients. abstract background: the prevalence of overweight (i.e, body mass index [bmi] > = 25 kg/m2) is increasing. new approaches to address this problem are needed. objectives: 1) to assess the effectiveness of distance counseling (i.e., by phone and e-mail/internet) on body weight and bmi, in an overweight working population. 2) to assess differences in effectiveness of the two communication methods. design and methods: 1386 overweight employees (67% male; mean age 43.9±8.6 years; mean bmi 29.6±3.5 kg/m2) were randomized to a control group receiving general information on overweight and lifestyle (n = 460), a phone based intervention group (n = 462) and an internet based intervention group (n = 464). the intervention took 6 months and used a cognitive behavioral approach, addressing physical activity and diet. the primary outcome measures, body weight and bmi, were measured at baseline and at six months. statistical analyses were performed with multiple linear regression. results: the intervention groups (i.e., phone and e-mail combined) lost 1.5 kg (bmi reduced by 0.5 kg/m2) over the control group (p = 0.000). the phone group lost 0.5 kg more than the internet group (p = 0.179). abstract objective: although an inverse gradient education-mortality has been shown in the general population, little is known about this trend in groups with higher risks of death.we examine differences in mortality by education and hiv-status among injecting drug users (idus) before and after introduction of highly active antiretroviral therapy (haart) in 1997. methods: communitybased cohort study of idus recruited in 3 aids prevention centres (1987) (1988) (1989) (1990) (1991) (1992) (1993) (1994) (1995) (1996) abstract background: pancreatic cancer is an aggressive cancer with low survival time, with health-related quality of life (hrqol) being of major importance. objectives: the aim of our study was to assess both generic and disease-specific hrqol in patients with pancreatic cancer. methods: patients with suspected pancreatic cancer were consecutively included at admission to the hospital. hrqol was determined with the disease-specific european organization for research and treatment of cancer (eortc) health status instrument and generic euroqol (eq-5d). results: a total of 57 patients (mean age 62 years ±11, 49% men) were admitted with suspected pancreatic cancer. of these patients, 45 (79%) had pancreatic cancer confirmed as final diagnosis. hrqol was significantly impaired in patients with pancreatic cancer for most eortc and eq-5d scales in comparison to norm populations. the ed-5d visual analogue scale (vas) and utility values were significantly correlated to the five functional scales, to the global health scale and to some but not all of the eortc symptom scales/items. conclusions: hrqol was severely impaired in patients with pancreatic cancer. there was a significant correlation between most eortc and eq-5d scales. our results may facilitate further economic evaluations and aid health policy makers in resource allocation. abstract background: organised violence has health impact both on those who experience the violence directly and indirectly. the numbers of people affected by mass violence is alarming. substantial knowledge on the long-term health impact of organized violence is of importance for public health and for epidemiology. objectives: to investigate research results of long term mental health impact of organised violence. design and methods: a search of papers for the keywords genocide, organised violence, transgenerational effects, mental health was carried out in pubmed, science citation index and psychinfo. results: the systematic review on the long-term health impact of genocide showed that exposure to organised violence has an impact on mental health. methodological strenghts and weaknesses varied between studies. the found mental health consequences were associated with the country of research and the time of study. overall data showed organised violence has transgenerational impact on mental health of individuals and societies. conclusion: longitudinal studies have to be carried out to get further insight into the long-term health effects of organised violence. discussion: research results on mental health effects of organised violence have to be analysed in the context of changing concepts of illness. overweight is increasing and associated with various health problems. there are no well-structured primary care programs for overweight available in the netherlands. therefore, we developed a 12-month multidisciplinary treatment program in a primary care setting. the aim of the present study is to determine the feasibility and efficacy of a multidisciplinary treatment program on weight loss and risk profile in an adult overweight population. hundred participants of the utrecht health project are randomised to either a dietetic group or a dietetic plus physiotherapy group. the control group consist of another 50 participants recruited from the utrecht health project and receives routine health care. body weight, waist circumference, blood pressure, serum levels, energy-intake and physical activity are measured at baseline, halfway and at the end of the treatment program. feasibility of the treatment program is assessed by response, compliance and program-associated costs and workload. efficacy is determined by analysing changes in outcome measures between groups over time using t-tests and anova repeated measurements. the treatment program is considered effective with at least a 5% difference in mean weight change over time between groups. positive evaluation of the multidisciplinary treatment program for overweight may lead to implementation in routine primary health care. abstract background: examining patient's quality of life (qol) before icu admission will permit to compare and analyze its relation with other variables. objectives: analyze qol of patients admitted to a surgical icu before admission and study its relation with baseline characteristics and outcome. design and methods: the study was observational and prospective in a surgical icu, enrolling all patients admitted between november 2004 and april 2005. baseline characteristics of patients, history of co morbidities and quality of life survey score (qolss) were recorded. assessment of the relation between each variable or outcome and the total score of qolss was performed by multiple linear regression. results: total qolss demonstrated worse qol in patients with hypertension, cerebrovascular disease, renal insufficiency, severely ill (as measured by saps and asa physical status), and in older patients. there was no relation between qol and longer icu los. conclusions: preadmission qol correlates with age, severity of illness, comorbidities and mortality rates but is an able to predict longer icu stay. discussion: qolss appears to be a good indicator of outcome and severity of illness. abstract background: transient loss of consciousness (tloc) has a cumulative lifetime incidence of 35%, and can be caused by various disorders. objectives: to assess the yield and accuracy of initial evaluation (standardized history, physical examination and ecg), performed by attending physicians in patients with tloc, using follow-up as a gold standard. design and methods: adult patients presenting with tloc to the academic medical centre between february 2000 and may 2002 were included. after initial evaluation physicians made a certain, likely or no initial diagnosis. when no diagnosis was made additional cardiological testing, expert history taking and autonomic function testing were performed. the final diagnosis, after 2 years follow-up, was determined by an expert committee. results: 503 patients were included. after initial evaluation, 24% of the patients were diagnosed with a certain and 40% with a likely cause for their episodes. overall diagnostic accuracy was 91% (95%ci 88-94%); 96% (95%ci 91-98%) for the certain diagnoses and 88% (95%ci 83-92%) for the likely diagnoses. conclusion and discussion: attending physicians make a diagnosis in 64% of patients with tloc after initial evaluation, with high accuracy. the use of abundant additional testing can be avoided in many patients. abstract background: the possibility of an influenza pandemic is one of the major public health challenges of today. risk perceptions among the general public may be important for successful public health measures to better control an outbreak situation. objectives: we investigated risk perception and efficacy beliefs related to an influenza pandemic in the general population in 8 countries in europe and asia. design and methods: telephone interviews were conducted in 2005. risk perception of an influenza pandemic was measured on a 5-point scale and outcome-and self-efficacy on a 4point scale (low-high). the differences in risk perception by country, sex and age were assessed with a general linear model including interaction effects. results: 3,403 persons were interviewed. the mean risk perception of flu was 3.14 and was significantly higher in europe (3.21) compared to asia (3.03) (p<0.001) and higher in women (3.23) than men (3.02) (p<0.001). outcome-and self-efficacy were lower in europe than asia. conclusion: in europe higher risk perceptions and lower efficacy beliefs were found as compared to asia. in developing preparedness plans for an influenza pandemic specific attention should therefore be paid to risk communication and how perceived self-efficacy can be increased. abstract background: increased survival of patients with cf has prompted interest towards their hrqol. objectives: 1.to measure hrqol and its predictors in cf patients cared for at the bambino gesuc hildren's hospital in rome; 2. to assess the psychometric properties of the italian version of the cf specific hrqol instrument (cystic fibrosis questionnaire, cfq). design and methods: crosssectional survey. all cf patients aged 7 years or more were asked to complete the cfq (age-specific format). psychological distress was assessed through standardized questionnaires in patients (achenbach and general health questionnaire, ghq) and their parents (ghq and sf-36). results: one-hundred-eighteen patients (58 males, 60 females, age range 7 to 39 years) participated in the study (response rate 97%). internal consistency of cfq was satisfactory (cronbach alpha from 0.60 to 0.88); all item-test correlation were greater than 0.40. average cfq standardized scores were very good in all domains (>70 on a 0-100 scale), except perceived burden of treatments (57) and degree of socialization (45). multiple regression analysis was performed to identify factors associated with different hrqol dimensions. conclusion: support interventions for these patients should concentrate on finding a balance between need to prevent infections and promotions of adequate, age-appropriate social interactions. abstract background: the metabolic syndrome (metsyn) -a clustering of metabolic risk factors with diabetes and cardiovascular diseases as the primary clinical outcomes -is thought to be highly prevalent with an enormous impact on public health. to date, consistent data in germany are missing. objective: the study was conducted to examine the prevalence of the metsyn (according to ncap atp iii-definition) among german patients in primary care. methods: the german-wide cross-sectional study run two weeks in october 2005 with 1503 randomly selected general practitioners included. blood glucose and serum lipids were analyzed, waist circumference and blood pressure assessed, data on smoking, dietary and exercise habits, regional and sociodemographic characteristics collected. abstract background: excessive infant crying is a common and often stress inducing problem than can ultimately result in child abuse. from previous research is known that maternal depression during pregnancy is related to excessive crying, but so far little attention is paid to paternal depression. objective: we studied whether paternal depression is independently associated to excessive infant crying. design and methods: in a prospective multiethnic population-based study we obtained depression scores of 3,451 mothers and 2,606 fathers at 20 weeks pregnancy using the brief symptom inventory, and information on crying behaviour of 2,747 infants at 2 months. we used logistic regression analyses in which we adjusted for depression of the mother, level of education, smoking and alcohol use. results: paternal depressive symptomatology was related to the widely used wessel's criteria for excessive crying (adusted odds ratio 2.34, 1.22 -4.49). conclusion: our findings indicate that paternal depressive symptomatology might be a risk factor for excessive infant crying. discussion genetic as well as other direct (e.g. interaction between father and child) or indirect (e.g. marital distress or poor circumstances) mechanisms could explain the found association. abstract background: in studying genetic background of congenital anomalies the comparison of affected cases to non-affected controls is popular method. investigation of case-parent triads uses observation of cases and their parents exclusively. methods: both casecontrol approach and log-linear case-parent triads model were implemented to spina bifida (sb) cases and their parents (61 triads) and 267 controls in analysis of impact of the c667t and a1298c mthfr polymorphisms on occurrence of sb. results: observed frequencies for 677tt genotype were 11,5% in sb children, 6,6% in mothers, 9,8% in fathers, 8,6% in controls and for 1298cc genotype were 4,9% of sb children, 4,9% of mothers, 11,5% of fathers and 7,9% of controls. both genotype frequencies in sb triads did not differ significantly from controls. case-control approach showed nonsignificant increase in risk of having sb for 677t allele carriers either in homozygous (or = 1,7) or heterozygous form (or = 1,2) and for 1298c allele carriers in heterozygous form (or = 1,3). log-linear model revealed significant relative risk of sb in children with both 677tt and ct genotype (rr = 3,77 and rr = 2,37 respectively). child's genotype at a1298c and mother's genotypes did not contribute to the risk. conclusions: caseparent triads approach adds new information regarding impact of parental imprinting on congenital anomalies. abstract background: previous studies showed an association of autonomic dysfunction with coronary heart disease (chd) and with depression as well as an association of depression with chd. however, there is limited information on autonomic dysfunction as potential mediator of the adverse effect of depression on chd. objectives: to examine the role of autonomic dysfunction as a potential mediator of the association of depression with chd. design/ methods: we used data of 1309 participants aged 45-83 years of the ongoing population-based cross-sectional carla study (54% male). time-and frequency-domain parameters of heart rate variability (hrv) as a marker of autonomic dysfunction were calculated. prevalent myocardial infarction (mi) was defined as selfreported physician-diagnosed mi or diagnostic minnesota code in the electrocardiogram. depression was defined based on the cesd-depression scale. logistic regression was used to assess associations between depression, hrv and mi. results: in ageadjusted logistic regression models, there was no statistically significant association of hrv with depression, of depression with mi, or of hrv with mi in men and women. discussion/conclusion: the present analyses do not support the hypothesis of an intermediate role of autonomic dysfunction on the causal path from depression to chd. abstract background: hypertension is an established risk factor for cardiovascular disease. however, prevalence of untreated or uncontrolled hypertension is often high (even in populations at high risk). objectives: to assess the prevalence of untreated and of uncontrolled hypertension in an elderly east german population. design and methods preliminary data of a cross-sectional, populationbased examination of 1556 men and women aged 45-83 years were analysed. systolic (sbp) and diastolic blood pressure (dbp) were measured and physician-diagnosed hypertension and use of antihypertensive drugs were recorded. prevalence of hypertension was calculated according to age and sex. results: of all participants, 78.5 % were hypertensive (81.8 % of men, 74.8 % of women). of these, 29.7 % were untreated, 43.8 % treated but uncontrolled, and 26.6 % controlled. women were more often properly treated than men. the prevalence of untreated hypertension was highest in men aged 45-55 years (60.9 %) and lowest in men and women aged > = 75 years (12.6 %). uncontrolled hypertension increases with age in both sexes. conclusion and discussion: in this elderly population, there is a high prevalence of untreated and uncontrolled hypertension. higher awareness in the population and among physicians is needed to prevent sequelae such as cardiovascular disease. abstract background: exposure to pesticides is a potential risk factor for subfertility, which can be measured by time-to-pregnancy (ttp). as female greenhouse workers constitute a major group of workers exposed to pesticides at childbearing age, a study was performed among these and a non-exposed group of female workers. objectives: to measure the effects of pesticide exposure on time-topregnancy. design and methods: data were collected through postal questionnaires with detailed questions on ttp, lifestyle factors, and work tasks (e.g. application of pesticides, re-entry activities, and work hours) during six months prior to conception of the most recent pregnancy. associations between ttp and exposure to pesticides were studied in cox's proportional hazards models among 398 female greenhouse workers and 524 referents. results: the initial fecundability ratio (fradjusted) for greenhouse workers versus referents was 1.11 (95%ci: 0.96-1.29). this fr proved to be biased by the reproductively unhealthy worker effect. restricting the analyses to fulltime workers only gave an fradjusted of 0.89 (95%ci: 0.67-1.19). among primigravidous greenhouse workers, an association was observed between prolonged ttp and gathering flowers (fr = 0.46, 95%ci: 0.18-1.19). conclusion and discussion: this study adds some evidence to the hypothesis of adverse effects of pesticide exposure on time-topregnancy, but more research is needed. abstract background: hfe-related hereditary hemochromatosis (hh) is an iron overload disease for which screening is recommended to prevent morbidity and mortality. however, discussion has risen on the clinical penetrance of the hfe-gene mutations. objective: in the present study the morbidity and mortality of families with hferelated hh is compared to a normal population. methods: c282yhomozygous probands with clinically overt hfe-related hh and their first-degree relatives filled in a questionnaire on health, diseases and mortality among relatives. laboratory results on serum iron parameters and hfe-genotype were collected. the self-reported morbidity, family mortality and laboratory results were compared with an age and gender matched subpopulation of the nijmegen biomedical study (nbs), a population-based survey conducted in the eastern part of the netherlands. results: twohundred-twenty-eight probands and 743 first-degree relatives participated in the hefas. serum iron parameters were significantly elevated in the hefas population compared to the nbs controls. also, the morbidity within hefas families was significantly increased for fatigue, hypertension, liver disease, myocardial infarction, osteoporosis and rheumatism. mortality among siblings, children and parents of hefas probands and nbs participants was similar. discussion: the substantially elevated morbidity within hefas families justifies further exploration for a family cascade screening program for hh in the netherlands. abstract objectives: to evaluate awareness levels and effectiveness of warning labels in cigarette packs, among portuguese students enrolled in the 7th to the 12th grades. design and methods: a cross sectional-study was carried out in may (2004) in a high school population (7th-12th grades) in the north of portugal (n = 1005). a confidential self-reported questionnaire was administered. warning labels effectiveness was evaluated by changes in smoking behaviour and cigarette consuption, during the period between june/2003 (before the implementation of the tobacco warnings labels in portugal) and may/2004. continuous variables were compared by the t-test for paired samples and kruskal-wallis test. crude and adjusted odds ratios and confidential intervals were calculated by logistic regression analysis. results: the majority of students (71.8%) have a high level of awareness about warning labels content. this knowledge was significantly associated with school grade and current smoking status. none of these variables was significantly associated with changes in smoking behaviour. although not reaching statistic significance, the majority of teenagers (75.4%) increased or kept their smoking pattern. awareness level was not associated with smoking prevalence or consumption decreases. conclusions: current warning labels are ineffective in changing smoking behaviour among portuguese adolescents. abstract background: injuries are an important cause of morbidity. the presence of pre-existing chronic conditions (pecs) have been shown to be associated with higher mortality. objectives: aim of this study is to evaluate the association between pecs and risk of death in elder trauma patients. methods: an injury surveillance, based on the integration between emergency, hospital, and mortality databases of lazio region, year 2000, was used. patients were the elder people visited at the emergency departments, and hospitalised. pecs were evaluated on the basis of the charlson comorbidity index (cci). to measure the effect of pecs on the probability of death, we used logistic regression. results: 8145 patients were admitted to the hospital. the 17.9% of the injured subjects were affected by one or more chronic conditions. risk of death for non urgent and urgent patients increased at increasing cci score abstract background: c-reactive protein (crp) was shown to predict prognosis in heart failure (hf). objective: to assess variability of crp over time in patients with stable hf. methods: we measured high-sensitivity crp (hscrp) 3 times (3-week intervals) in patients with stable hf. patients whose hscrp was >1 mg/dl or whose clinical status deteriorated were excluded. two consecutive hscrp measurements were available for 50 patients: 37 men, mean(sd) age 69.6(11.9) years, 82% depressed left ventricular systolic function. forty-four patients had a third measurement. using the cutoff point of 0.3mg/dl for prediction of adverse cardiac events we assessed the proportion of patients who changed risk category. results: median(p25-p75) baseline hscrp was 0.19mg/dl(0.12-0.34). hscrp varied largely particularly for higher levels. the 5th and 95th percentiles of differences between first two measurements were )0.20mg/dl and +0.55mg/dl. correlation coefficient between these measurements: 0.55, p<0.001. eleven (22%) patients changed risk category, kappa = 0.53, p<0.001. among patients whose first two measurements were concordant, 16.7% changed category in third measurement, kappa = 0.65, p<0.001. conclusion: large variability in hscrp in stable hf may decrease the validity of risk stratification based on single measurements. it remains to be demonstrated whether the pattern of change over time adds predictive value in hf patients. abstract background: instrumental variables can be used to adjust for confounding in observational studies. this method has not yet been applied with censored survival outcomes. objectives: to show how instrumental variables can be combined with survival analysis. design and methods: in a sample of 415 patients with type-1 diabetes who started renal-replacement therapy in the netherlands between 1985 and 1996, the effect of pancreas-kidney transplantation versus kidney transplantation on mortality was analyzed using region as the instrumental variable. because the hospital could not be chosen with this type of transplantation, patients can be assumed to be naturally randomized across hospitals. we calculated an adjusted difference in survival probabilities for every time point including the appropriate confidence interval (ci95%). results: the 5-year difference in survival probabilities between the two transplantation methods, adjusted for measured and unmeasured confounders, was 0.37 (ci95%: 0.18-0.57) favoring the pancreas-kidney transplantation. this is substantially larger than the intention-to-treat estimate of 0.13 (ci95%: 0.01-0.25) where policies are compared. conclusion and discussion: instrumental variables are not restricted to uncensored data, but can also be used with a censored survival outcome. hazard ratios with this method have not yet been developed. the strong assumptions of this technique apply similarly with survival outcomes. 11.2] . sir of coronary heart disease was 5.7 [95%ci: 4.8-6.7] and remained significantly increased up to 30 years of follow-up. cox regression analysis showed a 3.2-fold (95% ci, 1.6-6.4) increased risk of congestive heart failure after anthracyclines and a 5.3-fold (95% ci, 1.6-16.8) increased risk of coronary heart disease after radiotherapy to the mediastinum. conclusion: the incidence of several cardiac diseases was strongly increased after treatment for hl, even after prolonged follow-up. anthracyclines increased the risk of congestive heart failure and radiotherapy to the mediastinum increased the risk of coronary heart disease. abstract background: the concept of reproductive health is emerging as an essential need for health development. objectives: to know the opinions of parents, teachers and students about education of reproductive health issues to students of mid and high schools. design and methods: focus group discussions (fgd) as a qualitative research was chosen. a series of 24 group discussions with participation of 162 persons (64 students, 50 teachers, and 48 parents) was held. each group had included 6 to 9 persons. results: all the participants noted to a true need in education of puberty health in order to provide essentials for pre-adolescent students to adopt the psycho-and somatic changes of puberty. however, a few fathers and a group of mothers believed that education of family planning is not suitable for students. a need for education of aids and marital problems for students was the major concern in all groups. the female students emphasized a need for programming counseling in pre-marital period. conclusion: essentials in puberty health, family planning, aids and marital problems should be provided in mid-and high schools in order to narrow the knowledge gap of the students. abstract background: the association between social support and hypertension in pregnancy remains controversial. objective: the objective of this study was to investigate whether level of social support is a protective factor against preeclampsia and eclampsia. design and methods: a case-control study was carried out in a public high-risk maternity hospital in rio de janeiro, brazil. between july 2003-may 2004, all 225 cases, identified at diagnosis, and 459 controls, matched on gestational age, were included in the study. participants were interviewed about clinical history, socio-demographic and psychosocial characteristics. the principal exposure was the level of social support available during the pregnancy, using the medical outcomes study scale. adjusted odds ratios were estimated using multivariate conditional logistic regression. results: multiparous women with a higher level of social support had a lower risk of presenting with preeclampsia and eclampsia (or = 0.7), although this association was not statistically significant (95% ci 0.4-1.2). in primiparous women, a higher level of social support was seen amongst cases (or = 2.1; 95% ci 1.5-2.9). an interaction between level of social support and stressful life events was not identified. these results contribute to increased knowledge of the relationship between preeclampsia and psychosocial factors in low-income pregnant and puerperal women. abstract background: current case-definitions for cfs/me are designed for clinical-use and not appropriate for health needs assessment. a robust epidemiological case-definition is crucial in order to achieve rational allocation of resources to improve service provision for people with cfs/me. objectives: to identify the clinical features that distinguish people with cfs/me from those with other forms of chronic fatigue and to develop a reliable epidemiological case-definition. methods-primary care patient data for unexplained chronic fatigue was assessed for symptoms, exclusionary and comorbid conditions and demographic characteristics. 101 cases were assigned to disease and non-disease groups by three members of the chief medical officer's working group on cfs/me (reliability-cronbach's alpha 0.644). results: preliminary multivariate analyses were conducted and classification and regression tree analysis included a 10-fold cross-validation approach to prevent over fitting. the results suggested that there were at least four strong discriminating variables for cfs/ me with 'post-exertional malaise' being the strongest predictor. risk and classification tables showed an overall correct classification rate of 81.2%. conclusion: the analyses demonstrated that the application of the combination of the four discriminating variables (the defacto epidemiological case-definition) and predefined comorbid conditions had the ability to differentiate between cfs/me and non-cfs/me cases. abstract background: infection with high-risk human papillomavirus (hpv) is a necessary cause for cervical cancer. vaccines against the most common types (hpv16, hpv18) are being developed. relatively little is known about factors associated with hpv16 or hpv18 infection. we investigated associations between lifestyle factors and hpv16 and hpv18 infection. methods: 5031 uk women aged 20-59 years with a recent abnormal cervical smear underwent hpv testing and completed a lifestyle questionnaire. hpv16 and hpv18 status was determined using type-specific pcrs. associations between lifestyle factors and hpv status were assessed by multivariate logistic regression models. results: 16.5% (95%ci 15.4%-17.6%) of women were hpv16-positive. 8.6% (95% ci 7.9%-9.5%) were hpv18-positive. for both types, the proportion testing positive decreased with increasing age, and increased with increasing grade of cytological abnormality. after adjusting for these factors, significant associations remained between (i) hpv16 and marital, employment, and smoking status and (ii) hpv18 and marital status and contraceptive pill use. gravidity, ethnicity, barrier contraceptive use and socio-economic status were not related to either type. conclusions we identified modest associations between several lifestyle factors and hpv16 and hpv18. studies of this type help elucidate hpv natural history in different populations and will inform development of future vaccine delivery programmes. in ageing men testosterone levels decline, while cognitive function, muscle and bone mass, sexual hair growth, libido and sexual activity decline and the risk of cardiovascular diseases increase. we set up a double-blind, randomized placebo-controlled trial to investigate the effects of testosterone supplementation on functional mobility, quality of life, body composition, cognitive function, vascular function and risk factors, and bone mineral density in older hypogonadal men. we recruited 237 men with serum testosterone levels below 17 nmol/l and ages 60-80 years. they were randomized to either four capsules of 40 mg testosterone undecanoate (tu) or placebo daily for 26 weeks. primary endpoints are functional mobility and quality of life. secondary endpoints are body composition, cognitive function, aortic stiffness and cardiovascular risk factors and bone mineral density. effects on prostate, liver and hematological parameters will be studied with respect to safety. measure of effect will be the difference in change from baseline visit to final visit between tu and placebo. we will study whether the effect of tu differs across subgroups of baseline waist girth, testosterone level, age, and level of outcome under study. at baseline, mean age, bmi and testosterone levels were 67 (yrs), 27 (kg/m2) and 13.x (nmol/l), respectively. abstract at a student population, the carie's prevalence was 56,28%. objectives: to evaluate the efficiency between two types of oral health education programmes and the adherence towards tooth brushing. study design: case control study: 333 youngsters took part, 134 in the case group. an health education programme was carried out in 8 schools and included two types of strategies: a participative strategy (learning based on the colouring of the dental plaque) towards a case group; and a traditional strategy (oral expository method) towards a control group. during the outcome of the programmes, the oral health condition evaluation was done through cpo index, the adherence towards tooth brushing and the (iho's) oral hygiene index. results: in the initial dental exam the (iho) average was of 1,60. three months after the application of the oral health programme, there was a general decrease in the average of iho's to 1,30. discussion and conclusion: in the case group the decrease was higher: 0,36 to 0,20. the students submitted to a session of oral health education based on the colouring of the dental plaque showed an lower iho's average and higher knowledge. this can be due to the teaching session being more active, participative and demonstrative. abstract background: violence perpetuated by adolescents is a major problem in many societies. objectives: the aim of this study is to examine high school students' violent behaviour and to identify predictors. design and methods: a cross-sectional study was conducted in timis county, romania between may-june 2004. the sample consisted of 149 randomly selected classes, stratified proportionally according to grades 9-12, high school profile, urban and rural environment. the students completed a self administered questionnaire in their classroom. a weighting factor was applied to each student record to adjust for non-response and for the varying probabilities of selection. results: a total of 2908 students were included in the survey. during the last 12 months, 24.3% of adolescents got mixed into a physical fight outside school and 14.5% on school property. abstract background: drug use by adolescents has become an increasing public health problem in many countries. objectives: the aim of this study is to identify prevalence of drug use and to examine high school students' perceived risks of substance use. design and methods: a cross-sectional study was conducted in timis county, romania between may-june 2004. the sample consisted of 149 randomly selected classes, stratified proportionally according to grades 9-12, high school profile, urban and rural environment. the students completed a self administered questionnaire in their classroom. eighteen items regarding illicit drug use suggesting different intensity of use were listed. the response categories were 'no risk', 'slight risk', 'moderate risk', 'great risk' and 'don't know'. results: a total of 2908 students were included in the survey. the lifetime prevalence of any illicit drug was 5.3%. significant beliefs associated with drug use are: trying marijuana once or twice (p<0.001), smoking marijuana occasionally (p = 0.003), trying lsd once or twice (p = 0.035), trying cocaine once or twice (p = 0.001), trying heroine once or twice (p = 0.002). conclusion: the overall drug use prevalence is small. however, use of some drugs once or twice is not seen as a very risky behaviour. abstract background: the health ombudsman service was created in ceara´, brazil, in 1991, with the objective of receiving user opinions about public services. objectives: to describe user profiles, evaluating their satisfaction with health services and the ombudsman service itself. design and methods: a transversal and exploratory study with a random sample of 292 users who had used the service in the last three months. the data were analyzed with the epi info program. results: women were those who used the service most (74.1%). the users sought the service for complaints (64.7%), guidance (12.3%) and commendation (11.5%). users made the following complaints about health services: lack of care (57.8%), poor assistance (52.0%) lack of medication (8.6%). in relation to the ombudsman service, the following failures were mentioned: lack of autonomy (14.7%), delay in solving problems (8.0%) and few ombudsmen (6.6%). conclusion: participation of the population in use of the serviced is small. the service does not satisfy the expectations of users, it is necessary to publicize the service and try to establish an effective partnership between users and ombudsmen so that the population finds in the ombudsman service an instrument to put into effect social control and improve the quality of health services. in chile, the rates of breast cancer and diabetes have dramatically increased in the last decade. the role of insulin resistance in the development of breast cancer, however, remains unexplored. we conducted a hospital-based case-control to assess the relationship of insulin resistance (ir) and breast cancer in chilean pre and postmenopausal women. we compared 175 women, 33-86 y, with incident breast cancer diagnosed by biopsy and 209 controls with normal mammography. insulin and glucose were measured in blood and ir was calculated by homeostasis model assessment method. anthropometric measurements and socio-demographic and behavioural data were also collected. odds ratios (ors) and 95% confidence intervals (cis) were estimated by multivariate logistic regression. the risk of breast cancer increased with age. ir was significantly associated to breast cancer in postmenopausal women (or = 2.03, 95%ci = 1.11-3.74), but not in premenopausal (p>0.05). socioeconomic status and smoking appeared as important risk factors for breast cancer. obesity was not associated with breast cancer at any age (p>0.05). in these women, ir increased the risk of breast cancer only after menopause. overall, these results suggest a different risk pattern for breast cancer before and after menopause. keywords: insulin resistance; breast cancer; chile. abstract background: previous european community health indicators (echi) projects have proposed a shortlist of 82 indicators as a common conceptual structure for health information. the european community health indicators and monitoring (echim) is a 3-year project to develop and implement health indicators and to develop health monitoring. objectives: our aim is to assess the availability and comparability of the echi-shortlist indicators in european countries. methods: four widely used health indicators i) perceived general health ii-iii) prevalence of any and certain chronic diseases or conditions iv) limitations in activities of daily living (adl) were evaluated. our evaluation of available sources for these indicators is based on the european health interview & health examination surveys database (171 surveys in chile, breast cancer, obesity and sedentary behaviour rates are increasing. the role of specific nutrients and exercise in the risk of breast cancer remains unclear. the aim of the present study was to evaluate the role of fruits and vegetables intake and physical activity in the prevention of breast cancer. we undertook an age matched case-control study. cases were 170 women with breast cancer histologically confirmed and controls were 170 women with normal mammography, admitted to the same hospital. a structured questionnaire was used to obtain dietary information and measurement of physical activity was obtained from the international physical activity questionnaire. odds ratios (ors) and 95% confidence intervals (cis) were estimated by conditional logistic regression adjusted by obesity, socioeconomic status and smoking habit. a significant association was found with fruit intake (or = 0.57, 95%ci = 0.35-0.94). the consumption of vegetables (or = 0.91, 95%ci = 0.80-1.04), moderate (or = 1.00, 95%ci = 0.62-1.59) and high physical activity (or = 1.13, 95%ci = 0.51-2.50) were not observed as protective factors. in conclusion, the consumption of fruit is protective in breast cancer. these findings need to be replicated at chile to support the role of diet and physical activity in breast cancer and subsequence contribution in public health policy. keywords: diet; physical activity; breast cancer; chile. the role of trace elements in pathogenesis of liver cirrhosis and its complications is still not clearly understood. serum concentrations of zinc, copper, manganese and magnesium were determinated in 100 patients with alcoholic liver cirrhosis and 50 healthy subjects by means of plasma sequential spectrophotometer. serum levels of zinc were significantly lower (median 0.77 vs 11.0lmol/l, p = 0.001) in patients with liver cirrhosis in comparison to controls. serum levels of copper were significantly higher in patients with liver cirrhosis (23.71 vs 13.32lmol/l, p<0.001) as well as manganese (4.60 vs 0.02lmol/l, p = 0.001). concentration of magnesium was not significantly different between patients with liver cirrhosis and controls (0.94 vs 0.88 mmol/l, p = 0.060). there was no difference in trace elements concentrations between child-pugh groups. zinc level was significantly lower in patients with hepatic encephalopathy in comparison to cirrhotic patients without encephalopathy (0.60 vs 0.96lmol/l, p = 0.020). manganese was significantly higher in cirrhotic patients with ascites in comparison to those without ascites (6.05 vs 2.60lmol/l, p = 0.039). correction of trace elements concentrations might have beneficial effect on complications and maybe progression of liver cirrhosis. it would be recommendable to provide analyzis of trace elements as a routine. abstract background: respiratory tract infections (rti) are very common in childhood and knowledge of pathogenesis and risk factors is required for effective prevention. objective: to investigate the association between early atopic symptoms and occurrence of recurrent rti during first 4 years of life. design and methods: in the prospective prevention and incidence of asthma and mite allergy birth cohort study, 4146 children were followed from birth to the age of 4 years. information on atopic symptoms, potential confounders, and effect modifiers like passive smoking, daycare attendance and presence of siblings was collected at ages 3 months and 1 year by parental questionnaires. information on rti was collected at ages 1, 2, 3, and 4 years. results: children with early atopic symptoms, i.e. itchy skin rash and/or eczema or doctordiagnosed cow's milk allergy at 1 year of age had a slightly higher risk to develop recurrent rti (aor 1.20 (0.83-1.73); and 1.98 (1.06-3.70), respectively). the association between atopic symptoms and recurrent rti was stronger in children whose mother smoked during pregnancy and who had siblings (aor 4. 12 (1.47-11.49) the aim : the aim of the study was to assess the relative risk (rr) of obesity and abdominal fat distribution on the insulin resistance (ir), diabetes, hyperlipidemia and hypertension in polish population. materials and methods: 6000 subjects at age 35-75, were randomized and invited to the study. in 2838 participants anthropometric and blood pressure examination was performed. fasting lipids, fasting and after glucose load glucose and insulin were determined. ir was defined as the upper quartile of the homa-ir distribution for the normal glucose tolerant population. results: overweight and obesity was observed in 39,7% and 25,1% of subjects. visceral obesity was found in 2143 subjects (88,9%-men and 73,4%-women). rr of ir in obesity was 3,94 (95% ci:3,09-5,04), for obese subjects at age below 45 was 6,6 (95% ci:3,6-12,0). in men with visceral obesity rr of ir was the highest for men aged below 55. rr of diabetes was increasing with the increase of body weight, in obese subjects with abdominal fat distribution was 2,88 (95%ci:2,20-3,79). the same was observed for the hypertension and hyperlipidemia. conclusions: obesity and the abdominal fat distribution seems to be an important risk factor of ir, diabetes, hypertension, hiperlipidemia, especially in the younger age groups. abstract background: age as an effect modifier in cardiovascular risk remains unclear. objective: to evaluate age-related differences in the effect of risk factors for acute myocardial infarction (ami). methods: in a population-based case-control study, with data collected by trained interviewers, 696 consecutive male cases of first myocardial infarction (participation rate 98%) and 867 randomly selected male control dwellers (participation rate 70%) were compared. effect-measure modification was evaluated by the statistical significance of a product term of each independent variable with age. unconditional logistic regression was used to estimate ors in each age stratum (<46 years/>45 years). results: there was a statistically significant interaction between education (>9 vs. <5 years), sports practice, diabetes and age: the adjusted (education, ami family history, dyslipidemia, hypertension, diabetes, angina, waist circumference, sports practice, alcohol and caffeine consumption, and energy intake) ors (95%ci) were respectively 0.16 (0.07-0.33), 0.76 (0.45-1.28) and 8.35 (1.64-42.6 ) in younger, and 0.46 (0.30-0.69), 0.36 (0.24-0.52) and 1.84 (1.08-3.16) in older participants. conclusions: in males, age has a significant interaction with education, sports practice and diabetes in the occurrence of ami. the effect is evident in the magnitude but not in the direction of the association. abstract there are few studies on the role of diet in lung cancer etiology. thus, we calculated both, squamous cell and small cell carcinoma risks in relation to the frequency of consumption of vegetables, cooked meat, fish and butter in silesian male in industrial area of poland. in the case-control study, the studied population comprised 237 men with squamous cell carcinoma and 122 men with small cell carcinoma, and 649 healthy controls. multivariate logistic regression was employed to calculate lung cancer risk in the relation to simultaneous influence of dietary factors. the relative risk was adjusted for age and smoking. we observed a significant decrease in lung cancer risk related to more frequent consumption of raw vegetables, cooked meat and fish. however, stronger protective effect was reported for squamous cell carcinoma. frequent fish consumption significantly decreases the risk especially in cigarette smokers. the frequent consumption of pickles lowers squamous cell carcinoma risk in all cases but small cell carcinoma risk only in smokers. the presence of butter, cooked meat, fish and vegetables in diet significantly decreases the lung cancer risk especially in smokers. the association between diet and lung cancer risk is more pronounced for squamous cell carcinoma. abstract background: in functional disease research selection mechanisms need to be studied to assure external validity of trial results. objective: we compared demographic and disease-specific characteristics, history, co-morbidity and psychosocial factors of patients diagnosed, approached and randomised for a clinical trial analysing the efficacy of fibre therapy in irritable bowel syndrome (ibs). design and methods: in primary care 1078 patients were diagnosed with ibs by their gp in the past two years. characteristics were compared between (1) randomised patients (n = 108); (2) patients who did not give their informed consent (n = 235); (3) patients who decided not to participate (n = 270); and (4) those not responding to the mailing (n = 465). results: the groups showed no significance differences in age and gender (74% females, mean age 41 years, s.d. 12). patients consulting their gp for the trial compared to patients not attending their gp showed significant more severe ibs symptoms, more abdominal pain during the previous three months, and a longer history of ibs (p<0,001). patients randomised have more comorbidity (p = 0,001). conclusion and discussion: patients included in this ibs trial differ from no participating and excluded patients mainly in ibs symptomatology, history and comorbidity. this may affect the external validity of the trial results. abstract objectives: to evaluate smoking prevalence among teenagers and identify associated social-behavioral factors. study design and methods: a cross sectional-study was carried out in may (2004) in high school population (7th-12th grades) in the north of portugal (n = 1005). a confidential self-reported questionnaire was administered. crude and adjusted odds ratios and confidence intervals were calculated by logistic regression analysis. results: overall smoking prevalence was 19.5% (boys = 26.1%; girls = 14.6%) (or = 2.06; ci 95% = 1.50-2.83; p<0.001). smoking prevalence was significantly and positively associated with gender, smoking parents, school failure and school grade; in the group of students with smoking relatives, smoking was significantly associated with parents who smoke near the student (or = 4.32; ci 95% = 2.41-7.74; p<0.001); in the group of the secondary grade (10th-12th grades) smoking was significantly associated with belonging to 'non science-courses' (or = 1.81; ci 95% = 1.18-2.78; p = 0.007). conclusions: smoking is a growing problem among portuguese adolescents, increasing with age, prevailing among males, although major increases have been documented in the female population. parents' behaviours and habits have an important impact in their children's smoking behaviour. school failure is also an important factor associated with smoking. there is a need for further prevention programmes that should include families and consider students' social environment. abstract background: social environment of school can contribute to etiology of health behaviors. objective: to evaluate the role of school context for substance abuse in youth. design: a cross-sectional study was carried out in 2005, using self-completed classroomadministered questionnaire. subjects: from a representative sample of 2893 students, a sub-sample of 1880 students was selected (including 85/130 classes with at least 15 persons without missing data)*. methods: substance abuse was measured by: tobacco smoking at present, episodes of drunkenness and marijuana use in the lifetime. overall index was created as main independent variable, ranging 0-9 (cronbach's alpha = 0.71). class membership, type of school, gender, place of domicile, and school climate were included as contextual variables, measured on individual or group level. results: on individual level, the mean index was equal to 3.5 (sd = 2.9), and ranged from 3.1 in general comprehensive schools to 4.6 in basic vocational schools and from 1.0 to 7.4 for separated classes. about 16.3% of total variance in this index may be attributed to differences between classes. conclusion: individual differences in substance abuse in youth could be partly explained by factors at school level. * project no 2 po5d 064 27. abstract background: rates of c-section in brazil are very high, 33.8% in 2004. brazil illustrates an extreme example of medicalization of birth. c-section, as any major surgery, increases the risk of morbidity, which can persist long after discharge from hospital. objectives: to investigate how social, reproductive, prenatal care and delivery factors interact after hospital discharge, influencing post partum complications. design and methods: a cross-sectional study of 200 women gathered information through home interviews and clinical examination during post-partum. a hierarchical logistic regression model of factors associated with post-partum complications was applied. results: physical and emotional post partum complications were almost twice as high among women having c-section. most of this effect were associated with lower socioeconomic conditions which influences, were mainly explained by longer duration of delivery (even in the presence of medical indications), and less social support when returning home. conclusion: risk of c-section complications is higher among women from the lower socioeconomic strata. social inequalities mediate the association between type of delivery and postpartum complications. discussion: c-section complications should be taken into account when decisions concerning type of delivery are made. social support after birth, from the public health sector, has to be provided for women in socioeconomic deprivation. the relationship between unemployment and increased mortality was previously reported in western countries. the aim of this study was to assess the influence of the changes in unemployment rate on survival in general population in northern poland at the time of economic transition. to analyze the association between the unemployment and risk of death we collected survival data from 62736 death certificates and data on rates of unemployment from 8 regions of gdansk county from period 1991-1996. kaplan-meier method and cox proportional hazard model were used in univariate and multivariate analysis. a change of unemployment (percentage) in the year of death in the area of residence, sex and educational level (6 categories) were included into multivariate analysis. the change of unemployment rate was associated with significantly worse overall survival: hazard ratio 1.02 95% confidence interval 1.016 to 1.024. the highest risk associated with the change of unemployment in the area of residence was for death from congenital defects (hazard ratio 1.16 95% confidence interval 1.04 to 1.3) and for death from cardiovascular diseases (hazard ratio 1.036 95% confidence interval 1.032 to 1.042 abstract background: there is no evidence from randomized trials as to whether or not educational interventions improve voluntary reporting systems in terms of quantity or quality. objectives: evaluation of the effectiveness of educational outreach visits aimed at improving adverse drug reaction (adr) reporting by physicians design and methods: cluster-randomized controlled trial covering all health system physicians in northern portugal. four spatialclusters assigned to intervention group (n = 1388) received outreach visits tailored to training needs detected in previous study and 11 clusters were assigned to the control (n = 5063). the main was the total number of reported adr; the second was the number of serious, unexpected, high-causality and new-drug-related adr. a follow-up was conducted for a period of 30 months. results: the intervention increased reports as follows: total adr, 9.7-fold (p<0.0001); serious adr, 6.1-fold (p = 0.001); high-causality adr, 8.5-fold (p<0.001); unexpected adr, 32.6-fold (p<0.001); and newdrug-related adr, 8.2-fold (p = 0.002). the intervention had its maximum effect during the first four months (23.3-fold increase, p<0.001), yet the effect was nonetheless maintained over the four 4month periods post-intervention (p = 0.06). discussion and conclusion: physician training based on academic detailing visits improves reporting quality and quantity. this type of intervention could result in sizeable improvements in voluntary reporting in many countries. there were no evidence of differences in absolute indications between the years. conclusion: most of the increase in rates in the period may be attributable to relative and non-medical indications. discussion policies to promote rational use of c-sections should take into account the role played by obstetrician's convenience and the increased medicalization of birth on cesarean rates. abstract background: the changing environment has led to unhealthy dietary habits and low physical activity of children resulting in overweight/obesity and related comorbid conditions. objective: idefics is a five-year multilevel epidemiological approach proposed under the sixth eu framework to counteract the threatening epidemic of diet-and lifestyle-induced morbidity by evidence-based interventions. design and methods: a population-based cohort of 17.000 children 2 to 10 years old will be established in nine european countries to investigate the aetiology of these diseases. culturally adapted multi-component intervention strategies will be developed, implemented and evaluated prospectively. results: idefics compares regional, ethnic and sex-specific distributions of the above disorders and their key risk factors in children within europe. the impact of sensory perception, genetic polymorphisms and the role of internal/external triggers of food choice and children's consumer behaviour are elucidated. risk profile inventories for children susceptible to obesity and its co-morbid conditions are identified. based on controlled intervention studies an evidencebased set of guidelines for health promotion and disease prevention is developed. conclusions: provision of effective intervention modules, easy to implement in larger populations, may reduce future obesity related disease incidence. discussion: transfer of feasible guidelines into practice requires involvement of health professionals, stakeholders and consumers. abstract background: non-medically indicated cesarean deliveries increase morbidity and health care costs. brazil has one of the highest rates of caesarean sections in the world. variations in rates are positively associated with socioeconomic status. objectives: to investigate factors associated with cesarean sections in public and private sector wards in south brazil. design and methods: cross sectional data from post partum interviews and clinical records of 216 consecutive deliveries (112 in the main public and 104 in a private maternity) was analyzed using logistic regression. results: multiple regression showed privately insured women having much higher cesarean rates than those delivering in public sector wards (or = 9.4; ci95%: 4.5-32.6). obstetricians individual rates varied from 38%-100%. doctors working in both, public and private sectors had a higher rates of cesarean in private wards (p<0.01). wanting and having a cesarean was significantly more common among privately insured women. conclusion: women from wealthier families are at higher risk of cesarean, particularly those willing this type of delivery and whose obstetrician works in the private sector. discussion: women potentially at lower clinical risk are more like to have a caesarean. the obstetricians' role and women's preferences must be further investigated to tackle this problem. abstract background: in the netherlands, bcg-vaccination is offered to immigrant children and children of immigrant parents in order to prevent severe tuberculosis. the effectiveness of this policy has never been studied. objectives: assessing the effectiveness of the bcg-vaccination policy in the netherlands. design and methods: we used data on the size of the risk population per year (from statistics netherlands), number of children with meningitis or miliary tuberculosis in the risk population per year, and vaccination status of those cases (from the netherlands tuberculosis register) over the period 1996-2003. we estimated the vaccine efficacy and annual risk of acquiring meningitis or miliary tuberculosis by log-linear modelling and treating the vaccination coverage as missing data. results: in the period 1996-2003 13 cases of meningitis or miliary tuberculosis were registered. the risk for unvaccinated to children to acquire such a serious tuberculosis infection was 4.54 (95%ci 2.26-9.62) per 100000 per year; the reduction in risk for vaccinated children was 81% (95%ci 31-94%). conclusion and discussion: this means that, discounting future effects with 4%, a 1088 (95%ci: 560-2500) extra children should be vaccinated to prevent one extra case of meningitis or miliary tuberculosis. given that bcg-vaccination is relatively inexpensive, the current policy could even be cost-saving. abstract background: psychotic symptom experiences in the general population are frequent and often longlasting. objectives: the zurich cohort study offered the opportunity of differentiating the patterns of psychotic experiences over a span of 20 years. design and methods: the zurich study is based on a stratified community sample of 591 persons born in 1958 (women) and 1959 (men). the data were collected at six time points since 1979. we examined variables from two subscales of the scl-90-r -'paranoid ideation' and 'psychoticism' -using factor analysis, cluster analysis and polytomous logistic regression. results: two new subscales were derived representing 'thought disorders' and 'schizotypal signs'. continously high symptom load on one of these subscales (both subscales) was found in 7% (1.7%) of the population. cannabis use was the best predictor of continuously high symptom load in the 'thought disorders' subscale, whereas several variables representing adversity in childhood / youth were associated with continuously high symptom load in the 'schizotypal signs' subscale. conclusion and discussion: psychotic experiences can be divided at least in two different syndromes -thought disorders and schizotypal signs. despite similar longitudinal course patterns and also similar outcomes these syndromes rely on different risk factors, thus possibly defining separate pathways to psychosis. abstract background: the reasons for the rise in asthma and allergies remain unclear. to identify influential factors several european birth cohort studies on asthma and allergic diseases have been initiated since 1985. objective: the aim of one work package within the global allergy and asthma european network (ga2len), sponsored by the european commission, was to identify and compare european birth cohorts specifically designed to examine asthma and allergic diseases. methods: for each study, we collected detailed information (mostly by personal visits) regarding recruitment process, study setting, follow-up rates, subjective/objective outcomes and exposure parameters. results: by june 2005, we assessed 18 european birth cohort studies on asthma and allergic diseases. the largest 5 recruited over 3000 children each. most studies determined specific immunoglobulin e levels to various allergens or used the isaac questionnaire for evaluation of asthma or allergic rhinitis symptoms. however, the assessment of other objective and subjective outcomes (e.g. lung function or definitions of eczema) were rather heterogeneous across the studies. conclusions due to the unique cooperation within the ga2len project a common database was established containing study characteristics of european birth cohorts on asthma and allergic diseases. the possibility to pool data and perform meta-analyses is currently being evaluated. abstract background: birth weight is an important marker of health in infancy and health trajectories later in life. social inequality in birth weight is a key component in population health inequalities. objective: to comparatively study social inequality in birth weight in denmark, finland, norway, and sweden from 1980 to 2005. design and methods as part of the nordic collaborative project on health and social inequality in early life (norchase), register-based data covering all births in all involved countries 1980-2005 was linked with national registries on parental socioeconomic position, covering a host of different markers including income, education and occupation. also, nested cohort studies provide opportunity to test hypotheses of mediation. results: preliminary results show that the social inequality in birth weight, small for gestational age, and low birth weight has increased in denmark through out the period. also, preliminary results from finland, norway and sweden will be presented. discussion: crosscountry comparisons pose several methodological challenges. these challenges include characterizing the societal context of each country so as to correctly interpret inter-country differences in social gradients, along with dealing with differences in the data collection methods and classification schemes used by different national registries. also, strategies for influencing policy will be discussed. abstract background: modifying the availability of suicide methods is a major issue in suicide prevention. objectives: we investigated changes in the proportion of firearm suicides in western countries since the 1980's, and their relation to the change of legislation and regulatory measures. design and methods: data from previous publications, from the who mortality database, and from the international crime victims survey (icvs) were used in a multilevel analysis. results: multilevel modeling of longitudinal data confirmed the effect of the proportion of households owning firearms on firearm suicide rates. several countries stand out with an obvious decline in firearm suicides since the 1980s: norway, united kingdom, canada, australia, and new zealand. in all of these countries legislative measures have been introduced which led to a decrease in the proportion of households owning firearms. conclusion and discussion: the spread of firearms is a main determinant of the proportion of firearm suicides. legislative measures restricting the availability of firearms are a promising option in suicide prevention. abstract background: fatigue is a non-specific but frequent symptom in a number of conditions, for which correlates are unclear. objectives: to estimate socio-demographic and clinical factors determining the magnitude of fatigue. methods: as part of a follow-up evaluation of a cohort of urban portuguese adults, socio-demographic and clinical variables for 563 consecutive participants were collected through personal interview. lifetime history of chronic disease diagnosis was inquired (depression, cancer, cardiovascular, rheumatic, and respiratory conditions), anthropometry was measured, and haemoglobin determined. krupp's 9-item fatigue severity scale was applied and severe fatigue defined as mean score over 4. mean age (sd) was 62.3 (9.9) and 58.8% of participants were females. logistic regression was used to compute adjusted odds ratios, and attributable fractions were estimated using the formula ar = 1-s(?j/orj). results: adjusted for age and clinical conditions, female gender (or = 1.56, 95%ci: 1.08-2.26) and education (under 5-years schooling: or = 1.61, 95%ci: 1.10-2.34) were associated with severe fatigue. obesity (or = 1.87, 95%ci: 1.21-2.90) and diagnosed cardiovascular disease (or = 2.23, 95%ci: 1.28-3.90) also increased fatigue. attributable fractions were 21.1% for gender, 14.2% for education, 9.8% for obesity, and 10.9% for cardiovascular disease. conclusion: gender and education have large impact on severe fatigue, and, to a lesser extent, obesity and cardiovascular disease. abstract introduction: analysis of infant mortality allows identification of death contributing factors and assessment of child health care quality. objective: to study characteristics of infant and fetal mortality using data from a committee for prevention of maternal and infant mortality, in sobral, brazil. methods: all cases of infant deaths between 2002 and 2004 were analyzed. medical records were reviewed and mothers, interviewed. using a tool to identify preventable deaths (seade classification -brazil) the committee characterized causes of death. meetings with governmental groups involved in family health care took place to identify death contributing factors. results: in 2002, infant mortality decreased from 29.7 to 18.9. in the next 2 years there was an increase from 23.1 to 26.6. the increase in 2003 was due to respiratory illnesses. in 2004, was due to diarrhea. analysis of preventable deaths indicated a reduction from 32 to 20 deaths that could have been prevented by adequate gestational care, and an increase in preventable deaths by early diagnosis and treatment. conclusion: pre-natal and delivery care improved whereas care for children less than 1 yr old worsened. analysis of death causes allowed a reduction of infant mortality rate to 16.44 abstract objective: to identify dietary patterns and its association with metabolic syndrome. design and methods: we evaluated 2166 noninstitutionalised adults. diet was assessed using a semi-quantitative dietary frequency questionnaire, and dietary patterns were identified using principal components analysis followed by cluster analysis (k-means method) with bootstrapping (choosing the clusters presenting the lowest intra-cluster variance). metabolic syndrome (mets) was defined according to the ncep-atp-iii. results: the overall prevalence of metabolic syndrome was 20.6%. in the population sample 4 clusters were identified in females -1.healthy, 2.milk/soup; 3.fast food; 4.wine/low calories; and 4 in males -1.milk/carbohydrates; 2. codfish/soup; 3.fast food; 4.low calories. in males, using milk/carbohydrates as the reference and adjusting for age and education, high blood pressure (or = 1.72; 95%ci:1.04-2.85) and high triglycerides (or = 1.61;95%ci:1.00-2.60) were associated with the fast food pattern, and low calories pattern presented higher frequency of high blood pressure (or = 1.61; 95%ci:1.01-2.55). in females, after age and education adjustment, no significant association was found either with metabolic syndrome or its individual features and the dietary patterns identified. conclusion: we found no specific dietary pattern associated with an increased prevalence of metabolic syndrome. however, a fast food diet was significantly more frequent in males with dyslipidemia and high blood pressure. abstract aim: to determine the prevalence of stress urinary incontinence (sui) before, during pregnancy and following childbirth, and also to analyse the impact of a health education campaign about sui prevention, following childbirth in viana district, portugal. methods: participants (n = 336), interviewed during hospitalization, after birth and two months later at health centres, were divided into two groups: a first group of non-exposed and a second exposed to a health education campaign. this second group was encouraged to perform an exercise programme and given a 'suiprevention-treatment' brochure, approved by the regional health authority. results: sui prevalence was 5.4%(95%ci: 3.0-7.8) before pregnancy, 51.5%(95%ci: 46.1-56.9) during pregnancy and 10.2(95%ci: 6.8-13.7) four weeks after birth. less than half of the women with sui sought help from healthcare professionals. statistical significant differences were found between groups: sui knowledge level and practice of pelvic floor muscles re-education exercises were higher in the exposed group (2.6 and 5.1 times, respectively). conclusions: sui affects a great number of women but only a small percentage reveals it. this campaign improved women knowledge and modified their else behaviors. healthcare professionals must be aware of this reality, providing an early and continuous intervention that would optimise the verified benefits of this campaign. abstract background: social inequalities have been associated with poorer developmental outcomes, but little is known about the role of the area of residence. objectives: examine whether the housing infrastructure of the area modifies the effect of socio-economic conditions of the families on child development. design and methods: community-based survey of 3052 under-fives in southern brazil applied hierarchical multi-level linear regression to investigate determinants of child development, measured by a score from the denver developmental screening test. results: in multivariable models, the mean score of child development increased with maternal and paternal education and work qualification, family income and better housing and was higher when the mother was in paid work (all p<0.001). paternal education had an effect in areas of lower housing quality only; the effect of occupational status and income in these areas were twice as large as in better-provided areas (likelihood test for all interactions p<0.05). this model explained 37% of the variation in developmental score between the areas of residence. conclusion: the housing quality and sanitation of the area modified the effects of socioeconomic conditions on child development. discussion: housing and sanitation programs are potentially beneficial to decrease the negative effect of social disadvantage on child development. abstract background: it is known that both genetic and environmental factors are involved in the early development of type1 diabetes (t1d), and that incidence varies geographically. however we still need to explain why there is variation in incidence. objectives: in order to better understand the role of non-genetic factors, we decided to examine whether prevalence of newborns with high risk genotypes or islet autoantibodies varies geographically. design and methods: the analysis was performed on a cohort of 29912 newborns born to non-diabetic mothers, between september 2000 and august 2004, who were included in diabetes prediction in ska˚ne study (dipis) in sweden. neighbourhoods were defined by administrative boundaries and variation in prevalence was investigated using multi-level regression analysis. results: we observed that prevalence of newborns with islet autoantibodies differed across the 33 municipalities of ska˚ne (s = 0.16, p <0.01), with highest prevalence found in wealthy urban areas. however there was no observed difference in the prevalence of newborns with high risk genes. conclusion and discussion: newborns born with autoantibodies to islet antigens appear to cluster by region. we suggest that non-genetic factors during pregnancy may explain some of the geographical variation in the incidence of t1d. abstract background: risk assessment is a science-based discipline used for decision making and regulatory purposes, such as setting acceptable exposure limits. estimation of risks attributed to exposure to chemical substances are traditionally mainly the domain of toxicology. it is recognized, however, that human, epidemiologic data, if available, are to be preferred to data from laboratory animal experiments. objectives: how can epidemiologic data be used for (quantitative) risk assessment? results: we described a framework to conduct quantitative risk assessment based on epidemiological studies. important features of the process include a weight-of-theevidence approach, estimation of the optimal exposure-risk function by fitting a regression model to the epidemiological data, estimation of uncertainty introduced by potential biases and missing information in the epidemiological studies, and calculation of excess lifetime risk through a life table to take into account competing risks. sensitivity analyses are a useful tool to evaluate the impact of assumptions and the variability of the underlying data. conclusion and discussion: many types of epidemiologic data, ranging from published, sometimes incomplete data to detailed individual data, can be used for risk assessment. epidemiologists should better facilitate such use of their data, however. abstract background: high-virulence h. pylori (hp) strains and smoking increase the risk of gastric precancerous lesions. its association with specific types of intestinal metaplasia (im) in infected subjects may clarify gastric carcinogenesis pathways. objectives: to quantify the association between types of im and infection with highvirulence hp strains (simultaneously caga+, vacas1 and va-cam1) and current smoking. design and methods: male volunteers (n = 201) underwent gastroscopy and completed a self-administered questionnaire. participants were classified based on mucin expression patterns in biopsy specimens (antrum, body and incisura). hp vaca and caga were directly genotyped by pcr/reverse hybridization. data were analysed using multinomial logistic regression (reference: normal/superficial gastritis), models including hp virulence, smoking and age. results: high-virulence strains increased the risk of all im types (complete: or = 3.08, 95%ci:1.20-7.89; incomplete: or = 9.23, 95%ci:2.20-38.72; mixed: or = 6.27, 95%ci:2.55-15.43) but smoking was only associated with an increased risk of complete im (or = 2.99 95%ci:1.15-7.78). compared to non-smokers infected with lowvirulent strains, infection with the high-virulence hp increased the risk of im similarly for smokers (or = 11.00, 95%ci:3.59-33.71) and non-smokers (or = 9.65 95%ci:3.82-24.40). conclusion: gastric precancerous lesions, with different potential for progression, are differentially modulated by hp virulence and smoking. the risk of im associated with high-virulence hp is not further increased by smoking. abstract background: in may 1999, the portuguese government created the basic urgency units (buu). these buu must attend at least 40.000 persons, be open 24 hours per day, and be at maximum 60 minutes of distance to all the users. objectives: determine the optimal location of buu, considering the existing health centers, in the viseu district, north portugal. methods: from a matrix of distances between population and health centers an accessibility index was created (sum of distances traveled by population to reach a buu). the location-allocation models were used to create simulations based on p-median model, maximal covering location problem (mclp) and set covering location problem (sclp). the solutions were ranked by weighting the variables of accessibility (50%), number of doctors in the health centers (5%), equipments (20%), distance/time (20%) and total number of buu (5%). results: the best solution has 3 buu, 89 doctors, attends 59 000 users and the accessibility index is 8.859 km. conclusions: it was proved that it is impossible to attend all the criterion for creation of a buu. in some areas with low population density, to sum at least 40 000 persons in a buu, the travel time is necessarily more than 1 hour. background: a prospective observational study of fatigue in staff working a 10 day/5 off/8 night/5 off roster of 12 hour shifts was conducted at a fly-in/fly-out fertilizer mine in remote northern australia. objectives: to determine whether fatigue in staff increased: from the start compared to the finish of shift; with the number of consecutive shifts; and from day-compared to nightshift. methods: data of sleep diaries, the mackworth clock test and the swedish occupational fatigue inventory were obtained at the start and finish of each shift from august to november 2004. results: a total of 51 staff participated in the study. reaction times, sleepiness and lack of energy scores were highest at the finish of nights 1 to 4. the reaction times increased significantly at both the start and finish of day 8 onwards, and at the finish of night 7. reaction times and lack of motivation were highest during nightshift. conclusions: from the above results, a disturbed diurnal rhythm and decreased motivation during night-shift; and a roster of more than eight consecutive shifts can be inferred as the primary contributors to staff fatigue. discussion: the implications for changes to workplace practices and environment will be discussed. the aim of this survey was to assess the impact of a meta-analysis comparing resurfacing with nonresurfacing of the patella on the daily practice of experts. participants in this study were 87 experts which had participated in a previous survey on personal preferences regarding patella resurfacing. these experts in the field of patella resurfacing were identified by a thorough search of medline, an internet search (with googletm search engine), and personal references from the identified experts. participants of the 'knee arthroplasty trial' (kat) in the united kingdom were also included. two surveys were sent to the participants, one before and one after the publication of the meta-analysis. the response rate is 39 questionnaires or 45%. the vast majority of responders are not persuaded to change change their practice after reading the metaanalysis. this is only in part due to the fact that best evidence and practice coincide. other reasons given are methodology related, an observation which is shared by the authors of the review, which force the orthopedic community to improve its research methodology. reasons such as 'i do not believe in meta-analysis' either demands a fundamental discussion or demands the reader to take evidence based medicine more seriously. abstract background: patients with type 2 diabetes (dm2) have a 2-3 fold increased risk of cardiovascular disease. delegating routine tasks and computerized decision support systems (cdss) such as diabetes care protocol (dcp) may improve treatment of cardiovascular risk factors hba1c, blood pressure and cholesterol. dcp includes consultation-hours exclusively scheduled for dm2 patients, rigorous delegation of routine tasks in diabetes care to trained paramedics, and software to support medical management. objective: to investigate the effects of dcp, used by practice assistants, on the risk of coronary heart disease for patients with dm2. design and methods: in an open-label pragmatic trial in 72 general practices with 7893 patients, hba1, blood pressure and cholesterol were examined before and prospectively one year after implementation of dcp. the primary outcome was the change in the 10 year ukpds coronary heart disease (chd) risk estimate. results: the median 10 year ukpds chd risk estimate improved significantly from 21.7% to 19.0%. hba1 decreased from 7.2% to 6.9%, systolic blood pressure from 148.4 to 144.0 mmhg and total cholesterol from 5.1 to 4.7 mmol/l. (all p<0.01). conclusion: delegating routine task in diabetes care to trained paramedics and using cdss improves the cardiovascular risk of dm2 patients. tuberculosis in exposed immigrants by tuberculin skin test, ifn-g tests and epidemiologic abstract background: currently immigrants in western countries are only investigated for active tuberculosis (tb) by use of a chest x-ray. recent latent tuberculosis infection (ltbi) is hard to diagnose in this specific population because the only available test method, the tuberculin skin test (tst), has a low positive predictive value (ppv). recently interferon-gamma (ifn-g) tests have become available that measure cellular responses to specific m. tuberculosis antigens and might have a better ppv. objective: to determine the predictive value of tst and two different ifn-g tests combined with epidemiological characteristics for developing active tb in immigrants who are close contacts of smear positive tb patients. methods in this prospective cohort study 800 close contacts will be included. demographic characteristics and exposure data are investigated. beside their normal examination they will all have a tst. two different ifn-g tests will be done in those with a tst induration of ?5 mm. these contacts will be followed for 2 years to determine the occurrence of tb. results since april 2005, 13 municipal health services have started with the inclusion. preliminary results on the predictive value of tst, both ifn-g tests and epidemiological characteristics will be presented. abstract background: different factors contribute to the quality of ed (emergency department) care of an injured patient. objective: determine factors influencing the disagreement between er diagnoses and those assigned at hospital admission in injuried patients, and evaluate if disagreement between the diagnoses could have worsened the outcome. methods: all the er visits of the 60 emergency departments of lazio region for unintentional injuries followed by hospitalisation in 2000. concordant diagnoses were established on the basis of the barell matrix cells. logistic regression was used to assess the role of individual and er care factors on the probability of concordance. a logistic regression where death within 30 days was the outcome and concordance the determinant was uses. results: 22,892 injury er visits were considered. in 62.2% cases, the er and discharge diagnoses were concordant. higher concordance was found with increasing age and less urgent cases. factors influencing concordance were: the hour of the visit, er level, initial outcome, length of stay in hospital. patients who had non concordant diagnoses had a 30% higher probability of death. conclusions: a correct diagnosis at first contact with the emergency room is associated with lower mortality. methods: a cohort of consecutive patients treated for secondary peritonitis were sent the posttraumatic stress syndrome inventory (ptss-10) and impact of events scale-revised (ies-r) 4-10 years following their surgery for secondary peritonitis. results: from the 278 patients operated upon between 1994 and 2000, questionnaires were sent to the 131 long-term survivors of which 88% responded (n = 101). ptsd-related symptoms were found in 17% of patients by both questionnaires. patients admitted to icu (n = 39) were significantly older, with higher apache-ii scores, but reported similar ptsd symptomology scores compared to non-icu patients (n = 61). traumatic memories during icu and hospital-stay were most predictive for higher scores. adverse memories did not occur more often in the icu group than in the hospital-ward group conclusions: longterm ptsdrelated symptoms in patients with secondary peritonitis were very barthé lé my 53 c cabanas ruiz-carrillo 429 de la cruz den boon jimé nez-moleó n mü ller-nordhorn 36 national evaluation team 436 279 rich-edwards in the netherlands. design and methods we used the populationbased databases of the netherlands cancer registry, the eindhoven cancer registry (ecr) and the central bureau of statistics. patients from the ecr were followed until 1-1-2005 for vital status and relative survival was calculated. results: the number of breast cancer cases increased from 7900 in 1989 to 11.500 in 2003, an annual increase of 1.3% (p<0.001). the death rate decreased 1,4% annually (p<0.001), which resulted in 3400 deaths in 2003. the relative 5-yr survival was less than 50% for patients diagnosed in the seventies, this increased to over 80% for patient diagnosed since 2000, patients with stage i disease even have a 96% 5-yr relative survival. conclusion: the alarming increase in breast cancer incidence is accompanied with a serious improvement in survival rates. this results in a large number of women (ever) diagnosed with breast cancer, about 119,000 in 2005 of whom 80% demand some kind of medical care. abstract background: nine % of the population in the netherlands belongs to non-western ethnic minorities. perceived health is worse and health care use different from dutch natives. objectives. which factors are associated with ethnic differences in self-rated health? which factors are associated with differences in utilisation of gp care? methods: during one year all contacts with gps were registered. adult surinam, antillean, turkish, moroccan and dutch responders were included (total n: 10.252). we performed multivariate analyses of determinants of self-rated health and on the number of contacts with gps. results: self-rated health differ from native dutch: surinam/antillean (or 2.4) and turkish/moroccan patients (or 4.7/3.8) , especially in turkish/moroccan females. more turks visit the gps at least once a year (or 1.5). less surinamese (or 0.5) and antillean patients (or 0.9) visit their gps than the dutch do. people from ethnic minorities in good health visit their gps more often (3.9 -4.4 consults per year vs. 3.4). incidence rates of acute respiratory infections and chest complaints were significantly higher than in the dutch. conclusions: ethnicity is independently associated with self-rated health. higher use of gp-care by ethnic minorities in good health, points towards possible inappropriate use of resources. the future: do they fulfil it? first results of the limburg youth monitoring project abstract background: incidence of coronary heart disease (chd) and stroke can be estimated from local, population-based registers. it is unclear, to what extent local register data are applicable on a nationwide level. therefore, we compared german register data with estimates derived with who global burden of disease (gbd) method. methods: incidence of chd and stroke was computed with the gbd method using official german mortality statistics and prevalences from the german national health survey. results were compared to estimates from the kora/monica augsburg register (chd) and the erlangen stroke project in southern germany. results: gbd estimates and register data showed good agreement: chd (age group 25-74 years) 155,862 (gbd) versus 159,245 (register) and stroke (all ages) 157,104 versus 167, 892 incident cases per year. chd incidence among all age groups was estimated with the gbd method to be 250,000 per year (no register data available). chd incidence in men and stroke incidence in women were underestimated with the gbd method as compared to register data. conclusions: gbd method is a useful tool to estimate incidence of chd and stroke. the computed estimates may be seen as lower limit for incidence data. differences between gbd estimates and register data are discussed. abstract background: children with mental retardation (mr) are a vulnerable not much studied population. objectives: to investigate psychopharmacotherapy in children with mr and to examine possible factors associated with psychopharmacotherapy. methods: participants were recruited through all facilities for children with mental retardation in friesland, the netherlands, resulting in 865 participants, 4-18 years old, including all levels of mental retardation. the dbc and the pdd-mrs were used to assess general behavior problems and pervasive developmental disorders (pdd). information on medication was collected through a parent-interview. logistic regression was used to investigate the relationship between the psychotropic drug use and the factors dbc, pdd, housing, age, gender and level of mr. results: 10% of the participants used psychotropic medication. main factors associated with receiving psychopharmacotherapy were pdd (or 2.31) and dbc score (or 1.03). living away from home and mr-level also played a role whereas gender and age did not. dbc score was associated with clonidine, stimulants and anti-psychotics. pdd was the main factor associated with anti-psychotics use (or 5.7). discussion: psychopharmacotherapy is especially prevalent among children with mr and comorbid pdd and general behavior problems. although many psychotropic drugs are used off-label, specific drugs were associated with specific psychiatric or behavior problems. abstract background: increased survival in children with cancer has raised interest on the quality-of-life of long-term survivors. objective: to compare educational outcomes of adult survivors of childhood cancer and healthy controls. methods: retrospective cohort study including a sample of adult survivors (495) treated for childhood cancer in the three existing italian paediatric research hospitals. controls (501) were selected among siblings, relatives or friends of survivors. when these controls were not available, a search was carried out in the same area of residence of the survivors though random digit dialling. data collection was carried out through a telephone-administered structured questionnaire. results: significantly more survivors than controls needed school support (adjusted odds ratio -oradj-1.61, 95% ci 1.22-2.13); failed at least a grade after disease onset (oradj 1.46, 95% ci 1.09-1.97); achieved a lower educational level (oradj 1.77, 95% ci 1.27-2.45) and did not reach an educational level higher than their parents' (oradj 1.66, 95% ci 1.19-2.32). subject's age, sex, parents' education and area of residence were taken into account as possible confounders. conclusions: these findings suggest the need to provide appropriate school support to children treated for childhood cancer. abstract background: in italy supplementation with folic acid (fa) in the periconceptional period to prevent congenital malformations (cms) is quite low. the national health institute has recently launched (2005) a programme to improve awareness about the role of fa in reducing the risk of serious defects also by providing 0.4 mg fa tablets free of charge to women planning a pregnancy. objectives: we analysed cms that are or may be sensitive to fa supplementation in order to establish an adequate baseline to allow a fa impact assessment in the next years and to investigate spatial differences among cms registries, time trends and time-space interactions. design and methods data collected over 1996-2003 by the italian registries members of eurocat and icbdsr on births and induced abortions with neural tube defects, ano-rectal atresia, omphalocele, oral clefts, cardiovascular, limb reduction and urinary system defects. results: all the cms showed statistically significant differences among registries with the exception of ano-rectal atresia. the majority of cms by registry showed stable or increasing trends over time. conclusions results show the importance of fa intake during the periconceptional period. differences among registries indicate also the need of having a baseline for each registry to follow trends over time. abstract country-specific resistance proportions are more biased by variable sampling and ascertainment procedures than incidence rates. within the european antimicrobial resistance surveillance system (earss) resistance incidence rates and proportions can be calculated. in this study, the association between antimicrobial resistance incidence rates and proportions and the possible effect of differential sampling of blood cultures was investigated. in 2004, earss collected routine antimicrobial susceptibility test data from invasive s. aureus isolates, tested according to standard protocols. via a questionnaire denominator information was collected. the spearman correlation coefficient and linear regression were used for statistical analysis. this year, 735 of 1205 hospitals and 483 of 758 laboratories from 28 of 30 earss countries responded to the questionnaire. they reported of, overall, 18,729 s. aureus isolates. in the different countries, mrsa proportions ranged from <1% to 40% and incidence rates per 1,000 patient days from 0.26ae10-2 to 19.29ae10-2. overall, the proportions and rates highly correlated. blood culturing rates only influenced the relationship between mrsa resistance proportions and incidence rates for eastern european countries. in conclusion, resistance proportions seem to be very similar to resistance incidence rates, in the case of mrsa. nevertheless, this relationship appears to be dependent of some level of blood culturing. . key: cord-002774-tpqsjjet authors: nan title: section ii: poster sessions date: 2017-12-01 journal: j urban health doi: 10.1093/jurban/jti137 sha: doc_id: 2774 cord_uid: tpqsjjet nan food and nutrition programs in large urban areas have not traditionally followed a systems approach towards mitigating food related health issues, and instead have relied upon specific issue interventions char deal with downstream indicators of illness and disease. in june of 2004, the san francisco food alliance, a group of city agencies, community based organizations and residents, initiated a collahorarive indicator project called rhe san francisco food and agriculture assessment. in order to attend to root causes of food related illnesses and diseases, the purpose of the assessment is to provide a holistic, systemic view of san francisco\'s food system with a focus on three main areas that have a profound affect on urban public health: food assistance, urban agriculture, and food retailing. using participatory, consensus methods, the san francisco food alliance jointly developed a sec of indicators to assess the state of the local food system and co set benchmarks for future analysis. members collected data from various city and stare departments as well as community based organizations. through the use of geographic information systems software, a series of maps were created to illustrate the assets and limitations within the food system in different neighborhoods and throughout the city as a whole. this participatory assessment process illustrates how to more effectively attend to structural food systems issues in large urban areas by ( t) focusing on prevention rather than crisis management, (2) emphasizing collaboration to ensure institutional and structural changes, and (3) aptly translating data into meaningful community driven prevention activities. to ~xplore the strategies to overcome barriers to population sample, we examined the data from three rapid surveys conducted at los angeles county (lac). the surveys were community-based partic· 1patory surveys utilizing a modified two-stage cluster survey method. the field modifications of the method resulted in better design effect than conventional cluster sample survey (design effect dose to that if the survey was done as simple random sample survey of the same size). the surveys were con· ducte~ among parents of hispanic and african american children in lac. geographic area was selected and d1.v1ded int.o small c~usters. in the first stage, 30 clusters were selected with probability proportionate to estimated size of children from the census data. these clusters were enumerated to identify and develop a list of households with eligible children from where a random sample was withdrawn. data collectmn for consented respondents involved 10-15 minutes in-home interview and abstraction of infor· ma~ion from vaccine record card. the survey staff had implemented community outreach activities designed to fost~r an~ maintain community trust and cooperation. the successful strategies included: developing re.lat1on .w.1th local community organizations; recruitment of community personnel and pro· vide them with training to conduct the enumeration and interview; teaming the trained community introduction: though much research has been done on the health and social benefits of pet ownership for many groups, there have been no explorations of what pet ownership can mean to adults who are marginalized, living on fixed incomes or on the street in canada. we are a community group of researchers from downtown toronto. made up of front line staff and community members, we believe that community research is important so that our concerns, visions, views and values are presented by us. we also believe that research can and should lead to social change. method: using qualitative and exploratory methods, we have investigated how pet ownership enriched and challenged the lives of homeless and transitionally housed people. our research team photographed and conducted one-on-one interviews with 11 pet owners who have experienced home· lessncss and live on fixed incomes. we had community participation in the research through a partnership with the fred vicror centre camera club. many of the fred victor centre camera club members have experienced homelessness and being marginalized because of poverty. the members of the dub took the photos and assisted in developing the photos. they also participated in the presenta· tion of our project. results: we found that pet ownership brings important health and social benefits to our partici· pants. in one of the most poignant statements, one participant said that pet ownership " ... stops you from being invisible." another commented that "well, he taught me to slow down, cut down the heavy drugs .. " we also found that pet ownership brings challenges that can at times be difficult when one is liv· ing on a fixed income. we found that the most difficult thing for most of the pet owners was finding affordable vet care for their animals. conclusion: as a group, we decided that research should only be done if we try to make some cha.nges about what we have learned. we continue the project through exploring means of affecting social change--for example, ~eti.tions and informing others about the result of our project. we would like to present our ~mdmgs and experience with community-based participatory action resea.rch m an oral. presentarton at yo~r conference in october. our presentation will include com· mumty representation ~f. both front-hne staff and people with lived experience of marginalization and homdessness. if this is not accepted as an oral presentation, we are willing to present the project m poster format. introduction the concept of a healthy city was adopted by the world health organization some time ago and it includes strong support for local involvement in problem solving and implementation of solutions. while aimed at improving social, economic or environmental conditions in a given community, more significantly the process is considered to be a building block for poliq reform and larger scale 'hange, i.e. "acting locally while thinking globally." neighbourhood planning can he the entry point for citizens to hegin engaging with neighbours on issues of the greater common good. methods: this presentation will outline how two community driven projects have unfolded to address air pollution. the first was an uphill push to create bike lanes where car lanes previously existed and the second is an ongoing, multi-sectoral round table focused on pollution and planning. both dt•monstrate the importance of having support with the process and a health focus. borrowing from traditions of "technical aid"• and community development the health promoter /planner has incorporated a range of "determinants of health" into neighbourhood planning discussions. as in most urban conditions the physical environment is linked to a range of health stressors such as social isolation, crowding, noise, lack of open space /recreation, mobility and safety. however typical planning processes do not hring in a health perspective. health as a focus for neighbourhood planning is a powerful starti_ng point when discussing transportation planning or changing land-uses. by raising awareness on determmants of health, citizens can begin to better understand how to engage in a process and affect change. often local level politics are involved and citizens witness policy change in action. the environmental liaison committee and the dundas east hike lanes project resulted from local level initiatives aimed at finding solutions to air pollution -a priority identified hy the community. srchc supported the process with facilitation and technical aid. _the processs had tangible results that ultimately improve living conditions and health. •tn the united kmgdom plannm in the 60's established "technical aid" offices much like our present day legal aid system to provide professional support and advocacy for communities undergoing change. p2-15 (c) integrating community based research: the experience of street health, a community service agency i.aura cowan and jacqueline wood street health began offering services to homeless men and women in east downtown ~oronto in 1986. nursing stations at drop-in centres and shelters were fo~lowed by hiv/aids prevent10~, harm reduction and mental health outreach, hepatitis c support, sleeping bag exchange, and personal tdennfication replacement and storage programs. as street health's progi;ams expanded, so to~ did the agency:s recognition that more nee~ed t~ be done to. address the underl~ing causes of, th~ soct~l and economic exclusion experienced by its clients. knowing t.h~t. a~voca~y ts. helped by . evtd~nce , street he.alt~ embarked on a community-based research (cbr) initiative to 1dent1fy commumty-dnven research priorities within the homeless and underhoused population. methods: five focus groups were conducted with 46 homeless people, asking participants to identify positive and negative forces in their lives, and which topics were important to take action on and learn more about. findings were validated through a validation meeting with participants. results: participants identified several important positive and negative forces in their lives. key positive forces included caring and respectful service delivery, hopefulness and peer networks. key negative forces included lack of access to adequate housing and income security, poor service delivery and negative perceptions of homeless people. five topics for future research emerged from the process, focusing on funding to address homelessness and housing; use of community services for homeless people; the daily survival needs of homeless people and barriers to transitioning out of homelessness; new approaches to service delivery that foster empowerment; and policy makers' understanding of poverty and homelessness. conclusions: although participants expressed numerous issues and provided much valuable insight, definitive research ideas and action areas were not clearly identified by participants. however, engagement in a cbr process led to some important lessons and benefits for street health. we learned that the community involvement of homeless people and front-line staff is critical to ensuring relevance and validity for a research project; that existing strong relationships with community parmers are essential to the successful implementation of a project involving marginalized groups; and that an action approach focusing on positive change can make research relevant to directly affected people and community agency staff. street health benefited from using a cbr approach, as the research process facilitated capacity building among staff and within the organization as a whole. p2-16 (c) a collaborative process to achieve access to primary health care for black women and women of colour: a model of community based participartory research notisha massaquoi, charmaine williams, amoaba gooden, and tulika agerwal in the current healthcare environment, a significant number of black women and women of color face barriers to accessing effective, high quality services. research has identified several issues that contribute to decreased access to primary health care for this population however racism has emerged as an overarching determinant of health and healthcare access. this is further amplified by simultaneous membership in multiple groups that experience discrimination and barriers to healthcare for example those affected by sexism, homelessness, poverty, homophobia and heterosexism, disability and hiv infection. the collaborative process to achieve access to primary health care for black women and women of colour project was developed with the university of toronto faculty of social work and five community partners using a collaborative methodology to address a pressing need within the community ro increase access to primary health care for black women and women of colour. women's health in women's hands community health centre, sistering, parkdale community health centre, rexdale community health centre and planed parenthood of toronto developed this community-based participatory-action research project to collaboratively barriers affecting these women, and to develop a model of care that will increase their access to health services. this framework was developed using a process which ensured that community members from the target population and service providers working in multiculrural clinical settings, were a part of the research process. they were given the opportunity to shape the course of action, from the design of the project to the evaluation and dissemination phase. empowerment is a goal of the participatory action process, therefore, the research process has deliberately prioritized _ro enabling women to increase control over their health and well-being. in this session, the presenters will explore community-based participatory research and how such a model can be useful for understanding and contextualizing the experiences of black women and women of colour. they will address. the development and use of community parmerships, design and implementation of the research prorect, challenges encountered, lessons learnt and action outcomes. they will examine how the results from a collaborative community-based research project can be used as an action strategy to poster sessions v61 address che social determinants of women health. finally the session will provide tools for service providers and researchers to explore ways to increase partnerships and to integrate strategies to meet the needs of che target population who face multiple barriers to accessing services. lynn scruby and rachel rapaport beck the purpose of this project was ro bring traditionally disenfranchised winnipeg and surrounding area women into decision-making roles. the researchers have built upon the relationships and information gachered from a pilot project and enhanced the role of input from participants on their policy prioriries. the project is guided by an advisory committee consisting of program providers and community representatives, as well as the researchers. participants included program users at four family resource cencres, two in winnipeg and two located rurally, where they participated in focus groups. the participants answered a series of questions relating to their contact with government services and then provided inpuc as to their perceptions for needed changes within government policy. following data analysis, the researchers will return to the four centres to share the information and continue che discussion on methods for advocating for change. recommendations for program planning and policy development and implementation will be discussed and have relevance to all participants in the research program. women's health vera lefranc, louise hara, denise darrell, sonya boyce, and colleen reid women's experiences with paid and unpaid work, and with the formal and informal economies, have shifted over the last 20 years. in british columbia, women's employability is affected by government legislation, federal and provincial policy changes, and local practices. two years ago we formed the coalition ior women's economic advancement to explore ways of dealing with women's worsening economic situations. since the formation of the coalition we have discussed the need for research into women's employabilicy and how women were coping and surviving. we also identified how the need to document the nature of women's employability and reliance on the informal economy bore significanc mechodological and ethical challenges. inherent in our approach is a social model of women's health that recognizes health as containing social, economic, and environmental determinants. we aim to examine the social contexc of women's healch by exploring and legitimizing women's own experiences, challenging medical dominance in understandings of health, and explaining women's health in terms of their subordination and marginalizacion. through using a feminist action research (far) methodology we will explore the relationship between women's employability and health in 4 communities that represent bricish columbia's social, economic, cultural/ethnic, and geographic diversities: skidegate, fort st . .john, lumhy, and surrey. over the course of our 2 year project, in each community we will establish and work with advisory committees, hire and train local researchers, conduct far (including a range of qualitative methods), and support action and advocacy. since the selected communities are diverse, the ways that the research unfolds will 1·ary between communities. expected outcomes, such as the provision of a written report and resources, the establishment of a website for networking among the communities, and a video do.:umentary, are aimed at supporting the research participants, coalition members, and advisory conuniuces in their action efforts. p2t 9 (c) health & housing: assessing the impact of transitional housing for people living with hiv i aids currently, there is a dearth of available literature which examines supporrive housing for phas in the canadian context. using qualitative, one-on-one interviews we investigace the impact of transitional housing for phaswho have lived in the up to nine month long hastings program. our post<'r pr<·senta-t1on will highlight research findings, as well as an examination of transitional housing and th<· imp;kt it has on the everyday lives of phas in canada. this research is one of two ground breaking undertakings within the province of ontario in which fife house is involved. p2-20 (c) eating our way to justice: widening grassroots approaches to food security, the stop community food centre as a working model charles l.evkoe food hanks in north america have come co play a central role as the widespread response to growing rates of hunger. originally thought to be a short term-solution, over the last 25 years, they have v62 poster sessions be · · · 1· d wi'thi'n society by filling the gaps in the social safety net while relieving govemcome mst1tut1ona 1ze . . . t f the ir responsibilities. dependent on corporate donations and sngmauzmg to users, food banks men so th' . ·11 i i . are incapable of addressing the structural cause~ of ~u~ger. 1s pres~ntation w1 e~~ ore a ternanve approaches to addressing urban food security while bmldmg more sustamabl.e c~mmumt1es. i:nrough the f t h st p community food centre, a toronto-based grassroots orgamzanon, a model is presented case 0 e 0 h'l k' b 'id · b that both responds to the emergency food needs of communities w 1 e wor mg to. u1 ~ sustama le and just food system. termed, the community food centre model. (cfc), ~he s~op is worki?g to widen its approach to issues of food insecurity by combining respectful ~1rect service wit~ com~~mty ~evelop ment, social justice and environmental sustainability. through this approach, various critical discourses around hunger converge with different strategic and varied implications for a~ion. as a plac~-based organization, the stop is rooted within a geographical space and connected directly to a neighbourhood. through working to increase access to healthy food, it is active in maintaining people's dignity, building a strong and democratic community and educating for social change. connected to coalitions and alliances, the stop is also active in organizing across scales in connection with the global food justice movement. inner city shelter vicky stergiopoulos, carolyn dewa, katherine rouleau, shawn yoder, and lorne tugg introduction: in the city of toronto there are more than 32,000 hostel users each year, many with mental health and addiction issues. although shelters have responded in various ways to the health needs of their clients, evidence on the effectiveness of programs delivering mental health services to the home· less in canada has been scant. the objective of this community based research was to provide a forma· tive evaluation of a multi-agency collaborative care team providing comprehensive care for high needs clients at toronto's largest shelter for homeless men. methods: a logic model provided the framework for analysis. a chart review of 56 clients referred over a nine month period was completed. demographic data were collected, and process and outcome indicators were identified for which data was obtained and analyzed. the two main outcome measures were mental status and housing status 6 months after referral to the program. improvement or lack of improvement in mental status was established by chart review and team consensus. housing outcomes were determined by chart review and the hostel databases. results: of the clients referred 75% were single and 98% were unemployed. forty four percent had a psychiatric hospitalization within the previous two years. the prevalence of severe and persistent men· tal illness, alcohol and substance use disorders were 60%, 26% and 37% respectively. six months after referral to the program 37% of clients had improved mental status and 41 % were housed. logistic regression controlling for the number of general practitioner and psychiatrist visits, presence of person· ality or substance use disorder and treatment non adherence identified two variables significantly associ· ated mental status improvement: the number of psychiatric visits (or, 1.92; 95% ci, 1.29-2.84) and treatment non adherence (or, 0.086; 95% ci, 0.01-0.78). the same two variables were associated with housing outcomes. history of forensic involvement, the presence of a personality or substance use disorder and the number of visits with a family physician were not significantly associated with either outcome. conclusions: despite the limitations in sample sire and study design, this study can yield useful informa· tion to program planners. our results suggest that strategies to improve treatment adherence and access to mental health specialists can improve outcomes for this population. although within primary care teams the appropriate collaborative care model for this population remains to be established, access to psychiatric follow up, in addition to psychiatric assessment services, may be an important component of a successful program. mount sinai hospital (msh) has become one of the pre-eminent hospitals in the world by contributing to the development of innovative approaches to effective health care and disease prevention. recently, the hospital has dedicated resources towards the development of a strategy aimed at enhancing the hospital's integration with its community partners. this approach will better serve the hospital in the current health care environment where local health integration networks have been struck to enhance and support local capacity to plan, coordinate and integrate service delivery. msh has had early success with developing partnerships. these alliances have been linked to programs serving key target populations with _estabhshe~. points of access to msh. recognizing the need to build upon these achievements to remain compe~mve, the hospital has developed a community integration strategy. at the forefront of this strategy is c.a.r.e (community advisory reference engine): the hospital's compendium of poster sessions v63 community partners. as a single point of access to community partner information, c.a.r.e. is more than a database. c.a.r.e. serves as the foundation for community-focused forecasting and a vehicle for inter and intra-organizational knowledge transfer. information gleaned from the catalog of community parmers can be used to prepare strategic, long-term partnership plans aimed at ensuring that a comprehensive array of services can be provided to the hospital community. c.a.r.e. also houses a permanent record of the hospital's alliances. this prevents administrative duplication and facilitates the formation of new alliances that best serve both the patient and the hospital. c.a.r.e. is not a stand-alone tool and is most powerful when combined with other aspects of the hospital's community integration strategy. it iscxpected that data from the hospital's community advisory committees and performance measurement department will also be stored alongside stakeholder details. this information can then be used to drive discussions at senior management and the board, ensuring congruence between stakeholder, patient and hospital objectives. the patient stands to benefit from this strategy. the unique, distinct point of reference to a wide array of community services provides case managers and discharge planners with the information they need to connect patients with appropriate community services. creating these linkages enhances the patient's capacity to convalesce in their homes or places of residence and fosters long-term connections to neighborhood supports. these connections can be used to assist with identifying patients' ongoing health care needs and potentially prevent readmission to hospital. introduction: recruiting high-risk drug users and sex workers for hiv-prevention research has often been hampered by limited access to hard to reach, socially stigmatized individuals. our recruitment effom have deployed ethnographic methodology to identify and target risk pockets. in particular, ethnographers have modeled their research on a street-outreach model, walking around with hiv-prevention materials and engaging in informal and structured conversations with local residents, and service providers, as well as self-identified drug users and sex workers. while such a methodology identifies people who feel comfortable engaging with outreach workers, it risks missing key connections with those who occupy the margins of even this marginal culture. methods: ethnographers formed a women's laundry group at a laundromat that had a central role as community switchboard and had previously functioned as a party location for the target population. the new manager helped the ethnographers invite women at high risk for hiv back into the space, this time as customers. during weekly laundry sessions, women initiated discussions about hiv-prevention, sexual health, and eventually, the vaccine research for which the center would be recruiting women. ra.its: the benefits of the group included reintroducing women to a familiar locale, this time as customers rather than unwelcome intruders; creating a span of time (wash and dry) to discuss issues important to me women and to gather data for future recruitment efforts; creating a location to meet women encountered during more traditional outreach research; establishing the site as a place for potential retention efforts; and supporting a local business. women who participated in the group completed a necessary household task while learning information that they could then bring back to the community, empowering them to be experts on hiv-prevention and vaccine research. some of these women now assist recruitment efforts. the challenges included keeping the group women-only, especially after lunch was provided, keeping the membership of the group focused on women at risk for hiv, and keeping the women in the group while they did their laundry. conclusion: public health educators and researchers can benefit from identifying alternate congregation sites within risk pockets to provide a comfortable space to discuss hiv prevention issues with high-risk community members. in our presentation, we will describe the context necessary for similar research, document the method's pitfalls and successes, and argue that the laundry group constitutes an ethical, respectful, community-based method for recruitment in an hiv-prevention vaccine trial. p3-0t (c) upgrading inner city infrastructure and services for improved environmental hygiene and health: a case of mirzapur in u.p. india madhusree mazumdar in urgency for agricultural and industrial progress to promote economic d.evelopment follo_wing independence, the government of india had neglected health promotion and given less emphasis on infrastructure to promote public health for enhanced human pro uct1v_ity. ong wit r~p1 m astrucrure development, which has become essential if citie~ are to. act ~s harbmger.s of econ~nuc ~owth, especially after the adoption of the economic liberalization policy, importance _is a_lso ~emg g1ve.n to foster environmental hygiene for preventive healthcare. the world health orga~1sat10~ is also trj:'1!1g to help the government to build a lobby at the local level for the purpose by off~rmg to mrroduce_ its heal.thy city concept to improve public health conditions, so as to reduce th_e disease burden. this pape~ 1s a report of the efforts being made towards such a goal: the paper descr~bes ~ c~se study ?f ~ small city of india called mirzapur, located on the banks of the nver ganga, a ma1or lifeline of india, m the eastern part of the state of uttar pradesh, where action for improvement began by building better sanitation and environmental infrastructure as per the ganga action plan, but continued with an effort to promote pre· ventive healthcare for overall social development through community participation in and around the city. asthma physician visits in toronto, canada tara burra, rahim moineddin, mohammad agha, and richard glazier introduction: air pollution and socio-economic status are both known to be associated with asthma in concentrated urban settings but little is known about the relationship between these factors. this study investigates socio-economic variation in ambulatory physician consultations for asthma and assesses possible effect modification of socio-economic status on the association between physician visits and ambient air pollution levels for children aged 1 to 17 and adults aged 18 to 64 in toronto, canada between 1992 and 2001. methods: generalized additive models were used to estimate the adjusted relative risk of asthma physician visits associated with an interquartile range increase in sulphur dioxide, nitrogen dioxide, pm2.5, and ozone, respectively. results: a consistent socio-economic gradient in the number of physician visits was observed among children and adults and both sexes. positive associations between ambient concentrations of sul· phur dioxide, nitrogen dioxide and pm2.5 and physician visits were observed across age and sex strata, whereas the associations with ozone were negative. the relative risk estimates for the low socio-«onomic group were not significantly greater than those for the high socio-economic group. conclusions: these findings suggest that increased ambulatory physician visits represent another component of the public health impact of exposure to urban air pollution. further, these results did not identify an age, sex, or socio-economic subgroup in which the association between physician visits and air pollution was significantly stronger than in any other population subgroup. eco-life-center (ela) in albania supports a holistic approach to justice, recognizing the environ· mental justice, social justice and economic justice depend upon and support each other. low income cit· izens and minorities suffer disproportionately from environmental hazards in the workplace, at home, and in their communities. inadequate laws, lax enforcement of existing environmental regulations, and ~ea.k penalties for infractions undermine environmental protection. in the last decade, the environmental 1ust1ce m~ve~ent in tirana metropolis has provided a framework for identifying and exposing the links ~tween irrational development practices, disproportionate siting of toxic facilities, economic depres· s1on, and a diminished quality of life in low-income communities and communities of color. the envi· ~onmental justice agenda has always been rooted in economic, racial, and social justice. tirana and the issues su.rroun~ing brow~fields redevelopment are crucial points of advocacy and activism for creating ~ubstantia~ social chan~~ m low-income communities and communities of color. we engaging intensively m prevcnnng co'.'1mumnes, especially low income or minority communities, from being coerced by gov· ernmenta~ age_nc1es or companies into siting hazardous materials, or accepting environmentally hazard· ous_ practices m order to create jobs. although environmental regulations do now exist to address the environmental, health, and social impacts of undesirable land uses, these regulations are difficult to poster sessions v65 enforce because many of these sites have been toxic-ridden for many years and investigation and cleanup of these sites can be expensive. removing health risks must be the main priority of all brown fields action plans. environmental health hazards are disproportionately concentrated in low-income communities of color. policy requirements and enforcement mechanisms to safeguard environmental health should be strengthened for all brownfields projects located in these communities. if sites are potentially endangering the health of the community, all efforts should be made for site remediation to be carried out to the highest cleanup standards possible towards the removal of this risk. the assurance of the health of the community should take precedence over any other benefits, economic or otherwise, expected to result from brownfields redevelopment. it's important to require from companies to observe a "good neighbor" policy that includes on-site visitations by a community watchdog committee, and the appointment of a neighborhood environmentalist to their board of directors in accordance with the environmental principles. vancouver 1976-2001 michael buzzelli, jason su, and nhu le this is the second paper of research programme concerned with the geographical patterning of environmental and population health at the urban neighbourhood scale. based on the vancouver metropolitan region, the aim is to better understand the role of neighbourhoods as epidemiological spaces where environmental and social characteristics combine as health processes and outcomes at the community and individual levels. this paper builds a cohort of commensurate neighbourhoods across all six censuses periods from 1976 to 2001, assembles neighbourhood air pollution data (several criterion/health effects pollutants), and providing an analysis to demonstrate how air pollution systematically and consistently maps onto neighbourhood socioeconomic markers, in this case low education and lone-parent families. we conclude with a discussion of how the neighbourhood cohort can be further developed to address emergent priorities in the population and environmental health literatures, namely the need for temporally matched data, a lifecourse approach, and analyses that control for spatial scale effects. solid waste management and environment in mumbai (india) by uttam jakoji sonkamble and bairam paswan abstract: mumbi is the individual financial capital of india. the population of greater mumbai is 3,326,837 and 437 sq. km. area. the density of population 21, 190 per sq. km. the dayto-day administration and rendering of public services within gr. mumbai is provided by the brihan mumbai mahanagar palika (mumbai corporation of gr. mumbai) that is a body of 221 elected councilors on a 5-year team. mumcial corporation provides varies conservancy services such as street sweeping, collection of solid waste, removal and transportation, disposal of solid waste, disposal of dead bodies of animals, construction, maintance and cleaning of urinals and public sanitary conveniences. the solid waste becoming complicated due to increase in unplanned urbanization and industrialization, the environment has deteriorated significantly due to inter, intra and international migration stream to mumbai. the volume of inter state migration to mumbai is considerably high i.e. 20.89 lakh and international migrant 0.77 lakh have migrated to mumbai. present paper gives the view on solid waste management and its implications to environment and health. pollution from a wide varity of emission, such as from automobiles and industrial activities, has reached critical level in mumbai, causing respiratory, ocular, water born diseases and other health problems. sources of generation of waste are -household waste, commercial waste, institutional waste, street sweeping, silt removed from drain/nallah/cleanings. disposal of solid waste in gr. mumbai done under 1 incineration 2. processing to produce organic manure. 3. vermi-composting 4. landfill the study shows that the quantity of waste disposal of through processing and conversion to organic ~anure is about 200-240 m.t. per day. the processing is done by a private agency m/s excel industries ltd. who had set up a plant at the chincholi dumping ground in western mumbai for this purpose. the corporation is also disposal a plant of its waste mainly market waste through the environment friendly, natural pro-ces~ known as vermi-composing about 100 m.t. of market waste is disposed of in this manner at the various sites. there are four land fill sites are available and 95 percent of the waste matter generated m mumbai is disposed of through landfill. continuous flow of migrant and increa~e in slum population is a complex barrier in the solid waste management whenever community pamc1pat1on work strongly than only we can achieved eco-friendly environment in mumbai. persons exposed to residential craffic have elevated races of respiratory morbidity an~ ~ortality. since poverty is an important determinant of ill-health, some h~ve argued that t~es~ assoc1at1ons may relate to che lower socioeconomic status of those living along ma1or roads. our ob1ect1ve was to evaluate the association between traffic intensity at home and hospital admissions for respiratory diagnoses among montreal residents older than 60 years. morning peak traffic estimates from the emmej2 montreal traffic model (motrem98) were used as an indicator of exposure to road traffic outside the homes of those hospitalised. the influence of socioeconomic status on the relationship between traffic intensity and hospital admissions for respiratory diagnoses was explored through assessment of confounding by lodging value, expressed as the dollar average over road segments. this indicator of socioeconomic status, as calculated from the montreal property assessment database, is available at a finer geographic scale than socioeconomic information accessible from the canadian census. there was an inverse relationship between traffic intensity estimates and lodging values for those hospitalised (rho -0.23, p 3160 vehicles during che 3 hour morning peak), even after adjustment for lodging value (crude or 1.35, cl95% 1.22-1.49; adjusted or 1.13, cl95% 1.02-1.25). in montreal, elderly persons living along major roads are at higher risk of being hospitalised for respiratory illnesses, which appears not simply to reflect the fact that those living along major roads are at relative economic disadvantage. the paper argues that human beings ought to be at the centre of the concern for sustainable development. while acknowledging the importance of protecting natural resources and the ecosystem in order to secure long term global sustainability, the paper maintain that the proper starting point in the quest for urban sustainability in africa is the 'brown agenda' to improve che living and working environment of che people, especially che urban poor who face a more immediate environmental threat to their health and well-being. as the un-habitat has rightly observed, it is absolutely essential "to ensure that all people have a sufficient stake in the present to motivate them to take part in the struggle to secure the future for humanity.~ the human development approach calls for rethinking and broadening the narrow technical focus of conventional town planning and urban management in order to incorporate the emerging new ideas and principles of urban health and sustainability. i will examine how cities in sub-saharan africa have developed over the last fifty years; the extent to which government policies and programmes have facilitated or constrained urban growth, and the strategies needed to achieve better functioning, safer and more inclusive cities. in this regard i will explore insights from the united nations conferences of the 1990s, especially local agenda 21 of the rio summit, and the istanbul declaration/habitat agenda, paying particular attention to the principles of enablement, decentralization and partnership canvassed by these movements. also, i will consider the contributions of the various global initiatives especially the cities alliance for cities without slums sponsored by the world bank and other partners; che sustainable cities programme, the global campaigns for good governance and for secure tenure canvassed by unhabit at, the healthy cities programme promoted by who, and so on. the concluding section will reflect on the future of the african city; what form it will take, and how to bring about the changes needed to make the cities healthier, more productive and equitable, and better able to meet people's needs. heather jones-otazo, john clarke, donald cole, and miriam diamond urban areas, as centers of population and resource consumption, have elevated emissions and concentrations of a wide range of chemical contaminants. we have developed a modeling framework in which we first ~stimate the emissions and transport of contaminants in a city and second, use these estimates along with measured contaminant concentrations in food, to estimate the potential health risk posed by these che.micals. the latter is accomplished using risk assessment. we applied our modeling framework to consider two groups of chemical contaminants, polycyclic aromatic hydrocarbons (pah) a.nd the flame re~ardants polybrominated diphenyl ethers (pbde). pah originate from vehicles and stationary combustion sources. ~veral pah are potent carcinogens and some compounds also cause noncancer effects. pbdes are additive flame retardants used in polyurethane foams (e.g., car seats, furniture) 105fer sessions v67 and cl~ equipm~nt (e.g., compute~~· televisio~s). two out of three pbdes formulations are being voluntarily phased by mdustry due to rmng levels m human tissues and their world-wide distribution. pbdes have been .related to adv.erse neurological, developmental and reproductive effects in laboratory ijlimals. we apphed our modelmg framework to the city of toronto where we considered the southcattral area of 21 by 21 km that has a population of 1.3 million. for pah, local vehicle traffic and area sources contribute at least half of total pah in toronto. local contributions to pbdes range from 57-85%, depending on the assumptions made. air concentrations of both compounds are about 10 times higher downtown than 80 km north of toronto. although measured pah concentrations in food date to the 1980s, we estimate that the greatest exposure and contribution to lifetime cancer risk comes from ingestion of infant formula, which is consistent with toxicological evidence. the next greatest exposure and cancer risk are attributable to eating animal products (e.g. milk, eggs, fish). breathing downtown air contributes an additional 10 percent to one's lifetime cancer risk. eating vegetables from a home garden localed downtown contributes negligibly to exposure and risk. for pbdes, the greatest lifetime exposure comes through breast milk (we did not have data for infant formula), followed by ingestion of dust by the toddler and infant. these results suggest strategies to mitigate exposure and health risk. p4-01 (a) immigration and socioeconomic inequalities in cervical cancer screening in toronto, canada aisha lofters, rahim moineddin, maria creatore, mohammad agha, and richard glazier llltroduction: pap smears are recommended for cervical cancer screening from the onset of sexual activity to age 69. socioeconomic and ethnoracial gradients in self-reported cervical cancer screening have been documented in north america but there have been few direct measures of pap smear use among immigrants or other socially disadvantaged groups. our purpose was to investigate whether immigration and socioeconomic factors are related to cervical cancer screening in toronto, canada. methods: pap smears were identified using fee codes and laboratory codes in ontario physician service claims (ohip) for three years starting in 1999 for women age 18-41 and 42-66. all women with any health system contact during the three years were used as the denominator. social and economic factors were derived from the 2001 canadian census for census tracts and divided into quintiles of roughly equal population. recent registrants, over 80% of whom are expected to be recent immigrants to canada, were identified as women who first registered for health coverage in ontario after january 1, 1993. results: among 397,967 women age 18-41 and 328,885 women age 42-66, 55.3% and 55.5%, rtspcctively, had pap smears within three years. low income, low education, recent immigration, visible minority and non-english language were all associated with lower rates (least advantaged quintile:most advantaged quintile rate ratios were 0.84, 0.90, 0.81, 0.85, 0.83, respectively, p < 0.05 for all). similar gradients were found in both age groups. recent registrants comprised 22.5% of women and had mm;h lower pap smear rates than non-recent registrants (37.2 % versus 63. 7% for women age 18-41 and 35.9% versus 58.2% for women age 42-66). conclnsions: pap smear rates in toronto fall well below those dictated by evidence-based practice. at the area level, immigration, visible minority, language and socioeconomic characteristics are associated with pap smear rates. recent registrants, representing a largely immigrant group, have particularly low rates. efforts to improve coverage of cervical cancer screening need to be directed to all ~omen, their providers and the health system but with special emphasis on women who recently arrived m ontario and those with social and economic disadvantage. challeges faced: a) most of the resources are now being ~pent in ~reventing the sprea.d of hiv/ aids and maintaining the lives of those already affected. b) skilled medical ~rs~nal are dymg under· mining the capacity to provide the required health care services. ~) th.e comphcat1o~s of hiv/aids has complicated the treatment of other diseases e.g. tbs d) the ep1dem1c has led. to mcrease number of h n requiring care and support. this has further stretched the resources available for health care. orp a s d db . . i methods used on our research: 1. a simple community survey con ucte y our orgamzat1on vo · unteers in three urban centres members of the community, workers and health care prov~ders were interviewed ... 2. meeting/discussions were organized in hospitals, commun.ity centre a~d with government officials ... 3. written questionnaires to health workers, doctors and pohcy makers m th.e health sectors. lessors learning: • the biggest-health bigger-go towards hiv/aids prevention • aids are spreading faster in those families which are poor and without education. •women are the most affected. •all health facilities are usually overcrowded with hiv/aids patients. actions needed:• community education oh how to prevent the spread of hiv/aids • hiv/aids testing need to be encouraged to detect early infections for proper medical cover. • people to eat healthy • people should avoid drugs. implications of our research: community members and civic society-introduction of home based care programs to take care of the sick who cannot get a space in the overcrowded public hospitals. prl-v a te sector private sector has established programs to support and care for the staff already affected. government provision of support to care-givers, in terms of resources and finances. training more health workers. introduction: australian prisons contain in excess of 23,000 prisoners. as in most other western countries, reliance on 'deprivation of liberty' is increasing. prisoner numbers are increasing at 7% per annum; incarceration of women has doubled in the last ten years. the impacts on the community are great -4% of children have a parent in custody before their 16th birthday. for aboriginal communities, the harm is greater -aboriginal and/or torres strait islanders are incarcerated at a rate ten times higher than other australians. 25% of their children have a parent in custody before their 16th birthday. australian prisons operate under state and territory jurisdictions, there being no federal prison system. eight independent health systems, supporting the eight custodial systems, have evolved. this variability provides an unique opportunity to assess the capacity of these health providers in addressing the very high service needs of prisoners. results: five models of health service provision are identified -four of which operate in one form or another in australia: • provided by the custodial authority (queensland and western australia)• pro· vided by the health ministry through a secondary agent (south australia, the australian capital territory and tasmania) • provided through tendered contract by a private organization (victoria and northern territory) • provided by an independent health authority (new south wales) • (provided by medics as an integral component of the custodial enterprise) since 1991 the model of the independent health authority has developed in new south wales. the health needs of the prisoner population have been quantified, and attempts are being made to quantify specific health risks /benefits of incarceration. specific enquiry has been conducted into prisoner attitudes to their health care, including issues such as client information confidentiality and access to health services. specific reference will be made to: • two inmate health surveys • two inmate access surveys, and • two service demand studies. conclusions: the model of care provision, with legislative, ethical, funding and operational independence would seem provide the best opportunity to define and then respond to the health needs of prisoners. this model is being adopted in the united kingdom. better health outcomes in this high-risk group, could translate into healthier families and their communities. p4-04 (a) lnregrated ethnic-specific health care systems: their development and role in increasing access to and quality of care for marginalized ethnic minorities joshua yang introduction: changing demographics in urban areas globally have resulted in urban health systems that are racially and ethnically homogenous relative to the patient populations they aim to serve. the resultant disparities in access to and quality of health care experienced by ethnic minority groups have been addressed by short-term, instirutional level strategies. noticeably absent, however, have been structural approaches to reducing culturally-rooted disparities in health care. the development of ethnic-specific h~alth car~ systems i~ a structural, long-term approach to reducing barriers to quality health care for eth· me mmonty populations. methods: this work is based on a qualitative study on the health care experiences of san francisco chinatown in the united states, an ethnic community with a model ethnic-specific health care infrastrucrure. using snowball sampling, interviews were conducted with key stakeholders and archival research was conducted to trace and model the developmental process that led to the current ethnic-specific health care system available to the chinese in san francisco. grounded theory was the methodology ijltd to analysis of qualitative data. the result of the study is four-stage developmental model of ethnic-specific health infrastrueture development that emerged from the data. the first stage of development is the creation of the human capital resources needed for an ethnic-specific health infrastructure, with emphasis on a bilingual and bicultural health care workforce. the second stage is the effective organization of health care resources for maximal access by constituents. the third is the strengthening and stability of those institutional forms through increased organizational capacity. integration of the ethnic-specific health care system into the mainstream health care infrastructure is the final stage of development for an ethnic-specific infrastructure. conclusion: integrated ethnic-specific health care systems are an effective, long-term strategy to address the linguistic and cultural barriers that are being faced by the spectrum of ethnic populations in urban areas, acting as culturally appropriate points of access to the mainstream health care system. the model presented is a roadmap to empower ethnic communities to act on the constraints of their health and political environments to improve their health care experiences. at a policy level, ethnic-specific health care organizations are an effective long-term strategy to increase access to care and improve qualiiy of care for marginalized ethnic groups. each stage of the model serves as a target area for policy interventions to address the access and care issues faced by culturally and linguistically diverse populations. users in baltimore md: 1989-2004 noya galai, gregory lucas, peter o'driscoll, david celentano, david vlahov, gregory kirk, and shruti mehta introduction: frequent use of emergency rooms (er) and hospitalizations among injection drug users (idus) has been reported and has often been attributed to lack of access to primary health care. however, there is little longitudinal data which examine health care utilization over individual drug use careers. we examined factors associated with hospitalizations, er and outpatient (op) visits among idus over 14 years of follow-up. methods: idus were recruited through community outreach into the aids link to lntravenous experience (alive) study and followed semi-annually. 2,551 who had at least 2 follow-up visits were included in this analysis. outcomes were self-reported episodes of hospitalizations and er/op visits in the prior six months. poisson regression was used accounting for intra-person correlation with generalized estimation equations. hits: at enrollment, 73% were male, 95% were african-american, 33% were hiv positive, median age was 35 years, and median duration of drug use was 15 years. over a total of 37,512 visits, mean individual rates of utilization were 11 per 100 person years (py) for hospitalizations and 123 per 100 py for er/op visits. adjusting for age and duration of drug use, factors significantly associated with higher rates of hospitalization included hiv infection (relative incidence [ri(, 1.4), female gender (ri, 1.2), homelessness (ri, 1.6), as well as not being employed, injecting at least daily, snorting heroin, havmg a regular source of health care, having health insurance and being in methadone mainte.nance treatment (mmt). similar associations were observed for er/op visits except for mmt which was not associated with er/op visits. additional factors associated with lower er/op visits were use of alcohol, crack, injecting at least daily and trading sex for drugs. 10% of the cohort accounted for 45% of total er/op visits, while 11 % of the cohort never reported an op visit during follow-up. . . . lgbt) populations. we hypothesized that prov1dmg .appomtments .for p~t1~nts w1thm 24 hours would ensure timely care, increase patient satisfaction, and improve practice eff1c1ency. further, we anticipated that the greatest change would occur amongst our homeless patients.. . methods: we tested an experimental introduction of advanced access scheduling (usmg a 24 hour rule) in the primary care medical clinic. we tracked variables inclu~ing waiting ti~e fo~ next available appointment; number of patients seen; and no-show rates, for an eight week penod pnor to and post introduction of the new scheduling system. both patient and provider satisfaction were assessed using a brief survey (2 questions rated on a 5-pt scale). results and conclusion: preliminary analyses demonstrated shorter waiting times for appointments across the clinic, decreased no-show rates, and increased clinic capacity. introduction of the advanced access scheduling also increased both patient and provider satisfaction. the new scheduling was initiated in july 2005. quantitative analyses to measure initial and sustained changes, and to look at differential responses across populations within our clinic, are currently underway. introduction: there are three recognized approaches to linking socio-economic factors and health: use of census data, gis-based measures of accessibility/availability, and resident self-reported opinion on neighborhood conditions. this research project is primarily concerned with residents' views about their neighborhoods, identifying problems, and proposing policy changes to address them. the other two techniques will be used in future research to build a more comprehensive image of neighborhood depri· vation and health. methods: a telephone survey of 658 london, ontario residents is currently being conducted to assess: a) community resource availability, quality, access and use, b) participation in neighborhood activities, c) perceived quality of neighborhood, d) neighborhood problems, and e) neighborhood cohesion. the survey instrument is composed of indices and scales previously validated and adapted to reflect london specifically. thirty city planning districts are used to define neighborhoods. the sample size for each neighborhood reflects the size of the planning district. responses will be compared within and across neighborhoods. data will be linked with census information to study variation across socio-eco· nomic and demographic groups. linear and gis-based methods will be used for analysis. preliminary results: the survey follows a qualitative study providing a first look at how experts involved in community resource planning and administration and city residents perceive the availability, accessibility, and quality of community resources linked to neighborhood health and wellbeing, and what are the most immediate needs that should be addressed. key-informant interviews and focus groups were used. the survey was pre-tested to ensure that the language and content reflects real experiences of city residents. the qualitative research confirmed our hypothesis that planning districts are an acceptable surrogate for neighborhood, and that the language and content of the survey is appropriate for imple· mentation in london. scales and indices showed good to excellent reliability and validity during the pre· test (cronbach's alpha from 0.57-0.96). preliminary results of the survey will be detailed at the conference. conclusions: this study will help assess where community resources are lacking or need improve· ment, thus contributing to a more effective allocation of public funds. it is also hypothesized that engaged neighborhoods with a well-developed sense of community are more likely to respond to health programs and interventions. it is hoped that this study will allow london residents to better understand the needs and problems of their neighborhoods and provide a research foundation to support local understandmg of community improvement with the goal of promoting healthy neighborhoods. p4-08 (a) hiv positive in new york city and no outpatient care: who and why? hannah wolfe and victoria sharp introduction: there are approximately 1 million hiv positive individuals living in the united sta!es. about. 50% of these know their hiy status and are enrolled in outpatient care. of the remaining 50 yo, approx~mately half do not know their status; the other group frequently know their status but are not enrolled m any .sys~em of outpatient care. this group primarily accesses care through emergency departments. when md1cated, they are admitted to hospitals, receive acute care services and then, upon poster sessions v71 di5'harge, disappear from the health care system until a new crisis occurs, when they return to the emergency department. as a large urban hiv center, caring for over 3000 individuals with hiv we have an active inpatient service ".'ith appr~xi~.ately 1800 discharges annually. we decided to survey our inpatients to better charactenze those md1v1duals who were not enrolled in any system of outpatient care. results: 18% of inpatients were not enrolled in regular outpatient care: 2% at roosevelt hospital and 35% at st.luke\'s hospital. substance abuse and homelessness were highly prevalent in the cohort of patients not enrolled in regular outpatient care. 84% of patients not in care (vs. 33% of those in care) were deemed in need of substance use treatment by the inpatient social worker. 74% of those not in care were homeless (vs. 15% of those in care.) patients not in care did not differ significantly from those in me in terms of age, race, or gender. patients not in care were asked "why not:" the two most frequent responses were: "i haven't really been sick before" and "i'd rather not think about my health. conclusions: this study suggests that there is an opportunity to engage these patients during their stay on the inpatient units and attempt to enroll them in outpatient care. simple referral to an hiv clinic is insufficient, particularly given the burden of homelessness and substance use in this population. efforts are currently underway to design an intervention to focus efforts on this group of patients. p4.q9 (a) healthcare availability and accessibility in an urban area: the case of ibadan city, nigeria in oder to cater for the healthcare need of the populace, for many years after nigeria's politicl independence, empphasis was laid on the construction of teaching, general, and specialist hospital all of which were located in the urban centres. the realisation of the inadequacies of this approach in adequately meeting the healthcare needs of the people made the country to change and adopt the primary health care (phc) system in 1986. the primary health care system which is in line with the alma ata declaration of of 1978, wsa aimed at making health care available to as many people as possible on the basis of of equity and social justice. thus, close to two decades, nigeria has operated primary health care system as a strategy for providing health care for rural and urban dwellers. this study focusing on urban area, examimes the availabilty and accessibility of health care in one of nigeria's urban centre, ibadan city to be specific. this is done within the contest of the country's national heath policy of which pimary health care is the main thrust. the study also offers necessary suggestion for policy consideration. in spite of the accessibility to services provided by educated and trained midwifes in many parts of fars province (iran) there are still some deliveries conducted by untrained traditional birth attendants in rural parts of the province. as a result, a considerable proportion of deliveries are conducted under a higher risk due to unauthorised and uneducated attendants. this study has conducted to reveal the pro· portion of deliveries with un-authorized attendants and some spatial and social factors affecting the selection of delivery attendants. method: this study using a case control design compared some potentially effective parameters indud· ing: spatial, social and educational factors of mothers with deliveries attended by traditional midwifes (n=244) with those assisted by educated and trained midwifes (n=258). the mothers interviewed in our study were selected from rural areas using a cluster sampling method considering each village as a cluster. results: more than 11 % of deliveries in the rural area were assisted by traditional midwifes. there are significant direct relationship between asking a traditional birth attendant for delivery and mother age, the number of previous deliveries and distance to a health facility provided for delivery. significant inverse relationships were found between mother's education and ability to use a vehicle to get to the facilities. conclusion: despite the accessibility of mothers to educated birth attendants and health facilities (according to the government health standards), some mothers still tend to ask traditional birth attendants for help. this is partly because of unrealistic definition of accessibility. the other considerable point is the preference of the traditional attendants for older and less educated mothers showing the necessity of changing theirs knowledge and attitude to understand the risks of deliveries attended by traditional and un-educated midwifes. p4-12 (a) identification and optimization of service patterns provided by assertive community treatment teams in a major urban setting: preliminary findings &om toronto, canada jonathan weyman, peter gozdyra, margaret gehrs, daniela sota, and richard glazier objective: assertive community treatment (act) teams are financed by the ontario ministry of health and long-term care (mohltc) and are mandated to provide treatment, rehabilitation and support services in the community to people with severe and persistent mental illness. there are 13 such teams located in various regions across the city of toronto conducting home visits 1-5 times per week to each of their approximately 80 respective clients. each team consists of multidisciplinary health professionals who assist clients to identify their needs, establish goals and work toward them. due to complex referral patterns, the need for service continuity and the locations of supportive housing, clients of any one team are often found scattered across the city which increases home visit travel times and decreases efficiency of service provision. this project examines the locations of clients in relation to the home bases of all 13 act teams and identifies options for overcoming the geographical challenges which arise in a large urban setting. methods: using geographic information systems (gis) we geocoded all client and act agency addresses and depicted them on location maps. at a later stage using spatial methods of network analysis we plan to calculate average travel rimes for each act team, propose optimization of catchment areas and assess potential travel time savings. resnlts: initial results show a substantial scattering of clients from several act teams and substan· rial overlap of visit travel routes for most teams. conclusions: reallocation of catchment areas and optimization of act teams' travel patterns should lead to substantial savings in travel times, increased service efficiency and better utilization of resourc_~· ~e l'<!tenri~i modifications to catchment areas must be conducted with appropriate attention to specific clients servtce needs, service continuity and applicable regulations by the mohl tc. venice lido is a popular island within and outside italy because it hosts the international cinema festival yearly. only few people remember the island for its hospital, which, in the fifties, was one of the most important hospitals in italy and in europe, being a modern center for wind-, sun-and thermal-therapy. since the sixties, its fame became to drop away, since its structure was no longer adequate for the evolving medicine science. at the end of the seventies all the wards were moved into a new big building in the same area. at present the hospital is made up by about forty 'pavilions' (mostly partially used or empty) and a big building, disseminated in a 10 hectares area, on the sea front, on the 500 m long beach. the aim of my research is to suggest a realistic solution, sustainable on the functional use of the area according to basic local needs and economically realizable. i used a philological and multi-disciplinary method, more in detail: -from historical documents, i found what was the very first call of the property and how it adapted to the needs of the demographic development and the sanitary supply over time; -by contacting some operators from different fields, i realized which functions were suitable to the buildings in existence, to the population's needs and to the present sanitary supply. moreover the planning idea considers: -the debate going on between local people who strongly want to preserve the property, and die ones who want to renew it by different new opportunities; and -the regional sanitary politics, aiming at rationalizing the regional hospitals dislocation, and the budget needs. this plan analyzes and proposes some new alternative solutions to satisfy different needs. the different activities will be dealt out and the environmental fall will be limited as much as possible. after having analyzed its basic call, considered its environmental peculiarities and its position, verified the emerging needs of the local population, the plan proposes 5 different activities: the hospital; the social-rehabilitation center; the elderly house; the thermal center; the residential center; and other activities. such a plan wants to share in the solution of a basic problem by giving architectonic and functional dignity to an historical completely degraded area and by starting again a social-economical broken off process, by bringing in venice lido some fresh necessary elements for its so wished new throw. p4-14 (c) dilemma of free health care in spokane, wa david bunting introduction: the paper reports on the activities of project access spokane [pas], a physician sponsored initiative to provide uncompensated health care to low income, uninsured residents of spokane county wa. program providers included all county hospitals, over 600 physicians, other medical professionals, and specialized clinics. each prescription requires only a $4 co-payment. sponsored and administered by the county medical society, pas is funded by local and national foundations, private corporations, municipalities, civic organizations and individuals. method: the paper is based on a first year assessment report funded by pas, using hcfa [health care financing administration] insurance claim data documenting utilization rates, disease categories and donated charge information and patient cares [centralized applications, referrals and enrollment status) data. results: while essentially free for enrollees, the program involved real costs. an administrative organization to refer over 700 patients to any of over 800 providers had to be developed and staffed, using both paid and unpaid personnel. methods to identify potential patients and veri.fy eligibility. had to ~devised. patient appointments and transportation had to be scheduled and monitored. pu~hc relanons, provider solicitations and fundraising activities were continuous. information requirements regarding program operation were also significant. data reporting the volume. ~nd value of dona~ed medical services were necessary to demonstrate accomplishments and attr~ct addmon~l support. providers required assurances their contributions were both significant and eqmtable. funding sources sought evidence that their support had important consequences. however, generating this ~~ta proved difficult. many providers failed to submit appropriate insurance claims forms because .of a~dmonal donated effort and administrative cost, thereby not only reducing their own apparent conmbut1ons but also the overall significance of the program. conclusions: during its initial year, the estimated cost to deliver free health care was ~bout 5500 per enrollee. the lesson is that without an elaborate administrative structure and record keeping s.yst~~· efforts to provide free health care probably will fail. eligible enrollees c~n not be ~parated from in~hgi ble ones, care will not be accessed or delivered in an efficient manner, neither fundmg nor ~upport "". 1 11 be offered without evidence of tangible benefits, and providers will withdraw if they perceive mequ1table tteannent. v74 p4-1s (c) mobility in prostitution and the impact of health therese van der helm and henk sulman poster sessions introduction: many of the estimated 8.000 commer~ial ~ex wor~ers (c~w)in a'.'1~terdam ~~me from developing countries and eastern europe. to gain ins~ght mto their workmg and_ hvmg condinons the intermediary project (ip) at the municipal health serv1~e _contacts these women via ?utreach work on regular basis. since the new brothel law in october 2000 1s 1~troduc~d, ~sw ~rom outside the eu and who have no dutch residence permit are not allowed to work m prost1tut10n. smee then, many of these csw therefore have gone "underground." the consequences of the new law in the netherlands will be discussed with regard to the accessibility of csw and their risk for stl/hiv acquisition and unplanned pregnancies. methods: topics during outreach work are the interventions to increase the knowledge of safe sex and birth control for csw. written information is handed out in relevant languages and with addresses of health and social services. in conversations with the women, it appeared that many are not aware of these services. to provide easier access to health care for women, staff of the ip carries out free sti control csw working places, in windows brothels and sex houses. also, women are offered vaccination against hepatitis b (hbv). results: from january 2004 till july 2005 we approached 900 csw for first contact. one third was dutch; others were from developing countries, other eu countries and eastern europe. 350 sti consul· rations were done among non-iv drug using sex workers, of whom 50 % was dutch. of these, 2 % was diagnosed with syphilis, 1 % with gonorrhea, and 9% with chlamydia. of 234 women tested for hiv, none were infected. due to the high turnover of csw in .brothels, most wnmen were tested only once. among 845 csw tested for hbv -of whom one third is dutch -22 % had antibodies for hbv, 12 were carrier of hbv, most of whom came from hbv endemic areas. conclusions: sti control and hbv vaccination in brothels is an important support in health care. our findings suggest that csw do not play an important role in the transmission of sti. many csw are highly mobile and often not aware of the existing health and social services. continuous outreach is important to remain in contact with this mobile population. regulations in the new brothel law should not hamper contacts with (illegal) csw. heart disease (cho) is projected to become the leading cause of death. studies conducted in europe and the united states have proven a higher rate of cho in south asians who have migrated from south asia, most notably india, pakistan and bangladesh. approximately 50% of all heart attacks among south asian men occur under the age of 55; 25% of them occur under the age of 40-unheard of in any other population. associated risk factors such as diabetes, high blood pressure and cholesterol are also com· mon in this group. the population of south asians residing in nyc has more than doubled over the past decade to over 300,000, the majority being young, working-class and with limited health care access. many south asian men are employed as taxi drivers (4 out of 10 nyc taxi drivers are from south asial, working daily12 hour plus shifts. methods: acknowledging that this vulnerable, at-risk group was unavailable for outreach through conventional venues, three of the hospitals of the new york city health and hospital corporation, (elmhurst, queens and bellevue) conducted a one day outreach effort at nyc's jfk international air· ~rt's taxi holdin~ ar~a, ~here over one thousand taxis regularly assemble. bringing an outreach event directly to the taxi dnvers workplace, a tent was set up where cardiovascular-related health screenings, in~luding bl~ pressure, sugar, cholesterol, body mass index (bmi), were provided. results were shared with and explamed to the drivers and each participant received a south asian health education brochure. a total of 84 taxi drivers who identified as south asian were involved. rau/ts: participants were all male, ranging from 20 to 61 years; mean age, 41.5. screenings revealed 57% hypertensive; 46% had cholesterols over 200; 26% blood glucose over 160; 91 % had a bmi greater than 25. conc~on: a unique outreach activity, adapting to logistical, occupational limitations, is pre· se~ted. on-site f~back and explanation of results, reiterating and reinforcing the concern that south asia~. men are at mcreased danger for early coronary heart disease, and the dissemination of a culturally sensmve and r~levant brochure, may heighten awareness of prevailing cardiac risk factors in this immi· grant community. p4-17 (c) the community-hospital integration program framework: community-hospital panoenhips to improve the population's health john stevenson, richard blickstead, ann-marie marcolin, and sandi kendal v75 introduction: st. josephs health centre is a catholic community teaching hospital located in the heart of southwest toronto. st. joseph\'s was founded from a community-expressed need for hospital services, and since then has stayed committed to fostering a healthy community through collaboration and parmership. st. joseph's has developed an innovative model, the community-hospital integration program (chip), to strengthen st. joseph's partnerships with community stakeholders, and facilitates the building of links between community needs, service provision, and public policy outcomes to improve the health and wellness of the diverse neighbourhoods they together serve. methods: development of the chip framework st. joseph's health centre developed the chip framework through a multidisciplinary approach that included extensive international literature reviews, consultations, and key informant interviews with community service agencies and academics. to ensure active community voice, st. joseph's has hosted a number of community consultations including a community outreach forum attended by over ninety representatives from 68 community partners. results: the chip framework the chip framework aims to improve the health and wellness of the urban communities served by st. josephs health centre through four intersecting pillars: • raising community voices provides an infrastructure and process that supports community stakeholder input into health care service planning, decision-making, and delivery by the hospital and across the continuum of care; • sharing reciprocal capacity promotes healthy communities through the sharing of our intellectual and physical capacity with our community partners; • cultivating integration initiatives facilitates vertical, horizontal, and intersectoral integration initiatives in support of community-identified needs and gaps; and • facilitating healthy exchange develops best practices in community integration through community-based research, and facilitates community voice in informing public policy. the chip framework drives the complex inter-relationships between community-hospital engagement, reciprocal capacity-building, integration initiatives, and community-based research and evaluation, to create an interconnected network of health care services. the fluidity and simplicity of this framework, and its dedication to balancing community needs and hospital mandate, posits the st. josephs health centre's chip model as an integral component in building healthy and thriving communities. p4-18 (c) home based care promotion: improving acess to quality services and livelihood in the face of aids home based care is a service provided to persons affected/living with hiv/aids, a menu of care/support services at home/community. it is a prominent alternative approach. in uganda, hospital bed ocupacny is high, patient health care worker ratio deteriorating. empowering communities offers solutions to the problems; adressing cost, effectiveness of care. hiv/aids demands changes in attitudes, behaviour, approaches which is enhanced in home/community settings. for example art requires high levels of adherecnce, which medical workers have vety little opportunity to enforce. it also demands other support mechanisims in terms of nutrition, personal displine, etc which work best in stigma free environments. hence the relevance of home based care. this paper highlights the gaps that call for increased action in terms of home based care, examples of whre it has worked key challenges and recommendations for the future. p4-19 (c) health care for one ... health care for alli katharina kovacs burns introduction: at the surface, it appears that every person in canada _has. ~ccess to a publicly funded health care system. those living in urban centers should have the best ava1l~b1hty, chmce, and access to a variety of health care services because of the distribution of health care services, fac1lmes, and health professionals in concentrated in urban centers. this is not true for everyone -people with low income or who are homeless experience the challenges of social exclusion and being marginalized: there are many factors at play making it difficult for the latter group of people to access health care. service they need,.when they need them. health care is not as accessible or inclusive as intended. the quesuon to be explore.cl 1~: if health care is available and accessible to one person, what makes it not available to all people? the ~1gmfic~nce of having marginalized people accessing health care and other services includes e~hanced quality of hfe and decreased risks associated with being homeless, and cost savings in ion~ ter~ w1rh acute health care. methodology: community-based participatory research is applied m a case study on health care access and challenges experienced by low income and homeless people in one urban centre, edmonton, edmonton, and their challenges. the data is being gathered and ana_lyzed usmg basic m1x~d methods. results: the results will focus on how services can be more mtegrated and accessible to all people with low income and who are homeless. there will also be discussion about specific perceptions of not only the service providers but also of people with low income an~ who are homeless~ and vario~s decision makers. the results will be compared to the literature regardmg health care services access mother urban centers in canada and elsewhere. conclusions: recommendations will need to address social exclusion and other factors which can make health care and other services more available to all people in the community. the implications for health care will also be discussed. additional information will be gathered in the next phases of the study to develop a community services access model. p4-20 (c) availability and access exemplified: a case study beth hayhoe and ruth ewert introduction: access to health care in canada requires either the correct documentation or money. street youth have neither. in addition, health services in canada are designed by adults for adults. youth in general are often wary of having trust in adults with respect to their health concerns and frequently feel misunderstood. street youth are even more mistrustful of adults and public organizations, making their contact with health care professionals minimal. this combined with their risky behaviours and dangerous environment creates a population at risk for numerous health issues but with no place to have them investi· gated. at our non-government, not for profit health service designed specifically to provide a broad range of health care to street youth, professional services are provided almost entirely by volunteers. methods: using a retrospective analysis of the 11 years of data gathered from this organization and reviewing the initial reasons gathered from youth about their needs, the success of the health centre was examined. results: all the things youth had listed as being important in a health centre have been implemented, and even more things have been added to improve the breadth and quality of services offered. the use of the health centre has increased by more than six times since its opening in 1994. in addition, tens of thousands of visits have been paid to the health centre, costing the government and taxpayers nothing. as far as we know there is nothing else in canada that offers so many diverse and innovative services to youth in need. conclusion: it is clear from this case, that health care targeted at the needs of specific disadvan· taged populations can successfully provide them with appropriate health care. a model of accessible health care for marginalized populations can easily be developed for high impact and low cost from this successful case. toronto is one of the most ethno-racially diverse cities in the world of the estimated 2,529,280 toronto residents, 24% (597,218) live in scarborough population growth in scarborough is faster than toronto. scarborough's population increased by 6% from 1996 to 2001 while toronto increased only by 4%. toronto's population is projected to increase by 10% (252 000) in 2011 while scarbor· ough's will increase by 12%. (census canada 2001) low income, pove;ty, seniors, hidden homeless, new~omers to canada, the uninsured, are just a few of the issues concerning health care in our community. health care needs in scarborough are greatly impacted by diversity of ethnic and racial groups, poverty and settlement issues. this paper will share how the scarborough hospital (tsh) an urb~n communir_y hospital cares f~~ it~ community. tsh recognizes: •the changing community• b_arriers t~ accessing care • lnequalmes m health care the hospital in caring for its community pro· v1~es services that '!'e~e cu~turally, racially, and linguistically sensitive to our community. the paper will share the hospitals unique program on access and equity. the paper will share the needs in scar· borough and tsh's response to these needs: working in partnership with the local health committee, i:ne scarborough homeless co.mminee, the scarborough network of immigrant services organiza· nons a~d others. 1:'1e paper will also share the many initiatives this urban community hospital has taken viz. community and home programs in service areas such as mental health, haemodialysis day care, t~~ home oxyg~n program, the palliative at-home program, and above all support for the volunteer clinic for the uninsured. j"'"1tllu:lion: in canada's universal health care system it is generally assumed that everyone has equal access to health care. however, some immigrant groups in canada have historically been uninswed. these groups include failed refugee claimants, those overstaying their visas, and new immigrants in transition who are waiting to become eligible for health insurance. some estimates have suggested that at the present time there may be as many as one hundred thousand undocumented and thus uninsured immigrants in toronto alone. understandably, information on the characteristics of this marginalized population is very limited, since undocumented immigrants tend to have little contact with formal institutions. knowledge of the demographic characteristics of this population may aid in the development of health and social programs to better identify and meet the needs of undocumented immigrants in toronto. we conducted a review of all undocumented, uninsured patients, 15 years of age or older at access alliance multicultural community health centre (aamchc) between 1994 and 2004. demographic information such as age, gender, preferred language, length of time living in canada, selfreported education level and household income were recorded. rmdts: 72% of all adult patients at access alliance were undocumented and uninsured. 80% were under40years of age (with a median age of 30 years), 72% were women and only 19% spoke english. this group lived in canada for an average period of 2.2 years before they were first seen at aamchc. 74% of undocumented clients reported having completed at least a secondary or post-secondary education. 81% had self-reported household incomes of less than 20,000$/year, while 97% of households reported earning less than $30,000/year. the mean income per person in an average household was 425$/month. conchuions: uninsured individuals at aamchc were predominantly young females with limited knowledge of the english language. despite having attained a high level of education most were living well below the poverty line. recognition of these characteristics may assist in the development of health and social programs that are better adapted to meet the needs of undocumented immigrants. p4-23 (c) sharing expertise: a role for the hospital lactation consultant in the community. badrgrmuul: st. michael's hospital is a tertiary care hospital that serves a large inner city population in downtown toronto. in order to provide care to this population, the hospital has developed a number of unique outreach roles. one such role was developed to work with pregnant and breastfeeding women living in regent park, a social housing complex located near the hospital. the population of regent park includes new immigrants, refugees and the socially disadvantaged. approach: the outreach lactation consultant provides care, as part of the canada prenatal nutrition program, in the community prenatally, in the hospital during their inpatient stay and postnatally when they return to the community. the continuity of care enhances the probability of long term successful breastfeeding. aside from the health benefits of breastmilk, breastfeeding is especially important for women who are financially needy and must depend on food banks for formula. . . lason learned: aher two years of partnership, the relationship between the an-hospital ~stpar tum experience for breastfeeding mothers and the community postpartum support, the breastfeeding rate ~thin this community is high. the professional support and visibility of the 1:8ctation consultant, both m the hospital and in the community, contributes to the support of breastfee~m~.. . in light of ongoing funding constraints, this ha1son between hospital and community could be at risk and discontinued. in light of the benefits to the mother/baby dyad, the lactation consultant as a community partner in the canada prenatal nutrition program should be safeguarded. . lldpodiu:tion: although the importance of adequate health care in pregna~cy is well recognised, ethnic disparities in utilization of prenatal care still exist in many western coun~~es. a fun~amental factor in these disparities may be language proficiency, as it influences women's ab1hty. to ob~m and understand health information, to find the way in the health care system and to communicate with health care v78 poster sessions providers. we investigated the role of language proficiency in use and knowledge of folic acid as aspect of prenatal care in an urban multi-ethnic pregnancy c?hort. . . design: prospective cohort study. setting and parnc1pants: amsterdam ~regnant women attending obstetric care providers for their first antenatal visit (n= 8050). country of birth defined ethnicity: the netherlands, surinam, antilles, turkey, morocco, ghana, other non-~est~m (nw) and other western (w) country. main outcome measures: knowledge about and use of.fohc a~d (fa) supplements in pregnancy, and determinants of these in diffe~~t ethnic ~~ups. deterrrunants mcl~ded age, ed~ tion, parity, pregnancy intention and dutch prof1c1ency. stansncs: ~2 to co~p~re e~c groups, stranfied logistic regression (forward stepwise method) to explore determmants "'.'thm ethmc groups .. use of fa supplements was significantly lower among ghanaian, moroccan, turkish and other nw women (21%to41 %) than among dutch (86%) or other w women (78%). use amongsurinames and antillean women was intermediate (51%and60%). ethnic differences in fa knowledge were similar. knowledge was the strongest determinant of use in all ethnic groups, with odds ratios (ors) ranging from 10.9 to 42.0. language proficiency was the strongest determi~a~t of kno~ledge in ethnic groups with a mother tongue different from dutch (ors good vs. low proficiency ranging from 3.2 ro 16.0). educational level had a modifying role, as shown by an interaction effect between education and language proficiency in the nw group. here, the odds of having fa knowledge given a high education and good dutch proficiency was 20 times the odds given a good proficiency but low education. conclusions: appropriate periconceptional use of folic acid supplements in non-western ethnic groups is low, reflecting an absence of knowledge that is largely determined by the inability to speak and understand the language of the habitual country. tailored interventions using communication channels most likely to address (pregnant) women from ethnic minority groups are necessary. apan from specific interventions, our results are in support of strong incentives on language education despite current political debate. introduction: recent research suggests living in an economically disadvantaged neighborhood is asso· ciated with decreased likelihood of undergoing mammography and increased risk of late-stage breast can· cer diagnosis. long distances and travel times to facilities offering low-or no-cost mammography may be imponant barriers to adherence to mammography screening recommendations for residents of economically disadvantaged neighborhoods. the purpose of this study was to examine whether facilities providing low-and no-cost screening mammography were less spatially accessible in low-income neighborhoods in chicago, and the extent to which the relationship between neighborhood income and the spatial accessibility of facilities varied by the proponion of african-american residents in the neighborhood. methods: the sample consisted of 343 chicago neighborhoods. for each neighborhood, we con· structed three measures of the spatial accessibility of facilities: street network distance to the nearest facility, public transportation travel time to the nearest facility, and shortest automobile travel time to a facility. using 2000 decennial census data, we characterized the neighborhoods according to proportion of residents with incomes below the poverty line, proportion of residents in each of four raciavethnic groups (african-american, latino, white, and other), and population density. we used ordinary least squares (ols) and spatial exogenous lag regression to examine relationships. model 1 estimated the relationship between neighborhood poverty and the spatial accessibility of facilities, adjusting for raciaveth· nic composition and population density. model 2 added a multiplicative interaction term between neighborhood poverty and african-american. restllts: we identified deven facilities that provided low-or no-cost screening mammography to chicago residents in 2004. we found that the distance and travel times via automobile and public trans· portation to facilities generally decreased as neighborhood poveny increased. however, we also found that the ~egative associations between neighborhood poverty and two of the spatial accessibility mea· sures -distance and public transportation travel time -were less strong in neighborhoods with the highest proponions of african-american residents. among neighborhoods in the highest tertile for poveny, th~ mean distance and mean public transportation travel time to facilities were over twice as long in neighborhoods in the highest tertile than in those in the lowest tenile of african-american residents. . ~ persistent socioeconomic and racial/ethnic disparities in breast cancer stage at diagno-s11 ~nd su~1val suggest that ensuring an equitable distribution of affordable mammography is a worth-w~e policy .goal. the ~~dy sugges~ that ~ture investigations should consider both neighborhood soc1oecono1d1c charactensbes and rac1avethmc composition when examining the spatial distribution of health resources. , 2004) . epidemiological data suggest tha~ hiv prevalence among msm is over 1 % in some metropolitan cities, such .as beijing (ibid.). due to widespread homophobia in chinese society, however, this population remains invisible within current health/social services. lack of research on sexuality, specifically homosexuality, has impaired our understanding of health and health practices of chinese msm. focusing on the illness experiences of chinese msm with hiv/aids, this paper explores the socio-cultural impacts of hiv/ aids on this group. the data used for this paper were collected through semi-constructed in-depth face-toiace interviews with 21 adult plwhas (including 11 msm) in beijing, china. with the permission of the participants, the interviews were audio-taped or recorded in notes. the transcribed interviews and interview notes were analyzed by using n-vivo, a software program for qualitative data analysis. this phenomenological study aimed to understand the experiences chinese plwhas (including msm) from their own perspectives. results: it is found that the illness experiences of chinese msm with hiv/aids are profoundly shaped by the socio-cultural meanings of homosexuality, which are further complicated by the dominant discourses on hiv/aids in china. at a macro level, homophobia in the larger society has decreased the capability of this group to respond to this epidemic in a more efficient way. at a meso level, aids-phobia within the chinese msm circuits has prevented this group from openly confronting this disease and offering support to those who are already affected by it. at a micro level, however, these hiv-infected/ affected msm have tried their best to locate spaces to live and to construct hope for their future lives despite various barriers within family, community, and the larger society. this study suggests that facilitating chinese msm's response to the aids crisis urgently requires bridging awareness, commitment, knowledge and resources both within and without this group. it also illustrates the importance of understanding homosexuality in the local context of hiv i aids, which will be helpful for developing culturally sensitive hiv/aids programs for this population on the community, national and international levels. introduction: having a regular family doctor (rfd) is known to be positively correlated with a good medical follow up, including access to preventive and/or chronic care. inversely, a lack of primary care may lead to high rates of avoidable hospitalizations, especially among poor people and/or in underserved neighbourhoods. in such a matter, a recent comparative study showed that paris was better ranged than other cities, such as nyc, tokyo or london. nevertheless, despite a quasi universal health insurance and a high density of general practitioners, a noticeable fraction of the paris population does not have any regular physician and we aimed to understand who they are and for what reasons rhey don't have any rfd. mdbods: cross sectional population survey among a random sample of households in 2 ~nderpriv ileged neighbourhoods in paris inner city, performed in 2003, using a face-to-face quest10nna1re collecr-1ng more than 400 social and health characteristics. ruults: a quarter (26.3 %) of rhe study popularion did not have any rfd. this proporrion was iignificantly higher among male (or= 2.00, 95%ci = [ 1.41-2.781), younger (e.g. or 18 -29/> .s l _= 4._oo, 95"1.ci = (2.13-7.69)), and/or unemployed (or =2.01, 95%ci = ij .21-3.3411_ people. in multtvanate analysis, after a full adjustment on gender, age, health status, health insura~ce, income, occupat10n and tducation level, we observed significant associations between having no rfd and: ~arrtal and_ pare~t hood status (e.g. or single no kids/in couple+kids = 2.12, 95%ci = ( 1.26-3.59()~ quality of relattonsh1ps with neighbours (or bad/good= 3 .82, 95%ci = [ 1.84-7.94)), and length of residence m the neighbourhood (with a dose/effect statistical relationship). . co11clusion: gender, age, employment status, mariral and parenthood stat~s as well as ~e1gh bourhood anchorage seem to be major predictors of having a rfd, even when um.versa! health i~sur ance has reduced most of financial barriers. in urban contexts, where residential migrattons and single lift (or family ruptures) are frequent, specific information may be conducted to encourage people to ket rfd. :tu~y tries to assess the health effects and costs and also analyse the availability and accessibility to health care for poor. . methods: data for this study was collected by a survey on 300 households of the local community living near the factories and 100 households where radiation hazard w~s n?~ present. ~~art from mor· bidity status and health expenditure, data was collected ~n access, a~ail~b1.hty and eff1c1ency of healrh care. a discriminant analysis was done to identify the vanables that d1scnmmate between the study and control group households in terms of health care pattern. a contingent valuation survey was also undertaken among the study group to find out the factors affecting their willingness to pay for health insurance and was analysed using logit model. results: the health costs and indebtedness in families of the study group was high as compared to control group households and this was mainly due to high health expenditure. the discriminant analysis showed that expenditure incurred by private hospital inpatient and outpatient expenditure were significant variables, which discriminated between the two types of households. the logit analysis showed !hat variables like indebtedness of households, better health care and presence of radiation induced illnesses were significant factors influencing willingness to pay for health insurance. the study showed that study group households were dependent on private sector to get better health care and there were problems with access and availability at the public sector. conclusion: the study found out that the quality of life of the local community is poor due to health effects of radiation and the burden of radiation induced illnesses are so high for them. there is an urgent need for government intervention in this matter. there is also a need for the public sector to be efficient to cater to the needs of the poor. a health insurance or other forms of support to these households will improve the quality for health care services, better and fast access to health care facilities and reduces the financial burden of the local fishing community. the prevalence of substance abuse is an increasing problem among low-income urban women in puerto rico. latina access to treatment may play an important role in remission from substance abuse. little is known, however, about latinas' access to drug treatment. further, the role of social capital in substance abuse treatment utilization is unknown. this study examines the relative roles of social capital and other factors in obtaining substance abuse treatment, in a three-wave longitudinal study of women ages 18-35 living in high-risk urban areas of puerto rico, the inner city latina drug using study (icldus). social capital is measured at the individual level and includes variables from social support and networks, familism, physical environment, and religion instruments of the icdus. the study also elucidates the role of treatment received during the study in bringing about changes in social capital. the theoretical framework used in exploring the utilization of substance abuse treatment is the social support approach to social capital. the research addresses three main questions: ( t) does social capital predict parti~ipating in treatment programs? (2) does participation in drug treatment programs increase social capital?, and (3) is there a significant difference among treatment modalities in affecting change in ~ial capital? the findings revealed no significant association between levels of social capital and gettmg treatment. also, women who received drug treatment did not increase their levels of social capital. the findings, however, revealed a number of significant predictors of social capital and receiving drug ~buse treatment. predictors of social capital at wave iii include employment status, total monthly mcoi:rie, and baseline social capital. predictors of receiving drug abuse treatment include perception of physical health and total amount of money spent on drugs. other different variables were associated to treatment receipt prior to the icldus study. no significant difference in changes of social capital was found among users of different treatment modalities. this research represents an initial attempt to elucidate the two-way relationship between social capital and substance abuse treatment. more work is necessary to unden~nd. ~e role of political forces that promote social inequalities in creating drug abuse problems and ava1lab1hty of treatment; the relationship between the benefits provided by current treatment poster sessions v81 sctrings and treatment-seeking behaviors; the paths of recovery; and the efficacy and effectiveness of the trtaanent. and alejandro jadad health professionals in urban centres must meet the challenge of providing equitable care to a population with diverse needs and abilities to access and use available services. within the canadian health care system, providers are time-pressured and ill-equipped to deal with patients who face barriers of poverty, literacy, language, culture and social isolation. directing patients to needed supportive care services is even more difficult than providing them with appropriate technical care. a large proportion of the population do not have equitable access to services and face major problems navigating complex systems. new approaches are needed to bridge across diverse populations and reach out to underserved patients most in need. the objective of this project was to develop an innovative program to help underserved cancer patients access, understand and use needed health and social services. it implemented and evaluated, a pilot intervention employing trained 'personal health coaches' to assist underserved patients from a variety of ethno-linguistic, socio economic and educational backgrounds to meet their supportive cancer care needs. the intervention was tested with a group of 46 underserved cancer patients at the princess margaret hospital, toronto. personal coaches helped patients identify needs, access information, and use supportive care services. triangulation was used to compare and contrast multiple sources of quantitative and qualitative evaluation data provided by patients, personal health coaches, and health care providers to assess needs, barriers and the effectiveness of the coach program. many patients faced multiple barriers and had complex unmet needs. barriers of poverty and language were the easiest to detect. a formal, systematic method to identify and meet supportive care needs was not in place at the hospital. however, when patients were referred to the program, an overwhelming majority of participants were highly satisfied with the intervention. the service also appeared to have important implications for improved technical health care by ensuring attendance at appointments, arranging transportation and translation services, encouraging adherence to therapy and mitigating financial hardship -using existing community services. this intervention identified a new approach that was effective in helping very needy patients navigate health and social services systems. such programs hold potential to improve both emotional and physical health out· comes. since assistance from a coach at the right time can prevent crises, it can create efficiencies in the health system. the successful use of individuals who were not licensed health professionals for this purpose has implications for health manpower planning. needle exchange programs (neps) have been distributing harm reduction materials in toronto since 1990. counterfit harm reduction program is a small project operated out of a community health centre in south-east toronto. the project is operated by a single full-time coordinator, one pan-rime mobile outreach worker and two peers who work a few hours each week. all of counterfit's staff, peers, and volunteers identify themselves as active illicit drug users. yet the program dis~rib utes more needles and safer crack using kits and serves more illicit drug u~rs t~an the comb1~e~ number of all neps in toronto. this presentation will discuss the reasons behind this success, .s~1f1cally the extended hours of operation, delivery models, and the inclusion of an. extremely marg1~ahzed community in all aspects of program design, implementation and eva.luat1?n. ~ounterfit was recently evaluated by drs. peggy milson and carol strike, two leading ep1dem1olog1st and researchers in the hiv and nep fields in toronto and below are some of their findings: "the program has experienced considerable success in delivering a high quality, accessible and well-used program .... the pro· gram has allowed (service users) to become active participants in providing. services to others and has resulted in true community development in the best sense. " ... counterf1t has ~~n verr succe~sful attracting and retaining clients, developing an effective peer-based model an.d assisting chen~s ~1th a vast range of issues .... the program has become a model for harm red~ctmn progr~ms withm the province of ontario and beyond." in june 2004, the association of ?ntano co~mumty heal~~ <:en· ires recognized counterfit's acheivements with the excellence m community health initiatives award. in kenya, health outcomes and the performance of government health service~ have det~riorated since the late 1980s, trends which coincide with a period of severe resource constramts necessitated by macro-economic stabilization measures after the extreme neo-liberalism of the 1980s. when the govern· ment withdrew from direct service provision as reform trends and donor advocacy suggested, how does it perform its new indirect role of managing relations with new direct health services providers in terms of regulating, enabling, and managing relations with these health services providers? in this paper therefore, we seek to investigate how healthcare access and availability in the slums of nairobi has been impacted upon by the government's withdrawal from direct health care provision. the methodology involved col· leering primary data by conducting field visits to 8 health institutions located in the slum areas of kibera and korogocho in nairobi. purposive random sampling was utilized in this study because this sampling technique allowed the researcher(s) to select those health care seekers and providers who had the required information with respect to the objectives of the study. in-depth interviews using a semi-structured ques· tionnaire were administered ro key informants in health care institutions. this sought to explore ways in which the government and the private sector had responded and addressed in practical terms to new demands of health care provision following the structural adjustment programmes of the 1990s. this was complemented by secondary literature review of publications and records of key governmental, bilateral and multilateral development partners in nairobi. the study notes a number of weaknesses especially of kenya's ministry of health to perform its expected roles such as managing user fee revenue and financial sustainability of health insurance systems. this changing face of health services provision in kenya there· fore creates a complex situation, which demands greater understanding of the roles of competition and choice, regulatory structures and models of financing in shaving the evolution of health services. we rec· ommend that the introduction of user fees, decentralization of service provision and contracting-out of non-clinical to private and voluntary agencies require a new management culture, and new and clear insri· tutional relationships. experience with private sector involvement in health projects underlines the need not only for innovative financial structures to deal with a multitude of contractual, political, market and risks, but also building credible structures to ensure that health services projects are environmentally responsive, socially sensitive, economically viable, and politically feasible. purpose: the purpose of this study is to examine the status of mammography screening utilization and its predictors among muslim women living in southern california. methods: we conducted a cross-sectional study that included 202 women aged ::!: 40 years. we col· leered data using a questionnaire in the primary language of the subjects. the questionnaire included questions on demography; practices of breast self-examination (bse) and clinical breast examination (cbe); utilization of mammography; and family history of breast cancer. bivariate and multiple logistic regression analyses were performed to estimate the odds ratios of mammography use as a function of demographic and other predictor variables. . results: among the 202 women, 78% were married, 68% were 40-50 years old, and 20% had family h1story of breast cancer. thirty-two percent of the participating women never practiced bse and 32% had not undergone cbe during the past two years. the data indicated that 46% of the women did not have mammography in the last two years. logistic regression analysis showed that age (0r=5.1, 95% confi· dcnc~ interval (cl)=l.8-14.2), having clinical breast examination (0r=24.9, 95% cl=8.4-73.7), and practtce of self-breast examination (0r=2.6, 95% cl= 1.1-6.2), were strong predictors of mammography use . . conclusions: the data point to the need for intervention targeting muslim women to inform and motivate th.cm a~ut practices for early detection of breast cancer and screening. further studies are needed to investigate the factors associated with low utilization of mammography among muslim women population in california. we conducted a review of the scientific literature and° government documents to describe ditnational health care program "barrio adentro" (inside the neighborhood). we also conducted qualiurivt interviews with members of the local health committees in urban settings to descrihe the comm unity participation component of the program. rtsmlts: until recently, the venezuelan public health system was characterized by a lack or limited access w health care (70% of the population) and long waiting lists that amounted to denial of service. moit than half of the mds worked in the five wealthiest metropolitan areas of the country. jn the spring oi2003, a pilot program hired 50 cuban mds to live in the slums of caracas to provide health care to piople who had previously been marginalized from social programs. the program underwent a massive expansion and in only two years 20,000 cuban and 6,500 venezuelan health care providers were working acmss the country. they provide a daily average of 20-40 medical consultations and home visits, c1lly out neighborhood rounds, and deliver health prevention initiatives, including immunization programs. they also provide generic medicines at no cost to patients, which treat 80% of presenting ill-ij!m, barrio adentro aims to build 8,000 clinics (primary care), 1,200 diagnostic and rehabilitation ctnrres (secondary care), and upgrade the current hospital infrastructure (tertiary care). local health committees survey the community to identify needs and organize a variety of lobby groups to improve dit material conditions of the community. last year, barrio adentro conducted 3.5 times the medical visits conducted by the ministry of health. the philosophy of care follows an integrated approach where btalrh is related to housing, education, employment, sports, environment, and food security. conclusions: barrio adentro is a unique collaboration between low-middle income countries to provide health care to people who have been traditionally excluded from social programs. this program shows that it is possible to develop an effective international collaboration based on participatory democracy. low-income americans are at the greatest risk of being uninsured and often face multiple health concerns. this evaluation of the neighborhood health initiative (nh!), an organization which uses multiple programmatic approaches to meet the multiple health needs of clients, reflected the program's many activities and the clients' many service needs. nh! serves low-income, underserved, and hard-to-reach residents in the des moines enterprise community. multiple approaches (fourth-generation evaluation, grounded theory, strengths-and needs-based) and methods (staff and client interviews, concept mapping, observations, qualitative and quantitative analysis) were used to achieve that reflection. results indicate good targeting of residents in the 50314 zip code and positive findings in the way of health insurance coverage and reported unmet health needs of clients. program activities were found to match client nttds, validating the organization\'s assessment of clients. important components of nhi were the staff composition and that the organization had become part of both the formal and informal networks. nhi 1 1 positioned as a link between the target population and local health and social sc:rvice agencies, working to connect residents with services and information as well as aid local agencies in reaching this underserved population. p4-36 (c) welfare: definition by new york city maribeth gregory for an individual who resides in new york city, to obtain health insurance under the medicaid policy one must fall under certain criteria .. (new york city's welfare programs 2003) if the individual _is on ssi or earns equal to or less than $934 per month, he is entitled to receive no more than $5,600 m resources. a family the size of two would need to earn less than $942 per month to qualify for no greater than ss,650 worth of medicaid benefits. a family of three would qualify for $5,650 is they earned less than $942 per month and so on. introduction: the vancouver gay communiry has a significant number of asian descendan!l. because of their double minority status of being gay and asian, many asian men who have sex with men (msm) are struggling with unique issues. dealing with racism in both mainstream society and the gay communiry, cultural differences, traditional family relations, and language challenges can be some of their everyday srruggles. however, culturally, sexually, and linguistically specific services for asian msm are very limited. a lack of availability and accessibiliry of culturally appropriate sexual health services isolates asian msm from mainstream society, the gay community, and their own cultural communities, deprives them of self-esteem, and endangers their sexual well-being. this research focuses on the qualita· tive narrative voices of asian msm who express their issues related to their sexualiry and the challenges of asking for help. by listening to their voices, practitioners can get ideas of what we are missing and how we need to intervene in order to reach asian msm and ensure their sexual health. methods: since many asian msm are very discreet, it is crucial to build up trust relationships between the researcher and asian msm in order to collect qualitative data. for this reason, a community based participatory research model was adopted by forming a six week discussion group for asian msm. in each group session, the researcher tape recorded the discussion, observed interactions among the participants, and analyzed the data by focusing on participants' personal thoughts, experiences, and emotions for given discussion topics. ra11lts: many asian msm share challenges such as coping with a language barrier, cultural differ· ences for interpreting issues and problems, and westerncentrism when they approach existing sexual health services. moreover, because of their fear of being disclosed in their small ethnic communities, a lot of asian msm feel insecure about seeking sexual health services when their issues are related to their sexual orientation. conclflsion: sexual health services should contain multilingual and multicultural capacities to meet minority clients' needs. for asian msm, outreach may be a more effective way to provide them with accessible sexual health services since many asian msm are closeted and are therefore reluctant to approach the services. building a communiry for asian msm is also a significant step toward including them in healthcare services. a communiry-based panicipatory approach can help to build a community for asian msm since it creates a rrust relationship between a worker and clients. p4-38 (c) identifying key techniques to sustain interpretation services for assisting newcomers isolated by linguistic and cultural barriers from accessing health services s. gopi krishna lntrodaetion: the greater toronto area (gta) is home to many newcomer immigrants and other vulnerable groups who can't access health resources due to linguistic, cultural and systemic barriers. linguistic and cultural issues are of special concern to suburbs like scarborough, which is home to thousands of newcomer immigrants and refugees lacking fluency in english. multilingual community ~nterpreter. service~ (mcis) is a non-profit social service organization mandated to provide high quality mterpretanon services. to help newcomers access health services, mcis partnered with the scarborough network of immigrant serving organizations (sniso) to recruit and train volunteer interpreters to accompany clienrs lacking fluency in english and interpret for them to access health services at various locati?ns, incl~~ing communiry ~c:-lth centres/social service agencies and hospitals. the model envisioned agencies recruin~ and mcis ~.mm.g and creating an online database of pooled interpreter resources. this da.tabase, acces&1bl~ to all pama~~g ?rganization is to be maintained through administrative/member · ship fees to. be ~1d by each parnapanng organization. this paper analyzes the results of the project, defines and identifies suc:cases before providing a detailed analysis for the reasons for the success . . methods:. this ~per~ q~ntitative (i.e. client numben) and qualitative analysis (i.e. results of key •~ormant m~rv1ews with semce ~sers and interpreters) to analyze the project development, training and 1mplementanon phases of the project. it then identifies the successes and failures through the afore· mentioned analysis. poster sessions vss resljts: the results of the analysis can be summarized as: • the program saw modest success both ia l?lllls of numbers of clients served as well as sustainability at various locations, except in the hospital iririog. o the success of the program rests strongly on the commitment of not just the volunteer interprmr, but on service users acknowledgments through providing transponation allowance, small honororia, letter of reference etc. • the hospital sustained the program better at the hospital due to the iolume and nature of the need, as well as innate capacity for managing and acknowledging volunceers. collc/llsion: it is possible to facilitate and sustain vulnerable newcomer immigrants access to health !ul'ices through the training and commitment of an interpreter volunteer core. acknowledging volunteer commitment is key to the sustenance of the project. this finding is important to immigration and health policy given the significant numbers of newcomer immigrants arriving in canada's urban communities. nity program was established in 1993 to provide support to people dying at home, especially those who were waiting for admission to the resi<lential hospice. with the advent of haart and corresponding challenges for people living with hiv/aids in the community, the community program has developed a unique case management approach. this model features an interdisciplinary team providing a clientdrivcn service. the case manager provides continuity of care to clients in a variety of settings both within and outside of the health care system. a case study is used to demonstrate how formal and informal networks of support facilitate efficient and appropriate resource utilization to promote client health. this case study demonstrates the value of consistent coordination with a client who has complex physical, spiritual, substance use and mental health needs. the authors will show how they liaised with the housing authority, police, social services as well as the family physician, clinic staff and a hospital emergtncy room to ensure this client did not fall between the cracks. tarek hussain recognition of the importance of community involvement and sectoral cooperation in health and !ocial services, formalized in alma-ata declaration in 1978, was reinforced at riga meeting held at the mid·point between alma-ata and the year 2000. then at the 20th anniversary of alma-ata declaration, ir was declared that 'primary health care is everybody's business'. health does not exist in isolation. health cannot be defined only as an outcome of 'medical care' but also as one of 'social action'; the responsibility of disease prevention and health promotion rests not only on governments, but also with don·govemmentorgan izations, the community, and individuals. the major accomplishment to date may be that rhere is growing realization in the health sector that community involvement is more than a political right-it is absolute necessary. lessons have learned during the implementation of disease-specific l'cltical programmes, such as cdd, ari, and epi; first, integrated and holistic approaches to childcare art needed, and second, the need for community involvement has become evident. imc! is a broad inte-gra1ed strategy with an overall objective contributing to reducing child morbidity and mortality in developing countries. and one of the imci components, 'community !mci', which is now broadening ~s an entry point for child-focused community development initiatives. community jmcl/c~1ld health is ~n mtcgrated approach to the promotion of key family and community practices that have impact on: child growth and development, disease prevention, home care for sick, malnourished child~en, a.nd care-seekmg behavior and compliance with advice and treatment. the presentation addres~es, m brief, the ~evel opinent of community !mci, operational aspect of community/im cl, key strategies and tools ava1la~le for implementation of c/imci. the paper draws some successful programme examples on working logether for imc! with the community in various countries which had substantial benefns on programme outcomes. p4-4 t (c) healthy child screening: an innovative service initiative ann-marie marcolin and joyce allen . introduction: with mounting attention for creative and integrated models of c~re .that are populallon and community focused, the healthy child screening initiative achiev.es t~ese pnncipl~s and more! . • parkdale high park rotary (sponsorship) the heal~h ~h1ld scree?1?g is a ~opl~-centred model of care. agency and professional sector-specific silos are ehmmated, ~rov1dmg f~~1hes wit~ one-sto~ access to primary prevention services in a local school gym! children at nsk are rece1vmg early mtervent10n and appropriate referrals to the right care provider, at the right time a~d in t~e right place. further, with a complimentary focus on prevention, the program serves to keep at nsk children healthy. healthy child screening results: the service model is developed around four distinct phases: 1) planned outreach; 2) coordinated intake and registration; 3) interdisciplinary screening; and 4) targeted referral. since the fall 2003 and through six collaborative healthy child screenings 158 children ranging in age from 2 to 6 have benefited from this unique service model of care. conclusion: the presentation will provide practical information on the development and implementation of the model. there will also be a focus on lessons learned in building community service provider-hospital relationships. according to statistics canada (2001) 49% of the toronto population was born outside of canada and 21 % were new immigrants. immigrants often arrive in canada in superior health compared to the canadian born population, but they lose this health advantage over time. changes in immigrant health status over time may be attributed to a variety of factors including barriers to accessing and receiving care as well as limitations in the mainstream health service organizations and their approaches to health care delivery (hyman, 2001 ) . for example, immigrant women are less likely to receive pap tests, which places them at a greater risk for developing cervical cancer. similarly, immigrant women receive less mammography screening than their canadian counterparts. the immigrant women's health centre mobile health unit (mhu) was created as an alternative care delivery model to address the need for increased accessibility as well as culturally and linguistically appropriate reproductive health care. toronto western hospital and the immigrant women's health centre have formed a collaborative partnership which incorporates a primary care nurse practitioner and lay ethnocultural counselors providing care on the mhu. currently, a qualitative ethnonursing study is underway to understand the unique experiences of women using the mhu for their reproductive health care as well as the perspectives of the mhu health care providers. based on a literature review and preliminary findings from provider and participant interviews, the proposed presentation will address the themes of health status for immigrant and refugee women, accessibility issues as well strategies to improve their reproductive health care. we will discuss benefits as well as limitations to health care provision using this alternative service delivery model. michael carden, brian edlin, andrew talal, elizabeth getter, and marla shu lntrod.ction: to date most active drug users have not had access to treatment for hepatitis c virus (hcv) infection and substantial barriers continue to exist that interfere with treatment availability for this population. methods: active illicit drug users interested in pursuing hcv care and treatment were recruited in partnership w~th co~munity-based organizations (cbo's) in new york city. baseline data were collected on quahty of hfe, substance use patterns, depression, health care utilization, hcv health beliefs and other relev.ant variables. medical evaluations were conducted, including liver biopsy when indicated, an~ treatment ts ~ffered when no contraindications are present. participants also receive psychiatric evaluahons to determme the appropriateness of interferon treatment. renlts: fifteen individuals have been recruited to date and received an initial medical evaluation. the mean age was 40 years and _the average age of initial heroin or cocaine use was 16.8. eight (53%) ha~ been homeless at least once m the last 6 months and s (33%) were homeless for most or all of this penod. fourteen (93%) had a history of injection drug use with the mean age at first injection being 21 111s1frsewons v87 ,an. elrven persc.!ns (79%) reported inje~~ng .heroin or cocaine within the last 30 days while the .wing four (21 l'o) reported regular non-m1ect1on use of cocaine and street-obtained benzodiazepines. sijiy seven percent of the sample (n= 10) reported ever being referred to hcv treatment while 2 ( t 3 % ) ftponeddiattreann~nt had been offered by~ ~e.dical provider. none had ever received a liver biopsy or araanent. most believed that hcv was a s1gmf1cant threat to their health (80%) and that there was a pm)dchance they would eventually die if their hepatitis c was not treated (67%). though 7 individuals 147%1 believed that there was no cure for hcv, 13 (87%) reported that they would initiate treatment if i was recommended by their doctor. thirteen (87%) had a current psychiatric diagnosis including «pmsion, anxiety disorder, schizophrenia, schizoaffective disorder, and borderline and antisocial persooaliry disorders. among eight individuals who had the beck depression inventory administered, the mean score was 29.75. attendance rates were 83% (83/100) at scheduled medical and psychiatric 1ppointments and 50% (2/4) at liver biopsy. <andtuions: active drug users, despite experiencing multiple psycho-social problems, can be mgaged in hcv care using a multidisciplinary approach, but require intensive follow-up support. hcv aunnent of active drug users should not be dismissed. n-44 (c) antiretroviral therapy in mv infected infants: when to initiate therapy an african experience kingsley okonkwo, ademola adeyemo, israel sokeye, and nwaife umeike /""°""ction: as technology for early diagnosis of human immunodeficiency virus [hiv] improves, m to commence highly active antiretroviral therapy [haarn is yet to be fully evaluated. this prospective study describes our initial experience with early haart in hiv infected nigerian infants and rqions the outcome. we also analyzed the socioeconomic implications of early haart therapy in infants in the african setting. method: hiv infected infants were started on haart before 6 months and followed up at 4 mkly intervals.we monitored baseline and 3 monthly cd4 . conclusion: initial results suggest early haart before 6 months resulted. in improv~d out~ome in african children. treatment appears to be as effective as in developed counmes. in. a~nca as. m most developing countries with limited resources it is possible and effective to use haart m 1~~ants if p~oper llloniroring facilities are available. however the occurrence of long-term drug related tox1c1ty and mk of emergence of resistant viral strains create need for further evaluation of haart in infants. background: most risk factors for cardiovascular disease (cvd) can be mitigated through ~th clinical interventions and lifestyle change. we used data from a telephone survey of new york city (nyc) adults to characterize health care access and healthy behavior among those with three or more cvd risk factors. methods: the study population included respondents to the nyc community health survey 2002 (n= 9,674) self-reporting~ 3 of the following: smoking, diabetes, high cholesterol level, high blood pres· sure, body mass index >25, and age >45 (males) or >55 (females) (n=2,439). results: based on self-report, an estimated 1.447,000 (24%) of nyc adults have~ 3 or more cvd risk factors. this population is 51 % male, 47% white, 25% black, and 53% with s 12 years of education. most report good access to health care, indicated by having health insurance (95%), regular doctor (89%), their blood pressure checked within last 6 months (91 %), and their choles· terol checked within the past year (90% ). only 29% reported getting at least 20 minutes of exercise ~ 4 times per week and only 9% eating ~ 5 servings of fruits and vegetables the previous day. among current smokers, 59% attempted to quit in past 12 months, but only 32% used medication or counseling. implications: these data suggest that most nyc adults known to be at high risk for cvd have access to regular health care, but most do not engage in healthy lifestyle or, if they smoke, attempt effective quit strategies. more clinic-based and population-level interventions are needed to support lifestyle change among those at high risk of cvd. introduction: recently, much interest has been directed at "obesogenic" (obesity-promoting) (swinburn, egger & raza, 1998) built environments, and at geographic information systems (gis) as a tool for their exploration. a major geographical concept is accessibility, or the ease of moving from an origin to a destination point, which has been recently explored in several health promotion-related stud· ies. there are several methods of calculating accessibility to an urban feature, each with its own strengths, drawbacks and level of precision that can be applied to various health promotion research issues. the purpose of this paper is to describe, compare and contrast four common methods of calculating accessibility to urban amenities in terms of their utility to obesity-related health promotion research. practical and conceptual issues surrounding these methods are introduced and discussed with the intent of providing health promotion researchers with information useful for selecting the most appropria1e accessibility method for their research goal~ ~ethod: this paper describes methodological insights from two studies, both of which assessed the neighbourhood-level accessibility of fast-food establishments in edmonton, canada -one which used a relatively simple coverage method and one which used a more complex minimum cos1 method. res.its: both methods of calculating accessibility revealed similar patterns of high and low access to fast-food outlets. however, a major drawback of both methods is that they assume the characteristics of the a~e~ities and of the populations using them are all the same, and are static. the gravity potential method is introduced as an alternative, since it is ·capable of factoring in measures of quality and choice. a n~mber of conceptual and pr~ctical iss~es, illustrated by the example of situational influences on food choice, make the use of the gravity potential model unwieldy for health promotion research into sociallydetermined conditions such as obesity. co.nclusions: i~ ~ommended that geographical approaches be used in partnership with, or as a foun~ation for, ~admonal exploratory methodologies such as group interviews or other forms of commumty consultation that are more inclusive and representative of the populations of interest. qilhl in los angeles county ,,..ia shaheen, richard casey, fernando cardenas, holman arthurs, and richard baker ~the retinomax autorefractor has been used for vision screening of preschool age childien. ir bas been suggested to be used and test school age children but not been validated in this age poup. ob;taiw: to compare the results of retinomax autorefractor with findings from a comprehensive i!' examination using wet retinoscopy for refractive error. mllhods: children 5-12 years old recruited from elementary schools at los angeles county were iaml with snellen's chart and the retinomax autorefractor and bad comprehensive eye examination with dilation. the proportion of children with abnormal eye examination as well as diesensitiviry and specificity of the screening tools using retinomax autorefractor alone and in combinalion wirh snellen's chart. results of the 258 children enrolled in the study (average age= 8.5± 2.1 years; age range, 5-12 years), 6?% had abnormal eye examination using retinoscopy with dilation. for the lerinomax, the sensitivity was 85% (95% confidence interval [ci] 78%-90%), and the specificity was 31% (95% ci, 22%-41 o/o). simultaneous testing using snellen's chart and retinomax resulted in gain in 111sitiviry (94%, 95% cl= 89, 97), and loss in specificity (28%, 95% cl= 19%-38%). the study showed that screening school age children with retinomax autorefractor could identify most cases with abnormal vision but would be associated with many false-positive results. simuhaneous resting using snellen's chart and retinomax maximize the case finding but with very low specificiry. mdhotjs: a language-stratified, random sample of 2366 members of the college of family physicians of canada received a confidential survey. the questionnaire collected data on socio-demographic characteristics, medical training, practice type, setting and hcv-related care practices. the self-adminisratd questionnaire was also made available to participants for completion on the internet. batdti: response proportion was 33%. median age was 41 years (47% female) and the proporlionoffrench questionnaires was 26%. approximately 88% had completed family medicine residency lllining in canada; median year of training completion was 1995. sixty-seven percent, 38% and 29% work in private offices/clinics, community hospitals and emergency departments, respectively. regarding ~practices, 94% had ever requested a hcv test and 87% of physicians had screened for hcv iafrction in rhe past 12 months· median number of tests was 10. while 17% reported having no hcv-uaed patients in their practic~, 44% had 1-5 hcv-infected patients. regarding the level of hcv care provided, 4.3% provide ongoing advanced hcv care including treatment and dose monitoring for ctmduions: in this sample of canadian family physicians, most had pro~ided hcv screening. to •least one patient in the past year. less than half had 1-5 hcv-infected patients and 41 % provide ~:relared care the role of socio-demographic factors, medical training as wel_i as hcv ca~e percep-lldas 10 rhe provision of appropriate hcv screening will be examined and described at the time of the canference. '4-50 (c) healthcare services: the context of nepal meen poudyal chhetri """1tl.ction healthcare service is related with the human rights and fundamental righ~ of the ci~ ciaaiuntry. however, the growing demand foi health care services, quality heal~care service, accessib1b~ id die mass population and paucity of funds are the different but interrelated issues to .be ~ddressed. m nepat.1n view of this context, public health sector in nepal is among other sectors, which is struggling -.i for scarce resources. . . . nepal, the problems in the field of healthcare servic~s do not bnut ~o the. paucity of faads and resources only, but there are other problems like: rural -urban imbalance, regional unbalance, poster sessio~ f the ll ·m1 ·ted resources poor healthcare services, inequity and inaccessibility of the poor management o , . poor people of the rural, remote and hilly areas for the healthcare services and so on.. . . . · . i f ct the best resource allocation is the one that max1m1zes t e sum o m ivi ua s u11 · ea t services. n a , · h d' ·b · · · h . ·t effi.ciency and efficient management are correlated. it might be t e re istn utmn of mes. ence, equi y, . . . . 1 . income or redistribution of services. moreover, maximizanon of available resources, qua tty healthcare services and efficient management of them are the very important and necessary tools and techmques to meet the growing demand and quality healthcare services in nepal. p4-51 (a) an jn-depth analysis of medical detox clients to assist in evidence based decision making xin li, huiying sun, ajay puri, david marsh, and aslam anis introduction: problematic substance use represents an ever-increasing public health challenge. in the vancouver coastal health (vch) region, there are more than 100,000 individuals having some probability of drug or alcohol dependence. to accommodate this potential demand for addiction related services, vch provides various services and treatment, including four levels of withdrawal management services (wms). clients seeking wms are screened and referred to appropriate services through a central telephone intake service (access i). the present study seeks to rigorously evaluate one of the services, vancouver detox, a medically monitored 24-bed residential detox facility, and its clients. doing so will allow decision makers to utilize evidence based decision-making in order to improve the accessibility and efficiency of wms, and therefore, the health of these clients. methods: we extract one-year data (october 1, 2003 -september 30, 2004 from an efficient and comprehensive database. the occupancy rate of the detox centre along with the clients' wait time for service and length of stay (los) are calculated. in addition, the effect of seasonality on these variables and the impact of the once per month welfare check issuance on the occupancy rate are also evaluated. results: among the 2411 clients (median age 40, 65% male) who were referred by access! to vancouver detox over the one-year period, 1448 were admitted. the majority (81 %) of those who are not admitted are either lost to follow up (i.e., clients not having a fixed address or telephone) or declined service at time of callback. the median wait time was 1 day [q3-ql: 3-1], the median los was 5 days iq3-qt: 6-3], and the average bed occupancy rate was 83%. however, during the threeday welfare check issue period the occupancy rate was lower compared to the other days of the year 175% vs. 84%, p conclusion: our analysis indicates that there was a relatively short wait time at vancouver detox, however 40% of the potential clients were not served. in addition, the occupancy rate declined during the welfare check issuance period and during the summer. this suggests that accessibility and efficiency at vancouver detox could be improved by specifically addressing these factors. background: intimate partner violence (ipv) is associated with acute and chronic physical and men· tal health outcomes for women resulting in greater use of health services. yet, a vast literature attests to cultural variations in perceptions of health and help-seeking behaviour. fewer studies have examined differences in perceptions of ipv among women from ethnocultural communities. the recognition, definition, and understanding of ipv, as well as the language used to describe these experiences, may be different in these communities. as such, a woman's response, including whether or not to disclose or seek help, may vary according to her understanding of the problem. methods: this pilot study explores the influence of cultural factors on perceptions of and responses to ipv among canadian born and immigrant young women. in-depth focus group interviews were con· ducted with women, aged 18 to 24 years, living in toronto. open-ended and semi-structured interview questions were designed to elicit information regarding how young women socially construct jpv and where they would go to receive help. interviews were transcribed, then read and independently coded by the research team. codes were compared and disagreements resolved. qualitative software qsr n6 was used to assist with data management. . ruu~ts_: res~nses_abo~t what constitutes ipv were similar across the study groups. when considering specific ab.us1ve ~1tuanons and types of relationships, participants held fairly relativistic views about ipv, especially with regard to help-seeking behaviour. cultural differences in beliefs about normaive m;ile/femal~ relations. familial.roles, and customs governing acceptable behaviours influenced partictpants perceptions about what 1n1ght be helpful to abused women. interview data highlight the social l05ter srnfons v91 11111 suucrural _impact these factors ha:e on you?g women and provide details regarding the dynamics of cibnocultur~ m~uences on help-~eekmg behav10ur: t~e ro~e of such factors such as gender inequality within rtlaoo?sh1ps and t_he ~erce1ved degree of ~oc1al 1solat1on and support nerworks are highlighted. collc~ the~ findmgs unde~score the _1mporta_nc_e of understanding cultural variations in percrprions of ipv ~ relanon to ~elp-seekmg beha~1':'ur. th1s_mformation is critical for health professionals iodiey may connnue developmg culturally sensmve practices, including screening guidelines and protorol s. ln addition, _this study demonstr~tes that focus group interviews are valuable for engaging young romen in discussions about ipv, helpmg them to 'name' their experiences, and consider sources of help when warranted. p4-s3 (a) health problems and health care use of young drug users in amsterdam .wieke krol, evelien van geffen, angela buchholz, esther welp, erik van ameijden, and maria prins /11trod11ction: recent advances in health care and drug treatment have improved the health of populations with special social and health care needs, such as drug users. however, still a substantial number dots not have access to the type of services required to improve their health status. in the netherlands, tspccially young adult drug users (yad) whose primary drug is cocaine might have limited access to drugrreatment services. in this study we examined the history and current use of (drug associated) treatmmt services, the determinants for loss of contact, and the current health care needs in the young drug mm amsterdam study (yodam). methods: yodam started in 2000 and is embedded in the amsterdam cohort study among drug mm. data were derived from y ad aged < 30 years who had used cocaine, heroin, ampheramines and i or methadone at least 3 days a week during the 2 months prior to enrolment. res11lts:of 195 yao, median age was 27 years (range: 18-30 years), 72% was male and 83% had 1dutch nationality at enrolment. nearly all participants (97%) reported a history of contact with drug llt.lnnent services (methadone maintenance, rehabilitation clinics and judicial treatment), mental health car? (ambulant mental care and psychiatric hospital) or general treatment services (day-care, night-care, hdp for living arrangements, work and finance). however, only 61 % reported contact in the past six l!xlllths. this figure was similar in the first and second follow-up visit. among y ad who reported no current contact with the health care system, 87% would like to have contact with general treatment serl' icts. among participants who have never had contact with drug treatment services, 67% used primarily cocaine compared with 22% and 8% among those who reported past or current contact, respectively. saied on the addiction severity index, 70% reported at least one mental health problem in the past 30 days, but only 11 % had current contact with mental health services. concl11sion: results from this study among young adult drug users show that despite a high contact rm with health care providers, the health care system seems to lose contact with yao. since 87% indicatt the need of general treatment services, especially for arranging house and living conditions, health m services that effectively integrate general health care with drug treatment services and mental health care might be more successful to keep contact with young cocaine users. mtthods: respondents included adults aged 18 and over who met dsm-iv diagn?snc criteria for an anxiety or depressive disorder in the past 12 months. we performed two sets of logisnc regressmns. thtdichotomous dependent variables for each of the regressions indicated whether rhe respondenr_vis-ud a psychiatrist, psychologist, family physician or social worker in the _past_ 12 months. no relationship for income. there was no significant interaction between educatmn an mco~:· r: ::or respondents with at least a high school education to seek help ~rom any of the four servic p were almost twice that for respondents who had not completed high school. th . d ec of analyses found che associacion becween educacion and use of md-provided care e secon s · · be d · · ·f· ly 1 ·n che low income group for non-md care, the assoc1anon cween e ucatlon and was s1gm icant on -· . . . . use of social workers was significant in both income groups, but significant only for use of psychologists in che high-income group. . . . conclusion: we found differences in healch service use by education level. ind1v1duals who have nor compleced high school appeared co use less mental he~lt~ servi~es provided ~y psyc~iatrists, psycholo· gists, family physicians and social workers. we found limited e.v1dence _suggesting the influence of educa· tion on service use varies according to income and type of service provider. results suggesc there may be a need to develop and evaluate progr~ms.designe~ to deliver targeted services to consumers who have noc completed high school. further quahtanve studies about the expen· ence of individuals with low education are needed to clarify whether education's relationship with ser· vice use is provider or consumer driven, and to disentangle the interrelated influences of income and education. system for homeless, hiv-infected patients in nyc? nancy sahler, chinazo cunningham, and kathryn anastos introduction: racial/ethnic disparities in access to health care have been consistently documented. one potential reason for disparities is that the cultural distance between minority patients and their providers discourage chese patients from seeking and continuing care. many institucions have incorporated cultural compecency craining and culturally sensicive models of health care delivery, hoping co encourage better relacionships becween patients and providers, more posicive views about the health care system, and, ulcimacely, improved health outcomes for minority patients. the current scudy tests whether cultural distance between physicians and patients, measured by racial discordance, predicts poorer patient attitudes about their providers and the health care system in a severely disadvantaged hiv-infected population in new york city that typically reports inconsistent patterns of health care. methods: we collected data from 396 unscably housed black and latino/a people with hiv who reported having a regular health care provider. we asked them to report on their attitudes about their provider and the health care system using validated instruments. subjects were categorized as being racially "concordant" or "discordant" with their providers, and attitudes of these two groups were compared. results: the sample consisted of 256 (65%) black and 140 (35%) latino/a people, who reported having 80 (20%) black physicians, 49 (12%) latino/a physicians, 167 (42%) white physicians, and 100 (25%) physicians of another/unknown race/ethnicity. overall, 260 (75%) subjects had physicians of a different race/ethnicity than their own. racial discordance did not predict negative attitudes about rela· tionship with providers: the mean rating of a i-item trust in provider scale (lo=high and o=low) was 8.0 for both concordant and discordant groups, and the mean score in 13-icem relationship with provider scale (4=high and !=low) was 3.5 for both groups. however discordance was significantly associated with distrust in che health care syscem: che mean score on a 7-icem scale (5=high discrust and l=low distrust) was 3.4 for discordant group and 3.0 for che concordant group (t= 2.66, p= 0.008). we further explored these patterns separacely in black and lacino/a subgroups, and using different strategies ro conceptualize racial/ethic discordance. conclusions: in this sample of unscably housed black and latino/a people who receive hiv care in new york city, having a physician from the same racial/ethnic background may be less important for developing a positive doctor-patient relationship than for helping the patients to dispel fear and distrust about the health care system as a whole. we discuss the policy implications of these findings. ilene hyman and samuel noh . .abstract objectiw: this study examines patterns of mental healthcare utilization among ethiopian 1mm1grants living in toronto. methods: a probability sample of 342 ethiopian adults ( 18 years and older) completed structured face-to-face interviews. variables ... define, especially who are non-health care providers. plan of analysis. results: approximately 5% of respondents received memal health services from mainstream healthcare providers and 8% consulted non-healthcare professionals. of those who sought mental health services from mainstream healthcare providers, 3.1 % saw family physicians, 2.1 % visited a psychiatrist. and 0.6% consulted other healthcare providers. compared with males, a significantly higher proportion 1gsfer sessions v93 ri ftlnales consulted non-healthcare_ professionals for emotional or mental health problems (p< 0.01 ). tlbile ethiopian's overall use of mamstream healthcare services for emotional problems (5%) did not prlydiffer from the rate (6%) of the general population of ontario, only a small proportion ( 12.5%) rjerhiopians with mental health needs used services from mainstream healthcare providers. of these, !oj% received family physicians' services, 4.3 % visited a psychiatrist, and 2.2% consulted other healthll/c providers. our data also suggested that ethiopian immigrants were more likely to consult tradioooal healers than health professionals for emotional or mental health problems ( 18.8% vs. 12.5% ). our bivariate analyses found the number of somatic symptoms and stressful life events to be associated with an increased use of medical services and the presence of a mental disorder to be associated with a dfcreased use of medical services for emotional problems. however, using multivariate methods, only die number of somatic symptoms remained significantly associated with use of medical services for emooonal problems. diu#ssion: study findings suggest that there is a need for ethnic-specific and culturally-appropriate mrcrvention programs to help ethiopian immigrants and refugees with mental health needs. since there ~a strong association between somatic symptoms and the use family physicians' services, there appears robe a critical role for community-based family physicians to detect potential mental health problems among their ethiopian patients, and to provide appropriate treatment and/or referral. the authors acknowledge the centre of excellence for research in immigration and settlement (ceris) in toronto and canadian heritage who provided funding for the study. we also acknowledge linn clark whose editorial work has improved significantly the quality of this manuscript. we want to thank all the participants of the study, and the ethiopian community leaders without whose honest contributions the present study would have not been possible. this paper addresses the impact of the rationalization of health-care services on the clinical decision-making of emergency physicians in two urban hospital emergency departments in atlantic canada. using the combined strategies of observational analysis and in-depth interviewing, this study provides a qualitative understanding of how physicians and, by extension, patients are impacred by the increasing ancmpts to make health-care both more efficient and cost-effective. such attempts have resulted in significantly compromised access to primary care within the community. as a consequence, patients are, out of necessity, inappropriately relying upon emergency departments for primary care services as well as access to specialty services. within the hospital, rationalization has resulted in bed closures and severely rmricted access to in-patient services. emergency physicians and their patients are in a tenuous position having many needs but few resources. furthermore, in response to demands for greater accountability, physicians have also adopted rationality in the form of evidence-based medicine. ultimately, ho~ever, rationality whether imposed upon, or adopted by, the profession significantly undermines physu.:1ans' ability to make decisions in the best interests of their patients. johnjasek, gretchen van wye, and bonnie kerker introduction: hispanics comprise an increasing proportion of th.e new york city (nyc) populanon !currently about 25%). like males in the general population, h1spamc males (hm) have a lower prrval,nce of healthcare utilization than females. however, they face additional access barriers such as bnguage differences and high rates of uninsurance. they also bear a heavy burden of health problems lllehasobesity and hiv/aids. this paper examines patterns of healthcare access and ut1hzat1on by hm compared to other nyc adults and identifies key areas for intervention. . . . 148 9 01 5 8 9 01 and older are significantly lower than the nhm popu anon . 10 v. . 10, p<.05), though hi\' screening and immunizations are comparable between the two groups. conclusion: findings suggest that hm have less access t? healthcare than hf or nhm. hown1r, hm ble to obtain certain discrete medical services as easily as other groups, perhapsdueto!rtor are a hm. i i . subsidized programs. for other services, utilization among 1s ower. mprovmg acc~tocareinthis group will help ensure routine, quality care, which can lead to a greater use of prevennve services iii! thus bener health outcomes. introduction: cancer registry is considered as one of the most important issues in cancer epidemiology and prevention. bias or under-reporting of cancer cases can affect the accuracy of the results of epidemiological studies and control programs. the aim of this study was to assess the reliability of the regional cancer report in a relatively small province (yasuj) with almost all facilities needed for c3llcll diagnosis and treatment. methods: finding the total number of cancer cases we reviewed records of all patients diagnoicd with cancer (icd 140-239) and registered in any hospital or pathology centre from1999 until 2001 i n yasuj and all (5) surrounding provinces. results: of 504 patients who were originally residents of yasui province, 43.7% wereaccoulll!d for yasuj province. the proportion varies according to the type of cancer, for exarnplecancetsofdiglstive system, skin and breast were more frequently reported by yasuj's health facilities whereas cancmoi blood, brain and bone were mostly reported by neighbouring provinces. the remaining cases (56.3%1 were diagnosed, treated and recorded by neighbouring provinces as their incident cases. this is partly because of the fact that patients seek medical services from other provinces as they believed that the facil. ities are offered by more experienced and higher quality stuffs and their relative's or temporary acooiii' modation addresses were reported as their place of residence. conclusion: measuring the spatial incidence of cancer according to the location of report ortht current address affected the spatial statistics of cancer. to correct this problem recording the permanm! address of diagnosed cases is important. p4-60 (c). providing primary healthcare to a disadvantaged population at a university-run commumty healthcare facility tracey rickards the. c:ommuni~y .h~alth ~linic (chc) is a university sponsored nurse-managed primary bealthwt (p~c:l clime. the clm1c is an innovative model of healthcare delivery in canada that has integrated tht principles of phc ser · · h' . vices wit ma community development framework. it serves to provide access to phc services for members of th · · illi · dru is ii be . . e community, particularly the poor and those who use or gs, we mg a service-learning facil'ty f d · · · · · · d rionll h . . .,m.:. · t · . meet c ient nee s. chmc nursing and social work staff and srudents r·--· ipa em various phc activities and h .l.hont" less i . f . outreac services in the local shelters and on the streels to'"" popu auon o fredericton as well th chc · model iii fosterin an on oi : . • e promotes and supports a harm reduction . · local d!or an~ h ng ~art:ersh1p with aids new brunswick and their needle exchange program, w1tha ing condoms and :xu:t h:~~~e e~aint~nance therapy clients, and with the clie~ts themselves ~_r; benefits of receiving health f ucation, a place to shower, and a small clothing and food oai~· care rom a nurse p · · d d · --""~'i"· are evidenced in th r research that involved needsaans mvo ves clients, staff, and students. to date the chc has unacn-1 · sessment/enviro i . d ; •• '""""1ll eva uanon. the clinic has also e . d nmenta scan, cost-benefit analysis, an on-go...,,1"".'i'~ facility and compassionate lea x~mme the model of care delivery' focusing on nursing roles wi~ cj rmng among students. finally, the clinic strives to share the resu•p v95 . -arch with the community in which it provides service by distributing a bi-monthly newsletter, and plllicipating in in-services and educational sessions in a variety of situations. the plan for the future is coolinued research and the use of evidence-based practice in order to guide the staff in choosing how much n~ primary healthcare services to marginalized populations will be provided. n-61 (c) tuming up the volume: marginalized women's health concerns tckla hendrickson and betty jane richmond bdrotbu:tion: the marginalization of urban women due to socio-economic status and other determinants negatively affects their health and that of their families. this undermines the overall vitaliry of urban communities. for example, regarding access to primary health care, women of lower economic surus and education levels are less likely to be screened for breast and cervical cancer. what is not as widely reported is how marginalized urban women in ontario understand and articulate their lack of access to health care, how they attribute this, and the solutions that they offer. this paper reports on the rnults of the ontario women's health network (owhn) focus group project highlighting urban women's concerns and suggestions regarding access to health care. it also raises larger issues about urban health, dual-purpose focus group design, community-based research and health planning processes. mdhods: focus group methodology was used to facilitate a total of 30 discussions with 55 urban and 54 rural women across ontario from 2003 to 2005. the women were invited to participate by local women's and health agencies and represented a range of ages, incomes, and access issues. discussions focussed on women's current health concerns, access to health care, and information needs. results were analyzed using grounded theory. the focus groups departed from traditional focus group research goals and had two purposes: 1) data collection and dissemination (representation of women's voices), and 2) fostering closer social ties between women, local agencies, and owhn. the paper provides a discussion and rationale for a dual approach. rax/ts: the results confirm current research on women's health access in women's own voices: urban women report difficulty finding responsive doctors, accessing helpful information such as visual aids in doctors' offices, and prohibitive prescription costs, in contrast with rural women's key concern of finding a family doctor. the research suggests that women's health focus groups can address access issues by helping women to network and initiate collective solutions. the study shows that marginalized urban women are articulate about their health conctrns and those of their families, often understanding them in larger socio-economic frameworks; howtver, women need greater access to primary care and women-friendly information in more languages and in places that they go for other purposes. it is crucial that urban health planning processes consult directly with women as key health care managers, and turn up the volume on marginalized women's voices. women: an evaluation of awareness, attitudes and beliefs introduction: nigeria has one of the highest rates of human immunodeficiency virus ihivi seroprrvalence in the world. as in most developing countries vertical transmission from mother to child account for most hiv infection in nigerian children. the purpose of this study was ro. determine the awareness, attitudes and beliefs of pregnant nigerian women towards voluntary counseling and testing ivct! for hiv. mnbod: a pre-tested questionnaire was used to survey a cross section '.>f.240 pregnant women ~t 2 (lrlleral antenatal clinics in awka, nigeria. data was reviewed based on willingness to ~c~ept or re1ect vct and the reasons for disapproval. knowledge of hiv infection, routes of hiv transm1ssmn and ant1rnroviral therapy iart) was evaluated. hsults: 72% of the women had good knowledge of hiv, i 5% had fair knowledge while 1.1% had poor knowledge of hiv infection.48% of the women were not aware of the association of hreast milk feeding and transmission of hiv to their babies. majority of the women 87% approved v~t while 13% disapproved vct, 93% of those who approved said it was because vct could ~educe risk of rransmission of hiv to their babies. all respondents, 100% who accepted vc.i ~ere willing to be tnted if results are kept confidential only 23% accepted to be tested if vc.t results w.111 be s~ared w1.th pinner and relatives 31 % attributed their refusal to the effect it may have on their marriage whale 69 '-gave the social 'and cultural stigmatization associated with hiv infection for their r~fusal.s 9 % wall accept vct if they will be tested at the same time with their partners.81 ~0 of ~omen wall pref~r to breast feed even if they tested positive to hiv. women with a higher education diploma were 3 times v96 more likely to accept vct. knowledge of art for hiv infected pregnant women as a means of pre. vention of maternal to child transmission [pmtct) was generally poor, 37% of respondents wm aware of art in pregnancy. conclusion: the acceptance of vct by pregnant women seems to depend on their understanding that vct has proven benefits for their unborn child. socio-cultur al factors such as stigmatizationof hiv positive individuals appears to be the maj_or impedi~ent towards widespread acceptanee of ycr in nigeria. involvemen t of male partners may 1mpro~e attitudes t~wa~ds vct:the developmentofm novative health education strategies is essential to provide women with mformanon as regards the benefits of vct and other means of pmtct. p4-63 (c) ethnic health care advisors in information centers on health care and welfare in four districts of amsterdam arlette hesselink, karien stronks, and arnoud verhoeff introduction : in amsterdam, migrants report a "worse actual health and a lower use of health care services than the native dutch population. this difference might be partly caused by problems migrants have with the dutch language and health care and welfare system. to support migrants finding their way through this system, in four districts in amsterdam information centers on health care and welfare were developed in which ethnic health care advisors were employed. their main task is to provide infor· mation to individuals or groups in order to bridge the gap between migrants and health care providers. methods: the implementat ion of the centers is evaluated using a process evaluation in order to give inside in the factors hampering and promoting the implementat ion. information is gathered using reports, attending meetings of local steering groups, and by semi-structu red interviews with persons (in)directly involved in the implementat ion of the centers. in addition, all individual and groupcontaets of the health care advisors are registered extensively. results: since 2003 four information centers, employing 12 ethnic health care advisors, are implemented. the ethnicity of the health care advisors corresponds to the main migrant groups in the different districts (e.g. moroccan, turkeys, surinamese and african). depending on the local steering groups, the focus of the activities of the health care advisors in the centers varies. in total, around 2000 individual and 225 group educational sessions have been registered since the start. most participants were positive about the individual and group sessions. the number of clients and type of questions asked depend highly on the location of the centers (e.g. as part of a welfare centre or as part of a housing corporation). in all districts implementa tion was hampered by lack of ongoing commitment of parties involved (e.g. health care providers, migrant organization s) and lack of integration with existing health care and welfare facilities. discussion: the migrant health advisors seem to have an important role in providing information on health and welfare to migrant clients, and therefore contribute in bridging the gap between migrants and professionals in health care and welfare. however, the lack of integration of the centers with the existing health care and welfare facilities in the different districts hampers further implementation . therefore, in most districts the information centres will be closed down as independent facilicities in the near future, and efforts are made to better connect the position of migrant health advisor in existing facilities. the 2005 who report ranks the philippines as ninth among 22 countries with a high tb prevalence. about a fourth of the country's population is infected, with majority of cases coming from the lower socioeconomic segments of the community. metro manila is not only the economic and political capital of the philippines but also the site of major universities and educational institutions. initial interviews with the school's clinicians have established the need to come up with treatment guidelines and protocols for students and personnel when tb is diagnosed. these cases are often identified during annual physical examinations as part of the school's requirements. in many instances, students and personnel diagnosed with tb are referred to private physicians where they are often lost to follow-up and may have failure of treatment due to un monitored self-administered therapy. this practice ignores the school clinic's great potential as a tb treatment partner. through its single practice network (spn) initiative, the philippine tuberculosis initiatives for the private sector (philippine tips), has established a model wherein school clinics serve as satellite treatment partners of larger clinics in the delivery of the directly observed treatment, short course (dots) protocol. this "treatment at the source" allows school-based patients to get their free government-suppl ied tb medicines from the clinic each day. it also cancels out the difficulty in accessing medicines through the old model where the patient has to go to the larger clinic outside his/her school to get treatment. the model also enables the clinic to monitor the treatment progress of the student and assumes more responsibility over their health. this experience illustrates how social justice in health could be achieved from means other than fund generation. the harnessing of existing health service providers in urban communities through standardized models of treatment delivery increases the probability of treatment success, not only for tb but for other conditions as well. p4-66 (c) voices for vulnerable populations: communalities across cbpr using qualitative methods martha ann carey, aja lesh, jo-ellen asbury, and mickey smith introduction: providing an opportunity to include, in all stages of health studies, the perspectives and experiences of vulnerable and marginalized populations is increasingly being recognized as a necessary component in uncovering new solutions to issues in health care. qualitative methods, especially focus groups, have been used to understand the perspectives and needs of community members and clinical staff in the development of program theory, process evaluation and refinement of interventions, and for understanding and interpreting results. however, little guidance is available for the optimal use of such information. methods: this presentation will draw on diverse experiences with children and their families in an asthma program in california, a preschool latino population in southern california, a small city afterschool prevention program for children in ohio, hiv/aids military personnel across all branches of the service in the united states, and methadone clinic clients in the south bronx in new york city. focus groups were used to elicit information from community members who would not usually have input into problem definitions and solutions. using a fairly common approach, thematic analysis as adapted from grounded theory, was used to identify concerns in each study. next we looked across these studies, in a meta-synthesis approach, to examine communalities in what was learned and in how information was used in program development and refinement. results: while the purposes and populations were diverse, and the type of concerns and the reporting of results varied, the conceptual framework that guided the planning and implementation of each study was similar, which led to a similar data analysis approach. we will briefly present the results of each study, and in more depth we will describe the communalities and how they were generated. conclusions: while some useful guidance for planning future studies of community based research was gained by looking across these diverse studies, it would be useful to pursue a broader examination of the range of populations and purposes to more fully develop guidance. background: the majority of studies examining the relationship between residential environments and cardiovascular disease have used census derived measures of neighborhood ses. there is a need to identify specific features of neighborhoods relevant to cardiovascular disease risk. we aim to 1) develop methods· data on neighborhood conditions were collected from a telephone survey of s,988 fesi· dents in balth:.ore, md; forsyth county, nc; and new york, ny. a sample of 120 of the i.ni~~l l'elpondents was re-interviewed 2-3 weeks after the initial interview t~ measure the tes~-~etest rebab1~1ty of ~e neighborhood scales. information was collected across seven ~e1ghborho~ cond1~ons (aesth~~ ~uah~, walking environment, availability of healthy foods, safety, violence, social cohesion, and acnvmes with neighbors). neighborhoods were defined as census tracts or homogen~us census tra~ clusters. ~sycho metric properties.of the neighborhood scales were accessed by ca~cu~~.ng chronba~h s alpha~ (mtemal consistency) and intraclass correlation coefficients (test-r~test reliabilmes) .. pear~n s .corre~anons were calculated to test for associations between indicators of neighborhood ses (tncludmg d1mens1ons of race/ ethnic composition, family structure, housing, area crowding, residential stability, education, employment, occupation, and income/wealth) and our seven neighborhood scales. . chronbach's alphas ranged from .73 (walking environment) to .83 (violence). intraclass correlations ranged from .60 (waling environment) to .88 (safety) and wer~ high~~~ .7~ for ~urout of the seven neighborhood dimensions. our neighborhood scales (excluding achv1hes with neighbors) were consistently correlated with commonly used census derived indicators of neighborhood ses. the results suggest that neighborhood attributes can be reliably measured. further development of such scales will improve our understanding of neighborhood conditions and their importance to health. childhood to young adulthood in a national u.s. sample jen jen chang lntrodfldion: prior studies indicate higher risk of substance use in children of depressed mothers, but no prior studies have followed up the offspring from childhood into adulthood to obtain more precise estimates of risk. this study aimed to examine the association between early exposure to maternal depl'elsive symptoms (mds) and offspring substance use across time in childhood, adolescence, and young adulthood. methods: data were obtained from the national longitudinal survey of youth. the study sample includes 4,898 mother-child/young adult dyads interviewed biennially between 1992 and 2002 with children aged 4 to 16 years old at baseline. data were gathered using a computer-assisted personal interview method. mds were measured in 1992 using the center for epidemiologic studies depression scale. offspring substance use was assessed biennially between 1994 and 2002. logistic and passion regression models with generalized estimation equation approach was used for parameter estimates to account for possible correlations among repeated measures in a longitudinal study. rnlllta: most mothers in the study sample were whites (42%), urban residents (79%), had a mean age of 31 years with at least a high school degree (82%). the mean child age at baseline was 9 years old. offspring cigarette and alcohol use increased monotonically across childhood, adolescence, and young adulthood. differential risk of substance use by gender was observed. early exposure to mds was associated with increased risk of cigarette (adjusted odds ratio (aor) = 1.52, 95% confidence interval (0): 1.12, 2.08) and marijuana use (aor = 1.46, 95% ci: 1.02, 2.08), but not with alcohol use across childhood, adolescence, and young adulthood, controlling for a child's characteristics, socioeconomic status, ~ligiosity, maternal drug use, and father's involvement. among the covariates, higher levels of father's mvolvement condluion: results from this study confirm previous suggestions that maternal depressive symptoms are associated with adverse child development. findings from the present study on early life experi-e~ce have the potential to inform valuable prevention programs for problem substance use before disturbances become severe and therefore, typically, much more difficult to ameliorate effectively. the ~act (~r-city men~ health study predicting filv/aids, club and other drug transi-b~) study 15 a multi-level study aimed at determining the association between features of the urban enyjronment mental health, drug use, and risky sexual behaviors. the study is randomly sampling foster sessions v99 neighborhood residents and assessing the relations between characteristics of 36 ethnographically defined urban neighborhoods and the health outcomes of interest. a limitation of existing systematic methods for evaluating the physical and social environments of urban neighborhoods is that they are expensive and time-consuming, therefore limiting the number of times such assessments can be conducted. this is particularly problematic for multi-year studies, where neighborhoods may change as a result of seasonality, gentrification, municipal projects, immigration and the like. therefore, we developed a simpler neighborhood assessment scale that systematically assessed the physical and social environment of urban neighborhoods. the impact neighborhood evaluation scale was developed based on existing and validated instruments, including the new york city housing and vacancy survey which is performed by the u.s. census bureau, and the nyc mayor's office of operations scorecard cleanliness program, and modified through pilot testing and cognitive testing with neighborhood residents. aspects of the physical environment assessed in the scale included physical decay, vacancy and construction, municipal investment and green space. aspects of the social environment measured include social disorder, social trust, affluence and formal and informal street economy. the scale assesses features of the neighborhood environment that are determined by personal (e.g., presence of dog feces), community (e.g., presence of a community garden), and municipal (e.g., street cleanliness) factors. the scale is administered systematically block-by-block in a neighborhood. trained research staff start at the northeast corner of an intersection and walk around the blocks in a clockwise direction. staff complete the scale for each street of the block, only evaluating the right side of the street. thus for each block, three or more assessments are completed. we are in the process of assessing psychometric properties of the instrument, including inter-rater reliability and internal consistency, and determining the minimum number of blocks or street segments that need to be assessed in order to provide an accurate estimate of the neighborhood environment. these data will be presented at the conference. obj«tive: to describe and analyze the perceptions of longterm injection drug users (idus) about their initiation into injecting. toronto. purposive sampling was used to seek out an ethnoculturally diverse sample of idus of both genders and from all areas of the city, through recruitment from harm reduction services and from referral by other study participants. interviews asked about drug use history including first use and first injecting, as well as questions about health issues, service utilization and needs. thematic analysis was used to examine initiation of drug use and of injection. results: two conditions appeared necessary for initiation of injection. one was a developed conception of drugs and their (desirable) effects, as suggested by the work of becker for marijuana. thus virtually all panicipants had used drugs by other routes prior to injecting, and had developed expectations about effects they considered pleasureable or beneficial. the second condition was a group and social context in which such use arose. no participants perceived their initiation to injecting as involving peer pressure. rather they suggested that they sought out peers with a similar social situation and interest in using drugs. observing injection by others often served as a means to initiate injection. injection served symbolic purposes for some participants, enhancing their status in their group and marking a transition to a different social world. concl111ion: better understanding of social and contextual factors motivating drug users who initiate injection can assist in prevention efforts. 10 ma!onty of them had higher educational level (57%-highschool or higher).about 20.2 yo adffiltted to have history of alcohol & another 12.4% had history of smoking. only 3.2% people were on hrt & 3.1 % were receiving steroid. majority of them (81.2) did not have history of osteoporosis. 13.6% have difficulty in ambulating. only 8.8% had family history of osteoporosis. bmd measurements as me~sured by dual xray absorptiometry (dexa) were used for the analysis. bmd results were compare~ w1~ rbc folate & serum vitamin b12 levels. no statistical significance found between bmd & serum v1taffiln b12 level but high levels of folate level is associated with normal bmd in bivariate and multivariate analysis. conclusion: in the studied elderly population, there was no relationship between bmd and vitamin b12; but there was a significant association between folate levels & bmd. introduction: adolescence is a critical period for identity formation. western studies have investigated the relationship of identity to adolescent well-being. special emphasis has been placed on the influence of ethnic identity on health, especially among forced migrants in different foreign countries. methodology: this study asses by the means of an open ended question identity categorization among youth in three economically disadvantaged urban communities in beirut, the capital of lebanon. these three communities have different histories of displacement and different socio-demographic makeup. however, they share a history of displacement due to war. results and conclusion: the results indicated that nationality was the major category of identification in all three communities followed by origin and religion. however, the percentages that self-identify by particular identity categories were significantly different among youth in the three communities, perhaps reflecting different context in which they have grown up. mechanical heart valve replacement amanda hu, chi-ming chow, diem dao, lee errett, and mary keith introduction: patients with mechanical heart valves must follow lifelong warfarin therapy. war· farin, however, is a difficult drug to take because it has a narrow therapeutic window with potential seri· ous side effects. successful anticoagulation therapy is dependent upon the patient's knowledge of this drug; however, little is known regarding the determinants of such knowledge. the purpose of this study was to determine the influence of socioeconomic status on patients' knowledge of warfarin therapy. methods: a telephone survey was conducted among 100 patients 3 to 6 months following mechan· ical heart valve replacement. a previously validated 20-item questionnaire was used to measure the patient's knowledge of warfarin, its side effects, and vitamin k food sources. demographic information, socioeconomic status data, and medical education information were also collected. results: sixty-one percent of participants had scores indicative of insufficient knowledge of warfarin therapy (score :s; 80%). age was negatively related to warfarin knowledge scores (r= 0.27, p = 0.007). in univariate analysis, patients with family incomes greater than $25,000, who had greater. than a grade 8 education and who were employed or self employed had significantly higher warfarm knowledge scores (p= 0.007, p= 0.002 and p= 0.001 respectively). gender, ethnicity, and warfar~n therapy prior to surgery were not related to warfarin knowledge scores. furthermore, none of t~e. m-hospital tea~hing practices significantly influenced warfarin knowledge scores. however, panic1~ants who _rece1v~d post discharge co~unity counseling had significantly higher knowledge scores tn comp~r1son with those who did not (p= 0.001 ). multivariate regression analysis revealed that und~r~tandmg the ~oncept of 1?ternational normalized ratio (inr), knowing the acronym, age and receiving ~ommum1!' counseling after discharge were the strongest predictors of warfarin kn~wledge. s~1oeconom1c status was not an important predictor of knowledge scores on the multivanate analysis. poster sessions v101 ~the majority of patients at our institution have insufficient knowledge of warfarin therapy.post-discharge counseling, not socioeconomic status, was found to be an important predictor of warfarin knowledge. since improved knowledge has been associated with improved compliance and control, our findings support the need to develop a comprehensive post-discharge education program or, at least, to ensure that patients have access to a community counselor to compliment the in-hospital educatiop program. brenda stade, tony barozzino, lorna bartholomew, and michael sgro lnttotl#ction: due to the paucity of prospective studies conducted and the inconsistency of results, the effects of prenatal cocaine exposure on functional abilities during childhood remain unclear. unlike the diagnosis of fetal alcohol spectrum disorder, a presentation of prenatal cocaine exposure and developmental and cognitive disabilities does not meet the criteria for specialized services. implications for public policy and services are substantial. objective: to describe the characteristics of children exposed to cocaine during gestation who present to an inner city specialty clinic. mnbods: prospective cohort research design. sample and setting: children ages 5 to 15 years old, referred to an inner city prenatal substance exposure clinic since november, 2003. data collection: data on consecutive children seen in the clinic were collected over an 18 month period. instrument: a thirteen (13) page intake and diagnostic form, and a detailed physical examination were used to collect data on prenatal substance history, school history, behavioral problems, neuro-psychological profile, growth and physical health of each of the participants. data analysis: content analysis of the data obtained was conducted. results: twenty children aged 6 to 14 years (mean= 9.8 years) participated in the study. all participants had a significant history of cocaine exposure and none had maternal history or laboratory (urine, meconium or hair) exposure to alcohol or other substances. none met the criteria of fetal alcohol spectrum disorder. all were greater than the tenth percentile on height, weight, and head circumference, and were physically healthy. twelve of the children had iqs at the 19th percentile or less. for all of the children, keeping up with age appropriate peers was an ongoing challenge because of problems in attention, motivation, motor control, sensory integration and expressive language. seventy-four percent of participants had significant behavioral and/or psychological problems including aggressiveness, hyperactivity, lying, poor peer relationships, extreme anxiety, phobias, and poor self-esteem. conclusion: pilot study results demonstrated that children prenatally exposed to cocaine have significant learning, behavioural, and social problems. further research focusing on the characteristics of children prenatally exposed to cocaine has the potential for changing policy and improving services for this population. methods: trained interviewers conducted anonymous quantitative surveys with a random sample (n= 148) of female detainees upon providing informed consent. the survey focused on: sociodemographic background; health status; housing and neighborhood stability and social resource availability upon release. results: participants were 70% african-american, 16% white, 9% mixed race and 5% native american. participants' median age was 37, the reported median income was <s2,000 year, and 53% reported receiving a high school diploma or equivalent. women reported a number of health conditions rypical of underserved populations, including asthma (42%), sexually transmitted infections (39%), high blood pressure (19%), hcv (14%), diabetes (5%) and hiv (4%). nearly half (46%) did not anticipate having a place to stay for at least 30 days upon release. factors significantly associated housing stability upon release were: high family support score (adjusted odds ratio [aor) 6.15; 95% confidence interval (95% cl) 1.76, 21.61), high neighborhood stability score (aor 4.41; 95% cl 1.25, 15.52), wanting a commercial sex worker (csw) support group (aor 0.25; 95% cl 0.10, 0.62); and identifying as bisexual (aor 0.24; 95% cl 0.07, 0.75). women desired employment (95%), housing (84%), education (77%), drug treattnent (74%), help with custody of children (31 %), childcare (28%), and domestic violence suppon (20%) services. conclusions: female detainees represent one of urban centers' most marginalized pcjpwatioos. short periods of detention represent a unique opportunity for _interven?~ns bri~ co~s and public health institutions. service providers should collaborate ~1th local ~ails to .p~de a con1111uwnof care for female detainees upon release that includes transportation , housing, residential drug treallllcnt, employment, education, family reunification, childcare and domestic viol~nce su~rt. ~pecial attenlion is warranted to lesbian and bisexual women and csws, who may be especially margmalized &om family and service-based support networks. introduction: "health care and ethnic minority immigrants" examines how health care policy dil· ferences between canada and the united states impact the health-related hardships, access and use of preventative care, and health outcomes of urban ethnic minority immigrants in both countries. methods: the findings of this paper build on the results of my qualitative comparative study of hotel workers in vancouver, bc and seattle, wa that revealed greater health related hardships for similarly matched employees in seattle compared to vancouver. in this paper, i examine the generalizability of these findings at the cross-national level for similar ethnic minority immigrant groups. i compare the impact of health care policy differences on specific groups that have emigrated to cities in both canada and the united states. these include immigrants from china, viemam, philippines, west indies, africa, sri lanka, pakistan, and latin america. comparative statistical analysis -utilizing rel· evant data from statistics canada and the u.s. census -reveal the extent to which health policy differ· ences help explain how current health policy in the united states disadvantages urban ethnic minority immigrants. results: many ethnic minority immigrants are a part of the working poor, a group which disproportionately lacks health insurance coverage in the united states. their position in the labour market makes them most vulnerable to exclusion from health care services. the data reveals how current u.s. health policy creates barriers for recently arrived ethnic minority immigrants to access health insurance and care. it remains difficult to ascribe health outcome differences directly to policy differences because of the challenge in disentangling the complex interacting interventing variables, including income inequality, that determine health outcomes. yer suggestive evidence suggests that health policy in the united states is harming the health of urban ethnic minority immigrants. the current health policy regime in the united states harms the health access, care, and outcomes of urban ethnic minority immigrants. comparing the fortunes of similar immigrants in cana· dian and u.s. cities reveals these patterns of disadvantage and some of their consequences. these barriers are an understudied factor in the sociological literature on "segmented assimilation" and social exclu· sion. the paper ends with policy recommendatio ns to improve access to health care among ethnic minor· ity immigrants in both countries, with the goal of reducing health related hardships, and improving health outcomes. mass index deyu pan, richard baker, and keith norris badtgrou~ over the past 3 decades, there has been dramatic increase in prevalence of obesity in the us population. however, the relationship between obesity and the prevalence of cardiovascular dis· ease (cv~) risk factors in different race/ethnic groups over time is not well known. . ik~rgn: _we use 2 cross-sectional , nationally representative surveys: national health and nutri· t10nal examination survey (nhanes iii 1988 -1994 (n= 14 029) and nhanes 1999 nhanes -2002 , including white, black, and hispa~ic races who were no~preg~ant, aged 20 to 74 years. res11lt1: the preval~nce of high cholesterol level (~ 240 mg/dl), untreated high blood pressure (2: l40/90 mm hg) an~ diabetes were calculated according to bmi group (lean, <25; overweight, 25-29; and obese, 2: 30) for different race/ethnicity groups. over the approximately 10 years period (from 1988l ~94 ~o [1999] [2000] [2001] [2002] , reducrion in 3 cvd risk factors in non-hispanic white has been observed. for mmonty race/~hnicity groups, black and hispanic, there had been increases in prevalence in high blood fa pressure and diabetes. the lean group experienced larger increase in prevalence of those cvd risk ctors. . fo~~ the prevalence in cvd risk factors over time had reduced in most of the bmi ca1egoes r t e w ~~e population. however, for black and hispanic, prevalence of 2 of 3 cvd risk factors ave generauy uncreased, especially in overweight and obese groups. methods: strategies identified to achieve these goals include: developing meaningful neighbourhood and district boundaries for comparing health information, providing free access to neighbourhood health profiles (including relevant data at the smallest level for which valid rates could be calculated); mapping relationships of inequality at a variety of nested levels; providing a range of formats (maps, tables) to meet the needs of users; providing technical support; seeking user input to advance and improve the site; and conducting workshops to foster access and use of data for decision-making , advocacy and collaboration. an evaluation strategy is being developed to assess the efforts and impact of these strategies. a preliminary assessment of the results of the first six months of activity will be completed in october 2005. results: significant differences in health are shown at all the geographic levels indicating success in developing the boundaries. results tabulated for the first six months use of the site include: site visits; media use; reference/acknow ledgement of the site in other documents; number of contacts through presentations and workshops; feedback from users identifying strengths and limitations; and, response from health decision makers. members of the partnership are identifying additional tools and services to further support actions that reduce health inequalities. the assessment will be used to develop more specific goals, targets and monitoring mechanisms. conclusions: our experience with paper-based health profiles indicates that they have been used extensively for program planning and advocacy. the greater availability of information in a publiclyavailable web-based format is expected to translate into even greater usefulness and wider application. the web site has had considerable usage to date, extensive media coverage. site users and workshop participants have provided positive feedback and suggestions for next steps. the six month review will be available in october 2005. in india, more than 4 and a half people are hiv-positive and half a million have aids. india currently has the largest number of positive people in the world, oumumbering south africa and accounting for nearly one tenth of the global hiv/aids prevalence. the world bank predicts that by 2015, there will be 35 million hiv/aids cases in india. the central challenge facing hiv prevention efforts in south asia today is learning how to respond to the societal determinants of vulnerability to hiv. hiv/aids is an issue largely engulfed by social stigma. stigma and discrimination are often considered the foremost barriers to effective poster sess10ns v104 prevention and care initiatives. stigma can make a person afraid of disclosing their status~ ~yone el se, and may make them feel depressed or alone. stigma can .also le~d to poor adherence to medicanon, ~ likelihood to access health and social services, and less desire to hve. hiv+ men and women may beafraidtotd! their co-workers that they have hiv for fear of their reactions or for fear of losing their jobs. in a study 1 conducted of people living with hiv/aids in delhi, india ov~r. 2003-~, many respo~ts shared their experiences of discrimination in their families, in their communmes, an~ m health ~e settmgs. these findings will be shared in the workshop, and will be compa~ed to m~ ex~nences workmg as an ~ co~l~ at the center for aids prevention studies in san francisco, cahforma and congreso de lannos unidos m philadelphia, pennsylvania. the workshop will include an overview of hiv/aids in urban contexts in tht united states (los angeles, san francisco, new york, philadelphia) and south asia (delhi, hyderabad, chennai). differences in methods for outreach, prevention and treatment efforts between devdoped world and developing world contexts will be discussed. a large portion of the workshop will be centered on discussion. participants will engage in an exercise to categorize their ideas of stigma. the workshop will also include a powerpoint presentation on the quantitative data gathered from the survey. the number of homeless and runaway youth is increasing in toronto, which is currently home to 3 out of 4 youth in the gt a who live alone, and it is the preferred locale for the street-involved and homeless youth. the city's youth population is expected to grow by nearly 20% by 2011, the school dropout rate is rising, and there are is a paucity of empirical data on what works with these at-risk youth. over a two-year period, (2002) (2003) (2004) , youthlink-inner city, conducted an evaluation of the impact of a harm reduction program aimed at reducing street youth's risk of contracting/infecting others with the hep c virus, which has both short-term and long-term deleterious effects. demographic data from 102 street-youth, along with resources/services used, employment methods, type and frequency of drug use, health status, police contacts, and their views of program impact were analyzed using a standardized sur· vey. additionally, focus groups with youth, agency staff and community key informants were conducted, as well as in-depth interviews with three youth, over a sixth-month period. this paper details study results, which both inform both practice and future study about what works, why it works, and how best to work with these vulnerable youth. sho~ed .that the wasteland in this area was contaminated by as cd zn pb cu simultaneously. the con-ta~matton of as ~d was quit significant. the contamination problems and environmental issues in this region are very. serious. the awareness on environmental and health issues was investigated by spot survey and analysis. overall awareness among the residents in the region is very poor. the measures must be taken to assu~e t~e .sustainable economy development by local and central gorvernments. keywords nandan guangx1; mmmg area; environmental awareness. concern like, epileptic fits, vision problems, earache, cough of more than 3 weeks and urinary problems. ninety-five subjects did not take bath regularly and 42 were exposed to sex. the health problems identified are only of a particular point of time and it may be difficult to interpret the depth of "iceberg" of the street children's world also draw the health-illness continuum. periodic interaction and follow-up is very difficult as they generally disappear from the research setting due to their frequent mobility for survival measures. as per the prediction of the iceberg theory, only some problems may have been identified, larger problems in respect to their health may not have been identified. in spite of various limitations, this attempt had proven that, it is possible to enter the street children world, explore the iceberg of illnesses, and establish data of health-illness continuum through an effective nursing agency. it is recommended to deworm these children, provide nutritional education, establish "condom corners" and "street children help line" in the city and urban slum areas and undertake action research on their health. malnutrition is a serious problem in developing countries like bangladesh. malnutrition causes a great deal of child suffering. malnutrition is one of the major causes of morbidity and mortality among the child. the aim of present study was to investigate the nutritional status and its relation to socioeconomic conditions of urban disadvantaged child of under five years age. nutritional status was determined by anthropoemetric measurement(heig ht, weight, mid-arm circumference etc.). determination of total protein and serum albumin were done for biochemical examination. haematological examination was done by blood haemoglobin profile estimation by cynmethhaemoglob in method and determination of haematocrit value or packed cell volume (pcv). stool examination for ova of hook worm, round worm, trichuris species and other species were also done. relevant information on socioeconomic characteristics was recorded by interviewing the house hold head using pretested questionnaire. our study demonstrated that nutritional status of the children are positively correlated with family income, parents level of formal education and negatively related to the family size. the effect of family income on the nutritional status, haematological and biochemical indices of urban disadvantaged child under five will be discussed in detail which will help us to determine proper way of utilization of health care facilities exists in developing countries. introduction: with the increase in morbidity and reduction in mortality and with the introduction of highly active antiretroviral therapy (haart), there is increasing focus on the determinants of healthrelated quality of life (hrqol) in hiv-infection. the focus on the present study is to examine the relationship between social support, depression, and hiv disease severity, and the extent to which these variables impact on hrqol in adult men with hiv-infection. methods: as part of a larger ongoing natural history study focusing on the neurobehavioural complications of hiv and aids, we administered questionnaires to assess depression (beck depression inventory), social support, and hrqol (mos-hiv) to 366 adult men with hiv-infection. a structured interview was used to collect health information and data on hiv disease severity. physical and mental health summary scores (phs and mhs) were derived through principal components analysis. participants were grouped according to level of social support: "well supported" (n= 180), "moderately supported" (n=90), "little or ineffective support" (n=96). analysis of variance was conducted to assess the effects of three levels of perceived social support, depression status (present vs absent), and hiv disease severity (aids vs non-aids) on mental and physical health dimensions of hrqol. potential interaction effects were also evaluated. results: social support was found to have a significant effect on both mhs and phs. presence of depression was found to have a significant effect on mhs but not phs. hiv disease severity (presence of aids diagnosis) was found to have a significant effect on phs but not mhs. manov a analyses revealed no significant interactions effects. conclusions and implications: level of social support, presence of depression and hiv disease severity were shown to have independent effects on hrqol. feeling "well supported" appears to have significant benefits for mental and physical health. biological indicators of hiv disease appear to have a selective impact on physical health while presence of depression is related to significant reductions in mental health. the development and evaluation of behavioural interventions to improve perceived social support network and depression will likely result in significant improvements in health outcomes of adults with hiv and aids. introduction: ongoing medical advances have greatly enhanced the longevity of penons living with aids (plwa). however, for certain subgroups living with hiv/aids, including, members of minority groups, women and the economically underprivilege d, aids outcomes have not changed so favorably. one obvious factor to consider when explaining disparities in aids outcomes is the environ· ment within which an individual resides. few studies of aids outcomes have focused on how commu· nity setting influences the effectiveness of care delivery. the principle research questions were: 1) what is the relationship between the locations of areas with concentrations of pl wa and the distribution of both primary and ancillary service providers? 2) how has the widespread availability of haart (after 1996) impacted aids outcomes at the community level? 3) how do aids mortality and fatality rates vary when related community characteristics, such as household income, ethnic mix, and geographic access to primary and ancillary hiv/aids services are considered? we examine this issue across residential communities in the los angeles area. methods: los angeles county's comprehensive aids service providers database (compiled and maintained by aids project los angeles) was geo-referenced and distances between weighted mean population centers and the nearest hiv/aids service providers were calculated to provide a measure of access which was then merged with aids diagnosis and mortality data along with relevant socioeconomic and population indicators and for analysis using bivariate and multivariate statistics at the zip code level. results: there is a growing disparity in hiv/aids outcomes between low-income minority areas and affluent non-minority areas in the post-haart era (p = 0.002). ancillary aids services such as case management and counseling and testing are located near the places where low income hiv/aids service consumers are likely to live (p =.000). in spite of having more access to ancillary services low income areas continue to be associated with smaller decreases post-haart aids mortality rates (p=0.301). conclusions: given the increasing disparities in aids outcomes between lower and upper income communities in the post -haart era, more specific research into the capacities of aids services providers and the efficiency of their interventions is required. although it is clear that ancillary services are operating in the areas of greatest need, their effectiveness remains limited. understanding the reasons for t~is, be they lack of adequate resources for inner city service providers, failure to reach target popula· tmns or other causes, requires additional research. in 20?3, y.out~ who were able to speak either french or english and had been absent from their parent's/ c~regivers ~es.1dence for at least three consecutive nights took part in the survey which consisted of inter· viewer-adm1ms tered question~aires. p.arti~i~an~s were recruited from drop in centres in 7 cities across <?-nada.y~uth self-report as either using in1ect1on or non-injection drugs. statistical analyses were car· r1ed out using sas version 8. the 'home' is a contested site for many women living in urban areas. women living in poverty and using illicit drugs are largely excluded from participation in dominant 'home-base' gender roles of wife and mother because of economic disadvantage. they thus 'make home' in ways that are specific to their everyday experiences. while research has established links between housing, health and drug use, this literature does not tend to consider the meanings that home may have within the lives of women who lack access to adequate tenured living spaces. this presentation reports the findings of my master's thesis work. using grounded theory methodology within a poststructuralist feminist conceptual framework, i conducted in-depth, open-ended interviews with 11 women living in the toronto area. the women were recruited from within the community through posters at different social service agencies (e.g., drop-in centres, community health centres). they were asked to describe their housing experiences and what home meant to them over the course of their lives. through the data analysis process, a substantive theory of 'making home' for women living in poverty and using illicit drugs emerged. the central concept of making home is a continual process of learning about and interacting with the environment. the process of making home entails different subprocesses: finding home (knowing what is available and accessible, and accessing home), adaptation, and leaving home. the different meanings of home that women developed from their experiences and knowledge emerged as critical components for the process of making home. the women i interviewed were very mobile and experienced constant change with regards to home. home was not considered only in relation to physical living space. home could be made within a relationship or with regards to a possession. while dominant meanings of home relation to tenured living spaces are generally positive, my research indicated that home could also be a negative context. the presentation will describe my research process and findings as well as the theoretical and policy implications of my results. in the western democracies, social citizenship bundles the right to social provision (defined as a share of the social good, not necessarily proportionate to the market value of a citizen's contribution) with participation in the paid labour force. for this reason, social citizenship rights, which usually involve some kind of redistributive measures, are a key mechanism by which states ensure economic equality, or at least, economic equality of opportunity, but are also a mechanism of social exclusion. social rights are inscribed around a single kind of relationship, that which exists between a male family breadwinner and the paid labor market; those who make economic contributions that fall outside this relationship -such as unpaid care-work, or, work that occurs in shadow or underground economiesare to a greater or lesser degree barred from accessing citizen-based social provisions. furthermore, social provision that occurs outside of the breadwinner/market-eco nomy dyad is very often meanstested and is accompanied by regulatory state apparatuses (this includes a range of social services, from welfare payments, to child-care subsidies, to disability pensions). social citizenship is thus stratified; the legal relationship that is at the heart of social citizenship acts as a form of social closure against claims for a share of the social good made by those who are 'lesser' citizens than others. of particular interest in this paper is how citizenship inequalities translate into inequalities in the social provisions that emerge from economic participation: the right to safety on the job, protection from employer harassment, protection from the vagaries of the market as well the right to adequate, comprehensive, and appropriate health services. drawing on mixed methods, longitudinal data from adult sex workers (n= 170) located in two research sites with different social welfare regimes -one in canada and one in the u.s. -we examine the consequences of working in a "shadow" or "underground" economy on various facets of health and access to health services, taking into consideration the mediating role that citizenship constructs and social welfare regimes play in accessing other key social and economic determinants of health. methods: the study population included methadone patients (re)admitted at the mhs in the period from 1/1/1996 to 31/1/2002, born in the netherlands, morocco, surinam, dutch antilles or turkye, and officially registered in the population register of amsterdam. the population register was used to ascer· rain the vital status. causes of death were provided by the central bureau of statistics. mortality was categorised as hiv related, directly drug related (overdose) and other.mortality. results: the methadone patients had the following characteristics: 38 years of age at entry; 81% male; 37% ethnic minority; 37% ever injected. in total, 9558 personyear (py) of observation time and 173 deaths (18% hiv related, 14% overdose; 57% other) were observed. hence, the crude mortality rate was 18/1000 py (95% ci 16-21/1000 py). the percentage of (ever) injectors was higher among the native dutch than among the ethnic minorities, 51 % and 14 % respectively. higher rates were observed among native dutch drug users compared to those belonging to an ethnic minority (age adjusted hazard ratio (hr) 1.9 (95% ci 1.4-2.7). the age adjusted hr of (ever) injecting drug users versus non injecting users was 3.0 (95% cl 2.2-4.1 ). after additional adjustment for route of administration a non significant difference between the dutch and ethnic minorities remained (hr 1.3, 95% cl 0.9-1.9, p-value 0.151. conclusion: the mortality rate among the heroin users in amsterdam is strongly affected by the high prevalence of non-injecting drug use. moreover, this study confirms that differences in mortality between the native dutch and the ethnic minorities is related to differences in route of administration. the ongoing reduction of injecting drug use (due tot selctieve mortality, and switching route ofadministration and popularity of crack cocaine) may lead to a further reduction of mortality rates among heroin users in amsterdam. interventions preventing the initiation of injecting should be encouraged. . introduction: food insecurity is an inequality that is central in the lives of many low-income cana· d1ans. people lack food security when regular access to nutritious food is limited or variable due to high prices'. low income, lack of transportation or inadequate food distribution, or they become disadvan· taged m other w~ys through the acquisition of food. a group comprising academics, health profession· als, and commumty workers who have experience in food insecurity, developed a pilot study in ottawa that sought to und~rstand the lived experience of food insecurity. the study also used the united states department of agriculture (usda) community food security module. methods: a series of group meetings determined the best research approaches; questionnaires and consent forms were developed by a working group. twenty-three self-identified food insecure respon· dents were interviewed. the data were analysed using frequency distributions· the food security module was coded according to the usda coding guide, and open-ended responses w~re coded using a grounded approach. renlts: preliminary results from our pilot study have given the research team cause for considerable concern. out of 14 households without children, 11 experienced food insecurity with hunger; 5 ~ere at the severe l~vel. out of 9 households with children, 7 experienced food insecurity with hunger. ~•rst person reflecnons commonly featured feelings of depression low self-esteem and despair. participants' account tha d . an 1 cu ty gettmg to the store, severely limited putting knowledge and skills mto practice. l'oster sessions v109 conclusion: based on these early findings, our research team is looking to challenge what appear to be assumptions about poverty and food insecurity and for best ways to use this information. some policy approaches and interventions that encourage people to eat better and exercise more, may be missing the mark for low-income individuals, and may serve to maintain food insecurity. future research will build on this pilot. with methods augmentation, and a comprehensive knowledge dissemination plan, we hope co contribute to research and policy frameworks at all levels. ps-25 (a) mental health and the corrections system: population-based analyses in urban, semi-urban, and rural settings julian somers, robert watts, and michelle patterson introduction: according to recent epidemiological research, rates of mental disorders vary considerably across countries and across regions within countries. nevertheless, rates of mental disorders (including substance use disorders) are consistently higher in populations involved in the corrections sys-1em. courts have long recognized the heavy burden of mental illness within their purview, and have developed innovative programs to better manage the needs of such individuals. the majority of these innovations (e.g., specialized courts) exist in urban settings. however, few studies have examined the degree of variability in rates of different mental disorders between courts in urban and other settings (e.g., semi-urban, rural). variability between courts in different settings, if present, holds implications for needs-based resource planning. the present study was conducted as part of a long-term inter-ministerial collaboration in british columbia (bc). analyses were conducted on linked administrative data regarding population health and correctional services. a database was constructed including all individuals sentenced in bc in a single year (n=49,142). corrections records were matched to records of health services utilization (hospital and outpatient services) for mental disorders and substance use disorders in the years preceding sentencing. services for mental health and substance-related problems were aggregated into three groups: severe mental illness (smi); less-severe mental illness (lsmi); alcohol/other drug (ad). courts were grouped, based on their annual volumes, inro three categories: "urban"; "semi-urban" and "rural." rates of service use for mental disorders were compared between groups for 1-year and 5-years preceding sentencing. results: there were significant differences in the rates of mental disorders in courts of different size (urban, semi-urban, rural) . however, differences between the rates of disorders within each of these groups exceeded the discrepancies between groups. comparatively high and low rates of disorders were observed in courts of each size. moreover, the courts with the highest rates of certain disorders (e.g., ad) did not have the highest rates of other types of mental disorders (e.g., smi). conclusions: rates of mental disorders differed significantly among the annual populations sentenced across courts in bc. urban courts (which process comparatively large numbers of people) have implemented services to address the needs of the mentally ill. the present analyses strongly suggest that program development should be closely linked to the demonstration of need. the results caution that a uniform approach to court programs for the mentally ill is likely to be inefficient, over-supplying services in some settings and underestimating need in others. results: public settings used for injection are characterized by highly unhygienic conditions, the presence of unsafely disposed syringes, limited availability of sterile syringes and a lack of sterile water for injecting. a number of unsafe injection practices observed were common among public injectors. the presence of police officers nearby and the potential of assault by street predators fostered rushed injecting among those consuming drugs in public spaces. the ecological features of these environments encourage unhygienic and unsafe injecting practices, heighten risk for overdose and the transmission of blood borne viruses. introduction: approximately 13% of women experience depression in the first weeks or months after giving birth. although it has been argued that postpartum depression (ppd) is a culture-bound p~ nomenon, experienced only in western, industrialized countries, recent international research studies have confirmed that the prevalence of ppd is similar around the world. however, little is known about variables that may influence the experience of ppd in women from diverse cultures and immigrant women. research is needed to identify the role culture may play in the presentation of ppd (i.e., types of symptoms most commonly reported), how women from various racial, ethnic and cultural backgrounds perceive and attribute their symptoms of ppd, and finally, how culture can be appropriately addressed in ppd treatment programs. method: to examine the role of culture in ppd, semi-structured interviews and self-report question· naires were administered to clients of the women's health centre of st. joseph's health centre, tor· onto. participants were identified as either first generation canadians (relative newcomen) (n=8) or second generation canadian (parents were immigrants to canada) (n=6). data were collected qd these two groups of women based on: severity of depression, symptom presentation, perceived role of social supports and culturally-specific traditions, and barriers and responses to treatment. the interview data were analyzed using qualitative methods (thematic content analysis), and the following themes were identified: 1) stress about passing on their culture to their children, 2) lack of social support and feelings of isolation, 3) perceived importance or lack of importance of cultural based tra· ditions, 4) conflicts with family members. about cultural traditions and beliefs, 5) mental health stigma within ethnic communities and beyond, 6) race-and sex-based discrimination, and 7) language barriers. conclrllion: identifying the role culture plays in the presentation of ppd, and how women from diverse backgrounds perceive and attribute their symptoms of ppd, is critical in order to establishcultur· ally appropriate guidelines for treatment options. furthermore, information gathered from this study can be used to develop policies and resources for delivering culturally competent care for newcomer wo~ who are dealing with ppd as well as the issues around acculturation (i.e., language barriers, racism). llus is of particular importance for urban health centers which provide postpartum care to diverse groups of women, and particularly recent immigrants or newcomers. ps-~8 (al. contaminated 'therapeutic landscape': perceptions of the aamjiwnaang fint nation keyln smith and isaac luginaah . in~: this. paper pres;ents the findings of an ongoing study among the aamjiwnaang f!rst nanon. aam11wnaang is located m the heart of samia's 'chemical valley', surrounded by cherrucal ~(ants such as esso, imperial oil, shell, suncor energy, and canada's largest hazardous waste disposal sate. safety kleen. this fint nation community is located within the st. clair river •area of concem'. as destgna~ by health canada for the population of samia and the surrounding region. although this comm_umty, by way of. its proximity to the numerous chemical plants is already exposed to high levels pollu~on, recent che?ucal dumping in ~mjiwnaang, as well as a failed proposal for another ethanol plant m the community, only helped to mtensify community concerns about potential health impacts of exposure. research on the cultural beliefs and traditions of first nation communities has established that th~ ~isting rel~tionship between first nations people and 'mother earth' is not only physical, but also_ spmtual. in this study we explore how the complex relationship between the aamjiwnaang first naaon and 'mother earth' be ha · · · i .. may c ngmg 111 a contammated 'therapeutic' landscape. the study a so ~lores h?w aam11wnaang residents are coping with these changes and with the probable conramina· boa of their community. ra!jts: aamjiwnaang residents acknowledge that they are living in a contaminated environment and are being impacted by emissions from the surrounding 'chemical valley' especially for future generations, and have expressed concerns that members of the community and mother earth are 'sick' as a result of this exposure. while moving from that 'place' has been discussed, residents have strong personal and generational connections to the land and insist however, that aamjiwnaang is their 'home' and will remain that way despite growing community concerns about the impact from industry. the contribution of this study lies in the direct involvement of community leadership in designing and conducting this research and distributing the results to further local policy development regarding community concerns on the reserve. background: truck driver are at very high risk for drug abuse because the factor contributing to drug abuse among driver are multiple. it is important to gain an understanding of the key factors that contributing to drug abuse among truck drivers. methods: seventy-truck driver aged 25-35 years were conveniently selected from the population. all the participants were male. an interview schedule was developed in the light of literature data and data were collected by personal interview with informed consent in selected urban area of eastern part of nepal. results: a considerable percentage of truck driver have less knowledge about drug abuse, its effect on body and their complication. majority of the participants (90%) explained that lack of education, financial crisis were leading factors of drug abuse. the average numbers of respondents were believed that lack of meaning in life, marital disharmony. friendship with drug abuser, stress, tiredness, modernization of life pattern and freedom from the home pressure were the influencing risk factors to drug abuse. conchuion: this study reveals those truck drivers are at risk in urban area for developing drugs abuse, mostly influenced by social and environmental factors. hence, these groups should undergo certain educational programme to prevent not only drug abuse, but also prevent transmission of infectious disease among these groups. introduction: food insecurity is an inequality that is central in the lives of many low-income canadians. our group of university researchers, health professionals, and community developers conducted a study in ottawa with community workers who work with people identified as food insecure. the purpose of the study was to understand the nature of their work, and their perspectives, perceptions and experiences of the causes and consequences of food insecurity. (a parallel study was conducted with food insecure participants). methods: sampling was through local knowledge of organizations involved in the provision of food to community members. written permission for the researchers to contact workers in confidence was obtained from each organization. thirteen in-depth interviews were conducted. the interviews consisted of a number of open-ended questions. the data were collated, and analysed using a grounded approach. results: workers interviewed represented organizations that offered diverse programming and methods of food distribution intended to address the needs of the community. the provision of food was seen as a necessary response to address hunger that arose for the majority from poverty caused by low income, or levels of government income support and safety nets that were insufficient to support food requirements. workers reported that food requirements varied according to different. ethnic backgrounds, ages of recipients and family configurations, and with food preferences, and d'.etary (health) requirements. workers' observations of the effects of insufficient food on adults and children such as depression, low energy and non-participation or social disengagement matched those of food insecure respondents. food insecurity was cited as "another srressor among the mountain of problems." overall, workers presented a picture of a silent, stigmatized, poor population including children, and a lack of advocacy to address the issues. be tha th · ·ty the results suggest that workers and organizations, like the commuruty mem rs t ey msecun • · · · · f ilab'l' f food · t d ·n thei·r ab1'l1'ty to address food insecurity. l1m1tanons m terms o ava 11ty o , serve, are restnc e 1 . . funding, and donations appeared to set the para?1eters of pr~g:am r.espon~ to commuruty food msecurity. workers were concerned with program des1g": and a~m1mstranon that m general addr~d hunger on an emergency short-term basis, although food msecunty was long-ter_m for ~any. sustainable solutions that include knowledge translation strategies, and health and social pohcy responses were suggested and will be explored in future research that hopes to build on this pilot. background: socioeconomic deprivation as well as low levels of soc!al s.uppoi:r have .been associated with poor outcomes following cardiac surgery. pre-operative depression m ~anents with coron~ry artery disease awaiting cabg ranges from 27-47% and is an independent predictor of post-operanve mortality. since st. michael's hospital has a large inner city population, this study was designed to determine the both the prevalence of depressive symptomatology (ds) in patients awaiting cabg as well as its relationship with socioeconomic status (ses) and social support. methods: consecutive patients referred for isolated cabg were invited to complete the centre for epidemiological studies depression scale (ces-d) as well as a social support scale and a life stressors inventory. a ces-d score of 2: 16 represents mild ds and a score of 2:27 represents moderate to severe ds. participants also recorded information on functional status, perceived progression of heart failure, demographic and ses variables. all participants with ces-d scores 2: 16 were considered to have ds. results: of the 75 patients (75%) who returned the survey, 22 (29.3%) of participants had a ces-d score 2: 16 with 8 (10.7%) of those having scores suggestive of severe depression. females and those with ongoing medical concerns tended to have more ds (p= 0.06 and p= 0.07 respectively). age was not related to ds. perceived worsening of symptoms and increased ccs angina class were significantly related to the presence of ds (p= 0.03 and p= 0.03 respectively) but not the number of diseased heart vessels. satisfaction with personal relationships including having someone to confide in (p=0.01), feeling lonely (p= 0.04) and not having a partner (p= 0.007) were significantly related to ds. being very upset by a recent breakup in the immediate family was also significantly related to ds (p= 0.02). having greater than a grade 9 education was the only ses variable related to ds (p=0.06). multivariate logistic regression suggested that not being partnered and having low education were the most significant predictors of ds. conclnsion: pre-operative depression is present in at least one quarter of patients referred for cabg. since ds is related to poor outcomes following cabg, single patients with few social supports and low education should be considered at high risk for ds. these findings support the need for the development of supportive interventions in patients at risk in order to decrease post-operative morbidity. this study examines the relationship between childhood sexual abuse, sexual assault during adolescence, and hiv-risk-related behaviours in a sample of 919 homeless youths. over the past decade, there has been increasing research devoted to the impact of childhood sexual abuse. some studies have suggested that the experience of childhood sexual abuse is associated with substance use and abuse, at· risk sexual behaviour and subsequent higher rates of hiv infection (ompad et al., 2005; cinq-mars et al., 2003; brown et al., 1997) . other studies have found that childhood abuse, especially sexual abuse, is c_o~n among stree~ youth (noell et al. 1999 ). this study compares sexually abused males and females livtng on the street ~th non-sexually abused street youth, with regards to unsafe sexual behaviours and e~ures to potmnal t:dv sources (e.g., tattooing, body piercing and injection drug use). the hypothe-sis oft~ ~nt study is that the prevalence of hn-risk-related behaviours will be higher among street youth vtctuns of sexual abuse than those who have not been sexually abused. the sample includes 919 youths aged 13 to 25 who met specific criteria's for itinerancy (649 male and 270 female, with a mean ~of 19.4 y· and a standard deviation of 2.9). they were recruited through five organisations working ~th~ you~ and were~ of an ongoing cohort study. all youth completed a 45 to 60 minute ques· ~onnaue on their sexual behaviours, use of drugs and alcohol and other hiv risk behaviours. oral spec· unens for hiv testing were. also collected. a total of 357 (38.9%) youth reported at least one incident of ~i •~use/assault (1~1 girls (67.0% of all the girls) and 176 boys (27.2% of all the boys]). preliminary descnpnve analyses pomt to sexually abused/assaulted youth showing the highest prevalence of sexual poster sessions v113 at-risk behaviours. for example, 43.3% of sexual abuse/assault victims have engaged in prostitution in their lives compared with 13.4% in the non-sexually abused/assaulted group. in addition, 42.6% of sexual abuse/assault victims reported having injected drugs, compared with 32.0% in the non-sexually abused/assaulted group. more statistical analyses will bring other significant factors to light, especially when we analyze separately those victim of childhood sexual abuse as compare to those victim of sexual assault after childhood. elucidating the risk factors for getting involved in hiv-risk-related behaviours is important for the development of comprehensive and appropriate prevention and treatment intervention strategies. introduction: new immigrants and refugees to canada frequently emigrate from regions of the world where intestinal parasitic infections with worms are endemic. of note, some of these parasites area capable of surviving for years to decades within a given host and can have life threatening consequences many years after initial infection. thus, early diagnosis and treatment of intestinal parasitic worms is considered important in high risk immigrant populations, however there remains a lack of consensus regarding the best method of accomplishing this. diagnosing worm infections through stool examinations is costly and has limited sensitivity, while presumptive treatment of all immigrants, although advocated by some, is expensive and results in healthy individuals being unnecessarily treated. herein, we examine the utility of a hematologic marker (i.e. peripheral blood eosinophilia) as a screening instrument to identify parasitic worm infections in new immigrants to toronto. we identified 192 adults, 15 years of age or older, who were screened for intestinal parasitic infections by stool examination as part of a recently developed screening protocol at a downtown toronto community health centre. we examined the prevalence of infections with worms and subsequently evaluated the impact of several demographic factors on the presence of worm infections. we also determined the sensitivity and specificity of peripheral blood eosinophilia (defined as greater than 500 eosinophils per ml) as a marker for intestinal parasitic worm infections. results: overall, 21 % of the 192 immigrants tested had evidence of at least one worm infection on a single stool examination, while 4% of such individuals bad infections with multiple worms concurrently. age did not appear to be associated with the presence of worms, however 29% of males had evidence of worm infections compared with 16% of females (p= 0.03). immigrants from asia, sub-saharan africa, and central america had the highest burden of overall infection. the sensitivity and specificity of peripheral blood eosinophilia for worm infections was 24% and 92% respectively. conclusions: one in five recent immigrants presenting to a community health centre in downtown toronto had evidence of at least one intestinal parasitic worm infection. the highest burden of illness was in men and in those emigrating from less developed regions of the world. peripheral blood eosinophilia is a poor screening test for worm infections however its presence is highly suggestive of the existence of worms in new immigrants. more than a decade ago, the journal of american college health recommended that a national study be conducted to measure the health status of african american college students, 'both health disparities and [their] positive healthful behaviors' (fennell, 1994) . it was later decided that when exploring the level of health risk behaviors for african american students, gender is an important variable and should be included in the research (fennell, 1997) . at historically black college and universities (hbcus) college health researchers must tackle gender disparities through highly-effective health promotion and disease prevention programs. the purpose of this review is to examine the literature that addresses the overarching health behaviors (i.e. risky sexual behavior, poor diet, smoking, physical inactivity, etc.) of african american men who attend hbcus. despite the various social, cultural, and academic benefits of african american students who attend hbcus, the number of research studies that adequately address their health and health behaviors is limited. studies indicate that african american men who attend hbcus are actively engaged in poor health behaviors. compared to females at hbcus, african american men are more likely to behave in ways that could result in injuries and the use tobacco, alcohol, and ~ther dru~. the city of toronto has recently proposed to conduct a street count of the homeless. like proposals that have come before, this most recent proposal is controversial among many homeless advocates and service providers because it is perceived as intrusive, likely to undercount the target population, and unnecessary for addressing the problem. advocates of the count view it as necessary to gauge the scope of the problem and advise city leaders about how to most effectively direct resources ro.the various homeless services. this paper first reviews the history of efforts to count homeless populat10ns m toronto, describing the motivations and arguments of people on both sides of the issue. second, the paper reviews the methodological complexities of counting homeless populations, describing approaches that use shelter-counts, administrative data and street observations. those interested in counts for toronto and elsewhere can benefit from this review of approaches that have been proposed and carried out in other municipalities. third, the paper proposes a new community-base d strategy that joins the skills of methodologists, local experts, and service providers to ensure a fair and accurate count. the method of systematic social observation avoids some of the problems of early counts by utilizing a repeated identification approach to minimize undercount bias. the method also has the advantage of involving and compensating homeless individuals for assisting with the street count estimates. the estimation approach can be implemented on a rolling basis throughout the year. drug transitions) is a multi-level study aimed at examining the associations between features of the urban environment and mental health, drug use, and risky sexual behaviors. research participants are being recruited in 36 new york city (nyc) neighborhoods. an essential first step in the implementation of this study was to delineate boundaries for each target neighborhood that could then be used to establish sampling frames and as key units of analytic interest. although many neighborhood studies rely on pre-established definitions (e.g. those used for the census or administrative purposes), such definitions do not always reflect contemporary settlement patterns. we felt that street level observations were a neces· sary component of the definition process. methods: the procedures used to delineate neighborhoods were: (1) development of census block maps of targeted areas; (2) review of land use maps and census tract data to ensure, prior to going into the field, tha.t particular blocks are residential and likely to have sufficient population for recruitment purposes; and (3) field vislts and observation in each of the targeted areas. field observations focused on: housing characteristics, including housing type and condition; characteristics of commercial areas, such as likely customer base (e.g. local or no~, socio-economic status and ethnicity of customers); pedestrian volume (including con· gregauons of people m parks and outside stores or residences); obstructions to pedestrian traffic (e.g. ma1or thoroughfares, multi-block industry or institutions); and maintenance and use of open spaces. results: in making the final decisions regarding neighborhood boundaries and the inclusion or exclusion of particular. blocks, we considered a broad range of factors including evidence of homogeneity an~ heterogeneity (socmeconomic, ethnic, housing type, environmental) across blocks within and blocks ad1acent to a nei.ghborhood, and across the 36 sample neighborhoods; the potential for efficient recruit· ment of appropriate particip.ants (i.e. sufficient local pedestrian traffic); and boundaries used in reporting census data (s? that population data can be used in our analysis). . altho~gh utilization of field observations for neighborhood definitions is relatively time consuming (ap~~ox1mately 2 hours for a 12 block area, with more diverse neighborhoods taking even longer), we annc1p~t~ that it will substantially improve the quality and consistency of our data gath· ~rmg ~nd analyse~. spec1f1c e?'amples from neighborhoods defined through this process will be given dur· m~ this presentatmn. we will also discuss the merits and limitations of characterizing neighborhoods usmg street level observations. has been no consideration for how social networks are associated with sse. the objective of this study was to identify personal and social network characteristics associated with being a recipient of sse. in this cross-sectional study, idus who injected in the past 6 months were recruited from syringe exchange programs in montreal, canada, between april 2004 and january 2005. information on each participant and on the persons with whom contact had occurred in the past month were elicited using a structured, interviewer-administe red questionnaire. participants provided detailed demographic and drug use information on up to 5 idu members with whom drugs or injecting materials were shared. using logistic regression, personal and network characteristics were examined in relation to receipt of sterile syringes. res.its: of 277 idus, 39% reported receiving sterile syringes in the past month from another idu. the sample mean age was 33 years (range 18-55), 73% male, 91 % caucasian, and 85% cocaine injectors. in multivariate analyses adjusted for age and gender, recipients of sterile syringes were more likely than non-recipients to share drugs after preparation (0r=2.39(1.06-5.42 )), to require help or to have helped inject another idu (or= 3.48(1.60-7.60)), to have asked someone to get sterile syringes from a syringe exchange program (or=2.54[1.20-5.40 )), to lend syringes (or=2.44[1.16-5.16) ) and to use drug preparation water that was previously used by another iou (0r=2.46(1.42-4.28) ) during the past 6 months. recipients also had a higher rate of change (p=0.01) of idus in their drug injecting network during the past month. with respect to social networks, 45% ( 171/348) of idu network members were providers of sterile syringes and were more likely than non-providers to inject everyday (or= 2.50( 1.51-4.15)). when stratified by their role as a sexual partner or as someone who provides support (e.g. friend, family member), further risk behaviours were observed in relation to sharing injecting materials with the participant. conclusion: recipients of sterile syringes and their idu network members had several high-risk behaviours for infection with bloodborne diseases. sse may afford an opportunity for the dissemination of other salutary behaviours such as information sharing on safe injecting practices between recipients and distributors. furthermore, drug injecting networks may be an avenue to reach idus who may not otherwise be exposed to preventive measures. there are numerous sources of stigma and labelling of mental and physical illness. first, the sociocultural dimension to stigma and labelling clearly influences patients, families, health care professionals and society's perception and treatment of illness. this creates multiple challenges related to illness identification and recovery, particularly in culturally diverse societies. second, the media is a major source of stigma and stereotyping with regard to a variety of mental and physical illnesses. despite increased public knowledge of many illnesses, studies have shown that stigma has intensified over the years in certain cases. a third element of stigma and labels appears with the use of diagnosis as a solution to human problems with the result that difficult to treat patients are repudiated and social issues are unaddressed. this presentation will serve to outline the development of stigma, various expressions of stigma, and consequences of stigma. it will provide some practical recommendations for the reduction of stigma related to mental and physical illness. purpose: to assess the knowledge, attitude, and practice about immunization for parent of 2-3 years old hispanic and african american children in los angeles county (lac). methods: we conducted two cluster surveys in lac. the sample was selected with probability proportionate to estimated size at the first stage and simple random sample of children at the second stage. data were collected through interview. we absuacted vaccine coverage data from immunization record card (irc) at home or from clinic records. the participation was 81 % in hispanics and 83% in african americans populations. irc was not available at home for 26% of african american and 16% of hispanic children. results: all parents perceived their children got all necessary vaccine~. fa~orable attitudes to.w~rd immunization were reported by 82 % of african american and 90% of h1s?amc parents. '.he m~1ority of the parents (90% african american and 95% hispanic) agreed that vaccines prevent senous d1se~ses among children. regarding vaccine safety, significantly more hispanic parents (91 %) than african american parents (75%) mentioned that vaccines are safe. introduction: cervical cancer has been shown to be preventable by papanicolau tests in heterosexual women; however, the utility of papanicolau test in lesbians is controversial. cervical cancer is caused by the human papillomavirus (hpv) which is transmitted by sexual _intercourse; howev_er, its' transmission by homosexual intercourse is also controversial. the goal of this study was to review the evidence for papanicolau tests in lesbians. methods: a pub med, ovid ( 1996 ovid ( to 2005 , and cochrane library search was performed using the mesh headings "homosexuality , female," "vaginal smears," and "papillomavirus, human." in pub med, the clinical queries feature was used with "diagnosis" and "broad, sensitive" filters. a google advanced search of the internet was conducted with the terms "lesbian," "cervical cancer," and "pap rest." the url was limited to ".ca," ".edu," or ".gov." results: the search yielded 8 original articles and 4 reviews, but no cochrane reviews. none of the publications were canadian. 111 website hits were found and selected websites were reviewed. studies showed that lesbians have fewer papanicolau tests than heterosexual women; however, many reported risk factors for cervical cancer, including multiple past or current sexual partners (male and female), early age of first coitus, history of sexually transmitted diseases, and cigarette smoking. hpv has been detected in 13-30% of lesbians and 6-19% of lesbians who have never had sex with men. case studies of abnormal papanicolau tests in lesbians who have never had sex with men have also been reponed. sexual transmission of hpv among lesbians can be explained by several factors: 1) 53-99% of lesbians have had sex with men and 21-30% of lesbians continue to have sex with men. 2) hpv may be transmitted by sexual behaviours among women, like digital-vaginal sex, digital-anal sex, oral sex, and the use of insertive sex toys. 3) hpv transmission requires only skin-to-skin contact. genital hpv has been identified on human fingers. some professional organizations, like the society of obstetricians and gynecologists of canada and the american cancer society, recognize the need for papanicolau tests in lesbians. other organizations, like the canadian cancer society, do not have official policy statements. the current ontario cervical screening program does not specifically address lesbians. conclusion: although the data was limited, most studies recommended that lesbians should receive papanicolau tests. the frequency of these tests was controversial. policy makers and professional organizations should address the needs of this special population and make specific recommendations . monique chaaya, ahia sibai, hiam chemaitelly, and zana el roueiheb . literature concerning the mental and physical effect of work at an old age is contradictory. in addinon, urban environments are physically and socially harsh with reduced potential for income generation and employment and increased potential for depression. the present paper is an attempt to study how do work, or lack of work, link to the experience of depression among older adults in underprivileged lebanese urban communities. the data comes from a cross-sectional survey, where 740 elderly residing in 3 underprivileged communities in beirut, including a palestinian refugee camp, were successfully inter-v1ewed through face-to-face interviews. logistic regression was performed to assess the effect of work on depression ad_justing for many other covariates. data showed that 17.5% of people aged 60 years and more were still workmg. there was a highly protective effect of work on depression in elderly males (or= 0.342, 95% cl= 0.128-0.909). the current study is the first of its kind in the arab region and more work shou_ld be _don_e in this area. it is important for the lebanese government to consider elderly rights for social mclus10n m terms of employment opportunities. amam nuru-jeter, nancy adler, and burton singer . l~u~on:_ the socioeconomic gradient is perhaps the most persistent and significant finding in social epidem1ological research. the insistent nature of the ses effect is evidenced by its significance after acc?untmg for ~umerous confounds. the significance and magnitude of the effect, however, varies by ::•al group. evidence_ o_f the relative effect of race and ses is inconclusive. further, less attention has f ~ ptid to the specific interactions of race and ses than to examinations of which is a better predictor 0 d ~ th. ~sues are further complicated by the explanatory complexity of the various measures of ses anl . owht ey relate to the health of various social groups. understanding the specific nature of these re a11ons ips 1s necessary for guiding he ith d · i 1· · h a an soc1a po mes and programs aimed at improving t e poster sessions v117 health of our most disadvantaged groups, and therefore population health, overall. this study examines the synergistic effects of ses with both race and gender in predicting group differences in mortality. methods: analyses use data from the national longitudinal mortality survey (n= 559, 715) for the years 1979, 1980, and 1981-85; and were linked to the national death index for deaths occurring through 1985. results were confirmed using data from the national mortality followback survey for people who died in 1986 (n= 13,491) and the 1986 national health interview survey (denominator). we used correlation analysis and the standardized mortality ratio to examine ses (education and income), race, and gender as predictors of group differences in changes in mortality. results: for the total population, analyses support the income gradient showing significant declines in mortality ratios from low to high income along the income strata. education shows a significant drop in mortality with completion of high school and completion of college, exhibiting a threshold rather than a gradient effect. compared to whites, blacks receive diminishing health returns for each subsequent level of income and education; with whites closely mirroring the total population in ses thresholds. similarly, compared to men, women do not experience the same health gains at comparable ses levels. for education, black men and women only show significant mortality declines upon completion of high school. the ses gradient operates differently among race and gender subgroups. threshold effects suggest resource gains in life opportunities at particular milestones along the ses gradient. further, ses matters less for blacks and women compared to whites and men suggesting differing implications for health and social policy aimed at reducing disparities. objective: we assessed the impact of diabetes in a large puerto rican community of chicago by measuring the prevalence of diagnosed diabetes and calculating the diabetes mortality rate. methods: we analyzed data from a comprehensive health survey conducted in randomly selected households in community areas. questions on diagnosed diabetes and selected risk factors were asked. in addition, mortality data were analyzed in order to calculate the age-adjusted diabetes mortality rate. when possible, rates were compared to those found in other studies. results: the diabetes prevalence located in this community (20.8%: 95% cl= 10.1 %-38.0%) is one of the highest ever reported for puerto ricans. for instance, it is more than three times higher than the prevalence for the us (6.1 %) and twice the prevalence for puerto ricans in new york ( 11.3%) and puerto rico (9.3%-9.6%). diagnosed diabetes was found to be significantly associated with obesity (p=0.023). the prevalence was particularly high among older people, females, those horn in the us, and those with a family history. the diabetes mortality rate (67.6 per 100,000 population) was more than twice the rate for all of chicago (31.2) and the us (25.4). conclusions: understanding why the diabetes and mortality rates for puerto ricans in this commu· nity are so much higher than those of other communities is imperative. collaboration between researchers, service providers and community members can help address the issues of diabetes education, early screening and diagnosis and effective treatment needed in this community. introduction: sars is a respiratory illness that is spread from person to person through dose contact. this infectious disease outbreak was unusual due to the high rate of infection among health care workers. the aim of the study is to explore the demographic and attitudinal determinants of psychological distress due to sars among health care workers of a toronto hospital. methods: a total of 997 adult participants completed questionnaires co assess psychological distress (impact of event scale -jes) and attitudes to sars. of these, 845 participants completed the questionnaire during the sars i outbreak, and 152 participants completed the questionnaire during the sars ii outbreak. participants also provided information on demographic variables, including occupation and exposure to sars. principal components analysis was used to derive eight attitudinal scales: fear: system, protection, prevention, job stress, stigma, instrumental coping, and psychological copm~. l111ear regression analyses were applied to evaluate the associations of the demographic and amtudmal variables, as well as time, with psychological distress. . . regression analyses showed that time and higher scores on fear, 1ob stress, stigma'. and instrumental coping were associated with a higher total ies score: (r2 =.30). contrary to expectations, none of the demographic variables was associated with total ies score. conclusion: the presence of psychological distress in health care workers is indicative of intrusive or avoidant responses to thoughts, feelings, and memories associated with the sars outbreak. this study shows that ( 1) fear for one's health and the he~lth of.others, (2) ex~erien~in~ job stress, (3)_tbe per· ception of stigma, (4) usage of instrumental copmg skills, ~n~ (5) t1m_e s1grufi~an~ly c~nmb~te to increased psychological distress in health care workers. potential mterventmns during mfecttous diseaie outbreaks in health care settings should be targeted to minimize the impact of these factors. purpose: the purpose of this study was to expand knowledge regarding feeding practices, know!· edge and nutritional beliefs of mothers currently residing in the dominican republic (dr). the rising incidence of obesity in children is a major national health concern and obesity in first and second-generation immigrant children also continues to rise. we know that parents (particularly mothers) shape children's early diet patterns and that immigrant mothers experience additional challenges related to acculturation and assimilation into a new culture, however there is a paucity of literature concerning the effect of immigrant adaptation to american culture on the nutrition of children. in addition, new immigrant knowledge about the causes of obesity and the resulting health implications for childhood obesity has not been assessed and reported. this qualitative study used focus group methodology to discuss views and practices related to the introduction of food for infants and feeding practices for young children, along with a discussion on knowledge and beliefs related to the causes and health implications of child· hood obesity. ten dominican mothers' of young children (birth to 6 years old) who reside in a small town in the western frontier area of the dr were participants in the focus group. results from this srudy will be compared to results from an identical study that will be conducted in fall 2005 with new immi· grant mothers from the dr to the boston area. we will compare feeding practices, beliefs and knowledge about nutrition for young children between these two groups. methods: using participatory principles, a focus group design was used to interview a group of mothers in the dr. the investigator along with a bilingual translator conducted the focus group. the session was tape recorded and is currently in the process of being transcribed and translated. transcribed data will be systematically analyzed themes will be identified. a qualitative data analysis software will be used to organize and code the data according to the specific aims of the study. supporting quotations will be selected to substrate each theme. lmpli~tions for urban health practice: an ultimate goal of this study is to lay a foundation for understanding the process of acculturation on feeding practices of mothers when they immigrate to the us. understanding beliefs, knowledge and feeding practices that mothers use with young children will help m ~he ~evelopment of culturally and linguistically appropriate educational strategies and materials for use m primary prevention of pediatric obesity. in canada more than seventy-five percent of immigrants choose to stay in three major urban centers of toronto, montreal and vancouver. approximately fifty percent of the immigrants eventually set· tie m ~~e greater tor<_>nto area. there is mounting evidence that the increasing immigrant population has a_ sigmfic~nt health disadvantage over canadian-born residents. this health disadvantage manifests particularly m the ma1"ority of 1"mm1"gr t h h d be · · h . . . . an s w o a en m canada for longer than ten years. this group as ~n associ~te~ with higher risk of chronic disease such as cardiovascular diseases. this disparity twccb n ma1onty of the immigrant population and the canadian-born population is of great importance to ur an health providers d" · i i · b as isproporttonate y arge immigrant population has settled in the ma1or ur an centers. generally the health stat f · · · · · · h h been . us 0 most 1mm1grants 1s dynamic. recent 1mm1grants w o av_e ant •;ffca~ada _for less ~han ~en years are known to have a health advantage known as 'healthy imm1• ~ants r::r · ~:s eff~ 1~ defined by the observed superior health of both male and female recent immiimmigrant participation in canadian society particularly the labour market. a new explanation of the loss of 'healthy immigrant effect' is given with the help of additional factors. lt appears that the effects of social exclusion from the labour market leading to social inequalities first experienced by recent immigrant has been responsible for the loss of healthy immigrant effect. this loss results in the subsequent health disadvantage observed in the older immigrant population. a study on patients perspectives regarding tuberculosis treatment by s.j.chander, community health cell, bangalore, india. introduction: the national tuberculosis control programme was in place over three decades; still tuberculosis control remains a challenge unmet. every day about 1440 people die of tuberculosis in india. tuberculosis affects the poor more and the poor seek help from more than one place due to various reasons. this adversely affects the treatment outcome and the patient's pocket. many tuberculosis patients become non-adherence to treatment due to many reasons. the goal of the study was to understand the patient's perspective regarding tuberculois treatment provided by the bangalore city corporation. (bmc) under the rntcp (revised national tuberculosis control programme) using dots (directly observed treatment, short course) approach. bmc were identified. the information was collected using an in-depth interview technique. they were both male and female aged between 4-70 years suffering from pulmonary and extra pulmonary tuberculosis. all patients were from the poor socio economic background. results: most patients who first sought help from private practitioners were not diagnosed and treated correctly. they sought help form them as they were easily accessible and available but they. most patients sought help later than four weeks as they lacked awareness. a few of patients sought help from traditional healers and magicians, as it did not help they turned to allopathic practitioners. the patients interviewed were inadequately informed about various aspect of the disease due to fear of stigma. the patient's family members were generally supportive during the treatment period there was no report of negative attitude of neighbours who were aware of tuberculosis patients instead sympathetic attitude was reported. there exists many myth and misconception associated with marriage and sexual relationship while one suffers from tuberculosis. patients who visited referral hospitals reported that money was demanded for providing services. most patients had to borrow money for treatment. patients want health centres to be clean and be opened on time. they don't like the staff shouting at them to cover their mouth while coughing. conclusion: community education would lead to seek help early and to take preventive measures. adequate patient education would remove all myth and conception and help the patients adhere to treatment. since tb thrives among the poor, poverty eradiation measures need to be given more emphasis. mere treatment approach would not help control tuberculosis. lntrod#ction: the main causative factor in cervical cancer is the presence of oncogenic human papillomavitus (hpv). several factors have been identified in the acquisition of hpv infection and cervical cancer and include early coitarche, large number of lifetime sexual partners, tobacco smoking, poor diet, and concomitant sexually transmitted diseases. it is known that street youth are at much higher risk for these factors and are therefore at higher risk of acquiring hpv infection and cervical cancer. thus, we endeavoured to determine the prevalence of oncogenic hpv infection, and pap test abnormalities, in street youth. ~tbods: this quantitative study uses data collected from a non governmental, not for profit dropin centre for street youth in canada. over one hundred females between the ages of sixteen and twentyfour were enrolled in the study. of these females, all underwent pap testing about those with a previous history of an abnormal pap test, or an abnormal-appearing cervix on clinical examination, underwent hpv-deoxyribonucleic (dna) testing with the digene hybrid capture ii. results: data analysis is underway. the following results will be presented: 1) number of positive hpv-dna results, 2) pap test results in this group, 3) recommended follow-up. . the results of this study will provide information about the prevalence of oncogemc hpv-dna infection and pap test abnormalities in a population of street youth. the practice implic~ tions related to our research include the potential for improved gynecologic care of street youth. in addition, our recommendations on the usefulness of hpv testing in this population will be addressed. methods: a health promotion and disease prevention tool was developed over a period of several years to meet the health needs of recent immigrants and refugees seen at access alliance multicultural community health centre (aamchc), an inner city community health centre in downtown toronto. this instrument was derived from the anecdotal experience of health care providers, a review of medical literature, and con· sultations with experts in migration health. herein we present the individual components of this instrument, aimed at promoting health and preventing disease in new immigrants and refugees to toronto. results: the health promotion and disease prevention tool for immigrants focuses on three primary health related areas: 1) globally important infectious diseases including tuberculosis (tb), hiv/aids, syphilis, viral hepatitis, intestinal parasites, and vaccine preventable diseases (vpd), 2) cancers caused by infectious diseases or those endemic to developing regions of the world, and 3) mental illnesses includiog those developing among survivors of torture. the health needs of new immigrants and refugees are complex, heterogeneous, and ohen reflect conditions found in the immigrant's country of origin. ideally, the management of all new immigrants should be adapted to their experiences prior to migration, however the scale and complexity of this strategy prohibits its general use by healthcare providers in industrialized countries. an immigrant specific disease prevention instrument could help quickly identify and potentially prevent the spread of dangerous infectious diseases, detect cancers at earlier stages of development, and inform health care providers and decision makers about the most effective and efficient strategies to prevent serious illness in new immigrants and refugees. lntrodmction: as poverty continues to grip pakistan, the number of urban street children grows and has now reached alarming proportions, demanding far greater action than presently offered. urbanization, natural catastrophe, drought, disease, war and internal conflict, economic breakdown causing unemployment, and homelessness have forced families and children in search of a "better life," often putting children at risk of abuse and exploitation. objectives: to reduce drug use on the streets in particular injectable drug use and to prevent the transmission of stds/hiv/aids among vulnerable youth. methodology: baseline study and situation assessment of health problems particularly hiv and stds among street children of quetta, pakistan. the program launched a peer education program, including: awareness o_f self and body protection focusing on child sexual abuse, stds/hiv/aids , life skills, gender and sexual rights awareness, preventive health measures, and care at work. it also opened care and counseling center for these working and street children ar.d handed these centers over to local communities. relationships among aids-related knowledge and bt:liefs and sexual behavior of young adults were determined. rea.sons for unsafe sex included: misconception about disease etiology, conflicting cultural values, risk demal, partner pressur~, trust and partner significance, accusation of promiscuity, lack of community endorsement of protecnve measures, and barriers to condom access. in addition socio-economic pressure, physiological issues, poor community participation and anitudes and low ~ducation level limited the effectiveness of existing aids prevention education. according to 'the baseline study the male children are ex~ to ~owledge of safe sex through peers, hakims, and blue films. working children found sexual mfor~anon through older children and their teachers (ustad). recommendation s: it was found that working children are highly vulnerable to stds/hiv/aids, as they lack protective meas":res in sexual abuse and are unaware of safe sexual practices. conclusion: non-fatal overdose was a common occurrence for idu in vancouver, and was associated with several factors considered including crystal methamphetamine use. these findings indicate a need for structural interventions that seek to modify the social and contextual risks for overdose, increased access to treatment programs, and trials of novel interventions such as take-home naloxone programs. background: injection drug users (idus) are at elevated risk for involvement in the criminal justice system due to possession of illicit drugs and participation in drug sales or markets. the criminalization of drug use may produce significant social, economic and health consequences for urban poor drug users. injection-related risks have also been associated with criminal justice involvement or risk of such involvement. previous research has identified racial differences in drug-related arrests and incarceration in the general population. we assess whether criminal justice system involvement differs by race/ethnicity among a community sample of idus. we analyzed data collected from idus (n = 1,084) who were recruited in san francisco, and interviewed and tested for hiv. criminal justice system involvement was measured by arrest, incarceration, drug felony, and loss/denial of social services associated with the possession of a drug felony. multivariate analyses compared measures of criminal justice involvement and race/ethnicity after adjusting for socio-demographic and drug-use behaviors including drug preference, years of injection drug use, injection frequency, age, housing status, and gender. the six-month prevalence of arrest was highest for whites (32%), compared to african americans (25%) and latinos (27% ), in addition to the mean number of weeks spent in jail in the past 6 months (7.0 vs. 5.8 and 4.2 weeks). these differences did not remain statistically significant in multivariate analyses. latinos reported the highest prevalence of a lifetime drug felony conviction (48%) and mean years of lifetime incarceration in prison (13.3 years), compared to african americans (48%, 10.7 years) and whites (34%, 6.9 years). being african american was independently associated with having a felony conviction and years of incarceration in prison as compared to whites. the history of involvement in the criminal justice system is widespread in this sample. when looking at racial/ethnic differences over a lifetime including total years of incarceration and drug felony conviction, the involvement of african americans in the criminal justice system is higher as compared to whites. more rigorous examination of these data and others on how criminal justice involvement varies by race, as well as the implications for the health and well-being of idus, is warranted. homelessness is a major social concern that has great im~act on th~se living.in urban commu?ities. metro manila, the capital of the philippines is a highly urbanized ar~ w.1t~ the h1gh~st concentration of urban poor population-an estimated 752,229 families or 3,005,857 md1v1duals. this exploratory study v122 is the first definitive study done in manila that explores the needs and concerns of street dwdlent\omc. less. it aims to establish the demographic profile, lifestyle patterns and needs of the streetdwdlersindit six districts city of manila to establish a database for planning health and other related interventions. based on protocol-guid ed field interviews of 462 street dwellers, the data is useful as a template for ref!!. ence in analyzing urban homelessness in asian developing country contexts. results of the study show that generally, the state of homelessness reflects a feeling of discontent, disenfranchisem ent and pow!!· lessness that contribute to their difficulty in getting out of the streets. the perceived problems andlar dangers in living on the streets are generally associated with their exposure to extreme weather condirioll! and their status of being vagrants making them prone to harassment by the police. the health needs of the street dweller respondents established in this study indicate that the existing health related servias for the homeless poor is ineffective. the street dweller respondents have little or no access to social and health services, if any. some respondents claimed that although they were able to get service from heallh centers or government hospitals, the medicines required for treatment are not usually free and are beyond their means. this group of homeless people needs well-planned interventions to hdp them improve their current situations and support their daily living. the expressed social needs of the sucet dweller respondents were significantly concentrated on the economic aspect, which is, having a perma· nent source of income to afford food, shelter, clothing and education. these reflect the street dweller' s need for personal upliftment and safety. in short, most of their expressed need is a combination of socioeconomic resources that would provide long-term options that are better than the choice of living on the streets. the suggested interventions based on the findings will be discussed. . methods: idu~ aged i 8 and older who injected drugs within the prior month were recruited in 2005 usmg rds which relies on referral networks to generate unbiased prevalence estimates. a diverse and mon· vated g~o~p of idu "seeds." were given three uniquely coded coupons and encouraged to refer up to three other ehgibl~ idu~, for which they received $5 usd per recruit. all subjects provided informed consent, an anonymous 1~t erv1ew and a venous blood sample for serologic testing of hiv, hcv and syphilis anti~!· results. a total of 213 idus were recruited in tijuana and 206 in juarez, of whom the maion!)' were .male < 9 .l.4% and 92.2%) and median age was 34. melhotls: using the data from a multi-site survey on health and well being of a random sample of older chinese in seven canadian cities, this paper examined the effects of size of the chinese community and the health status of the aging chinese. the sample (n=2,272) consisted of aging chinese aged 55 years and older. physical and mental status of the participants was measured by a chinese version medical outcome study short form sf-36. one-way analysis of variance and post-hoc scheffe test were used to test the differences in health status between the participants residing in cities representing three different sizes of the chinese community. regression analysis was also used to examine the contribution of size of the chinese community to physical and mental health status. rmdts: in general, aging chinese who resided in cities with a smaller chinese population were healthier than those who resided in cities with a larger chinese population. the size of the chinese community was significant in predicting both physical and mental health status of the participants. the findings also indicated the potential underlying effects of the variations in country of origin, access barriers, and socio-economic status of the aging chinese in communities with different chinese population size. the study concluded that size of an ethnic community affected the health status of the aging population from the same ethnic community. the intra-group diversity within the aging chinese identified in this study helped to demonstrate the different socio-cultural and structural challenges facing the aging population in different urban settings. urban health and demographic surveillance system, which is implemented by the african population & health research center (aphrc) in two slum settlements of nairobi city. this study focuses on common child illnesses including diarrhea, fever, cough, common cold and malaria, as well as on curative health care service utilization. measures of ses were created using information collected at the household level. other variables of interest included are maternal demographic and cultural factors, and child characteristics. statistical methods appropriate for clustered data were used to identify correlates of child morbidity. preliminary ratdts: morbidity was reported for 1,087 (16.1 %) out of 6,756 children accounting for a total of 2,691 illness episodes. cough, diarrhoea, runny nose/common cold, abdominal pains, malaria and fever made up the top six forms of morbidity. the only factors that had a significant associ· ation with morbidity were the child's age, ethnicity and type of toilet facility. however, all measures of socioeconomic status (mother's education, socioeconomic status, and mother's work status) had a significant effect on seeking outside care. age of child, severity of illness, type of illness and survival of father and mother were also significantly associated with seeking health care outside home. the results of this study have highlighted the need to address environmental conditions, basic amenities, and livelihood circumstances to improve child health in poor communities. the fact that socioeconomic indicators did not have a significant effect on prevalence of morbidity but were significant for health seeking behavior, indicate that while economic resources may have limited effect in preventing child illnesses when children are living in poor environmental conditions, being enlightened and having greater economic resources would mitigate the impact of the poor environmental conditions and reduce child mortality through better treatment of sick children. inequality in human life chances is about the most visible character of the third world urban space. f.conomic variability and social efficiency have often been fingered to justify such inequalities. within this separation households exist that share similar characteristics and are found to inhabit a given spatial unit of the 'city. the residential geography of cities in the third world is thus characterized by native areas whose core is made up of deteriorated slum property, poor living conditions and a decayed environment; features which personify deprivation in its unimaginable ma~t~de. there are .eviden~es that these conditions are manifested through disturbingly high levels of morbidity and mortality. ban · h h d-and a host of other factors (corrupt10n, msens1t1ve leaders 1p, poor ur 1ty on t e one an , . · 1 f · 1 · · th t ) that suggest cracks in the levels and adherence to the prmc1p es o socta 1usnce. ese governance, e c . . . . . ps £factors combine to reinforce the impacts of depnvat10n and perpetuate these unpacts. by 1den· grou o . ·1 "id . . bothh tifying health problems that are caused or driven by either matena _or soc1a e~nvanon or , t e paper concludes that deprivation need not be accepted as a way. of hfe a~d a deliberate effon must be made to stem the tide of the on going levels of abject poverty m the third world. to the extent that income related poverty is about the most important of all ramifications of po~erty, efforts n_iu_st include fiscal empowerment of the poor in deprived areas like the inner c~ty. this will ~p~ove ~he willingness of such people to use facilities of care because they are able to effectively demand 1t, smce m real sense there is no such thing as free medical services. ). there were 322 men with hiv-infection included in the present study (mean age and education of 41.8 (sd=8.4) and 13.9 (sd=2.7), respectively). a series of multiple regressions were used to examine the unique contributions of symptom burden (depression, cognitive, pain, fatigue), neuropsychologic al impairment (psychomotor efficiency), demographics (age and education) and hiv disease (cdc-93 staging) on iirs total score and jirs subscores: ( 1) activities of daily living (work, recreation, diet, health, finances); (2) psychosocial functioning (e.g., self-expression, community involvement); and (3) intimacy (sex life and relationship with partner). resnlts: total iirs score (r 2 "0.43) was associated with aids diagnosis (ii= 0.11, p <0.01) and symptoms of pain (ii= -0.14, p < 0.01 ), fatigue (ji = -0.34, p < 0.001) and cognitive difficulties (p =0.30, p < 0.001 ). for the three dimensions of the iirs, multiple regression results revealed: ( 1) activities of daily living (r2=0.42) were associated with aids diagnosis (ii =0.17, p < 0.01) and symptoms of pain <p =-0j6, p < 0.01 ), fatigue (ji = -0.31, p < 0.001) and cognitive difficulties (ji =0.32, p < 0.001 ); (2) psychosocial functioning (r2=0.31) was associated with was associated with symptoms of fatigue (ii= -0.25, p <0.001) and cognitive difficulties <ii =0.19, p <0.001); and (3) intimacy (r2=0.17) was related to was associated with symptoms of fatigue (ij = -0.17, p < 0.01) and cognitive difficulties (ii= 0.19, p < 0.001 ). methods: the sif evaluation methodology involves a comprehensive database located at the sif, a randomly selected p~o.spective coh~rt of sif users, and two pre-existing external control cohorts. . . ~ts: in addmon to reporting process data and descriptions of the sif users, we report on data indicating that the establishment of the sif has been independently associated with reductions in public ~':°g ~ (p <?.001), and syringe sharing (aor =0.3[95%ci: 0.1 _ 0.7); p =0.013) and other unsafe m1ecnon pract1_ces_ (p ~ 0.010), and increased uptake of detox services (log-rank p =0.017). as well, we report on da~ md1cat1ng that the sif has not prompted adverse changes in community drug use patterns. the vancouver sif has been well accepted by the target population, and while adve~ events s~c~ as overdoses have occurred, these events have been successfully managed. externally compiled data indicate that the sif has been associated with substantial declines in public disorder !'oster sessions v125 associated with injection drug use, syringe sharing, and increased uptake of detox services. as well, the establishment of the sif has not exacerbated community drug use patterns. ongoing evaluation activities wiu involve assessing the impact of the sif on a variety of outcomes, including infectious disease transmission, fatal overdose, and utilization of health and social services. city, brazil, 1996 -2002 maria cristina almeida, waleska caiaffa, renato assum;iio, and fernando proietti dengue cases were described according to time, space, intensity, age, gender, onset of symptoms, residence address and census tract. spatial distribution of two groups (children and women over 64 years old and men aged 20-59) were compared, under assumption that they have distinct behaviors regarding their displacement around the city. analysis included local moran index, ripley\\'s k function and recurrence of census areas over time. about 99,559 cases were identified in seven epidemic waves. concentration of cases in small areas, followed by a spread either in space or time suggested endemic patterns. regarding age-gender groups, distinct patterns suggested that residence might not be a good proxy in determining the local of infection for men aged 20-59. dengue is shifting to endemic pattern in this city and transmission may not be sole related to home environment, suggesting that additional spatial information must be couected aiming efficient control measures. murukan kandamuthan and subodh kandamuthan lnl7uduction: illness or disablement of a child may affect the economic functioning of a family as it alters the employment pattern and earnings of parents this paper tries to assess the health status and the quality of life of disabled children, and how generally, severe disablement in a child affected their fami-lies\' finances, and to quantify any such effects the problems faced by children in their home and to provide information relevant to the formation of criteria for new or increased cash support. methods: a case-control study was done in the thiruvananthapuram district, capital city of kerala by selecting a random sample of 300 families with severely disabled children below 15 years and a random sample of 300 normal children matched for age and occupation of the parents. comparative and subjective data were collected. money spent on children\'s medical care, loss of earnings of the parents, and other economic burden to the family due to the disability of the child in the family. a discriminant analysis along with univariate analysis was done to assess the factors that mostly differentiate the disabled and normal children. the mean expenditure of the families with a disabled child was rs. 852/-per month, which is significantly higher than the corresponding expenditure of rs. 389/-per month of families with normal child, (t= 16.86, p <.00001). of the disabled children, 81 % were not getting any social security payments and 90% had no special concessions for medical and other educational purposes. the analysis of income and expenditure pattern indicated that financial impact of disablement in a child on the family is significant. the discriminant model results revealed that medical expenditure was a significant variable that differentiated the disabled and normal child. the study found that the health status and quality of life of the disabled children were far from satisfactory. this in fact affected the economic status of the disabled children. in addition to reduced earnings, there are extra costs for disabled children for travel, domestic help, medical care, and health care expenditures (hospital care, physician services, dentistry, drugs and others) for disabled individuals. a strong case can be made for their long-term care by improving the financial support to such families possibly through the introduction of an allowance specially to compensate for the earnings lost by parents due to the disability of their children. widows in india are considered disadvantage group of population. because they are characterized by pangs of separation from spouse, and consequently they go through mental agony, social ~s?lation, and economic dislocation. in addition to these, poverty, landlessness, homelessness, malnutr1non etc. endure serious deterioration of their health. according to census 2001, there are 44 million women are widowed and one fourth live in urban areas. there is a noticeable increase of urban widows from the previous census (almost half). the paper examines the type of disability and chronic ailment borne among elderly widows (60 years and above). fifty second round of national sample survey aske~ the individuals three sets of questions regarding their health: their status of health, whether they are physically poster sessions v126 immobile, and whether or not they have had any specific chronic illnesses. although health infrastruc-1 1 ·1 ble 1 ·n urban setting in india as compared to rural counterpart, prevalence of tures are arge y ava1 a . . . . . h · ·11 · h h"gher 1 "n urban areas analysis shows 1omt problems m old age qmte common c romc 1 ness is muc 1 • . . and nearly 44 percent elderly widows are suffering from this ail'.11ent in urban areas. one-fifth of widows are suffering from high/low bp. heart disease, diabetes and urinary problems are much ~ore pre~alent in urban areas though disabilities is comparatively lower in urban areas. however, the d~fference is not statistically significant. disability with respect to vision is more pronounced and one third_ of the total respondents have problems regarding eyesight. one fifths ofdderly widows are _ha.rd of hearing. though disability increases with age, similar trend is not observed with respect to chr~mc illness. the percepnon of self-health among elderly becomes poorer as their age increases. the perceived health status need not be always corrected to objective indicators of health. it is noted that around 27 per~en~ of those perceived their health as "excellenr" or "very good" are found to be suffering from chrome disease of1omts and 17 percent have visual disability. to conclude an elderly widow living in urban areas have similar health problems as she jives in rural areas. this can be easily explained, as they were not made aware to seek treatment from health facility. in addition, the study shows that the economic conditions are deterrent factors for their illness. it is essential that intervention should be taken up improving their economic conditions so that wellbeing of this most vulnerable group of the society can be taken care of. heart failure is a disease that affects nearly 15 million people world wide. the united states alone accounts for one third of this population. blacks are stricken with heart failure twice as often as whites. men are more likely to develop chf than women, however since the majority of the chf population are seniors, there are actually more women than men. congestive heart failure (chf) has become a pandemic. as the baby boomer generation ages, the number of chf cases will rise dramatically. (young, j. & mills, r.,2004). after the age of 45, each proceeding decade doubles the incidence level of chf. the average person has a 1 in 5 chance of developing heart failure within their lifespan according to the framingham study (nih.gov). individuals aging 65 or older compose over half of the entire documented heart failure population. in this age group, chf is the leading cause of hospitalization. many patients are continuously readmitted. it is estimated that the chf population will increase by one million within the next 25 years. mortality was at 50% for a two year period and 70% for five years (young, j. & mills, r.,2004 ). data from: aha as technology evolves, the understanding of the nature of heart failure has become clearer. in the beginning of the 20th century heart failure was diagnosed as a condition that presented with edema (swelling) in the extremities caused by water retention. treatment in the beginning of the past cenrury was limited to abdominal drainage and diuretics. the discovery of the heart's insufficient pumping ability in heart failure patients lead to new surgeries and devices such as heart transplants and ventricular assist devices (bridge until transplant is available). ventricular hypertrophy often occurs before the development of heart failure. hypertrophy is the term given for cardiac remodeling. cardiac remodeling also includes chamber dilation (young, j. & mills, r.,2004) . chf financial burden the us healthcare financing administration has ranked chf as the highest cost illness in the diagnose-related area. direct costs related to chf in the us for 2004 were nearly $26 billion. these costs included hospital admissions, physician fees, home health aids and medications. indirect costs were over $2 billion in 2004. loss of jobs or death due to chf was the criteria for this category (young, j. & mills, r., 2004). . introduction: the injection drug user quality of life scale (iduqol) is a relatively new scale ~es1gned to capture the unique and individual circumstances that determine quality of life among injection drug users (idus). the 20 life areas comprising the instrument were based on the research literature an~ ~ocus group discussions with idus. the purpose of the present study was to evaluate the content validity of t.h~ iduqol using judgmental methods based on subject matter experts' (smes) ratings. content vah~1ty refers to the de~ee to which elements of an assessment tool are representative of the construct of interest and appropnate for a given population. methods: data were obtained from six smes, from the field of idu research and practice, who ~ere. asked t.o evaluate various aspects of the iduqol, including the title of the instrument, administraon instruchons, clarity of the names and descriptions of each life area, response format, scoring instruc-no~s and examples, record form and whether each life area should be included in the instrument. sme ratings were made using either 3 or 4 point scales. sm es were also given the opportunity to comment on poster sessions v127 each section and to suggest whether important life areas had been overlooked, were redundant, not relevant, or in need of revision. (cvi) and the ~v.erage ~eviation index (ad) were used to evaluate smes' agreement on ratings of the content vahd1ty vanables. both measures provided support for the content validity of various aspects of the iduqol, although results from the stricter ad index noted some areas of disagreement, including the description of particular life areas (e.g., being useful, drugs, sex), the inclusion of some life areas (e.g., drug treatment, education, independence and free choice), and the ease of the scoring instructions. the findings from this study provide (a) content validity evidence to support the use of the iduqol as well as (b) recommendations to suengthen both the instrument (e.g., improved descriptions for some items) and the accompanying administration and scoring manual (e.g., an easier scoring template). changes made to the instrument and its manual make the iduqol even easier for researchers, practitioners, and program evaluators to use as a way of assessing, and tracking changes over time or as a result of interventions in, quality of life in injection drug users. introduction: strict adherence to prescribed regimens is required to derive maximal benefit from highly active antireuoviral therapy (haart) in persons living with hiv/aids (phas). adherence is a key determinant of the degree and durability of viral suppression. adherence is also essential in reducing the spread of hiv and ensuring that today's treatments remain effective for as long as possible. the objective of this study is to conduct a systematic review of the research literature on the effectiveness of education and patient support strategies for improving adherence to haart. methods: a systematic search of the core databases was performed from january 1996 until may 2005. randomized controlled trials examining the effectiveness of education and patient support interventions to improve the adherence to haart were considered for inclusion. only those studies that measured adherence at a minimum of six weeks were included. study selection, quality assessments, and data abstraction were performed independently by two reviewers. results: study heterogeneity with respect to differing populations, interventions, outcomes, and length of follow-up did not allow for meta-analysis. we included 19 studies involving 2, 159 ph as. sample sizes ranged from 22 to 367. study duration ranged from a single session to a variable number of sessions delivered over one year. many of the interventions involved the provision of an educational component to improve adherence and often addressed strategies to overcome barriers to adherence and the development of problem-solving skills. they ranged from simple interventions (e.g., the provision of reminder devices) to complex interventions (e.g., cognitive-behavioural therapy delivered by licensed psychologists). eleven of the 19 studies demonstrated a statistically significant advantage associated with the described adherence intervention. the advantage associated with adherence outcomes does not seem to translate into the more clinically relevant outcome of viral suppression. only 4 out of 12 studies that reported virological or immunological results found a significant effect associated with the intervention. the studies had several methodological shortcomings. conclusions: there is a need for standardization and methodological rigour in the conduct of adherence trials. some interventions may have a significant impact on improving adherence. further research is required before any specific adherence improving strategy can confidently be incorporated into standard clinical practice. focus groups were used to collect data from a purposive sample of treatmentexperienced participants. focus group data were analyzed using a grou~ded t~eory appr~ach. i:ne themes identified from the interviews were used to identify the effects of ant1rerrov1rals on quality of hfe. the content of the mos-hiv was appraised against the themes identified from our analysis. participants also completed the mos-hiv survey and were asked whether the survey covered all important aspects of quality of life on antiretroviral medications. results: five key informant interviews and five focus groups with 38 participants were used to identify effects on quality of life that are not directly ~aptu~ed by_ the mos-hiv health survey. our~~ showed that our participants described quality of hfe as mvol~mg_ a set of ~rsonal trad~ffs ~stay alive. in most cases, worsened quality of life was traded-off for gams 1~ longevlty from ~~canon use. these eff~'ts or tradeoffs included: ( 1) downstream consequences of side effects and toxlanes; (2) loss of lrufe. pende~t decision-making privileges, (3) having to choose drugs over ~areer; (~)burden of medication-taking responsibilities; and (5) living life under a pretense and havmg to hide-the net effect of the tradeoffs, or "prices" to pay led to what was described as "longevity with hn without hope and future~. conclusion: our study highlights five major themes summarizing the impact of haart on quality on life, and suggests that currently used scales for measuring quality of life do not a~atd~ cap~e these findings and the associated consequences. the conceptual framework for measuring quality of bfe in hiv should be reconsidered in order to better capture the important effects of the medications on quality of life. this may involve widening the boundaries of the definition of health-related quality oflife to include aspects such as finances, employment, and housing. we should further consider the development of a haart adverse effect specific instrument, using a broad definition of adverse effect in order to capture all types of adverse impacts of hiv treatments on quality of life. introduction: measles (rubeola) is the most contagious vaccine preventable disease of humans. while cases of measles are uncommon in canada today, the disease continues to be a leading cause of morbidity and death in the developing world. as a result of human migration, measles cases still occur in canada, primari~ among immigrants, returning travelers, and other susceptible groups. canada's national advisory council on immunizations (naci) recommends that immigrants without records of measles immunization be considered for vac:cination since these individuals may not have been appropriately vaccinated in their native country. on rhe other hand, natural immunity to measles in immigrants is likely to be high given the high incidence of disease in developing parts of rhe world. thus it remains unclear if the most efficient strategy to achieve high levels of measles immunity in immigrants should entail initial serologic screening followed by vaccination of susceptible individuals or preemptive vaccination of all persons lacking immunization records. understanding the epidemiology of measles immunity in immigrant populations could help guide such decisions. . methods: we identified 527 adults, 15 years of age or older, who were screened for serologtc immunity to measles as part of a recently developed screening protocol at a downtown toronto community health centre. we subsequently determined if these individuals had any immunization records from their native country or from within canada. we then examined the relationship between several demographic factors and immunity to measles. results: 93% of immigrants had no prior immunization records. overall, 93% of the 527 immigrants rested for immunity to measles were found to be immune; 88% of those under the age of 20, 93% of those between 20 and 39 years of age, 99% of those between 40 and 59 years of age, and 100% of those 60 years of age or older. gender, education status, household income, and immigration status were nor ~ssoc1ated wirh immunity to measles. immunity to measles was lowest among immigrants from eastern europe (8~%), whil~ immigrants from other regions of the globe had greater than 90% immunity. c~lusrons: immigrants and refugees appear to have reasonably high levels of immunity to mea· sics, possibly related to natural infection wirh the measles virus. immigrants from eastern europe appear to have slightly. lower l~vel~ of immunity to the measles virus. universal screening for immunity to meales or preemptive vac:cmauon may both be inefficient public health strategies, however further research is needed to corroborate these findings. nancy r~ss, stephane tremblay, saeeda khan, daniel crouse, mark tremblay, and jean-marie berrhelor o~ve: the speed of the rise in obesity in places like canada suggests that rather than a shift in the gcncnc_ com~sirion of the population, the root of the obesity pandemic is an environment that suprrs ~besity. this paper examines the influence of neighbourhood and metropolitan characteristics. bour~lts:. while accounting. for individual socio-demographics and behaviours, residents of neighs with a large proportmn of poorly educated individuals had higher bmis than those living in poster sessions v129 neighbourhoods with more highly educated individuals (p <.01 ). residing in a neighbourhood with a high proportion of recent immigrants was associated with lower bmi for men (p<.01), but not women. neighbourhood dwelling density, a proxy for walkability, was not associated with bm! for either sex. metropolitan sprawl was associated with higher male bmi (p=.02) but the effect was negligible for women (p=.09). bmi was significantly lower for women (p<.01) living in a city in the province of quebec, even after accounting for the influence of individual and neighbourhood covariates. conclusions: bm! was strongly patterned by individual-level social position in urban canada. the incremental influence on bmi of neighbourhood related to the neighbourhood's social conditions and not to their physical form. metropolitan sprawl was associated with higher bm! for men, a group with longer car-dependent commutes than women. the findings suggest that both individuals and their environments (both social and physical) influence the distribution of bmi in urban populations. introduction: urban environments have been linked to a range of human health issues. in singapore, prevalence of end stage renal disease (esrd) is predicted to rise (2633 in 1999 to 6000 in 2010 , kidney international, vol.67, 2005 . the clinical and economic burden of esrd has promoted development of strategies aimed at preventing the development and progression of chronic kidney disease. these include population based screening programs such as the national kidney foundation, sin-gapore\'s (nkfs) "partnership for prevention."the program, aims to reduce incidence of esrd through comprehensive intervention and screening for early detection of urinary abnormalities, blood pressure (bp), and random blood glucose (rbg). objective of this study is to examine gender, race and age wise prevalence of elevated bp, rbg and proteinuria. methodology: this current analysis includes 575,438 subjects, age 18 to 86 years, who underwent screening during september 1999 and december 2004. participants were asked to give demographic information and the history of diseases. tests were given to get clinical information such as proteinuria, blood glucose, sbp, and dbp. blood pressure abnormalities were defined according to ]nc vi criteria. proteinuria was defined as the presence of 1 plus or greater protein (equivalent to> 30 mg/di) on dipstick analysis. results: there were 296, 116 (51.5%) males. racial distribution was chinese (78.8% ), malay (8.8% ), indians (8. 7%) and others (3. 7% ).among participants, who were apparently "healthy" (asymptomatic and without history of dm, ht, or kd), gender and race wise % prevalence of elevated (bp> 140/90), rbg (> 140 mg/di) and positive urine dipstick for protein was as follows male: (20.5;6.9; 3.5) female:(13.6;5.0;3. 2) chinese:( 17.1;6.0;3) malay: (19.4;7.3;5.6) indian:( 15.9;7.5;3.0) others: (15.4;4.5;2.9) total:(l 7.1, 6.1,3.2). percentage of participants with more than one abnormality were as follows. those with bp> 140/90mmhg, 14% also had rbg> 140mg/dl and 6.4% had proteinuria> i. those with rbg> 140mgldl, 11 % also had proteinuria> 1 and 35% had bp> 140/90mmhg. those with proteinuria> 1, 18% also had rbg> 140mg/dl, and 38% had bp> 140/90mmhg. conclusion: we conclude that sub clinical abnormalities in urinalysis, bp and rbg readings are prevalent across all genders and racial groups in the adult population. the overlap of abnormalities, point towards the high risk for esrd as well as cardiovascular disease. this indicates the urgent need for population based programs aimed at creating awareness, and initiatives to control and retard progression of disease. introduction: various theories have been proposed that link differential psychological vulnerability to health outcomes, including developmental theories about attachment, separation, and the formation of psychopathology. research in the area of psychosomatic medicine suggests an association between attachment style and physical illness, with stress as a mediator. there are two main hypotheses explored in the present study: ( t) that individuals living with hiv who were upsychologically vulne~able" at study entry would be more likely to experience symptoms of depression, anxiety and phys1ca! illness over. the course of the 9-month study period; and (2) life stressors and social support would mediate the relat10nship between psychological vulnerability and the psychological ~nd physical outcomes. . (rsles), state-trait anxiety inventory (stai), beck depr~ssi~n lnvento~ (bdi), and~ _21-item pbys~i symptoms inventory. we characterized participants as havmg psychological vulnerability and low resilience" as scoring above 35 on the raas (insecure attachment) or above 120 on the das (negative expectations about oneself). . . . . . " . . ,, . results: at baseline, 55% of parnc1pants were classified as havmg low resilience. focusmg on anxiety, the average cumulative stai score of the low-resilience group was significandy hi~e~ than that of the high-resilience group ( 18.45 sd= 10.6 versus 9.57 sd= 8.6; f(l,80)= 16.74, p <.001). similar results were obtained for bdi and physical symptoms (f( 1,80)= 14.65, p<.001 and f( 1,80)= 5.50, p<.05, respec· tively). after controlling for resilience, the effects of variance in life stres".°rs averaged over time wa~ a_sig· nificant predictor of depressive and physical symptoms, but not of anxiety. ho~e_ver, these assooan~s became non-significant when four participants with high values were removed. s1id1larly, after controlling for resilience, the effects of variance in social support averaged over time became insignificant. conclusion: not only did "low resilience" predict poor psychological and physical outcomes, it was also predictive of life events and social support; that is, individuals who were low in resilience were more likely to experience more life events and poorer social support than individuals who were resilient. for individuals with vulnerability to physical, psychological, and social outcomes, there is need to develop and test interventions to improve health outcomes in this group. rajat kapoor, ruby gupta, and jugal kishore introduction: young people in india represent almost one-fourth of the total population. they face significant risks related to sexual and reproductive health. many lack the information and skills neces· sary to make informed sexual and reproductive health choices. objective: to study the level of awareness about contraceptives among youth residing in urban and rural areas of delhi. method: a sample of 211 youths was selected from barwala (rural; n= 112) and balmiki basti (urban slums; n= 99) the field practice areas of the department of community medicine, maulana azad medical college, in delhi. a pre-tested questionnaire was used to collect the information. when/(calen· dar time), by 2, fisher exact and t were appliedxwhom (authors?). statistical tests such as as appropriate. result: nearly 9 out of 10 (89.1 %) youth had heard of at least one type of contraceptive and majority (81.5%) had heard about condoms. however, awareness regarding usage of contraceptives was as low as 9.4% for terminal methods to 39.3% for condom. condom was the best technique before and after marriage and also after childbirth. the difference in rural and urban groups was statistically signif· icant (p=.0001, give confidence interval too, if you provide the exact p value). youth knew that contra· ceptives were easily available (81 %), mainly at dispensary (68.7%) and chemist shops (65.4%). only 6.6% knew about emergency contraception. only advantage of contraceptives cited was population con· trol (42.6%); however, 3.8% believed that they could also control hiv transmission. awareness of side effects was poor among both the groups but the differences were statistically significant for pills (p=0.003). media was the main source of information (65%). majority of youth was willing to discuss a~ut contraceptive with their spouse (83.4%), but not with others. 51.2% youth believed that people in their age group use contraceptives. 35% of youth accepted that they had used contraceptives at least once. 81 % felt 2 children in family is appropriate, but only 59.7% believed in 3 year spacing. . conclusion: awareness about contraceptives is vital for youth to protect their sexual and reproduc· tive health .. knowledge about terminal methods, emergency contraception, and side effects of various contraceptives need to be strengthened in mass media and contraceptive awareness campaigns. mdbot:ls: 740 elderly aged 60+ were interviewed in 3 poor communities in beirut the capital of f:ebanon, ~e of which is a palestinia~. refugee camp. depression was assessed using the i 5-item geriat· nc depressi~n score (~l?s-15). specific q~estions relating to the 3 aspects of religiosity were asked as well as questions perta1rung to demographic, psychosocial and health-related variables. results: depression was prevalent in 24% of the interviewed elderly with the highest proportion being in the palestinian refugee camp (31 %). mosque attendance significantly reduced the odds of being depressed only for the palestinian respondents. depression was further associated, in particular communities, with low satisfaction with income, functional disability, and illness during last year. condiuion: religious practice, which was only related to depression among the refugee population, is discussed as more of an indicator of social cohesion, solidarity than an aspect of religiosity. furthermore, it has been suggested that minority groups rely on religious stratagems to cope with their pain more than other groups. implications of findings are discussed with particular relevance to the populations studied. nearly thirty percent of india's population lives in urban areas. the outcome of urbanization has resulted in rapid growth of urban slums. in a mega-city chennai, the slum populations (25.6 percent) face greater health hazards due to overcrowding, poor sanitation, lack of access to safe drinking water and environmental pollution. amongst the slum population the health of women and children are most neglected, resulting in burden of both communicable and non-communicable diseases. the focus of the paper is to present the epidemiology profile of children (below 14 years) in slums of chennai, their health status, hygiene and nutritional factors, the social response to health, the trends in child health and urbanization over a decade, the health accessibility factors, the role of gender in health care and assessment impact of health education to children. the available data prove that child health in slums is worse than rural areas. though the slum population is decreasing there is a need to explore the program intervention and carry out surveys for collecting data on some specific health implications of the slum children. objective: during the summer of 2003 there was a heat wave in central europe, producing an excess number of deaths in many countries including spain. the city of barcelona was one of the places in spain where temperatures often surpassed the excess heat threshold related with an increase in mortality. the objective of the study was to determine whether the excess of mortality which occurred in barcelona was dependent on age, gender or educational level, important but often neglected dimensions of heat wave-related studies. methods: barcelona, the second largest city in spain (1,582,738 inhabitants in 2003) , is located on the north eastern coast. we included all deaths of residents of barcelona older than 20 years that occurred in the city during the months of june, july and august of 2003 and also during the same months during the 5 preceding years. all the analyses were performed for each sex separately. the daily number of deaths in the year 2003 was compared with the mean daily number of deaths for the period 1998-2002 for each educational level. poisson regression models were fitted to obtain the rr of death in 2003 with respect to the period 1998-2002 for each educational level and age group. results: the excess of mortality during that summer was more important for women than for men and among older ages. although the increase was observed in all educational groups, in some age-groups the increase was larger for people with less than primary education. for example, for women in the group aged 65-74, the rr of dying for 2003 compared to 1998-2002 for women with no education was 1.30 (95%ci: 1.04-1-63) and for women with primary education or higher was 1.19 (95%ci: 0.90-1.56). when we consider the number of excess deaths, for total mortality (>=20 years) the excess numbers were higher for those with no education ( 17 5. 7 for women and 46. 7 for men) and those with less than primary education (112.5 for women and 11-2 for men) than those with more than primary edm:ation (75.0 for women and -10.3 for men). conclusion: age, gender and educational level were important in the 2003 barcelona heat wave. it is necessary to implement response plans to reduce heat morbidity and mortality. policies should he addressed to all population but also focusing particularly to the oldest population of low educational level. introduction: recently there has been much public discourse on homelessness and its imp~ct on health. measures have intensified to get people off the street into permanent housing. for maximum v132 poster sessions success it is important to first determine the needs of those to be housed. their views on housing and support requirements have to be considered, as th~y ar~ the ones affected. as few res.earch studies mclude the perspectives of homeless people themselves, httle is known on ho~ they e~penence the 1mpacrs on their health and what kinds of supports they believe they need to obtain housing and stay housed. the purpose of this study was to add the perspectives of homeless people to the discourse, based in the assumption that they are the experts on their own situations and needs. housing is seen as a major deter· minant of health. the research questions were: what are the effects of homelessness on health? what kind of supports are needed for homeless people to get off the street? both questions sought the views of homeless individuals on these issues. methods: this study is qualitative, descriptive, exploratory. semi-structured interviews were conducted with homeless persons on street corners, in parks and drop-ins. subsequently a thematic analysis was carried out on the data. results: the findings show that individuals' experiences of homelessness deeply affect their health. apart from physical impacts all talked about how their emotional health and self-esteem are affected. the system itself, rather than being useful, was often perceived as disabling and dehumanizing, resulting in hopelessness and resignation to life on the street. neither welfare nor minimum wage jobs are sufficient to live and pay rent. educational upgrading and job training, rather than enforced idleness, are desired by most initially. in general, the longer persons were homeless, the more they fell into patterned cycles of shelter /street life, temporary employment /unemployment, sometimes addictions and often unsuccessful housing episodes. conclusions: participants believe that resources should be put into training and education for acquisition of job skills and confidence to avoid homelessness or minimize its duration. to afford housing low-income people and welfare recipients need subsidies. early interventions, 'housing first', more humane and efficient processes for negotiating the welfare system, respectful treatment by service providers and some extra financial support in crisis initially, were suggested as helpful for avoiding homelessness altogether or helping most homeless people to leave the street. this study is a national homelessness initiative funded analysis examining the experiences and perceptions of street youth vis-a-vis their health/wellness status. through in-depth interviews with 140 street youth in halifax, montreal, toronto, calgary, ottawa and vancouver, this paper explores healthy and not-so healthy practices of young people living on the street. qualitative interviews with 45 health/ social service providers complement the analysis. more specifically, the investigation uncovers how street youth understand health and wellness; how they define good and bad health; and their experiences in accessing diverse health services. findings suggest that living on the street impacts physical, emotional and spiritual well·being, leading to cycles of despair, anger and helplessness. the majority of street youth services act as "brokers" for young people who desire health care services yet refuse to approach formal heal~h care organizational structures. as such, this study also provides case examples of promising youth services across canada who are emerging as critical spaces for street youth to heal from the ravages of ~treet cultur~. as young people increasingly make up a substantial proportion of the homeless population in canada, it becomes urgent to explore the multiple ways in which we can support them to regain a sense of wellbeing and "citizenship." p5-77 (c) health and livelihood implications of marginalization of slum dwellers in provision of water and sanitation services in nairobi city elizabeth kimani, eliya zulu, and chi-chi undie . ~ntrodfldion: un-habitat estimates that 70% of urban residents in kenya live in slums; yet due to their illegal status, they are not provided with basic services such as water sanitation and health care. ~nseque~tly, the services are provided by vendors who typically provide' poor services at exorbitant prices .. this paper investigates how the inequality in provision of basic services affects health and livelihood circumstances of the poor residents of nairobi slums . . methods: this study uses qualitative and quantitative data collected through the ongoing longitudmal .health and demographic study conducted by the african population and health research center m slum communities in n ·rob" w d · · · · ai 1. e use escnpnve analytical and qualitative techmques to assess h~w concerns relating to water supply and environmental sanitation services rank among the c~mmumty's general and health needs/concerns, and how this context affect their health and livelihood circumstances. results: water (32%) and sanitation (20%) were the most commonly reported health needs and also key among general needs (after unemployment) among slum dwellers. water and sanitation services are mainly provided by exploitative vendors who operate without any regulatory mechanism and charge exorbitantly for their poor services. for instance slum residents pay about 8 times more for water than non-slum households. water supply is irregular and residents often go for a week without water; prices are hiked and hygiene is compromised during such shortages. most houses do not have toilets and residents have to use commercial toilets or adopt unorthodox means such as disposing of their excreta in the nearby bushes or plastic bags that they throw in the open. as a direct result of the poor environmental conditions and inaccessible health services, slum residents are not only sicker, they are also less likely to utilise health services and consequently, more likely to die than non-slum residents. for instance, the prevalence of diarrhoea among children in the slums was 31 % compared to 13 % in nairobi as a whole and 17% in rural areas, while under-five mortality rates were 151/1000, 62/1000 and 113/1000 respectively. the results demonstrate the need for change in governments' policies that deprive the rapidly expanding urban poor population of basic services and regulatory mechanisms that would protect them from exploitation. the poor environmental sanitation and lack of basic services compound slum residents' poverty since they pay much more for the relatively poor services than their non-slum counterparts, and also increase their vulnerability to infectious diseases and mortality. since 1991 iepas've been working in harm reduction becoming the pioneer in latin america that brought this methodology for brazil. nowadays the main goal is to expand this strategy in the region and strive to change the drug policy in brazil. in this way harm reduction: health and citizenship program work in two areas to promote the citizenship of !du and for people living with hiv/aids offering law assistance for this population and outreach work for needle exchange to reduce damages and dissemination of hiv/aids/hepatit is. the methodology used in outreach work is peer education, needle exchange, condoms and folders distribution to reduce damages and the dissemination of diseases like hiv/aids/hepatitis besides counseling to search for basic health and rights are activities in this program. law attendance for the target population at iepas headquarters every week in order to provide law assistance that includes only supply people with correct law information or file a lawsuit. presentations in harm reduction and drug policy to expand these subjects for police chiefs and governmental in the last year attended 150 !du and 403 nidu reached and 26.364 needles and syringes exchanged. in law assistance 740 (420 people living with aids, 247 drug users, 43 inject drug users, 30 were not in profile) people attended. 492 lawsuits filed 218 lawsuits in current activity. broadcasting of the harm reduction strategies by the press helps to move the public opinion, gather supporters and diminish controversies regarding such actions. a majority number of police officer doesn't know the existence of this policy. it's still polemic discuss this subject in this part of population. women remain one of the most under seviced segments of the nigerian populationand a focus on their health and other needs is of special importance.the singular focus of the nigerian family welfare program is mostly on demographic targets by seeking to increase contraceptive prevalence.this has meant the neglect of many areas of of women's reproductive health. reproductive health is affected by a variety of socio-cultural and biological factors on on e hand and the quality of the service delivery system and its responsiveness on the other.a woman's based approach is one which responds to the needs of the adult woman and adolescent girls in a culturally sensitive manner.women's unequal access to resources including health care is well known in nigeria in which stark gender disparities are a reality .maternal health activities are unbalanced,focusi ng on immunisation and provision of iron and folic acid,rather than on sustained care of women or on the detection and referral of high risk cases. a cross-sectional study of a municipal government -owned hospitalfrom each of the 6 geo-political regions in igeria was carried out (atotal of 6 ce~ters) .. as _part ~f t~e re.search, the h~spital records were uesd as a background in addition to a 3-week mtens1ve mvesuganon m the obstemc and gynecology departments. . . . : little is known for example of the extent of gynecological morbtdtty among women; the little known suggest that teh majority suffer from one or more reproductive tr~ct infect~ons. although abortion is widespread, it continues to be performed under ilegal and unsafe condmons. with the growing v134 poster sessions hiv pandemic, while high riskgroups such ascomn;iercial sex workers and their clients have been studied, little has been accomplished in the large populat10ns, and particularly among women, regardmgstd an hiv education. . . conclusions: programs of various governmentalor non-governmental agen,c1es to mvolve strategies to broaden the narrow focus of services, and more importan~, to put wo~en s reproducnve health services and information needs in the forefront are urgently required. there is a n~d to reonent commuication and education activities to incorprate a wider interpretation of reproducnve health, to focus on the varying information needs of women, men, and youth and to the media most suitable to convey information to these diverse groups on reproductive health. introduction: it is estimated that there are 250-300 youths living on the streets, on their own with the assistance of social services or in poverty with a parent in ottawa. this population is under-serviced in many areas including health care. many of these adolescents are uncomfortable or unable to access the health care system through conventional methods and have been treated in walk-in clinics and emergency rooms without ongoing follow up. in march 2004, the ontario government provided the ct lamont institute with a grant to open an interdisciplinary and teaching medical/dental clinic for street youth in a drop-in center in downtown ottawa. bringing 5 community organizations together to provide primary medical care and dental hygiene to the streetyouths of ottawa ages 12-20, it is staffed by a family physician, family medicine residents, a nurse practitioner, 2 public health nurses, a dental hygienist, dental hygiene students and a chiropodist who link to social services already provided at the centre including housing, life skills programs and counselling. project objectives: 1. to improve the health of high risk youth by providing accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. 2. to model and teach interdisciplinary adolescent care to undergraduate medical students, family medicine residents and dental hygiene students. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative:a) semi-structured interviews b) focus groups with youth quantitative:a) electronic medical records for 12 months b) records (budget, photos, project information). results: in progress-results from first 12 months available in august 2005. early results suggest that locating the clinic in a safe and familiar environment is a key factor in attracting the over 130 youths the clinic has seen to date. other findings include the prevalence of preventative interventions including vaccinations, std testing and prenatal care. the poster presentation will present these and other impacts that the clinic has had on the health of the youth in the first year of the study. conclusions: 1) the clinic has improved the health of ottawa streetyouth and will continue beyond the initial pilot project phase. 2) this project demonstrates that with strong community partnerships, it is possible meet make healthcare more accessible for urban youth. right to health care campaign by s.j.chander, community health cell, bangalore, india. introduction: the people's health movement in india launched a campaign known as 'right to health care' during the silver jubilee year of the alma ata declaration of 'health for all' by 2000 ad in collahoration with the national human rights commission (nhrc). the aim of the campaign was to establish the 'right to health care' as a basic human right and to address structural deficiencies in the pubic health care system and unregulated private sector . . methods: as part of the campaign a public hearing was organized in a slum in bangalore. former chairman of the nhrc chaired the hearing panel, consisting of a senior health official and other eminent people in the city. detailed documentation of individual case studies on 'denial of access to health care' in different parts of the city was carried out using a specific format. the focus was on cases where denial of health services has led to loss of life, physical damage or severe financial losses to the patient. results: _fourte_en people, except one who had accessed a private clinic, presented their testimonies of their experiences m accessing the public health care services in government health centres. all the people, e_xcept_ one person who spontaneously shared her testimony, were identified by the organizations worki_ng with the slum dwellers. corruption and ill treatment were the main issues of concern to the people. five of the fourteen testimonies presented resulted in death due to negligence. the public health cen· n:s not only demand money for the supposedly free services but also ill-treats them with verbal abuse. five of these fourteen case studies were presented before the national human right commission. the poster sessions v135 nhrc has asked the government health officials to look into the cases that were presented and to rectify the anomalies in the system. as a result of the public hearing held in the slum, the nhrc identified urban health as one of key areas for focus during the national public hearing. cond#sion: a campaign is necessary to check the corrupted public health care system and a covetous private health care system. it helps people to understand the structure and functioning of public health care system and to assert their right to assess heath care. the public hearings or people's tribunals held during the campaign are an instrument in making the public health system accountable. ps-82 (a) violence among women who inject drugs nadia fairbairn, jo-anne stoltz, evan wood, kathy li, julio montaner, and thomas kerr background/object ives: violence is a major cause of morbidity and mortality among women living in urban settings. though it is widely recognized that violence is endemic to inner-city illicit drug markets, little is known about violence experienced by women injection drug users (!du). therefore, the present analyses were conducted to evaluate the prevalence of, and characteristics associated with, experiencing violence among a cohort of female idu in vancouver. methods: we evaluated factors associated with violence among female participants enrolled in the vancouver injection drug user study (vidus) using univariate analyses. we also examined self-reported relationships with the perpetrator of the attack and the nature of the violent attack. results: of the 346 active iou followed between december 1, 2003 and may 6, 2005, 73 (21.1 %) had experienced violence during the last six months. variables positively associated with experiencing violence included: homelessness (or= 3.46, 95% ci: 1.66-7.21, p < 0.01), public injecting (or= 3.45, 95% ci: 1.43 -8.35, p < 0.01 ), frequent crack use (or= 2.99, 95% ci: 1. 72 -5.17, p < 0.01 ), recent incarceration (or =2.81, 95% cl: 1.38 -5.72, p < 0.01), receiving help injecting (or =2.77, 95% cl: 1.54-5.00, p < 0.01 ), shooting gallery attendance (or =2.46, 95% ci: 1.22 -4.93, p < 0.01 ), sex trade work (or =2.30, 95% cl: 1.35 -3.93, p < 0.01 ), frequent heroin injection (or= 1.96, 95% cl: 1.13 -3.40, p < 0.02), and residence in the downtown eastside (odds ratio [or] = 1.85, 95% ci: 1.09 -3.13, p < 0.02). variables negatively associated with experiencing violence included: being married or common-law (or =0.47. 95% ci: 0.25 -0.87, p < 0.02) and being in methadone treatment (or =0.53, 95% ci: 0.31 -0.91, p < 0.02). the most common perpetrators of the attack were acquaintances (48.0%), strangers (27.4%), police (9.6%), or dealers (8.2%). attacks were most frequently in the form of beatings (65.8%), robberies (21.9%), and assault with a weapon (13.7%). conclusion: violence was a common experience among women !du in this cohort. being the victim of violence was associated with various factors, including homelessness and public injecting. these findings indicate the need for targeted prevention and support services, such as supportive housing programs and safer injection facilities, for women iou. introduction: although research on determinants of tobacco use among arab youth has been carried out at several ecologic levels, such research has included conceptual models and has compared the two different types of tobacco that are most commonly used among the lebanese youth, namely cigarette and argileh. this study uses the ecological model to investigate differences between the genders as related to the determinants of both cigarette and argileh use among youth. methodology: quantitative data was collected from youth in economically disadvantaged urban communities in beirut, the capital of lebanon. results: the results indicated that there are differences by gender at a variety of ecological levels of influence on smoking behavior. for cigarettes, gender differences were found in knowledge, peer, family, and community influences. for argileh, gender differences were found at the peer, family, and community l.evels. the differential prevalence of cigarette and argileh smoking between boys and girls 1s therefore understandable and partially explained by the variation in the interpersonal and community envi.ronment which surrounds them. interventions therefore need to be tailored to the specific needs of boys and girls. introduction: the objective of this study was to assess the relationship between parents' employment status and children' health among professional immigrant families in vancouver. our target communmes v136 poster sessions included immigrants from five ethnicity groups: south korean, indian, chine~e, ~ussian, and irani~ with professional degrees (i.e., mds, lawyers, engineers, ma?~ger~, and uru~ers1ty professors) w11h no relevant job to their professions and those who had been hvmg m the studied area at least for 36 months. methodology: the participants were recruited by collaboration from three local community agencies and were interviewed individually during the fall of 2004. ra#lts: totally, 109 complete interviews were analyzed: 33 from south-east asia, 59 from south asia, 17 from russia and other eastern europe. overall, 14.5% were employed, 38.5% were underemployed, 46% indicated they were unemployed. overall, 58.5% were not satisfied with their current job. russians and other eastern europeans were most likely satisfied with their current job, while south-east asians were most satisfied from their life in canada. about 53% indicated that their spouses were not satisfied with their life in canada, while 55% believed that their children are very satisfied from their life in canada. in addition, around 30% said they were not satisfied from their family relationship in canada. while most of the responders ranked their own and their spouses' health status as either poor or very poor, jut 3% indicated that their first child's health was very poor. in most cases they ranked their children's health as excellent or very good. the results of this pilot study show that there is a need to create culturally specific child health and behavioral scales when conducting research in immigrant communities. for instance, in many asian cultures, it is customary for a parent either to praise their children profusely, or to condemn them. this cultural practice, called "saving face," can affect research results, as it might have affected the present study. necessary steps, therefore, are needed to revise the current standard health and behavioral scales for further studies by developing a new scale that is more relevant and culturally sensitive to the targeted immigrant families. metboda: database: 2003 national health survey (ministry of health www.msc.es). two thousand interviews were performed among madrid population (0.04% of the whole); 593 corresponded to older adults (0.04% of the 1. 7 million aged 50 years and over). study sample constitutes 95.3% (565 out of 593) of those older adults, who live in urban areas. demographic structure (by age and gender) of this population in relation to health services use (medical consultations, dentist visits, emergence services, hospitalisation) was studied using general linear model univariate procedure. a p0.005), while age was associated with emergence services use (26% of the population: 21 %, 28% and 45% of each age group) and hos~italisation (17% .oft~~ population: 13%, 20% and 31%, of each age ~oup) (p0.005) was fou~d with respect to dennst v1s1ts (18% vs 20%), medical consultations (29% vs 36%), and emergence services use (26% vs 26%), while an association (p= 0.005) was found according to hospitalisation (20% vs 16%). age. an~ g~der interaction effect on health services use was not found (p> 0.005), but a trend towards bosp1tal1sanon (p=0.04) could be considered. concl.uions: demographic structure of urban older adults is associated with two of the four health se~ices use studi~. a relation.ship ber_ween age. and hospital services use (emergence units and hospitalisanon), but not with ~ut-hosp1tal sei:vices (medical and dentist consultations), was found. in addition ro age, gender also contnbutes to explam hospitalisation. . sexua experiences. we exammed the prevalence expenences 10 relation to ethnic origin and other sociodemographic variables as wc1i as y1j7 die relation between unwanted sexual experiences, depression and agreuion. we did so for boys and prts separately. mdhods: data on unwanted sexual expcric:nces, depressive symptoms (ce.s-d), aggrc:uion (bohi-di and sociodemographic facron were collected by self-report quescionnairc:s administettd to 35 31 students in the: 2nd grade (aged 12-16) of secondary schools in amsterdam, the netherlands. data on the nature ol unwanted sexual experiences were collected during penonal interviews by trained schoolnursn. ltaijtj: overall prevalences of unwanted sexual experiences for boys and girls were 6.5% and 5.7% respectively. unwanted sexual experiences were more often ttported by turkish ( 17.1 %), moroc· an (10.4%) and surinamese/anrillian boys (7.4%) than by dutch boys (2.2%). moroccan and turkish girls, however, reported fewer unwanted sexual experiences (respectively 2.3 and 2.7%) than durch girls did (6.9%). depressive symptoms(or=4.6, cl=3.1-7.0) covert agression (0r•4.9, cl•3.2-7.7) and cmrt aggression (or= 2.6, cl• 1.6-4.4) were more common in girls with an unwanted sexual experi· met. boys with an unwanted sexual experience reported more depressive symptoms (or= 2.2; cl• i . .l· 3.9) and oven agression (or= 1.5, cl= 1.0-2.4) . of the reported unwanted sexual experiences rnpec· timy 17.5% and 73.5% were confirmed by male and female adolescents during a personal interview. cond11sion: we ..:an conclude that the prevalence of unwanted sexual experiences among turkish and moroccan boys is disturbing. it is possible that unwanted sexual experiences are more reported hy boys who belong to a religion or culture where the virginity of girls is a maner of family honour and talking about sexuality is taboo. more boys than girls did not confirm their initial disdosurc of an lllwalltc:d sexual experience. the low rates of disclosure among boys suggcsu a necd to educ.:atc hcahh care providen and others who work with migrant boys in the recognition and repomng of 1exu.il ... iction. viramin a aupplc:tmntation i1 at .h'yo, 1till far from tafl'eted 100%. feedinit pracn~:n panku· lerty for new born earn demand lot of educatton ernpha111 a• cxdu11ve hrealt fecdtnit for dnared rcnoj of 6 months was observtd in only 6.s% of childrrn thoulh colckturm w.11 givm 1n rn% of mwly horn ct.ildrm. the proportion of children hclow-2 waz (malnounshrdl .con" a• h!jh •• 42.6% anj "rt'i· acimy tc.. 11 compared to 1998 data. mother's ~alth: from all is 10 womm in ttprod~uvr •ill' poup, 83% were married and among marned w~ .\9% only w\"rt' u1mic wmr cnntr.-:cruve mt1h· odl 44% were married bdorc thc •ar of 18 yean and 27% had thnr ftnc prcicnancy hcftitt dlt' •icr nf 21 yean. the lt'f'vicn are not uutfactory or they arc adequate but nae unh1ed opumally. of thote' l'h mothen who had deliverrd in last one year, 80% had nailed 11ntmaral eum1nat1on 11 ira" oncc, .~o-... bad matt rhan four ttmn and ma1ortty had 1heir tetanus toxotd tnin,"t1or"'" nlht "'"'"· ljn1r11ned rn· win ronductrd 12.4% dchvcnn and 26% had home deh\'t'oc'i. ~md~: the tervtcn unbud or u111led are !tu than dnarame. the wr· l'kft provided are inadequate and on dechm reprcwnttng a looun1t ~p of h11hnto good coytti\#' ol wr· ncn. l!.ckground chanpng pnoriry cannoc be ruled out u °"" of thc coatnbutory bc10f. ps-ii ia) dcpn:wioa aad anuccy ia mip'mu ia awccr._ many de wn, witco tui~bmjer. jack dekker, aart·jan lttkman, wim gonmc:n. and amoud verhoeff ~ a dutch commumry-bucd icudy thawed 12-moarh•·prc:yalm«i al 17 .44'1. kw anx1· ay daorden and 13. 7% foi' dqrasion m anmttdam. nm .. 11p1tficantly hlllhn than dwwhrft .. dw ~thew diffamca m pttyalcnca att probably rdarcd to tlk' largr populanoa of napaan 111 ..\mturdam. <turkish 5%, moroccan 9%, and surinam 10%1. lndttd. ic'wt'll ltudla hatt ~ ~ high prevalena rata among migrant poupi in rbe ncdwrlands. howc'ytt au ttlluchn iuffenod from wry low raporne rara, or med screnung talel thac lack a ~y yabdarcd ~ in order to study the prevalence of depression and anxiety, and the (barriers to) use of mental health care among the different ethnic groups the following study was recently conducted: . the study consisted of a two-step approach. the first step was mcl~ded m the ~ h ith survey of 2004 (ahs), and consisted of three screening scales for depression and aruaety (klo, g::q-12 and mhl-5). in this survey all respondents were asked_ permission for~ second app~ 1:' 18t consisted of a structured interview containing the cidi for aruaety and depression, and questtollllalres on health care seeking, amongst others. all respondents who gave permission for a second approachwere invited by jetter for a suuctured interview with multilingual interviewers at home at a preset date and time in the following week. . in total, 439 dutch, 317 turkish, 322 moroccan and 124 surinam respondents took part in the ahs and gave permission for a second approach. in the second step, fo~ 21~ tur~h, 184m~roc can 87 surinamese and 320 dutch respondents, information from the extensive interview was available (res~nse rates between 60 and 70% ). since the data collection was completed only recently (june 2005), prevalence estimates can be presented at the conference for the first time. we have shown that with this approach it is feasible to achieve an acceptable response rate in a study on mental health among migrants. therefore we expect that this study will provide reli· able estimates of depression and anxiety in the turkish, moroccan and surinam migrants in amstw!3~· for the first time. in addition, insight into mechanisms underlying the differences between and within ethnic groups and into barriers to mental health care will provide pretexts for the improvement of pre· vention and mental health care for migrant groups. this study aimed to determine spatial patterns of mortality and morbidity of five major health problems in an urban environment: homicides, pregnancy among adolescents ((<20 years old), asthma hospitalization among young children(< 5 years old) and two mosquito-borne diseasesdengue and visceral leishmaniasis, during 1999-2003. all events were obtained through the city health database and, subsequently, geoproccsscd using the address of residence and the geographical and administrative division of the municipality, composed by 80 unit of planning (up), which in tum were formed, each one, by census tract units. two research questions were investigated: are there spatial patterns to the events dis· tribution, and moreover, are these patterns overlapping across space? we use thematic maps, index of comparative mortality/morbidity by up and the overlapped rank of the 20th worse up rates for each event. a spatial pattern of high rates of homicides, proportion of young mothers and hospitalization of asthma were overlapping in areas social and economically disadvantaged. for mosquito-borne diseases, high rates with great dispersion were found in unprivileged areas in contrast with very low rares among privileged ones. these results pointed toward a coexistence of heavier burden of diseases for those living in areas of the city where misery, poverty, lack of political public health may be modulating social health problems. a possible environmental intervention in one mosquito•bome disease might be playing a role in the occurrence of other. although with limitations, this study may provide useful information for a joint urban planning under the public perspective, articulated for use in health impact assessment. jalil safaei bdrod#aion: the association of socioeconomic status (ses), usually measured by income, and health status is an established result in bcalth studies. the poor and low income individuals have lower health sta· tus then_ those with higher incomes. in general. such finding has been usually obtained from sample surveys on speafic populations. a problem with many sample survey$ is that their results are not comparable aaoss ~ndaries as they may use different sampling methods, ask different questions, categorize the answers differently, or define groups differently. moreover, the sample data need to be standardized using the demographic: katurea of a ~ population. this study, however, uses the national population health survey (nphs) cycle 3 public use mictodata files which is based on a common survey template ·~~three~ area in canada, namely montreal, toronto, and vancouver. it also utili7.es the built-m stanclatdizaaon of the nphs data which accounts for its complex survey design. . ~:the stu~ usc:s two well-known measures of health inequalitythe relative index of meqaality and die concentranon indexto capture the extent of income related health inequality among poster sessions v139 urban female and male populations in each of the three metropolitan areas. personal income is classified into ten groups by the nphs with "no income" as the first group and "more than $60,000" as the last. health status is measured by three variables -having a chronic condition (chc), self assessed health (sah), and health utility index (hui) -using appropriate indices. alternative formulations are used to calculate the standard deviations of the estimated or calculated measures. the findings of the study suggest that the measured health inequality depends on the health measure used. for chc and hui the measured inequality indices do indicate poorer health for lower income individulas, however, they are not statistically insignificant. health inequalities are more pronounced when health is measured by sah. the results do not support any systematic ranking of the three metropolitan areas in terms of health inequalities. they do not reveal any systematic pattern of inequality between men and women, either. conclusions: despite the use of highly aggregated nphs data, income related health disparities are observed in the three metropolitan areas in canada. this is more the case with self perceived (sah) health. such disparities are preventable and call for broader health policies that address poverty and low income among other social determinants of health. introduction: the analysis of health indicators under the spatial perspective is configured as an important instrument in the detection of intra-urban differentials. this study aimed to examine the spatial distribution of the births occurred in belo horizonte, in 2001, analyzing the presence of spatial clusters of health indicators for newborns (rn) and their mothers, using data from the information system on live birth database (sinasc). method: for each covered area of the basic units of health (ubs), we calculated the proportion of: adolescent mothers, mothers with less than 8 years of schooling, first pregnancy, mothers with four or more pregnancies, dead babies born on previous pregnancies, stillbirths, cesarean section, less than four prenatal care attendance, moderate and severe hypoxemia in the 1st and 5th minutes of life, low or very low birth weight. we used empiric bayesian methods for smoothing the estimates. for spatial analysis, the indicators obtained from the global moran (i) index and local indicators of spatial association (lisa) were used. maps were built to allow the visualization of the spatial clusters. in all analysis, significance statistics was considered p~ 0.05. results: a total of 36, 12 7 births of residents in belo horizonte were registered in 200 i. the estimated bayesian proportions for the entire municipality was close to the one observed for all variables. analysis using lisa showed the presence of relevant spatial clusters for adolescent and low educated mothers, dead babies form previous pregnancies, cesarean section, low attendance to the prenatal care especially in area with low socio-demographic characteristics. three areas presented consistent clusters, with important spatial auto-correlation for almost all studied indicators. conclusion: the used methodology was configured as a great instrument of detection risk areas where clustering occurs. it can easily be incorporated in any surveillance system as a mechanism for controlling events related to births in the municipality. moreover, it can be applied to discriminate target areas for prompt public health interventions, such as improving health services access and the consolidation of better obstetric practices. introduction: gentrification, the displacement of low income and non-majority people out of longtime neighborhoods and residences is a global phenomenon. it has been identified as occurring in both developed and less developed countries and as inequality persists or increases, many communities are vulnerable to disruption and loss. while there may be some benefits to gentrification, these benefits are less likely to impact those who have been forced to move out of a gentrifying community or those who remain but economically stressed. . . . . this paper lays out a theoretical framework for 1dent1fymg and ~ddressm~. the_ health consequences of gentrification on residents living in a community prior .to o.r durmg gent~1~1cat.10n. by drawing on the literature of housing, sociology, health and urban plannmg, 1t places genmf1catt~n and neighborhood change into the context of other forces affecting th~ .hea.lth of vulnerable populations. it then proposes solutions to prevent or mitigate the impacts of genmf1cat1on. results: four main categories of consequences potentiallr re~ult from ~entr~fica~~n: !'°°r housing· related issues, spatial effects, mental health impacts and contr1bunons to racial ~spanttes m heal~. the housing issues include increased susceptibility to asthma, lead exposure, allergiesl~topy an~. acetdents/ injuries. spatial effects include reduced access to health ~are, reduce~ access to 1obslttadinonal food sources, decreased physical activity, and increased obesity. the __ pnmary mental health effects_ :ire increased stress increased risk of depression and disruption of trad1t1onal support networks. in addinon to the above he~lth issues, gentrification has the potential to increase racial disparities in health by reduc· ing access to long term and multi-culturally experienced health care provide~s. conclusions: public health practice provides a framework for addressmg the health consequences of gentrification. in this context primary prevention would involve preventing gentrification in the first place along with a renewed commitment to helping distressed communities a~~ im_proving the quality ~f life for long term residents. the next layer of meeting the challenges of gentrification would be to assjst long rime residents to stay in a community and thus potentially allowing them to participate in the bene~ts of gentrification (such as better public services). only if all these efforts fail -and these other prevennon strategies must be a priority, public policy should then work to help people and instirutions move to other communities through grants and the provision of alternative safe affordable housing and neighborhoods. sarah romans, marsha cohen, and tonia forte lnh'odlletion: there has been sustained interest in urban rural (ur) differences in mental health over the last 50 years of epidemiological research, with most studies reporting higher urban rates of mor· bidity, particularly when psychotic disorders have been studied. most recently, in britain, urban rates of non-psychotic disorder were greater than rural and semi-rural rates, both before and after the more adverse circumstances of urban dwellers were considered (paykel et al 2003) . surprisingly, there were no ur differences in help seeking. in canada, wang (2004) found greater urban rates for major depression only after he controlled for the confounding effects of race, immigration, employment and marital status, a result reminiscent of work from the us (blazer et 1985) . rural participants were less likely to have sought help for their mental health problems. in this study, we sought to examine urban/rural differences in rates of depression and help seeking in canada. method; data came from the 2000 canadian community health survey 1.2, a community survey conducted by statistics canada of people aged 15 and older, with the total sample size of 36,984 respon· dents, 77% response. analyses used weighted data; differences were assessed by chi-squared. ra.its: bivariate cross-tabulations showed a modest increase in 12 month depression rates for urban (5.4%) over rural (4.3%, p= 0.03) dwellers; there were no ur differences when the sample was examined separately by gender and age group ( 15-29, 30-44, 45-69) . in general, more urban (10.6%) than rural people (8. 7%, p= 0.002) had sought mental health treatment in the past year. there was no ur difference in helping seeking amongst those with depression (u 58.9%, r 50.1 % ns). amongst the whole population, helping seeking was gendered with more urban men accessing help (7.4%) than rural men (5.4%, p=0.004); this did not apply for women (13.7% vs 12.1% p=0.1). ~ons: the urban-rural demographic continues to generate intriguing findings, even recently when internal migration is common and people can seek out the environment most conducive to their health, ~th physical and mental. people with depression are a disadvantaged, frequently stigmatized group, with ~r quality of life a_nd often impaired function. unlike many other factors associated wi~h urban or rural hfe per se, depression can be treated. the low help seeking rates is a cause for concern, m both the ur~n and_ rural populations. it behooves researchers, policy makers and service planners to ensutt effective services are available for both humane and economic reasons. methods: using united states 2000 census income data, we assigned the 12 manhattan community districts to two major socioeconomic groups, manhattan i and ii. manhattan i is composed of community districts with average household incomes above the median for new york city; manhattan ii is those below. with public new york city department of health 1999 death records and 2000 us census data, we calculated a "standard" new york city population and estimated mortality rate distributions for manhattan i and ii. we then compared these age-adjusted actual mortality distributions with a standard t-test. results: we explored premature deaths using several cut-off points (before the ages of 65, 70, and 75), and with subcomparisons for males and females. every comparison showed the wealthier area, manhattan i, to have significantly lower premature mortality rates than the lower income manhattan ii. further, we compared age-adjusted mortality rates among the city's five boroughs, and found no significant differences based on local geography alone. conclusions: these findings suggest that in manhattan, characterized by its extremes of wealth and poverty, health status, as measured by premature mortality, does vary significantly with the local income level. in manhattan, the relative average income by community district varies as much as 4: 1. this ratio is greater than that found in the other cities we have studied: for example, the range among tokyo's kus is half that in manhattan, or about 2: 1. paris has shown the longest life expectancy and changing premature mortality rates. from our preliminary work, we expect to find less variation in premature mortality rates in comparable cities. this study will continue to explore the relationship of premature mortality rates and life expectancy to income levels and different health systems among wcp cities with a view to measuring health policy options. introduction: according to the world health organization (who), smoking-related illness is currently the world's second major cause of death, currently responsible for one out of ten adult deaths worldwide. the who's framework convention on tobacco control (fctc) aims to reduce tobaccorelated disease and deaths by changing national public policies. mexico, which, according to the who, had smoking prevalences of 32% among adults in 1998 and 23% among health care providers (hcps) in 1997, ratified the fctc in 2004. objective: to examine knowledge of and attitudes towards cigarette smoking and smoking cessation among hcps, and clinical practices regarding smoking cessation. methods: in june 2005, a convenience sample of hcps from one public clinic in urban oaxaca, mexico, part of mexico's national network of public health care clinics, were interviewed in spanish using a verbally administered questionnaire that was standard among all participants. during primary care outpatient visits, hcps were observed treating patients to assess the relative importance of smoking cessation as a health care priority. results: of the 18 hcps interviewed, including ten physicians, three nurses, and five medical students, 67% reported smoking regularly. all hcps reported assessing patients' history of smoking, knowledge of the health risks associated with smoking, and feeling qualified to discuss these risks with patients. all hcps reported counseling patients who currently smoked to quit. all hcps reported recommending nicotine replacement therapy (eg., patch and/or gum) and/or behavioral therapy (eg., psychologist, support groups) to patients who smoked. all hcps reported that there was no government funding for smoking cessation, and that all costs associated with smoking cessation were patients' out-of-pocket expenses. observation of hcp interaction with patients revealed that hcps always inquired about smoking history with new patients and rarely inquired about smoking history with returning patients. hcps were not observed counseling patients who reported current smoking on smoking cessation methods and its benefits. observation of the clinical environment suggested a focus on preventative child health (eg., immunization, water-borne illnesses), family planning, and chronic diseases (eg., diabetes, hypertension). conclusions: while the mexican government has made smoking cessation a public health priority and hcps report addressing smoking cessation, observation of hcps suggests: 1) smoking status is assessed only in new patients; and 2) smoking cessation methods are not addresse~. observ_atio~ of hcps and the clinical environment in a public clinic in oaxaca suggests that smoking cessation 1s of lower priority than other heath care issues. p6-04 (a) urban agriculture and food and nutrition security in kampala, uganda fiona yeudall, renee sebastian, abdelrahman lubowa, selahadin ibrahim, and donald cole introduction: urban agriculture is an important livelihood strategy contributing to household food security by increasing access and availability to food in urban settings (koc et al., 1999) . the purpose of poster sessions v142 rhis study was to examine relationships between child nutritional securiry outcomes, household food security, and urban agriculture activiries in kampala, uga~da. . . questionnaires assessing socio-demographic, farmmg and household food secunry (hfsi characreristics were administered to 270 households. food diversiry was ~lculate~ from ~e number of foods consumed over 24 hours for one child (2-5 years) per household. heigh~ weight,. nud-upper·ann· circumference (muac) and tricep skinfolds (tsf) were measured for the mdex child. z-sc.ores for height-for·age (haz), weighr-for-age (waz) and body mass index (zbmi) were ~~ulated usmg cen· rres for disease control and prevenrion reference data. z-scores for body composition measures were calculated using nhanes i and ii data for african americans. the lms method was used to c~.t for skewed z·score indices. all dara was checked for normaliry and univariable and backward mulnvanablc linear regression analysis conducted. ruwlts: household food securiry was significantly associated with wealth (b= 0. 71, p< 'a acre were more dependenr on assets for hfs. although sex of head of household was ~ot related to j-:ifs, it modi· fied relationships in rhar female headed households had greater food securtry when fai:mmg less than 1,4 acre compared ro male headed households, and vice versa. hfs was significantly associated with food diversiry (s=0.15, p). urbanization, especially in developing countries, has substantially increased the vulnerability of rhe mass of low-income urban dwellers. the livelihoods and quality of life for many of the poor espe· cially in larin america, asia, and africa, have deteriorated significantly over the years. urban areas are increasingly unable to provide for their populations, resulting in poverry, massive unemploymenr, job cuts, poor housing, lack of or poor public services, and a compromised health status. botswana, a country rhat lies in the sourhern parr of africa, has had its share of urban problems such as rhe mush· rooming of squarters and low-income urban sertlements. despite efforts to address the substandard living conditions in low-income urban areas, these problems have continued to grow. these living con· diuons are porenrially stressful to rhe residenrs and likely affects their health. the primary aim of the 11udy wa1 to examine the complex relationship between communiry-level stressors and interveners and health-related quality of life among residents of low-income neighborhoods in francistown, botswana. u1i"" a croa1-icctional quantitative design (both descriptive and explanatory) and using primarily cloae-mded interview• with a random sample of 388 residents, this study examined the role of chrome life 1trnson and environmental quality on overall health status qualiry of life) and the physical, psy· chological and level of independence domains of health. the major hypothesis of the study was that community-levrl stre1sor1 would influence health-related quality of life and that social capital would moderate these relationships. findings indicate that neighborhood quality is a powerful predictor of healrh 1tatu1 rhan socioeconomic status and individual life stressors. social capital was also found to he a 11111ificant positive predictor of healrh and also moderator of structural factors. social capital moderated the effects of low environmental quality on level of indrpendence and on physical health outcomn, but nor on psychological and global health outcomes. these findings suggest that as the environment get1 betttr. stresson are reduced, hence promoting berter health outcomes. the study ends with implication• for social justice, public health and social work practice, and research, focusing mostly on the ~ole of social capital and the environmental quality in predicting health outcomes. spt· cafically • anenhon should be focused on political and civic society's commitment for social justice and poveny alleviation, ~uction of the threat of insecuriry and violence; cultivating social capital and good governance; and improving the health and social environments, especially housing and environ· mental 1aiutanon to name a few. urban and other uprisings by non-elites that lead to transitions, can disrupt sexual and injection "risk" networks that transmit infectious diseases by changing mixing patterns. they can also weaken urban social networks, their associated protective norms and their informal social control mechanisms which can lead to increased sexual and drug risk behaviors and violence (fullilove 2004; wallace & wallace1998, aral 2002 , friedman & reid 2000 hankins et al 2002) . for example, the 1979 revolution and transition to theocratic rule, and subsequent urban and national conflicts, have been followed by many urban youth in iran engaging in clandestine high-risk sexual and drug behaviors. in palestine, conflicts and restrictions on movement have led to increased fatalities from chronic diseases due to limited access to hospitals and modern medical facilities (union of palestinian medical relief committees); and heroin use and violence-related blood exposure have also increased. social movements "from below" that are rooted both in urban social network dynamics and in underlying patterns of injustice can have both protective and risky effects. for example, the social movements that led to the collapse of the ussr and its dependent governments in other countries-with subsequent increases in sex trade, alcoholism, drug use, tuberculosis, hiv, stis, and mortality in many localities-were based originally on such city-based movements in eastern europe. their impacts on health were mediated by urban social dynamics and structures. some urban social movements have improved health by prevent· ing the spread of hiv, hepatitis and other diseases. examples include movements of (a) gays and lesbians and (b) drug users. these have been rooted in social networks that overlap with risk networks. theories of urban health should include social conflict as a core concept. mechanisms that generate conflicts and the pathways by which conflicts affect health should be a major part of urban health research agendas. p6-07 (c) demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital (lasuth) chest clinic john bako, adewale akeredolu, and wale alabi tuberculosis has become a resurgent public health problem in recent times in the world. because resources are limited, control programmes frequently must target population at greatest risk. the purpose of this study was to study the demographic characteristics of people seen with tuberculosis in lagos state university teaching hospital. a total of 76 patients who have been both radiologically and bacteriologically confirmed tuberculosis patients were used for this study between january and march. 57 (75%) were males, while 19 (25%) were females. notable risk factors among patients with tuberculosis were overcrowding (46.1 % ), homelessness ( 11.8%) cigarette smoking (22.4% ), alcoholism (30.3%), non vaccination (25%), secondary contact (36.8%) and poor knowledge (92. l 'x,). man· agement history patterns among the patients were herbs ( 13.2 'yo), orthodox medicine ( .h . .l'x.). intervention targeting early-identified groups may be an effective way to reduce the incidence of tuber· culosis. such intervention should focus on health education, modification of life style and improvement of standard of living. p6-08 (c) profiles in urban health in 9 cities of the americas in the countries of the americas, there is an increasing migration of national and international populations to urban centers. this presentation will focus on some of the issues created by this influx of populations, the ways that 9 cities in 8 countries are dealing with them, and the efforts to promote local participation and solutions in management and decision-making. the methodology used to collect this information has been to draw upon and analyze information produced by the mayor's and ministry of health and development offices in each of the cities under consideration. an analysis of the impact of urbanization on health and health determinants will be presented. the information covers issues such as health status by geographic areas within the cities, highlighting issues such as marginality, barriers and physical, economic and cultural constructs and inequities in the delivery of and access to essential services (such as health, education, water, and basic sanitation). issues of governance and citizen participation will be highlighted to provide insight in~o the balance of power and mechanisms for decision-making at the local level. part of the analysis will show the relationship between democratic processes and social participation. public ~olicies will be reviewed to indicate those that are most beneficial in promoting health and overcoming barriers to it, as well as ways of capitalizing on local assets and resources. final~y, evidence of effectiveness of various strategies will be indicated. the presentation will conclude wuh suggesuons for future strategic directions to improve the quality of life and the promotion of health in large urban centers of the americas. introduction: much of the illicit drug in mexico is concentrated in northern border areas. the 2000 mile border between the u.s. and mexico is also characterized by migration; the border crossing between tijuana, baja california, mexico and san diego, california, u.s.a. is rep~rt~dl~ the busiest land border crossing in the world. we attempt to describe the migration scene among m1ect1on drug users (idus) m tijuana and investigate service needs. methods: migration trends were investigated in a cross-sectional study conducted from february to june 2005 among idus in tijuana. enrollment criteria included informed consent, being 18 years or older, and having injected drugs within the prior month. subjects were recruited by respondent-dnven sampling and were administered a quantitative survey and serology for hiv, hcv, and syphilis. logistic regression was used to compare idus who had migrated to the u.s. versus those who had not. results: of 222 idus enrolled, 91 % were male and median age and age at first injection were 35 and 20, respectively. drug combinations injected most frequently in the past 6 months were heroin (35%1 and crystal methamphetamine mixed with heroin (53%). of those enrolled, 212 responded to quesnons on migration and drug treatment and were included in this analysis. although 76% had resided in tijuana for at least 5 years, 70% of users were born outside of baja california. working outside of mexico was common, with 38% working abroad in the last 10 years (94% in u.s.), and 17% in the past year. in the last 6 months, 10% of idus had crossed the border to the u.s., with 57% crossing at least once per month. those working outside of mexico in the past year were less likely to have ever received substance abuse treatment, [29% vs. 53%, or 0.38, ] and were marginally less likely to have received drug treatment in the past 6 months [6% vs. 18 %, or 0.28, 95% ci (0.06-1.2)]. drug use patterns, age and gender did not differ between migrants and non-migrants, although migrants were more likely to report being in need of substance abuse treatment (68% vs. 57%, respectively). conclusions: migration is common among idus in tijuana. maintaining drug treatment regimens and determining how to best target education and services to a highly mobile population pose challenges to officials on both sides of the border. these data underscore the need to develop coordinated binational prevention and treatment efforts. introduction: despite the expanding literature on the important role public policy plays in influencing the broader determinants of the public\'s health, profound differences exist among jurisdictions in rhe attention placed upon such activities. we take an international perspective on health by examining rhe d?minant public _health paradigms of canada, usa, uk, and sweden and exploring how these paradigms shape public health practice. _method: we carefully analyze governmental and public health agencies documents to discern ~he dommant para~igms driving public health approaches and practices. we also consider the unique paht1· cal and economic contexts within each nation and consider how these contexts drive public health pahcy and approaches. . . ~u~: the canadian and usa public health communities -with some exceptions --focus upon m~ividuahzed approaches to risk management. in contrast, the uk and swedish public health scenes are oriented toward broader approaches to health determinants. we find that the extent to which govern· ments, public health agencies and public health workers concern themselves with public policy approaches £<_> ~ddress ~ro.ad~r .determinants of health depends upon the particular health parad'.~ adhered. ~o withm each 1urisd1ctton. and whether a paradigm is adopted depends upon the ideologi~a and pol~ncal context of each nation. nations such as sweden that have a long tradition of public policies promonng social jus~ce an~ equity are naturally receptive to evolving population health concepts. '[he usa represen~ a ~bey en~ro~~t where such is~ues are clear!~ subordinate. ., our findings mdicate that there 1s a strong political component that influences pubh ~ealth a~proaches and practi~ within the jurisdictions examined. the implications are that those seek· m~ to raise the broader detennmants of the public's health should work in coalition to raise these issues with non-health organizations and age · ca d d th · badrgrollnd: in developed countries, social inequalities in health have endured or even worsened comparatively throughout different social groups since the 1990s. in france, a country where access to medical and surgical care is theoretically affordable for everyone, health inequalities are among the high· est in western europe. in developing countries, health and access to care have remained critical issues. in madagascar, poverty has even increased in recent years, since the country wenr through political crisis and structural adjustment policies. objectives. we aimed to estimate and compare the impact of socio· economic status but also psychosocial characteristics (social integration, health beliefs, expectations and representation, and psychological characteristics) on the risk of having forgone healthcare in these 2 dif· fercnt contexts. methods: population surveys conducted among random samples of households in some under· served paris neighbourhoods (n= 889) and in the whole antananarivo city (n= 2807) in 2003, using a common individual questionnaire in french and malagasy. reslllts: as expected, the impact of socioeconomic status is stronger in antananarivo than in paris. but, after making adjustments for numerous individual socio-economic and health characteristics, we observed in both cities a higher (and statically significant) occurrence of reponed forgone healthcare among people who have experienced childhood and/or adulthood difficulties (with relative risks up to 2 and 3.s respectively in paris and antananarivo) and who complained about unhealthy living conditions. in paris, it is also correlated with a lack of trust in health services. coneluions: aside from purely financial hurdles, other individual factors play a role in the non-use of healthcare services. health insurance or free healthcare seems to be necessary hut not sufficienr to achieve an equitable access to care. therefore, health policies must not only focus on the reduction of the financial barriers to healthcare, but also must be supplemented by programmes (e.g. outreach care ser· vices, health education, health promotion programmes) and discretionary local policies tailored to the needs of those with poor health concern .. acknowledgments. this project was supported by the mal>io project and the national institute of statistics (instat) in madagascar, and hy the development research institute (ird) and the avenir programme of the national institute of health and medical research (inserm) in france. for the cities of developing countries, poverty is often described in terms of the living standard~ of slum populations, and there is good reason to believe that the health risks facing these populations are even greater, in some instances, than those facing rural villagers. yet much remains to be learned ahour the connections between urban poverty and health. it is not known what percentage of all urban poor live in slums, that is, in communities of concentrated poverty; neither is it known what proportion of slum residents are, in fact, poor. funhermore, no quantitative accounting is yet available that would sep· arare the health risks of slum life into those due to a househoid•s own poverty and those stemminic from poveny in the surrounding neighborhood. if urban health interventions are to be effectively targeted in developing countries, substantial progress must be made in addressing these cenrral issues. this paper examines poverty and children's health and survival using two large surveys, one a demographic and health survey fielded in urban egypt (with an oversampling of slums) and the other a survey of the slums of allahabad, india. using multivariate statistical methods. we find, in both settings: ( 11 substan· rial evidence of living standards heterogeneity within the slums; (21 strong evidence indicating that household-level poverty is an imponant influence on health; and (3) staristically significant (though less strong) evidence that with household living standards held constant, neighborhood levels of poverty adversely affect health. the paper doses with a discussion of the implications of these findings for the targeting of health and poverty program interventions. p6-13 (a) urban environment and the changing epidemiological surfacr. the cardiovascular ~ &om dorin, nigeria the emergence of cardiovascular diseases had been explained through the concomitants o_f the demographic transition wherein the prevalent causes of morbidity and monality ~hangr pr~mmant infectious diseases to diseases of lifestyle or chronic disease (see deck, 1979) . a ma1or frustration m the v146 poster sessions case of cvd is its multifactural nature. it is acknowledged that the environment, however defined is the d · f · t' b tween agents and hosts such that chronic disease pathogenesis also reqmre a me 1an o mterac ion e . spatio-temporal coincidence of these two parties. what is not clear is which among ~ever~( potennal fac· · h b pace exacerbate cvd risk more· and to what extent does the ep1dem1olog1cal trans1· tors m t e ur an s ' . . . . tion h othesis relevant in the explanation of urban disease outlook even the developmg cities like nigeri~: thesis paper explorer these within a traditional city in nigeria. . . . the data for the study were obtained from two tertiary level hospitals m the metropolis for 10 years (1991) (1992) (1993) (1994) (1995) (1996) (1997) (1998) (1999) (2000) . the data contain reported cases of cvd in the two facilities for the period. adopting a series of parametric and non-parametric statistics, we draw inferences between the observed cases of cvds and various demographic and locational variables of the patients. findings: about 28% of rhe cases occurred in 3 years (1997) (1998) (1999) coinciding with the last year of military rule with great instability. 55.3% occurred among male. 78.8% also occurred among people aged 31-70 years. these are groups who are also likely to engage in most stressful life patterns. ~e study also shows that 63% of all cases occurred in the frontier wards with minor city areas also havmg their •fair' share. our result conformed with many empirical observation on the elusive nature of causation of cvd. this multifactoral nature had precluded the production of a map of hypertension that would be consistent with ideas of spatial prediction. cvd -cardiovascular diseases. mumbai is the commercial capital of india. as the hub of a rapidly transiting economy, mumbai provides an interesting case study into the health of urban populations in a developing country. with high-rise multimillion-dollar construction projects and crowded slums next to each other, mumbai presents a con· trast in development. there are a host of hi-tech hospitals which provide high quality care to the many who can afford it (including many westerners eager to jump the queue in their healthcare systems-'medical tour· ism'), at the same time there is a overcrowded and strained public healthcare system for those who cannot afford to pay. voluntary organizations are engaged in service provision as well as advocacy. the paper will outline role of the voluntary sector in the context of the development of the healthcare system in mumbai. mumbai has distinct upper, middle and lower economic classes, and the health needs and problems of all three have similarities and differences. these will be showcased, and the response of the healthcare system to these will be documented. a rising hiv prevalence rate, among the highest in india, is a challenge to the mumbai public healthcare system. the role of the voluntary sector in service provision, advocacy, and empowerment of local populations with regards to urban health has been paramount. the emergence of the voluntary sector as a major player in the puzzle of urban mumbai health, and it being visualized as voices of civil society or communiry representatives has advantages as well as pitfalls. this paper will be a unique attempt at examining urban health in india as a complex web of players. the influence of everyday socio·polirical-cultural and economic reality of the urban mumbai population will be a cross cutting theme in the analysis. the paper will thus help in filling a critical void in this context. the paper will thus map out issues of social justice, gender, equiry, effect of environment, through the lens of the role of the voluntary sector to construct a quilt of the realiry of healthcare in mumbai. the successes and failures of a long tradi· tion of the active advocacy and participation of the voluntary sector in trying to achieve social justice in the urban mumbai community will be analyzed. this will help in a better understanding of global urban health, and m how the voluntary sector/ngos fir into the larger picture. ba~und: o~er. half _of n~irobi's 2.5 million inhabitants live in illegal informal settlements that compose 5 yo of the city s res1dent1al land area. the majority of slum residents lack access to proper san· iranon and a clean and adequate water supply. this research was designed to gain a clearer understand· mg of what kappr · · · h f . . opnate samtanon means or the urban poor, to determine the linkages between gender, hvehhoods, and access to water and sanitation, and to assess the ability of community sanitation blocks to meet water and sanitation needs in urban areas. m~tbojs_: _a household survey, gender specific focus groups and key informant interviews were conducted m maih saba, a peri-urban informal settlement. qualitative and quantitative research tools were u~ to asses~ the impact and effectiveness of community sanitation blocks in two informal settlements. results ropna e samtarmn me u es not only safe and clean latrines, but also provision ° adequate drainage and access to water supply for cleaning of clothes and homes. safety and cleanliness poster sessions v147 were priorities for women in latrines. levels of poverty within the informal settlements were identified and access to water and sanitation services improved with increased income. environmental health problems related to inadequate water and sanitation remain a problem for all residents. community sanitation blocks have improved the overall local environment and usage is far greater than envisioned in the design phase. women and children use the blocks less than men. this is a result of financial, social, and safety constraints. the results highlight the importance a need to expand participatory approaches for the design of water and sanitation interventions for the urban poor. plans need to recognize "appropriate sanitation" goes beyond provision of latrines and gender and socioeconomic differences must be taken into account. lessons and resources from pilot projects must be learned from, shared and leveraged so that solutions can be scaled up. underlying all the challenges facing improving water and sanitation for the urban poor are issues of land tenure. p6-16 (c) integrating tqm (total quality management), good governance and social mobilization principles in health promotion leadership training programmes for new urban settings in 12 countries/ areas: the prolead experience susan mercado, faren abdelaziz, and dorjursen bayarsaikhan introduction: globalization and urbanization have resulted in "new urban settings" characterized by a radical process of change with positive and negative effects, increased inequities, greater environmental impacts, expanding metropolitan areas and fast-growing slums and vulnerable populations. the key role of municipal health governance in mitigating and modulating these processes cannot be overemphasized. new and more effective ways of working with a wide variety of stakeholders is an underpinning theme for good governance in new urban settings. in relation to this, organizing and sustaining infrastructure and financing to promote health in cities through better governance is of paramount importance. there is a wealth of information on how health promotion can be enhanced in cities. despite this, appropriate capacity building programmes to enable municipal players to effectively respond to the challenges and impacts on health of globalization, urbanization and increasing inequity in new urban settings are deficient. the who kobe centre, (funded by the kobe group( and in collaboration with 3 regional offices (emro, searo, wpro) with initial support from the japan voluntary contribution, developed a health promotion leadership training programme called "prolead" that focuses on new and autonomous structures and sustainable financing for health promotion in the context of new urban settings. methodology: country and/or city-level teams from 12 areas, (china, fiji, india, japan, lebanon, malaysia, mongolia, oman, philippines, republic of korea, tonga and viet nam) worked on projects to advance health promotion infrastructure and financing in their areas over a 9 month period. tools were provided to integrate principles of total quality management, good governance and social mobili1.ation. results: six countries/areas have commenced projects on earmarking of tobacco and alcohol taxes for health, moblization of sports and arts organizations, integration of health promotion and social health insurance, organizational reforms, training in advocacy and lobbying, private sector and corporate mobilization and community mobilization. results from the other six areas will be reported in 01..;obcr. conclusions: total quality management, good governance and social mobilization principles and skills are useful and relevant for helping municipal teams focus on strategic interventions to address complex and overwhelming determinants of health at the municipal level. the prolead training programmes hopes to inform other processes for building health promotion leadership capacity for new urban settings. the impact of city living and urbanization on the health of citizens in developing countries has received increasing attention in recent years. urban areas contribute largely to national economies. however, rapid and unplanned urban growth is often associated with poverty, environmental degradation and population demands that outstrip service capacity which conditions place human health at risk. local and national governments as well as multi national organizations are all grappling with the challenges of urbanization. with limited data and information available, urban health characteristics, including the types, quantities, locations and sources in kampala, are largely unknown. moreover, there is n? basis for assessing the impact of the resultant initiatives to improve health ~onditions amo~g ~o":1":1um ties settled in unplanned areas. since urban areas are more than the aggregation ?f ~?pie w~th md_1v1dual risk factors and health care needs, this paper argues that factors beyond the md1v1dual, mcludmg the poster sessions v148 · i d h · i · ment and systems of health and social services are determinants of the health soc1a an p ys1ca environ . of urban populations. however, as part of an ongoing study? ~s pape~ .addresses the basic concerns of urban health in kampala city. while applying the "urban hvmg conditions and the urban heal~ pen· alty" frameworks, this paper use aggregated urban health d~ta t~ explore the role of place an~ 111st1tu· tions in shaping health and well-being of the population m kampala by understanding how characteristics of the urban environment and specific features of the city are causally related to health of invisible and forgotten urban poor population: results i~dica~e that a .range o~ urb~n he~l~h hazards m the city of kampala include substandard housing, crowdmg, mdoor air poll.ut1on, msuff1c1ent a~d con· taminated water, inadequate sanitation and solid waste management services, vector borne .diseases, industrial waste increased motor vehicle traffic among others. the impact of these on the envtronment and community.health are mutually reinforcing. arising out of the withdra"'.al of city pl~nning systems and service delivery systems or just planning failure, thousands of people part1cularl~ low-mc~me groups have been pushed to the most undesirable sections of the city where they are faced with ~ va_r1ety ~f envj· ronmental insults. the number of initiatives to improve urban health is, however, growing mvolvjng the interaction of many sectors (health, environment, housing, energy, transportation and urban planning) and stakeholders (local government, non governmental organizations, aid donors and local community groups). key words: urban health governance, health risks, kampala. introduction: the viability of urban communities is dependent upon reliable and affordable mass transit. in particular, subway systems play an especially important role in the mass transit network, since they provide service to vast numbers of ridersseven of the 95 subway systems worldwide report over one billion passenger rides each year. surprisingly, given the large number of people potentially affected, very little is known about the health and safety hazards that could affect both passengers and transit workers; these include physical (e.g., noise, vibration, accidents, electrified sources, temperature extremes), biological (e.g., transmission of infectious diseases, either through person-to-person spread or vector-borne, for example, through rodents), chemical (e.g., exposure to toxic and irritant chemicals and metals, gas emissions, fumes), electro-magnetic radiation, and psychosocial (e.g., violence, workstress). more recently, we need to consider the threat of terrorism, which could take the form of a mass casualty event (e.g., resulting from conventional incendiary devices), radiological attack (e.g., "dirty bomb"), chemical terrorist attack (e.g., sarin gas), or bioterrorist attack (e.g., weapons grade anthrax). given the large number of riders and workers potentially at risk, the public health implications are considerable. methods: to assess the hazards associated with subways, a structured review of the (english) litera· ture was conducted. ruults: based on our review, non-violent crime, followed by accidents, and violent crimes are most prevalent. compared to all other forms of mass transit, subways present greater health and safety risks. however, the rate of subway associated fatalities is much lower than the fatality rate associated with automobile travel (0.15 vs. 0.87 per 100 million passenger miles), and cities with high subway ridership rates have a 36% lower per capita rate of transportation related fatalities than low ridership cities (7.5 versus 11.7 annual deaths per 100,000 residents). available data also suggest that subway noise levels and levels of air pollutants may exceed recommended levels. . ~: there is a paucity of published research examining the health and safety hazards associated with subways. most of the available data came from government agencies, who rely on passively reported data. research is warranted on this topic for a number of reasons, not only to address important knowled~ gaps, but also because the population at potential risk is large. importantly, from an urban perspecnve, the benefits of mass transit are optimized by high ridership ratesand these could be adversely affu:ted by unsafe conditions and health and safety concerns. veena joshi, jeremy lim. and benjamin chua ~ ~rban health issues have moved beyond infectious diseases and now centre largely on chrome diseases. diabetes is one of the most prevalent non-communicable diseases globally. 9 % of adult ¥151 benefit in providing splash pads in more parks. given the high temperature and humidity of london summers, this is an important aspect and asset of parks. interviewed parents claimed to visit city parks anywhere between 1 to 6 days per week. corrduion: given that the vast majority of canadian children are insufficiently active to gain health benefits, identifying effective qualities of local parks, that may support and foster physical activity is essential. strategies to promote activity within children's environments are an important health initiative. the results from this study have implications for city planners and policy makers; parents' opinions of, and use of city parks provides feedback as to the state current local parks, and modifications that should be made for new ones being developed. this study may also provide important feedback for health promoters trying to advocate for physical activity among children. introdt1clion: a rapidly increasing proportion of urban dwellers in africa live below the poverty line in overcrowded slums characterized by uncollected garbage, unsafe water, and deficient sanitation and overflowing sewers. this growth of urban poverty challenges the commonly held assumption that urban populations enjoy better health than their rural counterparts. the objectives of this study are (i) to compare the vaccination status, and morbidity and mortality outcomes among children in the slums of nairobi with rural kenya, and (ii) to examine the factors associated with poor child health in the slums. we use data from demographic and health survey representative of all slum settlements in nairobi city carried out in 2000 by the african population & health research center. a total of 3,256 women aged 15-49 from 4,564 households were interviewed. our sample consists of 1,210 children aged 0-35 months. the comparison data are from the 1998 kenya demographic and health survey. the outcomes of interest include child vaccination status, morbidity (diarrhea, fever and cough) and mortality, all dichotomized. socioeconomic, environmental, demographic, and behavioral factors, as well as child and mother characteristics, are included in the multivariate analyses. multilevel logistic regression models are used. l'nlimin11ry rest1lts: about 32 % of children in the slums had diarrhea in the two weeks prior to the survey, compared to 16% of rural children. these disparities between the urban poor anj the rural residents are also observed for fever (64% against 42%), cough (46% versus 20%), infant mortality (91/ 1000 against 76/1000), and complete vaccination (48% against 64%). preliminary multivariate results indicate that health service utilization and maternal education have the strongest predictive power on child morbidity and mortality in the slums, and that household wealth has only minor, statistically insignificant effects. conclruion: the superiority of health of urban children, compared with their rural counterparts, masks significant disparities within urban areas. compared to rural residents, children of slum dwellers in nairobi are sicker, are less likely to utilize health services when sick, and stand greater risk to die. our results suggest policies and programs contributing to the attainment of the millennium development goal on child health should pay particular attention to the urban poor. the insignificance of socioeconomic status suggests that poor health outcomes in these communities are compounded by poor environmental sanitation and behavioral factors that could partly be improved through female education and behavior change communication. introduction: historic trade city surat with its industrial and political peace has remained a center of attraction for people from all the comers of india resulting in to pop.ulatio~ explosio~ a~d stressed social and service infrastructure. the topography,dimate and demographic profile of the city 1s threat to the healthy environment. aim of this analysis is to review the impact of managemt'nt reform on health indicators. method: this paper is an analysis of the changing profile of population, sanitary infr~s~rucrure, local self government management and public health service reform, secondary health stat1st1cs data, health indicator and process monitoring of 25 years. . . health of entire city and challenge to the management system. plague outbr~ak (1994) was the turning point in the history of civic service management including p~blic ~e~lth service management. ~ocal self government management system was revitalized by reg~lar_ field v1s1ts o~ al~ cadre~, _decentraltzanon of power and responsibility, equity, regular vigilant momtormg, commumcanon facility, ream_approach and people participation. reform in public health service management was throu_gh stan~~rd1zed intervention protocol, innovative intervention, public private partnership, community part1c1panon, academic and service institute collaboration and research. sanitation service coverage have reached nearer to universal. area covered by safe water supply reached to 98%(2004) from 40% (1991) and underground drainage to 97% (2004) from 17% ( 1991) the overhauling of the system have reflected on health indicators of vector and water born disease. malaria spr declined to 1.23 (2004) from 23.06'yo(!991) and diarrhea case report declined to 1963(2004) from 3431 (2004). except dengue fever in 2002 no major disease outbreaks are reported after 1991. city is recipient of international/national awards/ranking for these achievements. the health department have developed an evidence and experience based intervention and monitoring system and protocol for routine as well as disaster situation. the health service and management structure of surat city have emerged as an urban health model for the country. introduction: the center for healthy communities (chc) in the department of family and com· munity medicine at the medical college of wisconsin developed a pilot project to: 1) assess the know· ledge, attitudes, and behaviors of female milwaukee public housing residents related to breast cancer; 21 develop culturally and literacy appropriate education and screening modules; 3) implement the developed modules; 4) evaluate the modules; and 5) provide follow-up services. using a community-based participatory research model the chc worked collaboratively with on-site nurse case management to meet these objectives. methods: a "breast health kick off event" was held at four separate milwaukee public housing sites for elderly and disabled adults. female residents were invited to complete a 21-item breast health survey, designed to accommodate various literacy levels. responses were anonymous and voluntary. the survey asked women about their previous physical exams for breast health, and then presented a series of state· ments about breast cancer to determine any existing myths. the final part gathered information about personal risk for breast cancer, the highest level of education completed, and whether the respondents h;td ever used hormone replacement therapy and/or consumed alcohol. responses were collected for descriptive analysis. results: a total of 45 surveys (representing 18% of the total female population in the four sites) were completed and analyzed. 89% reported that they had a physical exam in the previous rwo years. 96% of respondents indicated they never had been diagnosed with breast cancer. 85% reported having had a mammogram and 87% having had a clinical breast exam. those that never had a mammogram reported a fear of what the provider would discover or there were not any current breast problems ro warrant an exam. 80% agreed that finding breast cancer early could lower the chance of dying of cancer. over 92% reported that mammograms were helpful in finding cancer. however, 27% believed that hav· ing a mammogram actually prevents breast cancer. 14% indicated that mammograms actually cause cancer and 16% reported that a woman should get a mammogram only if there is breast cancer in her family. conclusion: this survey indicates that current information about the importance of mammograms and clinical breast exams is reaching traditionally underserved women. yet there are still critical oppor· tunities to provide valuable education on breast health. this pilot study can serve as a tool for shaping future studies of health education messages for underserved populations. located in a yourh serv· ~ng agency m downtow~ ottawa, the clinic brings together community partners to provide primary medical care. and dent~i hygiene t? the street youths of ottawa aged 12-20. the primary goal of the project is to provide accessible, coordinated, comprehensive health and dental care to vulnerable adolescents. these efforts respond to the pre-existing body of evidence suggesting that the principle barrier in accessing such care for these youths are feelings of intimidation and vulnerability in the face of a complex healthcare system. the bruyere fhn satellite clinic is located in the basement of a downtown drop-in and brings together a family medicine physician and her residents, a dental hygienist and her 2nd year students, a nurse practitioner, a chiropodist and 2 public health nurses to provide primary care. the clinic has been extremely busy and well received by the youth. this workshop will demonstrate how five community organizations have come together to meet the needs of high risk youths in ottawa. this presentation will showcase the development of the clinic from its inception through its first year including reaction of the youths, partnerships and lessons learned. it will also focus on its sustainability without continued funding. we hope to have developed a model of service delivery that could be reproduced and sustained in other large cities with faculties of medicine. methods: non-randomized, mixed method design involving a process and impact evaluation. data collection-qualitative-a) semi structured interviews with providers & partners b)focus groups with youth quantitative a)electronic medical records for 12 months records (budget, photos, project information). results: 1) successfully built and opened a medicaudental clinic which will celebrate its 1 year anniversary in august. 2) over 140 youths have been seen, and we have had over 300 visits. conclusion: 1) the clinic will continue to operate beyond the 18 month project funding. 2) the health of high risk youth in ottawa will continue to improve due to increased access to medical services. p7-11 (a) health services -for the citizens of bangalore -past, present and future savita sathyagala, girish rao, thandavamurthy shetty, and subhash chandra bangalore city, the capital of karnataka with 6.5 million is the 6th most populous city in india; supporting 30% of the urban population of karnataka, it is considered as one of the fastest growing cities in india. known as the 'silicon valley of india', bangalore is nearly 500 years old. bangalore city corporation (bmp), is a local self government and has the statutory commitment to provide to the citizens of bangalore: good roads, sanitation, street lighting, safe drinking water apart from other social obligations, cultural development and poverty alleviation activities. providing preventive and promotive heahh services is also a specific component. the objective of this study was to review the planning process with respect to health care services in the period since india independence; the specific research questions being what has been the strategies adopted by the city planners to address to the growing needs of the population amidst the background of the different strategies adopted by the country as a whole. three broad rime ranges have been considered for analysis: the 1950s, 1970s and the 1990s. the salient results are: major area of focus has been on the maternal and child care with activities ranging from day-care to in-patient-care; though the number of institutions have grown from 5 to the current day 79, their distribution has been far from satisfactory; obtaining support from the india population projects 3 and 8 major upgradarions have been undertaken in terms of infrastructure; over the years, in addition to the dispensaries of modern system of medicine, local traditional systems have also been initiated; the city has partnered with the healthy cities campaign with mixed success; disease surveillance, addressing the problems related to the emerging non-communicable diseases including mental health and road traffic injuries are still in its infancy. isolated attempts have been made to address the risks groups of elderly care and adolescent care. what stands out remarkably amongst the cities achievements is its ability to elicit participation from ngos, cbos and neighbourhood groups. however, the harnessing of this ability into the health sector cannot be said totally successful. the moot question in all the above observed development are: has the city rationally addressed it planning needs? the progress made so far can be considered as stuttered. the analysis and its presentation would identify the key posirive elements in the growth of banglore city and spell a framework for the new public health. introduction: anaemia associated with pregnancy is a major public health problem all over the world. different studies in different parts of india shown prevalence of anaemia between 60-90%. anaemia remains a serious health problem in pregnancy despite of strong action taken by the government of india through national programmes. in the present study we identified th~ social beha~iors, responsible for low compliance of if a tablets consumption in pregnancy at community level and intervention was given with new modified behaviors on trial bases. . in vadodara urban. 60 anganwadies out of 289 were selected from the list by random sampling for tips (trials of improved practices) study. . . participants: 266 pregnant women (132, intervention group+ 134, control. group) registered m the above 60 anganwadies. study was conducted in to three phases: phase: 1. formative research and baseline survey (frbs). data was collected from all 266 pregnant women to identify behaviors that are responsible for low compliance of ifa tablets. both qualitative and quantitative data were collected. haemoglobin was estimated of all pregnant women by haemo-cue. phase: 2. phase of tips. behaviors were identified both social & clinical for low compliance of ifa tablets consumption in pregnancy from frbs and against those, modified behaviors were proposed to pregnant women in the intervention group on trial bases by health education. trial period of 6 weeks was given for trial of new behaviors to pregnant women in the interven· tion group. phase: 3. in this phase, feedbacks on behaviors tried or not tried were taken from pregnant women in intervention group. haemoglobin estimation was carried out again in all 266 pregnant women. at the end of the study, messages were formulated on the bases of feedbacks from the pregnant women. results: all pregnant women in the intervention group had given positive feedback on new modified behaviors after intervention. mean haemoglobin concentration was higher in intervention group (10.04±0.11 gm%) than control group (9.60±0.14 gm%). ifa tablets compliance was improved in intervention group (95.6%) than control group (78.6%). conclusion: all pregnant women got benefits after trial of new modified behaviors in the intervention group. messages were formulated from the new modified behaviors, which can be used for longterm strategies for anaemia control in the community. introduction: in order to develop a comprehensive mch handbook for pregnant women and to assess its effect among them, a pilot study was carried out at the maternal and child health training institute (mchti), in dhaka, bangladesh. methods: from mchti a sample of 600 pregnant women was selected and all subjects were women who were attending the first visit of their current pregnancy by using a random sampling method. of the 600 subjects, 240 women were given the mch handbook as case and 360 women were not given the handbook as control. data on pre and post intervention of the handbook from the 240 cases and 360 controls were taken from data recording forms between the 1st of november 2002 and 31st of october, 2003 and data was analysed by using a multilevel analysis approach. this was a hospital-based action (case-control) research, and was applied in order to measure the outcome of pre and post intervention following the introduction of the handbook. data was used to assess the effects of utilisation of the handbook on women's knowledge, practice and utilisation of mch services. results: this study showed that the change of knowledge about antenatal care visits was 77.1% among case mothers. knowledge of danger signs improved 49.2 %, breast feeding results 31.5%, vaccination 32.0% and family planning results improved 60.3% among case. results showed some positive changes in women's attitudes among case mothers and study showed the change of practice in antenatal care visits was .u.5% in the case. other notable changes were: change of practice in case mother's tetanus toxoid (ti), 55.2%; and family planning 41.2%. in addition, handbook assessment study indicated that most women brought the handbook on subsequent visits (83.3%), the handbook was highly utilised (i.e. it was read by 84.2%, filled-in by 76.1 %, and was used as a health education tool by 80.4%). most women kept the handbook (99.5%) and found it highly useful (78.0%) with a high client satisfaction rate of 88.0%. conclusion: pregnant women in the case group had higher knowledge, better practices, and higher utilisation of mch services than mothers in the control groups who used alternative health cards. if the handbook is developed with a focus on utilising a problem-oriented approach and involving the recomendations .of end~users, it is anticipated that the mch handbook will contribute significantly to ensuring the quahry of hfe of women and their children in bangladesh. after several meetmgs to identify the needs of the community, a faso clinic was opened at ncfs. health care professionals from smh joined with developmental and social service workers from ncfs to implement the faso diagnostic process and to provide culturally appropriate after-care. the clinic is unique in that its focus is the high risk urban aboriginal population of toronto. it accepts referrals of not only children and youth, but also of adults. lessons learned: response to the faso clinic at native child and family services has been overwhelming. aboriginal children with f asd are receiving timely diagnosis and interventions. aboriginal youth and adults who have been struggling with poveny, substance abuse, and homelessness are more willing to enter the ncfs centre for diagnosis and treatment. aboriginal infants prenatally exposed to alcohol born at st. michael's hospital or referred by other centres have access to the developmental programs located in both of the partnering agencies. the presentation will describe the clinic's development, and will detail the outcomes described, including interventions unique to the aboriginal culture. p7-15 (c) seeds, soil, and stories: an exploration of community gardening in southeast toronto carolin taran, sarah wakefield, jennifer reynolds, and fiona yeudall introduction: community gardens are increasingly seen as a mechanism for improving nutrition and increasing food security in urban neighbourhoods, but the evidence available to support these claims is limited. in order to begin to address this gap in a way that is respectful of community knowledge and needs, the urban gardening research opportunities workgroup (ugrow) project explored the benefits and potential risks of community gardening in southeast toronto. the project used a community-based research (cbr) model to assess community gardens as a means of improving local health. the research process included interviews, focus groups, and participant observation (documented in field notes). we also directly engaged the community in the research process, through co-learning activities and community events which allowed participants to express their views and comment on emerging results. most of the research was conducted by a community-based research associate, herself a community gardener. key results were derived from these various sources through line-by-line coding of interview transcripts and field note review, an interactive and iterative process which involved both academic and community partners. results: these various data sources all suggest that enhanced health and access to fresh produce are important components of the gardening experience. they also highlight the central importance of empowering and community-building aspects of gardening to gardeners. community gardens were thought to play a role in developing friendships and social support, sharing food and other resources, appreciating cultural diversity, learning together, enhancing local place attachment and stewardship, and mobilizing to solve local problems (both inside and outside the garden). potential challenges to community gardens as a mechanism for communiry development include bureaucratic resistance to gardens, insecure land tenure and access, concerns about soil contamination, and a lack of awareness and under· standing by community members and decision-makers of all kinds. conclusion: the results highlight many health and broader social benefits experienced by commu· nity gardeners. they also point to the need for greater support for community gardening programs, par· ticularly ongoing the ongoing provision of resources and education programs to support gardens in their many roles. this research project is supported by the wellesley central health corporation and the centre for urban health initiatives, a cihr funded centre for research development hased at the univer· sity of toronto. p7-16 (c) developing resiliency in children living in disadvantaged neighbourhoods sarah farrell, lorna weigand, and wayne hammond the traditional idea of targeting risk reduction by focusing on the development of eff~ctive coping strategies and educational programs has merit in light of the research reportmg_ that_ ~10lupl.e forms of problem behaviour consistently appear to be predicted by increasing exposure to 1den_uf1able risk factors. as a result, many of the disadvantaged child and youth studies have focused on trymg to better _unde.r· stand the multiple risk factors that increase the likelihood of the development of at nsk behaviour m ch1ldren/youth and the potential implications for prevention. this in turn has led t_o. the conclus1on that community and health programs need to focus on risk reduction by helpm~ md1v1duals develop more effective coping strategies and a better understanding of the limitations of cenam pathologies, problematic v156 poster sessions coping behaviours and risk factors potentially inheren~ in high needs co~unities. ~owever, another ai:ea of research has proposed that preventative interventions should cons1de~ .~rotecnve fa~ors alo~~ with reducing risk factors. as opposed to just emphasizing problems, vulnerab1ht1es, and deficits, a res1liencybased perspective holds the belief that children, youth and their families. have strengths, reso~ce.s and the ability to cope with significant adversity in ways that are not only effective, but tend to result m mcreased ability to constructively respond to future adversity. with this in mind, a participatory research project sponsored by the united way of greater toronto was initiated to evaluate and determine the resiliency profiles of children 8 -12 years (n = 500) of recent immigrant families living in significantly disadvantaged communities in the toronto area. the presentation will provide an overview of the identified protective factors (both intrinsic and extrinsic) and resiliency profiles in an aggregated format as well as a summary of how the children and their parents interpreted and explained these strength-based results. as part of the focus groups, current community programs and services were examined by the participants as to what might be best practices for supporting the development and maintaining of resiliency in children, families and communities. it was proposed that the community model of assessing resiliency and protective factors as well as proposed best strength-based practice could serve as a guide for all in the community sector who provide services and programs to those in disadvantaged neighbourhoods. p7-17 (c) naloxone by prescription in san francisco, ca and new york, ny emalie huriaux the harm reduction coalition's overdose project works to reduce the number of fatal overdoses to zero. located in new york, ny and san francisco, ca, the overdose project provides overdose education for social service providers, single-room occupancy hotel (sro) residents, and syringe exchange participants. the project also conducts an innovative naloxone prescription program, providing naloxone, an opiate antagonist traditionally administered by paramedics to temporarily reverse the effects of opiate overdose, to injection drug users (idus). we will describe how naloxone distribution became a reality in new york and san francisco, how the project works, and our results. the naloxone prescription program utilizes multiple models to reach idus, including sro-and street-based trainings, and office-based trainings at syringe exchange sites. trainings include information on overdose prevention, recognition, and response. a clinician conducts a medical intake with participants and provides them with pre-filled units of naloxone. in new york, funding was initially provided by tides foundation. new york city council provides current funding. new york department of mental health and hygiene provides program oversight. while the new york project was initiated in june 2004, over half the trainings have been since march 2005. in san francisco, california endowment, tides foundation, and san francisco department of public health (sfdph) provide funding. in addition, sfdph purchases naloxone and provides clinicians who conduct medical intakes with participants. trainings have been conducted since november 2003. to date, nearly 1000 individuals have been trained and provided with naloxone. approximately 130 of them have returned for refills and reported that they used naloxone to reverse an opiate-related overdose. limited episodes of adverse effects have been reported, including vomiting, seizure, and "loss of friendship." in new york, 400 individuals have been trained and provided with naloxone. over 30 overdose reversals have been reported. over half of the participants in new york have been trained in the south bronx, the area of new york with the highest rate of overdose fatalities. in san francisco, 570 individuals have been trained and provided with naloxone. over 96 overdose reversals have been reported. the majority of the participants in san francisco have been trained in the tenderloin, 6th street corridor, and mission, areas with the highest rates of overdose fatalities. the experience of the overdose project in both cities indicates that providing idus low-threshold access to naloxone and overdose information is a cost-effective, efficient, and safe intervention to prevent accidental death in this population. p7-18 (c) successful strategies to regulate nuisance liquor stores using community mobilization, law enforcement, city council, merchants and researchers tahra goraya presenta~ion _will discuss ~uccessful environmental and public policy strategies employed in one southen:1 cahf?rmna commumty to remedy problems associated with nuisance liquor stores. participants ~111 be given tools to understand the importance of utilizing various substance abuse prevention str~tegi~ to change local policies and the importance of involving various sectors in the community to a~_1st with and advocate for community-wide policy changes. recent policy successes from the commultles of pa~ad~na and altad~na will highlight the collaborative process by which the community mobilized resulnng m several ordmances, how local law enforcement was given more authority to monitor poster sessions v157 nonconforming liquor stores, how collaborative efforts with liquor store owners helped to remove high alcohol content alcohol products from their establishments and how a community-based organiz,uion worked with local legislators to introduce statewide legislation regarding the regulation of nuisance liquor outlets. p7-19 (c) "dialogue on sex and life": a reliable health promotion tool among street-involved youth beth hayhoe and tracey methven introduction: street involved youth are a marginalized population that participate in extremely risky behaviours and have multiple health issues. unfortunately, because of previous abuses and negative experiences, they also have an extreme distrust of the adults who could help them. in 1999, toronto public health granted funding to a non governmental, nor for profit drop-in centre for street youth aged 16-24, to educate them about how to decrease rhe risk of acquiring hiv. since then the funding has been renewed yearly and the program has evolved as needed in order to target the maximum number of youth and provide them with vital information in a candid and enjoyable atmosphere. methods: using a retrospective analysis of the six years of data gathered from the "dialogue on sex and life" program, the researchers examined the number of youth involved, the kinds of things discussed, and the number of youth trained as peer leaders. also reviewed, was written feedback from the weekly logs, and anecdotal outcomes noted by the facilitators and other staff in the organization. results: over the five year period of this program, many of youth have participated in one hour sessions of candid discussion regarding a wide range of topics including sexual health, drug use, harm reduction, relationship issues, parenting, street culture, safety and life skills. many were new youth who had not participated in the program before and were often new to the street. some of the youth were given specific training regarding facilitation skills, sexual anatomy and physiology, birth control, sexually transmitted infections, hiv, substance use/abuse, harm reduction, relationships and discussion of their next steps/future plans following completion of the training. feedback has been overwhelmingly positive and stories of life changing decisions have been reported. conclusion: clearly, this program is a successful tool to reach street involved youth who may otherwise be wary of adults and their beliefs. based on data from the evaluation, recommendations have been made to public health to expand the funding and the training for peer leaders in order ro target between 100-200 new youth per year, increase the total numbers of youth reached and to increase the level of knowledge among the peer leaders. p7-20 (c) access to identification and services jane kali replacing identification has become increasingly more complex as rhe government identification issuing offices introduce new requirements rhar create significant barriers for homeless people to replace their id. new forms of identification have also been introduced that art' not accessible to homekss peoplt-(e.g. the permanent resident card). ar rhe same time, many service providers continue to require identifi· cation ro access supports such as income, housing, food, health care, employment and employmt·nt training programs. street health, as well as a number of other agencies and community health centres, h,1, been assisting with identification replacement for homeless peoplt· for a number of years. the rnrrt·nr challenges inherent within new replacement requirements, as well as the introduction of new forn1' of identification, have resulted in further barriers homeless people encounter when rrring to access t:ssential services. street health has been highlighting these issues to government identification issuing offices, as well as policy makers, in an effort to ensure rhar people who are homeless and marginalized have ac'ess to needed essential services. bandar is a somali word for •·a safe place." the bandar research project is the product of the regent park community health centre. the research looks ar the increasing number of somali and afri· can men in the homeless and precariously house population in the inner city core of down~own toronto. in the first phase of the pilot project, a needs assessment was conducted to 1dennfy barners and issues faced by rhe somali and other african men who are homeless and have add1cr10ns issues. th_e second phase of rhe research project was to identify long rerm resources and service delivery mechamsms that v158 poster sessions would enhance the abiity of this population to better access detox, treatment, and post treatment ser· vices. the final phase of the project was to facilitate the development of a conceptual model of seamless continual services and supports from the streets to detox to treatment to long term rehabilitation to housing. "between the pestle and mortar" -safe place. p7-22 (c) successful methods for studying transient populations while improving public health beth hayhoe, ruth ewert, eileen mcmahon, and dan jang introduction: street youth are a group that do not regularly access healthcare because of their mis· trust of adults. when they do access health care, it is usually for issues severe enough for hospitalization or for episodic care in community clinics. health promotion and illness prevention is rarely a part of their thinking. thus, standard public health measures implemented in a more stable population do not work in this group. for example, pap tests, which have dearly been shown to decrease prevalence of cer· vical cancer, are rarely done and when they are, rarely followed up. methods to meet the health care needs and increase the health of this population are frequently being sought. methods: a drop-in centre for street youth in canada has participated in several studies investigating sexual health in both men and women. we required the sponsoring agencies to pay the youth for their rime, even though the testing they were undergoing was necessary according to public health stan· dards. we surmised that this would increase both initial participation and return. results: many results requiring intervention have been detected. given the transient nature of this population, return rates have been encouraging so far. conclusion: it seems evident that even a small incentive for this population increases participation in needed health examinations and studies. it is possible that matching the initial and follow-up incentives would increase the return rate even further. the fact that the youth were recruited on site, and not from any external advertising, indicates that studies done where youth trust the staff, are more likely to be successful. the presentation will share the results of the "empowering stroke prevention project" which incor· porated self-help mutual aids strategies as a health promotion methodology. the presentation will include project's theoretical basis, methodology, outcomes and evaluation results. self-help methodology has proven successful in consumer involvement and behaviour modification in "at risk," "marginalized" settings. self-help is a process of learning with and from each other which provides participants oppor· tunities for support in dealing with a problem, issue, condition or need. self-help groups are mechanisms for the participants to investigate existing solutions and discover alternatives, empowering themselves in this process. learning dynamic in self-help groups is similar to that of cooperative learning and peertraining, has proven successful, effective and efficient (haller et al, 2000) . the mutual support provided by participation in these groups is documented as contributory factor in the improved health of those involved. cognizant of the above theoretical basis, in 2004 the self-help resource centre initiated the "empowering stroke prevention project." the project was implemented after the input from 32 health organizations, a scan of more than 300 resources and an in-depth analysis of 52 risk-factor-specific stroke prevention materials indicated the need for such a program. the project objectives were:• to develop a holistic and empowering health promotion model for stroke prevention that incorporates selfhelp and peer support strategies. • to develop educational materials that place modifiable risk factors and lifestyle information in a relevant context that validates project participants' life experiences and perspectives.• to educate members of at-risk communities about the modifiable risk factors associated with stroke, and promote healthy living. to achieve the above, a diverse group of community members were engaged as "co-editors" in the development of stroke prevention education materials which reflected and validated their life experiences. these community members received training to become lay health promoters (trained volunteer peer facilitators). in collaboration with local health organizations, these trained lay health promoters were then supported in organizing their own community-based stroke prevention activities. in addition, an educational booklet written in plain language, entitled healthy ways to prevent stroke: a guide for you, and a companion guide called healthy ways to pre· vent stroke: a facilitator's guide were produced. the presentation will include the results of a tw<>tiered evaluation of the program methodology, educational materials and the use of the materials beyond the life of the project. this poster presentation will focus on the development and structure of an innovative street outreach service that assists individuals who struggle mental illness/addictions and are experiencing homelessness. the mental health/outreach team at public health and community services (phcs) of hamilton, ontario assists individuals in reconnecting with health and social services. each worker brings to the ream his or her own skills-set, rendering it extremely effective at addressing the multidimensional and complex needs of clients. using a capacity building framework, each ream member is employed under a service contract between public health and community services and a local grassroots agency. there are public health nurses (phn), two of whom run a street health centre and one of canada's oldest and most successful needle exchange programs, mental health workers, housing specialists, a harm reduction worker, youth workers, and a united church minister, to name a few. a community advisory board, composed of consumers and professionals, advises the program quarterly. the program is featured on raising the roors 'shared learnings on homelessness' website at www.sharedlearnings.ca. through our poster presentation participants will learn how to create effective partnerships between government and grassroots agencies using a capacity building model that builds on existing programs. this study aims to assess the effects of broadcasting a series of documentary and drama videos, intended to provide information about the bc healthguide program in farsi, on the awareness about and the patterns of the service usage among farsi-speaking communities in the greater vancouver area. the major goals of the present study were twofold; ( 1) to compare two methods of communications (direct vs. indirect messages) on the attitudes and perceptions of the viewers regarding the credibility of messengers and the relevance of the information provided in the videos, and (2) to compare and contrast the impact of providing health information (i.e., the produced videos) via local tvs with the same materials when presented in group sessions (using vcr) on participants' attitudes and perceptions cowards the bc healrhguide services. results: through a telephone survey, 545 farsi-speaking adults were interviewed in november and december 2004. the preliminary findings show that 53% of the participants had seen the aired videos, from which, 51 % watched at least one of the 'drama' clips, 8% watched only 'documentary' clip, and 41% watched both types of video. in addition, 27% of the respondents claimed that they were aware about the program before watching the aired videos, while 73% said they leaned about the services only after watching the videos. from this group, 14% said they called the bchg for their own or their "hildren's health problems in the past month. 86% also indicated that they would use the services in the future whenever it would be needed. 48% considered the videos as "very good" and thought they rnuld deliver relevant messages and 21 % expressed their wish to increase the variety of subjects (produ\:e more videos) and increase the frequency of video dips. conclusion: the results of this study will assist public health specialists in bc who want to choose the best medium for disseminating information and apply communication interventions in multi\:ultural communities. introduction: many theorists and practitioners in community-based research (cbr) and knowledge transfer (kt) strongly advocate for involvement of potential users of research in the development of research projects, yet few examples of such involvement exist for urban workplace health interventions. we describe the process of developing a collaborative research program. methods: four different sets of stakeholders were identified as potential contributors to and users of the research: workplace health policy makers, employers, trade unions, and health and safety associations. representatives of these stakeholders formed an advisory committee which met quarterly. over the 13 month research development period, an additional 21 meetings were held between resc:ar~h~rs and stakeholders. in keeping with participant observation approaches, field notes of group and md1v1~ ual meetings were kept by the two co-authors. emails and telephone calls were also documented. qu~h tative approaches to textual analysis were used, with particular attention paid to collaborattve v160 poster sessions relationships established (as per cbr), indicators of stakeholders' knowledge utilization (as per kt), and transformations of the proposed research (as per cbr). results: despite initial strong differences of opinion both among stakeho~ders .an~ between stakeholders and researchers, goodwill was noted among all involved. acts of rec~proc1ty included mu.rual sharing of assessment tools, guidance on data utilization to stakeho~der orga~1zat10ns, and suggestions on workplace recruitment to researchers. stakeholders demonstrated mcreases m concep~ual. un~erstand ing of workplace health e.g. they more commonly discussed more complex,. psychosocial md1cators of organizational health. stakeholders made instrumental use of shared materials based on research e.g. adapting their consulting model to more sophisticated dat~ analysis. sta~ehol?~rs recogni_zed the strategic use of their alliance with researchers e.g., transformational leadership trainmg as a~ inducement to improve health and safety among small service franchises. stakeholders helped re-define the research questions, dramatically changed the method of recruitment from researcher cold call to stakeholderbased recruitment, and strongly influenced pilot research designs. owing a great deal to the elaborate joint development process, the four collaboratively developed pilot project submissions which were all successfully funded. conclusion: the intensive process of collaborative development of a research program among stakeholders and researchers was not a smooth process and was time consuming. nevertheless, the result of the collaborative process was a set of projects that were more responsive to stakeholder needs, more feasible for implementation, and more broadly applicable to relevant workplace health problems. introduction: environmental groups, municipal public health authorities and, increasingly, the general public are advocating for reductions in pesticide use in urban areas, primarily because of concern around potential adverse health impacts in vulnerable populations. however, limited evidence of the relative merits of different intervention strategies in different contexts exists. in a pilot research project, we sought to explore the options for evaluating pesticide reduction interventions across ontario municipalities. methods: the project team and a multi-stakeholder project advisory committee (pac), generated a list of potential key informants (kl) and an open ended interview guide. thirteen ki from municipal government, industry, health care, and environmental organizations completed face to face or telephone interviews lasting 30-40 minutes. in a parallel process, a workshop involving similar representatives and health researchers was held to discuss the role of pesticide exposure monitoring. minutes from pac meetings, field notes taken during ki interviews, and workshop proceedings were synthesized to generate potential evaluation methods and indicators. results: current evaluation activities were limited but all kls supported greater evaluation effons beginning with fuller indicator monitoring. indicators of education and outreach services were imponant for industry representatives changing applicator practices as well as most public health units and environmental organizations. lndictors based on bylaw enforcement were only applicable in the two cities with bylaws, though changing attitudes toward legal approaches were being assessed in many communities. the public health rapid risk factor surveillance system could use historical baseline data to assess changes in community behaviour through reported pesticide uses and practices, though it had limited penetration in immigrant communities not comfortable in english. pesticide sales (economic) data were only available in regional aggregates not useful for city specific change documentation. testing for watercourse or environmental contamination might be helpful, but it is sporadic and expensive. human exposure monitoring was fraught with ethical issues, floor effects from low levels of exposure, and prohibitive costs. clinical episodes of pesticide exposure reported to the regional poison centre (all ages) or the mother risk program (pregnant or breastfeeding women) are likely substantial underestimates that would be need to be supplemented with sentinel practice surveillance. focus on special clinical populations e.g., multiple chemical sensitivity would require additional data collection efforts . . conc~ons: broad support for evaluation and multiple indicators were proposed, though con-s~raints associate~ with access, coverage, sensitivity and feasibility were all raised, demonstrating the difficulty of evaluating such urban primary prevention initiatives. interventionists. an important aim of the youth monitor is to learn more about the health development of children and adolescents and the factors that can influence this development. special attention is paid to emo· tional and behavioural problems. the youth monitor identifies high-risk groups and factors that are associated with health problems. at various stages, the youth monitor chancrs the course of life of a child. the sources of informa· tion and methods of research are different for each age group. the results arc used to generate various kinds of repons: for children and young persons, parents, schools, neighbourhoods, boroughs and the municipality of rotterdam and its environs. any problems can be spotted early, at borough and neigh· bourhood level, based on the type of school or among the young persons and children themselves. together with schools, parents, youngsters and various organisations in the area, the municipal health service aims to really address these problems. on request, an overview is offered of potentially suitable interventions. the authors will present the philosophy, working method, preliminary effects and future developments of this instrument, which serves as the backbone for the rotterdam local youth policy. social workers to be leaders in response to aging urban populations: the practicum partnership program sarah sisco, alissa yarkony, and patricia volland 1"'"1tliu:tion: across the us, 77.5% of those over 65 live in urban areas. these aging urban popu· lations, including the baby boomers, have already begun encounter a range of heahh and mental hcahh conditions. to compound these effects, health and social service delivery fluciuates in cities, whit:h arc increasingly diverse both in their recipients and their systems. common to other disciplines (medicine, nursing, psychology, etc.) the social work profession faces a shortage of workers who are well-equipped to navigate the many systems, services, and requisite care that this vast population requires. in the next two decades, it is projected that nearly 70,000 social workers will be required to provide suppon to our older urban populations. social workers must be prepared to be aging-savvy leaders in their field, whether they specialize in gerontology or work across the life span. mllhotu: in 2000, a study conducted at the new york academy of medicine d<>1:umcntcd the need for improved synchroniciry in two aspects of social work education, classroom instruction and the field experience. with suppon from the john a. hanford foundation, our team created a pilot proj~"t entitled the practicum pannership program (ppp) in 11 master's level schools of social work, to improvt" aginr exposure in field and classroom content through use of the following: i) community-university partnrr· ships, 2) increased, diverse student field rotations, ll infusion of competcn1."}'·drivm coursework, 41 enhancement of field instructors' roles, and 5) concentrated student recruitment. we conductt"d a prr· and post-test survey into students' knowledge, skills. and satisfaction. icarlja: surveys of over 400 graduates and field inltnk."tors rcflected increased numlk-n of .1rrm:y· univmity panncrships, as well as in students placed in aging agencin for field placements. there wa1 11 marked increase in student commitments to an aging specialization. onr year por.t·gradu:nion rcvealrd that 93% of those surveyed were gainfully employed, with 80% employed in the field of aginic. by com· bining curricular enhancement with real-world experiences the ppp instilled a broad exposurr for llu· dents who worked with aging populations in multiple urban settings. coltdtuion: increased exposure to a range of levels of practicr, including clinical, policy/ajvocaq, and community-based can potentially improve service delivery for older adulh who live in elfin, and potentially improve national policy. the hanford foundation has now elected to 1uppon cxpantion of the ppp to 60 schools nationwide (urban and rural) to complement other domntic initiatives to cnhalk"c" holistic services for older adults across the aging spectrum. bodrgnn.ntl: we arc a team of rcscarcbcn and community panncn working tcj8c(her to develop an in"itepth understanding of the mental health needs of homeless youth ~ages 16 to 24) (using qualiutivc and quantitative methods 8' panicipatory rncarch methods). it is readily apparmt that '-neless youth cxpcricnce a range of mental health problems. for youth living on the street, menul illnew may be either a major risk factor for homelessnal or may frequently emcsge in response to coping with rhe multitudinous stressors associated with homclcslllcsi including exposure to violence, prasutt to pamaplte in v162 poster sessions survival sex and/or drug use. the most frequent psychiatric diagnoses amongst the homeless gencrally include: depression, anxiety and psychosis. . . . the ultimate ob1ective of the pr~am of rei:e~ is to ~evelop a plan for intervention to meet the mental health needs of street youth. prior t_o pl~nnmg mtervenbons, .it is necessary to undertake a comprehensive assessment ~f mental health needs m this ~lnerable populanon. thus, the immediate objective of this research study is to undertake a comprehensive assessment of men· tal health needs. . . melbotlology: a mixed methodology triangulating qualitative, participatory acnon and quantitative methods will capture the data related to mental health needs of homeless youth. a purposive sample of approximately 60-80 subjecrs. ages 16 to 24, is currently being ~ted ~participate from the commu.nity agencies covenant house, evergreen centre fo~ srrc;et youth, turning p?1?t and street ~ serv~. youth living on the street or in short -term residennal programs for a mmimum of 1 month pnor to their participation; ages 16 to 24 and able to give infonned consent will be invited to participate in the study. o..tcomes: the expected outcome of this initial survey will be an increased understanding of mental health needs of street youth that will be used to develop effective interventions. it is anticipated that results from this study will contribute to the development of mental health policy, as well as future programs that are relevant to the mental health needs of street youth. note: it is anticipated that preliminary quantitative data (25 subjects) and qualitative data will be available for the conference. the authors intend to present the identification of the research focus, the formation of our community-based team, relevance for policy, as well as preliminary results. p7-31 (a) the need for developing a firm health policy for urban informal worken: the case of despite their critical role in producing food for urban in kenya, urban farmers have largely been ignored by government planners and policymakers. their activity is at best dismissed as peripheral eveo, inappropriate retention of peasant culture in cities and at worst illegal and often some-times criminal· ized. urban agriculture is also condemned for its presumed negative health impact. a myth that contin· ues despite proof to the contrary is that malarial mosquitoes breed in maize grown in east african towns. however, potential health risks are insignificant compared with the benefits of urban food production. recent studies too rightly do point to the commercial value of food produced in the urban area while underscoring the importance of urban farming as a survival strategy among the urban poor, especially women-headed households. since the millennium declaration, health has emerged as one of the most serious casualties consequent on the poverty, social exclusion, marginalisation and lack of sustain· able development in africa. hiv/aids epidemic poses an unprecedented challenge, while malaria, tuber· culosis, communicable diseases of childhood all add to the untenable burden. malnutrition underpins much ill-health and is linked to more than 50 per cent of all childhood deaths. kenya's urban poor people ~ace ~ h~ge burde~ of preventable and treatable health problems, measured by any social and bi~ medical md1cator, which not only cause unnecessary death and suffering, but also undermine econonuc development and damage the country's social fabric. the burden is in spite of the availability of suitable tools and re:c=hnology for prevention and treatment and is largely rooted in poverty and in weak healah •rstems. this pa~ therefore challenges development planners who perceive a dichotomy instead of con· tmuum between informal and formal urban wage earners in so far as access to health services is con· cemed. it i~ this gap that calls for a need to developing and building sustainable health systems among the urban mformal ~wellers. we recommend a focus on an urban health policy that can build and strengthen the capacity of urban dwellers to access health services that is cost-effective and sustainable. such ~ health poli<=>: must strive for equity for the urban poor, displaced or marginalized; mobilise and effect1~ely use sufficient sustainable resources in order to build secure health systems and services. special anenti_on. should ~ afforded hiv/aids in view of the unprecedented challenge that this epidemic poses to africa s economic and social development and to health services on the continent. methods: a review of the literature led us to construct three simple models and a composite model of exposure to traffic. the data were collected with the help of a daily diary of travel activities using a sample of cyclists who went to or come back from work or study. to calculate the distance, the length of journey, and the number of intersections crossed by a cyclist different geographic information systems (gis) were operated. statistical analysis was used to determine the significance between a measure of exposure on the one hand, and the sociodemographic characteristics of the panicipants or their geographic location on the other hand. restlltj: our results indicate that cyclists were significantly exposed to road accidents, no matter of where they live or what are their sociodemographic characteristics. we also stress the point that the fact of having been involved in a road accident was significantly related to the helmet use, but did not reduce the propensity of the cyclists to expose themselves to the road hazards. condlllion: the efforts of the various authorities as regards road safety should not be directed towards the reduction of the exposure of the vulnerable users, but rather towards the reduction of the dangers to which they could face. keywords: cyclist, daily diary of activities, measures of exposure to traffic, island of montreal. p7-33 (a) intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods olumuyiwa akinbamijo intra urban disparities and environmental health: some salient features of nigerian residential neighbourhoods abstract urbanization panicularly in nigerian cities, ponends unprecedented crises of grave dimensions. from physical and demographic viewpoints, city growth rates are staggering coupled with gross inabilities to cope with the consequences. environmental and social ills associated with unguarded rapid urbanization characterize nigerian cities and threaten urban existence. this paper repons the findings of a recent study of the relationship between environmental health across inrraurban residential communities of akure, south west nigeria. it discuses the typical urbanization process of nigerian cities and its dynamic spatial-temporal characteristics. physical and socio-demographic attributes as well as the levels and effectiveness of urban infrastructural services are examined across the core residential districts and the elite residential layouts in the town. the incidence rate of cenain environmentally induced tropical diseases across residential neighborhoods and communes is examined. salient environmental variables that are germane to health procurement in the residential districts, incidence of diseases and diseases parasitology, diseases prevention and control were studied. field data were subjected to analysis ranging from the univariate and bivariate analysis. inferential statistics using the chi-square test were done to establish the truthfulness of the guiding hypothesis. given the above, the study affirms that there is strong independence in the studied communities, between the environment and incidence of diseases hence health of residents of the town. this assertion, tested statistically at the district levels revealed that residents of the core districts have very strong independence between the environment and incidences of diseases. the strength of this relationship however thins out towards the city peripheral districts. the study therefore concludes that since most of the city dwellers live in urban deprivation, urban health sensitive policies must be evolved. this is to cater for the urban dwellers who occupy fringe peripheral sites where the extension of facilities often times are illegally done. urban infrastructural facilities and services need be provided as a matter of public good for which there is no exclusive consumption or access even for the poorest of the urban poor. many suffer from low-self esteem, shame and guilt about their drug use. in addition, they often lack suppon or encounter opposition from their panners, family and friends in seeking treatment. these personal barriers are compounded by fragmented addiction, prenatal and social care services, inflexible intake systems and poor communication among sectors. the experience of accessing adequate care between services can be overwhelming and too demanding. the toronto centre for substance use in pregnancy (t-cup) is a unique program developed to minimize barriers by providing kone-stop" comprehensive healthcare. t-cup is a primary care based program located in the department of family medicine at st. joseph\'s health centre, a community teaching hospital in toronto. the interdisciplinary staff provides prenatal and addiction services, case management, as well as care of newborns affected by substance use. regular care plan meetings are held between t-cup, labour and delivery nurses and social workers in the y164 poster sessions maternity and child care program. t-cup also connects "'.omen with. inpatient treatment programs and community agencies such as breaking the cycle, an on-site counselmg group for pregnant substance users. · f · d d h ith method: retrospective chart review, qualitative patient ~ans action stu ~· an ea care provider surveys are used to determine outcomes. primary outcomes mclude changes m maternal su~tance use, psychosocial status and obstetrical complications (e.g. pre-rupture of membrane, pre-eclampsia, placen· ral abruption and hemorrhage). neonatal measures ~~nsisted of .bir~h pa_rame~ers, length of h~spital st.ay and complications (e.g. feral distress, meconium stammg, resuscitation, 1aund1ce, hypoglycemia, seventy of withdrawal and treatment length). chart review consisted of all t-cup patients who met clinical cri· reria for alcohol or drug dependence and received prenatal and intra-partum care at st. joseph's from october 2003 to june 2005. participants in the qualitative study included former and current t-cup patients. provider surveys were distributed on-site and to a local community hospital. raulb: preliminary evaluation has demonstrated positive results. treatment retention and satisfaction rates were high, maternal substance use was markedly reduced and neonatal outcomes have shown to be above those reported in literature. conclusion: this comprehensive, primary care model has shown to be optimal in the management of substance use in pregnancy and for improving neonatal outcomes. future research will focus on how this inexpensive program can be replicated in other health care settings. t-cup may prove to be the optimal model for providing care to pregnant substance users in canada. lntrod11ction: cigarette smoking is one of the most serious health problems in taiwan. the prevalence of smoking in 2002 is 48.1 % in males 5.9% in females aged 18 years and older. although the government of taiwan passed a tobacco hazards control act in 1997, it has not been strongly enforced in many places. therefore, community residents have often reported exposure of second hand smoke. the purpose of the study was to establish a device to build up more smoke-free environments in the city of tainan. methods: unique from traditional intervention studies, the study used a healthy city approach to help build up smoke-free environments. the major concept of the approach is to build up a healthy city platform, including organizing a steering committee, setting up policies and indicators, creating intersectoral collaboration, and increasing community participation. first, more than 80 enthusiastic researchers, experts, governmental officers, city counselors and community leaders in tainan were invited in the healthy city committee. second, smoke-free policies, indicators for smoke-free environments, and mechanisms for inter-departmen· tal inspections were set up. third, community volunteers were recruited and trained for persuading related stakeholders. lastly, both penalties and rewards were used for help build up the environments. raults: aher two-year (2003 aher two-year ( -2005 execution of the project, the results qualitatively showed that smoke-free environments in tainan were widely accepted and established, including smoke-free schools, smoke-free workpla~es, smoke-free households, smoke-free internet shops, and smoke-free restaurants. smoke~s were. effectively educated not to smoke in public places. community residents including adults and children m the smoke-free communities clearly understand the adverse effects of environmental tobacco smoke and actively participated anti-smoking activities. conclruions: healthy city platform is effective to conquer the barrier of limited anti-smoking rc:sources. nor. only can it enlar:ge community actions for anti-smoking campaigns, but also it can provide par_merships for collaboratjon. by establishing related policies and indicators the effects of smoke· free environments can be susta1·ned a d th · · · ' · n e progression can be monitored m a commuruty. these issues are used ~· oi::c it~ goals, weuha identifies issues that put people's health at risk. presently, team com~u:c: ran ee~tion !earns. (iats) that design integrative solutions ~tesj'°~ g om six to fifteen members. methods in order to establish wo-poster sessions v165 projects for weuha, the following approach was undertaken: i. a project-polling template was created and sent to all members of the alliance for their input. each member was asked to identify thdr top two population groups, and to suggest a project on which to focus over a 12-18 month period for each identified population. 2. there was a 47% response to the poll and the top three population groups were identified. data from the toronto community health profile database were utilized to contextualize the information supplied for these populations. a presentation was made to the steering committee and three population-based projects were selected, leaders identified and iats formed. three population-based projects: the population-based projects and health care issues identified are: newcomer prenatal uninsured women; this project will address the challenges faced by providers to a growing number of non-insured prenatal women seeking care. a service model where the barrier of "catchments" is removed to allow enhanced access and improved and co-ordinated service delivery will be pilot-tested. children/obesity/diab etes: using a health promotion model this team will focus on screening, intervention, and promoting healthy lifestyles (physical activity and nutrition) for families as well as for overweight and obese children. seniors health promotion and circle of discharge: this team will develop an early intervention model to assist seniors/family unit/caregivers in accessing information and receiving treatment/care in the community. the circle of discharge initiative will address ways of utilizing community supports to keep seniors in the community and minimize readmissions to acute care facilities. results/expected outcomes: coordinated and enhanced service delivery to identified populations, leading to improved access, improved quality of life, and health care for these targeted populations. introduction: basic human rights are often denied to high-risk populations and people living with hiv/aids. their rights to work and social security, health, privacy, non discrimination, liberty and freedom of movement, marriage and having a family have been compromised due to their sero-positive status and risk of being positive. the spread of hiv/aids has been accelerating due to the lack of general human rights among vulnerable groups. to formulate and implement effective responses needs dialogue and to prevent the epidemic to go underground barriers like stigma need to be overcome. objective: how to reduce the situation of stigma, discrimination and human rights violations experienced by people living with hiv/aids and those who are vulnerable to hiv/aids. methodology and findings: consultation meetings were strm.-rured around presentations, field visits, community meetings and group work to formulate recommendations on how govt and ngos/cbos should move forward based on objective. pakistan being a low prevalence country, the whole sense of compl;u:enc.:y that individuals are not subject to situations of vulnerable to hiv is the major threat to an explosion in th•· epidemic, therefore urgent measures are needed to integrate human rights issues from the very start of the response. the protection and promotion of human rights in an integral component of ;tll responses to the hiv/aids epidemic. it has been recognized that the response to hiv/aios must he multi sectoral and multi faceted, with each group contributing its particular expertise. for this to occur along with other knowlcdg<" more information is required in human rights abuses related to hiv/ aids in a particular scenario. the ~·on sultarion meetings on hiv/aids and human rights were an exemplary effort to achieve the same ohj<..:tivc. recommendations: the need for a comprehensive, integrated and a multi-sectoral appro;u.:h in addressing the issue of hiv/aids was highlighted. the need social, cultural and religious asp•·ct' to he: prominently addressed were identified. it was thought imperative measures even in low prevalence countries. education has a key role to play, there is a need for a code of ethics for media people and h<"alth care providers and violations should be closely monitored and follow up action taken. p7-38 (c) how can community-based funding programs contribute to building community capacity and how can we measure this elusive goal? mary frances maclellan-wright, brenda cantin, mary jane buchanan, and tammy simpson community capacity building is recognized by the public health agency of canada (phac) as an important strategy for improving the overall health of communities by enabling communities to addre~s priority issues such as social and economic determinants of health. in 2004/2005 phac.:, alberta/nwf region's population health fund (phf) supported 12 community-based projects to build community capacity on or across the determinants of health. specifically, this included creating accessible and sup· portive social and physical environments as well as creating tools and processes necessary for healthy policy development and implementation. the objective of this presentation is to highlight how the community capacity building tool, developed by phac ab/nwf region, can demonstrate gains in v166 poster sessions · · the course of a pror· ect and be used as a reflective tool for project planning and community capacity over . . . . i · a art of their reporting requirements, 12 pro1ect sites completed the community caparny eva uanon. s p . . th t i ii i'd d . building tool at the beginning and end of their ~ne-year prorect. e oo ~o ects va 1 an reliable data in the context of community-based health prorects. developed through a vigorous ~nd collabora11ve research process, the tool uses plain languag~ to expl~re nine key f~atures o~ commuruty cap~city with 35 't ch with a section for contextual information, 26 of which also mdude a four-pomt raong 1 ems, ea f fu d · scale. results show an increase in community capacity over the course o the nde prorects. pre and post aggregate data from the one-year projects measure~ statistic.ally si~n~ficant changes for 17 of the 26 scaled items. projects identified key areas of commumty capacity bmldmg that needed strengthemng, such as increasing participation, particularly among people with low incomes; engaging community members in identifying root causes; and linking with community groups. in completing the tool, projects examined root causes of the social and economic determinants of health, thereby exploring social justice issues related to the health of their community. results of the tool also served as a reflec· cion on the process of community capacity building; that is, how the project outcomes were achieved. projects also reported that the tool helped identify gaps and future directions, and was useful as a project planning, needs assessment and evaluation tool. community capacity building is a strategy that can be measured. the community capacity building tool provides a practical means to demonstrate gains in community capacity building. strengthening the elements of community capacity building through community-based funding can serve as building blocks for addressing other community issues. needs of marginalized crack users lorraine barnaby, victoria okazawa, barb panter, alan simpson, and bo yee thom background: the safer crack use coalition of toronto (scuc) was formed in 2000 in response to the growing concern for the health and well-being of marginalized crack users. a central concern was the alarm· ing hepatitis c rate ( 40%) amongst crack smokers and the lack of connection to prevention and health ser· vices. scuc is an innovative grassroots coalition comprised of front-line workers, crack users, researcher! and advocates. despite opposition and without funding, scuc has grown into the largest crack specific harm reduction coalition in canada and developed a nationally recognized sarer crack kit distribution program (involving 16 community-based agencies that provide outreach to users). the success of our coalition derives from our dedication to the issue and from the involvement of those directly affected by crack use. setting: scuc's primary service region is greater toronto, a diverse, large urban centre. much ofour work is done in areas where homeless people, sex trade workers and drug users tend to congregate. recently, scuc has reached out to regional and national stakeholders to provide leadership and education. mandate: our mandate is to advocate for marginalized crack users and support the devdopmentof a com.p.rehensive harm reduction model that addresses the health and social needs facing crack users; and to fac1htare the exchange of information between crack users, service providers, researchers, and policy developers across canada. owrview: the proposed workshop will provide participants with an overview of the devdopment of scuc, our current projects (including research, education, direct intervention and consultation), our challenge~ and s~ccesses and the role of community development and advocacy within the coalition. pre-senter~ will consist of community members who have personal crack use experience and front-line work· ers-, sc.uc conducted a community-based research project (toronto crack users perspectives, 2005) , in w~ich 1 s focus groups with marginalized crack users across toronto were conducted. participants iden· t1f1ed health and social issues affecti h b · · · d " red . . ng t em, arrsers to needed services, personal strategies, an oue recommendations for improved services. presenters will share the methodology, results and recommen· datmns resulting from the research project. conc/usio": research, field observations and consultations with stakeholders have shown that cradck shmoke~s are at an. increased risk for sexually transmitted infections hiv/aids hepatitis c, tb an ot er serious health issues health · ff, · ' ' · · . · issues a ectmg crack users are due to high risk behavmurs, socio· economic factors, such as homeless d. · · · · d · 1 . 1 . ness, 1scrsmmat1on, unemployment, violence incarceraoons, an soc1a 1so at1on, and a lack of comprehe · h i h · ' ns1ve ea t and social services targeting crack users. · · sinct · s, owever arge remains a gross underesurnaoon. poster sessions v167 these are hospital-based reports and many known cases go unreported. however teh case, young age at first intercourse, inconsistent condom use and multiple partnersplace adolescents at high risks for a diverse array of stls, including hiv. about 19% of female nigerian secondary school students report initiating sexual intercourse before age 13 years. 39% of nigerian female secondary school students report not using a condom the last time they had sexual intercourse. more than 60% of urban nigerian teens report inconsistent condom use. methods: 371 adolescents were studied, ages 12 to 19, from benin city in edo state. the models used were mother-daughter(119), mother -son(99), father -son (87), and father-daughter(66). the effect of parent-child sexual communicationat baseline on child\'s report of sexual behavior, 6 to 12 months later were studied. greater amounts of sexual risk communication were asociated with markedly fewer episodes of unprotected sexual intercourse, reduced number of sexual partners and fewer episodes of unprotected sexual intercourse. results: this study proved that parents can exert more influence on the sexual knowledge attitudes and practise of their adolescent children through desired practises or rolemodeling, reiterating their values and appropriate monitoring of the adolescents\' behavior. they also stand to provide information about sexuality and various sexual topics. parental-child sexual communication has been found to be particularly influential and has been associated with later onset of sexual initiation among adolescents, less sexual activity, more responsible sexual attitudes including greater condom use, self efficacy and lower self -reported incidence of stis. conclusions: parents need to be trained to relate more effectively with their children/wards about issues related to sex and sexuality. family -based programs to reduce sexual risk-taking need to be developed. there is also the need to carry out cross-ethnicaland cross-cultural studies to identify how parent-child influences on adolescent sexual risk behavior may vary in different regions or countries, especially inthis era of the hiv pandemic. introduction: public health interventions to identify and eliminate health disparities require evidence-based policy and adequate model specification, which includes individuals within a socioecological context, and requires the integration of biosociomedical information. multiple public and private data sources need to be linked to apportion variation in health disparities ro individual risk factors, the health delivery system, and the geosocial environment. multilevel mapping of health disparities furthers the development of evidence-based interventions through the growth of the public health information network (phin-cdc) by linking clinical and population health data. clinical encounter data, administrative hospital data, population socioenvironmental data, and local health policy were examined in a three-level geocoded multilevel model to establish a tracking system for health disparities. nj has a long established political tradition of "home rule" based in 566 elected municipal governments, which are responsible for the well-being of their populations. municipalities are contained within counties as defined by the us census, and health data are linked mostly at the municipality level. marika schwandt community organizers from the ontario coaliti~n again~t pove~, .along ":ith ~edical practitioners who have endorsed the campaign and have been mvolved m prescnbmg special diet needs for ow and odsp recipients, will discuss the raise the rates campaign. the organizati~n has used a special diet needs supplement as a political tool, meeting the urgent needs o.f .poor ~ople m toront~ while raising the issues of poverty as a primary determinant of health and nutrtnous diet as a preventative health mea· sure. health professionals carry the responsibility to ensure that they use all means available to them to improve the health of the individuals that they serve, and to prevent future disease and health conditions. most health practitioners know that those on social assistance are not able to afford nutritious foods or even sufficient amounts of food, but many are not aware of the extra dietary funds that are available aher consideration by a health practitioner. responsible nurse practitioners and physicians cannot, in good conscience, ignore the special needs diet supplement that is available to all recipients of welfare and disabiliry (ow and odsp). a number of toronto physicians have taken the position that all clients can justifiably benefit from vitamins, organic foods and high fiber diets as a preventative health measure. we know that income is one of the greatest predictors of poor health. the special needs diet is a health promotion intervention which will prevent numerous future health conditions, including chronic conditions such as cardiovascular disease, cancer, diabetes and osteoporosis. many communiry health centres and other providers have chosen to hold clinics to allow many patients to get signed up for the supplement at one time. initiated by the ontario coalition against poverty, these clinics have brought together commu· niry organizers, community health centers, health practitioners, and individuals, who believe that poverty is the primary determinant of poor health. we believe that rates must be increased to address the health problems of all people on social assistance, kids, elders, people with hiv/aids -everyone. even in the context of understaffing, it could be considered a priority activity that has potentially important health promotion benefits. many clients can be processed in a two hour clinic. most providers find it a very interesting, rewarding undertaking. in 2004 the ontario coalition for social justice found that a toronto family with two adults and two kids receives $14,316. this is $21,115 below the poverty line. p7-43 (c) the health of street youth compared to similar aged youth beth hayhoe and ruth ewert . lntrod~on: street youth are at an age normally associated with good health, but due to their risky ~hav1ours and th~ conditions in which they live, they experience health conditions unlike their peer~ an more stable env1r~nments. in addition, the majority of street youth have experienced significant physical, sexual ~nd em.ot1onal abuse as younger children, directly impacting many of the choices they make around their physical and emotional health. we examined how different their health really is. . , methodl: using a retrospective analysis of the 11 years of data gathered from yonge street mis· 510~ 5 • evergreen health centre, the top 10 conditions of youth were examined and compared with national tren~s for similar aged youth. based on knowledge of the risk factors present in the group, rea· sons for the difference were examined. d' ~its: street youth experience more illness than other youth their age and their illnesses can bt . irect t ·~kc~ to the. conditions in which they live. long-term impacts of abus~ contribute to such signif· ~~nt t e t 0 d~slpl air that youth may voluntarily engage in behaviours or lack of self care in the hope at t cir 1ve~ w1 perhaps come to a quicker end. concl11non: although it has ion b k h th' dy clearly shows 3 d'fi . h g ee~ no~n t at poverty negatively affects health, ~siu be used to make ; erence m t .e health of this particular marginalized population. the infonnanon can relates to th . ecommendatio.ns around public policy that affects children and youth, especially as it e1r access to appropriate health care and follow up. p7-44 (cl why do urban children · b gt . tarek hussain 10 an adesh die: how to save our children? the traditional belief that urban child alid. a recent study (dhs d fr 17 r~n are better off than rural children might be no longer v urban migrants are highata th om h c~untn~s i demonstrates that the child survival prospects of rural· er an t ose m their r j · · ·grants. in bangladesh, currently 30 million 0 ~r~ 0~1gm and lower than those of urban non-idi million. health of the urban 1 ~ p~e are hvmg m urban area and by the year 2025, it would be so the popu at1on 1s a key a eals that urban poor have the worse h 1 h . concern. recent study on the urban poor rev ea t situation than the nation as a whole. this study shows that infant poster sessions v169 mortality among the urban poor as 120 per thousand, which are above the rural and national level estimates. the mortality levels of the dhaka poor are well above those of the rest of the city's population but much of the difference in death rates is explained by the experience of children, especially infants. analyzing demographic surveillance data from a large zone of the city containing all sectors of the population, research showed that the one-fifth of the households with the least possessions exhibited u5 child mortality almost three times as high as that recorded by the rest of the population. why children die in bangladesh? because their parents are too poor to provide them with enough food, clean water and other basic needs to help them avoid infection and recover from illness. researchers believed that girls are more at risk than boys, as mothers regularly feed boys first. this reflects the different value placed on girls and boys, as well as resources which may not stretch far enough to provide for everyone. many studies show that housing conditions such as household construction materials and access to safe drinking water and hygienic toilet facilities are the most critical determinants of child survival in urban areas of developing countries. the present situation stressed on the need for renewed emphasis on maternal and child healthcare and child nutrition programs. mapping path for progress to save our children would need be done strategically. we have the policies on hand, we have the means, to change the world so that every child will survive and has the opportunity to develop himself fully as a healthy human being. we need the political will--courage and determination to make that a reality. p7-45 (c) sherbourne health centre: innovation in healthcare for the transgendered community james read introduction: sherbourne health centre (shc), a primary health care centre located in downtown toronto, was established to address health service gaps in the local community. its mission is to reduce barriers to health by working with the people of its diverse urban communities to promote wellness and provide innovative primary health services. in addition to the local communities there are three populations of focus: the lesbian, gay, bisexual, transgendered and transexual communities (lgbtt); people who are homeless or underhoused; and newcomers to canada. shc is dedicated to providing health services in an interdisciplinary manner and its health providers include nurses, a nurse practitioner, mental health counsellors, health promoters, client-resource workers, and physicians. in january 2003 shc began offering medical care. among the challenges faced was how to provide responsive, respectful services to the trans community. providers had considerable expertise in the area of counselling and community work, but little in the area of hormone therapy -a key health service for those who want to transition from one gender to another. method: in preparing to offer community-based health care to the trans community it was clear that shc was being welcomed but also being watched with a critical eye. trans people have traditionally experienced significant barriers in accessing medical care. to respond to this challenge a working group of members of the trans community and health providers was created to develop an overall approach to care and specific protocols for hormone therapy. the group met over a one year period and their work culminated in the development of medical protocols for the provision of hormone therapy to trans individuals. results: shc is currently providing health care to 281 registered clients who identify as trans individuals (march 31 2005) through primary care and mental health programs. in an audit of shc medical charts (january 2003 to september 2004) 55 female-to-male (ftm) and 82 male-to-female (mtf) clients were identified. less than half of the ftm group and just over two-thirds of the mtf group presented specifically for the provision of hormones. based on this chart audit and ongoing experience shc continues to update and refine these protocols to ensure delivery of quality care. conclusion: this program is an example of innovative community-based health delivery to a population who have traditionally faced barriers. shc services also include counselling, health promotion, outreach and education. p7-46 (c) healthy cities for canadian women: a national consultation sandra kerr, kimberly walker, and gail lush on march 4 2005, the national network on environment and women's health held a pan-canadian consultation to identify opportunities for health research, policy change, and action. this consultation also worked to facilitate information sharing and networking between canadian women working as urban planners, policy makers, researchers, and service workers on issues pertaining to the health of women living in canadian cities. methods: for this research project, participants included front-line service workers, policy workers, researchers, and advocates from coast to coast, including francophone women, women with disabilities, racialized women, and other marginalized groups. the following key areas were selected as topics for du.bnes i1 alto kading .:auk of end·sugr ieaal clileue ia singapore, accounting for more than so% of new can singapore (nkfs) to embark on a prevention program (pp) 10 empo~r d1ahc 1j1u1f dieir condition bttter, emphasizing education and disease sdf·managemen1 lkilla a. essennal camponenn of good glycaemic control. we sought 10 explore the effects of a 1pecialijed edu.:a11on pro· pun od glycacmic conuol, as indicated by, serum hba ic values budine serum hba ic values were determined before un<k-rgmng the education progr ;am, which couisted of comprehensive dietary advice, ideal weight goals, and improving lipid profiln. serum hbaic values were obtained ar 3,6,9 months later to determine impact of the program. analy11• wu done uling paired !·tests significant reduction in hba le levels from 0 ro 9 month• was observed in females, chinese race, older age group(> so yean). ohew-ibmi ~ 27.nwm2, wai11 hip ratio> l),up to primary and above secondary level education and those having om urine iclt showed that increasing hbalc levels (9) had increasing urmary protein (38.± 117; .18 ±i ih so± 136) and crearinine (s2.s ± 64 7s ± 71; ioi± 7s) levels fbg rnults showed that the management nf d1abetn m the nkfs preven· tion programme is effec;rive. results also indicated 1har hba le leve11 have a linnr trend wnh unnary protein and creatinine which are imponant determinants of renal diseate tal family-focused cinical palbway1 promoce politivc outcollln for ua inner city canu allicy ipmai jerrnjm1 care llctivirits in preparation for an infanr'' dilchargr honlr, and art m1endnl lo improve effi.:k'fl.:tn of c.are. 11lere i11 paucity of tttran:h, and inconsi1trncy of rnulta on 1ht-•m!*-1 of f1m1ly·fc"-'uw d1nm 1a: to determinr whrthrr implrmentation of family.focuted c:pt 1n 1 ntnn.tt.tl unit w"n mg an inner city 1;ommunity drcl't'aki leftarh of lf•y (i.osi and rromclll'i family uo•fkllon and rt.1j1 nest for dikhargr. md6odt: family-focuk"d cpi 1041 data wm coll«ted for all infant• horn btrwttn 29 and 36 wft"k• 1t"lal111mi atr who wrtt .1dm111ed to the ntonatal unit lmgdl of -.y 111. 9 n. 14.8 day'o p c o.osi ind pma .11 d•mr., ho.nr 137.3 t 1.3 n. 36.4 ± i. i wb, p < o.os) wett n«01fiamly f.lfrt 1n the pre.(]' poup. ~11.fxtmon icofn for famihn wrre high. and families noctd thc:y wnr mott prepued to ah thrar t..lby "'-· thett was .a cosi uving of s 1,814 (cdn) per patient d1teharpd home 1n the pmi-cp poap c.-pated 10 the p"''lfoup· cortclaion· lmplrmrnr.rion of family·foanrd c:p. in a nrona1.1i umt tc"fyidi an 1nnn an com· muniry decre.ned length of'"'" mft with a high dcgrft of family uujamon, and wrre coll~nt at least 35% percent of the kathmandu population lives in slum like conditions with poor access to basic health services. in these disadvantaged areas, a large proportion of children do not receive treatment due to inaccessibility to medical services. in these areas, diarrhea, pneumonia, and measles, are the key determinants of infant mortality. protein energy malnutrition and vitamin a deficiency persists and communicable diseases are compounded by the emergence of diseases like hiv/aids. while the health challenges for disadvantaged populations in kathmandu are substantial, the city has also experienced various forms of innovative and effective community development health programs. for example, there are community primary health centers established by the kathmandu municipality to deliver essential health services to targeted communities. these centers not only provide equal access to health services to the people through an effective management system but also educate them hy organizing health related awareness programs. this program is considered one of the most effective urban health programs. the paper/presentation this paper will review large, innovative, and effective urhan health programs that are operating in kathmandu. most of these programs are currently run by international and national ngos a) early detection of emerging diseases in urban settings through syndromic surveillance: 911 data pilot study kate bassil of community resources, and without adequate follow-up. in november 2003 shelter pr.oviders ~et with hospital social workers and ccac to strike a working group to address some of th~ issues by mcre.asing knowledge among hospital staff of issues surrounding homelessness, and to build a stro?g workmg relationship between both systems in hamilton. to date the hswg has conducted four w~lkmg to~ of downtown shelters for hospital staff and local politicians. recently the hswg launched its ·~ool.k1t for staff working with patients who are homeless', which contains community resources and gu1dehnes to help with effective discharge plans. a scpi proposal has been submitted to incre~se the capacity of the hswg to address education gaps and opportunities with both shelters and hospitals around homelessness and healthcare. the purpose of this poster presentation is to share hamilton's experience and learnings with communities who are experiencing similar issues. it will provide for intera~tion around shared experiences and a chance to network with practitioners across canada re: best practices. introduction and objectives: canadians view health as the biggest priority for the federal government, where health policies are often based on models that rely on abstract definitions of health that provide little assistance in the policy and analytical arena. the main objectives of this paper are to provide a functional definition of health, to create a didactic model for devising policies and determining forms of intervention, to aid health professionals and analysts to strategize and prioritize policy objectives via cost benefit analysis, and to prompt readers to view health in terms of capacity measures as opposed to status measures. this paper provides a different perspective on health, which can be applied to various applications of health such as strategies of aid and poverty reduction, and measuring the health of an individual/ community/country. this paper aims to discuss theoretical, conceptual, methodological, and applied implications associated with different health policies and strategies, which can be extended to urban communities. essentially, our paper touches on the following two main themes of this conference: •health status of disadvantaged populations; and •interventions to improve the health of urban communities.methodology: we initially surveyed other models on this topic, and extrapolated key aspects into our conceptual framework. we then devised a theoretical framework that parallels simple theories of physkal energy, where health is viewed in terms of personal/societal health capacities and effort components.after establishing a theoretical model, we constructed a graphical representation of our model using selfrated health status and life expectancy measures. ultimately, we formulated a new definition of health, and a rudimentary method of conducting cost benefit analysis on policy initiatives. we end the paper with an application example discussing the issues surrounding the introduction of a seniors program.results: this paper provides both a conceptual and theoretical model that outlines how one can go about conducting a cost-benefit analysis when implementing a program. it also devises a new definition and model for health barred on our concept of individual and societal capacities. by devising a definition for health that links with a conceptual and theoretical framework, strategies can be more logically constructed where the repercussions on the general population are minimized. equally important, our model also sets itself up nicely for future microsimulation modeling and analysis.implications: this research enhances one's ability to conduct community-based cost-benefit analysis, and acts as a pedagogical tool when identifying which strategies provide the best outcome. p7-06 (a) good playgrounds are hard to find: parents' perceptions of neighbourhood parks patricia tucker, martin holmes, jennifer irwin, and jason gilliland introduction: neighbourhood opportunities, including public parks and physical activity or sports fields hav~ been. iden.tified as correlates to physical activity among youth. increasingly, physical activity among children 1s bemg acknowledged as a vital component of children's lives as it is a modifiable determinant of childh~d obesity. children's use of parks is mainly under the influence of parents; therefore, the purpose of this study was to assess parents' perspectives of city parks, using london ontario as a case study.m~~: this qualitative study targeted a heterogeneous sample of parents of children using local parks w1thm london. parents with children using the parks were asked for 5 minutes of their time and if willing, a s.hort interview was conducted. the interview guide asked parents for their opinion 'of city parks, particularly the one they were currently using. a sample size of 50 parents is expected by the end of the summer.results: preliminary findings are identifying parents concern with the current jack of shade in local parks. most parents have identified this as a limitation of existing parks, and when asked what would make the parks better, parents agree that shade is vital. additionally, some parents are recognizing the v170 poster sessions focused discussions during the consultation: 1. women in _poverty 2. women with disability 3. immi· grant and racialized women 4. the built and _physica_l environment. . . . . r its· participants voiced the need for integration of the following issues withm the research and policy :::na; t) the intersectional nature of urban women's health i~sues wh~ch reflects the reality of women's complex lives 2) the multisectional aspect of urban wo_m~n s health, 1ss~es, which reflects the diversity within women's lives 3) the interse~roral _dynamics within _womens hves and urban health issues. these concepts span multiple sectors -mdudmg health, educat10n, and economics -when leveraging community, research, and policy support, and engaging all levels of government.policy jmplicatiom: jn order to work towards health equity for women, plans for gender equity must be incorporated nationally and internationally within urban development initiatives: • reintroduce "women" and "gender" as distinct sectors for research, analysis, advocacy, and action. •integrate the multisectional, intersectional, and intersecroral aspects of women's lives within the framework of research and policy development, as well as in the development of action strategies. • develop a strategic framework to house the consultation priorities for future health research and policy development (for example, advocacy, relationship building, evidence-based policy-relevant research, priority initiatives}.note: research conducted by nnewh has been made possible through a financial contribution from health canada. the views expressed herein do not necessarily represent the views of health canada.p7-47 (c) drugs, culture and disadvantaged populations leticia folgar and cecilia rado lntroducci6n: a partir de un proyecto de reducci6n de daiios en una comunidad urbana en situ· aci6n de extrema vulnerahilidad surge la reflexion sobre el lugar prioritario de los elementos sociocuhurales en el acceso a los servicios de salud de diferentes colectivos urbanos. las "formas de hacer, pensar y sentir" orientan las acciones y delimitan las posibilidades que tienen los individuos de definir que algo es o no problema, asf como tambien los mecanismos de pedido de ayuda. el analisis permanenre del campo de "las culturas cotidianas" de los llamados "usuarios de drogas" aporta a la comprension de la complejidad del tema en sus escenarios reales, y colabora en los diseiios contextualizados de politicas y propuestas socio-sanitarias de intervenci6n, tornandolas mas efectivas.mitodos: esta experiencia de investigaci6n-acci6n que utiliza el merodo emografico identifica elementos socio estructurales, patrones de consumo y profundiza en los elementos socio-simb61icos que estructuran los discursos de los usuarios, caracterizandolos y diferenciandolos en tanto constitutivos de identidades socia les que condicionan la implementaci6n del programas de reduccion de daiios.resultados: los resultados que presentaremos dan cuenta de las caracteristicas diferenciadas v relaciones particulares ~ntre los consumidores de drogas en este contexto espedfico. a partir de este e~tudio de caso se mtentara co1?1enzar a responder preguntas que entendemos significativas a la hora de pensar intcrvcnciones a la med1da de poblaciones que comparten ciertas caracteristicas socio-culturales. (cuales serian las .motivaciones para el cambio en estas comunidades?, cque elementos comunitarios nos ayudan a i:nnstnur dema~~a? • cque tenemos para aprender de las "soluciones" que ellos mismos encuenrran a los usos problemat1cos? methods: our study was conducted by a team of two researchers at three different sites. the mapping consisted of filling in a chart of observable neighbourhood features such as graffiti, litter, and boarded housing, and the presence or absence of each feature was noted for each city block. qualitative observations were also recorded throughout the process. researchers analyzed the compiled quantitative and qualitative neighbourhood data and then analyzed the process of data collection itself.results: this study reveals the need for further research into the effects of physical environments on individual health and sense of well-being, and perception of investment in neighbourhoods. the process reveals that perceptions of health and safety are not easily quantified. we make specific recommendations about the mapping methodology including the importance of considering how factors such as researcher social location may impact the experience of neighbourhoods and how similar neighbourhood characteristics are experienced differently in various spaces. further, we discuss some of the practical considerations around the mapping exercise such as recording of findings, time of day, temperature, and researcher safety.conclusion: this study revealed the importance of exploring conceptions of health and well-being beyond basic physical wellness. it suggests the importance of considering one's environment and one's own perception of health, safety, and well-being in determining health. this conclusion suggests that attention needs to be paid to the connection between the workplace and the external environment it is situated in. the individual's workday experience does not start and stop at the front door of their workplace, but rather extends into the neighbourhood and environment around them. our procedural observations and recommendations will allow other researchers interested in the effect of urban environments on health to consider using this innovative methodology. introduction: responding ro protests against poor medical attention for sexually assaulted women and deplorable conviction rates for sex offenders, in the late 1970s, the ontario government established what would become over 30 hospital-based sexual assault care and treatment centres (sactcs) across the province. these centres, staffed around the clock with specially trained heath care providers, have become the centralized locations for the simultaneous health care treatment of and forensic evidence collection from sexually assaulted women for the purpose of facilitating positive social and legal outcomes. since the introduction of these centres, very little evaluative research has been conducted to determine the impact of this intervention. the purpose of our study was to investigate it from the perspectives of sexually assaulted women who have undergone forensic medical examinations at these centres.method: women were referred to our study by sactc coordinators across ontario. we developed an interview schedule composed of both closed and open-ended questions. twenty-two women were interviewed, face-to-face. these interviews were approximately one-to-two hours in length, and were transcribed verbatim. to date, 19 have been analyzed for key themes.results: preliminary findings indicate that most women interviewed were canadian born (79'yo), and ranged in age from 17 to 46 years. a substantial proportion self-identified as a visible minority ( 37'x.). approximately half were single or never married (47%) and living with a spouse or family of origin (53%). most were either students or not employed (68%). two-thirds (68%) had completed high school and onethird (37%) was from a lower socio-economic stratum. almost two-fifths (37%) of women perceived the medical forensic examination as revictimizing citing, for example, the internal examination and having blood drawn. the other two-thirds (63%) indicated that it was an empowering experience, as it gave them a sense of control at a time when they described feeling otherwise powerless. most (68%) women stated that they had presented to a centre due to health care concerns and were very satisfied ( 84 % ) with their experiences and interactions with staff. almost all (89%) women felt supported and understood.conclusions: this research has important implications for clinical practice and for appropriately addressing the needs of sexually assaulted women. what is apparent is that continued high-quality medical attention administered in the milieu of specialized hospital-based services is essential. at the same time, we would suggest that some forensic evidence collection procedures warrant reevaluation. the study will take an experiential, approach by chroruclmg the impa~ of the transition f m the streets to stabilization in a managed alcohol program through the techruque of narrative i~:uiry. in keeping with the shift in thinking in the mental health fie!~ ~his stu~y is based on a paradigm of recovery rather than one of pathology. the "inner views of part1c1pants hves as they portray their worlds, experiences and observations" will be presented (charm~z, 1991, ~· 38~)-"i?e p~ of the study is to: identify barriers to recovery. it will explore the exj?cnence of ~n~t1zanon pnor to entry into the program; and following entry will: explore the meanmg ~nd defirutto~s of r~overy ~~d the impact of the new environment and highlight what supports were instrumental m movmg pan1apants along the recovery paradigm.p7-st (a) treating the "untreatable": the politics of public health in vancouver's inner city introdudion: this paper explores the everyday practices of therapeutic programs in the treadnent of hiv in vancouver's inner city. as anthropologists have shown elsewhere, therapeutic programs do not siinply treat physical ailments but they shape, regulate and manage social lives. in vancouver's inner city, there are few therapeutic options available for the treatment of 1-ilv. public health initiatives in the inner city have instead largely focused on prevention and harm reduction strategies such as needle exchange programs, safe injection sites, and safer-sex education. epidemiological reports suggest that less than a quarter of those living with hiv in the downtown eastside (dtes) are taking antiretroviral therapies raising critical questions regarding the therapeutic economy of antiretrovirals and rights to health care for the urban poor.methods: this paper is drawn from ethnographic fieldwork in vancouver's otes neighborhood focusing on therapeutic programs for hiv treatment among "hard-to-reach" populations. the research includes participant-observation at inner city health clinics specializing in the treatment of hiv; semi· structured interviews with hiv positive participants, health care professionals providing hiv treatment, and administraton working in the field of inner city public health; and, lastly, observation at public meetings and conferences surrounding hiv treatment.r.awlts: hiv prevention and treatment is a central concern in the lives of many residents living in the inner city -although it is just one of many health priorities afflicting the community. concerns about drug resistance, cost of antiretrovirals, and illicit drug use means that hiv therapy for most is characterized by the daily observation of their medicine ingestion at health clinics or pharmacies. daily observed treatment (dot) is increasingly being adopted as a strategy in the therapeutic management of "untreatable" populations. dot programs demand a particular type of subject -one who is "compliant" to the rules and regimes of public health. over emphasis on "risky practices," "chaotic lives," and "~dh~rence" preve~ts the public health system from meaningful engagement with the health of the marginalized who continue to suffer from multiple and serious health conditions and who continue to experience considerable disparities in health.~ the ~ffec~s of hiv in the inner city are compounded by poverty, laclc of safe and affordable houamg, vanous 1llegal underground economies increased rates of violence and outbreaks of ~~~·~ly tr~nsmitted infections, hepatitis, and tuberculosi: but this research suggests 'that public health uunauves aimed at reducing health disparities may be failing the most vulnerable and marginal of citiztl1s. margaret malone 1~ vi~lence that occurs in families and in intimate relationships is a significant urban, ~unity, and pu~hc health problem. it has major consequences and far-reaching effects for women, ~~--renho, you~ sen1on, and families. violence also has significant effects for those who provide and ukllc w receive health care violence · · i · · . all lasses, · is a soc1a act mvolvmg a senous abuse of power. it crosses : ' : ' ~ 11 s;nden, ag~ ~ti~, cultures, sexualities, abilities, and religions. societal responseshali ra y oc:used on identificatton, crisis intervention and services for families and individuajs.promoten are only "-"--:-g to add h · ' · i in intimate relationshi with"-~"'.". ress t e issues of violence against women and vjoence lenga to consider i~ m families. in thi_s p~per, i analyze issues, propose strategies, and note c~· cannot be full -...l'-~ whork towards erad1canng violence, while arguing that social justice and equity y -.1ucvcu w en thett are people wh mnhod: critical social theory, an analysis that addresses culturally and ethnically diverse communities, together with a population health promotion perspective frame this analysis. social determinants of health are used to highlight the extent of the problem of violence and the social and health care costs.the ottawa charter is integrated to focus on strategies for developing personal skills, strengthening community action, creating supportive environments, devdoping healthy public policies, and re-orientating health and social services. attention is directed to approaches for working with individuals, families, groups, communities, populations, and society.ratdts: this analysis demonstrates that a comprehensive interdisciplinary, multisectoral, and multifaceted approach within an overall health promoting perspective helps to focus on the relevant issues, aitical analysis, and strategies required for action. it also illuminates a number of interacting, intersecting, and interconnecting factors related to violence. attention, which is often focused on individuals who are blamed for the problem of violence, is redirected to the expertise of non-health professionals and to community-based solutions. the challenge for health promoters working in the area of violence in families and in intimate relationships is to work to empower ourselves and the communities with whom we work to create health-promoting urban environments. social justice, equiry, and emancipatory possibilities are positioned in relation to recommendations for future community-based participatory research, pedagogical practices for health care practitioners, and policy development in relation to violence and urban health. the mid-main community health center, located in vancouver british columbia (bc), has a diverse patient base reflecting various cultures, languages, abilities, and socio-economic statuses. due to these differences, some mid-main patients experience greater digital divide barriers in accessing computers and reputable, government produced consumer health information (chi) websites, such as the bc healthguide and canadian health network. inequitable access is problematic because patient empowerment is the basis of many government produced chi websites. an internet terminal was introduced at mid-main in the summer of 2005, as part of an action research project to attempt to bridge the digital divide and make government produced chi resources useful to a broad array of patients. multi-level interventions in co-operation with patients, with the clinic and eventually government ministries were envisioned to meet this goal. the idea of implementing multi-level interventions was adopted to counter the tendency in interactive design to implement a universal solution for the 'ideal' end-user [ 1 ), which discounts diversity. to design and execute the interventions, various action-oriented and ethnographic methods were employed before and during the implementation of the internet terminal. upon the introduction of the internet terminal, participant observation and interviews were conducted using a motion capture software program to record a digital video and audio track of patients' internet sessions. this research provided insight into the spectrum of patients' capacities to use technology to fulfil their health information needs and become empowered. at the mid-main clinic it is noteworthy that the most significant intervention to enhance the usefulness of chi websites for patients appeared to be a human rather than a technological presence. as demonstrated in other ethnographic research of community internet access, technical support and capacity building is a significant component of empowerment (2). the mid-main wired waiting room project indicates that medical practitioners, medical administrators, and human intermediaries remain integral to making chi websites useful to patients and their potential empowerment. (1) over the past 5 years the environmental yo~th alliance has been of~ering a.youth as~t. mappin~ program which trains young people in community research and evaluation. wh1~st the positive expenenc~ and relationships that have developed over this time attest to the success of this program, no evaluations has yet been undertaken to find out what works for t.he youth, what ~ould be changed, and what long term outcomes this approach offers for the youth, their local community, and urban governance. these topics will be shared and discussed to help other community disorganizing and uncials governments build better, youth-driven structures in the places they live.p7-55 (a) the world trade center health registry: a unique resource for urban health researchers deborah walker, lorna thorpe, mark farfel, erin gregg, and robert brackbill introduction: the world trade center health registry (wfchr) was developed as a public health response to document and evaluate the long-term physical and mental health effects of the 9/11 disaster on a large, diverse population. over 71,000 people completed a wfchr enrollment baseline survey, creating the largest u.s. health registry. while studies have begun to characterize 9/11 bealth impacts, questions on long-term impacts remain that require additional studies involving carefully selected populations, long-term follow-up and appropriate physical exams and laboratory tests. wtchr provides an exposed population directory valuable for such studies with features that make ita unique resource: (a) a large diverse population of residents, school children/staff, people in lower man· hattan on 9/11 including occupants of damaged/destroyed buildings, and rescue/recovery/cleanup work· ers; (b) consent by 91 % of enrollees to receive information about 9/11-related health studies; (c) represenration of many groups not well-studied by other researchers; (c) email addresses of 62% of enrollees; (d) 30% of enrollees recruited from lists with denominator estimates; and (e) available com· parison data for nyc residents. wfchr strives to maintain up-to-date contact information for all enrollees, an interested pool of potential study participants. follow-up surveys are planned.methods: to promote the wtchr as a public health resource, guidelines for external researcher.; were developed and posted on (www.wtcregistry.org) which include a short application form, a twopage proposal and documentation of irb approval. proposals are limited to medical, public health, or other scientific research. researchers can request de-identified baseline data or have dohmh send information about their studies to selected wfchr enrollees via mail or email. applications are scored by the wtchr review committee, comprised of representatives from dohmh, the agency for toxic subst~nces and disease registry, and wtchr's scientific, community and labor advisory committees. a data file users manual will be available in early fall 2005.~suits: three external applications have been approved in 2005, including one &om a non-u.s. ~esearcher, all requesting information to be sent to selected wtchr enrollees. the one completed mail· mg~~ wtchr enrollee~ (o 3,700 wfc tower evacuees) generated a positive survey response rate. three additional researchers mtend to submit applications in 2005. wfchr encourages collaborations between researchers and labor and community leaders.conclusion: studies involving wtchr enrollees will provide vital information about the long· term health consequences of 9/11. wtchr-related research can inform communities, researcher.;, policy makers, health care providers and public health officials examining and reacting to 9111 and other disasters. t .,. dp'"f'osed: thi is presentation will discuss the findings of attitudes toward the repeat male client iden· 1 ie as su1e1 a and substance us'n p · · · · i · 'd . . -1 g. articipants will learn about some identified effective strategies or service prov1 ers to assist this group of i · f men are oft · d bl men. n emergency care settings, studies show that this group 0 en viewe as pro emaric patient d i r for mental health p bl h h 5 an are more ikely to be discharged without an assessmen 200!) ea 1 1 rofr ems t. an or er, more cooperative patients (forster and wu 2002· hickey er al., · r y resu ts om this study suggest th · · ' ' l · d tel' mining how best to h 1 . d 1 at negative amtudes towards patients, difficu nes e · as well pathways l_e_ p patientsblan ~ck of conrinuity of care influence pathways to mental health care. • uc\:ome pro emat1c when p ti k · che system. m a ems present repeatedly and become "get stuc id methods: semi-structured intervie d . · (n=5), ed nurses (n=5) other ed ;s were con ucted with male ed patients (n=25), ed phys1oans ' sta (n= 7) and family physicians (n= 7). patients also completed a poster sessions v175 diagnostic interview. interviews were tape-recorded, transcribed verbatim and managed using n6. transcripts were coded using an iterative process and memos prepared capture emergent themes. ethics approval was obtained and all participants signed a detailed informed consent form.introduction: urban settings are particularly susceptible to the emergence and rapid spread of nt•w or rare diseases. the emergence of infectious diseases such as sars and increasing concerns over the next influenza pandemic has heightened interest in developing and using a surveillance systt·m which detects emerging public health problems early. syndromic surveillance systems, which use data b,1scd on symptoms rather than disease, offer substantial potential for this by providing near-real-rime data which are linked to an automated warning system. in toronto, we are piloting syndromic data from the 911 · emergency medical services (ems) database to examine how this information can be used on an ongoing basis for the early detection of syndromes including heat-related illness (hri), and influenza-like-illness (ill). this presentation will provide an outline of the planned desi_gn of this system and proposed evaluation. for one year, 911 call codes which reflect heat-related illness or influenza-like-illness will be selected and searched for daily using software with a multifactorial algorithm. calls will he stratified by call code, extracted from the 911-ems database and transferred electronically to toronto public health. the data will be analyzed for clusters and aberrations from the expected with the realtime outbreak and disease surveillance (rods) system, a computer-based public health tool for the early detection of disease outbreaks. this 911-ems surveillance system will be assessed in terms of its specificity and sensitivity through comparisons with the well-established tracking systems already in place for hr! and ill. others sources of data including paramedic ambulance call reports of signs and . this study will introduce complementary data sources t~ the ed ch1e~ complamt an~ o~~rthe-counter pharmacy sales syndromic surveillance data currently bemg evaluated m ~ther ontar~o cltles. . syndromic surveillance is a unique approach to proactive(~ dete~tmg early c.hangesm the health status of urban communities. the proposed study aims to provide evidence of differential effectiveness through investigating the use of 911-ems call data as a source of syndromic surveillance information for hr! and ili in toronto. introduction: there is strong evidence that primary care interventions, including screening, brief advi<:e, treatment referral and pharmacotherapy are effective in reducing morbidity and mortality caused by substance abuse. yet physicians are poor at intervening with substance users, in part because of lack of time, training and support. this study examines the hypothesis that shared care in addictions will result in decreased substance use and improved health status of patients, as well as increased use of primary care interventions by primary care practitioners (pcps). methods: the addiction medicine service (ams) at st. joseph's health centre's family medicine department is in the process of being transformed from its current structure as a traditional consult service into a shared care model called addiction shared care (asc). the program will have three components: education, office systems and clinical shared care. as opposed to a traditional consult service, the patient will be booked with both a primary care liaison worker (pcl) and addictions physician. patients referred from community physicians, the emergency department and inpatient medical and psychiatric wards will be recruited for the study as well as pcps from the surrounding community. the target sample size is 100-150 physicians and a similar number of patients. after initial consult, patient will be recruited into the study with their consent. the shared-case model underlines the interaction and collaboration with the patient's main pcp. asc will provide them with telephone consults, advice, support and re-assessment for their patients, as well as educational sessions and materials such as newsletters and informational kits.results: the impact of this transition on our patient care and on pcp's satisfaction with the asc model is currently being evaluated through a grant provided by the ministry of health & long term care. a retrospective chart review will be conducted using information on the patient's substance use, er/clinic visits, and their health/mood status. pcp satisfaction with the program will be measured through surveys and focus groups. our cost-effectiveness analysis will calculate the overall cost of the program per patient..conclusion: this low-cost service holds promise to serve as an optimal model and strategy to improve outcomes and reduce health care utilization in addict patients. the inner city public health project introduction the inner city public health project (icphp) was desi.gned to explore new an~ innovative ways to reach marginalized inner city populations that par-t1c1pate m high health-nsk beha~1ors. much of this population struggles with poverty, addictions, mental illness and homelessness, creatmg barriers to accessing health services and receiving follow-up. this pro1ect was de~igned to evaluat~ .~e success of offering clinics in the community for testing and followup of communicable diseases uuhzmg an aboriginal outreach worker to build relationships with individuals and agencies. v1n(demographics~ history ~f testi~g ~nd immunization and participation in various health-risk behaviors), records of tesnng and 1mmumzat1ons, and mterviews with partner agency and project staff after one year.. results: t~e chr ~as i~strumental in building relationships with individuals and partner agencies ' .° the c~mmun_1~ re_sultmg m req~ests for on-site outreach clinics from many of the agencies. the increase m parnc1pat10n, the chr mvolvement in the community, and the positive feedback from the agen? staff de~onstrated that.the project was successfully creating partnerships and becoming increasingly integrated m the community. data collected from clients at the initial visit indicated that the project was reaching its target populations and highlighted the unique health needs of clients, the large unmet need for health services and the barriers that exist to accessing those services. ~usion: the outreach clinics were successful at providing services to target populations of high health-nsk groups and had great support from the community agencies. the role of the chr was critical to the success of the project and proved the value of this category of health care worker in an urban aboriginal population. the unmet health needs of this disadvantaged population support the need for more dedicated resources with an emphasis on reducing access barriers. building a caring community old strathcona's whyte avenue, a district in edmonton, brought concern about increases in the population of panhandlers, street people and homeless persons to the attention of all levels of government. the issue was not only the problems of homelessness and related issues, but feelings of insecurity and disempowerment by the neighbourhood residents and businesses. their concerns were acknowledged, and civic support was offered, but it was up to the community itself to solve the problem. within a year of those meetings, an adult outreach worker program was created. the outreach worker, meets people in their own environments, including river valley camps. she provides wrap-around services rooted in harm reduction and health promotion principles. her relationship-based practice establishes the trust for helping clients with appropriate housing, physical and/or mental health issues, who have little or no income and family support to transition from homelessness. the program is an excellent example of collaboration that has been established with the businesses, community residents, community associations, churches, municiple services, and inner-city agencies such as boyle street community services. statistics are tracked using the canadian outcomes research institute homes database, and feedback from participants, including people who are street involved. this includes an annual general meeting for community and people who are homeless. the program's holistic approach to serving the homeless population has been integral, both in creating community awareness and equipping residents and businesses to effectively interact with people who are homeless. through this community development work, the outreach worker engages old strathcona in meeting the financial and material needs of the marginalized community. the success of this program has been surprising -the fact is that homeless people's lives are being changed; one person at a time and the community has been changed in how they view and treat those without homes. over two years, the program has successfully connected with approximately seventy-five individuals who call old strathcona home, but are homeless. thirty-six individuals are now in homes, while numerous others have been assisted in obtaining a healthier and safer lifestyles by becoming connected with other social/health agencies. the program highlights the roots of homelessness, barriers to change and requirements for success. it has been a thriving program and a model that works by showing how a caring community has rallied together to achieve prosperous outcomes. the spn has created models of tb service delivery to be used m part~ers~1p with phannaceunca compa-. · · -. t' ns cooperatives and health maintenance orgamzanons (hmos). for example, the mes, c1v1c orgamza 10 , . · b tb d' · spn has established a system with pharmaceutical companies that help patients to uy me 1cmes at a special discounted rate. this scheme also allows patients to get a free one-_month's worth of~ dru_g supply if they purchase the first 5 months of their regimen. the sy_s~e~s were ~es1gned to be cm~pattble with existing policies for recording and documentation of the ph1hppme national tuberculosis program (ntp). aside from that, stakeholders were also encouraged to be dots-enabled through the use of m~nual~ and on-line training courses. the spn initiative offers an alternative in easing the burden of tb sc:rv1ce delivery from rhe public sector through the harnessing of existing private-sector (dsos). the learnmgs from the spn experience would benefit groups from other locales that _work no~ only on ~ but other health concerns as well. the spn experience showcases how well-coordinated private sector involvements help promote social justice in health delivery in urban communities.p7-63 (c) young people in control; doing it safe. the safe sex comedy juan walter and pepijn v. empelen introduction: high prevalence of chlamydia and gonorrhoea have been reported among migrants youth in amsterdam, originating from the dutch antilles, suriname and sub-sahara africa. in addition, these groups also have high rates of teenage-pregnancy (stuart, 2002) and abortions (rademakers 1995), indicating unsafe sexual behaviour of these young people. young people (aged 12 -30) from the so· called urban scene (young trendsetters in r&b/hip hop music and lifestyle) in amsterdam have been approached by the municipal health service (mhs) to collaborate on a safe sex project. their input was to use comedy as vehicle to get the message a cross. for the mhs this collaboration was a valuable opportunity to reach a hard-to-reach group.mdhods: first we conducted a need assessment by means of a online survey to assess basic knowledge and to similtaneously examine issues of interest concerning sex, sexuality, safer sex and the opposite sex. second, a small literature study was conducted about elements and essential conditions for succesful entertainment & education (e&e) (bouman 1999), with as most important condition to ensure that the message is realistic (buckingham & bragg, 2003) . third a program plan was developed aiming at enhancing the stl/hiv and sexuality knowledge of the young people and addressing communication and educational skills, by means of drama. subsequently a safe sex comedy show was developed, with as main topics: being in love, sexuality, empowerment, stigma, sti, hivand safer sex. the messages where carried by a mix of video presentation, stand up comedy, spoken word, rap and dance.results: there have been two safe sex comedy shows. the attendance was good; the group was divers' with an age range between 14 and 50 year, with the majority being younger than 25 year. more women than men attended the show. the story lines were considered realistic and most of the audients recognised the situations displayed. eighty percent of the audients found the show entertaining and 60% found it edm:arional. from this 60%, one third considers the information as new. almost all respondents pointed our that they would promote this show to their friends.con.clusion: the s.h<_>w reached the hard-to-reach group of young people out of the urban scene and was cons1d_ered entert~mmg, educational and realistic. in addition, the program was able in addressing important issues, and impacted on the percieved personal risk of acquiring an sti when not using condoms, as well as on basic knowledge about stl's. introduction: modernity has contributed mightily to the marginality of adults who live with mental illnesses and the subsequent denial of opportunities to them. limited access to social, vocational, educational, and residential opportunities exacerbates their disenfranchisement, strengthening the stigma that has been associated with mental illness in western society, and resulting in the denial of their basic human rights and their exclusion from active participation in civil society. the clubhouse approach tn recovery has led to the reduction of both marginality and stigma in every locale in which it has been implemented judiciously. its elucidation via the prism of social justice principles will lead to a deeper appreciation of its efficacy and relevance to an array of settings. methods: a review of the literature on social justice and mental health was conducted to determine core principles and relationships between the concepts. in particular, fondacaro and weinberg's (2002) conceptualization of social justice in community psychology suggests the desirability of the clubhouse approach in community mental health practice. a review of clubhouse philosophy and practice has led to the inescapable conclusion that there is a strong connection between clubhouse philosophy-which represents a unique approach co recovery--and social justice principles. placing this highly effective model of community mental health practice within the context of these principles is long overdue. via textual analysis, we will glean the principles of social justice inherent in the rich trove of clubhouse literature, particularly the international standards of clubhouse development.results: fondacarao and weinberg highlight three primary social justice themes within their community psychology framework: prevention and health promotion; empowerment, and a critical pnsp<"<·tive. utilizing the prescriptive principles that inform every detail of clubhouse development and th<" movement toward recovery for individuals at a fully-realized clubhouse, this presentation asserts that both clubhouse philosophy and practice embody these social justice themes, promote human rights, and empower clubhouse members, individuals who live with mental illnesses, to achieve a level of wdl-heing and productivity previously unimagined.conclusion: a social justice framework is critical to and enhances an understanding of the clubhouse model. this model creates inclusive communities that lead to opportunities for full partic1pil!ion 111 civil society of a previously marginalized group. the implication is that clubhouses that an· based on the international standards for clubhouse programs offer an effective intervention strategy to guarantee the human rights of a sizable, worthy, and earnest group of citizens. to a drastic increase in school enrollment from 5.9 million in 2002 to 7.5 million in 200.s. however, while gross enrollment rates increased to 104°/., in the whole country after the introduction of fpe, it remained conspicuously low at 62% in the capital city, nairobi. nairobi city's enrollment rate is lower .than thatof all regions in the country except the nomadic north-eastern province. !h.e.d1sadvantage of children bas_ed in the capital city was also noted in uganda after the introduction of fpe m the late 1990s_-many_ education experts in kenya attribute the city's poor performance to the high propornon of children hvmg m slums, which are grossly underserved as far as social services are concerned. this paper ~xammes the impact of fpe and explores reasons for poor enrollment in informal settlements m na1rob1 city. methods: the study utilizes quantitative and qualitative schooling data from the longitudinal health and demographic study being implemented by the african population and health research center in two informal settlements in nairobi. descriptive statistics are used to depict trends in enrollment rates for children aged 5-19 years in slum settlements for the period 2000-2005. results: the results show that school enrollment has surprisingly steadily declined for children aged 15-19 while it increased marginally for those aged 6-14. the number of new enrollments (among those aged 5 years) did not change much between 2001 and 2004 while it declined consistently among those aged 6-9 since 2002. these results show that the underlying reasons for poor school attendance in poverty-stricken populations go far beyond the lack of school fees. indeed, the results show that lack of finances (for uniform, transportation, and scholastic materials) has continued to be a key barrier to schooling for many children in slums. furthermore, slum children have not benefited from fpe because they mostly attend informal schools since they do not have access to government schools where the policy is being implemented.conclusion: the results show the need for equity considerations in the design and implementation of the fpe program in kenya. without paying particular attention to the schooling needs of the urban poor children, the millennium development goal aimed at achieving universal primary education will remain but a pipe dream for the rapidly increasing number of children living in poor urban neighborhoods.ps-04 (c) programing for hiv/aids in the urban workplace: issues and insights joseph kamoga hiv/aids has had a major effect on the workforce. according to !lo 35million persons who are engaged in some form of production are affectefd by hiv/aids. the working class mises out on programs that take place in communities, yet in a number of jobs, there are high risks to hiv infection. working persons sopend much of their active life time in workplaces and that is where they start getting involved in risky behaviour putting entire families at risk. and when they are infected with hiv, working people face high levels of seclusion, stigmatisation and some miss out on benefits especially in countries where there are no strong workplace programs. adressing hiv/aids in the workplace is key for sucessfull responses. this paper presents a case for workplace programing; the needs, issues and recommendations especially for urban places in developing countries where the private sector workers face major challenges. key: cord-015324-y44sfr0c authors: nan title: scientific programme date: 2007-09-01 journal: pediatr nephrol doi: 10.1007/s00467-007-0558-3 sha: doc_id: 15324 cord_uid: y44sfr0c nan the kidney plays an important role in ion homeostasis in the human body. several hereditary disorders characterized by perturbations of renal magnesium reabsorption leading to hypomagnesemia were described over the past 50 years. only recently, mutations in renal ion channels and transporters have been identified in several of these diseases, following positional cloning strategies in families with these disorders. muations in the slc12a3 gene have been identified in patients with gitelman syndrome, an autosomal recessive disorders characterized by hypokalemia, hypomagnesemia and hypocalciuria. slc12a3 encodes the thiazide-sensitive na + , cl-cotransporter (ncc) in the distal convoluted tubule (dct), the nephron site of active renal magnesium reabsorption. the hypomagnesemia in gitelman syndrome has been shown to be secondary to the primary defect in ncc. mutations in the fxyd2 gene have been found in patients with autosomal dominant renal hypomagnesemia associated with hypocalciuria (idh). fxyd2 encodes the gamma-subunit of the na + , k + -atpase, which is expressed primarily in the kidney with the highest expression levels in dct and tal. hypomagnesemia in patients with idh can be severe (<0.40 mm) and cause generalized convulsions. the molecular mechanism for renal mg 2+ loss in this autosomal dominant type of primary hypomagnesemia remains to be elucidated. in patients with autosomal recessive hypomagnesemia with hypercalciuria and nephrocalcinosis (fhhnc) mutations in the cldn16 gene, and very recently also in the cldn19 gene, have been identified. these genes encode claudin16 and claudin19 respectively, which are essential components of the paracellular pathway for magnesium at the level of the thick ascending limb of henle's loop. mutations in trpm6, encoding the epithelial mg 2+ channel trpm6 in the apical membrane of dct cells, have been identified in patients with mg 2+ wasting and secondary hypocalcemia (hsh). this autosomal recessive disease is due to defective intestinal and renal mg 2+ (re)absorption, and affected individuals show neurologic symptoms of hypomagnesemic hypocalcemia, including seizures and muscle spasms during infancy. in my lecture, i will give an update on the proteins involved in magnesium reabsorption and the emerging pathophysiological understanding of hereditary disorders in which renal handling of this divalent ion is disturbed. transcriptional control of genes that regulate tissue patterning and the cell cycle is fundamental to normal renal development. the mammalian kidney arises from reciprocal inductive tissue interactions between the ureteric bud and the metanephric mesenchyme. these interactions result in growth and branching of the ureteric bud and its daughter collecting ducts, a process termed, renal branching morphogenesis, and formation of nephrogenic progenitors and mature nephrons. expression and activity of transcription factors in ureteric and metanephric mesenchyme cells determines the patterning of ureteric bud and metanephric mesenchyme derived tissue elements. this lecture will highlight transcription factors critical to renal branching morphogenesis and nephrogenesis, with particular emphasis on those factors that are mutated in humans with renal malformation. the regulation of transcription factor activity will be discussed in the context of growth factor signaling pathways downstream of wnts, bone morphogenetic proteins and sonic hedgehog and pathways such as notch that control cell differentiation. the complexity of transcriptional signaling will be highlighted in the normal and malformed kidney at the level of transcriptional factor interactions and target gene promoters that can be targeted by mutiple signaling pathways. t. benzing diseases of the glomerular filter of the kidney are a leading cause of end-stage renal failure. recent studies have emphasized the critical role of the slit diaphragm of podocytes for the size-selective filtration barrier of the kidney and revealed novel aspects of the mechanisms leading to proteinuria, both in inherited and acquired diseases. several critical structural protein components of the slit diaphragm have been identified. recently, it has been shown that slit diaphragm proteins, in addition to their structural functions, participate in common signaling pathways. this talk will focus on what is known about the importance of the podocyte for the function of the glomerular filter of the kidney. it will provide a snapshot of our current understanding of the signaling properties of slit diaphragm proteins and project a framework for further studies necessary to delineate the function and dynamics of the slit diaphragm protein complex and the pathogenesis of nephrotic syndrome. long-term survival of children with end-stage renal disease (esrd) has increased in the last 20 years but the mortality rate remains high. cardiovascular disease accounts for 40 to 50% of all deaths, infectious disease about 20%. a prolonged period of dialysis versus having a renal graft and persistent hypertension are mortality risk factors. the prevalence of all sorts of morbidities is high among those who have reached adulthood. nearly 50% of all these patients suffer from left ventricular hypertrophy and life threatening vascular changes; nearly one third has clinical signs of metabolic bone disease. this accounts for both dialysis and transplanted patients. the chance of getting cancer is 10 times increased as compared to the general population; skin cancer and non-hodgkin lymphomas are most reported. a long period of dialysis at childhood is associated with impairment of both cognitive and educational attainment in adulthood. yet, despite all these negative outcomes, the health perception of young adults with childhood onset esrd is good. unemployment under young adults on chronic dialysis with pediatric onset of disease is higher than among healthy age related peers, but much lower than among dialysis patients of the same age with adult onset of disease. an impaired social development in childhood is associated with an impaired mental health perception at adult age. research and therapy in children with esrd should focus not only on prevention of graft failure but also on prevention of co-morbidity, especially cardiovascular disease, life threatening infections and malignancies. early transplantation, more extended forms of frequent hemodialysis in those who can not be transplanted, a more rigorous treatment of hypertension, avoidance of calcium-containing phosphate binders, reduction of the chronic inflammatory state, and tailor made anti-rejection therapy after transplantation may all be targets to improve outcome in future patients. psychosocial care should be more focused on attainment of independency and preparation for adult life, i. e. schooling and job career. applying regenerative medicine to combat organ shortage laboratory of regenerative nephrology, edmond and lili safra children's hospital, sheba medical center, tel hashomer, sackler school of medicine, tel aviv university, tel aviv, israel organ transplantation has been one of the major medical advances of the past 30 years; however, it is becoming increasingly apparent that the supply of organs is limited and will not improve with current medical practice. regenerative medicine is focused on the development of cells and tissues for the purpose of restoring function through transplantation. when facing late stages of esrd, which necessitate whole kidney transplantation, organogenesis represents an alternative to combat organ shortage. indeed, previous data pinpoints a window of time in human and pig kidney organogenesis that may be optimal for transplantation into mature recipients. "window" transplants are defined by their remarkable ability to grow, differentiate and undergo vascularization, achieving successful organogenesis of urine-producing miniature kidneys with no evidence of trans-differentiation into non-renal cell types, lack of tumorigenicity and reduced immunogenicity compared to adult counterparts. in contrast, when dealing with earlier stages of esrd or acute renal disease, which allow for individual cell replacement, both bonemarrow derived and kidney specific stem cells, might be applicable. accordingly, we show in proof-of-principle experiments that a novel population of multi-potential stem cells derived from the adult murine kidney are capable of re-populating ischemically injured tubular cells, while hematopoietic stem cells (cd34+cd133+) or hemangioblastic progenitor cells can give rise to peritubular endothelial cells. thus, different types of biological materials (embryonic kidney, adult kidney, adult bone marrow) offer new and powerful strategies for future tissue development and regeneration in renal medicine. k. tory, é. kis, a. szabó, g. reusz 1st department of pediatrics, semmelweis university, budapest, hungary it is well known that chronic renal failure significantly increases the risk of cardiovascular mortality in adults. transplantation decreases this risk; however, it still exceeds that of the normal population. as the number of children on renal replacement therapy (including transplantation) has significantly increased in recent years, there has been a growing amount of evidence regarding the increased cardiovascular vulnerability of this specific patient group. one important factor of cardiovascular mortality in adults is the dysfunction of the autonomic nervous system, previously designated as autonomic neuropathy. in a series of studies using the conventional ewing tests as well as heart rate variability (hrv) monitoring we were able to show altered sympathovagal balance in children on peritoneal-and hemodialysis, that was at least partly reversible following renal transplantation. according to our data sympathetic overactivity plays a major role in the sympathovagal disequilibrium observed. correspondingly, beta-adrenergic blockade improves the decreased hrv in the young. early, accelerated arteriosclerosis is another important, recently recognized consequence of crf in children. arterial calcification leads to increased arterial stiffness deteriorating the cushioning function of the aorta. arterial stiffness can be assessed by the reproducible and non-invasive measurement of the pulse wave velocity (pwv). in adults, it was found to be a strong, independent predictor of cardiovascular mortality. hypertension, hyperphosphatemia/elevated serum calciumphosphate product and vitamin d deficiency are the principal factors associated with pwv. recently, pwv was also shown to be increased in children on dialysis. however, the difference to the normal population may only be apparent if a control group matched for body dimensions is used, because of the dependence of pwv on body dimensions and uremic children's significant growth deficit. furthermore, increased pwv could also be shown in children following renal transplantation (tx) indicating the persistence of these lesions even following successful tx. the data on the autonomic nervous system and arterial dysfunction in young patients point to the necessity of early prevention in order to avoid the cardiovascular complications of crf. this study was supported by grants otka-t046155-f048842-f042563 and ett 435/2006. nitric oxide (no) production is reduced in ckd due to decreased renal and widespread decreases in endothelial no production. possible causes of no deficiency are: 1). substrate (l-arginine) limitation; 2). increased levels of circulating endogenous inhibitors of nitric oxide synthase (particularly asymmetric dimethylarginine [adma]); 3). decreased nos protein abundance/activity. decreased l-arginine availability in ckd is likely due to perturbed renal biosynthesis secondary to damage to the renal parenchyma. in addition, inhibition of transport of larginine into endothelial cells and shunting of l-arginine into other metabolic pathways (e. g. arginase) will also decrease availability. elevated plasma and tissue levels of adma in ckd are functions of reduced renal excretion (minor), reduced catabolism by dimethylarginine dimethylamino-hydrolase (ddah) and possibly increased protein methylation. an increase in adma has emerged as a major independent risk factor in many forms of cardiovascular disease as well as end-stage renal disease (and probably ckd). decreased renal nos protein abundance and activity have been reported by us in multiple models of ckd in the rat. the neuronal (nos 1) isoform is always reduced in the presence of injury, and is preserved in settings where there is protection from damage (female; wistar furth rat vs. sprague dawley). generalized and nnos specific inhibition accelerates underlying renal injury and in vulnerable animals will cause injury in the absence of underlying renal disease. we also find that relaxin (rlx) mediated prevention and repair of damaged kidneys requires an intact no system in order to function. in summary, no deficiency can cause cardiovascular and renal disease, and ckd results in no deficiency, contributing to a vicious cycle that promotes progression. an intact no system is required for rlxmediated repair of kidney damage. no deficiency in ckd is likely due to many causes: decreased arginine synthesis/availability and transport; increased endogenous adma functioning as competitive inhibitor; decreased enzyme abundance and activity will all lead to reduction in no generation. in addition, the oxidative stress of ckd will further reduce nos activity, switch the nos to become oxidant generators and will scavenge no to form the harmful peroxynitrite. selected glomerulopathies due to single gene defects such as finnish type nephropathy, diffuse mesangial sclerosis alport/thin membrane disease and inherited lipid disorders and will be discussed. finnish nephropathy is due to mutations of nephrin, a major structural component of the slit diaphragm. over 50 nephrin mutations are known associated with variably absent slit diaphragms, originally thought to be specific for constitutional nephrin mutations. however, sporadic minimal change disease and membranous glomerulonephritis may have absent slit diaphragms suggesting that nephrin may participate in the nephrotic syndrome in nonhereditary diseases. dms is one cause of congenital nephrotic syndrome, characterized by podocyte proliferationis shared by wt1 (denys-drash syndrome), laminin α2 (pierson syndrome) and galloway-mowat syndrome mutations. alport nephritis is a paradigm in which only a subset of mutations may predict disease severity (col ivα5)). heterozygous alport is similar to thin membrane disease (tmd), but 25% of tmd harbor col (iv) α3 mutations and a subset has col ivα2. nail patella syndrome due to heterozygous loss of lmx1b gene which regulates col ivα3-5 expression during kidney development. in classic nail-patella pathology fibrillar collagen bundles within the gbm are identical in severe and mild disease. thus the mutation does not correlate with prognosis. a mutation overlap in factor h gene in lipid disorders such as dense deposit disease (ddd) and lcat underscores glomerular pathologies that ranges from classic ribbon-like deposits in ddd, to lucent gbm deposits characteristic of lcat, or subendothelial lipid pools in lipoprotein glomerulopathy. the importance of genetics underscoring the pathology is amply demonstrated but mutations may not determine prognosis. background genes, post-translational modification and or protein/protein interactions in podocytes or the gbm may act as phenotypic modifiers. acute renal failure (arf) has many different definitions. rifle criteria distinguish "risk, injury, failure, loss and end-stage renal disease" features of this event. classic forms include pathophysiological cases of renal hypoperfusion and direct parenchymal injury, as well as postrenal anatomical obstruction. microvascular mechanism is in general the effect of disturbed balance between vasoconstriction (in response to endothelin, angiotensin ii, thromboxane a2, leukotrienes and increased sympathetic nerve activity) and vasodilatation (in response to nitric oxide, pge2 and bradykinin). endothelial and vascular smooth muscles cells may undergo structural damage and increased leukocytes-endothelial adhesion is a cause of inflammation. cytoskeletal breakdown, loss of polarity, apoptosis, necrosis, desquamation of viable and necrotic cells with tubular obstruction are underlying mechanisms of acute tubular necrosis. ischemic and direct tubular injury dominate as causes of arf, however specific epidemiology is strictly age-related. sepsis and major surgeryrelated events are the most common causes of arf in hospitalized patients. data on genetic background of certain genes polymorphisms and susceptibility to specific risk factors in newborns and infants are conflicting. several prophylactic and therapeutic techniques are available, however not of universal value. appropriate fluid management is crucial in ischemic arf, classic hemolyticuremic syndrome and rhabdomyolysis, however fluid overload is the one of major predictors of poor outcome in children admitted to icu. neither "renal dose" of dopamine, nor loop diuretics change the outcome. involvement of extrarenal organs worsens the overall outcome, which is the poorest in patients with multi-organ failure. early introduced renal replacement therapy is one of the key modalities in icu-treated patients. continuous techniques are of major value. in specific cases, such as hepato-renal syndrome, albumin ("liver") dialysis serves as an effective bridge to liver transplantation. hyperostosis-hyperphosphatemia syndrome (hhs) is a rare recessively inherited disease, manifested by persistent severe hyperphosphatemia and self-remitting episodic bone pain with radiologic findings of periosteal reaction and cortical hyperostosis. hyperphosphatemia in this patient population is not counter-balanced by pth or vitamin d, posing a mirror image of two hypophosphatemic states which result from increased activity of fibroblast growth factor 23 (fgf23). the two hypophosphatemic disorders which result from enhanced urinary phosphate leak are: dominantly inherited hypophosphatemic rickets and tumor induced osteomalacia. this observation was the impetus to study the role of fgf23 in hhs. affected individuals were found to have low levels of the full length, biologically active fgf23, but markedly augmented amounts of the cleaved inactive fragments. patients were found to be homozygous for a mutation in the galnt3 gene encoding a peptide involved in mucin-type o-glycosylation. decreasing the expression of the galnt3 gene by rna interference resulted in augmenting processing of the intact fgf23. our research indicates that the primary defect in hhs is a state of underglycosylation of fgf-23 resulting from reduced expression of ppgantase-t3, due to mutations in galnt3, and leading to augmented processing at the cleavage site. these changes in fgf-23 would abolish its phosphaturic effect and lead to severe persistent hyperphosphatemia. this study provides the pathogenetic mechanism of the first mucin-type o-glycosylation defect identified. our observation lends further credence to the primary and essential role of fgf23 in phosphate homeostasis through a pth-independent pathway. this was substantiated most recently by several reports which showed that mutations in the fgf23 gene are responsible for familial hyperphosphatemic tumoral calcinosis (fhtc) . a further study showed that hhs and familial hyperphosphatemic tumoral calcinosis are allelic disorders with a founder mutation in our region. immune responses govern the outcome of many forms of chronic kidney disease. gene therapy offers the potential to modify immune genes to improve outcome. we will discuss the potential use of gene transduction as a therapy for chronic kidney disease. background: chronic proteinuric renal disease is a major cause of end stage renal disease in man. adriamycin nephropathy is a murine model of chronic proteinuric renal disease where initial chemical injury is followed by immune and structural changes that mimic human disease. foxp3 is a gene specifically expressed by regulatory t (treg) cells. forced expression of the gene foxp3 causes transduced t cells to develop a regulatory phenotype. we hypothesised that foxp3 transduced regulatory t cells could protect against renal injury in adriamycin nephropathy. methods: the retroviral vectors expressing foxp3 and green fluorescent protein (gfp) (foxp3/migr) and gfp alone (migr) were transfected into package cell lines ecopack2-293, which produced the two retroviruses. cd4+ t cells were isolated from spleen of balb/c mice and stimulated by anti-cd3 mab and il-2 for 24 hours and then were infected with either retrovirus. expression was confirmed and phenotypic and in vitro functional assays demonstrated a regulatory phenotype. one week after infection, the gfp+ positive cells were sorted. foxp3 and control vector (migr) transduced t cells were administered to adriamycin (adr)-induced progressive renal nephropathy in mice. results: adoptive transfer of the foxp3 transduced t cells protected against renal injury. urinary protein excretion was reduced; there was less renal injury as measured by glomerulosclerosis, and interstitial infiltrates. serum creatinine, glomerular sclerosis and tubulointerstitial alterations were significantly lower in adr-foxp3 group, compared to those without treatment (adr) and treated with control vector (migr) transduced group (adr+migr). the foxp3 transduced cd4 t cells also showed suppressive activity in vitro. we conclude that foxp3 induced t reg cells may have a therapeutic role in protecting against immune injury and disease progression in chronic proteinuric renal disease. the italkid project is a prospective, population-based registry that was started in 1990. prevalent and incident cases of chronic renal insufficiency (cri) in children and adolescents were identified throughout italy (total population base: 16.8 million children). the inclusion criteria were: i) creatinine clearance (ccr): <90ml/min/1.73m 2 bsa; and ii) an age of <20 years at the time of registration. as to december 31st, 2006 a total of 2026 patients had been registered. the incidence of cri was estimated 12.1 cases per million and the (point) prevalence 74.7 per million of the age-related population (marp). the probability of kidney survival at 20 years of age was significantly different depending on the ccr at study entry, being 63% in patients with mild renal insufficiency (ccr 51-75 ml/min), 30% in those with moderate renal insufficiency (ccr 25-50 ml/min) and 3% in those with severe renal insufficiency (ccr <25 ml/min). the patients with normal (<0.2) and low (0.2-1.0) upr/ucr compared to those with mild (>1.0), showed a significantly slower decline in ccr (deltaccr +0.2±3.62 and -0.6±3.67 vs -3.76±5.64 ml/min/yr) and a higher kidney survival (96.7 and 94.1 vs 44.9%). the incidence of renal replacement therapy (rrt) was 7.3/year/100 patients and the casefatality rate on conservative treatment 1.41%. patients showed a significantly different slope of ccr before pubertal growth spurt as compared to after: -0.31±4.02 ml/min/1.73mq/yrs and -3.1±5.04. a non-linear pattern of decline in the probability of kidney survival, with a steep decrease during pubertal and early post-pubertal age was observed: the overall probability of rrt at age 10 was estimated 9.4%, while 51.8% of the patients will eventually required rrt before the 2nd decade of life was over. suggesting that pubertal development triggers the progression of cri in children. treatment with angiotensin converting enzyme inhibitors did not significantly modify the naturally progressive course of hypodysplastic nephropathy. ambulatory blood pressure monitoring (abpm) is a relatively new technique of blood pressure assessment in children and adolescents that offers several distinct advantages over traditional methods of blood pressure measurement, including the ability to detect white coat and masked hypertension, as well as the ability to assess nocturnal blood pressure. the role of abpm in the diagnostic evaluation of pediatric patients with elevated blood pressure is well-established, and recent surveys have demonstrated that it is used quite often by pediatric nephrologists and other practitioners during the initial evaluation of elevated blood pressure. it is less well-established, however, what role abpm might play in hypertensive children and adolescents once hypertension has been diagnosed and treatment initiated. studies in adults have demonstrated that abpm can assess whether patients on antihypertensive medications have achieved goal blood pressure, or whether their hypertension has progressed in severity. abpm can be used to follow nocturnal blood pressure in patients with chronic kidney disease (ckd) and diabetes, facilitating early identification of non-dipping, which is a known risk factor for progression of ckd or development of diabetic nephropathy, respectively. abpm can also be incorporated into clinical trials of antihypertensive medications to help assess their efficacy and safety. while additional data supporting these applications of abpm to pediatric hypertension clearly need to be generated from well-designed clinical trials, we propose that there is ample justification to utilize abpm just as frequently after the diagnosis of hypertension as before. childhood obesity is increasing globally in epidemic proportions and affects children in both industrialized and non-industrialized nations. in the last 30 years the percentage of overweight or obese children has increased from 5% to almost 30%. if current trends continue, as many as 50% of children may be overweight or obese by the year 2010. obesity predisposes to development of the metabolic syndrome, which is defined in children as the presence of three or more of the following features: abdominal adiposity (bmi >95%ile), serum triglycerides >95%ile, serum hdl cholesterol <5% ile, fasting blood glucose >110 mg/dl, and/or hypertension (systolic or diastolic blood pressure >95%ile adjusted for age, gender and height). the metabolic syndrome occurs in about 5% of children, but in 30-50% of overweight children. the presence of the metabolic syndrome increases the risk for cardiovascular disease and chronic kidney disease almost ten-fold in adults. adipose tissue does not just store fat, but also has important endocrine and immune functions mediated through adipocytokines, including leptin, adiponectin, resistin, apelin and visfatin, and classical cytokines such as tnf-a and il-6. increased leptin, decreased adiponectin and increased inflammatory cytokines, which occur in obesity, are known to induce vascular endothelial dysfunction and increase blood pressure. increase in adipose tissue also leads to infiltration by monocytes, macrophages and lymphocytes, which are stimulated to produce additional cytokines that may contribute to the systemic inflammation associated with obesity and vascular inflammation associated with hypertension. screening for hypertension and metabolic syndrome in obese children is critical to allow early identification of the metabolic syndrome and aggressive early intervention to reduce the risks for progression to cardiovascular disease and chronic kidney disease in later life. therapeutic strategies must include lifestyle changes of weight loss, healthier diet and regular physical exercise as well as treatment of hypertension, hyperlipidemia or hyperglycemia. blood pressure (bp) regulation is affected by numerous physiologic, biochemical, genetic and environmental factors. it has been suggested that exogenous conditions affecting intra-uterine growth and development may pre-program individuals for hypertension, metabolic abnormalities and cardiovascular morbidity in later life. animal data and human autopsy findings support a link between intrauterine growth, nephron endowment and postnatal hypertension. conceptually, it appears increasingly unclear whether the association of birth weight and bp in later life is mediated by intrauterine growth retardation as suggested by various animal models, whether prematurity per se affects bp programming independent of the fetus, nutritional status, or whether postnatal circumstances statistically linked to low birth weight affect this relationship. we have designed a study to evaluate the relationship between gestational age, birth weight and bp abnormalities by applying abpm in a group of children born preterm with and without intrauterine growth retardation and a local control group of children born at term with appropriate weight. this study represents the first systematic assessment of 24-hour cardiovascular regulation in children and adolescents born preterm. our findings indicate that a fraction of these preterm born subjects has a selective nocturnal increase in systolic bp, resulting in an elevated prevalence of non-dipping. our analysis suggests that intrauterine growth retardation, rather than prematurity per se, is the major effector of the early cardiovascular abnormalities observed in preterm children. moreover, we have found that nocturnal systolic bp was closely linked to heart rate, pointing to a possible role of sympathetic hyperactivation. while little data is available regarding a link between low birth weight and/or prematurity and sympathoadrenal function in adult humans, a role of the sympathetic nervous system in the programming of adult hypertension has been consistently demonstrated in various animal models of fetal growth retardation. in conclusion, we detected subtle abnormalities of circadian bp regulation in those preterm born children who suffered from intrauterine growth retardation and this may reflect sympathetic hyperactivation. the intrinsic tendency of kidney disorders with reduced nephron mass to progress and the quest for renoprotective strategies are an ongoing focus of renal research. in adults, hypertension is not only a marker but also a major driving force of renal failure progression. renin-angiotensin system blockers (ace inhibitors and at1 receptor blockers) are preferred antihypertensive drugs in ckd due to their specific renoprotective effects beyond blood pressure (bp) control, mediated by their antiproteinuric, antiinflammatory and antifibrotic properties. it is less clear whether bp reduction to low-normal values has an additional salutory effect on gfr preservation. children suffer from a markedly different spectrum of renal diseases than adults, with a preponderance of hypo/dysplastic kidney malformations. hypertension and proteinuria are common but usually moderate. to elucidate the renoprotective efficacy of ace inhibition and strict bp control in children, the escape trial was launched by a consortium of 33 european pediatric nephrologists. a total of 400 children and adolescents with stage ii-iv ckd received a fixed dose of ramipril and were randomized to intensified (<50th percentile) or conventional bp control (50th-95th pct). 24 h-bp, proteinuria and gfr were monitored over a 5-year period. 24 h mean arterial pressure (map) was reduced by ramipril from 89 to 83 mm hg (i. e. from 1.5 to 0 sds) on average. subsequently, mean map was lowered further to 79 mm hg at 24 months in the intensified arm, and maintained around 83 mm hg (0.2 sds) in the conventional control arm (p<0.0001). on average 1.1 antihypertensive drugs were added to ramipril in the intensified and 0.4 in the conventional treatment arm (p=0.0001). treatment tolerability was excellent in both arms, with less than 3% dropouts due to side effects. in summary, ramipril was effective and well tolerated in children with ckd. it is possible and safe to target low-normal bp in children. final results regarding renal survival will be available in summer 2007 and presented at the ipna meeting. nephronophthisis and joubert syndrome: converging on convergent extension? nephronophthisis (nphp), an autosomal recessive cystic kidney disease, leads to terminal kidney failure in adolescence. nphp may be associated with retinitis pigmentosa (rp) in senior-loken syndrome (slsn) or with cerebellar vermis aplasia in joubert syndrome (jbts). we have identified by positional cloning 7 genes as mutated in nphp. the gene product of nphp1, nephrocystin-1, acts in focal adhesion signaling. by positional cloning we detected mutations in the nphp2/inversin gene as causing infantile nphp (type 2) with association of situs inversus or rp. we demonstrated expression of nphp1, 2 in primary cilia of renal epithelial cells, supporting a new unifying theory for the pathogenesis of cystic kidney diseases (watnick et al. nature genet 34: 355, 2003) , stating that the products of all genes mutated in cystic kidney disease in humans, mice, or zebrafish are expressed in primary cilia, basal bodies, or centrosomes of renal epithelial cells (hildebrandt et al. nature rev genet 6: 928, 2005) . identification of nphp3 mutations in nphp type 3 also revealed the cause of the renal cystic disease mouse model "pcy", for which treatment has been demonstrated. positional cloning of nphp4 led to the demonstration that its gene product, nephrocystin-4, is conserved in c. elegans and expressed together with nephrocystin-1 in ciliated head and tail neurons of the nematode. the role of primary cilia function for retinal-renal syndromes was confirmed by identification of the novel nphp5 gene. recently, several signaling pathways have been implicated in the downstream signaling pathways that connect ciliary/basal body function to the renal cystic phenotype. these include the wnt signaling/planar cell polarity pathways, and the hedgehog signaling pathway. we implicated the planar cell polarity signaling pathway in nphp by positional cloning of mutations in the gene nphp6/cep290 as causing joubert syndrome. abrogation of nphp6 function in zebrafish caused planar cell polarity (convergent extension) defects and recapitulated the human phenotype of joubert syndrome. further gene identification in nphp will result in the definition of functional networks of primary cilia, centrosomes, and planar cell polarity as they pertain to the pathogenic mechanisms of nphpassociated syndromes and other cystic kidney diseases. hnf1b is a transcription factor that is expressed in bile ducts, intestine, pancreas and renal epithelia. germ-line inactivation of the mouse hnf1β/tcf2 gene is embryonic lethal (e7.5) due to defective differentiation of the extra-embryonic visceral endoderm. hnf1β is later expressed in endoderm derivatives and in the mesonephros. to understand the function of hnf1b at later stages of development and during organogenesis, we applied a conditional inactivation based on a (cre-loxp) strategy. with the use of a cre recombinase that is expressed in renal collecting ducts and henle loops (ksp-cre) we found that hnf1b inactivation leads to polycystic kidney disease (pkd). this is reminiscent of the renal phenotype of patients carrying heterozygous mutations in tcf2/hnf1β. these patients suffer from maturity onset diabetes of the young type 5 (mody5) and at the same time from renal cysts (renal cysts and diabetes or rcad). this cystic phenotype is linked to the defective expression of pkhd1 and pkd2, two genes mutated in pkd patients. the cellular and molecular mechanisms underlying pkd are still poorly understood. it was recently speculated that planar-cell-polarity signalling (wnt) could be at the basis of cyst formation. maturation of nephrons during development is accompanied by a considerable lengthening of tubules. this process involves an intense proliferative phase without any increase in tubule diameter. interestingly, we discovered that the progeny of consecutive cell divisions are adjacent one another and oriented in parallel to the axis of tubules. this suggested that upon lengthening, cells divide according the tubule axis. in addition, 3d image reconstructions revealed that oriented cell division is due to the alignment of the mitotic spindle with the axis of the tubule. we hypothesized that oriented cell division could play an essential role in preventing tubular dilation during the massive proliferative phase that accompanies tubular elongation. indeed, our results indicated that both in ksp-cre-kidney-specific-hnf1β-deficient pups and in the pck rats, lacking the expression of pkhd1, the mitotic alignments were highly distorted. our results indicate that hnf1β plays a crucial role in activating the expression of genes involved in the control of tubular size maintenance during tubular elongation. emerging evidence suggests that the intravenous injection of bone marrow-derived cells improves renal function after acute tubular injury. examination of human transplant biopsies of female kidneys that had been transplanted into male recipients have shown the presence of tubular cells that co-express the y chromosome and epithelial markers. however, controversy exists as to whether the protective effect is due to engraftment of the cells in the injured tubule or an endocrine/paracrine effect of the injected cells. our studies demonstrate that intravenous infusion of whole bone marrow from male mice into female recipients results in the appearance of significant numbers of y chromosome + cells in the kidney interstitium, and rare y chromosome + cells in the tubules. the majority of the interstitial cells express leukocyte markers such as cd45. in addition, we have found that i. v. or i. p. injection of bone marrow stromal cells (msc, adherent non-hematopoietic marrow cells) into mice reduced the severity of cisplatin-or ischemia-induced aki. examination of these kidneys demonstrates that mscs enhance tubular cell proliferation and decrease tubular apoptosis after injury. examination of multiple tissue sections at 1 or 7 days after injury failed to reveal any examples of y chromosome cells within the tubules, and only rare examples of y chromosome cells within the renal interstitium. furthermore, exposure to conditioned medium from cultured mscs (msc-cm) significantly diminished cisplatin-induced death of cultured proximal tubule cells in vitro, while i. p. administration of msc-cm in the mouse markedly diminished the rise in bun associated with cisplatin injection. thus our data suggests that hematopoietic cells and their derivatives from adult bone marrow enter the kidney in response to injury where they are primarily localized to the interstitial space as inflammatory cells. in rare instances, these cells may differentiate into, or fuse with, tubular epithelial cells. in contrast, bone marrow mscs fail to enter the kidney in significant numbers, but can protect the endogenous tubular cells from toxic injury by secreting a factor or factors that limit apoptosis and enhance proliferation. renal hypodysplasia (rhd) is characterized by a reduced nephron number, small kidney size and disorganized renal tissue. a hereditary basis has been established for a subset of affected patients, suggesting a major role of developmental genes involved in early kidney organogenesis. gene mutations with dominant inheritance causing rhd, urinary tract anomalies and defined extrarenal symptoms have been identified in tcf2 (renal cysts and diabetes syndrome (rcad)), pax2 (renal-coloboma syndrome (rcs)), eya1 and six1 (branchio-oto-renal syndrome (bor)) for the most frequent of these syndromes. a recent study on a cohort of 100 patients with rhd and consecutive renal insufficiency demonstrated that 16% of them had mutations in one gene encoding for a transcription factor. the majority of mutations were identified in tcf2 (hnf1β) (especially in the subset with kidney cysts) and pax2. this study demonstrates that subtle extrarenal symptoms in syndromal rhd easily can be missed. genetic testing in children with rhd should be preceded by a thorough clinical evaluation for extrarenal symptoms, including eye, ear, and metabolic anomalies. the presence of these anomalies increases the likelihood of detecting a specific genetic abnormality. in addition, mutations in genes that are usually associated with syndromes can occur in patients with isolated rhd. the ret receptor, its ligand gdnf and the co-receptor gfra1 play a pivotal role during early nephrogenesis and enteric nervous development. in humans, activating ret mutations cause multiple endocrine neoplasia, whereas inactivating mutations lead to hirschsprung disease. while ret deficiency also causes renal hypodysplasia (rhd) in the mouse model, genetic abnormalities in ret have not been characterized in human isolated renal malformations to date. the ret mutations, y971f and s649l, reportedly predisposing to medullary thyroid carcinoma (mtc) were found in one and six patients respectively in the same rhd cohort. none of the patients or their carrier relatives had clinical evidence of mtc at the time of the study. our findings suggest that ret mutations predispose to both mtc and rhd, with a low penetrance for either disorder. interestingly, a gdnf mutation was found in addition to a ret mutation and to an eya1 mutation in a patient with the branchio-oto-renal syndrome suggesting an oligogenic inheritance. mutations in clcn5, the gene encoding the chloride/proton exchanger clc-5, underlie most forms of dent's disease, an x-linked nephrolithiasis syndrome that is always associated with low molecular weight proteinuria. clc-5 belongs to the clc gene family of chloride channels and transporters and, in addition to other sites, is expressed in apical endosomes of the proximal tubule. in these vesicles, it co-localizes with the proton pump and with endocytosed proteins. previously thought to be a clchannel, it is now known to mediate electrogenic cl -/h + -exchange. this notion remains compatible with a role in supporting the acidification of endosomes by providing an electrical shunt for the h + -atpase. to clarify the pathogenesis of dent's disease, we created a knock-out mouse model. it displayed low molecular weight proteinuria due to a largely reduced endocytosis by proximal tubular cells (fluid-phase and receptor-mediated). the acidification of renal cortical endosomes was reduced in the ko. the failure of the pt to endocytose pth led to an increased luminal, but not systemic concentration of this hormone. this, in turn, resulted in hyperphosphaturia due to a retrieval of the phosphate transporter napi-2a from the pt plasma membrane. nephrolithiasis can be explained by altered renal handling of pth and vitamind, all of which are secondary to the impaired endocytosis. there is an increased prevalence of nephrolithiasis in individuals with obesity, type ii diabetes, and the metabolic syndrome. in particular, uric acid constitutes a much higher percentage of stones in these patients compared to the general stone-forming population. we strived to examine the pathophysiologic connection between the metabolic syndrome and uric acid stones. in the vast majority of cases, the principal abnormality in uric acid stones is not hyperuricosuria but an excessively low urinary ph. uric acid nephrolithiasis is in fact a disease of 'urinary acidification' although there is no systemic metabolic acidosis in the classical sense because acid-base balance is achieved and no excessive acid is accumulated. however, the excretion of protons using low pk closed buffers rather than the high pk open buffer ammonia dictates a low urinary ph. since protonated uric acid has a sparingly low solubility compared to ionized urate, low urine ph promotes uric acid precipitation. thus uric acid nephrolithiasis is an innocent bystander of low urinary ph. the link between the metabolic syndrome and urinary ph as a continuous variable is explored by epidemiologic, human metabolic, and laboratory studies. in population-based studies in stoneformers, low urinary ph is associated with higher body weight. urinary ph is also lower with increasing number of features of the metabolic syndrome (waist circumference, high triglycerides, low high density lipoproteins, hypetension, hyperglycemia) and within each of the features, the severity of each parameter is inversely proportional to urinary ph. in metabolic studies in humans, low urinary ph is associated with low peripheral insulin sensitivity. when studied as in-patients on identical metabolic diets, patients with type ii diabetes and uric acid stone-formers have high net acid generation than normal volunteers. this alone lowers urinary ph although the reason for the elevated acid load is not clear at present. in addition to high acid generation, uric acid stone formers tend to use buffers other than ammonia to buffer protons in the urinary resulting in unduly acidic urine ph. when challenged with an acute acid load, the ammonium excretion response is markedly blunted in uric acid stone-formers. a similar urinary abnormally of acidic urine ph and underutilization of ammonia is seen in the zucker diabetic fatty (zdf) rat compared to their lean counterpart. these animals have peripheral insulin resistance, elevated serum free fatty acid and have significant steatosis in their kidneys. one abnormality in the kidney is reduced expression and activity of the na + /h + exchanger nhe3 which is the major transporter that excretes ammonium into the urine and its activity is stimulated by insulin. causality is supported by the fact that treatment of the animals with a thiazolidinedione partially reversed the fat infiltration, urinary acidification abnormality and reduced expressed of nhe3. the direct effect of fat on the renal proximal tubule was tested in cultured cells. provision of fatty acids beyond the oxidation capacity of the tubule leads to dose-dependent impairment of nhe3, generalized dysfunction and eventually cell death. a sub-cytotoxic dose of free fatty acid did not affect baseline nhe3 activity and expression but reduced the ability of insulin to activate nhe3. in summary, the metabolic syndrome is associated with increase acid generation that is independent of diet. this increased acid load is effectively excreted by the kidney. failure to maximally utilize the ammonium buffer system results in lower urinary ph and titration of urate to its insoluble form as uric acid and results in uric acid nephrolithiasis. part of the pathogenic mechanism maybe lipotoxicity from fat infiltration of organs. uric acid nephrolithiasis is an "innocent bystander" which is a sentinel of a more generalized alteration in acid generation and excretion. genetic hypercalciuria recurrent kidney stone production is one of the most common diseases of the bipedal human condition, occurring in up to 10% of the population in western societies. unlike four-footed animals who likely perish in the wild from a selection disadvantage from a painful calculus, human beings continue to function, and have the ability to express the biologic defects repetitively that result in a stone. idiopathic hypercalciuria, where a specific gene defect has not yet been established, is a shrinking subpopulation of recurrent calcium stone formers, as specific mutations and functional polymorphisms of genes intimately or distantly related to calcium homeostasis arise from the sequencing of the human genome applied to clinical stone disease. other postulated mechanisms can be sought for in this manner as well, and may await larger population-based studies. the familial nature of nephrolithiasis is clear and robust for most calcium-based stone formers, and may have a gender-specificity for that inheritance. the role of environment in its expression remains controversial. the systemic nature of genetic hypercalciuria may be seen through its associated effects on skeletal health and biology. between 25-33% of children with genetic hypercalciuria have abnormally low bone density measured by dual-energy absorptiometry that cannot be explained by correction for height or body mass. further, normalization of urinary calcium excretion with a variety of therapies is associated with improvements in bone density values over time. a proposal for re-classifying hypercalciuria pathogenetically will be presented, and linked to observational data across the world for successful therapeutic approaches. a call for a stone registry and more careful determination of etiology will be sought through the ipna congress. the systems that regulate blood pressure are plastic during development and can be permanently reset. experiments in animals show that it is surprisingly easy to produce lifelong changes in blood pressure by minor manipulations of the mother's diet before and during pregnancy. this phenomenon has been referred to as "programming". epidemiological and animal studies show that programmed effects operate within the normal range of growth and development, and influence the risk of hypertension, coronary heart disease and stroke in later life. a clinical study of 2003 people aged 62 years from the helsinki birth cohort showed that two different paths of growth preceded the development of hypertension. people already diagnosed as having hypertension had small body size a birth and low weight gain from birth to two years but grew rapidly after two. at age eleven years their body size was around the average. as adults they tended to be obese and insulin resistant. a second group of people had not been diagnosed but their blood pressures were classified as hypertensive under current definitions. they were short at birth, had low weight gain from birth to two years and remained small after two. at age eleven years they were short and thin. as adults they tended to be overweight and have atherogenic lipid profiles. the first path of growth is similar to that which leads to coronary heart disease in this cohort. the second path is that which leads to stroke. this paper will present data on the maternal and placental influences through which these paths originate. nephron number is a key feature of the conceptual paradigm positing that cardiovascular and metabolic diseases that arise during childhood and adulthood have their origin in events that occur during fetal life. in mammals, nephrons are derived from a subset of cells resident within the metanephric blastema. blastemal cells participate in reciprocal inductive tissue interactions with the ureteric bud. these interactions induce the ureteric bud to grow and branch. in turn, ureteric bud branches induce discrete populations of the metanephric blastema to undergo successive transitions resulting in the formation of mature nephrons. a distinct population of metanephric blastema cells in the stroma modulates branching morphogenesis and nephrogenesis. identification of genes that control both branching morphogenesis and nephrogenesis is providing insight into the molecular pathways that could be targeted by environmental, nutritional and hormonal factors that control fetal programming. this lecture will highlight the morphologic and cellular events critical to renal branching morphogenesis and nephrogenesis, and the gene networks that regulate or counter-regulate these events. these gene networks will then be considered in the light of non-genetic factors that modulate their activities. it is now accepted that early life environment can modulate adult phenotype, including the blood pressure. the likely primary mechanism is epigenetic modulation of gene expression during a sensitive period of fetal maturation, but the pathogenesis of the later development of hypertension is unclear. participation by extrarenal factors such as central regulation and peripheral vascular function has been evoked; however, a strong body of experimental evidence suggests that the "setpoint" for renal regulation of na balance and extracellular volume is altered. because both humans and many experimental models with prenatally programmed hypertension appear to have a decrease in the total number of nephrons, impaired filtration of na has been hypothesized to be an important pathogenetic factor. more recent evidence has suggested that postnatal inflammation and accumulation of reactive oxygen species in the renal interstitium may contribute to the genesis of hypertension by upregulating distal nephron na transport. furthermore, the role of renal vascular function remains to be determined. the different mechanisms are not mutually exclusive; it is conceivable that both a prenatal "priming" and a postnatal "second hit" are required for hypertension to become manifest. j. ingelfinger epidemiological studies published in the late 1980s by barker and his group -and since replicated in many populations -provide evidence of an inverse relationship between birthweight and risk of cardiovascular disease, hypertension, and renal dysfunction in adult life. both clinical studies and animal models have been used to investigate mechanisms underlying these observations [as cited in recent reviews. the concept that changes in the intrauterine milieu affect the growing fetus resulting in alterations in physiology and general health in later life has been termed perinatal programming or developmental origins of health and disease [dohad] . yet, despite a large and burgeoning literature about this phenomenon and its relationship to cardiovascular and renal disease, involved mechanisms remain elusive. maternal malnutrition or exposure to various medications or substances leads to an adverse in utero environment that may impair nephrogenesis, evident in experimental animal studies as well as in clinical reports in humans. nephron deficit at birth persists throughout life, creating "low glomerular endowment, " an important risk factor for hypertension and esrd in adulthood. for a number of years it has been hypothesized that nephron number may strongly influence blood pressure as well as susceptibility to renal disease in later life. recently clinicopathologic observations suggest that a relationship more directly. renal morphogenesis involves complex events in which many genes interact in the formation of the final kidney. when the normal pattern of nephrogenesis is interrupted, renal abnormalities may ensue. during renal development, two major events -ureteric bud (ub) branching and mesenchymal-to-epithelial transformation -greatly impact the outcome of renal morphogenesis. renal malformation accounts for approximately 40 percent of childhood renal failure and represents the end result of failure of fundamental embryonic processes in ub and metanephric mesenchyme (mm) lineages. this presentation will review the data concerning renal responses to perinatal challenges as these occur and later evolve during childhood. we will consider the implications and the data available concerning screening, follow-up and management of at-risk persons. generation of oxidized lipoproteins in obstructive nephropathy -atherogenic or fibrogenic? children's hospital and regional medical center, division of pediatric nephrology, seattle, united states chronic kidney disease, regardless of etiology, is characterized by a relentless progression of fibrosis that gradually destroys the normal renal architecture, particularly in the tubulointerstitium. obstructive uropathy accounts for approximately 35 percent of pediatric patients with chronic kidney disease (ckd) and end-stage renal disease (esrd). after post-natal relief of obstruction, the optimal treatment of children with obstructive uropathies remains unknown and for many the progression of ckd to esrd is inevitable. therapeutic options are limited by an incomplete understanding of fibrogenic pathways in the kidney. the major renal fibrotic pathways identified thus far can be broadly classified into those involved in transforming growth factor beta (tgf-b) activation, macrophage-mediated inflammation, angiogenesis, and extracellular matrix production/degradation. it is becoming increasing clear that key molecules have multiple roles in several of these pathways triggering fibroinflammatory events targeting specific cell types. oxidative stress represents an intersection of many of these fibroinflammatory pathways leading to cellular activation and tissue injury. oxidized lipoproteins accumulate in the circulation and renal interstitium in both experimental models and patients with ckd and esrd. many parallels have been drawn between atherogenesis and the pathogenetic mechanisms of progressive kidney destruction by fibrosis. although ckd is clearly associated with an increased cardiovascular risk, it is not clear whether oxidized lipoproteins amplify fibrogenic pathways in the kidney. research in our laboratory suggests that hypercholesterolemia increases injury severity in obstructed kidneys. scavenger receptors mediate the cellular effects of oxidized lipoproteins during atherosclerosis and activate both inflammatory and oxidative pathways. dietary and antioxidant therapies have clear benefits in animal models but limited efficacy in patients. our studies suggest that blocking key scavenger receptors leads to a significant attenuation of both oxidative and pro-inflammatory pathways during chronic injury by obstruction in hypercholesterolemic mice. interventions targeting scavenger receptor signaling may represent an alternative strategy to attenuate both the progression of ckd and cardiovascular disease. the resolution of injury and promotion of renal repair comprises a delicate balance between cell death and destruction of tissue architecture in relation to cell differentiation, maturation and extracellular matrix (ecm) remodeling. although many studies have focused on the cellular and molecular events leading to the development of renal fibrosis, less is understood about the process of renal repair and regeneration. this is despite the fact that the kidney has a significant capacity for regeneration and cellular replacement following acute damage. the present study describes the structural, functional, and expression profile analysis of endogenous renal repair and the regenerative potential of the kidney following reversal of ureteral obstruction (r-uuo) in the mouse.10 days after unilateral ureteral obstruction there is renal tubular cell loss, activation of an inflammatory cascade leading to widespread cortical interstitial fibrosis and the loss of normal medullary architecture. following 2 to 6 weeks after r-uuo there was marked tubular repair and regeneration of medullary components, ecm remodeling and decreased inflammatory cell infiltration. the structural repair observed at 6 weeks post-release of ureteral obstruction was associated with a 50-86% recovery of the glomerular filtration rate (gfr). expression profile analysis was performed to visualize patterns of gene expression that were differentially expressed in the repaired and remodeling areas following r-uuo. we are also interested in the regulation of cellular recovery and the processes involved in epithelial cell re-differentiation in regenerating tubules following injury. tubular epithelial cell cilia may play potential roles in directing the orientation of cell division and epithelial differentiation during the endogenous remodeling process. our results suggest that renal cilium lengthening may be an important factor in the response to injury and subsequent recovery of renal function. these studies propose that a lengthening of renal epithelial cilia increases their sensitivity to flow and reduces damaging epithelial dedifferentiation in the injured renal tubules. a better understanding of the key events involved in endogenous renal repair and remodeling may open the way to new interventions based on their manipulations aimed at acceleration of renal regeneration and prevention of scarring. soren nielsen has kindly agreed to present this topic, however was not able to submit an abstract. the final regulation of urinary k excretion in the fully differentiated kidney is accomplished in the distal nephron, including the cortical collecting duct (ccd), where cell k passively diffuses into the urine through apical k selective channels. the prevalence of the sk/romk channel and its high p o at the resting membrane potential has led to the belief that this channel mediates baseline k secretion. less easily detected is the bk channel which is characterized by a low p o at the physiologic resting membrane potential and [ca 2+ ] i . bk channels are activated by membrane depolarization, elevation of [ca 2+ ] i , and/or membrane stretch, and can be selectively blocked by iberiotoxin (ibx). we have reported that flow-stimulated net k secretion (jk) in the adult rabbit ccd is (i) blocked by ibx and (ii) associated with increases in net na absorption (jna) and [ca 2+ ] i , leading us to conclude that bk channels mediate this process. recent studies have examined the acute and chronic regulation of bk channel-mediated flow-stimulated jk. we reported that flowstimulated jk requires an increase in [ca 2+ ] i due to luminal ca 2+ entry and er ca 2+ release, microtubule integrity, and exocytic insertion of preformed channels into the apical membrane. channel expression is regulated long term during postnatal development and by dietary k intake. specifically, an increase in tubular fluid flow rate fails to elicit an increase in jk in the rabbit ccd until the 5 th wk of postnatal life, coincident with appearance of immunodetectable bk channels, whereas flow-induced increases in jna and [ca 2+ ] i in 2-wk-old ccds are "mature". a role for the bk channel in renal k adaptation has been suggested by the observation that dietary k loading leads to an increase in abundance of bk message in microdissected ccds with redistribution of immunodetectable channel proteins from an intracellular pool to the apical membrane. additionally, ccds isolated from k loaded animals demonstrate enhanced flow-stimulated jk compared to tubules from control fed animals. in sum, emerging evidence suggests that the bk channel plays a prominent role in distal k secretion in response to increases in urinary flow rate and dietary k intake. the late developmental appearance of this channel is compatible with the need of the growing animal to retain k early in postnatal life. recent advances in molecular genetics of hereditary hypomagnesemia substantiated the role of a variety of genes in human magnesium transport. this knowledge on underlying genetic defects helps to distinguish different clinical subtypes and gives insight into molecular components involved in magnesium transport. during the last four decades, numerous reports concerning inherited magnesium losing disorders have been published and their distinctive phenotypic features have been discussed. phenotypic characterization of affected individuals and experimental studies of appropriate animal models have contributed to a growing knowledge of renal magnesium transport mechanisms. the identification of the affected nephron segments, the different modes of inheritance and the observation of additional characteristic symptoms promoted a classification into different subtypes of inherited magnesium losing disorders. in general, primary magnesium wasting disorders are relatively rare. the prevalence of the more frequent entities, for example gitelman syndrome, has been estimated to be approximately 1: 50.000. for most of the other disease entities, relatively few cases have been reported in the literature. depending on the genotype, the clinical course is sometimes mild or even asymtomatic. therefore, the disease prevalence might be underestimated for some of these syndromes. magnesium transport has been intensively studied in humans and various animal models leading to accepted concepts underlying the pathophysiology of the different forms of hypomagnesemia. however, the electrophysiological characterization of magnesium pathways has been complicated by unintentional simultaneous measurement of other cations so that the molecular correlates mediating mammalian magnesium transport components remained undefined. a different approach to study components of magnesium transport arises from genetic analysis of families affected with magnesium wasting diseases. linkage studies enabled the localization of several genes involved in hereditary hypomagnesemia and in the last decade, a number of genes have been identified by positional cloning. these genes have provided first insight into mammalian magnesium transport molecules. distal renal tubular acidosis may be inherited as an autosomal dominant or recessive trait. mutations in three genes -slc4a1, atp6v1b1 and atp6v0a4 -are associated with the various forms of disease, and give rise to a wide spectrum of clinical severity. in general, dominant mutations do not affect ion transport function per se and do not affect hearing, whereas recessive disease is characterized by loss of function and deafness. some unusual functional consequences of mutations in ae1 and a4 proteins are mistargeting and loss of protein-protein interaction respectively, and these will be discussed. the heart in pediatric nephrotic syndrome y. frishberg shaare zedek medical center, pediatric nephrology, jerusalem, israel in recent years, the molecular bases of several conditions which lead to steroid-resistant nephrotic syndrome (srns) have been identified. the common denominator shared by these clinical entities is that they all result from structural defects in the glomerular barrier, thus explaining their unresponsiveness to immunosuppressants. for instance, the congenital ns of the finnish type is caused by mutations in the nphs1 gene encoding nephrin. a recessive form of srns was found to result from mutations in nphs2 encoding podocin which is specifically expressed in podocytes. we have previously shown that a founder mutation in nphs2 (r138x) is the prevalent cause of hereditary srns (55% of tested are homozygotes) among arab children in israel. interestingly, we noted that a number of patients who are homozygous for the r138x mutation in podocin have a co-existing cardiac disorder. only a few case reports described an association between srns and cardiac defects. we questioned whether the glomerular-barrier disorders, which have been considered to be kidney-specific, have implications on other organ-systems. thus, we systematically reviewed the cardiac status of these srns patients at the time of diagnosis while they had normal blood pressure and preserved renal function (31). cardiac anomalies were detected in 89% of children, the most common of which were cardiac hypertrophy and pulmonary stenosis. analyzing two control groups enabled us to conclude that cardiac disorders in homozygotes for mutations in nphs2 cannot be attributed to an association by chance or to a state of persistent ns. because human podocin mrna is expressed in fetal heart, we hypothesize that it may have a role in normal cardiac development and this will be an issue of further investigation. this is the first study showing a role for podocin in extra-renal tissues and therefore recommends early cardiac evaluation for timely medical management. cvd is the world-wide biggest obstacle to long-term survival of children and adolescents with ckd. mortality from cvd is excessively high on dialysis and continues to be a threat after renal transplantation. early diagnosis of the individual risk for cvd would enable preventive measures on an individual basis. however, prospective studies with hard end points -cardiac events -are difficult if not impossible to conduct in children and adolescents. on the other hand, the known high morbidity and mortality in elderly dialysis patients may largely result from pre-existing comorbidity (advanced atherosclerosis has been demonstrated in this age group at initiation of dialysis). for this reason, investigations in patients with childhood onset ckd may provide a diagnostic window to study the pathogenesis of cardiac and vascular changes in subjects without comorbidities. several studies using non-invasive measurements of surrogate markers for cvd have demonstrated a pattern of early systemic cvd, including changes in intima-media thickness (imt) of conduit arteries (aorta, a. carotis) and muscular arteries (a. femoralis), altered function of peripheral resistance arteries (venous occlusion plethysmography) and abnormalities in the heart (echocardiography). patients show a significant decrease in post-ischemic vascular reactivity with evidence of vascular stiffness and frequently have extraosseous calcifications often involving coronary arteries and heart valves. importantly, these studies have found little evidence for correlations with classical risk factors (except hypertension), but with abnormalities of calcium and phosphorus metabolism and their therapy, including the intake of active vitamin d preparations and calcium-containing phosphate binders. thus, patients with childhood-onset ckd are at high risk to develop systemic cardiovascular changes, which may represent a new disease originating from the survival of ckd, a previously deadly disease, and interventions for the prevention of renal osteodystrophy. this therapeutic challenge needs to be addressed with high priority to enable long-term survival of children with ckd. while their mere existence is still questioned by some investigators, lipid rafts have recently gained a large amount of attention because of their apparent involvement in various cellular processes, including signaling, membrane trafficking, polarization, and endo-as well as exocytosis of proteins as well as pathogens. membrane rafts have been defined as small (10-200 nm) heterogeneous, highly dynamic, sterol-and sphingolipid-enriched domains that compartmentalize cellular processes and that can sometimes be stabilized into larger platforms by protein-protein or proteinlipid interactions. rafts are of special interest for pediatric nephrologists for two reasons: 1. they play a critical role in immune cell activation, especially in the formation of the immunological synapse (is), and thus in many important disease processes affecting our patients, including -but not limited to -transplant rejection. beyond their participation in is formation, rafts also facilitate signaling through other immune cell receptors, such as the interleukin-2 receptors, where they may ascertain cytokine selectivity and specificity. 2. equally important, rafts serve as essential site for proper interactions between nephrin and podocin, thus establishing the integrity of the glomerular filter. general aspects of raft biology as well as their role in immune cell signaling will be reviewed in more depth in this presentation. raft involvement in glomerular filter formation and especially genetic aspects relevant to disturbances of this involvement and of the associated integrity of the filter, as seen in hereditary nephrotic syndromes, are discussed in subsequent presentations in this symposium. reports of familial forms of fsgs date back to 1956, with the observation of an autosomal recessive disease primarily within the finnish population. it is characterized by massive proteinuria in utero, with up to 20 to 30 grams of protein loss per day. nphs1 encodes a gene product termed nephrin that localizes to lipid rafts within the slit diaphragm of the podocyte. steroid-resistant nephrotic syndrome (srns) is an autosomal recessive nephrotic syndrome and manifests between 3 months and 5 years of age, rapid progression to esrd, and with few cases of recurrence after renal transplantation. the gene product is podocin (nphs2), located on 1q25-31. podocin most likely functions in the structural organization of the slit diaphragm and regulation of its filtration function. it has been shown to interact in vivo with both nephrin and cd2-associated protein (cd2ap), a cytoplasmic binding partner of nephrin. mutations in the alpha-actinin 4 gene (actn4), localized to chromosome 19q13 have been associated with autosomal dominant fsgs, characterized by adult onset disease of variable severity and rate of progression to esrd. fractions of the mutant protein have been shown to form large aggregates within podocytes ultimately compromising the function of the normal actin cytoskeleton, both through its abnormal function and toxic accumulation. recently, a disease-causing mutation for hereditary fsgs has been localized to chromosome 11q 21-22, and identified as the transient receptor potential cation channel, subfamily c, member 6 (trpc6). the missense mutation causes a highly conserved proline in the first ankyrin repeat of trpc6 to become a glutamine at position 112 (p112q). the trpc6 p112q mutation causes increased and prolonged calcium transients in transfected cells. the mutant channel also significantly enhances cation signals triggered by at1 receptor activation. biotinylation and immunostaining studies reveal that the mutation also appears to cause mislocalization of the ion channel to the cell surface. whereas previously reported mutations such as nphs1, nphs2 and actn4 have emphasized the importance of cytoskeletal and structural proteins in glomerular diseases, trpc6 related fsgs suggests an additional mechanism for renal disease pathogenesis. knowledge of trpc6 mediated calcium entry into cells may offer unique insights into therapeutic options for glomerular diseases. t. huber university hospital, department of nephrology, freiburg, germany the sense of touch relies on the ability of specialized sensory cells to convert mechanical stimulation into ionic currents. mechanoreceptor cells respond to external force by opening ion channels. recent findings highlight now a potential role for the mechanosensitive ion channel trpc6 at the glomerular filtration barrier. trpc6 localizes to the slit diaphragm and mutations of trpc6 cause familial glomerular disease. mutations of the phb-domain protein podocin are the most common cause of hereditary nephrotic syndrome and we demonstrate that podocin and mec-2, the closest homologue of podocin in caenorhabditis elegans, bind cholesterol to regulate the activity of associated ion channel complexes: deg/enac channels for mec-2 and trpc channels for podocin. both the mec-2-dependent activation of mechanosensation in c. elegans and the podocin-mediated activation of trpc6 channels requires cholesterol. our data suggest that the recruitment of cholesterol by podocin and mec-2 to ion channels plays an important role in regulating their activity. these findings promote the concept that podocin, similar to the function of mec-2, may be part of a mechanosensitive protein complex at the slit diaphragm of podocytes. isidro salusky has kindly agreed to present this topic, however was not able to submit an abstract is there a role for bisphosphonates in pediatric bone disease? f. santos hospital universitario central de asturias, universidad de oviedo, pediatria, oviedo, spain bisphosphonates are being increasingly and successfully utilized to prevent bone fractures and treat bone pain in children with severe osteoporosis from different origins. a largest experience has been accumulated with the administration of cycles of intravenous pamidronate in children with osteogenesis imperfecta. in addition, to the bone resorption inhibition mediated by their effects on osteoclasts, bisphosphonates given in large doses inhibit normal and ectopic mineralization. thus, bisphosphonates have also been used in children with hypercalcemia and in the treatment of calcinosis and heterotopic ossification, bisphosphonates have been administered to renal transplanted adults to prevent or treat bone loss induced by chronic administration of glucocorticoids and might also be useful in the management of urolithiasis in selected hypercalciuric patients. the potential clinical utilization of bisphosphonates in the prevention and treatment of vascular calcification in patients with chronic renal failure is now being explored, although no data on children in this clinical setting are available. a number of questions as to the precise clinical indications to start bisphosphonates' administration, the type of bisphosphonate to be used, the duration of the treatment, the best way to monitor its effectiveness and the risk of longterm toxic effects remain to be answered. water is the solvent in which all metabolic reactions occur. body water moves between compartments with diverse compositions that are separated by semi-permeable lipid membranes. water exchanges also occur between maternal and fetal blood separated by several layers of tissue, the so-called placental membranes. the fetus appears to be dependent on placental flow and perfusion pressure for the bulk of his water requirements, and the prostanoids play a significant role in the control of ureteroplacental and umbilicoplacental blood flows. osmotic and hydrostatic forces control placental water flux. the amniotic fluid (af) appears early during gestation and its volume increases rapidly. the net af volume turnover approximates 95% per day. major sources of af production are represented by fetal lungs secretions, and by fetal urine. the af is initially isotonic, and becomes hypotonic when significant amounts of dilute urine are produced by the fetus. disposal of water is effected by fetal swallowing of af and by the intramembranous (im) pathway, that is the route of absorption between the fetal circulation and the amniotic cavity. this route appears to play an important role in the overall regulation of af volume and composition. the fact that water crosses the im pathway in excess of solutes suggests a role for aquaporin water channels in allowing this transport. circumstantial evidence indicates that the im water flow is regulated by aquaporin 1. homeostatic changes in placental permeability could thus be up or down-regulated by the number of aquaporin water channels in the membrane. systemic lupus (sle) is a multigenic and multifactorial disease, characterized by b lymphocytes polyclonal activation with decreased tolerance, autoantibodies production and immune complexes formation. dna was initially thought to be the mayor auto-antigen, however, it is not immunogen and injection of dna-anti dna does not induce lupus nephritis. the complex of dna and histones (nulceosome) is provided with a positive electrical charge which favours the binding to heparansulphates in the gbm. in sle high levels of nucleosomes are present in circulation due to accelerated lymphocytes apoptosis or defective removal of apoptotic cells. lupus nephritis (ln) is consequent to deposition of immune complexes, activation of lymphomononuclear cells and reactivity of renal cells. the who classification of lupus nephritis has been recently reviewed by the isn/rps. the new classification takes into account a distinction between forms without endocapillary hypercellularity (mesangial or subepithelial deposits) and others with endocapillary hypercellularity (involving less or more than 50% with segmental or global distribution). prognosis and treatment of ln need a flexible therapy, tailored on histological picture and clinical data. steroids must be given at high doses for induction therapy but have drawbacks of heavy morbidity and mortality. the addition of immunosuppressive drugs improves the therapeutic index. the nih protocol used cyclophosphamide (cyc) pulses in severe ln (monthly pulse for 6 months followed by quarterly pulses for 1 year). more recent studies, comparing low with high doses cyc pulses, failed to prove a significantly different effect. for maintenance therapy of ln, mycofenolate mofetil may be a good alternative to cya or aza. rituximab, a chymeric monoclonal antibody anti cd20, which selectively and profoundly depletes b lymphocytes, has provided very interesting results in sle with poor response to classical therapy or in relapse. the possibility of rotating agents with different side effects may allow to lower the doses of steroids, to reduce drug-specific morbidity, and to improve the compliance of patients. efforts should be done to minimize steroids and cyc which are very effective but are the main responsible of invalidating and even lifethreatening complications. for half a century now, physicians have tried to classify vasculitic syndromes. classification of vasculitides is required to put in perspective the pathogenesis and therapeutic advances and to provide a uniform language, given the variation in the epidemiology of these diseases. the "american college of rheumatology" criteria have been used for classification and the chapel hill consensus criteria for definition purposes in children as well however they are based totally on adult criteria. taking into account the differences in children and the new developments in medicine a group of pediatricians have aimed to revise the classification of vasculitic syndromes encountered in children. the consensus group consisted of a multinational panel of experts who were pediatricians, pediatric rheumatologists and pediatric nephrologists. the delphi and nominal group techniques were used. this project has provided classification criteria for henoch-schönlein purpura, childhood polyarteritis nodosa, wegener granulomatosis and takayasu arteritis. this was an important task since appropriate classification criteria for vasculitis in children has been missing for far too long. we hope that the international and multispecialist composition of the expert group involved will facilitate the applicability of this classification for most vasculitic diseases in children seen around the world and will meet the needs of pediatricians. these criteria are now to be validated using a large registry for childhood vasculitides. anti-neutrophil cytoplasm antibodies (anca) are well established as a diagnostic marker for small vessel vasculitis, including wegener's granulomatosis and microscopic polyangiitis. there is increasing evidence that anca are directly involved in the pathogenesis of vascular inflammation in these disorders. in clinical studies, there is a clear relationship between levels of anca and the activity and extent of disease, and anca positivity confers an increased risk of relapse. rising titres of anca predict relapse, and two studies have shown that pre-emptive treatment of those with rising titres can prevent relapse. of great interest is the recent report of a newborn child who developed glomerulonephritis and lung haemorrhage after transplacental transfer of anca. in vitro experiments have shown that anca can activate cytokine primed neutrophils to release oxygen radicals, enzymes and inflammatory cytokines. this is achieved through both direct f(ab) 2 binding and fc receptor engagement. in co-culture, anca can induce neutrophil mediated killing of endothelial cells. in flow chamber studies, anca can induce neutrophil adhesion and transmigration across endothelial cell monolayers. more recently, anca have been shown to be pathogenic in experimental models of disease. high titre anti-mpo antibodies induced by immunisation of mpo deficient mice can transfer glomerulonephritis and vasculitis to naive recipients. immunisation of rats with mpo induces anti-mpo autoantibodies which lead to crescentic glomerulonephritis. intravital microscopy in this model confirms that anca can induce leukocyte transmigration and microvascular haemorrhage in vivo. however, many questions remain unanswered. some patients may have high levels of anca without disease activity, and others may have typical disease without detectable anca. it seems likely that t cells may be involved, not only in providing help for anca synthesis, but also in mediating tissue damage. it is also possible that an additional inflammatory stimulus, for example an infection is required, to enhance the inflammatory effects of anca. greater understanding of the role of anca in vascular inflammation will hopefully lead to safer and more effective approaches to treatment. hacettepe university, faculty of medicine, department of pediatric nephrology, ankara, turkey the therapy of vasculitic syndromes poses a problem for the caring pediatrician. the treatment of anca associated vasculitides will be presented to cover microscopic polyangiitis, wegener granulomatosis and churg strauss syndrome. treatment of all anca-associated diseases are similar. steroids and cyclophosphamide are the mainstay of induction treatment. in severe patients with kidney involvement steroids can be given in the form of intravenous methylprednisolone for 1-3 days (15-30 mg/kg/d, max.1 gr), followed by daily oral corticosteroids (1.5 mg/kg/d, max.60 mg/d). cyclophosphamide may be given at 2mg/kg/d p. o. or monthly iv pulses 0.75gr/sqm for at least 6 months. for maintenance treatment there are again many different regimens for oral corticosteroids. along with corticosteroids for maintenance regimen there are a number of protocols suggesting the continuation of cyclophosphamide. the cycazarem study has shown that the replacement of cyclophosphamide with azathioprine at 3 months was also as effective for disease control. methotrexate has also been shown to be an alternative for maintenance treatment. treatment of the childhood polyarteritis nodosa (pan) with systemic disease is similar to that of anca-related vasculitides. there are a number of non-anca associated vasculitides in childhood. the most frequent in childhood are henoch-schönlein purpura (hsp), kawasaki disease (kd) and takayasu arteritis (ta). the treatment of hsp is usually symptomatic. however, for severe kidney involvement with extracapillary proliferation and rapidly progressive disease severe immunosuppressive treatment is indicated. triple treatment with steroids, cyclophoshamide and dipyridamole have been given in various series. for kd intravenous immunoglobulin at a dose of 2g/kg still remains the first choice of treatment along with salicylates. for ta therapy depends on the extent of vessel invovlement: severe disease necessitates steroids and cyclophosphamide whereas for less intensive vessel involvement methotrexate and steroids may suffice. treatment period depends on the actiivty of the disease. lb. zimmerhackl haemolytic uraemic syndrome (hus) is the most common cause of acute renal failure in children. the syndrome is defined by the triad of microangiopathic haemolytic anaemia, thrombocytopenia and acute renal failure (creatinine over the 97 th percentile). world wide hus is increasing. in a german/austrian multicenter study we follow 628 children with hus occurring in the years 1997 to 2002.5 year follow-up data are now available www. hus-online. at. from this study the following results are obvious. hus affects predominantly children of kindergarten age. the median age at onset is 2,9 years. the majority of hus is of infectious origin. shigatoxin (stx) producing escherichia coli (stec, ehec) are present in over 80% of patients. the predominant shigatoxin type is type ii. hus is classified into two clinical subgroups. "typical" hus usually occurs after a prodrome of diarrhoea (d+hus), and "atypical" hus (ahus), which is not associated with diarrhoea (d-hus). the majority of d+hus worldwide is caused by ehec type o157: h7, which is transmitted to humans via different routes. however non-o157 groups are emerging and are predominant in europe. transmission of disease in elder patients is predominantly through food poisoning and direct contact to farm animals. in infants and small children direct transmission from human to human seems to be more likely. currently there are no specific therapies preventing the disease course. anti-shigatoxin antibodies are being tested by several companies. if this may prevent hus is open to study. otherwise the therapy at present is symptomatic. parenteral volume expansion before hus in patients with positive stx or ehec stool culture may counteract the effect of thrombotic process before development of hus and attenuate renal injury. use of antibiotics, antimotility agents, narcotics and non-steroidal anti-inflammatory drugs should be avoided during the acute phase in particular during the prodromal phase. from our own study the prevention is best done by preventing primary ehec infection. however, patients with severe course and long term sequelae should be screened for genetic abnormalities in the complement system. if auto antibodies against complement proteins or the vwf play an relevant role is under discussion. patients under one year of age at onset have a significant worse outcome and should be kept under surveillance. patients below 3 month of age are very likely to have an inborn error of complement or vwf and should be tested specifically. the european registry on hus and related disorders may help to determine these abnormalities: www. haemolytic-uraemic-syndrome. org. in order to improve long term outcome of these patients, increased awareness and an european (international?) task force is mandatory. in adults with chronic kidney disease, protein-energy malnutrition and inflammation are risk factors for death and accelerated cardiovascular disease. the "malnutrition-inflammation-cachexia syndrome" (mics); anorexia, increased basal metabolic rate, and loss of lean body mass is associated with low serum albumin, decreased protein intake, elevated c-reactive protein, and low serum cholesterol levels in adults. in children, mics manifests as growth retardation. clinical research focusing on the evolution of mics in pediatric ckd to understand its causes and consequences and how nutritional interventions alter its course may be the key to improving survival in ckd. baseline cross sectional data from the ongoing chronic kidney disease in children study, of children (n=335) aged 1-16yrs (mean=11.1yrs) with estimated gfr 30±90 ml/min/1.73 m 2 (mean iohexol gfr 38 ml/min/1.73 m 2 ) shows substantial growth retardation in ckd with median height percentile=23. greater height deficits are seen at lower gfr's. symptoms of decreased appetite and nausea are reported by 35% and 47% of those with gfr <30 respectively. mean ldl cholesterol is lowest in those with gfr <30 (97 vs 123mg/dl in gfr 30±40 ml/min/1.73 m 2 group). serum albumin declines as serum creatinine increases (r=-0.22). unlike previous reports in adult ckd, increases in crp were not associated with lower gfr at baseline. further exploration of the mics in pediatric ckd will be presented. the causes of growth failure in pediatric patients with chronic kidney disease (ckd) are multifactorial. it is an open question as to which factors play a key role in diminishing physical growth. it is also unclear which mechanisms may become pace makers for the therapeutic improvement of growth. furthermore, growth failure in children with ckd affects total body height, body proportions and composition as well as organ development. growth failure may also lead to disproportion which can only be identified by detailed anthropometric measurements. we were able to demonstrate that ckd patients have a specific age-dependent pattern of growth and distinct changes in segmental growth (trunk, arm and leg length) from birth to adolescence. leg growth in relation to other parameters of linear growth showed the most dynamic growth changes and emerged as the best indicator of growth in children with ckd. trunk growth had little synchronicity with leg growth. furthermore, we found that anthropometric measurements can be used as a diagnostic tool in distinguishing different sub-groups of ckd patients, for instance, children with syndromic ckd. in the heterogeneous group of patients with focal and segmental glomerulosclerosis, patients with schimke's disease were found to have a dramatically decreased sitting height/leg length ratio. as the disturbance in growth of ckd patients is a marker of the severity of the disease and of the quality of renal care, the annual analysis of growth failure from early childhood to adolescence should be used as a landmark information of the quality of medical care and as a helpful tool in differential diagnosis and of specific courses of ckd in sub-groups of patients. for example, patients with congenital or acquired renal diseases, dialyzed or transplanted patients and in gender differences. in addition, anthropometric measurements are able to identify specific growth patterns in children with ckd, which should be considered in the assessment of treatment efficacy such as in rhgh therapy. b. tönshoff, l. weber, b. höcker university children's hospital, 1st department of pediatrics, heidelberg, germany it is currently under debate whether steroid avoidance or late steroid withdrawal provides the best overall risk-to-benefit ratio in pediatric renal transplantation. late steroid withdrawal has the advantage over steroid avoidance that immunological high-risk patients and those with unstable graft function can easily be identified beforehand and be excluded from steroid-free immunosuppression. in order to further validate this approach, we performed a prospective randomized open-label multicenter trial in 41 low-risk pediatric renal transplant recipients (12 f, 29 m; mean age 10.1 yrs; range, 3.4 to 17.8) on csa (target trough level 100-200 ng/ml), mmf (1200 mg/m 2 per day) and methylprednisolone (3) (4) mg/m 2 per day), who were randomly assigned >1 year posttransplant to continue steroids or to withdraw over a period of 3 months. an interim analysis was performed at a mean observation period of 29 mo after study entry; 31 patients had been followed for at least 15 mo. there were 3 drop-outs (1 reversible acute rejection episode, 1 switch to sirolimus and 1 to tacrolimus). transplant function as assessed by calculated ccr remained stable in both groups, no graft was lost. prepubertal children off steroids gained relative height from baseline -1.5±0.5 sds to -0.9±0.6 sds after 2 yrs, while patients on steroids lost relative height (-1.1±0 .6 sds at baseline, -1.6±0.7 sds after 2 yrs); a comparable pattern was observed in pubertal patients. the standardized body mass in patients off steroids declined from 0.75±1.01 sds at baseline to 0.31±1.17 after 2 yrs (p<0.05), while it tended to increase in patients on steroids (baseline, 0.40±1.35 sds; after 2 yrs, 0.56±1.39). the rate of adverse events, mainly infections, was comparable in both groups. patients off steroids required less frequently antihypertensive medication (62%) than patients on steroids (93%). a significant reduction of serum cholesterol (by 20%) and triglycerides (by 13%) in response to steroid withdrawal was observed. conclusions: this interim analysis indicates that late steroid withdrawal in selected pediatric renal transplant recipients on csa and mmf is safe, allows catch-up growth and ameliorates cardiovascular risk factors. at the ipna meeting, full 12 month outcome data of all patients will be available. u. frei, j. noeldeke renal transplantation faces two major challenges: the organ shortage resulting in extended waiting times and an aging population resulting in increased death with a functioning graft. the eurotransplant senior program (esp) allocates kidneys within a narrow geographic area from donors aged >65 years to recipients >65 years regardless of hla. this analysis investigates the impact of the esp on waiting time, graft and patient survival. the esp group (n=1406, old to old) was compared to two groups allocated via the eurotransplant kidney allocation system (etkas) with either similar donor age [old to any (o/a), donor age >65, n=446] or recipient age [any to old, (a/o), recipient age 60-64, n=1687]. all patients were transplanted between 1999 and 2004. since initiation of the esp (1999), availability of elderly donors doubled and waiting time for esp patients decreased. local allocation led to shorter cold ischemia time (11.9 vs. >17.0 hours, p<0.001) and less delayed graft function (dgf, esp 29.7% vs o/a 36.2%, p=0.047) but 5-10% higher acute rejection rates. importantly, graft and patient survival were not negatively affected by the esp allocation scheme. the esp age matching of elderly donors and recipients is an effective allocation system for organs from elderly donors. the effect of age matching on the duration of the waiting time a. rahmel, m. slot, j. smits eurotransplant international, leiden, the netherlands in eurotransplant the proportion of children, i. e. patients aged under the age of 16 at time of registration, with end-stage renal disease (esrd) on the renal waiting list amounts to only 1.2%. despite this small proportion the eurotransplant kidney allocation system (etkas) specially addresses pediatric transplant candidates. in order to increase their chances of receiving a transplant in time children are assigned via etkas extra points for hla matching and receive an age bonus. in order to evaluate this allocation policy, the chances for receiving a kidney for patients in different age groups were evaluated. for the cohort of patients registered in the year 1999, a 5 year followup was obtained. for patients aged under 6 at time of registration [n=134] 47% and 81% received a kidney from a post-mortem donor, within 1 year and 5 years after listing. for children aged 6 to 10 [n=108] these rates were at 1 and 5 years after listing 31% and 67%, and for children between age 11 and 16 [n=192] 33% and 72% respectively. adult patients were less likely to receive an organ: 11% and 42% of patients aged between 16 and 64 were transplanted within 1 and 5 years after listing. senior esrd patients can benefit from the eurotransplant senior program (esp), their chances for a transplant were 28% and 61% within 1 and 5 years, respectively. the life span of a renal allograft is limited in time. in the eurotransplant experience 80% of the post-mortem kidneys used for transplantation in children failed within 20 years, compared to 70% for the living donor renal transplants (rtx). donor age is an important factor associated with long term renal allograft function. age matching between donor and recipient is hampered by the low number of pediatric donors. in the period 2000-2005, 78 heart beating kidney donors aged under 1 were reported and used for rtx, 69 donors were between 2 and 5 years of age, and 319 donors were between 6 and 16 years old. in the same period 9981 adult donors were reported and used for transplantation. in the period 2000-2005, 18% of the pediatric donor kidneys ultimately served a pediatric recipient. to improve the allocation of pediatric donors to pediatric recipients, et is in the process of implementing a rule giving pediatric recipients priority in case of pediatric donors. gender and sex hormones are playing a central role in the incidence and progression of different renal diseases. vascular tone, endothelial function and immune response are influenced by gender. in renal transplantation ischemic injury is always present. females are more resistant to postischemic renal failure than males. following ischemia/reperfusion injury renal vascular resistance decreases, allowing fast restitution of blood flow and oxygen supply in females. additionally, stabilization and preservation of tubular function following ischemia is achieved by the protection of na+/k+ atp-ase and heat shock protein activity contributing to the observed gender differences. posttransplant immune reactions also differ between genders. female gender predisposes to more severe acute rejection following kidney transplantation, partly due to differences in the effectivity of immunosuppressants used. ineffective immunosuppression in females, as well as different cytotoxicity profile of the drugs is contributing to more prone immune reactions shortly after transplantation resulting in more severe acute rejection. in contrast, similar to the slower deterioration of other renal diseases, progression of chronic graft failure is less pronounced in females in experimental and clinical settings. estradiol decreases profibrotic processes, preserves endothelial function and modifies influx of immune cells into the graft. the fine balance between alloantigen dependent immune reactions and alloantigen independent factors and its impact on longterm graft function is modified by gender. new evidences supporting the significance of sexual dimorphism following kidney transplantation may present the base of gender modified therapeutic approaches in the future. iga nephropathy: aetiology, incidence, and geographic distribution iga nephropathy (igan) is characterized by mesangial deposits of iga, proliferation of mesangial cells and expansion of matrix. the accumulation of iga and complement fractions within glomeruli was initially ascribed to deposition of iga immune complexes (igaic) due to mucosal immune response with predominant iga synthesis. this hypothesis has offered an explanation of the relationship between infections of the upper airways and gross hematuria. high levels of igaic have been detected in 30-70% of patients, mostly of polymeric iga1, and polymeric iga1 are detectable in renal deposits. this observation is consistent with hypothesis of either bone marrow or mucosal origin. however, no specific viral or alimentary antigens have been found in mesangial deposits, and the qualitative properties of polymeric iga1 have rather become of interest, particularly the glycosylation pattern of iga1. human iga1 is o-glycosylated with carbohydrate chains of n-acetyl galactosamine (galnac) and galactose (gal) which may be covered with sialic acid (neu5ac). patients with igan exhibit circulating iga1 with reduced gal and/or neu5ac and increased exposure of n-galnac. such aberrantly glycosylated iga can circulate in monomeric form or participate in the formation of autoaggregates/true immune complexes. it likely escapes clearance by hepatic receptors and has a preferential renal deposition by virtue of enhanced reactivity with the mesangial matrix components. the role of a triggering event has not ruled out. in recent reports, antigens of bacterial origin and the secretory tract component have been found in renal deposits, making scientists reconsidering again the role of bacterial infections. tonsils recurrent infections may provide a suitable aetiology for igan, and the effect of tonsillectomy on the long term outcome of igan is under evaluation. the prevalence of igan varies in different areas, due to ethnic and environmental factors, being particularly frequent in mediterranean europe, northern europe, asia and australia. it is still debated whether differencies in frequency, clinical features and disease progression among patients with igan from different countries are actually due to uneven distribution of this diseases or these discrepancies are due to the different criteria for performing renal biopsy. definition. igan is characterized by the presence of dominant (or codominant) mesangial deposits of iga on immunofluorescence microscopy, frequently with c3 and sometimes with igg or igm. classification. the glomeruli display a broad spectrum of histologic changes, related in part to the differences in the indication for the biopsy of the referring nephrologist. a number of classification systems have been used to describe the histologic manifestations of igan. two will be referred to here: the system of m. haas (ajkd 29:829-842, 1997 ): 1) minimal histologic lesion -the glomeruli exhibit no more than a minimal increase in mesangial cellularity, without segmental sclerosis or crescents. 2) fsgs-like -the glomeruli display focal segmental sclerosis in a pattern resembling primary focal segmental glomerulosclerosis, with at most a minimal increase in mesangial cellularity and no crescents. 3) focal proliferative glomerulonephritis (gn) -50% or fewer of the glomeruli are hypercellular. the increase in cellularity may be limited to mesangial areas, or there may be obstruction of glomerular capillaries by proliferated endocapillary cells. crescents may be present. 4) diffuse proliferative gn -more than 50% of glomeruli are hypercellular. the hypercellularity may be segmental or global, and crescents may be present. 5) advanced chronic gn -40% or more of the glomeruli are globally sclerotic, and/or there is 40% or more tubular atrophy or loss in the cortex. the system of s. emancipator (heptinstall's pathology of the kidney, lippincott-raven, philadelphia, 1998, pp 479-512) : a -normal/minimal glomerular lesions b -focal mesangial proliferation c -diffuse mesangial proliferation d1 -focal segmental endocapillary proliferation superimposed on mesangial proliferation d2 -focal segmental endocapillary proliferation alone e -diffuse endocapillary proliferation f -diffuse extracapillary proliferation (crescents in >70%), with or without endocapillary proliferation g -glomerulosclerosis (>70% of the glomeruli are sclerotic) h -unclassifiable or combined lesions diffuse proliferative gn (c) and focal proliferative gn (d1) are the major patterns of expression of glomerular injury. indicators of a poor outcome. these include a high proportion of glomeruli with crescents, numerous sclerotic glomeruli, interstitial fibrosis and tubular atrophy, extension of the iga deposits into the peripheral glomerular capillary walls, and hyaline arteriolosclerosis. differential diagnosis. mesangial iga deposits are present in henoch-schönlein nephropathy, and may be present in lupus nephritis, chronic liver disease, coeliac sprue, certain dermatologic diseases, and some rheumatologic diseases. iga nephropathy [igan] is defined by the presence of mesangial iga, but otherwise the histopathological and clinical features are very variable. we do not yet know sufficient about pathogenic mechanisms to understand whether igan is a single disease. although traditionally called an 'immune complex' disease there is no direct evidence that mesangial iga deposition in igan occurs through classical antigen-antibody interactions. mesangial cells do carry receptors for iga, which may play a key role in iga deposition and subsequent injury, but these are not yet fully characterised. mesangial iga in igan is polymeric iga1. there is no evidence of mucosal immune system overactivity, indeed there seems to be underproduction and abnormal t cell control of mucosal iga production, along with overproduction by the marrow of iga1 iga1 has a hinge region peptide structure which is a site for o-glycosylation. in igan circulating and mesangial iga1 both have abnormal o-glycosylation at the hinge region. the same defect is seen in henoch-schönlein purpura only when there is renal involvement. the glycosylation defect is not due to abnormal peptide structure of the hinge; the possibility that there is reduced activity of the key enzyme b1, 3 galactosyltransferase in b cells or plasma cells has not yet been confirmed. alternatively the glycosylation changes may reflect a shift in the production of mucosal type of iga1 to the marrow. while iga1 deposition is caused by disease mechanisms specific to igan, subsequent inflammatory and fibrotic events are probably driven by mechanisms common to other chronic glomerular disease. in some patients iga1 deposition is not followed by inflammation, in others inflammation resolves without fibrosis. cytokine and growth factor production by mesangial cells is a sufficient explanation for glomerular inflammation and fibrosis. however little is yet understood of any genetic or environmental influences which protect some patients from progressive renal injury. our recent controlled trials by the japanese pediatric iga nephropathy treatment study group demonstrated that treatment of children with severe iga nephropathy with prednisolone, azathioprine, heparin/warfarin, and dipyridamole for 2 years early in the course of the diseaseprevents immunological renal injury and progression of the disease. the majority of patients with iga nephropathy in our series are diagnosed early in the course of the disease, and the asymptomatic period before the discovery of urinary abnormalities is short. early diagnosis and early treatment is very important in iga nephropathy. 1. combined therapy for severe childhood iga nephropathy (j am soc nephrol 10: [101] [102] [103] [104] [105] [106] [107] [108] [109] 1999) . seventy-eight children with newly diagnosed iga nephropathy showing diffuse mesangial proliferation were randomly assigned to receive either the combined therapy of prednisolone, azathioprine, heparin-warfarin, and dipyridamole for two years (group 1) or the combination of heparin-warfarin and dipyridamole for two years (group 2). urinary protein excretion was significantly reduced in group 1 patients, but remained unchanged in group 2 patients. the percentage of glomeruli showing sclerosis was unchanged in group 1 patients, but significantly increased in group 2 patients. 2. steroid treatment for severe childhood iga nephropathy (clin j am soc nephrol, 1:511-517, 2006) . in this study we have compared the effects of prednisolone, azathioprine, warfarin, and dipyridamole (combination) with those of prednisolone alone in 80 children with newly diagnosed iga nephropathy showing diffuse mesangial proliferation. patients were randomly assigned to receive either the combination or prednisolone alone for two years. the primary endpoint was the disappearance of proteinuria, defined as urinary protein excretion <0.1 g/m 2 /day. thirty-nine of the 40 patients receiving the combination and 39 of the 40 receiving prednisolone completed the trial. thirty-six of the 39 patients (92.3%) receiving the combination and 29 of the 39 (74.4%) receiving prednisolone reached the primary endpoint by the two-year follow-up point (p=0.007 log-rank). the percentage of sclerosed glomeruli was unchanged in the patients receiving the combination, but increased in the prednisolone group (p=0.0003). the frequency of side-effects was similar in the two groups. long-term administration of recombinant human erythropoietin (epo) has become the most common way of treating anemia in chronic renal disease. standard amounts per unit body weight have been recommended for the initial dose. however, several authors have noted that the dose per unit body weight needed for a given response is higher in younger children than in older children or adolescents and that it is increasing with decreasing body weight. furthermore, for a given absolute dose of epo the outcome was investigated in adult hemodialysis patients, but no dependence was found in 54 patients weighing 45-86 kg. a similar model to the hemoglobin-time data of 8 children aged 8-15 years treated with epo for renal anemia did not find an impact of body weight on response when it was modelled in terms of absolute dose. in a similar analysis to the hemoglobin-time data 52 children and adolescents aged 5-20 years were analyzed, in order to more definitively answer the question if, for given absolute doses the hematopoetic response to epo in children depends on body weight. neither the dose response parameter e max and ed 50 showed dependence on body weight. the median hemoglobin response to a standard dose was similar to that reported for adults. it can be concluded that younger and smaller children need relatively more epo than older children. doses for children should be specified as absolute amounts rather than amounts per unit body weight. references: scigalla p. effect of recombinant human erythropoietin treatment on renal anemia and body growth of children with end-stage renal disease. in: baldamus ca, scigalla p, wieczorek l, et al, editors erythropoetic agents are the mainstay of treatment for renal anemia. although there are several different marketed forms of erythropoetin, they are not substantially different in their ability to stimulate erythropoesis. however, darbepoetin, which differs in one amino acid, and has additional glycosylation sites, has a longer half-life and therefore a presumed longer duration of action. this provides a theoretical advantage, suggesting that less frequent injections will be required. clinical experience and studies have confirmed that both erythropoetin (epo) and darbepoetin (dar) are effective to maintain hb values within the recommended range. also, though there is some experience with epo injected every couple of weeks, the overall evidence suggests that dar has a longer duration of action, and injections are required less frequently. for many children, particularly the pre-dialysis population, anemia is successfully controlled with dar injected every 3-4 weeks. however, this apparent advantage of dar is somewhat reduced because of the increased pain reported with dar injections compared to epo. both epo and dar have been used successfully in children of all ages. with epo, the doses required to maintain hb values appear to be increased in infants compared to older children; this may not be the case with dar, but there is much less experience with use of dar in infants. also, the administration of dar in infants is hindered by the need to inject portion of a unidose pre-filled syringe, which may introduce inaccuracies in dosing, is wasteful, and is not user-friendly. the side effect profile for each product is similar, and specifically each has been associated with development of hypertension, which is most likely with higher hb values. pure red cell aplasia has also been reported with each product. thrombocytosis has been reported with dar use. overall, there is little to recommend one product over the other. the need for less frequent injections may favor dar for use in most children beyond infancy, whereas it is easier to administer epo accurately in infants. how much iron is needed and how much is toxic? iron deficiency is the primary reason for ineffective erythropoiesis in patients with chronic kidney disease (ckd) who receive an erythropoiesis stimulating agent (esa). reasons for iron deficiency include inadequate dietary intake, blood loss from the gastrointestinal tract, frequent blood tests, loss of blood in the extracorporeal circuit of hemodialysis (hd), as well as the hepcidin related impairment of the intestinal absorption of iron and its release from the reticuloendothelial system. supplementation of iron can be by either the oral or intravenous (iv) routes, although the national kidney foundation-kidney disease outcomes quality initiative (k/doqi) strongly recommends the preferential use of iv iron in children and adult patients receiving hd. the k/doqi recommended target iron indices for all children on dialysis are a serum ferritin >100ng/ml and a transferrin saturation (tsat) >20%. while the serum ferritin should not regularly be >500 ng/ml, some such patients will achieve a higher hemoglobin value following an iv course of iron therapy. of the iv iron agents, the non-dextran products appear to be safest, and pediatric dosing recommendations exist for ferric gluconate and are currently being studied for iron sucrose. differences do exist for the clinical (e. g. proteinuria) and subclinical (e. g. oxidative injury) toxicities associated with the currently available iv iron products and should be taken into consideration when prescribed. until recently the major physiological function of erythropoietin (epo) was thought to be the induction of erythropoiesis. however, a growing body of evidence indicates that epo has tissueprotective properties and prevents ischemia induced tissue damage in several organs including the kidney. a main target of epo´s action is the endothelium, and one of the pivotal intracellular pathways mediating the beneficial effects of epo is the activation of akt, i. e. serine/threonine protein kinase b. as a result, akt phosphorylates the proapoptotic factor bad, which in turn causes inhibition of programmed cell death (apoptosis). moreover, experimental studies revelead that epo is a potent regulator of endotheial progenitor cell (epc) proliferation and differentiation. collectively, these data support the hypothesis that epo is a key molecule in the process of endothelial (vascular) repair and neoangiogenesis. treatment with rhuepo or analogues could therefore open new therapeutic strategies in regenerative cardiovascular medicine. introduction: africa as a continent is besieged by many health challenges including malaria, hiv (upwards of 60% of paediatric admissions), tuberculosis and malnutrition with an infant mortality rate (imr) ranging from 62(southern africa) to 132(mozambique). good health facilities are on the whole not available except in the extreme north and south of the continent with doctors/100 000 population in south africa 69 but in kenya only 13 and even lower in other parts of africa. renal disease: renal disease in adults is an unknown quantity with no information being available regarding children's renal disease, where many babies do not even have access to antenatal ultrasounds. situation in south africa: in reality, there are only 2 centres (cape town and johannesburg/ pretoria) doing paediatric dialysis and transplantation in significant numbers with small numbers interspersed in the rest of the country. this raises numerous issues: -accessibility for children to renal care -retaining minimum standards of care for children -both dialysis and transplantation -combined with adult units -central government funding in form of tertiary services grant for paediatric renal care -children not first priority on any transplant program in terms of organ allocation -private facilities vs state facilities -ethical decisions dialysis facilities: peritoneal dialysis (pd) first line therapy for acute renal failure, as can be performed in any setting with minimal equipment and expertise. in the setting at rxh, we have a greater than 60% survival in infants and children dialysed using pd even in a sophisticated intensive care setting. haemodialysis and chronic dialysis may not be easily available in most settings and realistically need transfer to one of the major centres. transplantation: again limited to only few centres, with at least 30% living related donations from family members. initial good 1 year (90%) and 5 year (80%) graft survival but results then deteriorating as patients enter their adolescent years often with little support and transfer to adult units in their early teens. controversial issues here include access to one kidney transplant only, no chronic dialysis if not suitable for transplant and transplantation in hiv positive recipients. conclusions: adequate resource allocation is required for paediatric renal care especially where resources are limited. immunosuppression remains the cornerstone of successful transplantation. in developing countries transplantation is mostly from living donors and transplant is thus a once in a lifetime chance. in this backdrop immunosuppression is a challenge as several issues have to be overcome. namely, non-availability of newer drugs, high costs and paucity of drug monitoring facilities. in most countries immunosuppression is based on a triple drug regimen of cyclosporin (cya), prednisolone (pred) and azathioprine (aza). in the last few years mmf and tacrolimus (tac) has been initiated in a few centres. several tailoring strategies have been employed taking into consideration costs, drug availability, tissue typing facilities and drug monitoring. firstly in hla identical transplants which constitute 15-20% of the total, cya based regimen are used. marked reduction to 1-2 mg/kg at 6 months and complete withdrawal at one year in rejection free transplants is safe with continuing of aza and pred. secondly several centres selectively use tac and mmf in cases with early rejection or transplants with >3 mismatches. it is possible to switch to cya or aza after 6 months on individual basis. thirdly induction protocol with atg for 3 days in transplants with >4 mismatches and in retransplants is cost effective. cost considerations have increased the use of generic calcinurin inhibitors with market share of 20-100% in different countries. co administration of p450 competitors has reduced doses of cya by 50-60% with considerable cost reductions. siut has been running a living related transplant program for more than 20 years with dialysis and follow-up of recipients and donors. keeping in mind economic constraints a model of government public partnership was developed which provides all facilities including drugs free of cost. we adopted a number of tailoring strategies e. g. strict monitoring, tailoring by hla match and donor age and use of biological agents in risk groups. in first 10 years we used parent drugs, however increasing costs necessitated use of generics after establishing bioequivalence in controlled trials. graft survival rates were maintained at 92% and 85% at 1 and 5 years. in conclusion, immunosuppression in developing countries require besides newer drugs, monitoring facilities, affordable costs and regular follow-up as transplantation for majority is once in a lifetime chance and failure equates with death. occurrence of infections following kidney transplantation is a major reason for hospitalization, and an important cause for renal dysfunction & mortality in developing countries. more than 50% renal transplant recipients get serious infections, with a 20-40% risk of mortality. infections in the first month after transplantation are similar to those in surgical patients; opportunistic pathogens and cmv predominate between 1-6 months; and tuberculosis (tb) after 6 months. the risk of tb in patients on maintenance dialysis & following transplantation is between 10-20%. the onset of tb is usually within 12 months of transplantation. clinical syndromes include pleuropulmonary tb, followed by disseminated tb, pyrexia of unknown origin and lymph node disease. demonstration of m. tuberculosis, on microscopy or culture might not be possible. nonrifampicin based treatment regimens (inh, pyrazinamide, ethambutol, fluoroquinolone for 3 months, followed by hef for 9 months) are used. inh prophylaxis (6-9 months) is advised in patients with tuberculin positivity or contact with active tuberculosis. cmv disease results in considerable morbidity & mortality; its timing is influenced by donor/recipient serological combination, state prior to transplantation, use of antilymphocyte induction therapy or preventive strategies. cmv disease is characterized by a non-specific febrile illness; features of enterocolitis, pneumonia, hepatitis, myocarditis, esophagitis, chorioretinitis & bone marrow involvement are variable; disseminated disease is rare. cmv disease exacerbates the net immunosuppression, increasing the risk for opportunistic infections. patients with cmv disease are also at risk for acute rejection and chronic allograft injury, atherosclerosis & vascular injury. diagnosis of cmv disease is based on a combination of viral serology, shell vial cultures, pp65 antigen assay and pcr. the cost of prophylaxis and treatment is a major limitation to the use of ganciclovir or valganciclovir. other infections in transplant recipients include malaria, p. carinii and fungi (cryptococcosis, candidiasis, mucormycosis, aspergillosis). infections are an important cause of morbidity & mortality in renal transplant recipients. their management continues to be challenging due to difficulties in diagnosis, unsatisfactory follow-up and cost of medications. ethical issues of renal replacement therapies n. orta, p. zibaoui, e. lara university of carabobo/insalud, pediatric nephrology, valencia, venezuela important ethical issues in pediatric nephrology (pn): genetic and molecular techniques, prenatal therapies for urinary anomalies, treatment of children with chronic renal disease (esrd). ecosonography can detect nephrourological anomalies and studies of amniotic fluid give information on chromosome alterations and renal function. particular situations, can lead to dilemmas related to pregnancy interruption and neonatal dialysis and transplantation (dt) possibilities. renal insufficiency (ri) presents at any age, and peritoneal, hemodialysis or hemofiltration could be applied. patients without structural abnormalities, ri secondary to toxics or isquemic nephropathies have better prognosis. these procedures are complicated and costly and increases, and may have secondary effects with ethical implications. treatment by dialysis developed in the 60's and inclusion of children was not considered. this has changed with advances in dt. since 1970's dt programs were setup for children, but received criticisms and considered unethical, but were continued because of familiar and humanitarian demands and today it is clear that children benefit with that. scientific societies recommend: 1. children who receive dialysis must meet the following criteria: -diagnosis of esrd, legal authorization, possibility of transplantation, acceptable quality of life; may not be rejected for economic, social or psychological reasons, nor gender, age, race or mental conditions. biopsies are the current 'gold standard' for monitoring transplant patients, but it has been shown that even mild rejection episodes, based on pathology grading, can have poor outcomes and even biopsies with normal early pathology can progress rapidly with chronic allograft injury. there is considerable inter-observer variability of biopsy pathology readings that adds an additional confounder to this method of analysis. identification of non-invasive biomarkers in blood or other fluids would allow for the possible elimination of frequent biopsies. hence, the identification of diagnostic and predictive non-invasive genomic markers will be a worthy tool to aid in the clinical monitoring of transplant patients. the use of dna microarrays as a hypothesis generation tool for determining gene expression differences across thousands of genes in a data set is increasing. recently, the use of microarrays has been applied to the transplant field and holds great promise for unraveling the mechanisms at play in various transplant processes and for identifying new tissue specific and non-invasive biomarkers predictive of clinical outcomes. as microarrays produce large amounts of data, bioinformatics tools are being developed to determine gene expression patterns. gene clustering and class prediction tools aid in the discovery of molecular signatures in different disease processes while literature mining, gene family analysis and pathway analysis help in understanding the biological relevance of these signatures. initial studies in acute rejection and graft dysfunction have produced possible markers for risk stratification of the rejection event and have suggested underlying mechanisms at play, that may now allow us to test novel drugs for treating specific acute rejection episodes. the most exciting application of microarrays lies in our ability to predict clinical outcomes by non-invasive serial monitoring, eliminate the requirement of transplant biopsies and individualize patient management by accurately predicting the patient's sensitivity to immunosuppression-sufficient to suppress the allo-response, yet insufficient to abrogate the innate response. responsible array data handling and accessible reporting will open new doors for transplant researchers through increased use of computers and collaborations towards these kinds of novel insights and treatment options for transplant patients in the future. this talk focuses on dna microarrays, their application to transplantation, and discusses some of their limitations and recent applications, as well as some key research studies where dna microarrays are applied to understanding the molecular differences in acute transplant rejection that segregate and likely control the differences in rejection treatment responsiveness as well as decline in graft function, as well as gaining insights into the different biological processes that govern these differences. the molecular pathogenesis of vur is not well understood. uroplakins (ups) are expressed in the urothelium and are developmentally regulated by rab27b and tbx genes. up ii and iiia-null mice exhibit a primary (1 o ) vur phenotype. using microarrays and rt-pcr, we analyzed gene expression in surgically-discarded ureteric tissue from children undergoing reimplantation for 1 o reflux, compared with adult living-related transplant donors as normal controls, as well as children with 2 o reflux (megaureter, duplicated ureters, and posterior urethral valves) as age-matched disease controls. we also studied urine protein profiles using 2-dimensional electrophoresis (2d-page) followed by time-of-flight mass spectroscopy (q-tof-ms). rt-pcr showed partial expression of ureteric upia, upib, upii and upiiia genes in patients with 1 o reflux. protein screening using western immunobloting confirmed that some uroplakins were undetectable. real-time rt-pcr revealed that ureteric up ia, up ib, upii, and up iiia gene expression decreased significantly, whereas upiiib gene expression increased at least 2-fold compared to controls. compared with patients with 2 o vur, the decrease of upiiia expression in those with 1 o reflux was highly statistically significant (p<0.00001). the expression of rab27b and tbx genes also decreased significantly in patients with 1 o and 2 o reflux as well. total urinary protein concentration increased by 6-fold in the 1 o vur patients without detectable renal scarring on dmsa scans; and increased further in patients with renal scarring, 13-fold for 1 o vur and 11-fold for 2 o vur patients. proteomic analyses of proteinuria revealed an overall increase of protein with mw>60.4 kda in the pi range 4.0 to 7.0 in patients. q-tof ms identified one predominant urinary protein of ~ 105 kda as sera-transferrin, which was confirmed by elisa quantitation. we hypothesize that the abnormal developmental expression pattern of the up, rab27b and tbx genes in vur patients results in abnormal urothelial functions, which lead to leakage and/or secretion of proteins into the urine, and that this occurs in the absence of scarring from urinary infections. further identification of these protein biomarkers may lead to non-invasive diagnostic tests for vur. biomarker discovery in acute kidney injury p. devarajan cincinnati children's hospital medical center, department of pediatric nephrology and hypertension, cincinnati, united states acute kidney injury (aki), previously referred to as acute renal failure (arf), represents a common and persistent problem in clinical medicine. despite significant improvements in therapeutics, the mortality and morbidity associated with aki remain high. a major reason for this is the lack of early markers for aki, akin to troponins in acute myocardial disease, and hence an unacceptable delay in initiating therapy. fortunately, the application of innovative technologies such as functional genomics and proteomics to human and animal models of aki has recently uncovered several novel genes and gene products that are emerging as biomarkers. the most promising of these are chronicled in this symposium. these include a plasma panel (ngal and cystatin c) and a urine panel (ngal, . since they represent sequentially expressed biomarkers, it is likely that the aki panels will be useful for timing the initial insult and assessing the duration of aki. based on the differential expression of the biomarkers, it is also likely that the aki panels will distinguish between the various types and etiologies of aki. however, they have hitherto been tested only in small studies and in a limited number of clinical situations. it will be important in future studies to validate the sensitivity and specificity of these biomarker panels in clinical samples from large cohorts and from multiple clinical situations. such studies will be markedly facilitated by the availability of commercial tools for the reliable and reproducible measurement of biomarkers across different laboratories. a. watson children and young people's kidney unit, notthingham university hospitals, nottingham, united kingdom the achievement of adequate chronic peritoneal dialysis in children requires close attention to clinical, dietetic and psychosocial aspects of care. successful dialysis is dependent upon excellent peritoneal access and swan neck coil catheters with downward facing exit sites are increasingly favoured with many placed laparoscopically. automated peritoneal dialysis is employed in most developed countries but adolescents may be given the choice of capd which may be the only modality available in developing countries. training and support by committed nursing staff are of paramount importance as is regular review by a paediatric renal dietitian. growth parameters should be regularly monitored and supplemental enteral feeding introduced early. many infants are nasogastrically fed, but the preferred route for supplemental enteral feeding is via a gastrostomy which can be placed at the same time as the pd catheter. dialysis fill volumes should be assessed in terms of body surface area and intra-abdominal pressure measurements. there can be discrepancies between urea and creatinine clearances and adequate dialysis includes combining clinical parameters with regular growth measurements as well as biochemical data including phosphate, calcium and parathyroid levels. peritoneal function tests are useful in monitoring progress but the greatest challenges are in sustaining long-term dialysis, particularly in infants where transplantation is likely to be delayed. support for the families with a respite care 'package' may delay or prevent burnout and possibly reduce peritonitis rates. conventonal pd solutions are acidic, contain unphysiological concentrations of lactate and glucose and highly toxic glucose degradation products (gdp), which are substrates for advanced glycation end product (age) formation. repeated administration induces epithelial to mesenchymal cell transition, loss of the mesothel cell layer, progressive submesothelial fibrosis and angiogenesis, ultimately leading to ultrafiltration failure. meanwhile pd solutions with an improved toxicity profile are available. multi chamber pd solutions separate glucose from the buffer at a very low ph, which largely prevents gdp formation. after mixture ph is close to normal. they are equally effective with regard to solute-and water transport, reduce inflow pain and systemic age load. dialysate effluent markers indicate increased mesothelial cell mass, reduced peritoneal inflammation and reduced angiogenesis. animal studies demonstrate preservation of pd membrane morphology and function, respective human biopsy data however are pending. a european paediatric multi centre trial accomplished recently elucidates the impact of the lactate and bicarbonate buffer. a randomized cross over trial in adult patients points to an improved preservation of residual renal function; a korean registry suggests improved technique and patient survival. icodextrin solutions reduce glucose and gdp exposure, improve extracellular fluid status, left ventricular mass and stabilize membrane function in anuric adult capd patients and should be beneficial in children, too. amino acid based solutions achieve similar clearance and ultrafiltration rates, reduce glucose and gdp load and allow for a phosphate free amino acid supply. the nutritional benefit however is questionable. other, thus far experimental strategies include addition of locally active compounds to pd fluids such as gdp scavengers, inhibitors of age formation and antifibrotic agents. surface active phospholipids may increase peritoneal contact area and ultrafiltration. gene therapy appears highly promising but is still far from being clinically applied. in summary, there is substantial evidence for increased biocompatibility of the recently introduced multi chamber and icodextrin based pd solutions. they should improved long term morbidity and mortality of pd patients; this however still needs to be proven. the impact of the ippr on the treatment of peritonitis b. a. warady children's mercy hospital and clinics, pediatrics nephrology, kansas city, united states the international pediatric peritonitis registry (ippr) is an initiative that was established to evaluate the safety and efficacy of largely opinion based peritonitis treatment guidelines in which empiric antibiotic therapy (1 st generation cephalosporin and ceftazidime or a glycopeptide and ceftazidime) was stratified by disease severity. forty-seven centers from 14 countries contributed data on 392 children and 501 peritonitis episodes treated in accordance with the guidelines. culturenegative peritonitis accounted for 31% of all episodes, with a marked regional variability in the incidence of this disorder, as well as in the peritonitis causative organisms. overall, 89% of cases achieved full functional recovery, a portion following relapsing peritonitis (9%). in-vitro evaluation revealed only 69% sensitivity of gram-positive organisms to a 1 st generation cephalosporin (eastern europe > north america) and 80% sensitivity of gram-negative organisms to ceftazidime. in contrast, 94% of gram-positive organisms and 93% of gram-negative organisms were sensitive to the combination of either a 1 st generation cephalosporin or an aminoglycoside. whereas the risk of empiric treatment failure was associated with the presence of a gram-negative infection (p=0.0004), neither the risk factors assumed by the guidelines nor the choice of empiric therapy were predictive of the final functional outcome of the peritonitis episodes. the data collected by the ippr will serve as an important source of evidence to be incorporated into revised pediatric peritonitis treatment guidelines. ch. aufricht medical university, pediatrics, vienna, austria peritoneal dialysis (pd) is a safe, cost effective and widely used form of renal replacement therapy in patients with end stage renal failure. however, up to a third of patients on pd will suffer from technical failure during their course. identification of the patients at highest risk would be of high clinical relevance. cytotoxicity of pd fluids due to low ph, hyperosmolarity, and/or high concentrations of lactate, glucose and its degradation products causes mesothelial cell injury that ranges from minor cellular dysfunction to overt (apo)necrosis. the same physicochemical properties of pdf that cause such cellular injury also induce pathways leading to repair and recovery. this so-called cellular stress response results in a switch of the cellular machinery from routine procedures towards reaction against stressors. the complex machinery of the cellular stress responses not only counteract direct toxic injury caused by pdf but also attenuate inflammation or other potentially deleterious cellular processes. infectious, uremic and toxic injuries might converge in cellular inflammation. whereas inflammatory processes triggered by infection protect the peritoneal cavity against invading microorganism, chronic sterile smoldering 'cytotoxic' inflammation may result in aberrant healing processes and peritoneal fibrosis. recently, polymorphisms of many proteins involved in relevant cellular responses have been described and related to altered resistance and/or susceptibility to pathogenetic processes with potential influence in pd. in this review, we will focus on key effectors of stress responses, of cellular inflammation and of fibrogenesis such as heat shock proteins (hsp), cytokines (il-6), chemokines (il-8) toll-like receptors (tlr) and growth factors. given the recently shown role of these 'players' for the interplay between mesothelial injury, inflammation and cytoprotection, these polymorphisms will likely be relevant for mesothelial cell damage during pd. taken together, the ability to understand -and ultimately modify -the risk profile of a given patient will be essential for tailoring individual pd therapies. the pathologic diagnosis of chronic allograft nephropathy (can) was introduced in 1993 by the banff classification system for renal allograft injury. it originally included at least four entities that it was acknowledged could not always be distinguished by biopsy: 1) chronic rejection; 2) chronic calcineurin inhibitor (cni) toxicity; 3) hypertensive vascular disease; 4) chronic infection and/or reflux (solez, ki 1993 44: 411) . over the ensuing decade, the definition of can has expanded and fluctuated such that some pathologists have come to use the term to mean a specific pathologic entity comprising "…progressive graft dysfunction accompanied by chronic interstitial fibrosis, tubular atrophy, vascular occlusive changes and glomerulosclerosis. " (nankivell, nejm 2003 349: 2326 , while others have suggested can should be used to describe all causes of renal allograft dysfunction involving fibrosis. the resulting confusion over terminology has in some ways hindered the growing awareness of the multiple discrete, diagnosable and often treatable diseases capable of causing chronic graft injury. these diseases include: 1) chronic (primarily antibody-mediated) rejection; 2) de novo and recurrent glomerular disease; 3) calcineurin inhibitor toxicity; 4) interstitial fibrosis and tubular atrophy without evidence of any specific etiology. to this list should be added other recognizable causes of late graft dysfunction such as polyoma virus infection and hypertension. in the new banff 2005 classification can will no longer be a diagnostic category (colvin, world transplant congress, 2006) . instead, the term sclerosis will be used to describe: "interstitial fibrosis/tubular atrophy, not otherwise specified, " or "if/ta nos. " the increasing use of protocol biopsies in clinically stable patients has dramatically increased awareness of the ongoing pathological changes almost every renal allograft appears to be undergoing almost from the first moments of engraftment. techniques are now available in most centers to reliably recognize the presence of chronic antibody-mediated rejection. these include: 1) typical morphological findings: lamination of glomerular basement membranes, arterial intimal fibrosis, interstitial fibrosis/tubular atrophy; 2) c4d staining in peritubular capillaries or glomeruli; 3) the presence of circulating donorspecific antibodies (takemoto ajt 2004 4: 1033 . treatment of late, chronic antibody-mediated rejection is in its infancy and may include use of anti-b cell antibody (rituximab), ivig, and/or plasmapheresis. calcineurin inhibitor toxicity can be more reliably identified by focusing on blood vessels in the allograft, primarily the location of hyaline deposits in the arterioles. nodular, peripheral hyalinosis is found almost exclusively in cni toxicity, whereas sub-endothelial and transmural hyaline deposits are non-specific and can be seen in hypertension, aging and diabetic nephropathy. there is increasing concern that recent gains in short-term renal allograft survival and reductions in acute rejection rates have not resulted in improved long-term graft survival. while this is likely due to multiple factors, including infections and malignancies associated with over immunosuppression, unrecognized (sub-clinical) acute cellular rejection (moreso ajt 2006 6: 747), and noncompliance in some patients, much evidence points to the primary role of cni toxicity in many if not the majority of chronically failing allografts maintained on cni's. experience with conversion from cni to sirolimus in adult patients has been reviewed in a recent editorial (betard nephrol dial transplant 2006 21: editorial comments) . in 10 studies involving nearly 400 patients, between 54% and 80% of patients with late allograft dysfunction failed to respond favorably to cni withdrawal and replacement with sirolimus. acute rejection episodes were rare, occurring in only six patients. common adverse effects included dyslipidemia, anemia and proteinuria. in one study, 32 of 50 patients developed proteinuria after conversion, 18 in the nephrotic range. pediatric experience with cni withdrawal has been limited (kerecuk, pediatr nephrol 2005 20: 1630 falger, pediatr transplant 2006 10: 565, hocker, pediatr transplant 2006 . our recent experience at stanford with cni withdrawal in 17 patients was not favorable, with 41% of patients experiencing an associated acute rejection episode (weintraub, wtc 2006) . prior history of acute rejection significantly increased the relative risk of acute rejection after cni withdrawal (rr=1.8), and proteinuria was common. patients with advanced chronic graft dysfunction were at increased risk for graft loss. in summary, the use of the term can to describe all causes of chronically failing renal allografts is to be discouraged in favor of a search for specific etiologies whenever possible. antibody-mediated rejection and cni toxicity are major causes of late allograft dysfunction. protocol biopsies are helpful in identifying patients with treatable causes of late allograft dysfunction. cni withdrawal/avoidance may be successful, but optimum patient selection criteria and withdrawal/replacement strategies have not been determined. pediatric experience to date with cni withdrawal has been limited, but it appears that late withdrawal after cni injury and graft dysfunction have become well established may be associated with inferior outcomes. prospective trials in pediatric patients are needed to address these issues. which immunosuppression in pediatric transplantation? p. hoyer university children's hospital, essen, germany recent results in pediatric renal transplantation have reached one year graft survival rates better than 90%. current immunosuppressive drugs should be classified according to their interference with the immunesynapsis as signal 1, signal 2 and signal 3 blocking agents. the variety of immunosuppressive drugs does allow more treatment combinations than the potential number of large scale studies in children. the definition of current unmet needs should guide employment of drugs. calcineurin inhibitors (cni) are still the basis of immunosuppression. individual risk profile leads to preferences for cyclosporine or tacrolimus. while in adults cni reduction seems to be the major goal, the search for steroid sparing or avoidance protocols has attracted major interest in pediatric transplantation. growth and body configuration as well as cardiovascular risk factors should be in the focus of research. antibody induction protocols, mainly with il-2 receptor antibodies, are increasingly popular, but efficacy is less clear than concluded from adult studies and might depend on initial combination therapy. mmf (cellcept®) or mpa (myfortic®) are effective drugs with cni sparing potential. early adequate dosing seems to be of greater importance than the choice of the cni, but the price to pay may be an increase in infectious complications. mtor inhibitors are promising in avoiding nephrotoxic side-effects; specific side effects on male gonadal function and possible interference with growth should be considered before any recommendation can be given. fty 720 would have been of especial interest for children because of maintaining viral infectious response, but phase-2 studies are on withhold. the vision of tolerance has stimulated research on regulatory t-cells; i. e. cd4 cd25+t-reg cells and the mastergene foxp3. the impact of lymphocyte depletion induction protocols with campath on operational tolerance needs further studies. newer drugs in development are isa 242, a cyclosporine analog without nephrotoxicity; a modified release form of tacrolimus which might improve compliance; the phosphokinase inhibitor aeb071 with the potential to avoid cnis; the jak3 inhibitor cyp 690, 550 which might interfere with signal 3 (il2 and il15-receptor); and lea29y (belatacept) with blocks costimulatory signals. according to the new european drug legislation some of these drugs will be subject for mandatory testing in pediatric patients to get marketing authorisation. the future might be a more tailored immunosuppression according to the induvidual needs of the patient. immunosuppression minimization strategies, under the umbrella of a newer generation of more powerful induction and maintenance immunosuppressants, are being increasingly applied to pediatric organ transplantation, with the greatest emphasis on minimization of steroids and calcineurin inhibitor agents. safe elimination of these steroids carry unprecedented advantages for reducing patient morbidity and chronic graft injury, but may also result in unanticipated changes in immunological homeostasis and drug pharmacokinetics, heralding closer surveillance for posttransplant infections and alterations in drug bioavailability and dosing, as well as break-through immunologic responses. in single center studies, pediatric renal transplantation appears safe without steroids. daclizumab first dose doubling and extended use for 6 months replaces steroids effectively without evidence of over-immunosuppression, and may be the pivotal causative for the reduced acute rejection seen in the face of steroid avoidance. this pilot protocol has been tested in a prospective, multicenter randomized us and canadian study. b. maecker, c. klein department of pediatric hematology/oncology, hannover medical school, hannover, germany posttransplant lymphoproliferative disorders are severe complications of immunosuppressive therapy after solid organ transplantation causing significant morbidity and mortality. to define prognostic factors, we have analyzed 55 pediatric solid organ graft recipients (kidney, liver, heart/lung) that were reported to the german ped-ptld registry. ptld was diagnosed at a median time of 29 months post organ transplantation with sigifcantly shorter lagtime in liver versus heart or renal graft recipients. the five-year overall and event-free survival was 68% and 59%, respectively. stage iv disease with bone marrow and/or cns involvement was independently associated with poor survival. no differences in outcome were observed between early and late onset ptld, monomorphic or polymorphic ptld, and ebv-positive or ebv-negative ptld, respectively. patients with burkitt-like ptld and c-myc translocations had very short survival. these factors should be important to consider for future prospective interdisciplinary trials that are urgently needed to define rational treatment strategies. cystinosis is an autosomal recessive lysosomal storage disorder affecting children and adults all over the world. in cystinosis cystine is trapped in the lysosomal compartment due to a defect in its egress transport protein cystinosin encoded by the gene ctns. by mechanisms still not fully understood this leads to tubular and glomerular kidney and other organ failures (e. g., thyroid, muscles) if left untreated. kidney involvement is prominent from shortly after birth on as renal tubular fanconi syndrome with the clinical consequences of failure to thrive and rickets. cystinosis is the single most common cause of renal fanconi syndrome in childhood. therefore, any recognition of renal glucosuria, generalized aminoaciduria, phosphaturia, small molecular weight proteinuria, polyuria, and metabolic acidosis (due to renal bicarbonate loss) should lead to prompt consideration of cystinosis as possible cause. this can be done utilizing biochemical analytical methods measuring the cystine content of polymorphonuclear leucocytes. corneal cystine crystals, seen in slit lamp examination, are pathognomic as well, but may not be visible before 16 months of age. left undiagnosed and untreated, patients will develop in addition to the existing tubular insufficiencies pronounced glomerular kidney failure often already present at diagnosis and inevitably leading to end stage renal failure typically at the end of the first decade of life. kidney failure in cystinosis presents differently from other forms of glomerular kidney failure because of the overlap of tubular and glomerular insufficiencies. kidney transplantation will be curative with respect to kidney function. specific treatment with cysteamine to lower the intralysosomal cystine content apparently is as important as before transplantation to prevent or attenuate other organ failures and therefore has to be continued after kidney transplantation. cysteamine treatment has been introduced in the 1970s and has been approved in the 1990s. early diagnosis and diligent treatment is able to prevent or ameliorate major organ complications. unfortunately, until now no newborn screening exists due to the biochemistry and cell biology involved. the high prevalence of a european founder mutation, i. e., a 57 kb deletion in the ctns gene, makes molecular based methods not feasible. lowe syndrome and dent's disease: two ends of a spectrum d. böckenhauer great ormond street hospital for children nhs trust, nephrology, london, united kingdom lowe syndrome and dent's disease are x-linked disorders; the former is a systemic disorder characterized by cataracts, mental retardation and proximal tubulopathy whilst the latter was originally described as an isolated kidney disorder with tubular proteinuria, hypercalciuria/ nephrocalcinosis and progressive renal impairment. mutations in ocrl1 underlie lowe syndrome, whereas the majority of cases with dent's disease are caused by mutations in clcn5. recently, mutations in ocrl1 have been identified in a subgroup of patients with dent's disease (also called dent-2). it is unclear, why some patients with ocrl1 mutations get dent's disease, while others develop lowe syndrome. however, careful clinical observation has revealed that dent-2 patients have evidence of systemic involvement. moreover, the degree of severity of symptoms in lowe syndrome is highly variable. thus, mutations in ocrl1 can cause a spectrum of symptoms, from tubular proteinuria and hypercalciuria to the full manifestations of lowe syndrome. here, we will review the clinical phenotype of the disorders, what is known about their pathophysiology and discuss genotype/phenotype correlation. fabry disease, the second most prevalent lysosomal storage disorder after gaucher disease, is an xlinked inborn error of the glycosphingolipid metabolic pathway and affects approximately 1:44,000 live births. mutations in the gene encoding alpha-galactosidase a, lysosomal hydrolase, lead to systemic glycosphingolipid deposition, resulting in profound dysfunction of neurological, renal, cardiac, and cerebrovascular systems. the initial phase begins in childhood or adolescence and is characterized by neuropathic pain, angiokeratomas, and ocular deposits. the later phase is distinguished by progressive cardiac, cerebral, and renal involvement, leading to multi-organ dysfunction and death. few patients have historically survived past their mid 50s. although renal involvement usually becomes prominent in adulthood, adolescents may develop proteinuria and decreased glomerular filtration rate. timely diagnosis is critical, given that the enzyme replacement therapy likely delays progression of the serious complications of fabry disease and may have potentially preventive benefits. specifically, there is growing evidence that initiation of enzyme therapy slows progression of chronic kidney disease (ckd); it remains unknown whether enzyme therapy in the currently employed doses can prevent ckd. pediatricians have a particularly important role in making the diagnosis, since they are likely to be the first providers to encounter fabry patients and thus initiate therapy before irreversible tissue injury develops. nephrologists should consider the diagnosis of fabry disease when a patients present with ckd with nephrotic or subnephrotic proteinuria, often with skin lesions (but these may be limited in distribution), episodic extremity pain, and/or psychiatric problems. further research is required to determine the efficacy of enzyme replacement therapy to prevent organ damage in children, to identify optimal therapeutic doses and schedules, and to define efficacy of additional treatments for fabry kidney disease, include angiotensin converting enzyme inhibitors and angiotensin receptor blockers. w. van't hoff great ormond street hospital for children nhs trust, pediatric nephrology, london, united kingdom children with a complete deficiency of methylmalonyl coa mutase develop both renal tubular and glomerular dysfunction. the renal tubular dysfunction is characterised by renal tubular acidosis, defective urinary concentration and hyporeninaemic hypoaldosteronism. a chronic interstitial nephritis also develops leading to long-term glomerular renal damage. chronic kidney disaes is not evident on routine testing as muscle mass is reduced and protein intake is markedly restricted. formal measurement of gfr using chromium 51 edta showed that 7 of 12 such mma patients have a gfr <60 mls/min/1.73 m 2 ), and by 12 years, 7 of 9 patients had a gfr <40. most mma patients with ckd do not have excess proteinuria nor hypertension. although vit b12 responsive mma patients in general have a more favourable outcome, late onset renal complications have been seen. in addition to ckd, mma patients can develop cardiomyopathy, pancreatitis, gut dysmotility and chronic or acute encephalopathy. management is based on a protein-restricted, high calorie diet, allopurinol to control hyperuricaemia, supplements of carnitine and metronidazole therapy to reduce production of propionate. haemodialysis has successfully cleared plasma mma and improved the metabolic and nutritional status. liver transplantation has been performed in a number of younger children, as enzyme replacement therapy, but is associated with a significant morbidity and mortality (including late neurological deaths). renal transplantation has been reported in a small number of older patients but it is not yet clear how good the graft outcome will be. combined liver-kidney transplantation has been undertaken again in small numbers, with a high morbidity and significant mortality although there are a very few remarkable survivors. so far, there are only centre specific experiences and unfortunately reviewing the literature will not give a full picture of long-term outcome and complications, due to the bias of the reported results towards favourable outcomes. there is a clear need to share data on the management of these rare patients in order to better understand the best approach. estimations of the extent of hiv disease in sub-saharan africa are that 26 million people are currently infected of which the total number of children is 2.1 million. worldwide it is thought that 2.3 million children are infected so it can be seen that the majority reside in africa. in south africa, we have a minimum of 250 000 hiv infected children aged less than 14yrs of age with only 15 000 on highly active anti-retroviral therapy (haart) at present. currently 40-60% of all paediatric admissions to hospital may be hiv related. hiv associated renal disease, is not yet well documented among children -especially from africa -but now with the growing availability of haart, this information has become more important for appropriate management. hiv renal disease presents in many forms, including including hiv-assoc nephropathy (hivan) and hiv immune complex kidney disease (hivick) amongst others. questions have now been raised as to whether a screening program should be introduced as haart, despite side effects and drug interactions, has revolutionised management if hiv infection detected early enough. transplantation which was thought previously to be an absolute contraindication and potential waste of valuable resource is now possible, provided there is maintenance of haart, hiv viral load is undetectable for >3 mths and cd4 >200cells/mul. there remains concern about feasibility in children with increased rejection, reduction of calcineurin inhibitors and infections such as recurrence of hepatitis c post-transplant. despite these concerns, studies in adherent adults have clearly shown that adult patients with hiv infection do better following transplantation than on dialysis. of concern, are some studies, showing that certain black patients may have a genetic predisposition to hiv infection. overall, transplantation can be successful in these patients provided the hiv disease is under control. however, hiv disease -including renal disease -remains a major problem in sub-saharan africa due to limited resources and lack of availability of drugs, where other health priorities may prevail. background. previous studies suggest that hiv-1 induces dysfunction and/or injury of endothelial cells, leading to the systemic release of fibroblast growth factor -2 (fgf-2). to date, the role that circulating fgf-2 may play in the pathogenesis of childhood hivan is not clearly understood. objective. here we sought to determine the potential role of circulating fgf-2 in the pathogenesis of hivan using wild type (wt) and hiv-tg 26 mice. methods and results. to determine whether circulating fgf-2 induced ultrastructural changes in renal glomerular endothelial cells and podocytes, we injected human recombinant fgf-2 daily for 10 days into fvbn wt and hiv-tg 26 mice (n=4 in each group). by electron microscopy we found that fgf-2 induced endothelial swelling and mild fusion of the foot processes in wt mice. these lesions were more severe in hiv-tg 26 mice, which showed enlargement of podocytes, protein reabsorption droplets, significant fusion of the foot processes, and collapsing glomerulopathy. subsequently, to confirm these findings in a different experimental model system, we used recombinant adenovirus carrying a secreted form of human fgf-2 (ad-fgf-2). four to five weeks old hiv-tg 26 mice without evidence of abnormal protenuria (urine protein/creatinine ratio (up/uc) <10), and their wild type littermates were injected with 5x10 8 plaque forming units (pfu) per mouse of ad-fgf-2 or control ad-lacz vectors through the retro-orbital (r. o.) venous plexus (n=6 per group). all mice were followed for three weeks. all hiv-tg 26 mice injected with rad-fgf-2 developed heavy proteinuria (up/uc >40). in addition, 50% showed elevated bun levels (>25 mg/dl) and renal histological lesions typical of hivan. in contrast, wt mice, developed transient and moderate proteinuria (up/uc <40), without renal failure or permanent renal damage. the number of animals with proteinuria in hiv-tg 26 mice injected with ad-lacz group was consistent with the natural history of the renal disease progression. control wt mice injected with ad-fgf-2 developed mild proteinuria (40%) that returned to normal values14-21 days after the injection. fgf-2 induced microcystic tubular dilatation and recruitment of mononuclear cells both in wt type and hiv-tg 26 mice, although the changes were more significant in the later group. conclusion. taken together, these results suggest that the accumulation of fgf-2 in the circulation of hiv-tg 26 mice induces glomerular endothelial and podocyte injury leading to the development of heavy proteinuria, renal failure, and the typical renal histological features of hivan. we conclude that the elevated levels of fgf-2 in the circulation of hiv-infected children may be a significant risk factor for the development and/or progression of hivan. human immunodeficiency virus associated nephropathy (hivan) is the third leading cause of kidney failure in young african american adults in the united states. the prevalence and natural history of the disease in children is not well documented. we have examined our experience in 315 children, aged 2 months to 22 years (mean age 9.4±0.3 years) with predominantly perinataly acquired hiv-1 infection from their mothers. since 1998, 286 of these children have been evaluated routinely for evidence of renal disease with quantitative assessment of proteinuria by random urine protein to creatinine ratios (upr/cr). renal functional studies included serum creatinine with estimation of glomerular filtration rate (egfr), urinalyses, renal scintigraphy, ultrasound and renal biopsy when possible. the patients were divided according to their level of proteinuria. those with nephrotic range proteinuria (upr/cr>1.0) were designated as hiv-ns (n=32; 11%). those with persistent intermediate range proteinuria (upr/cr: 0.2<1.0) were designated as hiv-pp (n=62; 22%). those with no proteinuria (upr/cr<0.2) were designated as having no nephropathy (hiv-non; n=192; 67%). the great majority of patients were treated with highly active antiretroviral therapy (haart), although those with hiv-ns had less time on treatment when their proteinuria was discovered. moreover, the virulence of the hiv infection as measured by viral load (vl) was significantly greater in those patients with proteinuria. also, viral load correlated positively with degree of proteinuria (r=0.5; p<0.0001). mortality as shown by kaplan-meier survival curves was significantly greater in the hiv-ns group as compared to the pp and non groups. renal failure occurred only in the group with nephrotic range proteinuria. during the past 25 years we have dialyzed 27 children with hiv infection in our end stage renal disease (esrd) program for a total of 660 patient dialysis months. since 1999, all patients are managed on hemodialysis due to the high occurrence of fungal peritonitis in our initial experience. survival has improved remarkably during the past 10 years with a median survival of 35 months (range 4 to 125 months). the next stage is to begin renal transplantation in those patients with adequate control of the hiv infection. aim: to determine the spectrum of severe renal disease in our hiv infected children; excluding severe sepsis and septic shock syndromes. indications for their referral, renal biopsy and histology relating to outcome. methods: retrospective analysis of all children referred to the paediatric renal service from the general wards and hiv clinic from january 1996 to december 2005. analysis includes age of presentation, sex, nutritional status, symptoms, renal function, histology, associated diseases including infections and follow-up. results: total of 60 children with a mean age of 6.6±0.7 years with a male: female ratio of 1:1.3. there was an overlap of symptoms but the commonest presenting symptom was haematuria in 50%, severe urinary tract infection and pyelonephritis in 23%, anasarca with or without any nephrosis in 33%, acute renal failure in 20%, chronic renal failure in 5%, severe electrolyte disturbances in 5%. renal biopsy was performed in 52 (86.7%) children. histogically 50% had immune complex disease (icd) of which 65.1% had lymphoid interstitial pneumonitis (lip).11.5% had fsgs of which one had lip but also had icd, 11.5% had severe interstitial nephritis, associated infectious changes in 11.5% and atn in 5.8%. one patient each had minimal change, mpgn, abdominal kaposi sarcoma and kidney/bladder stones. 33.3% had or were treated for pulmonary tuberculosis. mean follow-up was 12±12.9 months. death occurred in 16.7% (10). all patients with fsgs with some renal dysfunction and severe sepsis demised. conclusion: despite the high burden of hiv disease, severe renal complications have a low prevalence. good correlation of icd and lip (65.1%) but prognosis is good. pulmonary tuberculosis and infection is the main complications resulting in high mortality in nephrotic syndrome with fsgs. hiv associated nephropathy (hivan) is one of the most common causes of renal failure in hiv seropositive african americans. in the usa, hivan has become the third leading cause of end stage renal disease (esrd) in african americans over the age of 20. while the introduction of haart has decreased both the mortality and infectious complications of hiv infection, the incidence of hivan has reached a plateau and has not decreased. with reduced mortality, the prevalence of seropositive patients in the esrd program continues to increase dramatically. the histopathological findings of hivan include focal segmental glomerulosclerosis of the collapsing variant combined with microcystic tubule dilatation. the most common other diagnosis is mesangioproliferative glomerulonephritis associated with hepatitis c infection, a common comorbid condition. typical features of hivan include renal enlargement and echogenicity by ultrasound analysis. microscopic findings include coexistent microcystic tubule dilatation and glomerular involvement. usually there is mild to moderate tubulointerstitial inflammation, interstitial edema, and fibrosis as well. glomerulosclerosis is usually focal and segmental with collapse of the glomerular tuft and hypertrophy of visceral epithelial cells. hivan is caused by renal epithelial infection by hiv-1 in a susceptible host. clearly there are genetic factors, based on the racial predilection of this disease. patients with hivan are 5.4 times more likely to have a relative with renal failure. in susceptible individuals, hiv infection induces renal epithelial proliferation and apoptosis. the kidney represents a tissue-specific compartment in which hiv-1 can replicate in a previously unrecognized reservoir. while hivan is not currently considered to be an aids-defining condition, patients with hivan should be treated with haart. in some instances, haart has completely reversed the disease process, although it does not rid the kidney of virus. thus, in patients with hivan, the kidney is a true reservoir for replication competent hiv. whether this occurs in other forms of renal disease associated with hiv infection or in patients without renal disease remains to be determined. prenatal administration of dexamethasone causes hypertension in rats when they are studied as adults. renal sympathetic nerves directly innervate renal tubules and blood vessels and plays a role in the regulation of glomerular filtration rate and renal sodium excretion. we examined if renal nerves play an a role in mediating the hypertension in prenatal programming. pregnant sprague-dawley rats were injected daily with intraperitoneal dexamethasone between 15 th and 18 th day of gestation. renal norepinephrine concentration was measured at 3 weeks of age. renal denervation was preformed at age 6 weeks of age in control and prenatal dexamethasone treated rats and blood pressure was measured at age of 8 weeks. renal norepinephrine concentration was 338±25 ng/gr in controls and 591±82 ng/gr in the group that received prenatal dexamethasone (p<0.05). systolic blood pressure at 8 weeks of age was 124±1 mmhg in sham operated controls, 122±5 mmhg denervated controls (p=ns). blood pressure was elevated to 133±1 mmhg in dexamethasone treated sham operated group (p<0.05), but was normal at 115±1 mmhg in the dexamethasone treated denervation group. in conclusion, prenatal dexamthasone results in elevated renal norepinephrine levels. bilateral renal denervation normalized the systolic blood pressure in rats that received prenatal dexamethasone. these data are consistent with the renal nerve playing an important role in mediating the hypertension in prenatal programming by dexamethasone. objective: evaluation of clinical outcomes in surgically treated children with renovascular hypertension (rvh). methods: 35 rvh patients treated surgically at a single centre between 1979 and 2005 were retrospectively reviewed: 63% were male, 0.4-17.9 (median 7.6) years of age, with systolic blood pressure (sbp) 141 mmhg (105-300 mmhg). results: bilateral renal artery stenosis was present in 53%, midaortic syndrome(mas) in 40%, intrarenal disease in 49% and coexisting cerebral disease in 24% of patients. surgical procedures (n=47) included: a) nephrectomy (n=18), b) autologous surgery for both aortic reconstruction (n=1) and renal revascularisation (n=15) (renalartery reimplantation (n=4), renal bypass (n=9) and autotransplantation (n=2)) and c) synthetic graft interposition for renal revascularisation (n=6), aortic reconstruction (n=6) or both (n=1). the majority (92%) of patients who received synthetic grafts had vascular anatomy too complex for autologous surgery. technical failure leading to secondary nephrectomy occurred in 3 patients. postoperative complications were haemorrhage (n=5), septicaemia (n=4), and chylous ascites (n=1). there were no operative deaths. patients from the uk were followed up for 5.1 (0.05-16) years. sbp post-surgery improved (116 mmhg, range 90-160 mmhg, p<0.0001). outcomes were normal sbp without treatment (52%), improved (34%) or unchanged sbp (14%). reduction of sbp led to loss of contralateral kidney in 1 patient. 10 children required re-interventions (15 angioplasties and 6 surgical procedures) for progressive disease (n=6), narrowing of the synthetic graft (n=4) and re-stenosis of the autologous bypass (n=2). conclusion: rvh is a progressive disease of extensive nature. surgery benefited 86% of children when performed in conjunction with conservative therapy and, if indicated, interventional radiology. h. wong 1 unlike adults with predominant primary hypertension (htn), the majority of children diagnosed with htn traditionally suffered from secondary forms of htn. however, substantial changes have occurred to the demographics of pediatric population over the past 20 years. in addition, our definition, awareness and understanding of children with hypertension has also changed. we therefore retrospectively reviewed the current causes of htn in children followed in a single tertiary care pediatric nephrology referral center between january 2003 and december 2006. patients who were either diagnosed with or treated for htn at the time of their last visit where included. gender, height, weight, age at the time of diagnosis, causer of htn and casual blood pressure were recorded. out of 1554 patients, 399 (25.7%) were diagnosed with htn. the majority were males (n=249, 62%). median was 10 years (1 month-18 years) age at time of diagnosis and 13.4 years (1.7 months-19 years) at time of the last follow-up. secondary htn was the most common cause of pediatric htn (n=329, 82%) followed by primary (n=51, 13%) and then white coat (n=19, 5%). renal htn was the most common cause of secondary htn (307/329, 93%). for patients referred initially for assessment of htn (n=137), primary (n=43, 31%) and secondary (n=41, 30%) were the two most common diagnosis followed by normotension (n=38, 28%) and white coat htn (n=15, 10.9%). twenty two (5.5%) patients were diagnosed before the age of 1 year. out of 23 renal transplant patients, 18 had htn (78%). renal htn remains the most common cause of pediatric htn overall and continues to represent a large portion of children referred for htn. all children suspected of having htn should continue to have thorough investigations of renal disease to identify the underlying cause. m. sinha 1 , c. booth 1 , j. simpson 2 , n. dalton 3 , s. qureshi 2 , c. reid 1 , s. rigden 1 1 evelina childrens hospital, guys and st. thomas's nhs foundation trust, department of pediatric nephrology, london, united kingdom 2 evelina childrens hospital, guys and st. thomas's nhs foundation trust, department of pediatrics cardiology, london, united kingdom 3 king's college london, department of medicine, london, united kingdom background: hypertension (ht) is a frequent complication in paediatric tx patients. the evolution of end organ damage and its relationship to ht in these patients is not well described. aim: to study the predictive value of an abnormal 24-hour abp profile for end organ damage. methods: patients underwent simultaneous casual blood pressure (cbp), abpm, echocardiogram (lvh if lvmi >38g/m 2.7 ) and ecg assessment, with measurement of several biochemical cardiovascular risk markers. cbp data for 18-months prior to study date was analysed as time averaged z-score. results: we present initial results of a 5-year prospective study. 22 patients (16 male) aged 12.7y±3.4 (mean±sd) and 5.9y±2.6 since tx were studied. on the day of study all patients had normal cbp. 73% had lvh of whom 65% had abnormalities on abpm. overall, 55% patients had both abnormal abpm and lvh. 45% had other findings: 10% abnormal abpm but no lvh; 10% normal abpm but no lvh; 25% normal abpm and lvh. data were analysed for differences between 2 groups of patients, with and without lvh. bp alone was significantly associated with increased lvmi. time averaged cbp was normal in all patients although differed significantly between the 2 groups: systolic bp z-score [mean (ci)] 0.27 (0.57, -0.03) with lvh; -.31 (-0.09, -0.54) without lvh. there were significant differences by abpm criteria relating to several components of the abpm profile including mean arterial pressure, systolic and diastolic bp load. no difference was found between the groups for hb, ca*po4 product, ipth and cgfr. conclusions: we have found the majority of our renal transplant patients have normal cbp but have abnormal abpm in association with lvh. this suggests better control of hypertension should be achieved in patients who have abnormal abp profiles and lvh. a new group of patients with normal abpm but lvh has also been identified. background: obesity is an independent risk factor for renal failure. therefore, we compared the body composition of pediatric nephrology patients with the general child population over two decades. methods: 6, 575 patients with a mean age of 9.5±4.2 years were studied. in 4, 595 patients (70.0%), sufficient data were available to analyze body composition. body composition was measured as body mass index (bmi) z-score because of the age dependency, calculated on the basis of data from the national (usa) center for health statistics (2000) . results: enuresis (24.88%), hematuria (16.45%), recurrent urinary tract infections (11.98%) and proteinuria (11.17%) were the most common diagnoses. the bmi z-score of the pediatric nephrology patients increased significantly from 0.33±0.47 in 1985-1991 to 0.72±1.06 in 1992-1999 and 1.27±1.54 in 2000-2006. while the rate of this increase was not statistically different from that seen in the normal population, they consistently demonstrated a significantly higher bmi z-score (average +0.545) over time. nephrotic edema, non-nephrotic proteinuria and hypertension were not confounding factors. conclusions: patients seen in our pediatric nephrology service over two decades had a higher bmi than the average child population. this implies that these patients are at even greater risk for development of chronic kidney disease later in life. we recommend therapeutic intervention to address this potentially modifiable risk factor. objective: b cell dysregulation is believed to be involved in the development of childhood-onset systemic lupus erythematosus (sle). there is limited evidence regarding efficacy and safety of interventions targeting b cell in children. in our study we evaluated efficacy and safety of b lymphocyte depletion therapy. methods: data of 20 children (15% male) with sle aged 14.1 years (6.1-16.2) treated with rituximab in a single centre were retrospectively reviewed. biochemical parameters were evaluated before and after treatment, and the normalisation of the parameters was assessed as a primary outcome. results: prior to rituximab therapy all patients received extensive immunosuppressive agents. indications for rituximab therapy were chronic (n=13) or acute illness, in either relapsing sle (n=3) or first presentation (n=4). rituximab 750 mg/m 2 was intravenously administered twice within a 2-week period in combination with cyclophosphamide. patients were followed up for 1.5 years (0.1-3.6) . no serious side effects were seen, except for viral infections such as herpes zoster (n=5). all patients with high creatinine (n=5; 226±99 mmol/l) prior to rituximab showed a decline within 2 months (mo), achieving a stable level by 8 mo (69±14 mmol/l, p<0.03). all patients with hypoalbuminaemia (n=12; 28.6±4.2 g/l) improved (5 mo: 36.1±6.4 g/l, p<0.001). low c3 level (0.40±0.12 g/l) as seen in 12 patients prior to treatment resulted in an increase up to 5 mo (0.77±0.24 g/l, p<0.002). a decline of previously high anti-dsdna (n=13; 162±163 iu/ml) was observed in all patients (5 mo: 56±62 iu/ml, p<0.02). conclusion: rituximab is safe and effective when used in combination with standard immunosuppressive agents. further prospective studies are essential to evaluate the longterm safety of the drug. outcome of severe henoch-schönlein purpura nephritis treated with longterm immunosuppression m. shenoy, m. bradbury, l. lewis, n. webb royal manchester children's hospital, department of nephrology, manchester, united kingdom aims: to look at the long-term outcome of all children with severe henoch-schönlein purpura nephritis (hsn) treated with long term immunosuppression in a single centre over a ten year period. patients and methods: retrospective review of the records of 27 children (19 male) with iskdc grade 3b, 4, 5 and 6 hsn managed at our institution from 01/01/92 to 31/12/01 results: the mean age at presentation was 9.8 years (range 3.6-15.8 years). the median estimated glomerular filtration rate (egfr) at presentation was 91 ml/min/1.73 m 2 (iqr 51. 5-96.6 ) and urine protein: creatinine ratio (up: uc) was 556 mg/mmol (iqr 292-1363). the indication for biopsy was nephrotic syndrome in 9, nephrotic range proteinuria in 7, sub-nephrotic range proteinuria in 3, acute nephritis in 6 and nephritic-nephrotic syndrome in 2. a total of 25 patients were treated with weaning dose of steroids, of whom 22 were also commenced on long-term azathioprine (mean duration 8.9 months). 18 of these children received an 8-12 week course of oral cyclophosphamide (2-3 mg/kg/day) prior to azathioprine therapy (2-3 mg/kg/day). outcome: after a mean follow-up period of 7 years, 10 (37%) have made a complete recovery, 11 (40.7%) have persistent proteinuria but normal egfr, 2 (7.4%) have persistent proteinuria and are on anti-hypertensive therapy with normal egfr and 4 (14.8%) have progressed to esrd. older age at presentation was the only independent risk factor for poor outcome (12.8 years vs. 8.9 years, p=0.005). conclusions: despite treatment with cyclophosphamide, long-term steroids and azathioprine, a majority of children with hsn grade -3b on initial biopsy have persistent renal abnormalities on long term follow-up. only older age at presentation was associated with poor outcome. background: resent advances in podocyte biology indicated that the main cause of the heavy proteinuria in nephrotic syndrome (ns) is a dysfunction of slit diaphragm. on the other hand, the classical charge selective barrier is not likely to have a place in slit diaphragm. therefore we reevaluated the charge selective barrier function in ns and chronic glomerulonephritis using recently established charge selectivity index (csi; takahashi et al, pediatr res 59: 336, 2006) in comparison with dent disease. patients and methods: csi is a clearance ratio of igg (stokes einstein radius 49-60, pi 4.5-9.0) and iga (stokes einstein radius 61, pi 3. 5-5.5) . the assay of serum and urinary igg and iga was performed using laser nepherometry and enzyme immuno-assay. in order to evaluate the csi of normal glomerular filtrate, we measured the csi of dent disease. the urine of dent disease is considered to be a concentrate of filtered protein from normal glomerulus, without having a process of tubular protein reabsorption. thirty eight patients with podocyte diseases (focal and segmental glomerulosclerosis 4, finnish type congenital nephrotic syndrome 1, steroid sensitive nephrotic syndrome 33), 75 patients with chronic glomerulonephritis (iga nephritis 41, henoch-schönlein purpura nephritis 21, mesangiocapillary glomerulonephritis 5, alport syndrome 8) and 8 patients with dent disease, were analyzed. results and conclusion: csi (mean±sd) of podocyte disesses, chronic glomerulonephritis and dent disease was 1.12±0.25, 0, 42±0.31 and 0.18±0.04 respectively. the results apparently indicated that the charge selective barrier of gcw is working strongly in normal glomerulus, less strongly in podocyte diseases and not working in chronic glomerulonephritis. objectives: nphs2 mutations have been reported in familial and sporadic srns. we investigated the prevalence of nphs2 mutations among south-east asian chinese and their association with clinical outcomes. methods: genomic dna from 29 patients with primary sporadic srns (mean age at onset 5.4±4.0 years, range 0.58-12.0 years) and 45 cord blood controls were screened on all 8 exons and exonintron boundaries using direct sequencing. results: a missense heterozygous 871c>t mutation in exon 7 was identified in only one patient. polymorphisms 954t>c and1038a>g in exon 8 were detected in both groups. in the patient group, the genotypic frequency of tt, tc, cc at position 954 was 0.24, 0.55 and 0.21, and aa, ag and gg at position 1038 was 0.86, 0.14 and 0 respectively, consistent with hardy-weinberg expectations. there was no significant difference in allele frequencies between patients and controls. using binary logistic regression analysis, individual polymorphisms did not appear as informative predictors of poor clinical outcome, defined as persistent proteinuria or renal failure (p>0.05). on analyzing composite genotypes, carriers of at least a copy of the 954c allele were significantly associated with poor outcome (p=0.047, or=12.7, 95% ci: 1.03-157), while heterozygotes for 1038a>g were associated with good outcome (p=0.048, or=0.06, 95% ci: 0.004±0.979), suggesting possible interactions between the polymorphic sites. further analysis showed that the genotypic combination of 954tc/cc with 1038aa was more likely to have a poor clinical outcome. no significant linkage disequilibrium was detected between the two polymorphisms. conclusion: the concomitant occurrence of at least a copy of the 954c allele and the 1038aa genotype may be associated with poor clinical prognosis in srns but larger studies are needed to confirm these findings. renal hypodysplasia (rhd) is characterized by a reduced kidney size and/or maldevelopment of the renal tissue following disturbed organogenesis. numerous deletion mouse models of developmental genes have been established presenting with anomalies of the kidneys resembling rhd, among these the knock-out of bmp4 and six2. here, we report on the first human mutations in bmp4 and six2 identified in children with rhd, among these three different mutations in bmp4 in five unrelated patients (ser91cys, thr116ser, asn150lys) and three different mutations in six2 also in five unrelated individuals (leu43phe, pro241leu, asp276asn). overexpression assays in zebrafish demonstrated that ventralization and dorsalization caused by bmp4 and six2 overexpression, respectively, could be diminished after overexpression of mutant constructs expressing the human mutations identified. morpholino knock-down of zebrafish bmp4 and six2.1 reveals specific roles of these genes for pronephric development, affecting the expression of wilms tumor-1 (wt1) and glomerular development. rna analysis of cos7 and hek293 transfected with different bmp4 constructs showed a lower level of mrna abundance in bmp4 mutants, indicating a possible negative feedback of the mutants on their own mrna expression and/or stability. nonreducing western analysis revealed that s91c-bmp4 forms alternative protein complexes as compared to wildtype-bmp4, due to the formation of extra disulfide bonds. these studies implicate six2 and bmp4 as important players in the development of the renal system, and suggest that defects in these proteins could affect kidney development at multiple stages leading to the congenital defects observed in rhd patients. apoptosis is important in normal renal development in which regulation of cell numbers is critical. studies have shown that apoptosis occurs in non-cystic tubules in pre-uremic pkd kidneys, thus providing the mechanism whereby expansion of cysts is accompanied by loss of normal nephrons. to date, it is unclear which initiating factors (intrinsic, through mitochondrial damage or extrinsic, through ligand activation of death receptors) are responsible for apoptosis in pkd and whether they are the same in ad-and arpkd. aim: to elucidate the sequence of activation of intracellular apoptotic pathway(s) in both ad-and arpkd. methods: proteins were extracted from tissues of human ad-and arpkd kidneys and normal adult (nhk) and fetal kidneys (hfk). quantitative western immunoblot analysis was carried out for 7 markers of intrinsic and extrinsic apoptosis. immunohistochemical staining for these markers was performed on tissue sections of the same kidneys. results: markers of extrinsic apoptotic pathways, caspases 8 and 10, were significantly increased in ar-and in adpkd tissue by comparison to nhk and hfk tissues. these increases were seen in early stages of adpkd and were more pronounced later in the disease. for the intrinsic pathway, caspase 9 and bid were increased in hfk tissue, but unchanged in ad-and arpkd tissue compared to nhk tissue. staining for caspase 9 was found in hfk, but was absent in all other kidney tissues. staining for caspase 8 was seen in early adpkd and endstage (es) adpkd as well as in es arpkd. caspase 3 was identified as the main executing caspase of fetal development and adpkd, but wasn't seen in arpkd, where caspase 7 predominated. conclusion: induction of extrinsic pathways of apoptosis predominates in pkd and occurs early in the disease process in adpkd, but only later in arpkd. intrinsic apoptosis predominates during development. intrauterine growth restriction (iugr) is a risk factor for an aggravated course of renal diseases in later life. the influence of postnatal factors, eg. accelerated catch-up growth, is not well understood. we therefore analysed the influence of postnatal nutrition after iugr on the developement of later renal inflammation and fibrosis in the rat. iugr was induced by low protein diet (8% vs. 20%) in pregnant wistar dams. litter size was reduced to 6 or 10 male animals in iugr (lp6, lp10) and control animals (np6, lp10), respectively. animals were sacrificed on day 70. mean arterial blood pressure was similar in all four groups. lp6 -(31.7±6.4 ml/h/100 g) and np6 animals (37.68±16.6 ml/h/100 g) showed reduction of endogen creatinine clearance by 50% (vs. np10and lp10) (p<0.001). renal mrna expression of il6 (5, 7 x), tgfβ1 (1, 5 x) , endothelin 1 (2, 7x) und osteopontin (2, 3 x) was significantly higher in lp6 than in np6. lp6 showed the highest glomerulosclerosis-score ((0.39±0.07) (vs. np6 (0.1±0.07), lp10 (0.09±0.02) and, np10 (0.03±0.02)) (p<0.01). as marker of extra cellular matrix expansion glomerular collagen-iv deposition was significantly higher in lp6 (17.8±6.3%) (vs. np6 (14.3±4.0%), lp10 (7.4±4.0%) and np10 (7.2±1.9%)) (p<0.01). postnatal nutrition modifies the consequences of iugr in the kidney. increased postnatal nutrition of the individual animal is associated with aggravated renal inflammation and fibrosis after iugr. unilateral renal agenesis (ura): how intensively do we need to investigate and follow-up? s. rhodes, a. watson nottingham university hospitals, children and young people's kidney unit, nottingham, united kingdom a single kidney is one of the commonest urinary tract abnormalities in the general population. concerns remain about long-term outcomes with a reduced nephron mass and hence intensity of investigations and duration of follow-up. we identified 52 cases with ura (ectopic and pelvic kidneys excluded) from our nephrourology database between 1985 and 2006. 38 (73%) occurred in males and 25 (48%) had left ura. 27 (52%) were detected antenatally with 12/27 (44%) recognised in the last 2 years. median age of detection for postnatal ura was 7 mths (range 0.25-179 mths) with uti (29%) as the main indication for ultrasound scan (uss). 60% patients were classified as simple ura with no associated abnormality and 40% as complex with problems such as vesicoureteric reflux (vur)(21%), hydronephrosis or scarring. all cases reviewed had uss which showed compensatory hypertrophy in 25/52 (48%). 29/52 (56%) had dmsa scan and 24/52 (46%) micturating cystogram. of those antenatally detected single kidneys with normal initial uss none had vur, scarring, hypertension or proteinuria. these patients were discharged from follow-up at the median age of 6 mths (range 1-122 mths). all complex cases have continued under follow-up. conclusions: our data suggest that the incidence of antenatally detected ura may be increasing. investigations need to be individualised depending upon the initial uss. the value of routine dmsa and mcug in simple cases is questioned. most of these patients can be discharged after adequate documentation of compensatory hypertrophy of the normal kidney, absence of proteinuria, normal blood pressure and renal function. autosomal dominant pdk (adpkd) in childhood j. crocker, p. wornell, p. acott iwk health centre/dalhousie univeristy, division of nephrology, halifax, canada autosomal dominant polycystic kidney disease (adpkd) is the most common genetic kidney disease with 1 in 6 adults progressing to end-stage renal disease (esrd). a program for intervention in childhood at presentation with adpkd was developed and instituted in 1992. our long-term objective is to modify clinical parameters that may contribute to risk of development of esrd in adulthood. seventy children with adpkd (average age 11.47 yr) were followed, of which 10 (14%) had nephromegaly +/-cysts on antenatal ultrasound. modifiable risk factors were common including hypertension (22%), hyperlipidemia (54%), and proteinuria (7%). ace inhibitors were first line therapy for proteinuria and/or hypertension. ace inhibitors may modify cyst progression so they have been made available to non-hypertensive children as well. most patients with hyperlipidemia responded to dietary intervention with one patient developing gallstones. in the past 5 years we have focused on renal calculi, as this is a known risk for a subgroup of adults with poor prognosis. we noted 14 patients (20%) have glycinuria, which is a precursor to oxaluria. four patients have passed calculi with two of these being diagnosed by genetic linkage analysis for adpkd without radiographic cysts present. cerebral vascular studies of 14 patients with severe headaches revealed two with vascular structural anomalies. all adolescent females received counseling regarding appropriate contraception and their pregnancy risks of hepatic cyst progression. an early intervention program targeting modifiable risk factors of adpkd patients during childhood and adolescence may modify adult renal failure risk in this population. background: techniques of chronic infant dialysis have evolved during the past 2 decades but morbidity and mortality are not well described. methods: a retrospective review was performed on 45 infants -18 months of age with end stage renal disease (esrd) treated with maintenance dialysis during the past 23 years. the experience was divided into era 1 (1983 era 1 ( -1994 (n=23) and era 2 (1995 era 2 ( -2006 . dialysis modality, morbidity, and long term survival were assessed and compared between the 2 eras. results: all patients were begun on peritoneal dialysis (pd). there were 22 males and 23 females. age at initiation of dialysis was 4, 5 months. the predominant diagnoses were dysplasia/obstructive uropathy (n=24), autosomal recessive polycystic kidney disease (arpkd) (n=10), congenital nephrotic syndrome (cns) (n=7), other (n=4). overall survival is 38% (17/45) with current age of survivors ranging from 5 months to 23 years. mortality between era 1=70% and era 2=55% was not significantly different. fifteen (33%) survived to receive a kidney transplant. overall median survival is 3.1 years (era 1=3.5 years; era 2=3.1 years; p=0.97). conclusions: although long term survival is possible in infants with esrd, mortality and morbidity remain high. improved technologies for automated pd should address the needs of the infant <6 kilograms. joubert syndrome and related disorders (jsrd) are a group of autosomal recessive conditions characterized by a complex neuroradiological malformation resembling a molar tooth on imaging. clinically, jsrd are characterized by overlapping phenotypes presenting neurological signs and variable involvement of other organs such as kidneys (mainly nephronophthisis -nph), retina and liver. seventy-nine italian jsrd patients from 63 unrelated families were recruited in pediatric nephrology and neurology centers. medical records and brain mri were reviewed. patients without chronic renal failure (crf) underwent measurement of their glomerular and tubular function, a ddavp urine concentration test and a renal ultrasound. retinal examination was performed in most patients. seven patients younger then 18 years had normal renal function but were not fully tested. of the remaining 72 cases, 44 had no evidence of renal disease, 16 had developed crf mostly in their second decade of life, and 9 were younger then 11 years of age and had urinary concentration defects, of whom 5 also had hyperechogenic kidneys by renal ultrasound. when comparing this latter group with age-matched jsrd patients, no other tubular function abnormality was detected. in 13 multiplex pedigrees, no discrepancies in renal involvement between affected family members was observed. retinal involvement was significantly associated with renal disease. conclusions. evidence of interstitial renal disease was observed in one third of italian patients with jsrd. renal involvement should always be suspected in these patients, particularly if they have evidence of retinal dysplasia or other family members with symptoms related to nph. these patients should be assessed with a urine concentration test. we examined the course of 49 children with 56 primary obstructive megaureters (pom) treated in our hospital from 1994-2006. pom occurred more often in boys (71%, p<0.01) and on the left side (67%, p<0.05). 43 pom (77%) were only treated conservatively. four underwent immediate surgery following the first mag3 renography. one of these was nephrectomized after unsuccessful urinary diversion and persistent renal hypertension. of the 52 kidneys primarily managed conservatively, 9 needed a ureterocystoneostomy later on due to increasing obstruction. surgical correction of pom required a mean of 15 days of hospitalization (incl. temporary urinary diversion, removal of catheters and treatment of complications). one child required surgical revision of early post-operative ureteric stenosis. urinary tract infections (uti) were a common complication (n=66, mean 1.3 per patient). as utis occurred mainly in infants, hospital admission was commonly required (45%). only 14 children never acquired a uti (29%). eight patients had a poor outcome as defined by partial kidney function <40% on the affected side (n=6), atrophy on final ultrasound (n=3) or nephrectomy (n=1). the most potent predictor of reduced unilateral kidney function was a small kidney present from birth. secondary kidney growth failure occurred only in one case. the initial degree of obstruction on renography, but not the degree of hydronephrosis or size of megaureter predicted outcome. also, prenatal diagnosis of pom, surgical treatment and the occurrence of utis showed no association with outcome. in summary, the long-term prognosis of pom appears favorable. adverse outcomes were more closely related to congenital kidney size deficit than to the degree of obstruction. surgical interventions and the high uti incidence led to significant hospitalization times. r. bhimma, m. adhikari, k. asharam university of kwazulu-natal, maternal and child health, durban, south africa background: steroid resistant (sr) forms of ns have a poorer outcome in blacks compared to other racial groups. methods: 223 children with srns 1-16 years old were analysed retrospectively for the period 1976-2004. treatment schedules included oral cyclophosphamide with prednisone only (n=90); prednisone on alternate days with methylprednisolone and oral cyclophosphamide (n=117); oral prednisone on alternate days, 3 doses of intravenous methylprednisolone on alternate days and monthly doses of intravenous cyclophosphamide (n=10) or cyclosporine adjusted to a trough level of 150-200 mg/ml (n=6). we compared the clinical, biochemical characteristics and outcome of these children using different forms of therapies. results: 183 (82.1%) underwent renal biopsy.84 (45.9%) were indian and 99 (54.1%) were black. 66 (36.1%) had minimal change ns, 66 (36.1%) had focal segmental glomerulosclerosis (fsgs), 15 (8.2%) a proliferative form of ns, and 36 (19.7%) had other forms of ns. 58/84 (69.0%) indian children biopsied were in complete remission and 29/40 (72.5%) with mcd who were treated with oral cyclophosphamide and prednisone only achieved complete remission. 32/40 (80%) indian children not biopsied who received only oral prednisone and cyclophosphamide achieved complete remission. 20/99 (20.2%) black children who were biopsied achieved complete remission. none of the eight black children who were not biopsied given only oral cyclophosphamide and prednisone achieved complete remission. conclusion: since 80% of indian children with srns responded to a trial of oral cyclophosphamide and prednisone but none of the black children did, we propose the use of oral cyclophosphamide therapy in non black children before embarking on renal biopsy. mj. kemper, c. moeller, n. rink, m. van husen, de. müller-wiefel university of hamburg, pediatric nephrology, hamburg, germany introduction: ssns is often complicated by a refractory clinical course with frequent relapses and steroid dependency despite aggressive alternative immunosuppressive regimens. since recent immunological findings suggest an alteration of not only t-but also b-cell immunity in ssns (kemper 2003 (kemper , 2004 we hypothesized that that immunological targeting of b-cells with antibodies directed against cd20 (rituximab) is able to maintain remission (rm) in treatment refractory patients with ssns methods: a total of six patients with complicated courses of ssns had severe steroid-dependency and toxicity. all patients had previously been treated with cyclophosphamide, two patients relapsed on maintenance therapy with cyclosporine, one relapsed on additional levamisole and one on mmf. treatment was initiated at a median age of 13 (range 11-15.6) years and rtx was given at steroid induced rm at a dose of 4x 375 mg/m 2 bsa within 4 weeks. results: a complete b-cell depletion was induced for at least 5 months in all patients. rm could be maintained in all patients and steroid treatment could be discontinued after a median of 2.5 months (range 1-4.6) . also csa could be discontinued in the two patients on maintenance treatment. at current follow-up of 11.5 months (range 5-23.5) the two patients after csa discontinuation relapsed after 8.7 and 12.7 months, respectively, but responded after steroid induced rm-to a second course of rtx. all other patients remained in remission off treatment so far. no significant clinical side effects were noted. conclusion: in summary and conclusion, rtx seems to be a therapeutic option in complicated ssns. long-term follow-up and future prospective studies are necessary to further define the role of rtx in the treatment of refractory steroid sensitive nephrotic syndrome. efficient control of secondary hyperparathyroidism can be achieved by calcimimetics. they increase calcium sensing receptor (car) sensitivity to extracellular calcium. in r-568-treated uremic rats, proteinuria has been significantly reduced by calcimimetics. thus, we examined the potential direct effect of r-568 on podocytes. the car was expressed in cultured immortalized podocytes (quantative rtpcr, western blot) and in podocytes obtained from healthy and subtotally nephrectomized rats (immunohistochemistry). glomerular car abundance was increased by uremia and r-568. the car colocalized with the plasma membrane and intracellular filaments in cultured podocytes, but not with the caveolin 1-and 2-rich membrane fractions. we then studied the effect of r-568 on the mitogen-activated protein kinase (mapk) family. jnk was not activated. p38 showed a biphasic response pattern, whereas erk1/2 (and further downstream, p90 ribosomal s6 kinase) showed dose-(1-50 nmol/l) and time-dependent phosphorylation, resulting in the activation of the transcription factor camp response element binding protein (creb). creb phosphorylation induced bcl-xl expression and bad phosphorylation, both of which have prosurvival activity. specificity was confirmed by addition of mek 1/2 inhibitor u0126, which completely blocked r-568-induced creb phosphorylation. facs analysis revealed a significant, 50% decrease in puromycin-induced apoptosis in podocytes treated with r-568 for 48, 60 and 72 hrs. in conclusion, calcimimetics induced prosurvival gene expression in podocytes via mapk, protecting them from apoptosis. calcimimetics may have a direct renoprotective action beyond control of hyperparathyroidism in chronic kidney disease patients. we report our experience with plasma therapy in a family of three sisters from whom two are homozygous twins (patients b and c), presenting a missense mutation of the exon 23 of the human complement factor h gene (hf-1). the factor h concentration has always remained normal and no systemic complement activation has ever been detected. in a ten years period, the followings have been observed: 1/ no use of plasma exchange lead to immediate esrf of native kidneys (patient a); 2) conventional plasma therapy (10 sessions at presentation followed by repeated 10 ml/kg plasma infusions when relapse of hemolysis and thrombopenia) could not impede esrf (patient b); 3) the use of intensive pe at presentation (daily pe (40 ml/kg ffp until plasma creatinine normalization followed by one pe/2w indefinitely) lead to a normal gfr 5 years after presentation despite 2 relapses (patient c); 4/ no prophylactic pe for tx lead to immediate hus relapse and transplant loss (patient 1); 5) prophylactic pe allowed a successful tx in patient b (pl. creat 110 mcmol/l after 5 years); 6) early and intensive pe allowed complete normalization of several hus relapses after tx (patient b). conclusions: in fh mutation-related atypical hus, 1) intensive and indefinitely prolonged pe can allow a normal function of native kidney at long term; 2) prophylactic pe allows successful kidney tx; 3) early and intensive pe allow reversion of hus relapse after tx. the success of plasma therapy is bound to the followings: a/ the use of pe and not plasma infusion. b/ the prolongation of daily pe after normalization of hemolysis parameters, and further prophylactic pe. c/ the use of pe prophylaxis from before tx. d/ a minimum pes frequency of one/week in case of prophylactic treatment for tx. e/ immediate intensification of pe frequency in case of relapse. objectives of study: heparan sulfates (hss) are highly polyanionic sugar chains in the glomerular basement membrane (gbm) and have been reported to play an important role in the chargeselective permeability of the kidney. alterations in hs expression have been reported in a number of renal pathologies. in this study, we evaluated if degradation of hs in the gbm resulted in proteinuria in rats, using a controlled in vivo approach. methods: heparinase iii and neuraminidase were injected i. v. in 2-month old wistar rats at t=0 hr and t=8 hr, and kidneys were removed at t=24 hr. urine samples were taken at various time points. cryosections were stained for hs using specific antibodies, and for hs stubs (generated by heparinase). in addition, hs was evaluated at the electron microscopical level. neuraminic acid expression was analysed by peanut agglutinin lectin. the hs content in urinary samples was evaluated by agarose gel electrophoresis. urinary neuraminic acid was studied by an enzymatic colorimetric assay. presence of urinary albumin (proteinuria) was investigated by sds-page and by a competition elisa. results: injection with heparinase iii resulted in an almost complete absence of glomerular hs staining. cupromeronic blue staining was also greatly reduced in the gbm, further indicating that hs was largely degraded. staining for the hs proteoglycan core protein agrin was unaltered. in the urine a strong increase in hs was found, already at the first point in time of urine collection (2 hr after the first injection). however, no urinary albumin or other proteins could be detected at any point in time analysed. injection of rats with neuraminidase resulted in a major increase of albumin in the urine. conclusion: in conclusion, removal of hs from the gbm does not result in acute albuminuria, whereas removal of neuraminic acids does. introduction and methods: 192 children undergoing deceased (156) or living (36) donor kidney transplantation were randomized to receive tacrolimus, azathioprine, steroids and two doses of basiliximab (tas+b) or tacrolimus, azathioprine and steroids(tas). previously reported six month follow-up biopsy-proven acute rejection rates were 19.2% (tas+b) and 20.4% (tas). patient survival was 100% and graft survival 95% in both arms (am j transplant 2006; 6: 1666-72) . in this investigator-driven follow-up study individual outcome data were submitted annually to the coordinating centre. results: two year follow-up data were obtained for 144 (87.8%) of the 164 who completed the six month study. there was one death in the tas group occurring at month 20. there were 5 graft losses in the tas+b arm and 9 in the tas arm. all 5 graft losses in the tas+b arm occurred within the first 6 months. kaplan-meier estimates of 2 year graft survival were94.9% for tas+b and 89.5% for tas (p=0.28 breslow generalised wilcoxon test). episodes of biopsy proven acute rejection occurred in 23 in tas+b and 26 in tas, kaplan-meier estimates of freedom from rejection being 76.1% and 69.6% respectively (p=0.49). renal function did not differ significantly between the two arms; the median (iqr) plasma creatinine levels were 90 (74-113) in tas+b and 96 (77-115) in tas (p=0.94). similarly there was no evidence of a difference in either systolic or diastolic blood pressure between the two arms. there was one case of b cell ptld in the tas+b arm at 11 months in addition to two cases in the tas arm previously reported in the 6 month study. conclusions: the addition of basiliximab to a regimen of tacrolimus, azathioprine and steroids does not appear to result in an improvement in either acute rejection rate or graft survival at two year follow-up. further data collection is ongoing. chronic renal dysfunction is a major complication after heart transplantation (htx). the pathophysiology is not yet fully understood but is thought to be in part due to calcineurin inhibitor (cni) toxicity, and reducing cni exposure has become one of the main strategies aimed at ameliorating renal outcome in htx recipients. we previously reported a significant improvement of renal function in 14 htx children with biopsy-proven cni nephrotoxicity and chronic renal failure, 1 year after the reduction of cni dosage with a concomitant replacement of azathioprine by mycophenolate mofetil. we ought to determine whether this improvement was persistent after 3 years of follow-up, despite the histological lesions of chronic cni nephrotoxicity. gfr evaluated by annual inulin clearance had improved from a mean of 46.5±9.6 ml/min/1.73 m 2 (range 34-60) at time of the switch to 77.6±6.0 ml/min/1.73 m 2 (range 54-102) (p=0.019) one year after (67% improvement), and remained stable at 76.4±18.2 ml/min/1.73 m 2 (range 50-102) (p=0.76) 3 years after the switch. maximal urinary osmolality followed the same increase profile from 559±103 mosm/kg before the switch to 762±122 at one year and 736±154 after 3 years (p=0.64). meanwhile, the occurrence of serious adverse events such as infectious episodes, acute rejection and chronic allograft dysfunction as assessed by clinical examination, echocardiography and endomyocardial biopsies were not different from a control group of patients whose treatment was unchanged. no malignancy was observed in either group. in conclusion, reduction of cni dosage and replacement of azathioprine by mycophenolate mofetil lead to a safe and long-lasting improvement of renal function in children with heart transplants and cni-induced nephropathy. previous studies have demonstrated reduced bone mineral density (bmd) in some patients with idiopathic hypercalciuria (ih). reduced bmd during childhood may impact adult peak bone mass. bisphosphonates employed in adults with ih and reduced bmd resulted in conflicting outcomes. we evaluated the effects of oral bisphosphonate, alendronate (ale), in 3 patients with persistent ih and reduced bmd. patients presented at ages 6, 12, 13 yr, with hematuria/dysuria, 2 had recurrent urolithiasis, and all had ih (uca >4 mg/kg/24 hr). despite maximal traditional rx with low na/high k diet, thiazides, k-citrate, ih persisted (5.6-12 mg/kg/24 hr). at ages 10, 16 and 14.5 yr, dxa showed reduced bmd, and ale 10, 40 and 70 mg/once weekly was given for 15, 7 and 18 months, respectively. after 6 months of ale, uca decreased significantly compared to baseline (mean±sd, 3.0±1.9 vs. 6.3±1.8 mg/kg/24 hr, p<0.05). compared to baseline, bmd z scores 1 year after starting ale improved at the spine (-1.1±0.4 vs. -2.3±0.6, p<0.05) and hip (-1.9±0.3 vs. -2.3±0.2) . the decline in uca during ale rx correlated with the increased bmd z scores in the spine (r=-0.98, p=0.01) and hip (r=-0.93, p<0.05). height z scores, serum creatinine, ca, p, electrolytes and pth remained normal throughout the rx period and no further hematuria or new stones occured. in summary, ale normalized uca previously resistant to traditional rx, eliminated urinary symptoms and improved reduced bmd in children with ih. the use of a single oral weekly dose appears adequate and safe. larger prospective studies are needed to confirm these preliminary results. in addition to its classical role in the regulation of calcium (ca) and phosphate (po 4 ) homeostasis, vitamin d has important immunomodulatory and anti-inflammatory effects, that in turn can influence atherosclerotic vascular disease. we studied the impact of vitamin d levels and inflammation on vascular structure and function in children on dialysis. 59 children (age 13.4±4.1 yrs) on dialysis (mean duration 1.1±0.9 yrs) were studied. all children received 1α-hydroxyvitamin d 3 (alfacalcidol) . cumulative data on ca, po 4 and pth, doses of po 4binders and alfacalcidol were recorded.1, 25-dihydroxyvitamin d 3 (vit d) and high-sensitivity crp (hs-crp) levels were measured by 125 i radioimmunoassay and elisa respectively. all children had carotid intima-media thickness (cimt), pulse-wave velocity and cardiac ct for coronary calcification. 23 (39%) children had vit d deficiency (levels<40 pmol/l), 25 (42%) hadnormal levels (40±150 pmol/l) and 11 (18%) had high levels (>150 pmol/l). vit d positively correlated with serum ca, caxpo 4 and alkaline phosphatase. both cimt and calcification showed a bimodal distributionpatients with vit d levels <40 or >150 pmol/l were significantly more likely to have calcification or raised imt than those with vit d levels in the normal range. hs-crp levels independently predicted cardiac calcification (p=0.02) but not cimt. there was a strong inverse correlation between vit d levels and hs-crp (p<0.0001, r=-0.69). patients with vitamin d levels<40 pmol/l and hs-crp levels>10 mg/l had 6-fold greater calcification scores than subjects below these cutoffs. in conclusion, vit d deficiency is common despite treatment in children on dialysis. vit d may be an important mediator of vascular damage both through its hypercalcaemic and anti-inflammatory actions. severe growth failure remains one of the challenging problems in the care of children suffering from chronic renal failure (crf). although, rhgh has been proven to increase final adult height in prepubertal crf patients only limited data on its efficacy in the pubertal age-range are available. in addition, the impact of the underlying renal disease and the mode of renal replacement therapy on final height in these patients remain unclear. we report on final height data of 240 (47 female) severely growth-retarded crf patients (standardized height <-2 sds; database: kigs medical outcomes, pfizer). mean age at start of rhgh therapy was 13.7±3.0 years, standardized height was -3.6±1.2 sds and duration rhgh therapy was 4.6±2.5 years (range 1.0 to 14.2 years). at baseline 45% of the patients were on conservative treatment, 28% were on dialysis and 27% had a functioning renal allograft. in the whole study population mean standardized height was increased in the first treatment year and at attainment of final adult height by +0.4 sds and +1.2 sds, respectively (each p<0.0001 vs. baseline). prepubertal children aged less than 12 years at start of rhgh therapy showed the best growth response (+1.5 sds). in pubertal patients mean increase in standardized height was +1.2 sds, whereas growth response in patients with delayed onset of puberty (>+2 sd) was significantly lower (+0.8 sds; p=0.039 vs. other groups). the duration of rhgh therapy was positively associated with cumulative height gain. growth response was significantly lower in patients on long-term dialysis and in patients with nephropathic cystinosis. conclusion: rhgh therapy in severely growth retarded prepubertal and pubertal crf patients results in an increased final adult height. growth response is diminished in crf patients with markedly delayed onset of puberty. tightly regulated rankl/opg system is essential for normal bone remodelling. however, the exact roles of those osteogenic markers in uremic bone disease have yet to be defined. we therefore assessed the potential relationship of the rankl/opg system in bone biopsy proven secondary hyperparathyroidism (hpt) in dialyzed children. methods: 40 patients aged 13±1years were on ccpd for 14±4 months. s-ca, p, alk p'tase, pth, opg and rankl levels were measured. bone biopsies were obtained after double tetracycline labeling and none of the patients were treated with vitamin d for four weeks prior to biopsy. results: s-ca levels were 9.2±0.7 mg/dl, p: 6.1±1.5 mg/dl, alk p-tase: 401±297 u/l, pth: 898±415 pg/ml. bone biopsy findings revealed high turnover bone disease in 31 patients, 9 patients had normal bone formation rate (bfr). mean opg and rankl levels were 4.46±1.46 and 0.66±0.81 pmol/l, respectively (reference control=opg: 1.8; rankl: 0.42). opg correlated with bfr (r=0.473, p<0.01) and adjusted apposition rate (r=0.42, p<0.01), while inversely correlated with osteoid maturation time (omt) (r=-0.34, p<0.03) and mineralization lag time (r=-0.45, p<0.01). rankl/opg ratio was negatively correlated with mineral apposition rate (r=-0.35, p<0.03) and positively with omt (r=0.31, p<0.05). pth was correlated with bfr (r=0.40, p<0.01) and resorption area (r=0, 54, p<0.01), but not with any mineralization markers. there were no correlations between pth and opg or rankl. conclusion: opg, in contrast to rankl, exerts a dual effect on the skeleton by promoting mineralization and increasing bfr. these osteogenic markers might be of benefit in characterizing the turnover, mineralization and volume of the skeletal lesions of secondary hpt as recently recommended by kdigo. "sevcan bakkaloglu was supported by tübitak (scientific and technological research council of turkey). this study was supported by usphs grants dk-35423, dk-67563 and mo1-rr00865. " pth values are widely used to guide therapy for renal osteodystrophy in patients treated with maintenance dialysis yet target values are based on cross-sectional studies and discrepancies between bone formation rates (bfr) and pth have been described during intermittent calcitriol rx. thus, we evaluated the relationship between serum biochemical parameters and bone turnover during treatment with intermittent vitamin d sterols. 60 patients aged 13±1 yrs with biochemical and bone biopsy (bbx) proven 2 nd hpt received 8 months of vitamin d (1, 25d 3 or 1d 2 ) given in twice weekly oral dosing and phosphate binders. dose of vitamin d was titrated upwards monthly to maintain 1 st pth-ima(nichols r ) levels between 300-400 pg/ml. bbx was then repeated. s-ca, p, alk p-tase and pth by 1 st and 2 nd pth-imas were obtained monthly throughout therapy. baseline values were: p: 6.2±0.1 mg/dl, ca: 9.2±0.1 mg/dl, alk p-tase: 397±36 iu/l, 1 st pth-ima 940±55 pg/ml, 2 nd pth-ima: 510±41 pg/ml. final values were: p: 5.5±0.1mg/dl, ca: 9.4±0.1 mg/dl, alk p-tase: 324±35 iu/l, 1 st pth-ima: 565±43 pg/ml, and 2 nd pth-ima: 280±27. bone formation rate (bfr/bs) decreased from 114±8 to 55±5 um 2 /mm 2 /d (nl: 10-73.4); 72% achieved normal bone turnover. 2 nd pth-ima values were 40-50% lower than 1 st pth-ima levels; there was no difference in predictive capability of the two assays. patients achieving normal bfr/bs had 1 st pth-ima values of 508±44 pg/ml. the sensitivity, specificity and ppv of a 1 st pth-ima range of 300-600 pg/ml for normal bfr/bs were 70% (95% ci: 50-86%), 60% (26-88%), and 83% (61-95%) respectively. during therapy with intermittent vitamin d sterols, maintaining pth levels higher than currently recommended results in normal bfr/bs and prevents adynamic bone. maternal diabetes will induce abroad array of congenital malformation. consistently with these hypotheses, we observed the defects of renal development of diabetic pregnancy from late phase of embryogenesis to postnatal period in animal model (c57bl/6j mice). histological analysis of phenotypes revealed decreased glomerular numbers, glomerular hypertrophy and hypercellularity, as well as renal tubular detachment in sequential late phase of kidney development in the offspring of diabetic female mice. tunel assay showed signficinatly increased cell apoptosis in fetal kidneys of hyperglycemic group. rt-pcr and fish study of kidneys of fetal and newborn mice revealed that gdnf and early growth response alpha (egr-α) are two of crucial genes inhibited in hyperglycemic ambience. in human, we presumed that children of gestational hyperglycemic mothers have the same defects of renal development as our animal model similarly, thus we measured and compared echogram of kidney/liver echoenic ratio in 76 children born to gestational hyperglycemic mothers and 240 health children. interestingly, our human ultrasonic study indicated that after age of 6 months, the diabetic children had increased echogenic ratio of kidney/liver than the healthy age matched children (p<0.01). we also found that 26.3% of diabetic children had nonobstructive hydronephrosis. this simple sonographic procedure may provide a permissive was for clinicians to obtain the basis of long-lasting follow-up of these high-risk children as early as possible. keywords: diabetic embryopathy, renal development, glial cell line-derived neurotrophic factor, early growth response alpha, renal sonogram. genetic inactivation of spry 1 in mice results in increased number of ub branches and expanded gdnf, c-ret and wnt-11 expression domains (basson et al., dev. cell, 2005) , indicating that spry1 is a negative regulator of the gdnf-ret-wnt11 pathway. ang ii induced ub branching morphogenesis, partly via stimulation of egfr tyrosine kinase activity (yosypiv et al. jasn, 2006) . we tested the hypothesis that ang ii stimulates the gdnf-ret pathway via repression of spry1. cd1 mice metanephroi were dissected on embryonic (e) day e12.5, grown on filters in the presence or absence of ang ii (10 -5 m, n=5/group) for 24 hours and subjected to whole-mount ish with digoexigenin-labelled spry1, c-ret, wnt-11 and gdnf crna probes. spry1 mrna was expressed in ub branches and in condensing mesenchyme. c-ret and wnt-11 were expressed in ub tips, and gdnf-in the metanephron mesenchyme. ang ii downregulated spry1 expression in the ub. in contrast, c-ret and wnt-11 were induced by ang ii in the ub tip cells. gdnf expression in the mesenchyme was also upregulated by ang ii. in addition, ang ii stimulated ub tip cell proliferation, as determined by in vivo brdu in corporation (28.5±2.4 vs.9.7±1.2; p<0.001) compared to control. these findings suggest a model in which ang ii-mediated inhibition of spry1 gene expression releases. ret tyrosine kinase activity leading to upregulation of c-ret and its downstream target gene, wnt-11. enhanced wnt-11 expression, in turn, induces gdnf in the adjacent mesenchyme. this causes focal bursts of ub tip cell proliferation and branching. these results support the hypothesis that abnormal collecting system development in angiotensinogen, renin, ace or at1-deficient mice is at least partly due to aberrant regulation of the ub branching morphogenesis program. objectives of study: nephrogenesis requires a fine balance of many factors that can be disturbed by intrauterine growth restriction (iugr), leading to a low nephron endowment. our previous studies have shown that offspring born to mothers supplied low protein diets during pregnancy have fewer glomeruli than normal at birth in sd rats. the aim of this study was to identify the possible pathogenesis of abnormal nephrogenesis and decreased glomerular number in iugr by comparative proteomic approach. methods: iugr was induced in sd rats by isocaloric protein restriction in pregnant dams. kidney proteins were obtained from 6 neonatal normal rats (control group) and 8 iugr rats (iugr group) respectively. a series methods including 2-de, silver staining, mass spectrometry and database searching were used. the 2-de test was repeated three times in each group. results: after silver staining, the 2-de image analysis detected average 730±58 spots in iugr group and 711±73 spots in control group. the average matched rate was 86% and 81% respectively. the differential proteomic expression analysis found eleven protein spots were expressed only in iugr group and one in control group. seven protein spots were up-regulated more than 5 folds and two down-regulated more than 5 folds in iugr group compared with those in control group. these 21 protein spots were preliminarily identified, which were structural constituents of cytoskeleton including vimentin, cytokeratin 10, perlecan and b-actin, transcriptional factors including splicing factor, rho gdp dissociation inhibitor alpha and cell division proteinkinase 2, enzymes including retinal dehydrogenase1, transketolase and so on. conclusions: data from this study may provide, at least partly, valuable experimental evidence of proteins involved in the pathogenesis of abnormal nephrogenesis and decreased glomerular number in iugr. the aim of the study is to describe the natural history of tcf2/hepatocyte nuclear factor-1 beta linked disease in children. prenatal and postnatal renal evolution and extrarenal manifestations of 33 patients were reported. thirty one had prenatal diagnosis of developmental nephropathy: bilateral foetal hyperechogenic kidneys or a hyperechogenic kidney with a controlateral multicystic dysplastic kidney. 64% had cysts. the mean prenatal renal length was normal (0, 29 sd) . intrauterine growth was normal with median birth weight of 3.1 kg (range 1.6-3.6) and 30% were small for gestational age. after a mean follow-up of 79 months, the renal growth was impaired with a mean renal size of -0.78 sd. patients with a solitary functioning kidney showed no compensatory hypertrophy. thirty one patients developed bilateral nephropathy and 2 isolated unilateral multicystic kidney. twenty eight patients had cysts, mainly cortical bilateral microcysts. the mean gfr was 73.19±30.43 ml/min/sc. sixteen patients had stage 1 chronic kidney disease (ckd), four were classified as stage 2, eleven as stage 3 or 4 ckd and two were diagnosed with end stage renal failure. annual decline of the glomerular filtration rate was 3.4 ml/min. extrarenal manifestations included 3 patients with diabetes, one with exocrine pancreatic insufficiency, one with pancreatic hypoplasia without clinical symptoms and 4 with cholestasis. we found a complete heterozygous deletion of the tcf2 gene in 20 patients and nine different point mutations. three patients had the g76c mutation, 2 with unilateral mcdk and 1 with bilateral severe hypoplasia leading to early renal dysfunction. tcf2 gene anomalies are associated with low renal function decline but in some patients end stage renal failure appeared early in life. long term follow-up is needed to determine the incidence of extrarenal symptoms, particularly diabetes. objectives: although it has been observed more than one hundred years ago that the urinary tract is very resistant to infection, its antimicrobial mechanisms have not yet been systematically characterized. we sought to elucidate the expression and relevance of the antimicrobial peptide cathelicidin in this area. methods: in order to investigate the expression of cathelicidin in health, urine samples from healthy children, pieces of healthy renal tissue, and cell cultures were analyzed. to evaluate the expression of cathelicidin during infection, urine samples from children with urinary tract infection, a mouse model of ascendant pyelonephritis and cell culture experiments were employed. the relevance of cathelicidin production was tested by bacterial challenge of cathelicidin-deficient and neutropenic mice. in addition, we studied the in vitro effects of cathelicidin on the growth and multicellular behavior of bacteria as well as we tested sensitivity of clinical e. coli strains to the peptide. results: cathelicidin is expressed by epithelial cells of healthy urinary tract and excreted into urine in low concentrations. during urinary tract infection, the secretion of cathelicidin by epithelial cells significantly increases within minutes. invading neutrophils are the source of the second wave of cathelicidin. epithelial cathelicidin protects the urinary tract against bacterial infection while neutrophil-derived cathelicidin influences the severity of infection. cathelicidin displays multiple effects on bacteria. low concentrations of cathelicidin inhibit multicellular behavior, e. g. biofilm formation of e. coli, and high peptide concentrations kill bacteria. bacteria resistant to cathelicidin have an increased ability to invade the urinary tract. conclusion: the antimicrobial peptide cathelicidin is a key factor of the mucosal immunity of the urinary tract. the predictive value of procalcitonine (pct) plasma level for renal scarring after an acute pyelonephritis (apn) is still debated. during apn, the bacterial lipopolysaccharide of the membranes induce the release of tnf, il1 and il6. these cytokines lead to inflammation syndrome and fibrosis sequellae resulting from cell apoptosis induced by nitric oxide (no) release that is catalysed by no-synthase. the aim of this work was to clarify the physiological role of pct in renal parenchyma apoptosis and fibrosis caused by apn. we conducted a prospective study in children with a first apn episode (fever>38.5c°, crp>20 mg/l, monomicrobial urine positive culture>10.5 fcu/ml). we excluded patients with any concomitant infection, renal dysplasia or obstructive uropathy or grade 4-5 vur 133 children were enrolled (age 37.2 m, median 17 m). on admission, pct, crp and phospholipase a2 (pla2) were quantified in serum. scintigraphy with 99m tc-dmsa was performed on day 4 and 9 months later in case of initial abnormalities. fisher's test was performed and statistical significance was defined as p<0.05. results: on day 4, 107 (79%) presented renal parenchyma alterations, at 9 m 57 underwent control scan and 17 (28%) had renal scars. pla2 and pct levels were correlated with early dmsa lesion but not with renal scars at 9m. paradoxically, initial pct level was significantly lower in the presence of renal scars (4.19 vs 7.59 ng/ml, p<0.01). significant pct increase was observed in favourable progress (recovery 7.55 vs aggravation 3.34 ng/ml, p<0.01) and no difference between recovery and improvement evolution. these results suggest the protective effect of pct against apoptosis resulting from down-regulation of nitric oxide release; so high pct values could be interpreted with caution in apn. acute pyelonephritis (apn) may lead to renal scarring with later risk of hypertension and renal insufficiency. the aims of this study were to analyse prospectively renal scars progression with time and their impact on renal growth. methods: 52 patients (pts), aged from 0 to 18 years who presented scars on dmsa at 6 months after apn were included. in these children a second dmsa was done after 3 years. evolution of scars was analyzed following pre-established criteria independently by 3 observers. scar progression was classified as follows: 0=no change, 1=partial improvement, 3=total resolution. in addition a renal ultrasound was repeated to assess kidney growth using z-score. results: 104 renal units (52 pts: 32 f, 22 m) were studied. the incidence of vesicoureteral reflux (vur) was 34.6% (18/52). per renal units, vur were observed in 27/104 (26%); (51% vur grade (g) i, ii and 49% g iii, iv). there were 91 scars observed 6 month after apn which evolution over 3 years was as follow: 0=26% (24/91), 1=65% (59/91) and 2=9% (8/91). incidence of vur was higher in children presenting 3 scars; 5/7 (71%) against 12/45 (26%) in those with 1 or 2 scars. to identify factors interfering with renal growth, we analyzed potential confounding variables using robust linear regression. z-score was worsened with increased number of scars observed at 6 month after apn p<0.001) and improved with disappearance of vur (0.89 ci 0.001-1.7; p<0.05). conclusion: between 6 month and three years after apn, 82% of scars improved. in our population, the number of scars secondary to pna was the most important factor affecting renal growth. the second prognosis criterion was the correction of vur. prevention of pna and rapid treatment to avoid kidney scars seems to be the essential aim to preserve optimal kidney growth. v. smolkin 1, 2 , r. halevy 1, 2 , w. sakran 1, 4 , y. kennes 3 , a. koren 1, 4 1 ha'emek medical center, pediatric b, afula, israel 2 ha'emek medical center, pediatric nephrology unit, afula, israel 3 ha'emek medical center, bacteriology and microbiology laboratory, afula, israel 4 the ruth and baruch rappaport school of medicine, haifa, israel febrile urinary tract infection (uti) is a relatively common infection disease in childhood. children consider at risk for uti commonly receive prophylactic antibiotics to prevent recurrence of this urinary tract disease because of the risk of kidney scarring, which may lead to complications such as hypertension or end-stage renal disease. compliance with antibiotic prophylaxis after uti was assessed in 69 children, using a parent questionnaire and a urine test for antibacterial substances. thirty six children (1 st group) received prophylactic treatment during the period of 4 months (range 3-7months) and the other 34 patients (2 nd group) received antibiotic prophylaxis for a longer duration (12 months, range 11-16 months). in the first group of patients, 35 (98%) of parents reported giving the antibiotics every day in comparison with 30 (88%) in the 2 nd group. twenty nine (81%) of urine tests were positive for antibacterial substances in the 1 st group but only 16 (47%) in the second group. in the 1 st group of patients the difference in recurrent infection between regular takers and non-takers was statistically highly significant. no significant difference was found in recurrent uti rate in takers and non-takers in the 2 nd group. failure to understand the reason for prophylaxis and forgetfulness was found to be a main reason for non-compliance. imaging studies evaluating the kidneys and urinary tract are performed routinely after a febrile uti. evidence of their value in changing management or affecting long term outcome is limited. as part of a multicentre, rct (iris 1) evaluating different antibiotic regimes in the treatment of first febrile urinary tract infections, we undertook as a secondary objective, an evaluation of the diagnostic protocol. the imaging modalities (ultrasound, dmsa scintigraphy within 10 days and voiding cystogram within 1-2 months) were assessed for their ability to predict long term parenchymal damage. 337 children of 2 years of age or less at the time of investigation and who had normal renal function and antenatal ultrasound, were considered suitable for analysis of the diagnostic course. us was performed in 336 children with 288 (86%) normal, minor changes were noted in the remainder, apart from 1 case requiring a change in management in the form of a pyeloplasty for pelvi-ureteric obstruction. the cystourethrogram was performed in 323 of the children with 65 (20%) demonstrating vur. the cystogram was a poor predictor of long term damage, being positive for reflux in only 17 of the 39 children who subsequently developed scarring. an acute dmsa scan performed in all children, exhibited findings consistent with acute pyelonephritis in 212 (63%). a repeat dmsa scan at 12 months in those with evidence of acute pyelonephritis demonstrated a scarring rate of 24%. the data did not demonstrate the clinical efficacy of routinely performing scintigraphy in the acute phase or a cystourethrogram. our recommendations for a reasonable diagnostic work up in small children with their first episode of uti are 1) performance of a scintigram 6 months following the acute infective episode, and 2) close surveillance to identify eventual recidivists. introduction: focal segmental glomerulosclerosis (fsgs) has a high recurrence rate after renal transplantation (rtx). recurrence can lead to tx loss. disease recurrence (dr) seems to be influenced by genetic background. methods: 77 patients with childhood onset of biopsy proven fsgs who were transplanted were evaluated. genetic investigations of the nphs2 gene were done in 46 patients (59.7%). results: mean age at diagnosis was 6.06 years. first renal transplantation was performed at age of 12.3 years.18 patients received a living related (lrd), 55 a deceased donor (dd) graft. 4 patients data under investigation. 31 p (40.3%) recurred after a mean time of 6, 3 years, 5 p with lrd (27.8%) , 25 p with a dd (45.5%). 23 patients (29.9%) lost their graft after 6, 8 years, 15 patients due to recurrence. a second rtx was performed in 16 patients, 11 with dd, 2 with lrd, 3 patients data under investigation, with 71% dr. a third transplantation was performed in 7 patients and a fourth in one patient. screening for nphs2 mutations revealed 10 patients with mutation in the nphs2 gene, 9 homozygot, 1 heterozygot. all patients with a homozygote nphs2 mutation did not recur and only the one patient with a heterozygous mutation (1/10) recurred compared to 17/36 without a mutation (p<0.05). conclusion: living related transplantation was advantageous to decreased donor transplantation. patients with nphs2 mutations had a lower risk of recurrence after transplantation compared to patients without mutations. patients with fsgs should be screened for nphs2 mutations. objective: prospective ebv surveillance post tansplantation reduces incidence of acute rejection and risks of post transplant lymphoproliferative disorders (ptld). methods: prospective screening of ebv by polymerase chain reaction (pcr) and serology in all patients transplanted between 2003 -2006 . results: 27 patients transplanted between may 2003 and september 2006 . 22 were cadaveric and 5 live-related transplants. recepient ebv serology status was known but not on donors. basiliximab was used for induction and maintenance comprised of tacrolimus/azathioprine (aza) until 2004 and mycophenolate (mmf)/tacrolimus from 2004. all received corticosteroids. 17 had mmf/tacrolimus, 10 aza/tacrolimus. ebv screened within first week post transplant, weekly for a month, monthly for 6 months. when ebv pcr lv >5.0, mmf/aza was withdrawn, tacrolimus levels kept between 6-8 ng/ml. pcr/ serology is checked 2 weekly for 3 months, monthly for 6, until lv falls <5.0 and vca igg becomes positive. the mmf/aza is reintroduced. patients with ebv pcr lv <5.0 are kept on full immunosuppression while viral load and vca igg monitored. 17 ebv viraemia detected following prospective screening.1 was re-activation. 9 were symptomatic. onset varied 1 to 21.7 months post transplant (mean 4.3 months). 10 were on mmf/tacrolimus 7 received aza/tacrolimus. 12 had pcr lv>5.0 consequently maintained on tacrolimus an alternate day steroids for period of time. cmv patient and donor status was known and antiviral prophylaxis given to nonimmune. the use of antivirals made no impact on viral load. conclusion: no patient experienced acute rejection or ptld despite modification of therapy with our prospective screening programme. antivirals have no role in protecting or reducing viral load in already infected patients. graft attrition rate is highest in the first three months after renal transplantation. we analysed data in a recent cohort from all dutch centres for pediatric renal transplantation to determine incidence and causes of such early graft failure. methods: data from all pediatric renal transplants performed between 01-01-98 and 01-01-06 were analysed retrospectively. a common immunosuppressive protocol was used in all centres. thrombosis prophylaxis was given according to centre policy. early failure was determined as graft failure within 3 months after transplantation. prevalence of possible risk factors of graft failure identified by literature search were extracted from patient charts. data were analysed with univariate and multivariate logistic regression. results: the cohort consisted of 228 transplants. age of the recipients was 3-18 yrs (mean 10.9). there were 19 early graft failures (8.2%). major causes of graft failure were thrombosis (5.3%) and are(1.8%). univariate analysis identified an association of early failure with complications during surgery (or 10.0, p=0.00), cold ischemia time (or 1.1, p=0.026), side of graft donation (or 2.8, p=0.046) and diuresis in the first hour after transplantation (or 0.3, p=0.026). multivariate regression analysis showed that complications during surgery were associated with the risk of early failure (or 6.4, p=0.002), as were side of graft donation (or 5.7, p=0.015) and diuresis in the first hour after transplantation (or 0.3, p=0.038) . only the occurrence of complications during surgery was significantly associated with early graft failure due to thrombosis (or 13.6, p=0.006). conclusion: thrombosis is the major cause of early graft failure after renal transplantation in dutch children, especially after surgical complications. prospective studies are needed to determine whether early failure can be decreased by more rigorous prophylaxis. background: interleukin (il)-1 is a major contributor to inflammation and cell death during ischemia-reperfusion (ir) injury and its deleterious effects are mediated mainly by nuclear factor-κb (nf-κb) activation. receptor binding and signalling of il-1 can be blocked by the il-1 receptor antagonist (il-1ra). the aim of our study was to characterize the effects of il-1ra administration on inflammation, apoptosis and infiltration in renal ir injury. methods: renal ischemia was induced in lewis rats (n=7/group) by clamping of the left renal artery for 45 min followed by reperfusion of 24 h or five days respectively, when kidney were removed for histological and molecular analysis. results: treatment with il-1ra ameliorated ischemic renal tissue injury and inflammatory infiltration. futhermore, the number of apoptotic tubular cells was lower in il-1ra treated animals 24 h after ischemia, which was paralleled by a bax/bcl-2 mrna ratio towards anti-apoptotic effect. il-1ra reduced the expression of monocyte chemoattractant protein-1 (mcp-1) mrna 24 h and 5 days and that of intracellular adhesion molecule-1 (icam-1) expression 24 h after reperfusion in the kidney. conclusions: our results indicate that il-1ra treatment ameliorates renal ir injury and this protective effect might be mediated by reduced induction of nf-κb mediated mcp-1, icam-1 and the decreased ratio between bax and bcl-2 mrna expression. k. satomura, y. santo osaka medical center for maternal and child health, pediatric nephrology and metabolism, izumi, japan many studies have reported that angiotensin-converting enzyme inhibitor (acei) and angiotensin receptor blocker (arb) show renoprotective effects in adult patients with acquired renal diseases. however, these effects have not been studied in children with renal hypoplasia or dysplasia (rhd). in this study, we explored the renoprotective effects of these drugs in children with rhd. patients and methods: participants of the study were patients with rhd aged less than 15 years. a follow-up for more than one year was conducted in our outpatient clinic. the patients had chronic renal failure, and had not received acei or arb in the past. the change of glomerular filtration rate (gfr) per year, urinary protein/creatinine (up/cr) ratio, serum potassium levels, and blood pressure before the treatment with trandolapril or candesartan were compared with those of one year after the treatment. the estimated gfr was calculated by the schwartz formula. wilcoxon rank sum test was applied to evaluate the statistical significance. results: eleven patients were eligible for this study. the mean age of the patients was 8.4±2.6 years and the estimated gfr was 57.3±9.0 ml/min/1.73 m 2 when trandolapril or candesartan was administered. the change in the estimated gfr for a year significantly improved after the treatment with trandolapril or candesartan compared with the pre-treatment period (-6.1±5.4 vs. 1.9±5.9 ml/min/1.73 m 2 /year, p=0.003). the up/cr ratio significantly decreased at one year after the treatment compared with that before the treatment (0.67±0.62 vs. 0.49±0.53, p=0.041). the blood pressure and serum potassium level showed no significant changes. conclusion: these data suggest that treatment with acel or arb has beneficial effects on the renal function in children with mild to moderate renal failure due to rhd. objective of the study: postischaemic arf is influenced by sex hormones. dehydroepiandrosterone (dhea) pretreatment diminishes postischemic injury. previously we demonstrated that after renal ischaemia-reperfusion (i-r) injury the expression and activity of na, k-atpase (nka) is impaired in male rats. here we tested the impact of dhea on postischaemic survival, renal damage, mrna and protein expression of nka. methods: left renal pedicles of dhea (4.0 mg/kg/day) and propylene glycol, as vehicle (pg) treated male rats (g dhea and g pg , respectively) were clamped for 55 min followed by 2 (t 2 ) and 24 (t 24 ) hours of reperfusion. survival rate, histological damage, serum creatinine (cn) and urea nitrogen (bun) were investigated. the mrna expression and protein level of nka α1 and β1 subunit were also determined. sham operated animals served as control. results: dhea treatment was associated with better postischemic survival (p<0.05 g dhea vs. g pg ). postischaemic cn and bun were higher and renal histology showed more rapid progression vs. controls, however there was no difference between g dhea and g pg groups. mrna expression of nka α1 subunit was higher in g dhea vs. g pg at every time points, however it was decreased in i-r groups vs. controls (p<0.05). similar changes were observed in nka α1 protein level (p<0.05, g dhea vs. g pg in controls, t 2 , t 24 ). mrna and protein expression of α1 subunit were different only at t 24 (p<0.05, g dhea vs. g pg ). conclusions: our study indicates that nka is more protected from the detrimental effects of i-r injury in dhea treated animals, which might be a contributing factor of improved postischaemic renal function and could help to preserve cell and organ homeostasis even in male animals. the work was supported by otka f048842-t37578, bolyai and semmelweis grants. objective of study: recently bnp has been identified as a useful cardiac marker for risk stratification in adults. whether bnp has a similar diagnostic potential in pediatric population with ckd has to be established. the aim of the study was to assess the value of bnp to predict the cardiac dysfunction in children with ckd. methods: to test this suggestion, the relationship between plasma concentrations of bnp, echocardiographic parameters and cardiovascular risk factors (lipid profile, hypertension, secondary hyperparathyreoidism) has been evaluated. a cohort group consisted of 46 children and young adults (35 pts mean age x=16.12±5.14 years; 11 controls mean age x=14.73±5.04years). out of 35 studied pts 24 children were with ckd stage 4 and 5 k/doqi (12 pts ckd stage 4; 12 dialyzed pts) and 11 transplanted subjects with stable graft function (gfr=1.17±0.7 ml/s/1.73 m 2 ). results: no association was found between bnp and gfr and/or s-creat (p=0.12; p=0.1; p=0.44). the highest bnp plasma levels have been found in dialyzed children (620.77 pg/ml; resp. 75.98 pg/ml in tx; resp. 51, 85 pg/ml in ckd stage 4 group) as compared to controls (35, 25 pg/ml p<0,001). bnp was independently related to left ventricular mass (r=0.84; p<0.001) as well as to ejection fraction (r=-0.6; p<0.001) and preload (r=0.78; p<0.001). significant correlation between bnp and hypertension (r=0.608; p<0.001) has been observed. more over, bnp correlated with ipth (r=0.37; p<0, 05) and diastolic dysfunction (r=0.61; p<0, 001). plasma bnp concentrations did not significantly differ before/after dialysis procedure (p=0.07). conclusions: bnp is a sensitive marker for cardiac dysfunction in ckd children. however, prospective studies in larger group of pts are needed to confirm our preliminary data. we have reviewed the data of 20 patients with nephropathic cystinosis (nc) followed in our department since 1987. overall, 2 patients have died during the follow-up period. the mean follow-up was 17,6±6,7 yrs (range 6, 8) . 13/20 patients have initiated dialysis and 10/20 received a cadaveric renal transplant. univariate analysis showed that the time to reach a serum creatinine value of 2 mg/dl was significantly associated with the patient's age at the last follow-up (o. r. 1, 3/yr; p<0.001), the age at the beginning of cysteamine (mea) treatment (o. r. 1, 3/yr; p=0.006), the dose of mea (o. r. 0, 99/g, p=0.035) and the use of ace-inhibitors (o. r. 0, 15; p=0.014). by multivariate analysis, only the period of treatment (or 1, 24, p=0.037) and therapy with ace-inhibitors (or 0, 16, p=0.041) were significantly associated with better outcome. similar results were obtained when assessing the time to dialysis. there was a significant correlation between the dose of mea with intra-leucocytic cystine levels (ilc). by univariate analysis, the dose of mea expressed in mg/m 2 correlated more with the outcome then the dose expressed in mg/kg. statural growth was significantly associated by multiple correlation analysis only with growth hormone (gh) treatment (p<0.05). altogether, these results indicate that the renal prognosis of nc has been improving over the past two decades. this improvement may not be solely attributable to the introduction of mea for the treatment of nc. our data suggest that the overall management of these patients has improved, including more efficient symptomatic treatment of the fanconi syndrome and the use of medications such as ace inhibitors and gh. background: the chronic kidney disease in children (ckid) cohort study, targeted to enroll 540 children aged 1-16 yrs with chronic kidney disease (ckd) by estimated gfr (egfr schwartz) of 30-90 ml/min/1.73 m 2 aims to assess risk factors for kidney disease progression in children. objective: to describe the characteristics of the ckid cohort at study entry. design/methods: at the ckid baseline visit, gfr is measured by plasma disappearance of iohexol. children undergo physical exam, standardized bp measurements, blood and urine testing and parent and child interview. results: as of 01/16/07, 335 children had completed the baseline visit, median age 11.1 yrs, 71% caucasian, 16% african american, 62% male and 15% hispanic ethnicity. median age-adjusted height and weight percentiles were 23% and 42%, respectively. underlying cause of ckd was urologic, cystic or hereditary in 68%, 21% had acquired glomerular disease. median egfr at study entry was 54.6 ml/min/1.73 m 2 , 40% higher than the median iohexol-based gfr 38.5 ml/min/1.73 m 2 . 48% of participants reported a history of hypertension, 35% anemia, 11% seizures, and 7% depression. symptoms of headache, nausea, loss of appetite and weakness steadily increased in prevalence with lower gfr. assessment of family history in parents and grandparents revealed: high blood pressure 81%, high cholesterol 66%, kidney disease 29%, dialysis 12%, and kidney transplant 6%. conclusions: children with stage iii ckd have significant height deficits, hypertension, anemia, and seizure disorders. cross-sectionally, increasing non-specific symptoms are associated with lower gfr. collection of plasma, serum and genetic material will facilitate understanding of novel risk factors and biologic mechanisms underlying kidney disease progression and associated morbidities. aim: increased glomerular filtration rate (gfr) has been implicated in the development of diabetic nephropathy. large normal interindividual variations of gfr hamper the diagnosis of renal hemodynamic alterations. we examined renal functional reserve (rfr) in children with insulindependent diabetes mellitus (iddm) to assess if hyperfiltration occurs. methods: the renal hemodynamic response following dopamine infusion was examined in 51 iddm children (7.7±3.6 y) with a mean duration of diabetes of 6.2 years and compared to 34 controls. results: mean baseline gfr in diabetic children did not differ from control population (130.7±22.96 vs. 124.8±25 ml/min/1.73 m 2 ), whereas renal plasma flow was significantly lower (463.7±103.9 vs. 587.2±105ml/min/1.73 m 2 , p<0.001) and filtration fraction was increased (29±8 vs. 21±2%, p<0.001), compared to controls. the mean rfr was lower (p<0.001) than in control subjects (-0, 77±23 vs. 21±8 ml/min/1.73 m 2 ). conclusion: the observation that rfr is reduced or absent suggests that all children are in a state of glomerular hyperfiltration with increased intraglomerular pressure regardless of the baseline normal values of gfr. while measurements of rfr may be helpful in diagnosing the presence of hemodynamic changes, the relevance to development of diabetic nephropathy remains unknown. only 30-40% develops diabetic nephropathy, suggesting that glomerular hyperfiltration is only a concomitant risk factor. lp diet induces ischemic renal injury involving epithelial cells from osom. here, we tested whether hsp70 would stabilize renal na+k+atpase attachment to the cytoeskeleton during recovery from lp. after weaning, rats (n=8), were fed for 14 days with a lp diet (8%), then were recovered by means of a normal protein diet (24%rp) each group had an age-matched control group (24%, np). tissues from cortex and osom were homogeneized in buffer plus 0.1% triton x-100. protein levels were measured by western blot. in vitro coincubation of solublen on cytoeskeletal and insoluble cytoskeletal-associated fractions in the presence or absence of anti-hsp70 antibody was performed. interaction between proteins was determined by coimmunoprecipitation. increased na+k+atpase dissociation was shown in soluble fraction from osom as a result of lp diet vs. np (196.5±1.1 vs. 151±1.3, p<0.05). meanwhile, decreased hsp70 levels in the same fraction was shown (lp: 179.3±10.5 vs. np 224.7±1.85, p<0.05). translocation of hsp70 to the cytoeskeletal injured fraction associated with stabilization of na+k+atpase was shown in osom from lp, after in vitro coincubation of the cytoskeletal fraction of lp and non cytoskeletal fraction of rp. these effects were abolished by the addition of anti-hsp70 antibody. coimmunoprecipitation showed that the amount of hsp70 coprecipitating with na+k+atpase increased in lp osom, in rp results were similar to control. in cortex, absence of significant differences was shown in the na+k+atpase and hsp70 expression at in vivo and in vitro experiments among groups. in lp and rp cortex tissues, interaction of both proteins was similar to control. our results allow us to suggest that hsp70 has a critical protective role in the integrity of the cytoskeletal anchorage of na+k+atpase during recovery from ischemic lp injury in osom. tubular reabsorption of mg +2 occurs predominantly by paracellular flux in the thick ascending limb of the loop of henle. it is mediated by the, tight junction, mg +2 channel protein, paracellin-1, which is encoded by the gene pcln-1. cyclosporin a (csa), a widely used immunomodulatory drug, decreases tubular mg +2 reabsorption leading to urinary mg +2 wasting and hypomagnesemia. the exact molecular mechanisms of this modulation are unknown. in this study we examined the effect of csa on the paracellin-1 gene in renal cell lines and mouse kidney. the effect of csa on the pcln-1 gene promoter was examined. a plasmid, containing the human pcln-1 (hpcln-1) promoter (2.5kb) upstream to a luciferase reporter gene, was transfected into opossum kidney (ok) and human embryonic kidney (hek293) cells prior to exposure to 5 micrograms/ml csa for 24 hours. mice received csa (15 mg/kg/day) for up to 5 days. at 24 h intervals blood/urine mg +2 and ca +2 levels were determined and kidneys harvested for paracellin-1 mrna quantitation (real-timepcr) as well as protein quantification (western blot) and visualization (immunofluorescence). csa decreased hpcln-1 promoter activity by 25%-50% in transfected ok and hek293 cells, compared to control cells. csa-treated animals displayed hypomagnesemia with increasing urine mg +2 and ca +2 levels paralleled by a 20-30% decrease in pcln-1 mrna after 3 and 5 days of csa exposure. a similar effect on paracellin-1 protein expression inthe renal tubule was evident in response to csa treatment. csa may influence paracellin-1-mediated mg +2 transport at the transcriptional level. involvement of the calcineurin-dependent tonebp pathway or the calcineurin-independent map kinase pathway in this response is subject to future research. this effect of csa on the paracellin-1 gene may play a role in the renal magnesium wasting and hypomagnesemia induced by csa. it is well established that proteinuria induces tubular injury, which is closely associated with progressive decline of renal function. megalin has an important physiological role in the reabsorption of a variety of low molecular weight proteins along the proximal tubule. in this study, we examined whether megalin mediates tubular injury secondary to glomerular diseases. we utilized megalin knockout (ko) mice, in which 60% of proximal tubular cells have mosaic nullmutation in the megalin gene. to induce glomerular injury, these were mated with a transgenic line, nep25, in which selective podocyte injury can be induced by injection of immunotoxin, lmb2. megalin ko/nep25 mice were injected with lmb2 (0.625 ng/g bw) and analyzed 2 weeks later. they showed moderate proteinuria (upro/cr=80, vs 12.5 before lmb2) and mild tubular injury, which were comparable to those observed in nep25 mice with intact megalin gene injected with the same dose of lmb2. in the latter, megalin was still detectable in injured tubules. within each megalin ko/nep25 mouse, we compared megalin-intact (+) vs deficient (-) proximal tubular cells by immunostaining. the majority of megalin+ cells showed enhanced staining for albumin. in contrast, most megalin-cells were not stained for albumin. aquaporin-1, which is highly expressed in normal proximal tubules, was diminished in 39.7% of megalin+ cells, whereas it was diminished in only 11.3% of megalin-cells. some proximal tubular cells expressed mcp-1. in that, 69% of mcp-1 expressing cells were megalin+. the results suggested that megalin plays an important role in the reabsorption of massively filtered proteins in glomerular diseases, thereby contributing to proximal tubular cell injury. objectives of study: the hallmark of nephropathic cystinosis is lysosomal cystine accumulation, primarily leading to fanconi syndrome. although all tissues haveelevated cystine levels, it is not known why the kidney is first affected. it is postulated that decreased atp production in cystinosis results in defective proximal tubular reabsorption, a process driven by na, k-atpase. to study this hypothesis, we have monitored atp levels and viability in conditionally immortalized proximal tubular cells (ptc) of cystinosis and healthy controls. methods: urinary sediment of cystinotic patients and healthy controls was suspended ins supplemented culture medium. primary cultures were transfected with sv40 ts a58 t antigen allowing proliferation at 33°c and maturation at 37°c. to confirm the proximal origin of the cells 1) expression of aquaporin-1 (aqp1) and dipeptidyl-peptidase iv (dpp-iv) was demonstrated using immunoblot technique and 2) morphology was determined using em. ptc were matured at 37°c for 0-10 days, followed by cystine measurement using hplc and atp determination using luciferase assay. results are expressed as nmol/mg protein. results: colonies of cystinotic and control cell lines (n=2) with cobblestone morphology developed after 2 weeks and expressed aqp1 and dpp-iv, confirming their proximal origin. in cystinotic ptc, cystine levels increased from 2.0 at 33°c to 7.5 after 10 days at 37°c compared to 0.3 in controls. intracellular atp decreased in cystinotic ptc during 10 days from 8.8to 1.6, while atp levels in controls remained stable (range 9.7-13.7). atp levels inversely correlated with cystine accumulation in cystinotic ptc (r=-0.95, p=0.005). conclusion: decreased atp levels in conditionally immortalized ptc during 10 days maturation suggest that alterations in atp levels are involved in tubular dysfunction in cystinotic patients. aquaporin ( 13 aqps have been identified to date. aqp1 conveys 50% of the peritoneal water transport in pd. cell migration and angiogenesis are altered in aqp1 ko mice; erythrocyte pco 2 depends on aqp1. human peritoneal mesothelial cells (hpmc) from non-uremic patients and a human mesothelial cell line (met-5a) were incubated with conventional (c-pdf), icodextrin (ico), bicarbonate (b-pdf) and lactate based double chamber pd solution (l-pdf). mrna was measured by real time rtpcr, and protein by western blot and immunocytochemistry. hpmc and met-5a express aqp1, 3, 9 and 11. incubation of met-5a and hpmc with c-pdf, ico and l-pdf did not change aqp1 and 3 expression compared to medium. in contrast, incubation with b-pdf increased aqp1 and 3 mrna and protein in both hpmc (24 h aqp1 mrna: 262±21, aqp3: 3226±634%) and met-5a (aqp1: 1860±1180, aqp3: 2025±1624%). the effect on aqp1 was in part explained by differences in ph, the effect on aqp3 was largely independent of ph. addition of 34 mmol/l of bicarbonate to l-pdf increased aqp1 and 3 mrna (l-pdf+bic: aqp1: 983±110, aqp3: 326±26%). aqp9 expression was suppressed by all three pd fluids (b-pdf: 25±2.4, l-pdf: 16±9.6, c-pdf 75%: 26±11%), aqp11 was up regulated by b-pdf (377±37%). b-pdf improved hpmc migration. we for the first time demonstrate the expression of four different aqps in peritoneal mesothelial cells. they are markedly regulated by pd-solutions. the upregulation of aqp1, 3, and 11 by bicarbonate based pdf may have important implications on long term peritoneal membrane function, wound healing and neoangiogenesis. the regulation of cx3cl1 (fractalkine) by thromboxane a2 in inflammation there is marked leukocyte infiltration into the damaged tissue. chemokines recruit and direct leukocytes to the injured site. the chemokine cx3cl1 is up-regulated in renal inflammation such as glomerulonephritis and allograft rejection. thromboxane a2 (txa2), a potent vasoconstrictor in the kidney, is also pro-fibrotic. txa2 is up-regulated early in inflammation and its effects are mediated by binding to the tp receptor. the aim of this study was to examine the effect of txa2 on cx3cl1 expression. we previously showed that cx3cl1 recycles between the cell surface and an internal compartment. cell surface cx3cl1 is cleaved by the enzyme, tace, to yield the soluble species of the chemokine. we generated human ecv-304 cells stably expressing cx3cl1 and treated cells with a tp agonist. levels of cx3cl1 were quantitated by western blotting. cx3cl1 decreased by 30-60 min after tp stimulation, but recovered by 4h. using flow cytometry, we found that cell surface levels of cx3cl1 decreased by 30 min, but began to recover before levels of total cx3cl1 were replenished. to verify if early recovery of cx3cl1 was due to redistribution from the internal to the plasma membrane compartment, we used fluorescence recovery after photobleaching (frap). after 60 min tp stimulation decreased endocytosis of cx3cl1 was seen. we postulated that loss of cell surface cx3cl1 is due to cleavage by tace. accordingly, a tace inhibitor prevented early loss of cx3cl1 after tp stimulation. in summary, txa2 induces rapid proteolytic shedding of cell surface cx3cl1 by tace, but later increases expression of cx3cl1 at the cell surface by inhibiting internalization of the chemokine. this could release the soluble chemotactic protein from the cell adhesive transmembrane protein, promoting leukocyte recruitment initially, whilst promoting leukocyte adhesion later in the time course. the response to steroid therapy is used to characterize idiopathic nephritic syndrome (ins) as steroid sensitive (ssns) or steroid resistant (srns). ssns pathogenesis has been associated with activation of t-cells and srns has been associated with activation of tgfb1 and progression to chronic kidney disease. our objective was to determine differences in the urinary excretion of inflammatory cytokines; opn, icam1 and tgfb1, between ssns (n=12), srns (n=12), and controls (ctr, n=12) in an attempt to identify specific biomarkers of steroid sensitivity or lack thereof. for this purpose, we used a protein array high-throughput technique and confirmed the findings by elisa. in addition, we performed immunohistochemistry (ihc) for the above cytokines on renal biopsy samples. mean age, gender, race, body mass index, and estimated glomerular filtration rate were not statistically different among three groups. there were no statistically significant differences between ssns and srns in regard to the presence of hypertension, ace treatment, and renal histology (p=0.99, 0.22, and 0.99, respectively) . urinary excretion of icam1, opn, and tgfb1 were statistically significantly higher in ins subjects vs. ctr. urinary icam1 and opn were higher in ssns than in srns (p=0.005 and p=0.0002, respectively). however, the urinary excretion for tgfb1 was similar in ssns and srns. the ihc failed to reveal differences in renal tissue expression of the studied cytokines. there was no correlation between urine and kidney tissue expression. in summary, our preliminary data suggest that urinary opn and icam1 may serve as biomarkers of ssns. this assumption needs to be tested prospectively. methods: this is an interim report of this single center study on proteinuria in hiv positive children. there are 250 children aged 0-18yrs. registered in our hiv clinic. all children attending the outpatient clinic or seen on admission are studied. questionnaires included bio and clinical data. blood pressure was measured in all children. a clean catch or bag urine is obtained from all and urine biochemistry done on an aliquot. patients found to have proteinuria 1+ or above are referred to the nephrology unit. their urine is quantitated (timed urine collection), renal function, renal ultrasound and cd4 count estimated. anf, le cells, fbc including platelet count and genotype will be assayed. a renal biopsy will be performed for nephrotic range proteinuria. result: eighty children positive for hiv have been studied. there were 41 males and 39 females giving a ratio of 1.1: 1. their mean and median ages were 3.28yrs and 3.25 years respectively. all had normal blood pressures, renal ultrasound, and renal function. fifteen of the 80 children (18.8%) had 30-100mg/dl proteinuria; 19 (23.8%) haematuria. their mean cd4 + cell count was 316.9/mm 3 , range 180-1267. there was no significant difference between low cd4 + count and the presence of proteinuria (p>0.3). seventy seven of the patients had vertical transmission of hiv; two acquired the infection from blood transfusion; one from scarification marks. conclusion: there is a high prevalence of proteinuria among children with hiv infection in our region. hiv positive children should be screened and intervention instituted to avert or delay the onset of chronic renal failure. carotid intima media thickness (cimt) and brachial artery flow mediated dilatation (fmd) are novel indices of subclinical atherosclerosis. we studied these indices in children with nephrotic syndrome (ns) using high resolution ultrasonography (hrus). 52 children with ns (42 ssns;10 srns) of 24-207 months duration and 50 normal sibling controls underwent cimt and fmd determination using a 7.5 mhz us probe. routine biochemistry, lipid profile and hscrp were carried out to look into associations with cimt and fmd. statistical analysis was carried out using epiinfo 6.0. cases and controls were similar in age, sex, growth and egfr. mean maximum cimt (+-95% ci) (in mm) was higher in the ns group (0.435 +-0.014; range 0.333-0.570) vis-a-vis controls (0.398+-0.091; range: 0.345-0.490) (p<0.01). srns and ssns cases were similar (0.441+-0.037 vs 0.434+-0.015 mm, p=0.36). nephrotic children showed significantly lower fmd (10.56+-4.16% vs 17.39+-3.94%, p=0.02). cimt and fmd varied with frequency of relapses in last 12 months (0.415+0.035mm, 10.27+-5.68% (no relapses); 0.449+-0.019 mm, 7.57+-5.39% (>3 relapses). children with ns had mean hscrp of 5.25+-0.57 mg/l. on univariate analysis, cimt correlated with disease profile at onset (r=0.33, p<0.01), fmd (r=-0.23, p=0.02), male sex (r=0.23, p=0.02), bmi (r=0.23, p=0.02), cyclosporine exposure (r=0.5, p<0.01), total cholesterol (tc) (r=0.34, p<0.01), ldl (r=0.33, p<0.01), vldl (r=0.29, p<0.05), triglycerides (r=0.33, p<0.05), atherogenic index (ai) (r=0.33, p<0.01) and creatinine (r=0.25, p=0.03). fmd correlated with systolic blood pressure, age, bmi, weight, total cholesterol, vldl and triglycerides (p<0.05). to conclude, hrus can detect early atherosclerosis using fmd and cimt as the indices in children with nephrotic syndrome with disease duration of 20 years and more. a ten-year old girl, who presented with biopsy proven acute severe changes of type 1 membranoproliferative nephritis (mpgn1) appears to have shown complete resolution of her disorder after nine months mycophenolate moffetil (mmf) (cellcept -roche) added to relatively rapidly reducing steroids. she presented aged nine years with incidental finding of significant proteinuria and upper tract haematuria when presenting with abdominal pain. blood pressure, chemical renal function and haematology were normal. c3 and total haemolytic complement were at the lower limit of normal. renal biopsy showed light microscopy (lm) changes of markedly enlarged glomeruli with significantly increased mesangial cellularity and matrix, together with 'double contours' of basement membrane. inmmunofluorescence (if) was strongly positive for igg and c3. electron microscopy (em) showed mesangial cell interposition into the basement membranes. she was treated with iv pulse methylprednisolone, followed by high dose oral prednisolone (pnl). after one month, mmf 500mg bd was added as pnl was tailed to alternate day therapy. pnl was reduced more quickly than usual due to difficulty with side effects and excellent clinical response. within three months of mmf, proteinuria and haematuria had disappeared. blood pressure and renal function have remained normal throughout treatment. after nine months, while on 0.5mg/kg alternate day pnl and 500mg bd mmf, repeat biopsy showed normal sized glomeruli on lm with no significant changes, no positive staining on if and normal em without mesangial interposition. this case suggests that mmf may be a key drug in management of mpgn1. g. stringini, e. malagnino, f. emma bambino gesu children's hospital and research institute, department of nephrology and urology, rome, italy serum creatinine values may vary considerably between normal subjects. these variations are in part secondary to differences in muscle mass, body composition and creatinine tubular secretion. in addition, low nephron number, which is influenced by genetic and intrauterine factors, is associated with increased incidence of arterial hypertension, late-onset proteinuria and chronic renal failure. despite compensatory glomerular hypertrophy, autopsy data indicates that kidneys with fewer glomeruli tend to be significantly smaller. on these bases, we have hypothesized that a significant part of the variance of normal serum creatinine levels is related directly to individual differences in renal size. to test this hypothesis, we have reviewed the data of 1746 renal ultrasound examinations performed at our institution between 1991 and 2006. patients were selected if they had conditions that should not influence renal size (low tract uti, enuresis, bladder instability, idiopathic hypercalciuria), if they had normal gfr and an ambulatory blood pressure measurement. analyses were performed after expressing renal length, serum creatinine levels and blood pressure values as standard deviation scores (sds) corrected for gender, age, height and weight, by multiple nonlinear regression analysis. a significant negative correlation was found between serum creatinine levels and renal length (p<0.001). when renal length measurements were grouped in quartiles, serum creatinine sds was on average 0.37 sds higher in the 1st quartile (small kidneys), in comparison with the 4th quartile (large kidneys). no correlation was found between kidney length and single measurements of ambulatory blood pressure. these data indicate that renal size is accountable for a significant part of the variance in serum creatinine levels that is observed in the normal pediatric population. henoch-schönlein purpura (hsp) is the commonest small vessel vasculitis of childhood. henoch-schönlein purpura nephritis (hspn) is the major determinant of long term prognosis in hsp. the objective of this randomised controlled trial was to determine the effect of early prednisolone treatment on the development and progression of nephropathy in children with hsp. methods: children under 18 years of age, with a diagnosis of hsp, presenting to secondary care centres in england and wales were randomly assigned to receive either placebo or prednisolone (2mg/kg/day (max 80mg) for 7 days, followed by 1mg/kg/day for 7days (max 40mg)). patients, parents, paediatricians and investigators were 'blinded' to assignment of treatment or placebo. the primary outcome measure was the determination of the presence or absence of proteinuria, defined as urine protein: creatinine ratio (up: uc) >20mg/mmol, 12 months after initial presentation in treated and untreated patients. results: 353 children with hsp were randomised. 181 patients were assigned to receive prednisolone (group a) and 172 patients were assigned to receive placebo (group b). 36 patients in group a and 27 patients in group b did not complete the study. there was no difference in the incidence of proteinuria at 12 months, in patients receiving prednisolone (19/145) compared with those receiving placebo (15/145) or=1.32, 95% ci 0.59-2.94, p=0.49. conclusions: this is largest prospective randomised placebo-controlled trial of the role steroids in hsp in the literature to date. this study provides compelling evidence of absence of a beneficial effect of early treatment with prednisolone in the development of nephropathy 12 months after disease onset in children with hsp. while quality of life (qol) is generally assumed to be poor on dialysis and to improve markedly after kidney transplantation, systematic assessments of qol in children have not been performed to date. to date, we have examined general and health-related qol in 35 children and adolescents with esrd aged 4-16 years treated by hemodialysis (hd; n=7), peritoneal dialysis (pd, n=8) or renal transplantation (tx, n=20), using a well-established instrument (kindl) comprising an ageadapted set of questionnaires (kindl). the obtained measures of overall and item-specific qol were transformed to standard deviation scores (sds). general qol was close to normal and did not differ significantly between hd (-0.37±1.58 sds), pd (-0.20±1.04) and tx (-0.12±0.95). psychological well-being was better in children on pd (0.54±1.04) than after tx (-0.53±1.30, p=0.05) and on hd (-0.98±1.73, p=0.06). physical wellbeing did not differ between treatment groups (hd: -0.39±1.19, pd: 0.10±1.21, tx: (-0.16±1.06). qol related to family life tended to be compromised in dialyzed (-0.87±1.58) vs. tx children (-0.11±0.88, p=0.07) . social interaction with friends was considered moderately impaired by all patient groups (hd: -0.89±1.92, pd: -1.15±1.26, tx -0.82±1.44). self-esteem was close to normal in all groups (hd: -0.3±0.85, pd: -0.27±1.35, tx 0.21±.0). in summary, our preliminary results suggest that subjective qol is remarkably good in children with esrd, with surprisingly small differences between treatment modalities. tx appears to be perceived beneficial with respect to the integrity of family life but provides poorer psychological qol than pd, possibly due to the constant concern with graft loss. background: gfr is determined in the ckid cohort study by plasma disappearance of iohexol (igfr). updated serum creatinine (scr)-based formulas (sgfr=k ht/scr) are needed for bedside clinical use. objective: derive formulas based on enzymatic scr to estimate gfr in the ckid study in children aged 1-16 yrs with sgfr of 30-90 ml/min/1.73 m 2 . methods: from 253 children, height (ht, meters), igfr, and scr & bun (mg/dl) by bayer advia 2400 were obtained. gfr was estimated from regression models: a(ht/scr) b (35/bun) c where a is gfr if ht=scr and bun=35; b and c are exponents. results: 60% (n=152) were male; median age=11, scr=1.4, bun=31 and igfr=38. formulas ranged from an updated schwartz formula (a=40.4, b=1, c=0; r 2 =0.66), to sex-specific (a=38.8, b=0.98, c=0 in girls, and a=40.5, b=0.79, c=0 in boys), which yielded r 2 =0.69, to the most complex (a=37.7, b=0.86, c=0.16 in girls, and a=39.7, b=0.69, c=0.16 in boys), which yielded r 2 =0.71, higher (p<0.001) than the r 2 of the updated schwartz formula. by random selection of 127 of 253 subjects in 100 independent trials, we assessed the predictive ability of each formula on the other 126 observations. sex-specific formulas produced unbiased results and increasing precision with increasing complexity. the updated schwartz underestimated igfr in boys by 3% (p<0.001) and overestimated igfr in girls by 4% (p<0.001). conclusions: scr, ht, sex, and bun together provided unbiased estimates of igfr and explained 71% of its variability in children with igfr of 14 to 76 ml/min/1.73 m 2 . extrapolation to ht/scr of 3 (normal body habitus and kidney function) and bun of 10 yielded predictions of 118 ml/min/1.73 m 2 for gfr in girls and 104 boys. including cystatin c and broadening the gfr range to include normal levels are data being collected by ckid to extend the formulas and provide wider clinical utility. f. hussain, m. mallik, a. watson nottingham university hospitals, children and young people's kidney unit, nottingham, united kingdom considerable variation exists between units in terms of techniques used for renal biopsy. the bapn agreed an audit using published standards and a questionnaire was sent to all 13 uk paediatric nephrology centres. 11 agreed to a prospective audit between 1/1/05 and31/12/05. the survey revealed information leaflets are sent pre-biopsy in 5 (45%) centres with only one using play preparation. 6 (55%) routinely perform biopsies as daycase procedures (dc); 6 (55%) use general anaesthetic (ga). realtime ultrasound is the favoured method in 8 (73%) of centres. biopsies are performed by nephrologists only in 4 (36%), nephrologists with radiologists in 5 (45%) and radiology alone in 2 (19%). of 531 biopsies (352 native), 164 (31%) were performed as a dc with 262 (49%) being done under ga. the mean age of patients was 11yrs (range 0.8±18.9yrs). the standard for the number of passes of native kidneys (<3 in 80%) was achieved in 86.4% with no significant difference between grade of operator or nephrology/radiology speciality. standard number of passes in transplanted kidneys (<2 in 80%) was achieved in 73.4%. adequate tissue was obtained for diagnosis in 97.5% (standard >95%). the significant complication rate (macroscopic haematuria and/or delay indischarge) was higher than the set standard of <5% at 7.3%. there was no significant difference in complication rates whether the biopsy was performed as a dc or inpatient procedure (p=0.73) or whether ga or sedation was used (p=0.8). conclusions: the survey highlights significant variation in practice with limited use of preparation materials and dc. the results may enable individual units to reflect upon their techniques and complication rates and has stimulated constructive debate about indications and training issues. objective: to characterize bp in children enrolled in the ckid study, an observational cohort study of children 1-16y old with schwartz estimated gfr of 30-90 ml/min/1.73 m 2 . design/methods: 3 bp's were obtained using an aneroid sphygmomanometer. gfr was measured by iohexol disappearance. bp was classified according to the 4th report on bp in children. hypertension (htn) was defined as bp-95th percentile (uncontrolled), or as self-reported htn plus current treatment with antihtn meds. pre-htn was defined as bp 90th-95th percentiles. results: 284 children (mean age 11±4y; 60% male) were studied. mean gfr was 41±14 ml/min/1.73 m 2 and mean ckd duration was 7±4y. for sbp, 139/280 (49.6%) subjects had htn of these, 59 subjects (21%) had uncontrolled htn. 14 additional subjects (5%) had pre-htn. of subjects with systolic htn, only 57% had measured sbp<90th percentile, and among the 73 subjects with measured sbp>90th percentile, only 32 (44%) were taking antihtn meds. for dbp, 136/280 subjects (48.6%) had htn of these, 53 subjects (19%) had uncontrolled htn. 30 subjects (11%) had pre-htn. of subjects with diastolic htn, just 52% had measured dbp <90th percentile, and among the 83 subjects with measured dbp>90th percentile, only 35 (42%) were taking antihtn meds. among children with gfr<50 ml/min/1.73 m 2 , the prevalence of systolic or diastolic htn appeared to increase with decreasing gfr. conclusions: a significant proportion of children enrolled in the ckid study suffer from elevated bp. nearly 40% of children with ckd had measured bp>90th percentile, and more than 50% of these children were not receiving antihypertensives, indicating that htn in pediatric ckd is frequently under-or even untreated. long-term follow-up of the ckid cohort should reveal the effect of elevated bp on ckd progression. background: we recently demonstrated elevated excretion of the putative urinary biomarkers tgf-β and et1 in a large cohort of children with ckd. tgf-β excretion was highest in kidney disorders associated with marked tubulointerstitial fibrosis, such as obstructive uropathy, nephronophthisis and pkd. aim: to investigate the course and predictive value of urinary tgf-β and et1 excretion in children with ckd undergoing ace inhibition (acei). methods: to date, 165 patients have been followed for 2 years and 91 patients for 3 years in a prospective, interventional trial investigating the nephroprotective efficacy of acei w/out intensified blood pressure control. results: average bp was reduced to the mid normal range. proteinuria initially decreased by 50%, but gradually reincreased to baseline levels within 3 years. urinary tgf-β excretion, which was initially elevated 3-fold above healthy controls, continuously decreased during treatment from 32.6±31.5 ng/g creatinine to 27.4±20.7, 20.6±44.0, and 18.4±20.5 after 1, 2, and 3 years, respectively (p<0.001). in contrast, et1 excretion increased by 100% within the first 2 years of follow-up. neither baseline nor the change in tgf-β and et1 excretion during treatment predicted the short-or long-term antihypertensive, antiproteinuric response to acei or ckd progression rate. conclusions: the marked reduction of urinary tgf-β excretion probably reflects the antifibrotic effect of acei but, at least over 3 yrs of observation, does not predict the early and late course of proteinuria and ckd progression. hence, urinary tgf-β appears to be a biomarker of tubulointerstitial disease activity rather than of global disease progression. the surprising increase of et1 excretion may reflect the induction of compensatory hemodynamic mechanisms during acei. cardiovascular complications are the most important cause of death in pediatric patients with endstage renal disease. therefore early diagnosis and treatment are very important. brain natriuretic peptide (bnp) is released in response to volume overload or conditions that cause ventricular stretch. the aim of the study was to investigate whether bnp can be used for early diagnosis of cardiac complications in pediatric patients with esrd. twenty-four patients on peritoneal dialysis (mean age 13.3±4.4 years), 21 patients on hemodialysis (mean age 15.0±3.6 years) and 39 sex and age matched healthy children (mean age 12.4±3.0 years) were included the study. plasma bnp levels were significantly higher in the patient group than those in the control group (590.4±765.8 vs 159.0±23.7 pg/ml, respectively, p<0.05), but there was no significant difference between hemodialysis and peritoneal dialysis patients. in patients with hypertension, bnp levels, left ventricular systolic and diastolic diameters were significantly higher than those in the patients without hypertension. in patients with higher crp levels, bnp levels were significantly higher than those in the patients with low crp levels. bnp levels had a positive correlation with left ventricular mass index (r=0.32, p=0.04) and a negative correlation with ejection fraction (r=-0.59, p<0.001) and shortening fraction (r=-0.55, p<0.001) significantly. there was no significant relation between bnp levels and anemia, dialysis duration, and dialysis modality. in conclusion, high plasma bnp level is significantly correlated with dilated left ventricle and it may be useful as a biochemical marker for identification of pediatric dialysis patients with cardiac dysfunction. we observed a high prevalence of left ventricular hypertrophy (lvh) and impaired lv contractility in children with stage ii-iii chronic kidney disease (ckd) (jasn 2006 , jasn 2007 . in a prospective, open-label assessment in 84 children receiving ace inhibition (ramipril 6 mg/m 2 /d) with or without additional antihypertensive medication, we evaluated by echocardiography lv mass (lvm), geometry and myocardial mechanics at baseline and after 12 (n=65) or 24 mos (n=55) of treatment. lvh was defined by lvm index>38 g/m 2 and concentric geometry by relative wall thickness>0.375 (95 th normal percentile). lv systolic function was assessed at the midwall level by circumferential shortening (ms). normalized 24 h mean arterial blood pressure (bp) was reduced from 1.3±1.4 at baseline to 0.0±1.4 and -0.5±1.0 sds after 12 and 24 mos respectively. lvmi was reduced significantly after 12 (from 34.0±8.4 to 31.6±8.0 g/m 2.7 , p<0.02) and 24 mos (from 34.4±7.6 to 31.9±9.7, p<0.05). of those patients presenting with lvh at baseline, lvm regressed to the normal range in 10/19 (53%) after 12 mos and in 10/18 (55%) after 24 mos. the prevalence of concentric lv geometry remained unchanged (baseline: 8%, 12mos: 9%, 24mos: 7%). age and afterload-corrected myocardial function increased from 93±15% to 100±13% at 24mos (p<0.005). the changes in lvm and myocardial performance were independent of the randomized bp target and gfr. change in lvm was correlated with change in hemoglobin level (r=0.30, p<0.05) and change in myocardial function with change in bp level (r=0.39, p<0.05). in conclusion, fixed-dose ace inhibition and tight bp control induce regression of established lvh in the majority of children with stage ii-iii ckd. this is associated with a normalization of myocardial contractility. objectives of the study: periods with insufficient erythropoietic activity may occur during the erythropoietin (epo) treatment in chronic haemodialysis (hd). we determined the effects of a short-term suspension of epo therapy on various oxidative stress parameters during a 12-week follow-up in hd patients. methods: the antecedent epoetin beta (eb) treatment was suspended for 10 days. after that, 9 patients received eb two times a week and 7 patients received darbepoetin alfa (da) once weekly. concentrations of whole blood oxidized and reduced glutathione (gssg, gsh) and various haematological parameters were determined weekly. erythrocyte malondialdehyde (e-mda) and the activities of erythrocyte superoxide dismutase, catalase and glutathione peroxidase were determined at weeks 0, 4 and 12. results: the ratio gssg/gsh was increased in both groups after continuation of the suspended epo therapy (p<0.05 and p<0.01 week 1 vs. the baseline in the da and eb group, respectively) and also at week 9 (p<0.01 and p<0.001 vs. the baseline in the da and eb patients, respectively). the activities of the antioxidant enzymes were increased at week 4 in both groups (p<0.05 vs. the baseline for da and p<0.001 vs. the baseline for eb), and returned to their week 0 levels by week 12. the e-mda level decreased in both groups (p<0.05 week 12 vs. the baseline for da and p<0.05 weeks 4 and 12 vs. the baseline for eb). conclusions: a short-term suspension of epo therapy caused characteristic time-dependent changes in the oxidative stress. the ratio gssg/gsh increased at weeks 1 and 9. activities of the antioxidant enzymes were elevated at week 4, resulting in an improvement in lipid peroxidation. these results might have implications in certain conditions with transient alterations in the erythropoietic activity in hd patients. rrf has been associated with better nutritional status both in adults and children on peritoneal dialysis and in adults on chronic hd. there are no data on the influence of rrf on nutrition in children on chronic hd.179 three-days dietary reports and simultaneous urea kinetic monitoring of 30 children, adolescents and young adults on chronic hd (age: 4.3-24.5 years) were retrospectively analyzed. protein catabolic rate, an index of nutrition adequacy, was normalized by body weight (npcr). in patients with rrf, total kt/v (kt/vtot) was calculated summing hd kt/v(kt/vhd) and rrf (evaluated by residual urea clearance ku-). in all patients, npcr and dietary protein intake (ndpi) were significantly correlated (p<0.0001). kt/vtot was correlated with npcr(p<0.0001) while correlation between kt/vhd and npcr was not significant (p: 0.11). in patients with rrf, ku resulted significantly associated with npcr (p<0.0001) while kt/vhd was not (p: 0.10). npcr was significantly higher in patients with rrf (1.46±0.41 vs 1.03±0.33 g/kg/day; p<0.0001). patients on recombinant growth hormone (rhgh) treatment showed npcr higher than those without rhgh (1.34±0.41 vs 1.01±0.39 g/kg/day; p<0.0001). however, in a multiple regression model including age, the use of rhgh, rrf, kt/vtot and kt/vhd, npcr resulted significantly associated only with rrf (b: 0.128; p<0.0001). inconclusion: in children, adolescents and young adults on chronic hd treatment, rrf is associated with better nutrition. rrf positively affects nutrition independently from hd efficiency and rhgh effects. possible hypothesis are a more selective (although decreased) depuration and the positive influence of water excretion maintenance on food intake. more efforts have to be made in order to maintain rrf in children on chronic hd. during the past three years, six women have undergone chronic haemodialysis during pregnancy at the pediatric renal unit of the adelaide women's and children's hospital. five have delivered normal infants at between 33 and 38 weeks gestation; one is presently at 28 weeks gestation, with an apparently normal fetus. four were already receiving chronic haemodialysis at the time of conception; the others began dialysis at 20 weeks gestation. the protocol includes six days per week dialysis for at least two hours per treatment. a number of practical and emotional issues have arisen, with major potential psychosocial hazards, including: unplanned pregnancy due to ignorance of fertility; precipitation onto the dialysis program; acceptance of increased dialysis time; concerns regarding effects of drugs and dialysis/kidney failure on the fetus; the likelihood of prematurity; the perceived difficulties of motherhood while on a chronic dialysis program; loss of income, social networks and independence. the program has been successful due to the cooperative approach from the multidisciplinary team consisting of nephrologists, obstetricians, obstetric physicians dialysis nurses, midwives, dieticians, physiotherapists, psychiatrists and social workers. the social worker has provided counselling and coordinated transport and assistance with housework, childminding and other day to day tasks. although the program has had overall success, there have been a number of pitfalls worth discussing, including those arising from the complex interactions between the members of the various disciplines, and those involved in maintaining the balance of clinical and psychosocial needs of the women. (median 17.5) , weight from 4.5 to 15.4 kgbw (median 9). the vascular access was a central catheter (kt) in 12 children, an arteriovenous fistula (avf) in 6, avf and kt alternatively in 14 patients. duration of hd ranged from 1 to 63 m (median 14.5).35 dual lumen tunnelled cuffed kt were inserted in 26 children through the internal jugular vein [ijv]), surgically in 8, percutaneously in 27. all kt have had an immediate good function. nine kt were exchanged over a guide wire for dysfunction. kt infections with positive blood culture were successfully treated in 8 cases. duration of kt ranged from 1 to 20 m (median 5). at the end of the follow-up, 7 kt were still in function, 6 removed for a mature avf, 11 after renal transplantation (rt), 1 for improved gfr and 1 failed. patency of the venous network after withdrawal of kt was assessed in 16 children (doppler 3, mri 13) and showed normal patency in 6, ijv thrombosis in 5, brachiocephalic thrombosis in 3 and stenosis in 2. thirty avf were created in 20 children, distal in 18 (60%). immediate patency was obtained in all cases except 1. the median blood flow ranged from 350 to 1800 ml/min/m 2 (median 750). following the primary surgery, 41 repeated surgical procedures included a superficialization of the vein in 10, refection for stenosis or thrombosis in 9, reduction of overflow in 3, 2 nd avf creation in 10 and ligation after rt in 9. percutaneous transluminal angioplasty was performed in 5 children. duration of patency ranged from 1 to 168 m (median 36.5). in conclusion, hd is feasible in small children. nevertheless, kt are associated with risk of venous occlusion and obtention of a reliable avf frequently need several interventions, altogether leading to a limitation of hd indications in young children. 1994-2005, 60 (19%) were <2 years of age. the underlying disorders were congenital nephropathies in 70% (malformations 33%, hereditary 37%) and acquired diseases in 30%. living related donation (ld) was performed in 59% and preemptive tx in 33%. immunosuppressive (is) protocol varied considerably between the countries and over time.1-year graft survival (gs) was 96% in ld and 87% in grafts from deceased donors (dd). gs improved significantly for dd grafts with time. the number of acute rejections (ar) during the first year posttx was significantly lower in ld recipients, in tac-treated children and during the second half of the study period. this improvement over time was also seen in separate analysis of cya-treated children. the proportion of rejection-free patients increased in all countries. median height sds at tx was -1.8 (-8.3 to +1.7)(boys -1.9, girls -1.6). height sds increased to -1.5 at 3 years posttx. conclusions: gs results were excellent and the frequency of ar low, especially in children with ld grafts and tac treatment. interesting differences between the countries concerning donor source, preemptive tx, is and use of protocol biopsies were found. n. marcun varda, a. gregoric maribor teaching hospital, department of pediatrics, maribor, slovenia objectives: essential hypertension (eh), identifiable in children, is associated with cardiovascular (cv) diseases in adulthood. the aim of our study was to evaluate the presence of some traditional and non-traditional cv risk factors in our children and young adults with eh in the search for additional cv risk. the prevalence of metabolic syndrome (ms) was also investigated. methods: a total of 104 children and young adults, diagnosed with eh, were included in our study. they were compared with a control group of 50 healthy children, matched for sex and age, with regards to specific aspects in the history, body mass index (bmi), waist: hip ratio, full blood count, crp, serum cholesterol, hdl cholesterol, ldl cholesterol, triglycerides, uric acid, glucose, insulin, fibrinogen, homocysteine, apolipoprotein a1, apolipoprotein b and lipoprotein (a). in addition, the prevalence of ms was calculated. ms was defined as having three or more ms components according to the national cholesterol education program's adult treatment panel iii criteria, tailored for children. results: the differences in values of bmi, crp, platelets, triglycerides, uric acid, apolipoprotein a1, apolipoprotein b and homocysteine between the hypertensive patients and the controls were statistically significant. in all hypertensives positive family history of hypertension in the first or second generation was revealed. overweight (bmi >90 th percentile for age and sex) was identified in 40%, obesity (bmi >97 th percentile) in 24%, abnormal glucose homeostasis in 23%, high serum triglycerides in 42% and low hdl in 48% of the hypertensives. ms was present in 48% of these children and in 6% of our controls. conclusion: we demonstrated that children and young adults with eh differ from the population of healthy children in some specific cv risk factors, and are therefore at an increased cv risk. background: rtd is a rare autosomal recessive disease of differentiation of fetal kidneys with poorly developed proximal tubules. fetal and neonatal findings include oligohydramnios, preterm birth and neonatal death due to pulmonary hypoplasia, anuria and hypotension. mutations in genes in the renin-angiotensin system (ras), encoding for angiotensinogen, renin, angiotensin converting enzyme and angiotensin ii receptor type 1, have been revealed. we report the first rtd patients surviving the neonatal period and still being alive. both patients had affected siblings demised in utero or neonatally. case 1: oligohydramnios, birth at 38 weeks, 2850 grams. neonatal course: pulmonary hypoplasia, pneumothorax, hypotension and anuria with ventilation (4 weeks) and dialysis (2 days) . current findings at 15 years: creatinine 200 umol/l, normal blood pressure. genetic and functional analysis: homozygous mutation of angiotensinogen gene (1124g-a); very low angiotensinogen concentration (21.4 ng/ml; normal 1024-275), absent plasma renin activity (normal 1.5-3.0 ng/ml/h) despite very high active renin (199 pg/ml; normal 22-11). case 2: oligohydramnios, birth at 35 weeks, 2520 grams. neonatal course: mild respiratory distress, hypotension and anuria with oxygen (1 day) and dialysis (5 months) . current findings at 10 years: renal transplantation at age 4 years, good graft function. genetic and functional (as neonate) analysis: homozygous mutation of renin gene (1124g-a); very low active renin (<2.5 pg/ml; normal 24-850). conclusions: rtd is caused by inactivating mutations in genes encoding the ras resulting in chronic low perfusion pressure of the fetal kidney. genetic and functional analysis of ras contributes to diagnosis of rtd. this observation extends the rtd phenotype from a uniformly fatal to a more favourable disease. objectives of study: to evaluate the relationship between serum uric acid (ua), new onset essential hypertension (eh) and endothelial dysfunction (ed) in the youth. methods: 29 subjects with abpm proved new onset eh (aged 19, 9±3, 5 years, bmi 28, 9±3, 5 kg/m 2 ), 36 overweight/obese normotensive youth (oo) matched for age and bmi, and 73 age matched healthy normotensive controls (nt) with normal weight were enrolled. ua, total cholesterol, hdl, ldl, triglycerides and creatinine were analyzed in blood, glomerular filtration rate (gfr) was calculated according to schwartz formula and endothelial function was assessed using flow-mediated dilation (fmd, %). results: new onset eh was associated with overweight/obesity in 90% of subjects. serum ua levels were significantly higher in eh than oo (381±92 vs.336±72 umol/l, respectively, p<0, 05), in eh than nt (381±92 vs.277±62 umol/l, respectively, p<0, 0001), and in oo than nt (336±72 vs.277±62 umol/l, respectively, p<0, 0001). total cholesterol, hdl, ldl and triglycerides were significantly higher in eh and oo compared with nt (p<0, 0001). no significant differences were found in lipidograms between eh and oo. serum creatinine and gfr did not differ significantly between the groups. fmd was significantly lower in eh comparing with oo and nt (5,49±4,83 vs.12,75±3,47 vs. 14,55±5,32%, respectively, p<0, 0001) and in oo comparing with nt (12,75±3,47 vs.14, 55±5,32%, respectively, p<0, 05). conclusions: new onset eh in the youth is associated with overweight/obesity, higher serum ua and ed. ua may play a causal role in the pathogenesis of eh and commonly with eh and proatherogenic serum profile contributes to ed in overweight/obese hypertensive youth. objective of study: fibromuscular dysplasia (fmd) is a systemic arteriopathy of the small and medium sized vessels. it is the first cause of renal arterial stenosis (ras) in childhood. the aim of this study was to describe the natural history of fmd in children. we analysed all the data of 12 children with fmd. results: mean age at diagnosis was 4 years 9 months old. hbp was discovered fortuitously in 5 cases, after symptoms of malignant hypertension in 7. in all cases bp values corresponded to severe hypertension (mean bp of 190/105 mmhg). extra renal localizations were found in half of the patient, and the most frequent pathological arteries were the superior mesenteric and the carotida. the mean number of arterial stenosis at diagnosis was 2 per patient. seven patients had a primary fmd with familial history for 1 patient. in the others fmd were associated with polymalformatif syndromes: reported by grange (2), moya-moya disease (2), neurofibromatosis type i (1). after a median follow-up time of 81 months the number and severity of stenosis increase at 6 arteries per patient. these lession, although to a lesser extend, were already observed as soon as 30 months of follow-up. percutaneous transluminal renal artery angioplasty were proposed in 6 cases when the bp was uncontrolled indeed a multi antihypertensive therapy with severe renal stenosis (>80%) or when renal growth was impaired. prognosis is severe with cardiologic complications (10/12) and 1 death. conclusions: intimal form of fmd accounts for the majority of multivisceral fmd. at diagnosis several hypertension is almost present. vascular ultrasonography imaging techniques is usefull in follow-up. a conservative treatment has to be privilegied. this disease is evolutive with increase of pathological arteries number, aggravation of stenosis degree and sometimes renal function impairment. objective: the effect of over weight on blood pressure elevation (bp) is more frequently present in childhood. several studies have demonstrated the efficacy of angiotensin-converting enzyme inhibitors (acei) therapy in obese hypertensive adults, but data on children are very limited. methods: 110 obese (bmi: z score >2.5 sd) primary hypertensive (systolic ordiastolic blood pressure >95th) children (aged 6-7 years) were enrolled to this single centre prospective study. patients received ramipril (0.1-0.15 mg/bwkg/day) once daily. office and ambulatory bloodpressure measurements and serum biochemical analysis were performed at start and after 1 and 6 months of treatment. 36 patients (23,7%) hadimpaired glucose tolerance (igt) on oral glucose tolerance test (ogtt). results: 94 (85,5%) patients completed the six months ramipril therapy. reduction in 24-hour mean arterial pressure (map) was 4, 95 mmhg (-1, 02sd) after 1 month and 10, 14 mmhg (-2,05 sd) 6 months treatment respectively. bp was reduced with equal efficacy during day-and night time. 3/110 (2, 7%) patients were lost during the follow-up. 15 (15,9%) patients with high uric acid levels also were treated with allopurinol. eleven patients (10%) received second antihypertensive medication because of the blood pressure remained uncontrolled. (7 pts metoprolol, 4 pts amlodipine) 8 (7,2%) patients suffered recurrent cough, but otherside effect has not observed. the serum glucose and insulin levels havenot changed significantly during the follow-up. conclusion: oncea day given ramipril significantly decreases the blood pressure inobese hypertensive children. it is effective, tolerable and safe bloodpressure lowering monotherapy in childhood. further studies and longer follow-up are necessary to prove its long term beneficial effect in the childhood metabolic syndrome combined with hypertension. hw. zhang, j. ding, f. wang, yf. wang peking university first hospital, department of pediatric nephrology, beijing, people's republic of china objectives of study: females with x-linked alport syndrome (xlas) have variable phenotypes, from microscopic hematuria to chronic renal failure, which can not be clarified solely by mutation features of col4a5 gene. x-inactivation has been suspected to be one of the responsible reasonsfor this phenomenon, but no definite correlation has been demonstratedso far. in order to confirm whether the phenotypes of xlas femalescorrelate with x-inactivation, we analyzed the xinactivation patternsin peripheral blood cells in 36 xlas females and in skin fibroblasts in12 xlas females. methods: the x-inactivation analysis was performed using hpaiipredigestion of dna followed by polymerase chain reaction (pcr) of thehighly polymorphic cag repeat of the androgen receptor (ar) gene. results: results showed that the average x-inactivation levels of the mutant allele decreased while the degree of proteinuria increased, there was anegative correlation between the degree of proteinuria and thex-inactivation ratios of the mutant allele in blood cells (r=-0.474, p=0.006). however, there was no correlation between the degree of proteinuria and the x-inactivation ratios of the mutant allele in skin fibroblasts (r=-0.131, p=0.701). though 7 of 12 patients (58.33%) had the similar x-inactivation ratios in both blood cells and skin fibroblasts, there was also no correlation between the x-inactivation ratios of the mutant allele in skin fibroblasts and that in peripheral blood cells (r=0.180, p=0.575). conclusion: we concluded that the x-inactivation ratios in blood cells correlated with the degree of proteinuria, which might explain partially the diverse phenotypes in female xlas patients. more studies, including post-transcription regulation, environmental factors, and so on, are still needed. objective: to report frasier syndrome (fs) with wt1 mutation and abnormal expression of podocyte molecules which is the first case in mainland china. methods: peripheral blood cells were analyzed for chromosome karyotype and wt1 gene mutation. the ratio of +kts/-kts isoforms was quantified with genescan and genescan software. expressions of podocyte molecules were detected by immunohistochemical staining. result: the patient presented with steroid-resistant fsgs and male pseudohermaphroditism. the wt1 ivs 9 +5 g>a mutation was found in one allele in the proband, but not in her parents. the ratio of +kts/-kts was 0.67 in the proband, and was 1.35 and 1.42 in her mother and father, respectively. podocyte molecules expression altered in normal-and abnormal-appearing glomeruli. wt1 expression showed diffuse nuclear staining with less obvious speckles compared with that in controls. wt1 (antibody against c-terminal) displayed strong, normal, faint and negative stained podocyte nuclei within the same glomerulus. the staining intensity of wt1 (antibody against the n-terminal) was very faint. conclusion: taking clinical data, pathology, karyotype analysis and genetic testing together, we diagnosed the first case of fs in mainland china, which prompts there might be more cases underdiagnosed. wt1 displayed diffuse nuclear staining with less visible speckles compared to controls, supporting the view of the differential nuclear localization of kts isoforms. our study further confirmed that wt1 mutation resulted in abnormal expression of podocyte molecules in glomeruli of fs, though we did not know whether this phenomenon directly or indirectly resulted from loss of wt1 regulation. dent disease is an x-linked disorder characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis, calcium nephrolithiasis and the development of renal insufficiency after the middle age. so far, two genes responsible for the development of dent disease have been identified, i. e., clcn5 and ocrl1. ocrl1 was originally identified as a causative gene for lowe syndrome. in japan, igarashi et al. described for the first time that idiopathic tubular proteinuria in japan is identical to dent disease by mutational analyses. most of japanese patients with dent disease are identified by annual urinary screening as chanced proteinuria and several clinical phenotypes, such as incidence of nephrocalcinosis and long term outcome of renal function remains to be elucidated. furthermore, identification of ocrl1 as a second causative gene for dent disease has made the understanding of dent disease more complex. here we report 90 patients with dent disease phenotype with the results of genetic analyses and clinical features. out of 90 patients in 90 different families, 58 mutations (64%) in clcn5 were identified. in the 32 patients with no clcn5 mutations, genetic analysis in ocrl1 is ongoing, and at the moment 4 different mutations in ocrl1 ((i127stop, r301c, r476w and r318h) were identified. the remaining patients are now beeing investigated. among the patients in whom clcn5 mutations were detected, hypercalciuria are not always present. in several elderly patients, mild renal function impairment is present. there are similar clinical phenotypes between patients with clcn5 or ocrl1 mutations, but serum levels of ldh and ck are likely to be higher in those with ocrl1 mutations. in summary, we will present genotype and phenotype heterogeneity in japanese dent disease, and will discuss the clinical spectrum of dent disease. a. gulati 1 , s. sethi 1 , j. lunardi 2 , m. kabra 1 , n. gupta 1 , p. hari 1 , a. bagga 1 1 all india institute of medical sciences, 1st department of pediatrics, new delhi, india 2 hôpital de la tronche, genetics, grenoble cedex. france, france objectives: to study the clinical features and genetic basis of patients with lowe syndrome and identify female carriers. methods. case records of 6 patients with lowe syndrome presenting to this hospital, between 3-7 yr old, were reviewed. the clinical features were recorded and glomerular and tubular functions assessed. a detailed genetic analysis was performed on dna extracted from peripheral blood of patients and their mothers, which involved sequencing of all 23 exons of the ocrl1 gene. results: all patients showed failure to thrive, bilateral congenital cataracts, refractory rickets, delayed motor and language milestones and proximal renal tubular acidosis with fanconi syndrome. the mean schwartz gfr was 90 ml/min/1.73 sq. m. genetic analysis showed distinct mutations of ocrl1 gene in all patients studied. we report 4 new mutations having identified the variants c.779 a>g and c.853 g>t in exon 10, the variant c.1183_1184 ins t in exon 12 and c.2351-2 a>g in intron 22 in 4 independent patients. we also found 2 previously described mutations involving the region c.2309_2310 del tg and c.2377 c>t in exon 21. four of 6 mothers were heterozygous carriers. all genotypically proven carriers showed characteristic lenticular opacities. conclusion: the identification of mutations in the ocrl1 gene provides confirmation of the diagnosis of lowe syndrome. the new mutations described in north indian children expand the range of mutations that give rise to this condition. these observations have important implications for molecular diagnosis and genetic counseling in families with lowe syndrome. juvenile nephronophthisis (nph), an autosomal recessive nephropathy, is the most common genetic cause of chronic renal failure in childhood. in 10-15% of known cases, nph is associated with joubert syndrome (js), a neurological disorder described in patients with cerebellar ataxia, mental retardation, hypotonia and respiratory dysregulation. mutations in three genes, ahi1, nphp1 and nphp6 have been identified in patients with nph and js. as nphp1 mutations usually cause isolated nephronophthisis, the factors which predispose to the development of neurological symptoms in some patients are poorly understood. to determine such genetic factors and to assess the mutation rate of ahi1, nphp1 and nphp6 in nph and js, a cohort of 30 families with nph and at least one js-related neurological symptom was screened for mutations in these genes. thirteen (43%) and 8 (27%) unrelated patients were homozygous or compound heterozygous for nphp1 and nphp6 mutations, respectively. in 4 patients (13%) without nphp1, nphp6 or ahi mutations, mutations in a novel gene (nphp8/cors7) encoding a ciliary protein have been identified. interestingly, 7 of the 13 patients with nphp1 mutations carried either a heterozygous truncating mutation in nphp6 (1 patient), a heterozygous missense mutation in ahi1 (1) or the ahi1 variant r830w (5) . the variant r830w affects an amino acid conserved in vertebrates and predicted to be 'possibly damaging' by polyphen software. in conclusion, nphp1, nphp6 or nphp8 mutations can be found in 83% of patients with nph and js in our cohort. our finding that half of all patients with nphp1 mutations carry a mutation or a damaging variant in nphp6 or in ahi1 strongly supports the notion that epistatic effects provided by these genes contribute to the appearance of neurological symptoms in patients with nphp1 mutations. molecular cytogenetic techniques such as array-based cgh have been instrumental in the identification of microimbalances associated with syndromic phenotypes. we investigated 10 patients with unclear syndromic nephropathies (e. g. urinary tract malformations, focal segmental glomerulosclerosis, and persistent hematuria/proteinuria) and additional clinical features, such as mental retardation, heart defects or growth abnormalities. array-cgh analysis was performed with a whole-genome array with 8000 large insert clones providing an average resolution of <0.5mb. results: in one 16-year old female patient presenting with microhematuria, proteinuria, mental retardation including severe speech impairment, senso-neuronal hearing loss, and recalcitrant focal epilepsy, we detected a microdeletion in chromosomal bands xq22.3-q23. this deletion was verified by fish, found to be uniallelic, 2.2-3.7mb in size, and not to be inherited from the mother. electron microscopy of kidney biopsy showed splitting of the lamina densa and a thin basal membrane, which is diagnostic for alport syndrome. high-resolution cranial magnetic resonance imaging including white fibre tracking revealed a severe neuronal migration disorder with subcortical band heterotopia (double cortex syndrome), i. e. a second band of cortical neurons within the white matter below the true cortex. conclusions: in 10 patients with unclear syndromic nephropathies, we identified a female with a contiguous gene syndrome at xq22.3-q23. the microdeletion includes the x-linked alport syndrome gene col4a5 and the lisx gene associated with subcortical heterotopia, mental retardation and epilepsy. thus, the phenotype observed in our female patient combines features of the amme-complex (alport syndrome, mental retardation, midface hypoplasia, elliptocytosis) with x-linked lissencephaly. (29 f, 29 m; 17.80±6 .50 yrs, hemoglobin 9.67±1.08 gr/dl, ferritin 2827±1895 mg/dl) were enrolled. lipid profile, acute phase proteins (apps) were measured. renal tubular functions, plasma vegf level, urinary nag/cre ratio were determined. abpm and imt measurements were performed. the results were compared with healthy controls. results: mean 24-hour, day and night systolic-blood pressure (sbp), diastolic-bp (dbp) and mean arterial pressure values were comparable to that of control group. dipping in dbp was less in tm (19.03% vs 23.73%; p<0.05). the ratio of patients with less than 10% dipping in sbp (non-dippers) was higher in tm (51.9% vs 35.0%, p<0.05). mean plasma vegf level was 30.16±22.95 pg/ml [2.69-112.25] in tm, was within normal range (<10 pg/ml) in controls. apps were normal. imt of common carotid artery (cca) was 0.455±0.050 mm in tm group and 0.273±0.039 mm in controls, (p<0.01); imt of internal carotid artery (ica) was 0.344±0.037 mm in tm group and 0.203±0.041 mm in controls (p<0.01). positive correlations were found between vegf and microalbuminuria, b2-microglobulin and homosistein; between nag/cre and microalbuminuria; between cca-imt and age, and a negative correlation between cca-imt and ferritin. conclusions: renal tubular damage, abnormalities in abpm, increase in vegf and increase in cca-imt and ica-imt occur when the patients are asymptomatic and routine laboratory test are normal. optimal hemoglobin levels and deferoxamine therapy do not prevent the development of renal and vascular damage. l. sylvestre 1 , e. santos 1 , p. granzotto 2 , e. siqueira 2 , l. moreira 2 , l. rispoli 2 , n. mendes 2 , r. meneses 1 1 hospital pequeno principe, pediatric nephrology, curitiba, brazil 2 centro universitario positivo unicenp, curitiba, brazil introduction: hypertension is frequently underdiagnosed in children. early diagnosis and a planned follow-up is helpful in detecting and preventing the harmful long-term consequences of hypertension. therefore, we created a specific outpatient clinic to have a better follow-up of these patients. material and methods: we reviewed the files of patients from the outpatient clinic of hypertension, from the dept. of pediatric nephrology in hospital pequeno principe, curitiba, brazil, followed for more than 3 months, from march 2005 to december 2006. we analyzed demographic and anthropometric data, diagnosis, staging of hypertension, presence of target-organ damage and treatment. results: 72 patients were eligible, 40 boys, mean age at the first visit 6.3 years old, mean follow-up of 11 months. mean bmi=18.92 (44% overweight and obese). secondary hypertension was present in 47% of the cases, predominantly due to parenchymal renal disease; essential hypertension associated to overweight and obesity in 19 patients (27%) and there was no established diagnosis yet in other 19 patients. fifty-five patiens performed at least one abpm of 24 hours, 46 showed hypertension. twelve from 69 patients showed left ventricular hypertrophy and 18 from 61 patients had abnormalities of the retinal vasculature associated to hypertension. the most frequent drugs used to treat hypertension were ace inhibitors (49) and calcium channel blockers (47). conclusion: our data are in accordance that secondary hypertension is frequent in children, mostly associated to renal disease. furthermore, we could detect a large number of obese hypertensive children and adolescents. target-organ abnormalities are not as frequent as in adults but need to be monitored. intrauterine growth retardation (iugr) is characterized by low nephron number with or without reduced kidney size. leptin, an important hormone in the regulation of body fat massand weight, is decreased in fetuses with iugr. in the present study, weexamined the effects of leptin in a metanephric mesenchymal cell line ms7. ms7 is generated from the metanephroi of embryonic day 11.5 homozygous mouse transgenic for h-2kb-tsa. incubation of ms7 withleptin 1, 10, 50, 100 or 500 ng/ml for 24 h did not affect either [ 3 h]-thymidine incorporation or cell number. on the other hand, [ 3 h]-leucine incorporation was significantly increased by leptin in a dose dependent manner (120±9%, 123±2%, 130±3%, and 131±3% of control by 1, 10, 50, and500 ng/ml, respectively). protein/dna was also increased 1.7-fold by leptin 10 ng/ml. leptin 10 ng/ml activated both erk and p38. the levels of phosphorylated-erk (p-erk) and phosphorylated-p38 (p-p38) , as assessed by western blot analysis, started to increase at 10 min, peaked at 30 min (1.6-and 1.7-fold increase respectively) remaining elevated at 1, 2, and 6 h, and began to decrease at 12 h returning to the baseline level at 24 h. the levels of p-erk and p-p38 at 30 min were increased by leptin in a dose dependent manner (1.2-, 1.6-, 1.6-, and 1.7-fold increase by 1, 10, 100, and 500 ng/ml respectively). the levels of total erk and p38 remained unchanged. increase in [ 3 h]-leucine incorporation stimulated by leptin 10 ng/ml was completely inhibited by coincubation with a mek inhibitor pd98059 5 μm or a p38 inhibitor sb203580 5 μm. these results demonstrate that leptin induces hypertrophy of metanephric mesenchymal cells via erk and p38. the hypertrophic effect of leptin may play a role in normal renal development and may explain reduced kidney size in a hypoleptinemic state, iugr. objectives of study: to investigate the mechanism of nephron deficit in rat model of intrauterine growth retardation (iugr). methods: a rat model of iugr was built by maternal low-protein (6%) dietthroughout pregnancy. newborn male pups were chose as our studyobjects. the proliferation and apoptosis in kidney was showed by ki-67 detection and tunel method. expression of wt1, bcl-2, bax, and p53 mrnas in renal tissue were examined by real-time pcr, and expression of wt1 and bcl-2 gene products in renal tissue were examined by immunohistochemistry and western blot. the final number of glomeruli was determined at 2 weeks of age when nephrogenesis has finished. results: at 2 weeks postnatally, iugr offspring had fewer glomeruli per kidney than those in controls (p<0.001). in iugr newborns, tunel positive cells were more numerous in the nephrogenic zone. renalwt1 and bcl-2 mrna levels were significantly reduced in newborn iugrpups, and the bcl-2 mrna/bax mrna ratio was also decreased, but therewas no change in the expression of p53 mrna. in iugr newborns, the wt1and bcl-2 protein expressions were significantly decreased, and the irimmunostaining were also suppressed in the nephrogenic zone. conclusions: these results suggest that reduction of nephron number in iugr rat may be associated with enhanced apoptosis in kidneydevelopment. decreased wt1 and bcl-2 expressions and reduction of the bcl-2/bax ratio may contribute to the molecular mechanisms behind these findings. objective of the study: the aim of this study was to identify risk factors for urinarytract infection (uti) during follow-up of children with isolatedantenatal hydronephrosis. methods: between 1999 and 2006, 192 patients were diagnosed with isolated fetal renal pelvicdilatation (rpd) and were prospectively followed. after initialclinical and imaging evaluation, us scans, clinical examination, andlaboratory reviews were scheduled at 6-month intervals. the event ofinterest was time until occurrence of first episode of uti. cox's regression model was applied to identify variables that wereindependently associated with the uti. results: a total of 192patients were included in the analysis (140 boys and 52 girls) themedian fetal rpd was 10 mm (iq range, 7.8±14) and 95 patients (49.5%) presented bilateral rpd. seventyeight (41%) infants presented urinarytract anomaly. the most frequent detected uropathy was upjo (55), followed by primary vur (16), and megaureter (7). median follow-up timewas 24 months (iq range, 12-39 months). during follow-up, uti occurred in 27 (14%) of the 192 children. the incidencerate of uti was 5 episodes per 1000 person-month. the incidence rate of uti has decreased from 7.2 episodes per 1000 person-month in the first year of life to 3.3 in the second year, and to 1.4 after the third year. by survival analysis, the risk of uti for the whole series was estimated in 8.5% at 12 months, 14% at 24 months, and 21% at 36 months of age. after adjustment, two variables were independent predictors of uti during follow-up: female gender (rr=2.2, 95% ci, 1.04-4.8, p=0.03) and presence of uropathy (rr=4.6, 95% ci, 1.8-11.4, p=0.001). conclusion: according to findings, in a cohort of antenatal hydronephrosis, girls with vur or urinary tract obstructionhad a higher risk of uti during follow-up. objective of the study: to identify predictive factors of resolution of fetal renalpelvic dilatation (rpd) in a cohort of medically managed children. methods: between 1999 and 2006, 192 patients were diagnosed with isolated rpd and were prospectively followed. of 192 infants, 165 (86%) were clinically managed. after initial clinical and imaging evaluation, us scans, clinical examination, and laboratory reviews were scheduled at 6-month intervals. the event of interest was rpd resolution, regardedas renal pelvis <5 mm on two consecutive renal sonograms. cox's regression model was applied to identify variables that were independently associated with the event. results: a total of 165 patients were included in the analysis and uropathy was diagnosed in 51(31%) infants. median follow-up time was 22 months (interquartile range, 12 to 37 months). during follow-up, 60 (36%) patients presented rpd resolution. by survival analysis, the estimate of rpd resolution for the whole series was 23% at 12 months, 39% at 24 months, and 42% at36 months of age. the median time for rpd resolution was estimated at 49 months (95% ci, 36-62). in the survival analysis, three variables were found to be significantly associated with resolution of rpd during follow-up: mild fetal rpd, grades 1-2 (sfu grading system), and presence of uropathy. after adjustment, only absence of uropathy remained as an independent predictor of rpd resolution (rr=3.6, 95% ci, 1.7-7.4, p<0.001). conclusion: according to these findings, it was estimated that rpd resolution occurs in about half of the patients without uropathy at 2 years of age. objective: to study clinical and pathological characteristics of antineutrophil cytoplasmic autoantibody (anca)-positive glomerulonephritis(gn). methods: clinical data of thirteen patients during 5 years, with anca-positive gn were analyzed. results: of patients with anca-positive gn with an average age of 8.8±2.5 (5) (6) (7) (8) (9) (10) (11) (12) (13) (14) years, 11 patients were female and 2 were male. the average course was 2.2±1.9 months. 8 cases onset between december and february. there was 3, 5, 2 cases whose chief complaint on admission was anaemia, swollen and hematuria respectively. the main clinical symptoms were: anaemia (100%), hematuria/proteinuria (100%), renal functional lesion (100%), edema (76.9%), oliguresis (38.5%), hypertension (61.5%), arthralgia (30.8%), rash (15.4%), abdominal pain (46.2%), fever (7.7%). laboratory tests: bun, scr and esr were high while hemoglobin was low in all patients. mpo-anca was positive in 13 cases c3 was normal in 4 cases and low in 9 cases. pathology features: all glomeruli are affected and show different degree of segment and glomus sclerosis. there was different degree of capsula glomeruli thickening. glomerulus capillary loop was necrotic, nuclear leukocytes and cell debris could be seen. inflammatory cell interstitial infiltration with lymphocyte and plasmocyte. endotheliocyte of small vessels of interstitial was swelling and vessel wall was edema, necrosis and glassy degeneration. immunofluorescence showed no or small immune complex deposition and showed pauci-immune gn. conclusion: onset of patients with anca-positive gn was hiding and there were nonspecific clinicalsymptoms in the early stage that reduced late diagnoses until esrd. female patients was predominant. renal pathology showed segment necrotic nephritis interstitial inflammation and polyangitis. the disease had unfavourable prognosis. background: renal function maturation isn't achieved at birth. vlbw infants exposed to intensive care have an increased risk of developing renal function impairment. moreover, we showed that ibu was associated with a significant impairment in renal function at one week of life in vlbw infants. objective: to evaluate renal function development in infants treated with ibu for pda closure as compared to infants not exposed to ibu, during the first month of life. methods: multicentric prospective cohort study of 27 to 31 weeks gestation (ga) infants exposed or not exposed to ibu within the first 5 days of life. infants presenting with renal impairment at birth, urinary tract malformation, or contraindication to ibu were excluded. infants exposed to ibu were paired to controls according to ga, centre and crib score. creatinine clearance (ml/min/1.73 m 2 ) was measured for glomerular filtration rate evaluation. fractional excretion of sodium (fena%), micro-albuminuria (mg/l) and alpha1-microglobinuria/creatininuria (1/ucr: mg/mmol) were also measured once a week up to 1 month of life results: 120 infants were studied, half exposed to ibu. birth weight was 1100±278 g (mean±sd), and ga 28±1 wks. results are presented in the table: *p=0.02;**=0.01;***<0.01. j. rouillard lafond, mp. morin, c. girardin centre hospitalier universitaire de sherbrooke, département de pédiatrie, sherbrooke, canada objectives of study: many studies have focused on the negative effects of low birth weight, especially caused by intra-uterine growth restriction, on adult renal function. however, few have addressed the impact of extreme prematurity (<28 weeks) on renal function of these children during their later childhood and adolescence. the aim of the present study is to estimate the renal outcome of this population, by determining blood pressure, glomerular filtration rate, fractional excretion of sodium and microalbuminuria in 24 children (11 girls and 13 boys) aged 7 to 18 years old (mean age 12) born between 24-28 weeks of gestation (mean: 27 weeks). methods: during one encounter, height, weight and blood pressure were measured for each subject. blood tests were conducted to quantify creatinine, electrolytes and cystatin c. microalbumine, creatinine and electrolytes were dosed in one micturition. pertinent risk factors of renal damage in their perinatal history were noted. results: renal insufficiency, defined by a clearance of less than 90 ml/min/1,73 m 2 , was present in 3 subjects (22%) when estimated by schwartz formula (84,67-86,20 ml/min/1,73 m 2 ) and in 1 (4%) when estimated by cystatin c (47,4 ml/min/1,73 m 2 ). furthermore, 5 (20%) children presented an elevated fractional excretion of sodium (1, 19-1, 56%) . finally, 8 children (33%) presented microalbuminuria, with albumin/creatinine ratio greater than 2,0 mg/mol (2,04-17,25 mg/mol) . those children presented more episodes of hypotension during neonatal period (p=0,028) and have a tendency to have had neonatal asphyxia more than the others (p=0,065). conclusions: these results suggest that children born extremely preterm may present renal insufficiency and sign of tubulopathy as early as adolescence, with microalbuminuria possibly announcing upcoming glomerulopathy. organogenesis isregulated by epithelial-mesenchymal interactions that take place in theembryonic kidney between the metanephric mesenchyme (mm) and theepithelium of the ureteric bud (ub). the mm expresses signals thatregulate ureteric branching while the ub signaling leads to inductionof nephrogenesis. as a response to the ub signals the mm cellscondense, aggregate, epithelialize and undergo simple morphogenesis togenerate segmented nephrons during kidney organogenesis in connectionto ureteric bud branching. we reported earlier that mutagenesis of fgf8 function from the whole embryonic mesoderm leads to kidney failure. activation of wnt-4 gene expression encoding another essential signal for nephrogenesis also depends on fgf8 function (perantoni et al., 2005) . given the important role of fgf8 in kidney development we targeted fgf8 roles in urogenital system (ugs) development with an ugs specific cre line pax 8 cre. pax8 credeletion was expected to recombine the floxed genome in the nephronprecursors, ureteric bud and the wolffian duct derivatives. in crossesbetween fgf8 c/c and fgf8 n/+ ; pax8 cre mouse lines fgf8 gene was deleted successfully. as a result the whole ugswas affected. the kidney was severely reduced in size. newborn nullmice were born alive but died within 24 hours likely due to kidneyfailure. in the deficient kidney the organization of theproximal-intermediate segments of the developing nephron was disturbed. marker analysis with in situ hybridization was consistentwith serious defects in nephrogenesis. we conclude that fgf8 functionis involved in the control of wolffian duct development andsegmentation of the assembling nephron. the zellwegerspectrum disorders (zsds) are characterized by a generalized loss of peroxisomal functions caused by deficient peroxisomal assembly. clinical presentation and survival are heterogeneous. although most peroxisomal enzymes are unstable in the cytosol of peroxisomedeficient cells of zsd patients, a few enzymes remain stable among which alanine: glyoxylate aminotransferase (agt). its deficiency causes primary hyperoxaluria type 1 (ph1, mim 259900), aninborn error of glyoxylate metabolism characterized by hyperoxaluria, nephrocalcinosis, and renal insufficiency. despite the normal level of agtactivity in zsd patients, hyperoxaluria has been reported in several zsdpatients. we aimed to determine the prevalence of hyperoxaluria in zsds and tofind clinically relevant clues that correlate with the urinary oxalate load. methods: we reviewed medical charts of 31 dutch zsd patients with prolonged survival (>one year). results: urinary oxalate excretion was assessed in 23 and glycolate in 22 patients. hyperoxaluriawas present in 19 (83%), and hyperglycolic aciduria in 14 (64%). renal involvement with urolithiasis and nephrocalcinosis was present in five of whichone developed end-stage renal disease. the presence of hyperoxaluria, potentially leading to severe renal involvement, was statistically significant correlated with the severity of neurological dysfunction. discussion: zsd patients should be screened by urinalysis for hyperoxaluria and renal ultrasound for nephrocalcinosis in order to take timely measures to preventrenal insufficiency. menkes disease is a very rare x-linked recessivedisorder of copper metabolism. the frequency is 1: 250.000 live births. mutations in the atp7a gene are described, which encodes for aintracellular copper-binding membrane protein. pathogenetically a defect in copper absorption is responsible for inadequate synthesis of copper requiringenzymes and causes multisystemic manifestations. the clinical picture ischaracterized by early neurodegenerative symptoms like muscular hypotony andcerebral seizures. the patients also present with the so called kinky hair, hyperelastic skin, and anomalies of the kidneys and the urinary tract. wereport on a patient of non consanguineous parents of german origin. theprenatal ultrasound did not show any malformations. birth at 35 weeks ofgestation. postnatally a softening of the cranial bones and a vesicoureteralreflux iv° with dilatation of the renal pelvis combined with a subpelvicureteral stenosis had been observed, which were operated at the 2 nd month of life. at the age of 3 months the patient presented with seizuresand abnormal hair structure. within the diagnostic course menkes diseasehas been suspected and the nonsense mutation parg980x has been identified inthe atp7a gene. the mother is not a conductor, a mutation in thegermline cannot be excluded. conclusion: the combination of urinary tract malformations and neurodegenerative symptoms should let you think of the very rare menkes disease. introduction: primary hyperoxaluria type 1 (ph1) is an inborn error of glyoxylate metabolism due to the deficient activity of the hepatic peroxisomal enzyme agt (alanine: glyoxylate aminotransferase). it leads to excessive endogenous oxalate production. patients develop urolithiasis and renal insufficiency. the contribution of specific precursors in the pathway leading to endogenous oxalate synthesis is not known. this is warranted to design appropriate treatments. we aimed to test the contribution of different precursors to oxalate synthesis. methods: wild type mouse hepatocytes were incubated with different potential precursors of glyoxylate, either in the presence or absence of alanine. in the absence of alanine flux through agt is deficient thereby mimicking agt deficiency. similar experiments were also performed in hepatocytes from agtdeficient mice. results: oxalate production was found to be highest with glyoxylate as substrate in the absence of alanine, whereas oxalate production was lower with glycolate, hydroxypyruvate, glycine, fructose, and ethylene glycol. the results obtained in wild-type hepatocytes incubated in the absence of alanine were comparable to those obtained in hepatocytes from agt-deficient mice. upon addition of alanine to wild-type mouse hepatocytes, however, resulted in 30% lower rates of oxalate production, in contrast to hepatocytes from agt deficient mice. discussion: hepatocytes derived from agt deficient mice represent a good model to study the contribution of different precursors to oxalate production in ph1. s. grisaru 1 , c. geary-joo 2 , f. snider 2 , j. cross 2 1 university of calgary, department of pediatrics, calgary, canada 2 university of calgary, department of biochemistry and molecular biology, calgary, canada gcm1 (glial cell missing), is a transcription factor necessary for the formation of placental syncytiotrophoblast in mice. gcm1 mutant mice die before nephrogenesis at embryonic day (e) 10. during early murine development gcm1 expression is limited to the placenta. however, immediately after birth, gcm1 is increasingly expressed in the kidney in proximal tubular cells in the outer medulla. we recently reported successful rescue the gcm1 null phenotype using a tetraploid aggregation approach (jasn vol.17, 2006) . since our previous report, further analysis of the aggregation products confirmed only 3 homozygous mutants (2 males and a female) obtained from six hundred and twenty five transferred aggregate embryos resulting in 121 live pups. abnormal cortico-medullary patterning was demonstrated by histology analysis of adult gcm1 null mice kidneys. this abnormality was further defined by immunohystochemical detection of known nephron segment-specific markers (aquaporin-7, aquaporin-2 and tamm-horsfall protein) in gcm1 null kidney sections. to define the expression of gcm1 in human kidneys, commercially available anti-human gcm1 polyclonal antibodies were used to detect gcm1 protein in tissue sections of newborn kidneys obtained from autopsies. gcm1 was detected by immunohystochemistry in the renal cortex in tubular structures with cells having a brush border suggestive of proximal tubules. gcm1 signal was not detected in the renal medulla. conclusion: in humans, gcm1 is expressed in renal proximal tubules at birth whereas in adult mice its mutation is associated with abnormal renal cortico-medullary ultrastructure. this effect may represent a primary role for gcm1 in late renal development and patterning, or structural changes occurring postnatally secondary to alterations of tubular physiology caused by gcm1 inactivation. objectives: lupus nephritis (ln) in singapore children treated with cyclophosphamide and/or azathioprine has a poor prognosis with a reported 10-year renal survival of 59%. this study examined the long-term outcome of children with lupus nephritis using a new protocol comprising pulse intravenous methylprednisolone, mmf ± cyclosporine. method: twenty-one children with ln (age range at start of treatment 3.7-14.8 years) who were treated between the years 1995 to 2007 were included in this retrospective study. mmf dose was 1200 mg/m 2 /day. mean duration of follow-up was 3.6±2.0 (range 1.3-8.6) years. treatment outcome was defined by systemic lupus erythematosus disease activity index (sledai), renal function, proteinuria and serologic markers. effect of steroids on growth was assessed by height standard deviation score (htsds). statistical analysis was performed using wilcoxon signed rank test. results: at presentation, 72% had nephritic-nephrotic syndrome, 14% had nephrotic syndrome, while 14% had renal failure requiring dialysis. renal biopsy classification (who) was ii in 19%, iii in 24%, iv in 33%, and v in 24%. comparing pre-mmf treatment and current follow-up parameters respectively, sledai (17.4±8. objectives of study: to understand the effects of response gene to complement 32 (rgc-32) in tgf-β1 induced epithelial-mesenchymal transition (emt) on human renal proximal tubular epithelial cells (hptecs). methods: constructed rgc-32 expression plasmids and rgc-32 sirna hairpin plasmids, transient transfected them into hptecs in vitro, and then treated hptecs with tgf-β1 (5ng/ml) or vehicle alone for indicated time (0, 30min, 2h, 8h, 24 h) . rt-pcr and western blot were used to determine the expression of a-sma, ecm (col-i, fn1). the mrna expressions of e-cadherin and sm22a were detected by rt-pcr. results: (1) the promoting effects of rgc-32 on emt. instead of stimulation with tgf-β1, the hptecs, those overexpressed rgc-32 gene, de novo obtain the ability to produce markers of myofibroblast phenotype (a-sma, col-i and fn) and sm22a gene, as well as lost the capability of expressing e-cadherin gene. (2) the eliminating effects of rgc-32 sirna on emt that induced by tgf-β1. after stimulation of tgf-β1 for 24 hours, the expression of a-sma, col-i, and fn as well as sm22a gene in hptecs, those rgc-32 genes were interfered with rgc-32 sirna, were significantly decreased than that in controls. conclusions: rgc-32 was an important regulator for tgf-β1 and its downstream signalling smad proteins on emt. background: low birth weight is associated with a low nephron endowment. this may predispose to hyperfiltration and cascading proteinuria particularly if obesity develops. our report relates to an emerging population of children with proteinuric kidney disease in our multiethnic community. methods: forty-two obese children (mean age 14±5 years) with proteinuric kidney disease (kd) were studied. twenty-four were of normal birth weight (nbw>3000 grams) and 18 were of low birth weight (lbw<1200 grams). there was a female (24/42=57%) and an ethnic predominance (23 african, 16 hispanic). degree of proteinuria was determined by the random urine protein (pr) and albumin (alb) to creatinine (cr) ratios (upr/cr and ualb/cr). renal function (egfr) was estimated from the schwartz formula. body mass index was used as a measure of obesity (>95% centile). insulin resistance was measured by the homeostatic model assessment (homa). kidney tissue was obtained in 28 of the patients for pathology and histomorphometry. results: average bmi was 96±4% tile. fasting insulin and homa scores were not significantly different in the obese nbw versus obese lbw children. renal biopsy specimens revealed focal glomerulosclerosis (fsgs) in the majority of patients (23/28=83%). progression to end stage kidney disease was significantly greater in lbw compared to nbw children with a median renal survival of 11 years, p<0.01. glomerulomegaly as measured by glomerular diameter was similar in obese patients and significantly greater than non-obese controls with fsgs. conclusions: obesity appears to be a confounding factor in the development of glomerulosclerosis and progression of kidney disease in children. low birth weight and concomitant low nephron endowment may contribute to disease progression, especially in those of african and hispanic descent. objective: to determine long term outcome and prognostic factors of iga nephropathy in a large single center cohort of pediatric patients. patients and methods: we have reviewed the medical charts of 79 patients with biopsy proven igan that have been followed at our institution from 1983 to 2004, with a minimal follow-up of 2 years. follow-up data, including proteinuria >500 mg/24 h or the need for ace-is therapy, chronic renal failure (crf) and hypertension were analysed after 2 years and 5 years of follow-up. data from 60 patients with follow-up longer than 5 years were also available (mean follow-up 9.9 years, range 5-24 years). 61% of patients received therapy (cyclophosphamide in 10 patients and/or steroid±ace-is in the remaining). clinical features at the onset, histology class (lee and haas) and treatment during the first 2 years were analysed by multivariate analysis against the above mentioned dependet variables. results: the average follow-up was 7.85 years (range 1-24 years). presentation symptoms included macroscopic hematuria in 76% of patients. at the end of follow-up, renal function was normal in 94% patients, 3 patients have reached end-stage renal disease and 2 had chronic renal failure. proteinuria or the need for aceis at 2 years was significantly associated with the age of onset (or: 1.30 [1.09-1.56] ) and proteinuria at the onset (or: 1.86 [1.05-3.32] ). crf was significantly associated with familial igan (or>10). hypertension at onset was significantly associated with persistent hypertension during follow-up (or: 8.82 [1.55-50] . conclusion: taken together, these data indicate that the overall prognosis of igan is good during childhood and that the worst prognostic factor for development of crf is familial igan. overall, histological classification had a poor correlation with the outcome of the disease. this study was designed to compare three urinary protein expert systems for profiling proteinuria (pu) in children with kidney diseases. freshly voided urine was collected from 61 children with glomerular diseases, 19 children with tubular diseases and 25 healthy children aged 3-16 years. 23 out of 80 children with renal disease had a glomerular filtration rate (gfr) <90 ml/min/1.73 m 2 . the urinary protein expert systems were 1. albumin/total protein ratio (apr), 2. alpha-1microglobulin/alpha-1-microglobulin + albumin algorithm (aaa), and 3. the complex upes algorhithm (using serum creatinine, urinary total protein, alpha-1-microglobulin, albumin, igg, alpha-2-macroglobulin and dipsticks). apr correctly identified glomerular pu in 47 of 61 (77%) children with glomerular diseases, tubular pu in 16 of 19 (84%) children with tubular diseases and normal pu in 23 of 25 (92%) healthy children. aaa correctly identified glomerular pu in all 61 (100%) children, tubular pu in 18 of 19 (95%) children, and all 25 healthy children were characterized as having no pathological pu. upes differentiated the type of pu in children with glomerular diseases into glomerular (50/61 patients) and mixed glomerulo-tubular (6/61 patients). tubular pu in children with partial or complete renal fanconi syndrome was identified in 16/19 patients and described as mixed glomerulo-tubular pu in 3/19 patients. mixed glomerulo-tubular pu was only found in children with ckd stages 2-5 of glomerular and tubular diseases. in conclusion, urinary protein expert systems may be used to distinguish between glomerular and tubular pu. the aaa algorithm had the highest reliability when compared with the two other expert systems and the accuracy was not negatively influenced by a decrease of gfr. however, upes provided additional information on mixed glomerulo-tubular pu in patients with a low gfr. background: the three lmw proteins cystatin c (cys), β2-microglobulin (β2-m) and β-trace protein (β-tp) are useful markers of gfr. cys is particularly well suited for the detection of incipient renal failure. however, corticosteroid medication has been shown to stimulate cys production. aim of the study: analysis of the effect of corticosteroid therapy on the correlation between gfr and the three lmw markers. patients: 119 patients (47 f, 72 m; median age 10.9 years, range 0.2 to 18.9) with malignant (n=47) or nephrological (n=72) diseases underwent a single-shot inulin clearance. the respective lmw proteins were measured by particle-enhanced immuno-nephelometry. 27 children received corticosteroids (prednisone or dexamethasone) in a mean dosage of 28 mg/m 2 /d of prednisone equivalent (pred/bsa). multiple linear regression analysis was performed between the lmw markers as dependent and both gfr and steroid-dose as independent variables. results: mean gfr was 77.2±27 ml/min/1.73 m 2 , mean cys 1.08±0.5 mg/l, β2-m 2.17±1.33 mg/l and β-tp 0.97±0.57 mg/l. cys was highly correlated with the reciprocal of gfr (p<0.0001) but not with corticosteroid-dose (p=0.138), whereas both β2-m and β-tp were highly correlated (p<0.0001) with both the reciprocal of gfr and the reciprocal of pred/bsa. discussion: using gold-standard gfr measurements, we cannot confirm earlier reports indicating an increase in serum cys during corticosteroid medication. by contrast, steroids significantly lowered both β2-m and β-tp serum concentrations. we conclude that at least in patients with mild renal insufficiency cys -unlike β2-m and β-tp -appropriately reflects gfr also during steroid therapy. this further supports the concept of cys being a superior marker of incipient renal failure. objective: to repeatedly follow kidney function since onset of type1diabetes and evaluate whether gfr can predict development of micro-or macroalbuminuria or end stage renal disease. design: observational cohort study. methods: since 1978, all diabetic patients undergo renal function tests every 2nd to 3rd year from onset. 363 children, 204 boys, have done 1640 clearance studies. 81 healthy children and young adults, 5-30 years of age, served as controls. gfr was evaluated by clearance of inulin during water diuresis and continuous infusion. results: gfr during the first 15 years after onset of diabetes was significantly higher than that of controls (mean 130-142 vs. 116 ml/min/1.73 m 2 ). at onset, 2 and 5 years after, boys had significantly higher gfr than girls (mean 135, 148, 146 vs. 128, 134, 133 ml/min per 1.73 m 2 ) but after 8 years no differences were found between sexes. the occurrence of microalbuminuria, albuminuria during the first 15-20 years was analysed and mean of gfr of 0, 2 and 5 years, 2 and 5 years, 2, 5 and 8 years and all those gfrs separately were compared between patients still normoalbuminuric, microalbuminuric and macroalbuminuric after 10 and 20 years resp. no significant differences were found between the groups. moreover the change in gfr from 0 to 5, 2 to 5 and 2 to 10 and 5 to 10 years were also compared between the groups and no significant differences were found.8 young adults reached end stage renal disease (esrd) after 15-29 (median 20) years and comparing their gfrs during the first 5-8 years with those still normoalbuminuric after 20 years, no significant difference was found. conclusions: hyperfiltration is found in children with type 1 diabetes during the first 12-15 years from onset and hyperfiltration was equally seen during the first 5-8 years in those children who in the future developed normo-, micro-, albuminuria and/or esrd. background: hiv associated nephropathy (hivan) remains an important entity despite the use of highly active anti-retroviral therapy (haart). our objectives were to determine the prevalence and severity of renal manifestations in a cohort of hiv infected children during the haart era. methods: a retrospective analysis was conducted on 286 children infected with hiv. renal assessments included quantitation of proteinuria, radiologic abnormalities, and renal function. persistent proteinuria (pp) was defined by urine protein to creatinine ratio (upr/cr) >0.2 detected on at least two measurements 1 month apart. renal sonography and mag 3 renal scintigraphy were categorized according to the presence of bilateral increased echogenicity and/or nephromegaly, and cortical retention and/or diffuse parenchymal disease, respectively. hivan was considered in those children that had pp associated with any radiological abnormalities. results: of the 286 children, 98.6% were perinatally infected. eighty-five (29.7%) had pp. of these, 46 had pp alone, while 39 (13.6%) developed hivan. the mean age of onset of hivan was 9.4±0.8 years. overall mortality at the time of analysis was 3.8% and it was highest in those with hivan. viral load (vl) >100, 000 copies was significantly associated with hivan. creatinine clearance was significantly decreased in patients with hivan. conclusions: the prevalence of pp in our population of perinatally infected children remains high (29.7%), with at least half of them showing evidence of hivan. persistently high vl (>100, 000 copies) was associated with the presence of hivan. a spectrum of renal related disorders is a frequent occurrence in hiv infected children and should be sought with periodic urinalysis, quantitation of proteinuria and renal function, and imaging and/or histopathological studies. mmf has shown to be effective in adult ln, whereas only anectodical data are reported in childhood. we evaluated mmf in 15 children with ln, 11 f/4 m, mean age: 12.4±3.9 yrs, proteinuria >3 g/day, decreased c3 and increased anti-dsdna serum levels, normal renal function. renal biopsies, before mmf, showed the following classes (weening) : iv in 8 cases, iii in 1, ii in 5, vi in 1. before mmf: 2 patients have received i. v. cyp; 2 more received aza and csa but were in flare-up of disease; the remaining 11 were newly diagnosed patients. each patient received three i. v. metilprednisolone pulses and thereafter mmf (plus oral prednisone(p): 1 mg/kg/day) was administered (mean dose: 29±7.7 mg/kg/day; through level: 3.6±1.2 μg/ml). outcome was monitored by sledai score, renal function, proteinuria. in 11 children p was tapered and, after 4.6±2.3 month mean time, stopped; 4 children were receiving p (0.3 mg/kg/day). the mean followup is 35±16 months. sustained clinical remission was observed: proteinuria was absent in all, in 10 patients an increase of serum c3 and c4 and a decrease of anti-dsdna levels was seen. significant steroid sparing effect was obtained: hypercorticysm dramatically improved. of the 15 patients 8 achieved 2 years of mmf treatment and in them, at this time, a serial second renal biopsy was performed: histopathological activity indices reduced (8.76±2.55 vs. 5.3±6.97, p<0.01), whereas chronicity indices did not change (3.47±1.56 vs. 3.3±3.31). no haematological and/or gastrointestinal side effects were observed. our pilot study suggests that mmf represents a good alternative to traditional therapy in the treatment of sle in children, and in controlling disease activity and as steroid sparing agent without significant side effects over the entire period of therapy. mmf has shown to be effective, during treatment, in mantaining remission of childhood sd and csad ns, but few data are available on the mmf long term effectiveness after drug stopping. we report the results of two years mmf treatment in 33 children with sd and csad ns. the characteristics of sd and csad groups were, respectively: 19 patients, 11 boys, mean age 6.7 yrs vs. 14 pts, 11 boys, mean age: 11.6 yrs (p<0.005); first episode ns mean age: 3.4 yrs vs. 6.3 yrs; ns mean duration: 2.9 yrs vs. 7.4 yrs (p<0.001); mean steroid therapy duration: 2.2 yrs vs. mean csa therapy duration: 3.2 yrs; histologic features: fsgs 2, mc 17 vs. fsgs 9, mc 5. in both groups mmf was started after remission was achieved with prednisone administered at the last relapse. mmf treatment: lenght: 24 months; mean dose: 27.8±4, 1 mg/kg/day; plasma through level: 3.6±1.2 mcg/ml; non responder: patient presenting a ns relapse during mmf. in sd group 17(83%) and in csad 12 (85%) subjects were responders. in 14 patients of sd group and 10 patients of csad group p could be withdrawn over a mean period of 11.3 months, so that ns remission was sustained just by mmf; remaining patients were receiving p at a mean dose of 0.3 mg/kg/a. d. two years mmf treatment was accomplished in 26/33 (78%) patients. at 24.3±5 months mean followup since mmf withdrawal, 6 (23%) patients (4 of sd and 2 of csad group) relapsed after 9.3 months (3.2-12.1) mean time no haematological or gastrointestinal side effects were observed. our results demonstrate that two years mmf treatment in sd and csad ns children is effective not only in maintaining remission during therapy, but also in achieving persistent remission after withdrawal of drug in a significant rate (>70%) of patients; the side effects and the rate of mmf dependence are negligible with respect to those of steroids and csa. information on long-term renal function following treatment for wilms tumor (wt) are relatively scanty. previous studies reported a worrying late development of microalbuminuria (uma), hypertension (hpt) and even reduction in glomerular filtration rate (gfr). the aim of the present study was to evaluate the long-term renal outcome in a cohort of patients who underwent uninephrectomy for wt. glomerular function (as creatinine clearance by cockroft-gault formula) was calculated and uma (as uma/ucr ratio) as well as urinary b 2 microglobulin excretion were detected. 24-hours ambulatory blood pressure monitoring was also recorded. fifteen patients (11 f) with a median age at wt diagnosis of 4.4 yrs (range 1.8-16.6) were studied. the median follow-up was 13.3 yrs (10.2±19.3). eight patients had been classified as wt stage 1 and 7 as wt stage ii. all patients had been treated with unilateral total nephrectomy and chemotherapy. two of the children had also been addressed to radiotherapy. the primary disease did not recur in any of the patients. the median age at time of investigation was 18, 3 yrs (range: 12, 7-30, 4). none of them had a gfr below normal limit (mean gfr was 109.8±26.8 ml/min/1.73 m 2 ). urinary b 2 microglobulin excretion was normal (mean ub 2 /ucr: 0.5±0.3) in all of the patients. the mean uma/ucr ratio, was 0.13±0, 1 with only 1 patient exhibiting higher then normal values (uma/ucr ratio: 5, 3). the 24 hr blood pressure was normal in all patients with a mean systolic and diastolic blood pressure sds of -0.5±0.7 and -0.1±0.8, respectively. we conclude that as far as renal function, unilateral total nephrectomy combined with chemotherapy for low-stages wt can be look at as a safe treatment although it might be wise to monitor renal function at 5-year interval. classicaly, patients are divided into monosymptmatic enuresis (mne) and non-monosymptomatic enuresis, however, there is upcoming evidence that this subtyping might be artificial. the aim was to register the characteristics of nocturnal diuresis-rate and bladder volume in both subtypes. methods: retrospective analysis of 1000 consecutive patient-files, age 6-18, primary consulting for enuresis in a tertiary center. registration of incontinentia diurna (id) and maximal functional bladder volume (vmax), 24 hours urine-collections in 4 day and 4 nighttime-collections with uosmol and diuresis-volume (dv) and-rate. patients are divided into a mne and nmne-group. results: 1) vmax is significantly lower than bladder volume for age, 2) nocturnal polyuria is only present in 1/3 patients, 3) nocturnal diuresis is >vmax, 4) there is a significant linear correlation between nd and the nocturnal/daytime-diuresis-ratio, indicating fluid intake dependency. 5) there is a negative correlation between nd and urinary osmolality. 6) but the positive correlation between total nocturnal osmotic excretion and nd is much stronger. this unexpected observation cannot be explained by the classical primary vasopressin-theory. conclusion: our data show (almost) no statistical difference between the mne and nme-groups, suggesting a continuum instead of 2 separate identities. both groups have a significant low vmax and nocturnal polyuria. the observation of the extremely strong correlation of nocturnal polyuria with the high osmotic excretion and high 24 h urine-production suggests that nocturnal diuresis-rate is highly fluid-and nutrition-dependent, and therefore more attention should be given to this part of the urotherapy. a. deguchtenaere, a. raes, j. dehoorne, r. mauel, e. vanlaecke, p. hoebeke, j. vande walle there is increasing evidence that a subgroup of patients with nocturnal polyuria may have an abnormal circadian rhythm of tubular sodium which may result in vasopressin resistance. the pathogenesis of this phenomenon remains to be elucidated. however if the increased sodiumexcretion overnight results in the ddavp-resistance, decrease of the sodium-excretion-overnight may respond in subsequent ddavp response. aim of the study: retrospective study on the circadian rhytm of diuresis-rate and osmotic excretion in basal condition and subsequent during introduction of ddavp, diet and furosemide. results + discussion: 1) baseline-values show significant lower uosmol and higher diuresis-rate overnight compared to controls. striking is the >40% part of electrolytes to explain the high osmotic excretion. 2) introduction of ddavp results in a normalization of nocturnal uosmol, but despite a significant decrease of uosmol overnight, nocturnal polyuria persists. 3) protein-and sodium-restriction results only in slight differences, but of course we do not have data on the compliance. 4) furosemide in the morning results in a significant increase of daytime diuresis, osmotic and sodium-excretion, but as compensation decreased nighttime diuresis, osmotic and sodiumexcretion. 5) in 8/10 cases the antidiuretic effect results in an anti-enuretic effect. conclusion: this pilot study clearly demonstrates that introduction of early morning furosemide results in significantly lower nocturnal diuresis. because the urinary osmolality remains high, this correlates with decreased nocturnal osmotic excretion associated with increased osmotic excretion (sodium) during daytime. background: the elasticity of the vessel walls decreases with age, this process is dramatically speeded up by uremia. as an early indicator of arteriosclerosis pulse wave velocity (pwv) increases along with arterial stiffness. aim: to establish normal values for pwv in healthy children; to compare it with children on dialysis. patients, methods: pwv was measured with a pulsepen device in 116 healthy children and young adults (age range 6-23 years) as well as in 10 uremic children (14,4±4 years) (crf) treated by hemodialysis (n=7) or peritoneal dialysis (n=3). two control groups of 10-10 childrens were formed using the database of healthy children: one matched for age (a-c) and one adjusted for height and weight (h/w-c). blood pressure, heart rate, serum calcium (ca), phosphate (p) , and parathyroid hormone levels were also determined. results: a significant linear correlation was found between pwv and age (r=0, 60), height (r=0, 49), weight (r=0, 43), (p<0, 01), systolic blood pressure (r=0, 38) and heart rate (r=-0, 24) (p<0, 05). crf patients were smaller by 15, 3 cm than a-c (p<0, 05), and younger than h/w-c by 4, 5 years (p<0, 01). pwv in crf (5, 68±0, 96 m/s) did not differ significantly from a-c (5, 04±1, 18), however it was elevated in comparison to h/w-c (4, 51±0, 55 p<0, 01). serum p, caxp and pth was increased in crf (p<0, 001) conclusion pwv is higher in children with crf as a sign of increased arterial stiffness. controls matched for height and weight should be used in states of severe growth retardation. a number of established risk factors potentially responsible for arterial dysfunction are present in crf. ngal has been identified as an early marker of acute renal failure (arf). sepsis in very low birth weight (vlbw) infants is associated with arf more often than recognized. the aim of this study is to determine whether ngal represents a marker of renal impairment in vlbw infants affected by sepsis. samples of urine of 36 vlbw infants were prospectively collected for weekly measurement of ngal. after evaluation of the clinical course, 2 groups were identified: group sepsis includes 14 infants affected with 16 septic events associated with some degree of renal impairment and group normal includes 22 uncomplicated vlbw infants. a mouse model of sepsis was created in 11 neonatal mice by intra-peritoneal introduction of salmonella lipopolysaccharide. kidneys were harvested 24 hours after the challenge, and ngal mrna was quantified by real time pcr. ngal values of the normal group did not differ with gestational age or post-natal age of the neonates. the upper bound of the 95th percentile confidence interval was 40 ng/ml. the median value of ngal in the sepsis group at 7 days before the septic event was 75 ng/ml and during sepsis was 150 ng/ml: these values were not significantly different, but both were significantly higher (p<0.001) than the median of the normal group (10 ng/ml). once sepsis had been treated, the median value of urinary ngal was similar to normal (10 ng/ml p=0.17). changes in urine ngal concentration paralleled changes in serum creatinine. sepsis induced animal models showed a dramatic increase of ngal mrna in kidney tubules that paralleled acute renal failure. these neonatal animal and human data suggest that ngal may be an early marker of renal impairment in septic vlbw babies. further investigation is necessary to more exactly define the temporal relationship between the onset of sepsis/arf and rise in urine ngal concentration. we report 4 cases of acute renal failure (arf) associated with orellanus syndrome, a cortinarius mushroom poisoning. grand-father, mother, father and son presented with arf 1 week after gastrointestinal symptoms and 2 weeks after repetitive ingestion of wild mushrooms. critically arf was observed for the 11 year-old boy: anuria, severe metabolic disorders (hyponatremia 124 mmol/l, hyperkaliemia 9 mmol/l, serum creatinine 1137 mmol/l, blood urea 54 mmol/l). renal biopsy was performed for the grand-father, father and son (day 6, 9 and 8 respectively after presentation) and showed similar lesions: severe tubulointerstitial nephritis (tin) with tubular necrosis and interstitial fibrosis. renal replacement therapy was necessary for the father and the son. the mother recovered completely in two weeks without dialysis while renal function improved slowly for the two men. the boy is still hemodialyzed 5 months later. his main problem is uncontrolled hypertension. the diagnosis was confirmed 3 weeks later since fungal spores of cortinarius orellanoides were observed in the contaminated meal by light microscopy. the severity of the disease seems to be related to the toxin quantity: the 40kg boy ate mushrooms as much as his father and grand-father, the mother ate much less. cortinarius spp poisoning is an exceptional paediatric cause of arf. gastrointestinal disorders are the main symptoms of the initial phase of the poisoning appearing 3 days after the mushrooms ingestion. the renal phase is delayed (median 8.5 days) characterized by arf secondary to tin. the toxin effects are dose-related, explaining the severity of the boy's symptoms. the prognosis is severe with 60% of end stage renal failure. currently no treatment is available. although rare, mushroom poisoning should be considered in the differential diagnoses of arf with tin. l. mendels, ah. bouts, j-c. davin, j. groothoff emma children's hospital/academic medical center, pediatric nephrology, amsterdam, the netherlands background: inchronic dialysis, tertiary hyperparathyroidism (th) is clinically revealed by persistent combined high parathyroid hormone (pth), normalor high total serum calcium (tca) and normal phosphate levels. sincethe introduction of bicarbonate containing dialysate in peritoneal dialysis (pd), we have observed combined high tca and pth level sunusually early after onset of dialysis therapy. in most of the secases, ionized calcium (ica) levels were low. we aimed to investigate the extent of this discrepancy and its association with the mode of therapy. methods: serum ica, tca, pth, bicarbonate and capillary ph were assessed over 2 years in 10 pediatric pd, 11 hemodialysis (hd) and in 9 transplanted (tx) patients. associations between tca, pth and ica were analyzed. results: comparedto tx patients, we found in pd and hd patients a lower mean ica/tcaratio (both p<0.0001), an increased mean tca-ica (p<0.001 and p <0.01, respectively), and a higher number of combined normal/increased tca and decreased ica and increased pth values (44.7% and 32.3%, respectively for pd and hd, vs.0% for tx). alow ica/tca was associated with a high capillary ph (r=-0.51; p<0.0001), a high venous bicarbonate (r=-0.34, p=0.001) and a lowage (r=0.21, p=0.02). conclusions: ica levels are warranted for monitoring calcium phosphate homeostasis in dialysis patients, especially in young pd patients. the use of only tca levels might lead to an inadequate treatment with vitamin d, and henceinduce the development of autonomous hyperparathyroidism in these patients. preterminal renal failure (prf)and end-stage renal disease in children and adolescents are associatedwith an increased risk of atherosclerosis and cardiovascular disease. oxidative stress is one of the pathogenetic factors that could possiblybe influenced by therapeutic interventions. we investigated biomarkers of oxidative stress in 12 children (median age 9.6 years) with prf (median gfr 43 ml/min/1.73 m 2 , range 15-86) andin 11 children (median age 11.9 years) under peritoneal dialysis (pd)and 13 healthy age-matched controls (c). plasma samples wereinvestigated for malondialdehyd (hplc) and carbonyl groups in proteins(elisa) as biomarkers for oxidative stress as well as the plasmaantioxidative substances vitamin c (photometric), vitamin e (hplc), ubichinols (hplc), sulfhydryl groups in proteins(photometric), erythrocyte resistance to radicals and the total radicaltrapping antioxidant capacity (trap). in both patient groups prf and pdwe found a depletion of sulfydryl groups and ubichinol-10 and a reducedresistance of erythrocytes to radicals. malondialydehyd (p<0.05) andcarbonyl groups (p<0.01) were elevated in the pd group compared tocontrols. conclusion: from these studies we concludethat in children under peritoneal dialysis biomarkers of oxidativestress are elevated. moreover antioxidative defenses in preterminalrenal failure as well as under peritoneal dialysis are impaired. significant acute renal failure due to non-steroidal anti-inflammatory drugs: inpatient setting in united states non-steroidal anti-inflammatory drugs (nsaid) are freely available over-the counter. many children routinely use them without medical supervision. fourteen inpatients mean age of 15.0±2.84 years (4 males, 10 females), were referred to nephrology for acute renal failure. based on history, biochemistry, imaging and urinalysis the diagnosis of acute renal failure due to nsaid was made. all patients admitted to taking ibuprofen and six also consumed naproxen. the exact doses of either could not be scientifically determined as none were prescribed by a physician. none of the patients had underlying renal diseases at the time of admission. nine patients had proteinuria and 12 had hematuria (including one with gross hematuria). one patient had nephrotic syndrome but resolved spontaneously without steroids and has remained in remission for 2 years. two patients required dialysis. only one of the dialyzed patient required steroid therapy for recovery of renal function. all data are expressed as mean±sd. the mean duration of hospitalization was 6±4.3 days. the mean serum creatinine at the peak of renal failure was 3.97±4.74 mg/dl (range 1.2-16.6). all patients recovered renal function with normalization of serum creatinine to 0.72±0.15 mg/dl (range 0.5-1, p<0.01). however, the duration from onset to normalization of serum creatinine was 48±63 days; indicating many patients had abnormal renal function for aprolonged period. in conclusion, nsaids pose significant risk of renal failure forsignificant duration and as an entity may be under recognized. objectives: treatment with growth hormone (gh) improves growth retardation of chronic renal failure. cdna microarrays were used to investigate gh-induced modifications in gene expression in the growth plate of uremic young rats, the organ where longitudinal growth takes place. methods: rna was extracted from the tibial growth plate from two groups (n=10) of young rats: uremic (nx) and uremic treated with 3.3 mg/kg/day of intraperitoneal gh for one week (nxgh). after reverse transcription, agilent technology was used to analyze differential gene expression by microarrays containing 21, 000 rat probes (four hibridizations were performed). most expressed genes were detected using linear models and bayesian methods. to confirm gene expression changes shown by the chips, some genes known to play a physiological role in growth plate metabolism were analyzed by real-time quantitative polimerase chain reaction (qpcr). the ribosomal protein l4 (rpl4) expression did not show changes in the array and was used as the housekeeping gene. results. gh modified the expression of 224 genes, 195 being upregulated and 29 down-regulated. the assay was validated by the qpcr results, which confirmed the sense of expression modification found in the arrays for insulin like growth factor i (down), insulin like growth factor ii (up), collagen 5 alpha 1 (down) and proteoglican type 2 (up) . conclusions: this study shows for the first time the profile of growth plate gene expression modifications caused by gh treatment in experimental uremia. the further analysis of selected individual genes, whose expression is differentially modified by gh will contribute to explain the mechanism of the stimulating effect of gh on growth in chronic renal failure. objectives of study: children with chronic renal failure have an increased risk of cardiovascular disease. this is associated with endothelial dysfunction, a key pathophysiological factor in atherosclerotic disease. circulating endothelial progenitor cells (epcs) have the potential to repair endothelial damage and promote angiogenesis. in adults, the number of epc in peripheral blood correlates with endothelial function and reduced epc levels are associated with a higher incidence of cardiovascular events. we aimed to investigate if children on long-term hemodialysis (hd) therapy have reduced epc levels. methods: we quantified circulating epc in 12 pediatric hd patients before a midweek hd session and 11 healthy age-matched controls. epc are a subfraction of the haematopoeietic stem cells (hsc) expressing both hsc-marker cd34 and the vegf-receptor-2 kdr. using flow cytometry, epcs were identified as cd34+kdr+ cells and quantified relative to the number of granulocytes in the sample. results: the number of epcs in the peripheral blood was significantly reduced in hd patients (12.0±1.9 vs 29.0±7.3/10 5 granulocytes, 59% reduction; p=0.03). the total number of circulating hsc also tended to be lower in hd patients (71.2±7.3 vs 112.8±23.7/10 5 granulocytes, 39% reduction; p=0.09). conclusion: the number of circulating epcs is significantly reduced in children on long term hd. reduced epc levels may contribute to endothelial dysfunction and accelerated atherosclerosis in children on long term hd. future studies are needed to identify the cause of this deficiency and to evaluate if increasing epc levels provides therapeutic benefit. objectives: darbepoetin alfa (aranesp ® ) is a novel erythropoiesis stimulating protein that has been shown in adult trials to have safety and tolerability equivalent to recombinant human erythropoietin. however, to date there is only limited published data on the use of aranesp inpaediatric patients. the objective of this study was to determine the safety and efficacy of darbepoetin in children with chronic and endstage kidney disease. methods: from 2003 to 2006, 30 children with either chronic or end stage kidney disease were enrolled in a prospective observational study. the initialdose of darbepoetin was 0.45 mcg/kg weekly (either iv or sc) and subsequent dose was titrated to achieve haemoglobin (hb) between 110 and 130 g/dl. results: data analysis to date includes 22 patients (16 male : 6 female) whose agesranged from 1 month to 17 years (mean 9 years). hb improved significantly with darbepoetin treatment from mean 84 g/dl (range 64-107) at start of treatment to 115 g/dl (range 81-147, p<0.001) at completion. the mean starting dose was 0.55 mcg/kg/week (range 0.4-0.9) which was not significantly different to the dose atthe end of the study (0.57 mc/kg/week, range 0.5-2.5). however, there was a significant change in the frequency of administration, with 85% commencing on weekly treatment, but only 25% still on weekly treatment at the end of the study (p<0.001). the most common treatment interval in stable patients was fortnightly (40%) but a significant number tolerated even longer intervals (25% dosed every 3 weeks or longer). injection pain was common, but there were no other significant adverse events. conclusions: darbepoetin alfa is a safe and effective therapy for anaemia associated with kidney disease. the majority of children will maintain satisfactory haemoglobin at a dosing interval of every 2 weeks orgreater. high prevalence (43%) of left ventricular hypertrophy (lvh) and impaired systolic myocardial function in children with mild-to-moderate chronic renal failure (crf) were observed in previous studies (jasn2006, jasn2007). in adult patients with uncomplicated arterial hypertension, lv mass (lvm) exceeding compensatory value for body size and cardiac workload (inappropriate or ilvm) is associated with poor prognosis, independently of lvh. we tested in crf children if increased lvm compensates or exceeds the expected values for individual cardiac load and if ilvm is associated with impaired cardiac function. complete anthropometrics, biochemical profile and doppler echocardiograms were obtained in 24 children (age 11.5±5.2 yrs; gfr 48.7±30.3 ml/min/1.73 m 2 ). ilvm was defined above 109% of the value predicted for individual body size, gender, and stroke work and lvh was defined as lvm/m 2.7 >38 g/m 2.7 . 9 patients showed ilvm. children with ilvm had higher mean age and lower heart rate as compared to patients with appropriate lvm (both p<0.05), without differences in blood pressure, bmi and gfr. after controlling for differences in age, gender distribution and presence of lvh, patients with ilvm showed similar cardiac geometry and diastolic function parameters compared to children with compensatory lvm (p=ns). in contrast, presence of ilvm was associated with lower lv ejection fraction (53.5±3.7% vs 63.0±3.6%) and lower midwall fractional shortening (15.9±1.8% vs 18.6±1.4%)compared to children with compensatory lvm (both p<0.01), indicating impaired lv chamber performance and reduced systolic myocardial function. in conclusion, in 37.5% of children with mild-to-moderate crf, lvm is inappropriately increased for individual cardiac workload and body size. presence of ilvm is associated with reduced systolic function, independently of age, gender and presence of lvh. pediatric nephrology centers were enrolled. age groups of the patients were as follows: 41.9% newborn, 19.7% 2-12 months, 23.7% 13 months -10 years, 14.7% 11-18 years. underlying diseases were prematurity (30.1%), malignancy (10.7), congenital heart diseases (chd, 16.0), urologic disorders (7.3%). low fluid intake was noticed in 35% of cases.50.4% of cases developed arf after they have been hospitalized. time to diagnose arf was longer in the surgery department (4.32±5.01 days) compared to pediatrics (1.12±3.33 days), p<0.05. thirty-nine percent of patients were on mechanical ventilation (mv) before the diagnosis of arf, an additional 6.2% needed mvl after the diagnosis of arf. arf was prerenal, intrinsic and obstructive in 37%, 61% and 2% respectively. hemodialysis and peritoneal dialysis was performed in 9.1% and 21.9% of cases. mortality was 31.8%; and it was secondary to non-arf related causes in 79.5% of cases; presence of mv, intrinsic arf, prematurity, chd, malignancy and being in intensive care unit were poor prognostic factors. conclusion: our nationwide data suggest that nephrologist, intensivist and pediatrician should focus on risk groups to prevent and to diagnose arf earlier. appropriate fluid intake and earlier consultation to a nephrologist are simple but may be effective measures to prevent arf.. hemolytic uremic syndrome is characterized by the triad of hemolytic anemia, acute renal failure, and thrombocytopenia. recent studies have shown that shiga-toxins (st) may stimulate apoptotic cell death in renal tubular cells, but the underlying molecular mechanisms remain to be elucidated. in the present study, confluent llc-pk1 cells were exposed to st and cell death was studied with morphological and biological assay. in llc-pk1 cells st was found to induce apoptotic cell death in a dose-and time-dependent manner. the expression of calpain and bax were significantly up regulated by st, while the expression of bcl-2 was down regulated. cell death was completely inhibited by a specific calpain inhibitor, but not by a broad caspase inhibitor, zvad-fmk, implicating a caspase-independent pathway via calpain. moreover, we found that serum factors could trigger a survival signal against st-induced cell death through pi3k/akt pathway. in conclusion, activation of calpain mediates st-induced renal proximal tubular cell death, and the expression of bcl-2 and bax were oppositely altered. stimulation of pi3k/akt signalling protects cells against death. verocytotoxin (vt)-producing e. coli (vtec) infection represents the main cause of hemolytic uremic syndrome (hus) in children. a nationwide surveillance system of hus was introduced in italy in may 1988 to follow the trend of vtec infections. for each patient, epidemiological and clinical information was collected by a standardized questionnaire. laboratory diagnosis of vtec infection was based on the detection of vtec and free vt in stools and of antibodies to the lipopolysaccharide (lps) of serogroups, o26, o103, o111, o145, and o157 in the sera. the immuno-detection of vt on circulating neutrophils was also performed on some patients. as of december 2005, 481 cases have been notified, accounting for a mean annual incidence of 0.31x100,000 in the 0-14 age group with a significant difference among the regions (from 0.15 to 1.1); median age of patients: 23 months, 53% males. most cases (53%) occured in summer from june to september. seventy-nine per cent of the cases had prodromal symptoms such as bloody diarrhea (26%) and non-bloody diarrhea (51%). five patients (1.0%) died from the disease. stools and/or sera were collected from 380 cases. evidence of vtec infection was observed in 255 cases (67%). the vtec serogroups most commonly detected were o157 (37% of the vtec-positive patients), followed by o26, o145, o111 and o103. the number of cases associated with non-o157 infections increased over time: from 1997 the o26-associated cases are the most frequent. during the surveillance-period 4 epidemic clusters have been registered: 1992-lombardia, 1995-veneto, 1997 and 2005 campania. the role of vesico-ureteral reflux (vur) as a predisposition for acquired renal scarring with urinary tract infections (uti) has been questioned in recent years. few studies have investigated baseline factors associated with chronic nephropathy in severe reflux. we aimed to evaluate dmsa scans in children having any degree of primary vur associated with uti in order to identify variables that are predictors of the presence and/or development of renal scar. data of patients with proven uti who have primary vur were evaluated retrospectively. patients and renal units were classified as scar (+) and scar (-) by dmsa results. the following parameters were assessed with respect to their relation to presence of renal scarring: sex, age at diagnosis, grade (g) of reflux, number of subsequent utis (on new renal scars). there were 138 patients (m/f: 53/85, median age 42 months) and 212 refluxing units. variables increasing the likelihood of scar detection were: male gender (32/53 vs. 35/85, p=0.043; or 2.2), >26 months of age (for girls only; 31/59 vs. 4/26, p=0.003; or 6.1), g iv-v reflux (or 9.1 vs. g i-iii reflux and 23.3 vs. no reflux). all boys having g iv-v reflux and girls over 26 months of age having g iv-v reflux had very high rate of scarring compared to the rest (21/23 vs. 46/115, p=0.0001, or 15.8 and 14/16 vs. 53/122, p=0.002, or 9.1, respectively). however, variables increasing the likelihood of new/progressive scar development were only the presence of previous scar (or 8.3) and uti number >1 (or 3.0). neither uti number nor new/progressive scar development was affected by vur grade. in conclusion, the most predictive variables for the presence of renal scarring among children presenting with a uti were male gender, age (being >26 months; only for females) and grades iv-v reflux, while new/progressive scar development was associated with presence of previous scar and uti number. d. hothi 1 , e. harvey 1 , c. goia 2 , d. geary 1 1 hospital for sick children, department of pediatric nephrology, toronto, canada 2 hospital for sick children, educational, toronto, canada introduction: adequate ultrafiltration (uf) is necessary for good health in dialysis dependent patients. however uf can be hindered by development of intradialytic symptoms and hypotension. objectives: to determine whether sodium ramping, uf profiles and mannitol could improve uf without increasing intradialytic morbidity in children. method: a standardized hd practice was instituted in our unit. we prospectively analysed 506 dialysis treatments from 11 chronic patients with routine scheduled hd, 4hrs x3-4/wk. results: uf volumes between 3.2 to 9.7% of the dry weight were achieved. mannitol reduced the risk of developing intradialytic symptoms by 64% (p<0.05) without altering the risk of hypotension, with a mean uf volume of 6.2% of the dry weight. a linear sodium ramp (148-138mmol/l) increased the odds of intradialytic symptoms (p=0.10) and hypotension (p<0.05), with no difference in the mean uf volume. all uf profiles increased the risk of intradialytic symptoms but the effect was not statistically significant except with profile 2 (stepwise reduction of uf during procedure). achievement of dry weight was least likely with uf profile 2 (p<0.05); there was no statistical difference in the mean uf volume between them all. conclusion: uf volumes higher than the traditional recommendations of 5% of the dry weight can be achieved in children. the use of mannitol increased the uf volumes and reduced symptoms without increased hypotensive episodes. objective: innate immunity and urinary tract response play a central role int he development of urinary tract infection (uti), in which heat shock protein (hsp)70 and toll-like receptor 4 have a key position. patients and methods: hspa1b a(1267)g and tlr4 a(896)g genotypes were determined using allele-specific polymerase chain reaction in 103 patients treated with recurrent urinary infection. allelic prevalence was related to reference values of 235 healthy controls. clinical data were also reviewed and statistically evaluated. results: hspa1b (1267)gg genotype and hspa1b (1267)g allele occurred more frequently in uti patients versus controls (p=0.0001) and both were associated with a higher risk of renal scarring (p=0.012 and 0.049, respectively). tlr4 (896)ag genotype and tlr4 (896) g allele had also higher prevalence among uti patients than controls (p=0.031 and 0.041, respectively). the combination of carrying ag genotype at both sites meant the greatest risk for uti (p=0.05). conclusion: our data indicate an association between the carrier status of hspa1b (1267)g and tlr4 (896) one of the major goal of hemodialysis adequacy is to achieve the fixed endsession body weight, so called dry weight, in order to limit overhydration and thereby cardiovascular risks. the prescribedultrafiltration, can induce hypotensive episodes and thereby limit thedry weight achievement. on line equipments offer the assessment of theblood volume (bv) and its relative variation. the bv is derived fromdirect measurement of the hematocrite. weroutinely use such an equipment (fresenius a 2008 c) over all thesessions since february 2002, conducting to a clinical experience of 7800 bvm curves. these registered curves could be related to thehemodialysis prescription parameters (uf, nad, td, kt/v) to the dryweight, the blood pressure and to the clinical dialytic symptoms. thisexperience conducts us to define the normal bv curve over a sessionand its variations. starting dialysis induces an acute initial (5 to 30 min) decrease of bv, 5 to 8%, mostly asymptomatic: extra corporeal circuit filling; this initialdecrease is a sign of normality. there after the normal bv curve should be flat; uf rate/amount being compensated by the plasma refilling rate: iso osmotic dialysis, no symptoms, no cramps, no hypotension, no vomiting. incase of no bv decrease over the dialysis session, the patient isoverloaded: reduce his dry weight. in case of a decrease of the bvhigher than 10%, there is a hypotensive risk: uf rate/amount, dryweight, sodium dialysate, sodium temperature and kt/v urea (cellular water shift) should be individually adapted conducting to arefilling curve. the effectiveness on the bv of these individual changein dialysis prescription can be directly, on line attested by the bvmcurve: plasma refilling capacity test. the bv changes reactivity is rapid, 5 to 15 min. renalscarring following acute pyelonephritis (apn) in children is a frequentcomplication which may impair renal growth. its pathophysiology includes host response, bacterial virulence, associated malformationand/or renal dysplasia. we prospectively studied virulence factors of e. coli isolates from children with a first episode of apn (fever >38.5 c°, crp >20 mg/l, monomicrobial e. coli positive culture >10*5 cfu/ml). we excluded patients with anyconcomitant infection, renal dysplasia or obstructive uropathy (us examination, renal length <2 sd) or grade 4-5 vur. renal scarring was evaluated by dmsa scan performed 6 to 9 months after apn. 383 patients were included in a multicentre prospective randomized study comparing short vs long i. v. treatment with ceftriaxone as a first line antibiotic treatment [in press]; 161 out of them fulfilled criteria for virulencestudy. six virulence genes were investigated by multiplex pcr (pap, sfa, afa adhesine genes; cnf1, hly toxin genes, aeraerobactin gene) and the k1 capsular antigen was researched by latextest. we identified 21 distinctive virulence profiles; 99% of e. coli strains had one or more virulence factors; 64% expressed the aer genewith at least one adhesin or one cytotoxic factor. renal scars occurredin 18% of cases and low grade (1-2-3) vur was detected in 46%. statistical analysis did not show any correlation between the presenceof scars and e. coli virulence pattern. in addition, scarring was not correlated with the antibiotoc regimen but was correlated with grade 3 vur (p 0.002). most e. colistrains associated with apn in children show several virulence factors, mainly adhesins and cytotoxins, but their profile was not correlated with renal scarring. background: acute lobar nephronia (aln), a severe renal parenchymal inflammatory disease, ranging between acute pyelonephritis (apn) and frank abscess formation, has been diagnosed with increasing frequency due to the advancement of non-invasive diagnostic modalities and the development of systematic diagnostic schemes. e. coli is the most common bacterialpathogen isolated from the urine samples of aln patients and the associated percentage is significantly higher than those among the patients with first time urinary tract infections. this prospective study was conducted to elucidate and differentiate the bacterialvirulence factors associated with aln and apn in pediatric patients. methods: patients included in the present study were those suspected of anupper uti and underwent a systematic scheme of ultrasonographic, ct and tc99m-dmsa evaluation for the differential diagnosis of aln andapn. exclusion criteria were any evidence of underlying diseases orurinary anatomical anomalies except vur. the e. coli isolates from the urine samples of patients were screened with pcr analysis for various urovirulence genes. pulsed-field gelelectrophoresis was used to analyze the genetic association of theisolates. results: a total of 88 patients were enroled. forty-six patients were diagnosed as aln, while the other 42 cases were apn. diverse genotypes were found among the e. coli isolates in either group. among the pathogenetic determinants examined, multivariate logistic regress analysis indicating that a papg ii allele was the only significant urovirulence factor associated with aln (p<0.005; odds ratio, 17.16). conclusions: while no specific genetic lineage was identified among the e. coli isolates studied, a papgii gene was found strongly associated with the cause of aln among pediatric patients without underlying disease other than vur. 0-<21 yr during 1996-2005 were sent to leading paediatric nephrologists of 13 asian countries/regions. those having national renal registry were to use the registry data. results: data from 11 countries/regions were returned (incl. 3 national registries), namely china, hong kong sar, india, indonesia, japan, malaysia, pakistan, philippines, singapore, south korea & thailand. a total of 2275 esrd patients were reported: 772 on peritoneal dialysis (pd), 678 on haemodialysis (hd), & 825 transplant (tx) of 34%, 30% & 36% respectively. chronic pd: capd and automated pd (apd) were the main modes of pd at ratio of 2.6 to 1. only 3 countries had apd morethan capd. peritonitis rate ranged from 1 episode in 3 to 50 patient-months, and seemed less common in those having more apd. chronic hd: hd comprised of 47% chronic dialysis, mostly adolescents. a-v fistula wasused in 76%, and permanent catheter 15% for vascular access. background: current data suggest the role of chronic inflammation and lipid disorders in atherogenesis. the aim of the study was to evaluate established and new markers of atherosclerosis in apd and hd pediatric patients and to assess whether the method of dialysis has an impact on those factors. methods: soluble(s) e-selectin, il-4 and il-12 concentrations were evaluated by elisa in sera of 18 apd patients on, 9 hd patients and 15 controls. hscrp levels were assessed by nephelometry. the lipid profile (total cholesterol (chol), hdl-chol, ldl-chol, triglycerides (tgl)) was also estimated. results: se-selectin concentrations in dialyzed patients were higher than in controls (apd p<0.0001; hd p<0.0001) and in apd were increased vs. hd (p<0.05). there were no differences in median values of il-4, il-12 and hscrp between examined groups. chol levels were increased only in apd vs. controls (p<0.05). hdl-chol concentrations were decreased in all dialyzed patients when compared to controls (apd p<0.0001; hd p<0.01), without difference between apd and hd. ldl-chol in apd and hd were higher than in controls (apd p<0.0001; hd p<0.05), but failed to differentiate between two dialysis modalities. tgl levels behaved in the same way. conclusions: the elevated se-selectin concentrations in all patients show the role of endothelium in atherogenesis in ckd children. thus, the se-selectin augmentation may serve as an early marker of endothelial activation, appearing prior to inflammation (unchanged hscrp, il-4). increased seselectin and cholesterol levels in apd patients prove that children on peritoneal dialysis are more prone to atherosclerosis than those on hemodialysis. background: end-stage renal disease (esrd) is associated with an increased risk of cardiovascular morbidity and mortality. according to recent data, arterial stiffness measured by aortic pulse wave velocity (pwv) and augmentation index (aix) is a strong independent predictor of cardiovascular mortality in adult esrd patients. few studies have been reported regarding arterial stiffness in the paediatric renal population. methods: aortic pwv and aix (difference between the first and the second systolic peaks on the aortic pressure waveform divided by the pulse pressure) were determined in 14 haemodialysis children (10 boys; age 12±4 years) by applanation tonometry using a sphygmocor device. seven of the hd patients (5 boys; age 12±3.5 years) received a renal transplant (tx) and were restudied (6±2 months post tx). the immunosuppressive regimen included basiliximab induction, cyclosporine, mycophenolate mofetil, and steroids. results: in the hd population, aortic pwv (6.3±1.3 m/s) was correlated with age (p=0.019), weight (p=0.036), height (p=0.0036) and systolic blood pressure (p=0.0038). in the transplanted cohort aix decreased in six children out of seven after transplantation (7.57±9.45% on hd versus -6.57±19.7% after tx). no significant change was observed for aortic pwv (6.37±1.18 m/s on hd versus 6.86±1.87 m/s after tx). objective: to study the pathogenic role of host and escherichia coli virulence factors in the development of e. coli febrile urinary tract infection (uti) in children with acute cystitis (ac), acute pyelonephritis (apn) and renal scar. materials and methods: isolates recovered from 125 children consecutively admitted to the hospital with e. coli febrile uti that diagnosed as ac (n=36) or apn (n=89) were retrospectively enrolled into this study. virulence genes of e. coli, that included papg genes (classes i-iii), aer, cnf1, fimh, hlya, afa, sfa/foc, iha, usp, irone and ompt, were detected by polymerase chain reaction analysis. results: young age (=<5 months), male sex were more frequently associated host factors for patients with apn, but old age (>5 months) and female sex were more frequently associated with renal scar formation. after multilogistic regression analysis, with regard to e. coli virulence factors, the papg class ii gene might play a more important role in the development of e. coli apn. however, iha was significantly higher in young children with acute pyelonephritis. afterwards, age, gender, duration of fever before admission, and crp level were considered as potential confounders for the further multivariate analyses, specifically estimating the relative risks of e. coli genotypes to the incidence of acute pyelonephritis and renal scar by age group and the existence of vesicoureteral reflux. odds ratios with 95% confidence intervals for each variable were utilized to estimate the relative risk of acute pyelonephritis and renal scar. in addition, there were no differences between young children and old children, if we excluded the factor of vesicoureteral reflux (vur). conclusion: both host and e. coli virulence factors contribute to the development of febrile uti, apn and renal scar. since 2/06 we have started an acute peritoneal dialysis (duration 1-61 days) in 8 infants (age 7 days to 9 months) with the use of the baxter acute set for children under constant warming of the complete dialysate inflow tract to 37 °c (barkey system). as dialysate solutions we chose a glucose/bicarbonate/lactate solution (physioneal 40) in all patients and in 4 patients a mixture of this solution with a 1.1% amino acid solution (nutrineal) in a 3:1 ratio. the body weight before the renal insufficiency was 1.3 to 5.2 kg. in 5 patients the renal failure followed cardiothoracic surgery. the handling of the system was easy. because of obstruction by omentum and fibinous layers, respectively, the dialysis catheter had to be cleared surgically in 2 patients. body temperature could be kept constant and in the normal range, even with low body weight and intensive dialysis (as measured by dialysate volume per kg body weight and day). in the infants dialyzed with the glucose/amino acid-mixture a decreased loss of albumin through the dialysate (as measured by the necessary intravenous albumin substitution), a better glucose homeostasis (less episodes of hyperglycemia and less need for insulin infusions) as well as a better acid-base control (less episodes of metabolic alkalosis) could be found. the detected tendency to a better homeostasis (concerning body temperature, serum albumin, blood glucose and acid-base) with this dialysis system and the used dialysate solutions could help to increase the survival chances of infants with renal failure. this will be evaluated prospectively. objectives: varicella-zoster-virus (vzv) infection can cause significant morbidity and mortality in the immunocompromised patient. since there is no clear correlation between antibody titers and protection monitoring after vzv vaccination is unclear. patients and methods: serum samples of nineteen pediatric transplant recipients were investigated for vzv igg antibody titers and avidity (elisa test). a relative avidity index (rai) <40% showed evidence for low-avidity antibodies, an rai >60% high-avidity antibodies, borderline avidity inbetween. the control group consisted of 27 healthy children. 22 had suffered from varicella infection after wild-virus contact, 5 had undergone varicella vaccination. as there was no difference between diseased and vaccinated controls both subsets were treated as one group. results: median vzv igg antibody titers were 560 u/ml (range 100-2600) for transplanted children and 790 u/ml (range 50-2300) for control subjects (n. s.). median rai was 83% for transplant patients and 90% for controls (p=0,04). there was no correlation between rai and antibody titers in either group. rai increased significantly with time after vaccination or infection in both groups. despite protective antibody titers after vaccination and an rai of 68% one transplant recipient showed a moderate vzv infection that required antiviral treatment. postinfectious course showed an increase of rai up to nearly 100%. conclusion: vzv igg antibody avidity might be a pathbreaking parameter regarding decision making for a second vaccination before transplantation or preemptive treatment in a transplanted patient in case of exposure. in japan, almost half of children with esrd received renal transplantation and more than 90% of those were living kidney transplants from their parents. burden of esrd during childhood frequently causes psychosocial problems in their families, including parental relationship problems. we investigated how parental divorce or death affected the choice of renal transplantation in children. patients and methods: in 68 children younger than 20 years old who started renal replacement therapy in our hospital, percentages of the children losing a parent or parents by divorce or death were investigated. we compared renal transplantation rates and percentages of fathers as kidney donors between those living with both parents and those without. results: in observation periods (4.2±3.3 years), 43 (63%) received renal transplants from 40 living and 3 deceased donors. nineteen children (28%) lost a parent or parents by divorce (n=16) or death (n=3). in all divorced families, mothers got parental authority. ten parents divorced during ckd period, 2 after start of dialysis, and 4 after transplant. of 49 children living with both parents, 31 (63%) transplanted with kidneys from 9 fathers, 20 mothers, and 2 deceased donors. of 16 children whose parents divorced, 11 (69%) transplanted from 4 fathers (2 just before and 2 after their divorce), 5 mothers and 2 other family members. however, in 3 children at least one parent died, only 1 (33%) transplanted from a deceased donor. conclusion: a high parental divorce rate from ckd period was observed in children with esrd, suggesting burden of the disease on their families. renal transplantation was preferred even in divorced families and divorced fathers still were willing to donate kidneys to their children. objective of study: to determine the importance of gastrointestinal evaluation in pre-transplantation phase in pediatrics with end stage renal disease (esrd). methods: twenty four children with esrd (13 female, 11 male) mean age 14.7 (±3.4) years on maintenance hemodialysis were included in this study. upper gastrointestinal endoscopies were performed and four gastric antral and duodenal biopsy specimens were obtained for urease test and histological study for all patients. serum gastrin levels were measured in all patients, too. a control group was chosen to compare the rate of h. pylori infection using student's t. test. results: gastrointestinal symptoms were present in 16 (67%) of 24 patients. seventeen (71%) patients had abnormal upper gastrointestinal endoscopic findings. h. pylori was detected in 66% of patients and 20% in control group (p<0.001). in symptomatic patients 75% had abnormal endoscopic findings and 63% had positive urease test for h. pylori infection. while, in asymptomatic cases these rates were 30% and 75%, respectively. seventy one percent of patients with gastrointestinal lesions and 50% of patients with normal endoscopic examination were infected. high serum gastrin levels in infected and non-infected patients were detected in 75% and 12.5%, respectively (p<0.001). conclusion: we demonstrated a significant number of patients with peptic ulcer diseases and h. pylori infection and secondary hypergastrinemia. this study showed that, clinical symptoms are not a reliable predictor of gastrointestinal problems. our results emphasize the importance of periodic, and also pre-transplant gastrointestinal evaluation in these patients to find out their problem and manage appropriately. key words: renal failure, hemodialysis, peptic ulcer disease, helicobacter pylori, hypergastrinemia. background: preservation of a stable allograft function in children following renal transplantation (rtx) depends on various factors including genetic variability. the gene of the angiotensin i converting enzyme (ace) has been shown to influence allograft function. we therefore analysed various polymorphisms of the renin-angiotensin system in 91 children following rtx and 32 kidney donors and associated genotypes with loss of renal function. patients and methods: 91 children and adolescents (60 male, 31 female, mean age at transplantation 9.7±5.2 years) with stable renal function and observation period exceeding 6 months were included. mean follow-up time was 5.4 years (0.5 to 16 years). dna was extracted from all recipients and 32 donors and genotyped using rflp. the following polymorphisms were studied: renin 18 g/a; ace i/d; angiotensinogen (agt) 235 met/thr and angiotensin ii receptor type-1 (at1r) 1166 a/c. the slope of glomerular filtration rate (gfr) was determined by linear regression analysis and correlated with the genotype. results: allelic frequencies were not different from healthy controls. genotypes of renin, agt and at1r showed no significant association with the slope of gfr but patients homozygous for the ace-d-allele had a significantly steeper decline of gfr when compared to homozygous carriers of the ace-i-allele (slope dd: -4.3±0.8 vs. ii: -1.3±1.1; p=0.035). the dd-genotype was also present in 11 out of 32 donors and in four cases a dd-recipient received a kidney from a dd-donor. those four patients showed a more pronounced decline of gfr (-5.2±0.5; p=0.002 ). in addition, dd-recipients had a significantly increased systolic and diastolic blood pressure before rtx. conclusions: the dd-genotype is associated with a faster, non-immunological loss of graft function which has to be evaluated in prospective studies. year large single-center review b. warshaw, l. hymes, l. greenbaum, s. amaral from1995-2006, 207 children received renal transplants at emory university/children's healthcare of atlanta of whom 29 (14%) had nephroticsyndrome (ns) as their primary diagnosis (27 fsgs, 2 minimal change). all children received calcineurin-based immunosuppression. thirteen children (45%) developed recurrent ns within the first week post-transplant and received plasmapheresis (pp) 3-5 times weekly. nine (70%) had complete resolution of proteinuria. two who responded to pp suffered graft loss fromlate recurrences of ns at 7 years. ns did not resolve with pp in 4 children who suffered either delayed function (1) or early cessationof function (3); each of the latter lost their grafts within the first 3 months. 16 patients did not have recurrences of ns. comparison of these 2 groups showed significantly increased riskfor recurrence with younger patient age (p<0.006), interval <3 years from onset of ns to esrd (p<0.02), and living donor source (7/9=78% ld vs 6/20=30% dd; p<0.02). no differences were seenfor hla match, donor age, gender, or african american race. actuarial graft survival for children with recurrence was 70% at1 year and 60% at 2 years vs. 100% & 92% for patients without recurrence. conclusions: ns recurred in 45% of children with ns as their primary cause of esrd. risk factors for recurrence included younger age, interval <3 years from onset of ns to esrd, and living donors. most recurrences responded to pp (70%); failure to respond was associated with delayed or early cessation ofrenal function & early graft loss. the incidence of recurrence was strikingly high (78%) among living donor recipients, suggesting a need to explore prophylactic strategies such as preemptive pp in this group. methods: a single-centre retrospective case-controlled study including 24 children <3 yr (g1) and 24 matched kidney tx recipients older than 3 yr ofage (g2). patients were matched for donor type and tx period. kaplan-meier method was used for patient and graft survival. results: 23 tx were performed using deceased donors in both groups. median recipient age, weight and height at tx in g1 were 1.5 [0.6-2.7] yr, 9.1 [5.6-11.1] kg and 74.8 [64.5-87.0] cm, respectively, while median age in g2 was 11.2 [3.3-17.2] yr. hypoplasia-dysplasia wasmore frequent in g1 (42 vs 21%). median hla-dr mismatch, time ondialysis and number of blood transfusion before tx were not different. in g1, kidneys were placed intraperitoneally and most of vascular anastomoses were done on distal aorta (83%) and inferior vena cava (88%). median follow-up was 8.7 [0.02-15.9] yr and 6.5 [0.3-15 .6] yr ing1 and g2, respectively. patient survival was 94% at 5 yr and 88% at 10yr in g1; 3 patients died in g1 (2 ptld, 1 recurrence of primary disease), none in g2. fiveyear graft survival was 79% in g1 and 77% in g2. acuterejection episodes occurred in 46% in g1 and in 67% in g2 (p 0.15 ). chronic rejection led to 3 late graft losses in g2 (5.2 to 6.9 yrafter tx) vs 0 in g1. renal function did not differ between the 2 groups during the first 5 yr post tx. the average height gain was better in g1 at 5 yr post tx (+1.3 sds vs. -0.1). primary disease recurrence was observed in 4 cases (1 in g1) causing graft lossin 3 cases. two arterial thromboses were observed in g1 causing 1 earlygraft-loss. conclusion: the outcome after cadaveric kidney transplantation is as good in children under 3 yr of age at transplantation as in older recipients in our experience. c. garcia, v. bittencourt, d. malheiros, a. tumelero, j. antonello, a. oliveira, v. garcia cancer is an increasingly recognized problem associated with immunosuppression. recent reports, however, suggest that sirolimus (srl) has anti-cancer properties that could address this problem. aim: to report a retrospective analysis of preliminary results of 6 patients who received srl because of post-transplant de novo malignancies in a consecutive cohort of 348 pediatric kidney recipients. patient and methods: we retrospectively evaluated the efficacy and safety of srl in 6 pediatric renal transplantation recipients, who were 12±7 years when converted to srl. the 6 post-transplant de novo malignancies were: gall bladder and hepatic leiomyoma (n=1), wilms tumor in the native kidney (n=2), ptld (n=2) and hpv-associated neoplasia. the immunossupressive regimen at the malignancy diagnosis was tacrolimus/cyclosporin, mmf/azathioprin and prednisone. all were converted to double immunossupression with sirolimus at a standard dose of 2mg/day (tl5-10ng/ml) and prednisone. patients with ptld were also treated with rituximab, and the patients with wilms tumor received chemotherapy. mean follow-up after srl conversion is 35±25 months. results: all patients were maintained with srl and pred without rejection, with good renal function and no cancer recurrence (follow-up 6 to 75 months). the patients with wilms tumor are still on chemotherapy. follow-up control after srl conversion in the 6 patients: conclusion: although the intraperitoneal group had characteristics associated with increased surgical risk (they tended to be younger and smaller, with a higher incidence of aortic anastomoses and a higher incidence of multiple vessels), surgical complications were significantly lower than expected in the extraperitoneal group 7% v. 33%. objective of study: proteinuria is a frequent complication in adult patients after renal transplantation (r-tx) and is associated with poor graft survival. in children, there are no studies focusing primarily on proteinuria after r-tx. the aim of this study was to investigate the prevalence of proteinuria in children after r-tx and to evaluate changes of proteinuria during a 2-yr study on intensified antihypertensive therapy. methods: protein excretion was measured in 24-hr urine and proteinuria defined as >96 mg/m 2 /day. proteinuria was investigated at baseline, 1 and 2 years after intensifying of the antihypertensive therapy in children with uncontrolled hypertension at baseline (i. e. additional antihypertensive drugs given to children with blood pressure >95. pc). 33 children (13.7±4.3 yrs) out of 45 from our center fulfilled inclusion criterias (>6 months after r-tx, no acute rejection (ar) in the last 3 months, no recurrent fsgs). results: the prevalence of proteinuria was 82% at baseline, 76% after 1 year (ns) and it decreased to 52% after 2 years (p<0.05). the mean protein excretion was 256±303 mg/m 2 /day at baseline, 224±208 after 1 year (ns) and it decreased to 134±88 after 2 years (p<0.01). mean number of antihypertensive drugs increased from 2.1±0.9 drugs/patient to 2.7±0.8 after 2 years (p<0.01). mean nighttime bp decreased significantly after 2 years. the number of patients on ace-inhibitors increased from 19% at baseline to 39% after 2 years (p<0.05). conclusions: this is the first study on proteinuria in children after r-tx. it showed that proteinuria is a frequent finding in transplanted children and that intensified long-term antihypertensive treatment using ace-inhibitors can decrease not only bp but also proteinuria in these patients. allograftrejection involves t cell activation and proliferation and multipleinflammatory components. monocyte chemotactic peptide-1 (mcp-1) is achemoattractant and activating factor for monocytes. interleukin-6 (il-6) may contribute to monocyte recruitment, results intubulointerstitial damage. cytotoxic lymphocytes induce target cell death by ligation of the fas-fasligand. allelic polymorphisms in recipient genes coding for them reported to beassociated with variations of outcome in renal transplantation. the aim was to investigate impact of mcp-1 -2518 a/g and il6-174 g/c, fas-670 a/g polymorphisms on acute allograft rejection (ar). there were 20 males and 27 females, 19±4.6 years meanly; 21 of the graftscame from living-related donors, 26 were from cadavers. the controlgroup consisted of 150 unrelated, healthy individuals with similar ageand sex. ar group was composed by 17 patients experienced at least one ar episode within the first 6 months of transplantation. the non ar group was comprised by 30 kidney transplant patients without ar. there was no significant difference between renal transplant patients and healthy controls in genotype distribution of allelic frequencies of il-6, fas and mcp-1 polymorphisms. while il-6 and fas gene polymorphisms had no effect on the incidence of ar episodes, there was significant association with mcp-1. the distribution of the genotypes for mcp-1 -2518 a/g in ar group were aa/ag/gg 23, 6%, 64, 7%, 11, 7% respectively. the distribution of the genotypes for mcp-1 -2518 a/g was aa/ag/gg 60%, 30%, 10% in nonar group respectively. the carriage of g allele at -2518 position of mcp-1 gene has a significant association with ar (or: 4, 87, 95%, ci: 1, 27-18, 5). the il-6 and fas gene polymorphisms had no effect on the incidence of ar. mcp-1 -2518 g allele carriage increases the ar risk in turkish renal transplant patients. the high recurrence rate of focal segmental glomerulosclerosis (fsgs) in transplanted kidney recipients suggests the hypothesis that such patients have a circulating factor that changes glomerular capillary permeability. serum from patients with fsgs increases glomerular permeability to albumin, and this permeability factor was partially identified as a protein. the removal of this protein by plasmapheresis (pp) decreases proteinuria. object: the aim of this paper is to provide data about the therapeutic effect of pp in fsgs children with recurrence in the transplanted kidney. methods and results: twenty eight pediatric kidney transplant recipients had fsgs as cause of renal failure from 1990 to 2007 in our center, confirmed by biopsy pre-transplant. seventeen of these (60.7%) had a recurrence (proteinuria >1 g/m 2 per day associated with hypoalbuminemia). the mean age was 12±4.3 years, 85, 7% were caucasians and 67, 8% were performed with living donor. since 2001, patients who presented fsgs recurrence were treated with 10 cycles of pp (3 cycles/weekly), initiated immediately post-recurrence (n=11). immunosuppression comprised of cyclosporin in high doses (c 2 levels of 1700-1800 ng/ml) or tacrolimus (tl=10 mg/dl), mycophenolate sodium or mofetil (until 1997 azathioprine was used) and prednisone. among patients who received pp (n=11), 7 (63.6%) achieved a complete remission. there were no cases of remission among those six patients who were not treated with pp. those who achieved remission after pp had no recurrence. the patients treated with pp had infectious complications: one patient had cytomegalovirus disease and two patients had varicella. conclusion: pp appears to be effective in treating recurrent fsgs following kidney transplantation. it should be started as soon as possible. because the calcineurin inhibitors (cni) cyclosporin a (csa) and tacrolimus (tac) are drugs with a narrow therapeutic index, individualization of cni dosage by therapeutic drug monitoring is indisputable. however, the optimal strategy for monitoring cni therapy is currently under debate. dosing of cnis according to the molecular effect of the drug on its target cells could optimize immunosuppressive therapy with cnis. for this purpose, we developed a reliable, precise, and robust whole blood assay based on the measurement of the expression of three nfat-regulated genes (il-2, ifng and gm-csf) in pma/ionomycin-stimulated lymphocytes before and 1.5 (tac, c 1.5 ) or 2 hrs (csa, c 2 ) after oral drug intake. the inhibition of genes in this assay is independent from other commonly used immunosuppressive drugs and reflects calcineurin inhibition expressed as residual nfat activity. in a pilot study, 40 patients (mean age 14 yrs, mean time period posttransplant 42 mo.) were analyzed. in csa-treated patients (n=12), a mean c 2 concentration of 380 ng/ml (range, 180-900 ng/ml) corresponded to a mean residual nfat-activity of 32% (range, 3-115%) ; the correlation between individual residual nfat-activity and c 2 was moderate (r=0, 59, p<0.05). at a csa-c 2 of 400 ng/ml, the residual nfat-activity varied between 8% and 25%. in tactreated patients (n=28), a mean c 1.5 concentration of 18 ng/ml (range, 6-54 ng/ml) corresponded to a mean residual nfat-activity of 40% (range, 7-70%); the correlation between individual residual nfat-activity and c 1.5 was also only moderate (r=0, 60, p<0.05). conclusion: these data indicate that there is a considerable inter-patient variability of residual nfat-activity at a given maximal cni blood concentration. ongoing studies are validating this assay regarding clinical outcome criteria of immunosuppression such as acute rejection and infections. hus due to antibodies against factor h (husafhab) is a very rare disease for which a limited experience in its management is available. we present a case of husafhab who was transplanted but lost her graft after only 4 mos. in aug 2002 a 5-mos old child was admitted for a d-hus which did not go into remission and required chronic peritoneal dialysis. no fh and mcp gene mutation were detected nor adamst-13 activity was decreased. afhab were not searched at that time. in apr. 06 the child underwent cadaver renal transplant (rtx). the immunosuppressive regimen was basiliximab-prednisone-cyclosporine-mycophenolate mofetil. fifteen days after rtx, following surgery for urinoma, the child exhibited an hus relapse with thrombocytopenia, haemolytic anemia and increased serum creatinine (scr). high afhab were detected (2400 au/ml). four plasma exchanges (pe) were performed over 2 wks with a drop of afhab to control level (196 au/ml) and a remission of hus. until the end of aug, afhab remained low (<400 au/ml) and the child was well (scr range: 0.6-1.2 mg/dl). in early aug, the patient was shifted to tacrolimus for severe hypertrichosis with a fluctuation of its plasma level (lower recorded value: 1.4 ng/ml) signs of acute rejection developed and 4 metilprednisolone (mtp) pulses brought scr to baseline level. in oct. 06, following an urti, the child presented with severe proteinuria (upr/ucr: 15, 6) without other clear signs of hus recurrence. since afhab were increased (849 au/ml), pe was restarted but an acute hemorrhagic complication (hemotorax) occurred and pe had to be interrupted. septicemia followed and the child became anuric. the renal biopsy performed 3 days later showed signs of glomerular and vascular thrombotic microangiopathy. renal function did not recover despite mtp pulses and 4 pe. in nov the child was back to pd and in dec the graft was removed. background & aims: recently, the role of nitric oxide (no) in the pathogenesis of idiopathic nephrotic syndrome (ins) has been intensively investigated. however, its rapid turnover has made us impossible to investigate the quantity and the source. as we have developed a novel method for quantitative analysis for no by a new fluorescent indicator, 4, 5-diaminofluorescein (daf-2), its amount produced by both t and b lymphocytes in ins was studied. methods: five children with steroid-sensitive ins (mean age: 4.0 y) were included in this study, together with 7 children with other renal diseases (mean age: 5.0 y) such as chronic glumerulonephritis and alport syndrome with significant amount of proteinuria, and 10 healthy adults (mean age: 28.0 y) for the control. no production from cd3+ cell and cd19+ cell was investigated by a flow cytometry using daf-2. results were expressed as mean fluorescence intensity and were compared among the groups. results: the amount of no produced by cd3+ cell and cd19+ cell in children with ins was significantly greater than those in children with other renal diseases and healthy adults (cd3+ cell: 57.5±6.8 [mean±sd], 27.6±7.0, and 21.7±2.1, respectively; cd19+ cell: 35.7±3.5, 24.9±3.9, and 18.9±2.3, respectively, p<0.05). additionally, both cd3+ cell and cd19+ cell during nephrotic relapse produced more no than in nephrotic remission (p<0.05). discussion: patients with relapsing ins showed increased production of no by both t and b lymphocyte. these findings indicate that no plays some role in the pathogenesis of ins and suggest that an abnormal immune system may exist not only in t but also in b lymphocytes. a. bagga, a. sinha, s. menon, p. hari aim: the treatment of patients with srns is challenging. based on suggestions that b-lymphocytes are crucial in the pathogenesis of nephrotic syndrome, we examined the efficacy of rituximab (rtx) in patients with srns refractory to standard therapies. methods: six patients (4 with initial, 2 late resistance), 3-16 yr old, were included; biopsy showed minimal change & focal segmental glomerulosclerosis in 3 each. all had previously received iv high-dose steroids, alkylating agents & calcineurin inhibitors (cni) for 2-14 yr with periods of partial (pr; urine 1-2+) or complete remission (cr; urine trace/negative). all now had srns refractory to 6-months treatment with cni. rtx (375 mg/sq. m) was infused iv every week for 4 weeks. therapy with cni and/or alternate-day prednisolone, & cotrimoxazole prophylaxis was continued. patients were monitored for proteinuria and renal functions. results: at a median interval of 4 wk following the last rtx dose, cr was seen in 4 & pr in 2 patients. remission was sustained in 4 patients, despite tapering doses of steroids & cni. one case had relapse of nephrotic syndrome 6-months later, which responded to steroid treatment. at median follow-up of 28 wk, cr, pr and recurrence of nephrotic proteinuria (3-4+) were seen in 3, 2 and 1 patients respectively. mean urine albumin-to-creatinine ratio was 8.9 at baseline and 0.9 at followup; respective blood levels of albumin were 1.4 and 3.7 g/dl & cholesterol 481 and 221 mg/dl (all p<0.01, anova); difference in leukocyte counts and levels of igg were not significant and none had serious infections. conclusions: this is the first report on the efficiacy of rtx in sustaining remission in patients with srns. therapy with this agent appears promising for difficult srns, with a better risk/benefit profile than other medications. quantitative or functional deficiency of factor h results in uncontrolled complement activation and is an important cause of familial hemolytic uremic syndrome (ahus). factor h-related proteins (fhr) constitute a protein family which share structural and most likely functional similarities to factor h. we here describe complete deficiency of fhr-1/-3 as novel cause of ahus. factor h and fhr-1/-3 were quantified by elisa and were further analyzed by western blot using specific antibodies. complement activation was determined by measuring c3 and c4. serial hgb (g/dl), platelet, creatinine (mg/dl), and ldh (u/l) were measured. a 12 year old girl presented with a 5 day history of lethargy, pallor, vomiting and hypertension. hgb was 6 g/dl, platelets 40x10 9 /l and creatinine was 6.8 mg/dl. initial therapy consisted of packed red cell and platelet transfusion, followed by steroid therapy. representation occurred 7 weeks later with hypertension, edema, persistent anemia thrombocytopenia and renal dysfunction (creatinine 4.5 mg/dl). renal biopsy demonstrated features of chronic thrombotic microangiopathy. low c3 levels indicated activation of the complement system. while western blot analysis showed normal factor h level, fhr-1/-3 was absent. by repetitive plasma infusion and plasmapheresis, the cycle of hemolysis and thrombocytopenia could be disrupted. chronic periodical plasma infusion q 14 days resulted in regression of renal impairment to a degree (current baseline creatinine 1.5 mg/dl). in conclusion, fhr-1/-3 are thought to have co-factor activity and play a role in complement activation in ahus. deficiency of fhr-1/-3 may lead to a subclinical form of ahus such that patients may initially present with features of chronic renal failure. however, factor replacement therapy may lead to regression of renal impairment. s. choudhry objectives of the study: the aim of the study is to investigate the long term prognosis ofsevere childhood iga nephropathy after 2 years combined therapy. patients: we examined 39 patients who had entered thejapanese pediatric iga nephropathy treatment study group between 1990and 1994, had been treated with 2 years combined therapy (combinationof prednisolone, azathioprine, dipyridamole and heparin/warfarin) andhad been followed for more than 3 years after the therapy. significantproteinuria is defined as more than 0.2g/m 2 /day. results: mean age at onset was 11.4 years (4-16 years), proteinuria at diagnosis was 1.11±0.84 g/m 2 /day, proteinuria after the combined therapy was 0.17±0.22g/m 2 /day and mean follow-up period after the combined therapy was 7.2 years (3.2-9.9 years). proteinuria improved in all patients during thecombined therapy (p<0.0001). the final prognoses were as follows: 21 patients (54%) showed no proteinuria, 15 (38%) showed proteinuria withnormal renal function and 3 (8%) proteinuria with decreased renalfunction. we compared the clinical and pathological parameters betweenpatients with proteinuria (n=18) and those without proteinuria (n=21) at the last observation. period between disease onset and start of treatment, glomeruli showing crescents before the combined therapy (%) and glomeruli showing pathological changes after the combined therapy (%) were the significant risk factors for the proteinuria at the last observation. logistic multivariable analysis revealed that glomeruli showing pathological changes after the combined therapy (%) was theonly independent risk factor for the proteinuria at the last observation. conclusions: pathological activity of nephritis at the end of the combined therapy might correlate well with the final proteinuria and the long term prognosis. s. arun, a. bagga, s. bhatnagar, p. hari, s. menon, s. saini aim: relapses in ssns of ten follow minor infections and are associated with perturbed t-cell function. based on data that zn supplements modulate t-cell function and reduce risk of infections, we examined its efficacy in reducing relapses in patients with ssns. methods: in this double blind rct, 81 consecutive patients with ssns 1-16 yr old, stratified into frequent (fr=52) and infrequent (ifr=29) relapsers, were randomized to 12-months therapy with zn (10 mg daily) or placebo. patients with fr also received long-term, alternate day prednisone. relapse and infection rates were monitored monthly. blood levels of zn, sil2r, il4 and interferon (ifn) were measured at baseline, relapse andend of study. results: patientsin the zn (n=40) and placebo (n=41) groups had similar baseline clinical & laboratory features. the former showed 20% lower frequency of relapses (difference in means -0.2; 95% ci -0.7, 0.3) with trend towards reduction from 6-months onward. a higher proportion (44.7%) of patients in the zn group had sustained remission compared toplacebo (27.5%). reduction in relapse rates was higher in fr receiving zn vs. placebo (-0.3; ci -0.9, 0.3); respective sustained remission was seen in 46% and 16% patients (relative risk 0.5; ci 0.3, 0.9; p 0.02). no differences were found in infection rates, and levels of zn, sil2r & il4; levels of ifn were higher in those receiving zn compared to placebo (p=0.02). conclusions: zn supplementation for 1-yr was effective in maintaining remission and reducing relapse rates. the effect was mediated not by reducing infections but perhaps through effect on th1 cytokines. while zn therapy appears promising, these results need confirmation in patients with frequent relapses and perhaps at a higher dose. background: n-glycosylation process in the endoplasmic reticulum (er) is tightly regulated and orchestrated by many factors such as chaperones and energy systems. we showed that adequate nglycosylation is crucial for nephrin to assemble to the plasma membrane (jasn, 2002) . additionally we recently demonstrated that the er stress evoked by glucose starvation induces hypoglycosylated nephrin retained in the er, which is rescued by dexamethasone (dex) (ki, 2006) and immunosuppresant: mizoribine (mzr) (submitting). in the present study, we tested whether other er stress inducer, hypoxia, could also interfere the alteration of nephrin n-glycosylation system and whether dex and immunosuppressants rescue its defective process. methods: nephrin-expressing cell line was cultured either in 21% o 2 or 1% o 2 for 24 hours in the presence or absence of dex, mzr and cyclosporin a (csa), followed by western blot analysis with nephrin, cytochrome c. intracellular atp concentrations were measured by the highperformance liquid chromatography. protein expression of cyclophilin d (cyp-d), a component of mitochondrial permeability transition pore (mptp), was tested in the samples from human glomeruli and cultured podocyte. results: hypoxia induced hypoglycosylated nephrin. csa, but not dex and mzr, inhibited the formation of this hypoglycosylated nephrin and rescued mature form. csa inhibited the increase of cytochrome c in the cytoplasm caused by hypoxia. in addition, csa partially rescued the decrease of intracellular atp. cyp-d was distinctly observed in human glomeruli and located in podocytes. conclusion: csa inhibit the formation of hypoxia-induced hypoglycosylated nephrin through protecting the mptp opening via selectively binding to cyp-d in the mitochondria, resulting in a recovery of atp. csa may exert direct action on the alteration of nephrin biogenesis induced by the er stress. background and objectives: in two previous randomized controlled trials (rcts) we showed that treatment of severe childhood iga nephropathy (iga-n) with diffuse mesangial proliferation using prednisolone, azathioprine, heparin-warfarin, and dipyridamole reduced immunologic renal injury and prevented any increase of sclerosed glomeruli. in one of the two rcts we also showed that treatment with prednisolone alone did not prevent a further increase of sclerosed glomeruli. accordingly, the immunosuppressant is considered to play an important role in the combination therapy. often however, we were unable to complete the azathioprine regimen due to its severe side effects. therefore we considered that a different, but effective immunosuppressant would be worth trying. mizoribine, like azathioprine, is an antimetabolite that exerts its immunosuppressant effect by inhibiting lymphocyte proliferation. design, setting, participants, and measurements: in this pilot study, we administered mizoribine instead of azathioprine as part of the combination therapy for treatment of 23 children with severe iga-n and evaluated the efficacy and safety of the regimen. results: eighteen patients reached the primary endpoint (urinary protein/creatinine ratio <0.2) during the two-year treatment period. the cumulative disappearance rate of proteinuria determined by the kaplan-meier method was 80.4%. mean urinary protein excretion was reduced from 1.86 g/m 2 /day to 0.20 g/m 2 /day (p<0.0001). after treatment, the mean percentage of glomeruli showing sclerosis was unchanged in comparison with that before treatment. no patients required a change of treatment due to side effects. the efficacy and safety of the mizoribine combination seems to be acceptable for treatment of children with severe iga-n. objectives of study: alport syndrome is a hereditary renal disease which is normally diagnosed by either histopathological studies or a genetical analysis. we attempted to diagnose alport syndrome by means of immunofluorescence staining of cultured cells with collagen type 4 alpha chains obtained from voided human urine specimens. methods: the cells were cultured from the voided human urine of 1 patient with x-linked alport syndrome, 1 patient with sporadic alport syndrome, and 1 patient with autosomal-dominant alport syndrome. for comparison purposes, controls cells were cultured from the voided human urine of 1 patient with iga nephropathy, 1 patient with fsgs, and 1 patient with purpura nephritis. the cultured cells were stained by immunofluorescence techniques with collagen type 4 alpha 1, 2, 3, 4, and 5 chains. results: in the cultured cells of the controls staining for collagen type 4 alpha 1 and 2 chains were observed both in the extracellular matrix and in the cytoplasm while for the staining of collagen type 4 alpha 3, 4, and 5 chains were observed in the cytoplasm. in cultured cells of xlinked and sporadic alport syndrome staining of collagen type 4 alpha 5 chain was lost or attenuated. in the cultured cells of autosomal-dominant alport syndrome the staining patterns of collagen type 4 alpha 3, 4, and 5 chains were observed. the staining patterns of the collagen type 4 alpha 5 chain in cultured cells of alport syndrome correlated with that observed in renal biopsies obtained from alport syndrome patients as reported previously. hence, the staining of cultured cells with the collagen type 4 alpha 5 chain obtained from voided human urine may therefore be a potentially useful means of diagnosing alport syndrome in a non-invasive manner. the aim of our study: was to examine zeta chain expression in cd4+, cd8+ t cells and nk cells from ins children in active phase of the disease and in remission and to assess the effect of 24 h and 72 h anti-cd3 + ril-2 stimulation on zeta chain expression. we enrolled 11 ins children in relapse before initiating the therapy, 12 ins children in complete remission of proteinuria on prednisone for 2-4 weeks (2mg/kgbw/d) and 15 age-matched controls. zeta expression was determined by flow cytometry as mean fluorescence intensity (mfi). results: cd4+cells: mfi in relapse was higher than in remission and in controls. anti-cd3 + ril-2 stimulation had no impact on zeta expression in acute phase and in cotrols, but increased mfi values after 72h in pts with remission. cd8+cells: zeta expression stayed unchanged irrespective of the examined group or antibody stimulation. nk cells: there were no differences between mfi values before stimulation and in relapse after stimulation. in remission and in controls antibody stimulation decreased zeta expression. in controls, mfi values for nk cells were higher than those for cd4+ and cd8+ populations, but this preponderance disappeared after 72h stimulation. in remission, that nk cell predominance vanished after 24 h stimulation. in relapse, mfi values in all cells were comparable and stimulation had no impact on lymphocyte proportions. urinary protein, creatinine, and scd80 were measured. scd80 was measured using a elisa kit. scd80 was expressed as ng/g of urine creatinine. data were analyzed using anova and spearman rank correlation (src) tests. 1) scd80 urinary concentrations in patients with mlns in relapse were higher than patients in remission, healthy controls and other patients with proteinuria (anova p 0.0001) but similar to those seen in sle. 2) in patients with mlns relapse, scd80 concentration did not correlate with urine protein/creatinine ratio (src, r: 0.1719, p: 0.297) 3) in 3 patients with mlns, serial urine scd80 concentrations were measured over a period a time. scd80 was increased at the time of relapse and decreased toward normal range weeks before patients went into remission. conclusion: urinary scd80 is elevated in mlns patients in relapse. this increased urinary concentration is not due to the proteinuria, since scd80 was not elevated in other patients with glomerulopathies and proteinuria. upregulation of podocyte scd80 during relapse may play a role in the pathogenesis of proteinuria in mlns. aim: patients with mpgn type ii/dense deposit disease (ddd) and atypical haemolytic uremic syndrome (ahus) secondary to defective complement control are found to have a high prevalence of y402h polymorphism of factor h gene (cfh), which is linked to age-related macular degeneration (amd). however, no studies have looked into an ocular phenotype of children with complement based renal diseases, yet. methods: in two pediatric nephrology centres all patients with mpgn ii/ddd and ahus were identified and screened prospectively for the presence of y402h polymorphism and drusen maculopathy. all patients have been on immunomodulatory therapy at the time of screening. results: four children were identified (male:female=3:1) with mpgn ii/ddd and ahus. there were two children in either group. the median (range) age at examination was 8.6 years (3.5 to 13.3 years). of the four patients, all were found to have the y402h polymorphism. none of the patients had evidence of drusen at the time of examination. two patients with mpgn ii/ddd and one patient with ahus had additional factor h mutations, which were thought to be responsible for the renal disease. conclusion: in our study of children with mpgn ii/ddd and ahus we found a 100% prevalence of the y402h polymorphism of factor h gene, which puts these patients at higher risk for drusen maculopathy. therefore, all children with either mpgn ii/ddd or ahus should be screened for y402h polymorphism; and if found positive have regular follow-up ophthalmologic examination. in the future, should y402h be proven to be of functional significance with respect to complement control, there would be a role for plasma infusion or replacement of purified factor h for the treatment of both the renal and the ocular phenotype. we previously demonstrated that angiotensin-(1-7) is an endogenous ligand for the g-protein coupled receptor mas. the aim of this study was to evaluate the role of angiotensin-(1-7) mas receptor in kidney structure and function by using transgenic mice with genetic deletion of the receptor mas. mas -/-(knockout) mice were compared to mas +/+ (wild type) mice regarding renal function parameters and kidney histology. the animals were housed in metabolic cages to obtain 24-hour urine samples for measuring urinary volume, osmolality and microalbuminuria. at the end of the experiment, mas -/-and mas +/+ mice were sacrificed by decapitation to harvest the kidneys for histological analysis and immunofluorescence of collagen types iii and iv. the quantification of collagen expression was determined by confocal microscopy (zeiss lsm510). urinary volume was significantly reduced in mas -/-mice as compared to mas +/+ animals (1.32±0.49 vs. 1.80±0.83 ml/24 hs in mas +/+ mice, p<0.05). this change was associated with an increase in urinary osmolality (3846±796 vs. 3219±840 mosm/kg in mas +/+ mice, p<0.05) and albumin excretion (0.23±0.16 vs. 0.04±0.02 mg/24 hs in mas +/+ mice, p<0.05). the histological analysis showed a significant reduction in the glomerular diameter in mas -/-mice as compared to mas +/+ animals (51.84±0.73 vs. 58.25±0.79 μm in mas +/+ mice, p<0.05), where as any significant change was observed in tubular diameter. the immunofluorescence of mas -/-kidneys revealed a marked increase of the expression of collagen types iii and iv in periglomerular region as well as in external and internal medulla. collagen iv was also augmented in mesangial area of mas -/-mice. these results suggest that the receptor mas is critical for the regulation of renal structure and function. a circadian rhythm in calciuria is evident with a peak after 18:00 h, a lower excretion overnight and a nadir in the early morning. during the peak period both ca/creat ratio (figure) and calcium output frequently surpass the reference values of 0.21mg/mg and 4 mg/kg/day respectively. conclusion: a significant circadian variation in calciuria is evident in normal school age children, with peaks surpassing commonly used reference values for hypercalciuria. this peak excretion is independent from urine output, glomerular filtration and intake. the average 24 h excretion of 4 mg/kg is rarely surpassed despite this peaks. the management of children with secondary hyperparathyroidism is complicated and should start early in the course of renal insufficiency. in spite of an optimal management hyperparathyroidism is sometimes uncontrolled and calcimimetics like cinacalcet hydrochloride which directly stimulates calcium sensing receptors and potently suppress pth secretion are an alternative to parathyroidectomy. they are very promising agents, but paediatric experience is lacking. a 11 years old girl with a bardet biedl syndrome without medical care came last year with end stage renal failure. thanks to daily hemodialysis, serum phosphate level was kept within normal limits and phospho-calcic product remains below 4.4 as recommended. in spite of this treatment, serum pth level increased to 1297 ng/l. this toxic hyperparathyroidism with optimal monitoring of serum calcium, phosphate, vitamin d levels led us to start calcimimetics. a 1,5 mg/kg cinacalcet dose was administrated and induced a decline of pth level to 684 ng/l one month later. a 11 years old boy with recessive polycystosis and chronic renal failure was treated with calciumbased phosphate binders and sevelamer hydrochloride but with a poor compliance and a free diet which led him to hyperparathyroidism (pth to 813 ng/l). in addition, a parathyroid gland hyperplasia with two adenoma was individualized. start of calcimimetics treatment (less than 1mg/kg) led to a rapid decline in pth level from 813 ng/l to 457 ng/l. the two adenoma decreased in size. in case of hyperparathyroidism, with close monitoring of serum calcium, phosphate, alkaline phosphatase and vitamin d levels, calcimimetics are an excellent alternative to surgery, with safe use and low dose in these cases. preliminary favourable experience has been reported in children but paediatric experience is lacking. side effects result from chronic administration of steroids. the aims of this study are to analyze graft function and metabolic effects of low dose and withdrawal of steroid therapy. this is a single center pilot, one arm and prospective study. methylprednisone (mp) was decreased to 0.07±0.03 mg/kg/day (low dose) after 4 months. we studied changes in graft function, height velocity, lipid profile, body composition and bone mass after 1 year of low dose mp and after a 2 nd year following mp withdrawal. patients received daclizumab induction; tacrolimus and mycophenolate mofetil. the inclusion criteria was 1 st living related graft and pra <10%; 16 patients were enrolled and total follow-up was 2.5 years. age at transplantation was 3.1-21 years, 5 females, 9 prepubertal, 7 postpubertal patients. patients and graft survival were 100%, acute rejection (ar) occurred after 14 months of mp withdrawal in 2/9 (22%) prepubertal patients (banff 97, 1b). in prepubertal patients, at the moment of steroid withdrawal and 1 year later creatinine clearance was 99.7±15.2 and 82.9±3.9 ml/min/1.73 m 2 , p<0.001; height velocity 6.9±2.5 and 7.4±2.9 cm/year, p: ns, with a height increment of 0.31±0.1 sds, p<0.05 during the last year of follow-up. graft function did not change in postpubertal patients. in all patients at the moment of steroid withdrawal and 1 year later lipid profile was normal; fat body mass 10.0±6.7 and 9.2±5.5 kg, p: ns; lean body mass 29.3±11.4 and 31.7±12.8 kg, p<0.02; total skeleton bmd -1.0±0.6 and -0.7±0.8 sds, p: ns and lumbar spine bmd -1.3±1.04 and -0.86±0.86 sds, p<0.05. this study demonstrates that low dose and steroid withdrawal allow catch up growth, normal lipid profile with no fat accumulation. steroid withdrawal prevents bone loss with increment of lean body mass, but with a concerning rate of ar and graft function deterioration in prepubertal patients. children with x-linked hypophosphatemic rickets (xlh) usually present with progressive disproportionate stunting. we therefore conducted a 3 year randomized controlled trial on theeffect of rhgh therapy on body anthropometry (28 parameter) in 16prepubertal children with xlh (each 8 patients in rhghandcontrol-group). age at baseline was 7.3±2.0 yrs (mean±sd), height was -3.2±0.8 sd, calcitriol dosage was 23 ng/kg x day, and phosphate dosagewas 55 mg/kg x day (each p>0.05 rhgh-vs. control-group). results: within the whole study population longitudinal bodydimensions were more affected than transversal body dimensions aswell as circumferences (extremities/trunk). leg length (-3.7±0.9 sd; p<0.0001) was the most impaired longitudinal parameterexplaining 90% of the overall variability of total body height, whereassitting height (-1.7±0.8 sd) was the best preserved longitudinalparameter. longitudinal body dimensions were significantly increased after 12 months rhgh-treatment (height +0.72±0.18 sd; sitting height +0.61±0.39 sd, leg length +0.57±0.55 sd; arm length +0.74±0.59 sd; each p<0.001). in contrast, progressive stunting was noted in control patients (height -0.16±0.42 sd; sitting height -0.01±0.24 sd; leg length -0.1±0.56 sd; arm length -0.01±0.26 sd; each p<0.001 vs. rhgh-group). rhgh treated patients showed a significant increase in all transversal body dimensions (each p<0.001), as well as a decrease in skin folds (range -0.2 up-to -0.9 sd; each p<0.001). one year rhgh treatment in severely growth retardedprepubertal children with xlh leads to improvement of longitudinal bodydimensions, harmonization of body (i. e. transversal body dimensions & body proportions), and decrease of body fat. thalassemia is an hemolytic anemia characterized by decreased production of β globin. the chronic hemolysis requires frequent bloodtransfusions that caused hemosiderosis, including iron deposition in the kidney. removal of excess iron via iron chelators, the most commonof which is desferal produce iron excretion in urine and stool. few studies have been published, the studied patients, mostly adults, exhibited proteinuria, aminoaciduria, low urine osmolarity and excess secretion of the proximal tubular function markers, n-acetyl-d-glucoseaminidase (nag) and β2 microglobulin. the iron accumulation may causes lipid oxidative peroxidation and this oxidative process cause's tissue damage. in this study we examined 40 thalassemia major patients treated with desferal. the degree of hemosiderosis was determined by measuring serumiron and ferritin. 12 children without iron metabolism disorders orrenal disease serve as controls. the renal and tubular function was analyzed. no differences in creatinine clearance, blood hco3, na and k fe, tmp/gfr was found. serum uric acid was equal in the two groups but itsurine excretion was significantly higher in the thalassemic group probably due to persistent hemolysis. the nag level and its ratio to creatinine were significantly higher compared to the control group. the results of our work showed that most of the thalassemic patients have sub clinical disturbances in tubular function and high nag in theurine. these results raise the question of treating thalassemic patients with oral chelators which removes iron from cells preventing the oxidative process; moreover, and add antioxidants which may prevent the deposition of iron in tissues. in light of these findings, it would be advisable to routinely check glomerular and tubular function as part ofthe follow-up in these patients. objectives of study and methods: little information is available on the long-term follow-up in patients with biallelic mutations in the two genes slc12a1 and kcnj1, encoding the bumetamidesensitive na-k-2cl cotransporter and the in wardly rectifying renal potassium channel, respectively. we evaluated the long-term follow-up (>7 years) in 12 patients with these two forms of bartter syndrome. the slc12a1 and kcnj1 genes were screened by dhplc and sequencing techniques. results: the long-term follow-up period was 7 to 22 years, median 11, after diagnosis, in 8patients with mutations in slc12a1 (4 homozygotes, 4 compound heterozygotes) and 4 patients with mutations in kcnj1 (2 homozygotes, 2 compound heterozygotes) genes. medical treatment with indo methacin at last follow-up control including supplementation with potassium in 7patients and medical treatment with indomethacin in 10 patients (meandose 1.1 mg/kg/day). in two patients (one with slc12a1 and another one with kcnj1 mutations) growth hormone (gh) deficiency was detected with specific tests. both patients were treated with recombinant human gh. at the end of follow-up, body height was <3° percentile for agein 2 of the 12 patients, 1 of whom with gh deficiency and body weightwas <3° percentile for age in 3 patients (none of them with gh decifiency conclusions: these data demonstrate that some patients with biallelic mutations inthe slc12a1 and kcnj1 genes tend to present slight impaired glomerular kidney function after a median follow-up of 11 years and that growth retardation and gh deficiency are often present in these patients. the cytosolic c-terminus of nhe3 does not mediate its apical localization or baseline activity -implications for blood pressure and ph homeostasis the epithelial sodium proton exchanger, nhe3, is expressed in the apical membrane and subapical endosomes of the proximal tubule. apical localization is fundamental to proximal tubular na+, water and hco3-absorption, a process necessary for the maintenance of plasma ph and blood pressure. moreover the redistribution of nhe3 between these compartments alters its activity. for example, acute hypertension leads to an increased endomembrane accumulation of nhe3 and pressure natriuresis. nhe3 is composed of a n-terminus with 12 transmembrane helices and a cytosolic c-terminus. the former is necessary for sodium-proton exchange while the latter regulates activity. the goal of our studies was to evaluate the contribution of the cytosolic c-terminus to apical localization and therefore to nhe3 function. to this end we generated a series of nhe3 constructs with sequential deletions in the cytosolic c-terminus. all constructs contained an extracellular epitope tag to facilitate the delineation between cell surface and endomembrane nhe3. stable renal epithelial cell lines were generated expressing each construct. surprisingly, even when the entire c-terminus was deleted nhe3 was still detectable at the apical membrane. we proceeded to evaluate the activity of the truncated exchangers and found they retained activity. finally, we assayed the attachment of nhe3 to the actin cytoskeleton (a process thought to be mediated by the c-terminus), by measuring their solubility in the weak detergent triton x-100 and by measuring their mobility in the plane of the plasma membrane. both assays confirmed that exchangers lacking the c-terminus retained their association with the plasma membrane. in conclusion, the cytosolic c-terminus of nhe3 is not necessary for apical localization nor baseline nhe activity. further studies will be needed to confirm its role in specific regulatory processes. background: ibu is used as a safer alternative to indomethacine for pda treatment. however, safety/efficacy balance has not been extensively studied. animal and a few clinical studies suggested that ibu might also have significant side effects. objective: to evaluate renal function at one week of life in infants treated with ibu as compared to infants not exposed to ibu, within the first days of life. methods: multicentric prospective cohort study of 27 to 31 weeks gestation (ga) infants exposed or not exposed to ibu. infants presenting with renal impairment at birth, urinary tract malformation, or contraindication to ibu treatment were excluded. infants exposed to ibu were paired to controls according to ga, centre and crib score. creatinine clearance (ml/min/1.73 m 2 ) was measured for glomerular function evaluation; fractional excretion of sodium (fena) and 1microglobinuria/creatininuria (1/ucr) for tubular function evaluation. results: 120 infants were studied: 60 exposed to ibu for pda closure with 83.3% efficiency and 60 controls. birth weight was 1100±278 g (mean+sd), and ga 28.2±1.2 wks. glomerular filtration rate (gfr) significantly decreased on day 7 in ibu exposed infants. noteworthy, diuresis remained in the normal range, but was significantly lower after ibu treatment (given on day 2) as compared to controls. antiresorptives, particularly bisphosphonates (bp), offer a promising treatment inpediatric bone disease. bp have been successfully used to treat childrenwith osteogenesis imperfecta (oi), secondary osteoporosis, fibrousdysplasia, hypercalcemia. concerns exist regarding bone mineralizationand bone growth and transient adverse reactions. according to available literature, bp were successfully used in ~1000 children, intravenous pamidronate (pm) being the most frequently used one (>500 children, mostly with oi), followed by alendronate (al) (~300 patients with oi, secondary osteoporosis, hypercalcemia), risedronate, etidronate, zoledronate, clodronate, olpadronate. oi treatment with bp resulted in an increase in bmd, improved growth, relief from pain, mobility improvement, improved quality of life and a drop in fracture rate there are sparse data comparing oral and i. v. bp. oral and i. v. bp seem to have a similar effect in children with oi. daily al therapy seems to be safe and effective in children with oi, and daily or weekly administration of al led to increase in bmd in patients with secondary osteoporosis. there is scarcity of randomized, double blind, placebo-controlled or active comparator trials with bp in children. currently, double-blind, placebo-controlled study with risedronate andactive comparator trial with intravenous zoledronate in children with oi are planned. bp therapy should be used in context of a well-runclinical program with specialist knowledge in the management of pediatric metabolic bone disorders. other emerging antiresorptive agents include denosumab, glucacon-likepeptide-2 and calcitonin tablets. these drugs are tested in phase iii trials in adults. their applicability to children is likely to be discussed in the coming years. the current kdigo recommendations on classification or renal osteodystrophy recommend assessment of three areas of bone histology: turnover, mineralization, and volume. while lesions of bone turnover are prevalent in children treated with dialysis, little is know about the prevalence of mineralization defects and their response to therapy with vitamin d sterols and phosphate binders. we evaluated the skeletal mineralization (osteoid thickness (o. th.) and osteoid maturation time (omt)) in 207 patients ages 13±1 years treated with maintenance dialysis who were not receiving vitamin d sterol therapy. serum biochemical markers were: ca: 9.2±0.1 mg/dl, p: 6.2±0.2 mg/dl, pth: 660±40 pg/ml, alk p'tase: 390±21 iu/dl. 53% of patients with high turnover bone disease (95% ci: 43-62%) and 29% (18-41%) of patients with normal or adynamic bone had abnormal skeletal mineralization as reflected by both a prolonged omt and widened o. th. subsequently, a subset of 103 patients underwent treatment with calcitriol and calcium carbonate. while serum pth levels decreased by 36% (p<0.05) and bone formation rate decreased by 41% (p<0.05) with therapy, there was no change in o. th or omt from baseline. indeed, 67% (55-77%) of patients had abnormal mineralization after therapy. we conclude that mineralization defects are prevalent in children treated with dialysis and are not affected by current therapeutic options. further studies are needed to determine the pathophysiology and optimal treatment of these defects. introduction: clara cell secretory protein (cc16) is a protein synthesized primarily by non-ciliated bronchiolar epithelial cells, the clara cells. like other low-molecular size proteins, plasma cc16 is rapidly eliminated by glomerular filtration and reabsorbed by proximal tubular cells. this protein has been rarely studied in the paediatric age. the sensitivity of cc16 in urine was compared to that of b 2-microglobulin (b 2m) and n-acetyl-b-d-glucosaminidase (nag conclusions: cc16 is a good marker of the proximal tubular function. cc16 is related better with the urinary b 2m elimination, since both are low-molecular size proteins that are reabsorbed by the proximal tubule. sd. kim, bs. cho kyunghee university hospital, pediatrics, seoul, south korea background: many studies have demonstrated that arb prevents renal progression in patients with glomerular nephritis or diabetic nephropathy by inhibition of hmc proliferation and reduce of extracellular matrix expansion and glomerulosclerotic changes. however, the molecular effects of arb in cultured hmc have not been completely defined. we investigated differential gene expression by arb treatment on cultured hmc according to time sequence using cdna chip (affymetrix). methods: mc was grown in dmem with 10% fbs and then arb was treated on cultured mc. rnas of hmc at different time points (4, 8 , and 24 h after arb treatment and no treatment) were compared using affymetrix cdna chip. to validate the patterns of gene expression analyzed by the microarrays, some genes were selected and semi-quantitative rt-pcr was performed. results: among genes, humoral immune response, cytokine activity, il-8 receptor binding, chemotaxis, cell cycle arrest, and morphogenesis associated genes were down-regulated for 4, 8, and 24 h after arb treatment. they also showed different clustering according to their changing patterns. conclusion: the present study demonstrates profile of gene expression as time goes by after arb treatment on proliferation of human mc. gene expression by arb treatment on cultured hmc showed sequential changes. our results showed that chemotaxis and immune response associated genes were suppressed by arb treatment on hmc. further evaluation of individual genes will be conducted to elucidate molecular mechanism. podocin is the major component of the slit diaphragm, the site responsible for size and charge selectivity of filtration. mutations in the nphs2 gene, which encodes podocin can lead to steroidresistant nephrotic syndrome (srns). in this work we studied whether genetic changes of podocin might predispose to the development of sporadic non-familial srns in childhood. we screened for podocin mutations 50 children (26m/24f; mean age 11.9±0.7 years) with sporadic srns and 50 healthy controls. renal biopsy in srns patients revealed mesangial proliferative glomerulonephritis (n=21), focal segmental glomerulosclerosis (fsgs; n=13), membranoproliferative glomerulonephritis (n=13) and membranous nephropathy (n=3). the mean age of onset of srns was 8.8±0.7 years. all 8 exons of podocin gene of patients with srns and controls were amplified and direct dna sequencing was performed. there is one novel nonsense heterozygous mutation of c.328 g>t p.87glu>stop was identified in the 1 st exon of nphs2 gene in srns child with fsgs who has renal transplantation at the age of 2 years without recurrence of fsgs in her graft. we found one kind of single nucleotide polymorphism c.872+7a>g in the 7 th exon of nphs2 gene in 6% (3/50) srns patients (2 with fsgs; 1 with membranoproliferative glomerulonephritis) and 10% (5/50) children in controls. allele frequency of this polymorphism of the nphs2 gene in srns patients and controls was not different significantly. our results indicate that mutation-detected rate in the nphs2 gene in russian children with sporadic srns was 2%. the low mutation-detected rate and identified polymorphism c.872+7a>g in nphs2 gene unlikely predispose to the development of sporadic srns in russian children. further determining the slit diaphragm genetic profile of children with sporadic srns is warranted in order to improve disease classification and tailoring of treatment. for diagnose of essential hypertension is necessary except all causes of secondary hypertension (sh). case: family history of 17-year-old female patient was unremarkable for hypertension, incl. renal diseases. during last 6 months she had often headaches with intermittent vertigo. she was not anywhere examined. at admission on intensive care unit patient had headache, her pulse rate was 130/min, respiratory rate 12/min, bp (right arm) was 220/180 mmhg and the lower extremity bp 225/188 mmhg. other physical examination was normal, incl neurological exam. fundoscopy of the eyes did not show any evidence of hypertensive retinopathy. cardiac ultrasound showed mild left ventricular hypertrophy. abnormal laboratory parameters (without medication) were: hypokalemia (3.0 mmol/l), metabolic alkalosis (ph 7.48, hco 3 26.3 mmol/l), low urinary output of sodium (22 mmol) and chloride (<18 mmol), high urinary output of potassium (34 mmol). renal function tests were normal and no abnormalities were detected by renal ultrasonography, incl. doppler exam of renal blood flow. by large hormonal analyse were detected high plasma renin activity (pra; 12.8 ng/ml/hod; n.r. 0.5-1.9) and very mild increased serum aldosterone (ald; 0.63 nmol/l; n.r. 0-0.60). during the ct renal angiography was found solid mass in the upper part of the left kidney. a partial left nephrectomy was performed and histological exam revealed juxtaglomerular cell tumor (so-called reninoma, re). after the resection we stopped subsequently patients antihypertensive therapy. in a 3-month follow-up our girl was normotens. re is a very rare cause of sh. re typically present during adolescence or young adulthood. this cause of severe sh should be considered along renal artery stenosis in adolescents presenting with secondary hyperaldosteronism or in causes with renin-secreting tumor of non-renal origin. we report our preliminary molecular findings in twelve turkish cystinosis patients. the patients were 3 to 22 years; male/female ratio was 7: 5. all presented initially with severe failure to thrive, polyuria and polydipsia. cystinosis was diagnosed at age 1 month to 6 years. six of the patients reached end stage renal failure at ages ranging from 6.5 to 15 years necessitating renal replacement therapy; 3 are currently on hemodialysis, one is on capd, and two were transplanted. while three of remaining 6 have renal fanconi syndrome with proteinuria, 3 had kidney failure in varying degrees. molecular analyses involve an initial multiplex pcr, checking for the presence or absence of 57 kb founder deletion, and subsequent sequencing of the 9 coding exons of ctns. interestingly, none of the 12 nephropathic cystinosis patients carried the 57 kb deletion. instead, one patient had a new homozygous 10 kb deletion of exons 4 to 9 of ctns. one patient was homozygous for a known 4 bp deletion in exon 3, i.e., c.357del gact. two patients were homozygous for new missense mutations in exons 7 and 9, i.e., c.451g>a (r151g) and c.518a>g (y173c), respectively. the most common mutation in our turkish patients was a new exonic splice site mutation in exon 9, i.e., c.681g>a (e227e). of 24 alleles studied, 7 carried this mutation, which is expected to disrupt proper splicing. two patients were compound heterozygous for one of the above-mentioned mutations and a known missense mutation in exon 12, i.e., c.1015g>a (g339r). in two patients, we could not find any disease-causing mutation; in two patients, we could find only one disease-causing mutation. in summary, cystinosis patients of turkish ancestry show ctns mutations different from those of western european patients. these findings will be of relevance for molecular-based screening and diagnostic methods for cystinosis. introduction: the association of hypertension with bell's palsy in adults has been reported from 4-11%, but there is few data in children. the presence of bell's palsy in children requires a complete evaluation for hypertension, solid tumors, leukemia, neurofibroma, and trauma. hypertensive children usually present with clinical manifestations of underlying disease, but with substantial elevation, symptoms of hypertension develop. although headache, dizziness, blurred vision and seizure are common neurologic symptoms of hypertension, but facial paralysis is not a wellrecognized presenting feature of hypertension in children. case report: this paper describes two severely hypertensive children who referred to children's hospital of tabriz with periferal hemifacial nerve paresis and initial diagnosis of bell's palsy. case 1: a 12 years old girl who admitted with blood pressure of 230/120 mmhg on admission. renal ultrasound study revealed left small size kidney and renal scintigraphy followed by angiography confirmed renovascular hypertension. case 2: a 5 years old boy with blood pressure of 180/100 mmhg on admission. sonography of kidneys was normal except for a small size (4 mm) stone in left kidney. renal scintigraphy and angiography were normal. all other evaluations for etiology of hypertension including cardiac and endocrine investigations were negative. treatment of hypertension with antihypertensive drugs resulted in complete recovery of facial paresis in both cases within 3-4 months. conclusion: unilateral peripheral facial nerve paresis is a rare presentation of hypertension in children. unawareness of this presentation may result in delay in diagnosis of hypertension which may increase further with steroid therapy for bell's palsy. to uncover the frequency and the spectrum of nphs2 mutations in egyptian children with non familial steroid-resistant nephrotic syndrome (srns), 16 patients were screened by pcr-singlestrand confirmation polymorphism analysis of nphs2 gene followed by direct sequencing. nphs2 mutations were evident in 5 patients (31.3%) who were bearing five novel mutations including two frame shift mutations (713-714insg and 132-133insg), two missense mutations (556a>c and 647t>a) and a silent mutation (408a>t). there were no phenotypic or histological characteristics of patients bearing nphs2 mutations, apart from the earlier onset of the disease, compared to those who were not bearing mutations. in conclusion, nphs2 mutations are prevalent in egyptian children with non-familial srns and this may in part explain the less favorable prognosis reported in these patients. , which is an inherited systemic disease of connective tissue primarily affecting the skin, retina, and cardiovascular system, also leads to rvh. these symptoms of pxe are usually apparent in adulthood and rarely observed in children. here, we describe a very rare pediatric case of rvh caused by pxe. case report: a 6-year-old boy was noticed to have severe hypertension (183/128 mmhg) when he was admitted to our hospital for an operation for exotropia. he had no previous or family history of pxe or hypertension. laboratory examination showed that plasma renin (517.0 pg/ml) and aldosterone (71.3 ng/dl) concentrations were markedly elevated. his systolic and diastolic blood pressure (bp) decreased 12.7% and 22.2% from baseline after administration of captopril, respectively. a computerized tomographic scan of his abdomen showed multiple calcified vessels in kidneys and spleen. yellowish papules on the bilateral axillary regions and inguinal area were detected. characteristic histological changes of pxe such as elastic fiber mineralization and calcification were noticed in the biopsy of affected skin lesions. conclusion: pxe is characterized clinically by high heterogeneity in the age of onset and extent and severity of organ system involvement. although its symptoms usually appear in the second or third decade of life, gastrointestinal bleeding and acute myocardial infarction have been reported in childhood. we should also consider pxe as one of the causes of rvh in children, because its prognosis depends largely on the extent of extracutaneous organ involvement. the clcnkb gene is rarely reported as having a large deletion mutation, but all cases reported previously were large homozygous deletions and a large heterozygous deletion is impossible to detect by direct sequencing. patients and methods: this report concerns a genetic analysis of 5 japanese patients with type iii bs. to identify the mutations in the clcnkb gene, we used polymerase chain reaction (pcr) and direct sequencing to investigate all exons and exon-intron boundaries in the patients and their family members. to detect large heterozygous deletion mutations of the clcnkb gene, we conducted semi-quantitative pcr amplification using capillary electrophoresis. results: four mutations were identified, comprising 1 novel 2 bp deletion mutation (c.1334_1335delct), an entire heterozygous deletion and a heterozygous deletion mutation of exon 1 and 2 of the clcnkb gene. the nonsense mutation w610x in the clcnkb gene was detected in all patients (2 of them were homozygous and 3 were heterozygous) and this finding indicates that this nonsense mutation is likely to constitute a founder effect in japan. two patients had large heterozygous deletion of the clcnkb gene, which was proved by semi-quantitative pcr amplification. conclusions: capillary electrophoresis is a new method and extremely useful for detecting large heterozygous deletions, and should be employed to examine type iii bs cases in whom only a heterozygous mutation has been detected by direct sequencing. obesity defined as body mass index (bmi) above 95 th percentile for age and gender is regarded as a risk factor for cardiovascular (cv) target organ damage (tod) in children and adults with ph. however, when using percentile-based definition of obesity one may miss children at risk of cv complications. the aim of the study was to compare sensitivity of traditional definition of obesity (bmi>95 th pc) and bmi thresholds (tbmi) for cv complications described by katzmarzyk et al. (2004) majority of children with idiopathic nephrotic syndrome (frequent relapsers, steroid dependent and steroid resistant) require adjunctive therapy. the response to cyclophosphamide (cp) in these children is variable and difficult to predict. there may be an effect of polymorphic expression of gst on the remission with cp. in this study, we have tried to evaluate the correlation of gst polymorphism and response to cp therapy in these children we studied gst polymorphism in 73 consecutive children (54 males, 19 females) with steroid sensitive (n=44) and steroid resistant (n=29) nephrotic syndrome, receiving cp therapy. we evaluated the inter-relationships between gstm1, gstt1, and gstp1 genotypes and correlated it with the response to cp therapy in these children. the mean age of onset was 5.2±4.4 years. out of 73 children, 67% children responded to cyclophosphamide therapy. the null genotype of gstm1 and gstt1 was observed in 39.7% and 64.4% respectively while val105 genotype of gstp1 was seen in 22% children. there was no significant correlation among the various individual genotypic combinations. however, a trend was seen towards remission in children with a combination of gstp1 polymorphism with gstt1 null genotype (p=0.08) or combination of gstp1 polymorphism with gstm1 wild type genotype (p=0.0885) another important finding in our study was that there was a significantly higher frequency of val105 allele of gstp1 in responders to cyclophosphamide as compared to nonresponders (p=0.01). the results indicate that the presence of the val105 allele correlates with the response to cyclophosphamide in these children. gst gene polymorphism may be a significant therapeutic tool in the management of children with idiopathic nephrotic syndrome receiving therapy. objectives of study: primary vesicoureteral reflux (vur) is a common pediatric disease that may lead to reflux nephropathy and end-stage renal disease. the renin-angiotensin system (ras) was proposed to be associated with primary vur. the objective of this study was to investigate whether the gene polymorphisms of the ras are involved in primary vur and correlation with the severity of vur in taiwanese children. methods: we studied the angiotensin ii type 2 receptor (at2r) c3123a gene polymorphism for association with susceptibility to primary vur and disease severity in 100 vur children and 60 healthy controls. fifty four of the 100 vur patients had low-grade vur (grade i-iii) and 46 had high-grade vur (grade iv and v). to analyze the polymorphisms in the c3123a of at2r gene, the snp genotyping assay were performed. the genotypic frequency and allele frequency for four ras genes were analyzed to detect the correlation between the patients with mild, severe vur, and healthy control. results: we found that the c3123a of at2r gene was associated with the development and severity of vur. significantly higher c and lower a allele frequencies were presented in vur patients (c allele 0.67 and a allele 0.33) compared with controls (c allele 0.56 and a allele 0.44, p<0.005). the similar results were observed in both mild (c allele 0.73 and a allele 0.27) and severe (c allele 0.62 and a allele 0.38) vur compared with controls (p<0.005). the cc genotype was higher in vur patients compared with controls (p<0.005). conclusions: at2r c3123a gene polymorphism was associated with the development and the severity of vur in taiwanese children. it raises the possibility to utilize the genotype of at2r as a risk factor to evaluate the development and severity of primary vur. results: stone analysis led to diagnosis of cystinuria in 12 patients (1% of all), but only 5 were children (1.4% of the paediatric stone patients). age at diagnosis in three patients was 17-30 years and in four 30-49 years. time from first manifestation (pain 7x, gross haematuria 3x, urinary retention 2x, uti 4x) until diagnosis was 0-2 years in seven, 5-10 in three and even 34 and 39 years in two. renal function was impaired in 1 patient (ckd stage ii). the urinary cystine test was positive in all 9 patients with cystine stones examined, but was negative in 2 family members thus excluding cystinuria in them. family history of urinary stones was positive in two; the brother of one had died of renal failure due to bilateral urolithiasis. conclusions: delays in diagnosis of cystinuria in armenia are unacceptable. production of tablets containing nickel/dithionite which is non-toxic in contrast to brand test (cyanide/nitroprusside) is planned and could allow screening of all patients with stones of unknown origin. background: classically, childhood hypertension has always been recognized as secondary and frequently demanded an exhaustive etiological investigation. however, in the last two decades, many studies have been shown that pediatric patients also present primary hypertension and, sometimes, the adult disease probably begins during childhood. the aim of this study was to analyze a cohort of patients followed-up at a single tertiary unit (belo horizonte, brazil). methods: in this retrospective cohort study, the records of 220 diagnosed with arterial and followed at our unit between 1994 and 2004 were analized. a data base was used for statistical analysis. results: of 220 patients, 53.2% were male and 46.8% female. the distribution of patients according to the age at diagnosis was: 0-1.99 years, 3(1.4%), 2 yr-6.99 yr, 51 (23.2%), 7 yr-11.99 yr, 55 (25%), and 12 yr, 111 (50.4%). the causes for hypertension were: renal diseases in 172 (78%), primary hypertension in 33 (15%), renovascular disease in 9 (4%) and ohers in 6 patients (3%). the comparison between primary hypertensive subjects and patients with renal diseases showed that, although blood pressure was similar at admission, a better control was achieved in the first group (p<0.05). the frequency of overweight and/or obesity was higher in primary than in secondary hypertension ( nephrnophthisis (nphp) is a very rare cause of crf in korea. identification of five genes mutated in nphp subtypes 1-5 has linked the pathogenesis of nphp. ten percent of affected individuals have retinitis pigmentosa, constituting the senior-löken syndrome. we experienced juvenile-onset crf with leber's amaurosis in two sibilings. case 1: a 10-year-old boy presented with pale appearance. he had severe renal impairment and visual disturbance, but no symptom of polyuria and polydipsia. his past annual school screening urinalysis was normal. his growth and development were normal except opthalmological findings and pallor. case 2: his 14-years-old sister also had a visual disturbance and was found to have crf. there was no specific problem during perinatal period. opthalmologic findings were similar to her brother's. nphp1 and 5 on chromosome 2q13 was analyzed by direct sequencing. sequencing of mitochondrial dna-mbol digestion for 14484 mutation was analyzed by pcr-sequencing and rflp. electroretinogram revealed a decreased in amplitude of a and b waves. on the kidney biopsy, some of glomeruli were globally sclerotic. remaining showed no cellular proliferation or capillary wall thickening. interstitium was diffusely fibrotic and in which were scattered lymphocytes. most tubules were preserved well but a few dilated tubules were intermingled. no positive reaction for immunoglobulines or complements in if. by em, tubular membranes showed thickening, splitting and disintegration. nphp1 and 5 genes were not identified. there was no transition mutation at mitochondrial dna nt.11778, 3480, 14484, 15257. late-onset senior-löken syndrome were diagnosed in these cases even though there were no polyuria and polydipsia of initial symptoms of nphp and nphp1 and 5 were not identified. we need to identify other known or novel mutation genes. nail-patella syndrome (nps) is an autosomal dominant disease characterized by classic tetrad of dysplastic nails, absent or hypoplastic patellae, elbow dysplasia, and iliac horns. some patients manifest nephropathy and adult-onset glaucoma. nps is associated with mutations in the lmxib gene. there is marked inter-and intrafamilial variability in the phenotypes. in this study, phenotype-genotype correlation was analyzed in 7 unrelated korean children with nps. the probands were 3 boys and 4 girls. they manifested dysplastic nails (7/7, 100%), absent or hypoplastic patellae (6/7, 86%), elbow dysplasia (4/7, 57%), iliac horns (3/7, 43%) and nephropathy (2/7, 29%) . four missense mutations/2 in the lim-b domain (h114q and l127p) and 2 in the homeodomain (r200q and a213p)/and 1 frame-shifting deletion (c,680dela) were identified in the lmxib gene.r200q and a2123p are known to be common mutations, and r200q was detected in 3 patients in this study. autosomal dominant inheritance was identified in 3 patients by phenotype and genotype analysis of the family members and in 2 patients by phenotype analysis only. remaining 1 patient had de novo r200q mutation. one patient and her mother with r200q mutation developed nephrotic syndrome, which progressed to end-stage renal disease (esrd). another patient with h114q mutation had asymptomatic proteinuria with microscopic hematuria, and her father had esrd. galucoma was not detected in any patients or family members affected. there were inter-and intrafamilial variability of the phenotypes, but no genotype-phenotype correlation was identified. this is the first study to characterize mutations in the lmx1b gene in korean patients with nps. r200q is a common mutation in korean, also. the mechanism underlying the phenotypic variations and predisposing factors to the development nephropathy remain unknown. the pathological mechanism which would be responsible for higher production of digitalis similar compounds in essential arterial hypertension (ah), would be a genetically defect kidney, which causes difficulty in na + excretion. higher intake of salts can be an etiological factor inessential ah only patients with inherited abnormalities of thetransport mechanisms in the cell membrane.the objective of the studywas to establish the incidence and type of ah and frequency of genetic factor in the investigated population of 3000 school children (age 7-16years). in children with essential and borderline ah we evaluated the activity of erythrocyte membrane na+, k+-atpase in the presence ofvarying atp concentrations. atp, adp and amp levels and lipid peroxides (as tbars) in the erythrocytes and tbars in plasma were measured. our data have shown that the prevalence of ah is lowest in 7-8 years oldchildren, while it is the highest in 15-16 years oldchildren. essential ah was established in 11 (0.36%) and borderline in 17 (0.56%) children. genetic factor were found in 54.5% of children with essential ah and in 60.4% of children with borderline ah. but, statistical analyses of the first and second degree relatives of children with essential and borderline ah suggested normal prevalence of hypertension. atp, adp and amp levels, as well as, lipid peroxides were not significantly altered compared to healthy children. kinetic profileof erythrocyte plasma membrane na+, k+-atpase activity revealed the presence of noncompetitive (allosteric) inhibition of enzyme activityin the children with essential and borderline ah. the differences in the kinetic properties of na+, k+-atpase between two investigated groups of children suggested that this dynamic model could be used as potential biological marker for early diagnosis and differentiation of these two type of ah. majority of these patients were obese and with increasing body weight nighttime hypertension became prominent in these patients. objectives: it has been shown that weight gain is directly related to increase inblood pressure. the objective of this study was to analyze the frequency of overweight/obesity in children/adolescents with primary hypertension (ph) and the relationship between the overweight/obesityand the stage of hypertension (h). methods: we analyzed the data of 113 patients aged 10-17.5 years (m 65; f 48) diagnosed with primary hypertension. overweight/obesity was defined asperc. of bmi -85/95 c. the stage of hypertension was determined according to the 4 th report on the diagnosis, evaluation,and treatment of high blood pressure in children and adolescents of the nhlbi working group. results: out of 113 pts, prehypertension was found in 10 pts (8.9%), stage i h in 30 (26.5%) and stage ii h in 73 pts (64.6%). stage ii h was more frequentin boys (69% vs. 58% in girls). combined systolic/diastolic h was found most frequently, in 58 pts (51.3%), isolated elevation in systolic blood pressure (bp) was found in 47 pts (41.6%), while only 8 pts (7.1%) had isolated elevation in diastolic bp. sixty-one pts (53.98%) were found overweight/obese; of which 33 (54.1%) above 95c bmi. theobese children were predominantly found to have stage ii h: 84.8% ofthe obese children. none of the obese children had prehypertension. contrary to the general perception, boys were found more frequently overweight/obese (67.2% boys vs. 32.8% girls). conclusion: our data shows that stage ii ph is not rare also in theteen-age group. frequently it is accompanied with overweight/obesity, especially in boys. we can conclude that the roots of ph in the adultage are already set from the childhood. our efforts should focus onearly diagnosis of ph and include prevention of obesity as the possible contributing factor for the development of ph. objectives of study: alport syndrome (as) is a progressive renal disease characterized by hematuria, progressive renal failure, high-tone sensorineural hearingloss and ocular lesions. xlinked dominant alport syndrome (xlas) isthe major inheritance form, accounting for almost 80% of the cases, caused by mutations in col4a5 genes. there are no good cures available for as at present, but there are some patients who requestfor prenatal diagnosis and genetic counciling. this study performed thefirst prenatal diagnosis in chinese as family. methods: the entire coding sequence of col4a5 mrna of peripheral blood lymphocytes was amplified using nest pcr to screen mutations in a chinesexlas family. mutation analysis of the fetus was performed on both cdna-based level and dna-based level of amniocytes. fetus sex was determined by pcr amplification of sry as well as karyotypes analysis. maternal cells contamination was excluded by linkage analysis. results: mutation screen showed that there was a g to a substitution at position 4271 in exon 46 of col4a5 gene (c.g4271a), it was subsequently confirmed at genomic dna level by pcr amplification of exon 46 of col4a5gene. the mutation was identified in the index case, family members aswell as the pregnant lady. the prenatal diagnosis showed that fetus didnot carry the same mutation as the mother detected by both cdna-basedand dna-based mutation analysis. pcr amplification product of sryas well as karyotypes analysis revealed a male fetus. linkage analysis of the three x chromosome markers showed that there was no contamination of maternal cells in amniocytes. conclusion: after mutation identification of col4a5gene in a large chinese as family, a successfully prenatal diagnosis was performed in one of the female members in this family based on both cdna as well as genomic dna level of amniocytes. objectives of study: alport syndrome (as) is a clinical and genetic heterogenousdisease. autosomal recessive as (aras) is caused by mutations in col4a3 and col4a4 genes, accounting for 10% of the cases. thin glomerular basement membrane nephropathy (tbmn), is also caused by mutations in col4a3 and col4a4genes, inherited as an autosomal dominant trait. differentiation between early stages of aras and tbmn may be difficult in clinic, itdepends on gene mutation analysis of col4a3 or col4a4. methods: the whole entire coding regions of col4a3 and col4a4 mrna of peripheral blood lymphocytes were analyzed using reverse transcription polymerase chain reaction (rt-pcr) and direct sequencing to screen mutations in three chinese aras families, the corresponding exon with flanking intronic sequence was further amplified to confirm the abnormality. results: both the entire coding regions of col4a3 and col4a4 mrna were successfully amplified and completely sequenced by seven overlapping pcr products, respectively. results showed that there were 10 variations of col4a3 and 4 variations of col4a4, respectively. among the 10 variations of col4a3,three were snp reported previously, four were new snp, one nonsense mutation, one small insertions and one splicing mutation, the latter three were the pathogenic mutations for the three families, respectively. all the four variations of col4a4 were snp reported previously. we concluded that rt-pcr and direct sequencing using peripheral blood lymphocytes rna is a practical, sensitive and feasible approach for analysis col4a3 and col4a4 gene variants in autosomal recessive alport syndrome patients, which offers a useful, inexpensive and timesaving approach for systematic gene analysis in patients with aras. objectives of study: gitelman syndrome (gs) is an autosomal recessive tubular disorder characterized by metabolic alkalosis, hypokalemia, hypomagnesemia and hypocalciuria. the majority of gs patients carry inactivating mutations of the slc12a3 gene encoding the sodiumchloride cotransporter located in the distal convoluted tubule. this study aimed to detect mutations in a chinese family with gs. methods: two brothers presenting muscle weakness, hypokalemic metabolic alkalosis, hypomagnesemia and hypocalciuria were clinically diagnosed as gitelman syndrome. the two brothers, as well as their healthy brother and parents, were detected for mutations in slc12a3 gene by direct pcr for each exon and then sequencing on genomic dna extracted from peripheral blood cells. results: the two patients were found to have the same compound heterozygous mutations (c.917c>t and ivs 14-8t>c) in the slc12a3 gene. the two mutations were also detected in paternal and maternal genomic dna, respectively. the unaffected brother had one mutation (c.917c>t) only. conclusion: a novel compound heterozygous mutation on the slc12a3 gene was revealed in a chinese family with gs. the objective: to determine the clinical value of ambulatory blood pressure monitoring (abpm) in pediatric kidney disease. methods: 83 patients with common kidney diseases aged from 5-16 yrs were enrolled. 24-hour abp were performed by welch allyn abpm6100. the number of cases whose ccr>90mmol/l/1.73 m 2 , ccr 60-89 mmol/l/1.73 m 2 , ccr 30-59 mmol/l/1.73 m 2 , ccr 15-29 mmol/l/1.73 m 2 and ccr<15 mmol/l/1.73 m 2 is 64, 4, 5, 1 and 9, respectively. seven patients only took fosinoprilto control blood pressure did abpm again more than one weeks after therapy. 1141 healthy children performed in german in 1997 was used asthe normal data. casual bp was measured by sphygmomanometer. 23 children took echocardiography to calculate left ventricular mass index (lvmi). results: the incidence of nocturnal hypertension was significantly higher than that of diurnal hypertension (p<0.001).theincidence of non-dipper in 83 children with kidney disease was 68.7%. nocturnal dipping rate in the patients was significantly lower than that in the healthy children (p<0.01). the incidence of masked hypertension and white coat hypertension inchildren with kidney disease were 3.6% and 9.1% respectively. nocturnal systolic and diastolic dipping rate of the children with lupus nephritis and acute glomerulonephritis were lower than those of the children with henoch-schönlein purpura nephritis (p<0.05). lvmi hadpositive correlation with 24-hour diastolic blood pressure load (r=0.414, p=0.036), but it had no correlation with casual bp. after taking fosipril, 24-h, diurnal and nocturnal average abp decreased significantly (p<0.05). nocturnal dipping rate increased, but did not reach statistical difference (p>0.05). conclusions: abpm was an effective tool for diagnosis and management of hypertension in childhood with kidney disease. identification of 6 novel mutations in the col4a5 gene of japanese patients with x-linked alport syndrome background: alport syndrome consists of nephritis, often progressing to renalfailure, and sensorineural hearing loss. x-linked phenotype (omim#301050) is the result of mutation in the gene for the alpha-5 chain of collagen iv (col4a5). objectives of study: to find mutations causing x-linked alport syndrome in japanese patients. patients and methods: diagnosis criteria of alport syndrome were proteinuria, familial history of renal failure andchanges of gbm in electron microscopy. to identify the mutations in the col4a5 gene. results: for the time being we finished genetic analysis of 8 patients with suspected x-linked alport syndrome, 6 males and 2 females. we identified mutations in 7 of 8 patients; 6 of them were novel mutations. they comprise: 2 nonsense mutations, 2 missense mutations and 3 mutations of splicing acceptor site resulting in exon skipping or truncation, and establishing of premature stop codon. in previous reports of x-linked alport syndrome, mutation detection rate was around 60%. the present study provides a detection rate of 87.5%, although our number of examined cases is limited. conclusions: direct sequencing of rt-pcr and pcr products is efficient method of finding mutations in col4a5 gene. we found mutations in high percentage of investigated patients. objectives of study: to make a genetic diagnosis of juvenile nephronophthisis for a chinese boy. methods: analyze the presentation, family history, laboratory investigations, and histological features of a patient suspected of juvenile nephronophthisis, make a clinical diagnosis. to confirm the diagnosis on genetic level by pcr amplification of satellite markers located within the known homologous deletion of nphp1,including del-2, del-9, del-16, del-5-(5)2, del-10 and markers outside the deletions (ranbp11/12 and d2s1896)as control. results: the boy was nine years old, he was admitted becauseof renal failure for 6 months. this case manifested by school age, negligible onset, anemia, polyuria, renal failure at 9 years old,without hypertension and abnormal urine analysis. his sister presented with anemia at 1 year old, and died of uremia at 6 years old.laboratory investigations showed no proteinuria and hematuria. thekidney size is normal, and the cortical medullary boundary is obscure.the histological features consist of the disintegration of tubularbasement membrane, the atrophy and dilation of renal tubules, theinterstitial cell infiltration and fibrosis. he was suspected asjuvenile nephronophthisis. by pcr amplification, we found the missingof the satellite markers of del-2, del-9, del-5-(5)2 and del-10, which indicate that there is the common large homologous deletion (250kb) in the child's nphp1. conclusions: nephronophthisis is the major hereditary cause ofchronic renal failure. the boy was suspected of nephronophthisis because of chronic renal failure, family history, normal kidney sizeand hitological features. according to the age of renal failure, he was suspected as juvenile nephronophthisis. the diagnosis was confirmed by gene analysis. it is the first juvenile nephronophthisis case for chinese confirmed by gene analysis. cutaneous small-vessel vasculitis is a rare condition in children and is commonly associated with a wide spectrum of systemic inflammatory conditions, malignancies, infections or drug hypersensitivities. enalapril is anangiotensin-converting enzyme inhibitor, commonly used for the treatment of hypertension. cutaneous vasculitis due to enalapril has very rarely been reported and only with adults. we report a case of an 8-yea-old boy presented with a pruritic eruptionover his lower legs that started 6 hours after he had initiated treatment with enalapril at a dose of 0.5 mg/kg/daily. he had a history of hypertension due to a shrieked right kidney since infancy and he wason treatment with nifedipine and propranolol for the last three years. this medication was discontinued because it was ineffective, the day before initiation of enalapril. clinical examination revealed palpable purpuric lesions involving lower legs and ankles. he was otherwise well. a skin biopsy of the lesions showed leucocytoclastic vasculitis of small vessels. abnormal investigations were elevated c-reactive protein, esr and leucocytosis. further laboratory tests including creatinine, liver function tests, urineanalysis, antinuclear antibody, cryoglobulins, viral serology, complement levels, were normal or negative. enalapril was discontinued and he was started oral prednizolone and ceterizine over the next ten days. the skin eruption regressed rapidly. cutaneous vasculitis induced by enalapril is a rare adverse effect and it is essential a prompt recognition and withdraw of the suspicious drug. objectives of study: barttin, the gene product of the bsnd gene involved in bartter's syndrome with sensorineural deafness, is an essential b-subunit for clc-ka and clc-kb chloride channels, and it is expressed in the kidney as well as in the inner ear. one patient affected by deafness and renal bartter phenotype without bsnd mutations has been previously reported with simultaneous mutations in both clcnkb (responsible for classic bartter syndrome) and clcnka genes. we report here on a new case of a 6-months-old boy presenting such a disease. a severe polyhydramnios was detected during the pregnancy. he presented also polyuria, growth retardation, nephrocalcinosis and sensorineural deafness. laboratory studies revealed metabolic alkalosis (plasma hco3 47,7 mmol/l), hypokalemia (2,4 mmol/l), hypercalcuria (cau/cru 1,6 mg/mg) and elevated plasma renin (320 pg/ml). the aim of the study was to identify the cause of the severe renal salt wasting and sensorineural deafness in this patient. methods: dna sequencing analysis was performed on the bsnd, clcnkb, and clcnka genes. results: no mutation was detected in the bsnd gene. we identified a reciprocal partial homozygous deletion of exons 1-6 for the clcnkb gene and theloss of exons 7-19 for the clcnka gene. conclusions: the disruption of both clc-ka and clc-kb chloride channels leads to a syndrome clinically not distinguishable from bsnd, characterized by severe salt wasting and deafness. this digenic disorder is due to simultaneous mutations on the two genes clcnka and clcnkb respectively. the tight topology of the highly homologous clcnka genemight predispose to an unequal crossing over leading to partial orcomplete deletions of the clcnkb gene. we hypothesize that thischimaeric resulting gene interferes with the correct function of both the channels clc-ka and clc-kb, and leads to a bsnd-like phenotype. familiary hypomagnesemia with hypercalciuria and nephrocalcinosis (fhhnc) is a nautosomal recessive tubular disorder that is frequently associated with progressive renal failure. mutations in cldn16 which encodes the renal tight junction protein paracellin-1 were identified as the underlying genetic defect. in this work we present a gipsy family with fhhnc in which the mother and daughter both showed homozygous mutations in the cldn16 gene. a three-year-old girl was investigated after acute pyelonephritis and was found to have medullary nephrocalcinosis, hypomagnesemia (0,5 mmol/l), hypercalciuria (10,5 mg/kg/d), hypermagnesuria (femg 15%) and incomplete distal renal tubular acidosis. her renal function was normal. her mother demonstrated also bilateral medullary nephrocalcinosis, hypomagnesemia (0.2 mmol/l) with high femg (86%), moderate renal failure (creatinine 234 umol/l) and high ipth levels (398 pg/ml). as a child she had afebrile seizures, but serum mg levelwas not measured. index patient's uncle had history of recurrent passage of calculi in childhood, bilateral medullary nephrocalcinosis, normocalcemic hypercalciuria but his serum mg was not determined. he developed obstructive uropathy due to impaction of the calculus in urethra and eventually progressed to terminal uremia and later was transplanted. mutational analysis confirmed that the index case, motherand uncle were homozygous for the common mutation in the cldn16gene (leu 151 phe), while the father was heterozygous. we present a new family from macedonia with fhhnc with unusual presentation over two generation. mutational analysis confirmed also the diagnosis of fhhnc in the uncle although as a child he was considered to have idiopathic hypercalciuria. thus, serum mg should be routinely checked in children with nephrolithiasis/nephrocalcinosis. m. pan ' czyk-tomaszewska, j. s ' ladowska, j. so l /tyski, m. roszkowska-blaim arterial hypertension is one of the complications of reflux nephropathy. the aim of the study was to assess the risk factors of arterial hypertension in children with primary vesicoureteric reflux (vur). we studied 150 children aged from 4 to18 years mean 9±3.3, 82 with unilateral and 68 with bilateral vur. in all children ambulatory blood pressure monitoring (abpm) and 99m tc dmsa renal scanning (dmsa) were performed and z score body mass index (z-score bmi) were calculated. the following criteria were examined as predictive risk factors: age, gender, age at diagnosis andat resolution of vur, period between diagnosis and resolution of vur,grade of vur, type of vur (unilateral or bilateral), treatment modality (medical, surgical), z-score bmi, grade of dmsa and birth weight. results: i grade of dmsa scan was diagnosed in 27 children, iigrade in 85, iii grade in 31 and iv in 7 patients. hypertension (hp) was diagnosed in 20 children (13%). the mean value of z-score bmi in children with hypertension was significantly higher in comparison withchildren with normal blood pressure (0.043±0.21 and 0.74±0.86). the multivariate discriminate analysis showed that zscore bmi and grades of dmsa scars were significant risk factors for developing arterial hypertension in children with vur. both parameters had the same influence on development of hypertension (standardized coefficient of discriminate analysis 0,748 and 0,736 respectively). conclusion: the development of hypertension in children with vur is associated with higher bmi and higher grades of renal scars in dmsa scan. grange syndrome comprises arterial stenoses with hypertension, brachy syndactyly, bone fragility, learning disability, and cardiac defects and it has been reported in the members of two families up to now. we report here a 14-year-old boy with hypertension, multiple arterial stenoses, microcephaly and brachysyndactyly. severe hypertension (200/120 mmhg) was detected on his routine control for acute rheumatic carditis and he was hospitalised for investigation. he had no complaints. his parents were first degree relatives. his physical examination revealed microcephaly, bilateral brachysyndactyly between the forth and the fifth fingers of hands and the second and the third fingers of feet. complete blood count, electrolytes, renal, thyroid, and hepatic functions and acute phase reactants were all in normal limits. echocardiography showed aortic and mitral insufficiency and left ventricular hypertrophy. renal and cerebral magnetic resonance angiographies demonstrated stenoses at bilateral renal, internal carotid, superior cerebral and posterior cerebellar arteries. association of hypertension with microcephaly and finger abnormalities and multiple arterial stenosis suggested grange syndrome. chromosomal analysis showed 46 xy karyotype. hypertension persisted despite triple antihypertensive agents and percutaneous renal angioplasty was performed leading to a reduction of antihypertensive medication. with this case report we wanted to remind the recognition of this extremely rare syndrome in a hypertensive child with multiple morphological abnormalities and percutaneous angioplasty as a treatment modality in cases with persistent severe hypertension. hypertension is usually indicative of an underlying disease process in children. the combination of severe hypertension with hyponatremia is called hyponatremic hypertensive syndrome (hhs). in this report we present a case of hhs. the boy was referred to our hospital at the age of 7 years old with generalized tonic clonic convulsion. his past history was insignificant and positive findins of the patients were as follows: hypertension (170/115 mm/hg), agressive behaviors after convulsive period, metabolic alkalozis (blood gases, ph: 7,51, hco 3 : 24,8, pco 2 : 27,3), hypocloremia (87 meq/l), hypokalemia (3 meq/l), hyponatremia (123 meq/l), low urine density, polyuria and high serum aldosterone levels (1000 pg/ml, range: 20-240). the serum renin, cortisol, tyroid and antidiuretic hormones were within normal range. abdominal color doppler ultrasound were revealed double renal arteries in both kindneys. cranial and abdominal tomography examinations and cebrospinal-fluid examination were normal. the diagnosis of hhs was suggested based on these clinical and laboratory findins and therapy of nifedipine was started. the arterial pressure improved with this therapy. in hss due to renal ischemia, activation of renin angiotensin system which induce pressure natriuresis and thus, thence hyponatremia. we think that presence of renal arterial anomaly might be a cause of an ischemic condition and activation of renin-angiotensin-aldosterone system in our patient. also, activation of aldosterone could enhance with hyponatremia and it could be suppressed of renin secretion in our patient. [hadtstein et al. hypertension 2004] . the aim of this study was to analyze whether children with renal scars have altered rhythms of mean arterial pressure (map) and heart rate (hr). study design: ambulatory 24-hour blood pressure profiles of 61 untreated patients with renal scars associated with recurrent urinary tract infections and vur were investigated and compared to 938 healthy controls. results: pre-pubertal, but not pubertal patients with renal scars displayed a number of significant differences to controls. before puberty, the mesors of map and hr were significantly elevated, and the peak-trough difference of the 24 h curve was blunted by 7.5 mm hg for map and 7.8 bpm for hr. the amplitudes of 24 h and 8h map rhythms were blunted by 2.0 and 1.5 mmhg, and those of 24 h and 12h hr rhythms by 1.9 and 1.2 bpm (all p<0.05). pubertal patients did not display any abnormalities of bp or hr rhythms. we did not find any correlations of the degree of renal scarring, bmi or gfr with the abnormalities in cardiovascular rhythms. conclusion: in summary, pre-pubertal children with renal scarring due to vur show blunted circadian and ultradian rhythms of bp and hr. this phenomenon may reflect subtle alterations of autonomous nervous signaling in children with damaged kidneys; it remains to be addressed whether such abnormalities constitute an independent cardiovascular risk factor. mutations in the eya1 gene are associated with bor/bo syndrome and rarely with an isolated renal phenotype. we present a family from macedonia displaying a novel eya1 gene mutation. a six-year-old female was found to have bilateral grade iii vesicoureteral reflux (vur) after an episode of acute pyelonephritis. mutational analysis detected a novel eya1 gene mutation [an inframe 3bp deletion (c.4_6delttg), resulting in l2del of eya1a]. she had no clinical stigmata for bor/bo syndrome. the paternal grandmother died due to end stage renal failure. all first grade relatives underwent detailed physical and ophtalmological examination, audiometry, ultrasound screening of the urinary tract and mutational analysis of the eya1 gene. the father and older sister were mutation carriers and both had normal ultrasound findings. the physical examination did not reveal abnormalities suggestive for bor/bo syndrome, except the sister had esotropia/ hypermetropia and horizontal nystagmus. the male sibling was found to have mild hydronephrosis on the left side. he was not a mutation carrier and cystographic study was not performed at that time. on repeat ultrasound examination he demonstrated dilatation of the right prevesical ureter. the cystography revealed presence of right sided vur grade iii. in conclusion: we present two siblings with vur; although eya1 gene mutation was found in one of them, it can not be incriminated for the renal phenotype in this family, as co-segregation of the mutation with the vur does not occur in all affected members of the family. decision to perform cystographic study should be still based on clinical grounds. associations asymmetric dimethylarginine (adma) is a novel predictor of cardiovascular (cv) outcomes in adults. aim: to evaluate adma in children with hypertension. subjects: 23 children (4 girls/19 boys; median age: 15 yrs) with primary (n=10) and secondary (n=13) hypertension. methods: adma levels were analyzed by elisa method. in study subjects antropometrical data, ambulatory blood pressure monitoring (abpm), left ventricular mass index (lvmi), carotid artery intimamedia thickness (cimt), 24-hour urinary albumin excretion (uae) and serum biochemical markers (lipids, uric acid) were also evaluated. results: adma concentration was positively correlated to serum uric acid (r=0.42, p<0.05) and uae (r=0.45, p<0.05). when analyzed in boys separately, more apparent correlation was found for uae (r=0.57) and a tendency for adma to be associated with lvmi r=0.44, p=0.059). interestingly, when analysis restricted to older children (above the median age), adma correlated to lvmi more significantly (r=0.65, p<0.05). no relation was found of adma to cimt, lipids, and abpm parameters. moreover, patients with left ventricular hypertrophy (43%) and microalbuminuria (55%) had a tendency for higher adma values compared to those without these abnormalities (2.5±0.83 vs 1.74±1.1 μmol/l, p=0.081 and 2.39±1.23 vs 1.66±0.74 μmol/l, p=0.13, respectively). when data analyzed on the basis of adma values, patients in the top quartile showed the worst profile. when compared to the lowest quartile, they had higher lvmi (p<0.05), higher uae (p<0.05; inter-quartile comparison p=0.012), and higher uric acid concentration (p=0.052). conclusions: the associations of adma with known factors of cv damage found in this study provide evidence that adma is closely linked to the early cv dysfunction in hypertensive children. nephrogenic diabetes insipidus (ndi) is a disease characterized by unresponsiveness of distal tubule and collecting duct to vasopressin. although ndi usually presents with polydipsia and polyuria, most infants do not have any of these symptoms and presentation is with features of dehydration like fever, constipation, vomiting, failure to thrive and developmental delay. so, the diagnosis is usually delayed until hypernatremia is noted. almost all infants go through a period of hypogammaglobulinemia at approximately the 5th-6th months of age. at this time, the serum ig g level reaches its lowest point, and many normal infants begin to experience recurrent respiratory tract infections. the clinical findings of ndi and transient hypogammaglobulinemi of infancy (thi) may be seen at the same period. here, we report a five-month old boy with ndi. on his history, he was admitted because of recurrent fever attacks and was diagnosed as thi when he was three-months-old. on his follow-up, hypernatremic dehydration was detected and he was diagnosed as ndi. at the time of diagnosis, he had intracranial calcification secondary to delayed diagnosis of ndi. in infants with ndi, recurrent fever attacks due to dehydration may occur and incorrectly lead to think as an infectious disease. we think that this report can be an important warning for clinicians. we analyzed nphs1, nphs2 and neph1 gene in 8 japanese cns patients independent of the patients in previous report (k.i. 2005) from different japanese group which suggested that the mutation of nphs1 was not a major cause of cns in japanese patients. we extracted genomic dna from leukocytes and analyzed all exons and exon-intron boundaries for nphs1, nphs2 and neph1 using polymerase chain reaction and direct sequencing after informed consent had been obtained. the study was approved by the ethics committees of okayama university medical school. results: we found compound heterozygous mutations of nphs1 in 4 patients and homozygous mutations in 2 patients. one of these 2 homozygous mutations was already reported in paper from europe and was not found in more than 50 healthy japanese. another one cause defection of trafficking to the membrane as we reported before (k.i.2000 (k.i. , ajkd 2002 . the other 2 patients have only heterozygous mutation in nphs1 that healthy parent also has. we could find any mutations in neither nphs2 nor neph1 in the 2 patients with heterozygous mutation. one of these 2 patients has mild form of cns. another one has neither expression of nephrin nor podocin protein on kidney tissue by immunohistochemistry. interestingly, 4 patients out of 8 have the same mutation in nphs1 as nt2515(delc). parents who have this mutation heterozygously were from neighboring prefectures. all mutations including this mutation but one have never been reported out of japan which was isolated from continent. all amino acids substituted by missense mutations which seem to be causative were preserved among mouse, rat and human. conclusions: our studies clearly demonstrated that nphs1 is a major cause of cns even in japanese patients. moreover, nt2515(delc) is a common mutation in japanese cns patients like fin major or minor. long-term survival of childhoodonset ckd is mainly limited by the manifestation of cardiovasculardisease (cvd). the development of early stages of cvd can be assessedby non invasive methods, e.g. flow mediated vasodilation (fmd) ofperipherial arteries and measurement of intima media thickness (imt) of the common carotid artery. wetherefore performed fmd and imt investigations in 24 children and adolescents (mean age 15.8±5.1 years) suffering from ckd (mean gfr 44±33 ml/min/1.73 m 2 ) on conservative treatment (n=11), dialysis treatment (5 hd, 1 pd) and after renal transplantation (n=7), and in 24 sex-and age-matched healthy controls. ckdpatients showed significantly decreased fmd (5.2±3.1% vs 9.8±2.3%, p<0.001), where as imt did not significantly differ between patients and controls (0.48±0.06mm vs 0.46±0.08 mm, p=0.13). within the ckd group the presence of arterial hypertension tended to be associated with increased imt (0.48±0.006 vs 0.45±0.05 mm, p=0.05). in contrast, duration of ckd, mode of renal replacement therapy and degreeof renal dysfunction was not significantly associated with fmd and imt findings. conclusion: children and adolescents suffering from ckd show decreased arterial elasticity irrespective of the mode of renal replacement therapy, the rebycontributing to increased long-term cardiovascular morbidity and mortality. the genetic researches have shown the connection between the essential hypertension and angiotensinogen gene. the researches of preeclampsia also showed the connection with angiotensinogen gene. according to established connection of angiotensinogen gene with essential hypertension and also preeclampsia the aim of our research was to determine by the help of m235t, g-6a anda-20c polymorphisms of angiotensinogen gene whether there is a genetic disposition for essential hypertension in those children whose mothers had preeclampsia. at the same time we wanted to establish whether the polymorphisms of angiotensinogen gene can be connected with preeclampsia in women in our population. two groups of children were studied: children of mothers who had preeclampsia and children of mothers without hypertensive disease in the pregnancy. we also studied two groups of mothers: mothers who had preeclampsia and mothers without hypertensive disease in the pregnancy. m235t, g-6a and a-20c polymorphisms of angiotensinogen gene were performed using the pcr method. in investigating the differences between the two groups of children no statistically significant differences were found in m235t,g-6a and a-20c polymorphisms of angiotensinogen gene. in investigating the differences between two groups of mothers no statistically significant differences were found in genotype distribution. the results of our study failed to confirm that with help of m235t, g-6aand a-20c polymorphisms of angiotensinogen gene we might establish genetic disposition for essential hypertension in those children whose mothers had preeclampsia. we did not confirm the association between m235t, g-6a and a-20c polymorphism of angiotensinogen gene and preeclampsia either. (11) previously treated also with cyclosporine. before start of fosinopril treatment all had proteinuria 0.7-4.2 g/24 h and gfr >60 ml/1.73 m 2 /min. all active steroid and immunosuppressive treatment were discontinued. eleven children also were treated with calcium channel blockers to control hypertension. after twelve months of fosinopril (0.3-0.4 mg/kg) treatment a dna analysis for ace-gene polymorphism was performed. three patients carried ii, 10-id and 4-dd gene polymorphism of ace gene. no significant differencein proteinuria at start of fosinopril treatment between all polymorphism types was observed. all 3 patients with ii polymorphism had a good antiproteinuric effect of fosinopril with more than 4-fold decrease in proteinuria in comparison with just 2,3 fold decrease in id polymorphism and no response in dd. renal function remained stable in all children except of 2 with id and 2 with dd gene polymorphism who demonstrated decrease in gfr. we suggest that ii polymorphism of ace gene may be associated with better antiproteinuric effect of acei while dd predicts poor response. wider study is required to confirm genetic predisposition for ace blockade efficacy in proteinuric diseases. introduction: dent disease is x-linked recessive proximal tubulopathy, due to mutations in the clcn5 gene. it is characterized by low molecular weight proteinuria, hypercalciuria, nephrocalcinosis and progresive renal failure. aim: case report of patient with short stature and proximal tubulopathy where dent disease is determined by gene analysis. method: seven-year-old boy is refered after endocrinological exemination where abdominal ultrasound showed nephrocalcinosis. there are anamnestic data neither of oedema, macrohaematuria, nor poliuria or hypertension. there are also no data of chronic renal failure in the family. we describe detailed diagnostic procedures performed in the boy and his family. results: we determined: proteinuria (1,8 g/day), elevated urinary excretion of beta-2microglobuline, microscopic hemathuria, hypercalciuria (8-10 mg/kg/day), nephrocalcinosis, decreased tubular reabsorption phosphate (65-72%). values of grow hormone, parathormone on thyroid hormone are normal. except hypercalciuria, which is registered in patient's mother, all other analysis performedin family members are betwen referent values. diagnosis is finalized by mutation analysis, which has showed s244l substitution on cncl5. mutation carrier is mother with normal fenotype. conclusion: dent disease is rare x-linked nephrocalcinosis. definitive diagnosis ofthis proximal tubulopathy which leads to progressive renal demage, is not possible without evidence of gene mutation in renal chlor channel. introduction: the segmental renal infarction is a rare disease, allthough it is more frequent in children than in adults and can be clinically veryrelevant. objective: we describe the clinical course of two children with idiopaticsegmental renal infarction who suffered severe arterial hypertension. cases description: the typical clinical picture of this disease, as seen in our twopatients, is characterized by metabolic alkalosis, hyponatremia, hypokaliemia, hyper-reninemia, hyperaldosteronism and renal salt lossfrom the contralateral enlarged kidney. hypertension was diagnosedduring the study of haematuria in the first case and due to ahypertensive emergency in the second case. the ethiology was found tobe renovascular in both patients, involving the occlusion of small renal arteries causing segmental renal infarction. our first patient was treated with partial nephrectomy, and the second patient wastreated with antihypertensive medication given the impossibility ofremoving the renal infarcted area. conclusions: in the clinical picture, the sodium depletion with increased urinary volume of the contralateral healthy kidney can be explained by the goldblatt model. the gold standard test for the diagnosis is theselective renal arteriography, which is the most sensible and specifictest for diagnosing renovascular hypertension secondary to a segmental renal infarction because it helps identifiing the segmentary artery ofthe infarcted area, this being the source of increased focal renin production. the definitive treatment is the surgical segmentectomy. if segmentectomy is not feasible because of the localization of the infracted area as inour second patient, a medical treatment is needed. conclusion: although an inverse association between birth weight/blood pressure has been suggested in several large studies, interpretation is still controversial. in our study, we have found only a weak inverse correlation between birth weight and pad (abpm): no statistical significance has been found among other variables, although graphs show a trend of low birth weight children towards hypertension. probably a long term follow-up is necessary. he took longer to have improvement, but his calcemia, phosphatemia and alkalinephosphatase are normal. the coding region of the vdr was amplified by pcr and directly sequenced. results: three mutations (two novels) were identified. two patients had anovel mutation in exon 7, changing the amino acid glutamine to glutamicacid at position 259 (q259e). one patient had a novel mutation in exon 8 changing glycine to valine at position 319 (g319v). those mutations are in the ligand binding domain and belong to the patients with better control of the disease. one had mutation in exon 3, in the dna binding domain, changing arginine to a stop codon at position 73 (r73x) and it was from the patient with worse response to the treatment. conclusions: two novel mutations are presented in the vitamin d receptor and it could be possible to do a correlation between the clinical evolution and the localization of the mutations. we aimed to evalute the effects of intrauterine growth retardation (iugr) on blood pressure (bp) in small for gestational age (sga) children. 23 sga children (6f,17m) aged 9.4±3.9 y (5 preterm and 18 term) and 13 (8f, 5m) agematched control with appropriate for ga (aga) were included in the study. 24-hr ambulatory blood pressure monitoring (abpm)was performed using an oscillometric device (mobilograph). 95th centile limit was set according to published data sets, nocturnal threshold was 10% less than awake limits. bp was classified as normal if the mean sbp is <95th percentile and sbp load is >25%. nocturnal bp dip for sbp and dbp were evaluated. in 2 sga and in 1 aga case, office sbp were above 95th%, all dbp values were normal in both groups. according to the mean of 52 abpm records, 2 systolic,1 diastolic ht were determined in sga group, and 3 systolic, no diastolic ht were in aga group. there were 9 sga and 5 aga children whose sbp load over 25%, and only 5 of them remarked as hypertensive according to mean sbp values. 5 children considered as hypertensive had significantly higher sbp loads than those that were not hypertensive(38% vs 10%, p<0.05). abpm records were not different between preterm and term sgas. sga group had lower nocturnal bpdip for sbp and dbp in comparison to aga group(13.5% vs 14.5% for sbp,15.4%vs 18.1%for dbp, p: 0.62). although it was not statistically significant, the frequency of non-dipper children was higher in sga group (22.7%) than those in aga group (8.3%). except the lower nocturnal bp dip and higher sbp loads in sga group which may be a marker for further hypertension, no clear association between being sga and hypertension could be found in our study population. pres is a rare clinico-radiological entity associated with acute hypertension, renal insufficiency and immunosuppressive therapy. it is typically reversible but cases with irreversibility had rarely been reported. we report 2 contrasting cases of pres associated with renal disease, one with full recovery and the other subsequently had epilepsy. first patient had steroid sensitive nephrotic syndrome with acute hypertension, fluid overload and acute renal failure while the second patient had severe flare of lupus nephritis with malignant hypertension, renal failure and thrombotic thrombocytopenia. both had acute onset of drowsiness, blindness and seizures and mri findings of subcortical oedema in the parietal-occipital-temporal regions. while the second patient had full recovery, the first patient developed temporal epilepsy and repeat mri showed mesial temporal sclerosis. pres is attributed to capillary leak from functional cerebral vascular changes of hypertension, rather than infarction. prolonged vascular disruption may lead to ischemia resulting in neurological sequelae and chronic epilepsy. using mri, pres can be readily diagnosed and normalisation of blood pressure is imperative in patients at high risk of pres. efforts have been done to describe the significance of various genetic polymorphisms (snps) in acute renal failure (arf). available reports do not investigate the predictive value of snps in disease forecasting, because so many interacting factors influence arf that classical statistical methods become unstable. high-dimensional nonparametric methods such as random forest technique overcome this problem and help to identify each clinical and genetic factor that possibly contributes to disease. we tested the classification value of basic clinical data available at birth and 19 snps in arf of 111 preterm infants. we determined the relative importance score (ri) of each parameter in classification. low birth weight and gestational age had the highest ri; just few snps had medium ri, while the majority of snps had small ri. then we created variable-patterns and searched for pattern with the highest accuracy of classification. for each complication, the accuracy was 0.71 solely basic clinical data were considered. if snps were incorporated, the accuracy of classification for arf was not improved. in contrast with previous observations these findings suggest that the snps do not provide additional information about arf-risk of the general preterm population. conclusions: srbd in children with elevated blood pressure is higher than that of the general pediatric population. the prevalence appears highest in patients with pre-hypertension and may be higher in patients with essential and secondary hypertension than in patients with white-coat hypertension. the renal phenotype in lowe syndrome is similar to dent's disease a 22-month-old girl presented with heart failure due to severe hypertension (200/120). doppler ultrasonography (us) revealed a right renal artery stenosis. biological findings showed normal serum creatinine (scr) (35 mmol/l), hyponatremia (131 mmol/l) and hypokalemia (3 mmol/l). aldosterone plasma level was increased as were epinephrine (429 pg/ml n<185) and norepinephrine (1230 pg/ml n<450) plasma levels measured 3 times. renal arteriography confirmed the presence of a nearly obstructive right renal artery stenosis with a normal left kidney. pta failed to improve signifcantly the renal artery flow. in the following hours after pta, her scr level increased, up to 160 mmol/l. doppler us showed an unchanged right kidney but 3 hypoperfused area in the left kidney confirmed by the tc 99 -dmsa scan. both aspects were strongly in favor of focal ischemic events. secondarly, her renal function improved but hypertension remained difficult to control autotransplantation of the right kidney was then done, but unfortunately, thrombosis of the right renal artery occured in the following hours. six months later, her plasma creatinine level is of 55 mmol/l. her cardiac function is normal but she has to remain on antihypertensive drugs. what exactly happened during arteriography in her left kidney, in order to provoke such ischemic injury, knowing that the left renal artery was not catheterized during arteriography and pta? one hypothesis is that arterial vasospasms occured, explained by a high vasospastic predisposition due to enhaced cathecolamines secretion. such increased has already been drescribed in patients with renal artery stenosis. this case raised the question of preparing patients in this condition with efficient antispasm therapy agents before radiological vascular investigations are done. rtd is a cause of oligohydramnios leading to potter's sequence and neonatal anuria. it is characterized by absent or hypoplasic proximal tubules. these lesions can be secondary to non genetic conditions involving renal hypoperfusion. genetic forms of rtd have autosomal recessive transmission. mutations of genes encoding for the renin-angiotensin system have been reported. evolution is most often severe with in utero or neonatal death. case report: this boy was born at 38 weeks of gestation with oligohydramnios, arthrogryposis, large fontanels with poor calvarian ossification. he was referred to intensive care unit for respiratory distress, low blood pressure (bp) unresponsive to vasopressors and anuria (plasma creatinine 370 μmol/l at day 3). renal ultrasound (us) showed enlarged kidneys with bilateral cortical hyperechogenicity. weaning from ventilation and vasoactive drugs was possible at day 7. glomerular filtration recovered (plasma creatinine 45 μmol/l at day 26). at age 10, the child is well with normal growth and a mild chronic renal insufficiency (creatinine clearance 75 ml/min/1,73 m 2 ). bp is in the low normal ranges with plasma renin x40 over the upper range of normal values and normal plasma aldosterone. on renal us, kidney volume normalized with persistent cortical hyperechogenicity. genetic study revealed compound heterozygous mutation in the gene encoding angiotensin converting enzyme. one is a nonsense mutation (r1209p), the other is a truncating mutation (k601fsx640). it is possible that the first mutation is less deleterious than the other and this could partly explain the unusually favourable evolution of this rtd. in conclusion, this is a rare report of a child with autosomal recessive rtd surviving after neonatal period. further functional studies are needed to explain this unusual phenotype. data on hbp in children are very limited, and it is unclear how much it is specific in pediatric patients. the objective of our study was to determine the reproducibility of hbp in children and adolescents. automatic omron 705-cp devices, which have been validated for use in children and adolescents, were provided to all families. hypertensive children measured blood pressure (bp) every minutes, three times consecutively in the morning or early afternoon, and three times in the evening during 13 days. the reproducibility of hbp was quantified using repeated measures analysis of variance test and the sd of differences between average hbp values of consecutive days. confidence interval (ci) was calculated. we studied 41 patients (14 girls, 27 boys); mean age was 12,1 year, range 4-18 years. there were 78 measurements of systolic blood pressure (sbp) and diastolic blood pressure (dbp). in the morning or early afternoon the mean sbp and dbp were 110,9 mmhg (sd 10, 65) (95% ci 107, 5-114, 3 mmhg) and 64, 4 mmhg (sd 9, 08) (95% ci 61, 4-67, 3 mmhg), respectively. in the evening the mean sbp and dbp was 111,6 mmhg (sd 10,14) (95% ci 108,3-114,8 mmhg) and 65,0 mmhg (sd 8,83) (95% ci 62,2-67,9 mmhg). the mean average difference between the daily measurements of sbp and dbp were analyzed with each period and were not statistically significant (p>0.05). on the basis of these results, we conclude that self-monitoring of blood pressure at home in children has good reproducibility and is not influenced by white coat effect. case report: a 3-year-old caucasian girl presented with history of severe polyuria and polydipsia of few months duration. past history was significant for head injury and possible seizure activity at age 1 yr. there was no history of headaches, vomiting, or visual problems. family history negative for di. physical examination was essentially normal. basal plasma and urine osmolality, and plasma vasopressin were 294 and 96 mosm/kg, and <0.5 pg/ml, respectively. at the conclusion of water deprivation test these readings were 309 and 98 mosm/kg, and 31.3 pg/ml, respectively. however, urine osmolality increased to 493 mosm/kg after desmopressin injection, confirming the diagnosis of cdi. mri scan revealed absence of the bright spot on t 1 weighted images. genetic analysis detected avp gene mutation a19t, where the normal alanine at amino acid position 19 is changed to threonine. elevated levels of plasma vasopressin after water deprivation were misleading and intriguing. we believe that elevated plasma vasopressin, although immunoreactive was devoid of biological activity. conclusion: molecular genetic evaluation should be performed in all children with cdi without an identifiable cause, even in the absence of a positive family history of cdi. mutations of the nphs2 gene encoding podocin lead to autosomal recessive corticoresistant nephrotic syndrome, focal and segmental glomerulosclerosis (fsgs), and early end-stage renal disease (esrd). in mice, podocin inactivation by homologous recombination results in diffuse mesangial and glomerular sclerosis, esrd and death within the first 5 weeks of life. this early demise precludes extensive study and elucidation of the molecular pathways engaged by podocin in the mature kidney. we have, therefore, generated a novel mouse model in which a tamoxifeninducible creer-loxp system allows for conditional inactivation in a temporal fashion in podocytes. following tamoxifen administration in nphs2 flox/-, cre+ mice, cre expression was noted in 88% of glomeruli and in 60-70% of podocytes. two weeks after cre induction, podocin expression is decreased in podocytes correlating with the appearance of selective albuminuria at 10-16 days. this progresses to massive, nonselective proteinuria by 4 weeks, along with high blood pressure and impaired renal function. optical microscopy of kidneys showed no lesion at 1 week and fsgs progressively developed by 4 weeks along with tubular lesions. however electron microscopy revealed a partial foot process effacement at 1 week with no significant albuminuria that extends by 2 weeks along with abnormalities of the basement membrane and development of albuminuria. no mesangial or vascular lesion has been noted, differentiating it from our previous podocin null model in which renal development may be affected by podocin loss or nephrotic syndrome. this model will allow a better understanding of the mechanisms underlying the development of nephrotic syndrome and the role of podocin in the mature kidney, and will be crucial to test new therapeutic approaches. glomerulonephritis is a group of diseases with complex etiology, pathogenesis, morphological features and clinical course. the renin-angiotensin and coagulation systems genes are important group of candidate genes involved in pathogenesis of chronic renal diseases. the purpose of our study was to analyze the association of genetic polymorphisms of these genes with glomerular kidney diseases. the study population consisted of 181 patients with immunological glomerular kidney diseases and 19 patients with renal failure with glomerulonephritis as primary disease. the control group consisted of 80 healthy subjects. by means of the polymerase chain reaction (pcr) the following polymorphisms were evaluated: insertion/deletion (i/d) polymorphism in intron 16 of the angiotensin-converting enzyme gene (ace), 4g/5g polymorphism of the plasminogen activator inhibitor-1 (pai-1). no significant association was found between the ace and pai-1 allele and genotype frequencies and the disease. more progressing of glomerulonephritis current was marked at patients with simultaneous has dd genotype of ace gene and 4g/4g gene pai-1(c 2 =9,1; p=0,008). our results suggest that ace i/d and pai-1 4g/5g polymorphism is an important modifying gene in the progression of glomerulonephritis. captopril objectives: secondary causes of hypertension such as renovascular hypertension are more abundant in children unlike adult population. the objective of this retrospective study is to assess the use of captopril renography (cr), which provides a non-invasive approach in the differential diagnosis of hypertension. patients and methods: clinical, radiological and scintigraphic data of a total of 64 patients were analyzed. there were 22 girls and 42 boys (mean age: 13±3 years). none of the patients had parenchymal renal disease or reduced renal function. all patients were orally hydrated before scintigraphic study. cr was performed 1 hour after orally captopril administration and iv furosemide injection was done simultaneously with 1-5 mci tc99m-mag3. when post-captopril study was normal, baseline scintigraphy was not performed. computed tomography angiography (cta) was performed in 11 and gadolinium-enhanced magnetic resonance angiography (mra) was performed in 8 children in addition to routine renal doppler ultrasonography (dus). results: nineteen out of 64 patients had other comorbid diseases as follows: obesity n=10, previosly-diagnosed fibomuscular dysplasia n=3, n=2 neurofibromatosis, n=2 demyelinating diseases, n=1 bartter and n=1 turner syndrome. cr was normal in 48 patients. in 8 children abnormal cr findings in correlation with radiological methods were reported. correlation with radiological methods could not be done due to suboptimal technique in 7 patients, of whom dus in 5 obese children could not be interpreted. in the other 1 patient, although cr was abnormal, radiological methods could not confirm scintigraphy. conclusions: captopril renography is a useful and simple-to-perform imaging modality in children suspected of having renovascular hypertension. takayasu's arteritis (ta) is a chronic, inflammatory, large-vessel vasculitis affecting the aorta and its main branches, which causes stenosis, occlusion, rarely aneurysm and distal ischemia. the disease is most common in young women, it is rare in inviduals before the age of 16 years. clinical presentation may be heterogeneous. in this report, we present a pediatric patient with ta who had hypertension as the sole manifestation of multipl critical arterial involvement but no other symptoms. a 14-year-old boy was admitted with hypertension. the acute-phase reactants were moderately elevated with an erythrocyte sedimentation rate 70 mm/h, and a c-reactive protein value of 26 mg/l. serologic tests including ana, anti-ds dna, c and panca, complement c 3 , and c 4 were negative and other laboratory data were normal. mr angiography showed multiple severe stenosis or occlusions of the thoracic and abdominal aorta together with bilateral renal arteries, and saccular aneurysm in the abdominal aorta. immunosuppressive treatment including pulse steroid and methotrexate was prescribed. the patient underwent angioplasty of bilateral renal arteries and suprarenal aorta, and a stent was placed in the right renal artery. ta should be kept in mind in the differential diagnosis of hypertension in children, even if they do not have other associated symptoms of the disease. human urotensin ii is the most potent vasoconstrictor which circulates in the plasma of healthy individuals. it was suggested that it has an endocrine role in sodium handling and even in metabolic syndrome. the aim of this study was to investigate the role of u-ii in obese adolescents with hypertension. fourteen obese adolescents with essential hypertension (group 1) were compared with thirteen age-and sex-matched obese adolescents with white-coat hypertension (group 2). they underwent twenty-four hour abpm and echocardiographic investigation, complete physical examination, including adiposity indexes. plasma and urinary levels of u-ii were measured by ria. obese adolescents in group 1 have significantly higher blood pressure measurements than those in group 2 confirmed by abpm. there was no significant difference in left ventricular mass index between two groups. no significant difference was found in plasma u-ii concentrations (pg/ml) between group 1 and group 2 (35.23±4.90 and 35.98±5.74, respectively), whereas mean urinary u-ii level (pg/mg urinary creatinine) was significantly higher in group 2 than that of group 1 (28.80±6.83, 44.44±16.78, respectively). considering the renal synthesis and vasoactive role of u-ii, these results suggest that u-ii may have a role in adolescents with white-coat hypertension. distal renal tubular acidosis (drta) and deafness is a rare autosomal recessive disease characterized by severe metabolic acidosis in childhood and inappropriately high urinary ph along with sensorineural hearing loss. the disease is caused by defects in the atp6v1b1 gene. the aim of the present study was to determine the molecular basis for drta with deafness in eight patients from four families (a-d) in israel. molecular testing was done by sequencing the coding exons of the atp6v1b1 gene in one affected child from each family. a population screen was performed for mutations found in family a. the results yielded a different mutation in the atp6v1b1 gene, as follows: families a and d: missense mutation, 1037c>g (p346r), in addition to a single nucleotide polymorphism (2t>c) in the first codon; family b: insertion mutation, 1155-1156insc (i386fs); family c: a novel nonsense mutation, 340 c>t (r114x). in conclusion, the phenotype of drta and deafness concurs with mutations in the atp6v1b1 gene. in the present study, four families of different origins with the same phenotype had three different genotypes, indicating that there is no single common mutation in israel. these findings have implications for genetic counseling during pregnancy and testing of families. the fact that all the patients that were examined have harbor mutations in the atp6v1b1 gene, pointed for the specific clinical phenotype. making correct and early clinical diagnosis is a fundamental step in finding the molecular basis of this rare disorder. delta f508 is the most common cystic fibrosis (cf) mutation worldwide. the prevalence is approximately 70% in caucasian and 14-55% in asian while f311l is demonstrated in only 0.2%. homogenous delta f508 mutation is recognized as the most common genotype however there are small numbers of cf patients having delta f508/f311l. in the present study we report a 2 year-old thai boy, originated from north india, presented with recurrent episodes of febrile illness, hyponatremia, hypokalemia and metabolic alkalosis since 4 months of age. he was transferred to our hospital for further investigation. blood chemistry revealed serum electrolytes: sodium 122, potassium 3.69, chloride 79.7, bicarbonate 33.8 meq/l, and urine electrolytes: sodium<10, potassium 45.7, chloride<10 meq/l. after intravenous fluid administration, hyponatremia and metabolic alkalosis improved. dna sequencing analysis of his blood demonstrates compound heterogenous mutation for delta f508 and f311l in cftr gene. t to g transversion at nucleotide 2694 and g to a transversion at nucleotide 4521 are found without altering amino acid encoding gene. in conclusion, we report a rare case of cf with delta f508/f311l genotype presented with recurrent hyponatremia and metabolic alkalosis. awareness of electrolyte abnormalities during febrile illness, proper genetic counseling and long-term follow-up are necessary in this patient. objectives of study: about 10% of families with congenital nephrogenic diabetes insipidus (ndi) have mutations in the aquaporin 2 gene (aqp2), which codes for the vasopressin-sensitive water channel. only seven aqp2 mutations are known to cause a dominant form of the disease. in this study we performed genetic and clinical studies in a 5 generation family with autosomal dominant inheritance of a partial di phenotype. methods and results: the proband (man, 37 yrs old) was initially diagnosed with partial central diabetes insipidus due to antidiuretic effect of ddavp. his daughter (1.3 yrs old) also showed polyuria and polydipsia which was responsive to high doses of intranasal ddavp. the pedigree was consistent with an autosomal dominant inheritance pattern. sequence analysis of the entire coding region of the avp gene and aqp2 gene was performed in the proband and his affected daughter and in 2 unaffected family members. the avp gene was normal in all subjects. in the two affected patients but not in the healthy subjects we identified a novel missense mutation in one allele of exon 4 of the aqp2 gene (c.760c>t) which predicts a substitution in the c-terminal part of the aqp2 protein (p.r254w). conclusion: partial ndi can be caused by heterozygosity for a p.r254w substitution of the aqp2 water channel. the substitution is likely to significantly alter the c-terminal tail of aquaporin 2 which is important for proper trafficking to the apical plasma membrane. the preservation of some residual antidiuretic function indicates that some aqp2 tetramers are processed correctly. the study further illustrates the importance of molecular diagnostic tools in establishing a correct differential diagnosis in familial cases of di. a background and aim: dent's disease is a renal tubulopathy characterized by low-molecular-weight proteinuria, hypercalciuria, nephrocalcinosis and nephrolithiasis. mutations in the clcn5 gene encoding the chloride/proton exchange transporter clc-5 cause this disease. we have described an alu insertion in clcn5 that leads to exon 11 skipping in the patient's mrna. in this study, we investigated the consequence of this mutation on the function of two putative exonic splicing enhancers (eses) in exon 11 and the role of alu 5'-end sequences on splicing inhibition. methods: minigenes were constructed by inserting exon 11 and exon 11-alu with their intronic flanking sequences into the exon trap vector. artificial mutations were introduced by site-directed mutagenesis. plasmids were transfected into cos7 cells by electroporation. pre-mrna splicing analysis was performed by rt-pcr. the ese finder web resource was used to predict the mutagenesis effects on the eses. results: alteration of one of the putative eses, the predicted binding site for srp40, induced exon 11 skipping. restoration of this site within the alu sequence promoted the incorporation of exon 11-alu in the mrna. however, restoration of both eses leaving the alu sequence intact resulted in exon skipping. furthermore, substitution of the eses for the first seven nucleotides of the alu element, and insertion of this sequence next to the eses increased exon skipping. deletion or modification of the alu 5'-end enhanced exon 11 inclusion in the mrna. in the patient carrying the clcn5 alu insertion, dent's diseases is caused by disruption of an ese and by inclusion of splicing inhibitory sequences leading to exon skipping. this work was supported by grant pi042620 from fondo de investigación sanitaria. factor h-associated hemolytic uremic syndrome (fhd-hus) is a rare disease with incomplete penetrance. it is not clear why and how carriers of the same mutation will eventually develop or not develop the disease and this uncertainty is sometimes responsible for anxiety in the carriers badly affecting their quality of life (particularly of parents with children carrying the mutation). in the attempt of estimating disease risk in subjects with factor h gene mutation, the 6 families of fhd-hus patients (all of which had a documented mutation on the scr20) currently being treated at our center, were screened to identify the carriers after having been informed on the purpose of the analysis. twenty-eight subjects (age range 0-89 yrs), out of 55 analyzed, revealed heterozygous mutations in the carboxy-terminal region of fh1 gene (51%). among subjects carrying the mutation, 9 (32%) had exhibited the disease at a mean age of 12 years (range 0.2-32), 6 of which (67%) before age 10, whereas the remaining 19 subjects (mean age of 53 yr -range 11-89) were healthy at time of the study. the figure shows the probability of carriers to be hus-free by age (no event occurred after age 32 yrs). in the meantime that predisposing factor are identified, the presented survival curve (fig.1) can be an useful tool to estimate the residual risk of hus in individual carriers according to their specific age. cerebello-oculo-renal syndrome (cors) (also called joubert syndrome (js) type b) and meckel (mks) syndrome belong to the cilliopathy group of developmental autosomal recessive disorders associated with primary cilium dysfunction. nephronophthisis (nphp), the most frequent genetic cause of renal failure in children and young adults, is associated with retinal degeneration and cerebellar vermis aplasia in cors. mks is characterizd by renal cystic dysplasia, central nervous system malformations and hepatic developmental defects. these syndromes are genetically heterogenous: mutations in ahi1 and nphp1 can cause cors and mutations in mks1 can lead to mks, while mutations in mks3 and nphp6 are found in both syndromes. using snp mapping, we identified missense and truncating mutations in a novel genee, nphp8, in both cors and mks. interestingly, all sequence changes were either nonsense or frameshift mutations in fetuses with mks whereas patients with cors had either only one or no truncating mutation. we then show that inactivation of nphp8 mouse orthologue recapitulates the cerebral and renal defects of cors/mks. we further demonstrate that nphp8 protein co-localizes at the basal body/centrosomes with nephrocystin-6 and nephrocystin-4, the protein products of both nphp6 and nphp4, known disease genes for nphp. in addition, missense mutations of nphp8 protein found in cors patients diminishes its interaction with nephrocystin-4. taken together. our findings demonstrate that mutations of this novel ciliary gene can cause the multiorgan syndromes of either cors or mks, which therefore represent a continuum of the same underlying disorder. severe antenatal bartter's syndrome ga 25 + 4, bw: 750 g). both had classical signs of antenatal bs including very poor thrive, polyuria (5-10 ml/kg b.w./h) and responded to indomethacin treatment. direct sequencing was performed on pcr-amplified genomic dna. the entire coding region of both genes was analyzed. the kcnj1 gene was normal but both children were homozygous for a single base substitution (39671t>a) in exon 12 of the slc12a1 gene predicting a premature stop codon (y538x). the parents of both children and two siblings were heterozygous for the same mutation. by restriction enzyme analysis, the 39671t>a substitution was absent among 100 chromosomes from healthy subjects. conclusion: two children with severe antenatal bs were identified and the clinical phenotype was characterized. we identified in both children a novel mutation causing a premature stop codon of the bumetanide-sensitive-sodium-potassium-chloride co-transporter (nkcc2). despite large potassium supplements and indomethacin treatment, both children show persistent polyuria, vomiting, and insufficient thrive. background: mutations of nphs1 encoding the transmembrane slit diaphragm protein nephrin cause congenital nephrotic syndrome of the finnish type, characterized by massive proteinuria and the development of nephrotic syndrome before 3 months of age. about 70 different nphs1 mutations have been described. a large number of these are missense mutations resulting in single amino acid replacement mostly located in the extracellular domain. some nphs1 mutations have been associated with mild phenotypes responding to angiotensin-converting enzyme and prostaglandin synthesis inhibition. patient history: we report on a son of consanguineous turkish parents with a novel nphs1 alteration and steroid-resistant congenital nephrotic syndrome. after normal pregnancy and delivery at 37 weeks of gestational age the boy presented with edema and proteinuria at the age of 2 months. he responded to angiotensin converting enzyme inhibitor treatment reducing his proteinuria from a maximum of 66 g/g creatinine to 10 g/g creatinine and allowing him to develop normally until the age of 7 months when cardiovascular insufficiency in the course of a hyperpyretic infection led to hypoxic encephalopathy. genetic testing revealed a homozygous in-frame 3-bp insertion in exon 11 of nphs1. both parents were found to be heterozygous. no mutations were found in nphs2 or in exons 8 and 9 of wt1. the alteration results in an insertion of a glycine in an extracellular immunoglobulin domain of nephrin. the pathogenicity of this alteration is unclear. nephrin may be misfolded and mislocalized as in some missense mutations of the extracellular domain. alternatively the alteration might lead to an altered extracellular homo-and heterodimerization of nephrin. functional studies are currently underway to determine the effect of this novel alteration in nphs1. objectives of study: interleukin 1 receptor antagonist (il-1ra) gene polymorphism has been found to affect disease susceptibility and activity in several inflammatory diseases. we investigated the association between il1ra gene polymorphism and childhood nephrotic syndrome (ns) in a turkish population. methods: we analyzed the genetic polymorphism of il-1ra gene in 91 patients with childhood ns and 100 healthy controls by using pcr. five alleles of the il-1ra gene were identified and designated as il-1ra*1, il-1ra*2, il-1ra*3, il-1ra*4, and il-1ra*5, according to the variable number of tandem repeats in intron 2. results: in the ns group, the allele frequencies of il-1ra*1, il-1ra*2, il-1ra*3, il-1ra*4, and il-1ra*5 were 74.7, 13. 2, 4.4, 2.2, and 5 .5% compared with 58%, 28%, 1%, 0%, and 12% in the controls. a high allele frequency of il-1ra*1(x 2 =5.28, p=0.021) and a lower allele frequency of il-1ra*2 (x 2 =6.31, p=0.012) were found in childhood ns. the other polymorphisms were not significantly different from normal controls. conclusions: a high allele frequency of the il-1ra*1 allele may affect the disease susceptibility in childhood ns. objectives of study: congenital anomalies of the urinary tract (caut) are common in humans, and the incidence is increasing with recent advances in prenatal ultrasonographic examinations. interstitial fibrosis, which correlates with infiltration of inflammatory cells is common finding in the kidney with long-term ureteral obstruction. up-regulation of monocyte chemoattractant protein-1 (mcp-1), may be a common regulatory pathway involved in the progressive renal damage with any etiologies leading to interstitial fibrosis. mcp-1 gene polymorphism -2518 a/g had been suggested to influence circulating mcp-1 levels and gene expression thus, might be one of the genetic markers for progression of renal damage. our aim was to investigate the frequency of mcp-1 genotypes and allele -2518g in patients with caut. objectives of study: congenital urological anomalies are well recognized as causing renal dysfunction. on the other hand, patients without congenital anomalies but with urinary bladder dysfunction (bd) could also develop renal parenchymal damage. it has been reported that angiotensin converting enzyme (ace) i/d polymorphism was a risk factor for renal parenchymal damage in certain renal diseases including vesicoureteral reflux. the aim was to determine i/d polymorphism as a potential risk factor for renal parenchymal damage in patients with congenital obstructive uropathy and to compare them to patients born with normal anatomy and innervation of bladder, sphincter and pelvic floor but which could develop upper urinary tract abnormalities. objectives od study: to determine the frequency of pyelocaliceal dilation (pcd) in asymptomatic infants and its connection with presence of other urinary tract anomalies (uta) and urinary tract infection (uti). methods: ultrasonographic screening (us) of urinary tract (ut) was performed on unselected population of 1000 healthy infants ranging between 7 days and 6 months of age (511 boys and 489 girls). kidneys were divided into two groups according to grade of pcd. group i consisted of kidneys with pcd, whose anterio-posterior diameter was 5-10 mm, while patients from the group ii had a-p diameter wider than 10 mm.patients were followed up (ranging 5-58 months) by serial ultrasound examinations and with other methods for presence of uti and uta if necessary. results: in examined population 2,2% had uta, and 8,4% had uti. pcd was found in 74 infants (7,4%). in the group i, consisted of 63 infants (35 males and 28 females) pcd increased during the time in 3,2% infants, remained unchanged in 11,1%, decreased in 14,3%, and disappeared in 71,4% patients. uta was found in 4 (6,3%) infants, and uti in 9 (14,3%) infants. in the group ii, consisted of 11 male infants, pcd has not changed in 5 (45,4%) infants, decreased in 2 (18,2%), while dilation disappeared in 4 (36,4%) patients. uta was found in 6 (54,5%), and uti in 4 (36,4%) infants. conclusions: us of ut is useful and valuable method for detecting pcd. our results indicate that mild pcd in infants increases the risk for uta approximately 3 times and uti 2 times, while severe pcd raises the risk for uta approximately 24 times, and uti 4 times. early diagnosis and early treatment of uta and alertness for possible uti should be the final goal of the kidney damage prevention. therefore we recommend that us of ut should be done in all children in the first months of life. in order to determine factors involved in kidney development, the spatial and temporal expression pattern of intermediate filaments (cytokeratins, vimentin) , epithelial growth factor (egf) and transforming growth factor alpha (tgf-α), was investigated in developing kidneys (mesonephros and metanephros) of 5-9 week human embryos. immunohistochemistry for detecting specific antibodies was used on paraffin sections. in the 5-9 week human mesonephros, vimentin was moderately expressed in all mesonephric structures, while cytokeratins were seen only in the mesonephric nephrons. moderate to strong expression to egf and tgf-α detected in all mesonephric structures, decreased with advancing development. in the 5-6-week metanephros, vimentin was mildly expressed in all metanephric structures. later on, its expression increased in collectin system and interstitium. in the 5 th developmental week, first to appear were cytokeratins 8 and 19 in the ureteric bud and ampullae, while from the 8 th week onward, both cytokeratins showed increasing expression in the collecting system and nehrons. at early stages, egf and tgfá showed moderate to strong reactivity in the collecting system, the metanephric mesenchyme and cups. from the 7 th week onward, expression of both factors decreased in differentiating nephrons. expression of all investigated developmental factors was in line with subsequent mesonephric degeneration. expression pattern of intermediate filaments in the metanephros might be associated with mesenchimal to epithelial transformation of developing nephrons. some mutations of cytokeratins are lethal, while others might lead to some multifactorial disorders. egf and tgf-α expression patterns of the metanephros indicate their role in induction, proliferation and growth of metanephric structures. their disturbed expression might cause reduction in kidney growth. we have demonstrated that renin-angiotensin system (ras) and mitogen-activated protein kinase (mapk) family constribute to the renal development. growing evidences indicate that aldosterone, a final element or ras, is an independent and powerful mediator of various renal disease. purpose of this study was to evaluate the role of endogenous aldosterone in renal development including cell proliferation and apoptosis, and the expression of mapk family. newborn rat pups were treated with spironolactone (200 mg/kg/d) in olive oil or vehicle for 7 d. to identify cellular changes, kidneys were examined for proliferating cell nuclear antigen (pcna) by immunohistochemical (ihc) stain, and apoptotic cells by tunel stain. immunoblot, ihc stain and rt-pcr for mapks, phospho-mapks, and p53 gene were performed. spironolactone treatment resulted in decreased body weight, decreased pcna-positive proliferating cells and increased tunel-positive apoptotic cells, especially renal cortical epithelial cells (p<0.05). in the spironolactone-treated group, c-jun n terminal kinase (jnk)-2 and phospho-jnk-2 protein expressions were significantly increased, whereas extracellular signal -regulated kinase (erk)-2 and p38 protein expressions were sigificantly decreased compared with the control group (p<0.05) in immunoblot and ihc stain. expressions of erk-1, phospho-erk-1 and 2, and p53 sere not changed by spironolactone treatment. in rt-pcr, erk-2 and p38 mrna expressions were significantly increased in the spironolactone-treated group (p<0.05). we conclude that aldosterone inhibition in the developing rat kidney decreases cellular proliferation and increases apoptosis, and modulates the expressions of jnk-2, erk-2 and p38. mapk family expression may be implicated to differentially participate in aldosterone-related intracellular signaling pathways in the developing kidney. objectives: early detection of anomalies of the kidney and urinary tract (ut) helps to prevent complications but is hampered in moldova by diagnostic and logistic problems. to assess the extent of late diagnosis we studied the clinical data of all children referred to us for suspected ut infection (uti) in 2004/5 and found to have renal or ut anomalies. methods: 92 children (27 males; age 3 months-15 years) found to have anomalies of the kidney and ut and treated conservatively were studied (newborns and infants <3 months were seen elsewhere). work-up included ultrasonography in all, voiding cysto-urethrography (vcug) in 40%, urography in 57% and scintigraphy in 3% of patients. results: reasons for referral were febrile uti (38%); abdominal pain (31%), diarrhea and vomiting (16%), enuresis (9%) and dysuria (6%). uti was confirmed by urine culture in two thirds of cases. age at diagnosis of renal or ut anomaly was <1 year in 9%, 1-3 years in 6%, 3-7 years in 7%, 7-10 years in 30% and >10 years in 48%. renal hypo/dysplasia was found in 14, solitary kidney in 10 and a horseshoe kidney in 9 children. anomalies of the ut included hydronephrosis due to ureteral obstruction (13 up and 11 uv-obstruction), vesico-ureteral reflux (8), duplex systems (17) and bladder anomalies or mild infravesical obstruction (10). serum creatinine was in the normal range in all children. urolithiasis was found in 2 patients. conclusions: anomalies of the kidney and ut were diagnosed in nearly half beyond the age of 10 years, thus with considerably delay. based on the results of this study a new strategy of renal ultrasound screening in newborns including prenatal diagnosis and of closer co-operation with referring physicians has been implemented. objective of the study: the purpose of this study was to report the outcome of infants with antenatal hydronephrosis. methods: between may 1999 and june 2006, all patients diagnosed with isolated fetal renal pelvic dilatation (rpd) were prospectively followed at asingle tertiary renal unit. inclusion criteria were presence of rpd equal to or greater than 5 mm on prenatal ultrasound after 28 weeks gestation, at least six-months of follow-up, and at least two postnatalus scans. the events of interest were presence of uropathy, rpd resolution, urinary tract infection (uti), and hypertension. rpd was classified as mild (5-9.9 mm), moderate (10-14.9 mm) and severe (>15 mm objective of the study: the aim of this study was to compare the accuracy of ultrasound renal parameters to discriminate between significant uropathy and idiopathic renal pelvis dilatation. methods: 193 neonates who were found to have isolated fetal renal pelvis dilatation (rpd) underwent systematic investigation and were prospectively followed. a us scan was performed after the first week of life and all infants underwent vcug. neonates with rpd larger than 10 mm were examined by renal scintigraphy. receiver-operating characteristic (roc) plots were constructed to determine the accuracy of three indexes: fetal rpd, postnatal rpd, and sfu grading system. results: a total of 193 infants were included in the analysis. ninety-five fetuses (49%) presented bilateral renal pelvis dilatation. seventy-nine infants (41%) presented urinary tract anomaly, corresponding to 95 renal units. the most frequent detected uropathy was ureteropelvic junction obstruction (61), followed by primary vesicoureteral reflux (26), and megaureter (8) conclusions: our data support the view that fetal and postnatal us renal parameters are useful markers to identify infants with clinically significant uropathies. there was no significant difference in performance among the indexes. objective of the study: the aim of this study was to evaluate the diagnostic accuracy of ultrasound (us) renal parameters to identify vur in infants withisolated antenatal hydronephrosis. methods: 193 neonates who were found to have isolated fetal renalpelvis dilatation (rpd) underwent systematic investigation and wereprospectively followed. a us scan was performed after the first week of life and all infants underwent vcug. neonates with rpd larger than 10mm were examined by renal scintigraphy. receiver-operating characteristic (roc) plots were constructed to determine the accuracy of three indexes: fetal rpd, postnatal rpd, and sfu grading system. results: a total of 193 infants were included in the analysis. seventeen infants (8.8%) presented vur, corresponding to 26 renal units. to discriminate between renal units with and without vur areaunder the curve (auc) was estimated by the roc curve, which was 0.52 (95% ci=0.47-0.57), 0.58 (95% ci, 0.53-0.63), and 0.55 (95% ci, 0.50-0.60) for fetal rpd, postnatal rpd, and sfu grading system, respectively. there was no statistically significant difference between the indexes. the optimal threshold for fetal rpd was 7 mm with a sensitivity of 69% (95% ci, 48-86) and specificity of 45% (95% ci, 40-51), for postnatal rpd the respective figures were: 54% (95% ci, 33-73) and 72% (95% ci, 67-77) for the cut-off of 8.8 mm. conclusions: our data shown that the magnitude of rpd is a poor predictor of presence of primary vur. there was no significant difference in performance among the indexes. objetive: we investigated the prevalence of renal calcification in children with autosomal ressecive polycystic kidney disease (arpkd) and studied the metabolic changes thats could cause this complication. methods: 9 patients with arpkd. 6 girls/3 boys; range age 2 m to 15 y. criteria inclusion presence typical imaging findings: enlarged kidney and diffusely increased renal echogenicity and poorly defined renal margins on sonography; suggestive imaging features with positive results renal or liver biopsy, results 7 patients, 5 girls and 2 boys, range of age 9-15 y, had ct scan renal clacification bilaterally. without renal clacifications <1 year. 7 children renal calcifications, 7 sistemic hypertension, 4 portal hypertension and gastrointestinal bleeding and one renal colic. renal insufficiency 6 patients, it was mild in 3 (gfr >50 ml/min/1,73 mt 2 ), moderate in 2 (gfr 30-50), and severe in one (gfr<30). all with renal insufficiency had distal tubular acidosis. hypocitraturia urine 7 patients. urinary calcium, uric acid, oxalates, and cystines normal in all. tuberoussclerosis (tsc) -an autosomal dominant inherited genetic disorder -is characterized by development of hamartomatous growths in many organs.two causative genes, tsc1 (chromosomal locus 9q34) and tsc2 (chromosomal locus 16p13.3) have been identified. tsc2 gene is adjacent to pkd1, the major gene for autosomal dominant polycystic kidney disease (adpkd) on chromosom 16p13 and contiguous germline deletion of both genes results in severe polycystic kidney disease phenotype at birth. at 6 months of age bilateral abdominal masses were occasionally palpatedin a previously healthy girl. ultrasonography demonstrated enlarged (approximately 15 cm) kidneys with multiple large cysts resembling those seen in adpkd. renal function and blood pressure was normal. suspicion of tuberous sclerosis was raised due to numerous hypopigmented cutaneous macules on the trunk and extremities. echocardiography demonstrated 2 rhabdomyomas in the left ventricle with no hemodynamic significance. an isolated juxtapapillary astrocytoma was found in the left eye. her psychomotor development was normal with no history of seizures. cerebral magnetic resonance imaging revealed multiple subependymal nodules with noobstruction of the cerebral fluid pathways. by multiplex ligation-dependent probe amplification (mlpa) a large dna deletion was identified spanning from tsc2 exon 10 to pkd1 exon 46 permitting the diagnosis of tsc2-pkd1 contiguous gene syndrome. cardiac rhabdomyoma and cutaneous manifestations were found in her father as well but no renal changes. at 3 years of age the girl is doing fine with ace blockers against hypertension. renal function is still normal. the size of the cardiac rhabdomyomas is diminishing while the cerebral and ocular hamartomasare unchanged. this additional report focuses tsc in an infant presenting with polycystic kidneys and cutaneous lesions. improvements in ultrasound technology and the appropriate timing of antenatal ultrasound has led to refined prenatal diagnosis and enhanced accuracy of diagnosis of fetal renal anomalies and makes it possible to treat obstructive and/or refluxing uropathies before the onset of clinical symptoms.a retrospective review of 165 patients; 44 girls (26,7%) and 121 boys (73,3%) admitted to our clinic between january 1999-december 2006 with antenatal urinary anomalies were investigated to determine the urinary tract anomalies, and the follow-up results are presented. routine prophylaxis was started at admision and the imaging studies were performed. the mean gestational age at detection was 28,4±5,87 weeks. the mean age of admittance was 32,95±29,63 days and the average follow-up period was 19,15±26,05 months. antenatal ultrasonoghrapy examination showed anomalies in 220/330 renal units. of these 220 antenatally observed renal units, 216 had postnatal urinary tract anomalies. of these 216 postnatally observed renal units, 235 urinary tract anomalies were detected (multiple urinary tract anomalies in 48 patients) ( table 1) . fifty-two (31,5%) children had 59 surgical interventions such as; ureteroneocystostomy, pyeloplasty, nephroureterectomy, puv resection. eighty-one (49%) of our patients had urinary tract infection during follow-up and renal scar was detected in 58 (35%) patients. acute renal failure developed in 6 patients and chronic renal failure developed in 3 patients and three patients died. we conclude that all infants with fetal urinary abnormalities should be evaluated, so that we can recognize and treat congenital anomalies that may affect renal function or cause urinay tract infection, renal scarring. the majority of patients with fetal urinary anomalies can be managed safely with close conservative follow-up. fetal urinary tract obstruction at 50 days gestation (e50) produces small kidneys with cysts, whereas obstruction at 60 days (e60) generates large kidneys with cysts. in the present study, we investigated the mechanism for the generation of small kidneys by urinary tract obstruction at an earlier gestational age, e50. fetal lambs underwent urethral and urachal ligation at e50 (n=17) or e60 (n=39). fetal lambs were delivered by c-section 5, 7, 20 days after obstruction, or at term (145 days gestation). unoperated kidneys of e50, e60, e80, and at term served as controls. the percentage cystic area of kidneys obstructed at e50 and e60 was not different 5 days after obstruction (17±5% vs 17±6%). after 7 days, however the percentage of cystic area became larger in kidneys obstructed at e50 (40±17% vs 23±5%), and was significantly larger 20 days after obstruction (51±18% vs 17±17%). proliferating cells, detected by pcna staining, were found in cysts and tubules of obstructed kidneys increasing toward term, and were more abundant in kidneys obstructed at e60. on the other hand, pcna-positive cells in the nephrogenic zone were reduced in obstructed kidneys. the decrease was more prominent in kidneys obstructed at e50. apoptotic cells, identified by tunel staining, were detected in the inner medulla of obstructed kidneys equally in kidneys obstructed at e50 and e60 during the fetal stage. at term, tunel-positive cells were rarely present in normal kidneys or kidneys obstructed at e50, but were found abundantly in the interstitium and occasionally in cysts and tubules of kidneys obstructed at e60. in conclusion, urinary tract obstruction at an earlier gestational age produces small kidneys by inhibition of mesenchymal cell proliferation, which may be due to compression by cysts. a. results: detrusor hyperreactivity, most commonly in i and iv or v grade was found in 47.9% of vur children. the maximum detrusor pressure was above 70 cm h 2 0. detrusor-external dyssymetry was found in 17% of children, most frequently in grade i and iv or v grades, and detrusor-internal dyssymetry was recognized in 19.4% of children with vur, most frequently in grade i and iv or v. in 12.5% of children with i-iii grade of vur cystometric capacity was reduced but 1 child with v grade had increased capacity of the urinary bladder. glomerular filtration according to schwartz equation was normal and independent of vur grade. decrease in osmolality below 800mosm/kg h 2 0 in nocturnal urine was only detected in the group of children with iv and v grade of vur,. there was no correlation between detrusor tension and osmolality of urine and glomerular filtration rate. conclusions: 1). dysfunction of the lower urinary tract, with detrusor hyperactivity was detected, as the most frequent dysfunction in 74% of children below 2 year old with i-v degree of vur, 2). the maximun detrusor pressure in the voiding phase was highest in grade i and iv iv-v reflux children. hypomelanosis of ito was first described as a disorder characterized by unusual unilateral or bilateral macular hypopigmented whorls, streaks and patches. subsequently, neurologic, skeletal and ocular involvement were described. kidney involvement has only been exceptionally reported. herein, we describe a case of a male infant with hypomelanosis of ito and renal involvement. the patient was born at 40 weeks of gestation by cesarian delivery. the ultrasound scan at 34 weeks of gestation revealed bilateral enlargement of kidneys, decreased corticomedullary differentiation and cysts located in the cortical and subcapsular regions. these findings were confirmed at two months of life by ct scan. skin examination showed hypopigmented linear and round diffuse lesions located on the right leg and arms. the ophthalmological examination showed anterior capsular and posterior subcapsular cataract of the left eye. as previously reported in other cases of hypomelanosis of ito, the patient presented a transient leucocytosis (max 30.000/mm 2 ) during the first 8 months of life.the renal biopsy showed a classic picture of glomerulocystic kidney disease, whereas the skin biopsy confirmed the clinical diagnosis of hypomelanosis of ito.three other cases of kidney disease in hypomelanosis of ito have been reported. of these, one case presented abnormalities of the glomerular basement membrane, and one case presented with polycistic kidney disease. the third case had renal cystic dysplasia with a histological picture containing glomerular cysts. alltogether these reports suggest that genes involved in hypomelanosis of ito are important for normal renal development and may be implicated in cystogenesis, when mutated. here we report on a male newborn (birth weight 3070 g, length 51 cm) who presented with progressive edemas, oliguria and failure to thrive during the first week of live. on clinical examination he showed bilateral microcoria and decreased muscle tone. laboratory work-up revealed large proteinuria (28 g/g creatinine), hypoalbuminemia (13 g/l) and renal failure ( objectives. to investigate the incidence, nature, and management of associated genitourinary malformations in children with multicystic dysplastic kidney (mcdk). methods. in this retrospective study, we analyzed the medical records and imaging studies of 24 children with mcdk. in 20 children (83%) anomalies of the urinary tract were suspected prenatally in ultrasound studies. in the remaining 4 children the diagnosis of mcdk was made postnatally. results. the male/female sex ratio was 8: 16. the left side was involved in 11(46%) children. voiding cystourethrography was done in 14 (58%) children, the isotopic 99m tc-dmsa scan of the kidney in 15 (63%). urogential anomalies were present in 10 (42%) children. among them, contralateral urologic anomalies were found in 3 patients (vesicoureteral reflux in 2 and hydronephrosis in 1), and ipsilateral in 8 (vesicoureteral reflux in 1, ureterocele in 3, and hydroureter in 2). genital abnormalities such as uterine didelphys and hydrocele were found in 2 children. fourteen (58%) patients underwent follow-up examinations with ultrasonography (mean follow-up 4.15 years, range 7 months to 12 years). compensatory hypertrophy of the contalateral kidney was found in most children and decreased size of ipsilateral dysplastic kidney was found in 9 out of 14 children with follow-up. no cases of hypertension or tumor developed during the follow-up. conclusion. ultrasound can be used safely to diagnose unilateral mcdks and associated genitourinary malformation. although the risk of hypertension and development of malignancy is low, follow-up evaluation of contralateral renal function and genitalia will be needed. in cases of hydronephrosis and/or urinary tract infection, voiding cystourethrography is necessary and possibility of association with genital anomalies should be considered until the puberty. a. background: ectopic ureter is a rare anomaly. its incidence is at least four times higher in females and also more than 80% of the ectopic ureters drain duplicated systems in females. the most common presenting symptoms of an ectopic ureter are urinary tract infection and incontinence. diagnosis is often delayed and may remain undiagnosed until adulthood. case report: a 3-month-old girl was admitted to our hospital with the complaints of fever and discomfort. her mother recognized intermittent dribbling of urine while changing her napkin. physical examination revealed fever (38.3 °c), diaper dermatitis and intermittent dribbling of urine. urinalysis revealed leukocytouria, acute phase reactants were elevated (crp: 1.45, esr: 27) and renal function tests were normal. the patient was hospitalized with the diagnosis of acute pyelonephritis. tc99m dimercaptosuccinic acid (tc-dmsa) scan revealed an increase in the size of the right kidney and decreased uptake in the upper half of the same kidney. ultrasound was performed with the suspicion of an ectopic ureter and it showed right duplicated kidney with marked dilatation of the upper collecting system. the ureter was also dilated in its whole length and ended ectopically distal to the bladder. contrast-enhanced magnetic resonance urography (mru) demonstrated right obstructed duplicated system with vaginal ectopic insertion of upper pole ureter. discussion: this case was presented to underscore the role of careful physical examination in the diagnosis of this rare anomaly that is by paying attention to the complaints of the family. ultrasound is the initial, important diagnostic modality in these patients especially if done by experienced radiologists. the diagnosis can be confirmed with mru by depicting the exact insertion of the ectopic ureter. objectives of study: to evaluate the occurrence and severity of vesicoureteral reflux (vur) in young infants with a history of mild prenatal hydronephrosis. the usefulness of voiding urosonography (vus) in the diagnosis of vur was also evaluated. methods: forty seven infants (31 males, 16 females) with a history of mild prenatal hydronephrosis, diagnosed between 21 st to 30 th week of gestation, were enrolled in the study. postnatal ultrasound was performed within the first month of life. voiding cystourethrography (vcug) and at the same time, contrast-enhanced harmonic vus was performed at the age of 1.5-2.5 months. results: the prenatal ultrasound revealed an anterior-posterior pelvic diameter of 5-7 mm in 33 fetuses and 7-10 mm in 14. postanatal ultrasound showed an anterior-posterior pelvic diameter of 5-7 mm in 34 infants and 7-10 mm in 13. vur was found in 9 of 47 (19.1%) infants (grade i: 2, ii: 4, iii: 3). the vur was detected by both vcug and vus in 4 of 9 children, only by vcug in 2 and only by vus in 3 of 9 infants. the vur that was missed by vcug was more severe (grade ii and iii), compared with this one missed by vus (grade i). conclusions: even though prenatal hydronephrosis was associated with a quite important occurrence of vur, this was of mild or moderate severity. comparison between the two imaging modalities showed that the vur missed by vus were with no clinical significance (grade i), whereas the vur missed by vcug were more severe. although further study is needed, vus could be an alternative method, mainly in girls, in whom the imaging of the urethra is not necessary, thus avoiding the radiation exposure. early treatment with indomethacin in a neonate with a bartter syndromea case report neonatal bs is a rare genetic disorder characterized by sodium, potassium and chloride urinary wasting, hypokalemic metabolic alkalosis with hyperreninemia and hyperaldosteronism in the absence of hypertension and high level of urinary prostaglandins. indomethacin therapy is controversial because of toxicity for gut and kidney. a premature boy of unrelated couple was born by cesarean section at 28 weeks because of early rupture of membranes and fetal distress. birth weight was 900 g, length 36 cm and apgar score 2/6/8. pregnancy was complicated by severe polyhydramnios. baby was mechanically ventilated for first 12 hours and treated with antibiotics because of suspected sepsis. marked polyuria and dehydration were present from 1st week. metabolic parameters revealed hypokalemia, hyponatremia and hypochloremic metabolic alkalosis. serum creatinine was slightly elevated and gfr in normal ranges. blood pressure was normal with raised plasma renin activity and aldosterone level. sodium excretion via urine and level of renal and systemic prostaglandins were increased. nephrocalcinosis was detected on us from 2 week. additonally to electrolyte supplementation indomethacin was started on the 18th day at a dose of 1 mg/kg/day. in first 2 months child experienced 4 septic episodes, candida pyelonephritis and was operated because of bowel obstruction. dna analysis of affected child found 2 new mutations in romk gene: p185l and q289x in herited from parents who carried one mutation each. at 18 months height and weight are at 3 and head circumference at 50 percentile with slightly retarded psychomotoric development. he continues on 1.2 mg/kg/day indomethacin therapy. blood electrolyte profile is normal without supplements. us shows no progression of nephrocalcinosis. early treatment with indomethacin may prevent life-threatening complications and reduce the development of nephrocalcinosis. nimuselide, a cox2 inhibitor is widely used in india for relief of pain and fever. we describe 6 cases of fetal renal abuse leading to neonatal renal failure due to maternal ingestion of nimuselide in the third trimester of pregnancy. results: all 6 patients were diagnosed as having renal failure in the first few days of life.there were 5 boys and one girl.. all the mothers had normal pregnancies except for oligohydramnios that was detected during the last 2 months of pregnancy in all cases.4 children presented with anuria from birth. the remaining two had non-oliguric renal failure with metabolic acidosis as the presenting feature in one and poor feeding and lethargy in the other. usg revealed normal sized kidneys. one patient also showed increased echogenicity. 3 out of the 4 anuric children underwent peritoneal dialysis for a period varying from 3 to 4 weeks without recovery of renal failure. the remaining 3 were managed conservatively. two of these patients are now in chronic renal failure at ages 2 and 5 years. only one patient recovered completely after 5 days of anuria. all the mothers had taken nimuselide in the last trimester for periods varying from few days to several weeks for relief of pain or fever. some of them had taken multiple courses of short duration. the mother of the child who recovered completely had taken nimuselide in the last 5 days before delivery. renal biopsy done in one baby revealed renal tubular dysgenesis. conclusion: nimuselide intake in the last trimester of pregnancy can be associated with oligohydramnios and neonatal renal failure that can be irreversible. renal tubular dysgenesis may be the underlying pathology. objectives of study: pkd is the most common inherited renal disease. aim of ours study was to analyse clinical and laboratory features of the different types pkd. patients and methods: we described the clinical presentation of 47 children with pkd (26 boys, 21 girls) diagnosed in pediatric nethrology department between 1989 and 2007. the patient's age range was from 3 months till 18 years. we retrospectively studied the family histories, clinical and biochemical data (physical examination, level of arterial blood pressure, blood and urine creatinine levels, serum levels of urea, glomerular filtration rate), ultrasonography, scintigraphy. results: the analysis of the family histories revealed adpkd in 27 patients (14 boys, 13 girls), arpkd in 6 (2 boys, 4 girls) and nondifferential pkd in 14 (10 boys, 4 girls) children. pkd diagnosed by antenatal ultrasound in 6 cases (2 adpkd, 4 arpkd). the mean follow-up adpkd were 4,4 year (range 1 -13 years), arpkd -5,3 year (range 1 -14,5 years). conclusion. patients with arpkd demonstrated the early beginning of an arterial hypertension and progressing chronic renal failure. one girl with neonatal form of arpkd died. chronic renal failure developed in 9 (19,1%) cases of pkd. objectives: this prospective study was to answer the question on the need of long-term follow-up and correlation of renal functions with the age at surgery and grade of o.u. prior to surgery in patients after surgery of obstructive uropathy (o.u.). methods: selected biochemical markers of glomerular and tubular functions and ultrasonographic findings in 62 patients (40 boys) who underwent surgery due to uni-or bilateral o.u. of grade iii. and iv. (age at surgery <12 months) in 1994-1997 were examined at mean age of 6.3±0.9 years. the results were compared to 32 healthy controls and/or to reference values according to age. consequently, patients were devided into groups according to the age at surgery (0-3 months, 4-6 months, 7-12 months) and grade of o.u. prior to surgery. results: serum concentration of cystatin c (s-cysc) was significantly higher in patients when compared to control group (p<0.001). while s-creatinine was within reference interval in all patients, s-cysc was increased in 63.3% when compared to reference interval. decreased tubular resorption and concentration ability was found in 67% and 26% patients, respectively. non-specific aminoaciduria was detected in 42.9% patients. on ultrasound, 66.7% kidneys after surgery had residual dilatation of renal pelvis. the differences in renal functions in patients according to their age at first surgery were not significant except for u-nag activity with significant negative linear trend with higher age at surgery. the grade of o.u. prior to surgery did not have significant influence on renal functions. conclusions: mild tubular dysfunction and slightly reduced gfr in the part of patients make longterm nephrologic follow-up reasonable. our results support the trend of postponing early postnatal surgical intervention in patients with positive ultrasound screening of o.u. and normocreatininemia. objectives of study: to evaluate, during almost five years of follow-up, the changes among preoperative and postoperative renal function in 46 infants (36m/10f) with prenatal severe hydronephrosis (hn) and upj obstruction. methods: upj obstruction was diagnosed by a mag3 renal scan, performed at 4-6 weeks of age to establish baseline differential renal function; surgery was made if there was evidence of obstruction injury, and/or progression of hn and/or symptoms. the group was re-imaged 3 months after surgery, after 6 months, 1 year and then annually. results: initial differential renal function was moderate in 41.6% of males and in 30% of females and good in 58.4% and in 70% respectively. also,75% of kidneys required surgery because of declining function, with mean differential renal function in the affected kidney of 32% that improved to 44% already at 3 months after pyeloplasty. there was no significant functional improvement, in the kidneys that underwent correction because of increased hn or symptoms and final renal function was >40%. after pyeloplasty t was >30 min. in 21% and 20-30 min. in 79% of cases (p<0.05) there was no statistically significant correlation between initial grade of hn and initial renal function. surgical treatment was performed between 9-16 months of age and there was no significant difference in postoperative results, ascribed to patient age at surgery. ma values, greater than controls at diagnosis, reduced at 18 months after surgery in all, but 16% of children. during the follow-up, the mean ccr and bp values were in normal range for age in all children. conclusions: our findings showed improvement also in kidney with preoperative uptake less of 40%. this may be to explain in according to an inverse correlation between degree of renal dysplasia and gestational age. objective of study: is to determine the postnatal course and follow-up of children with fetal hydronephrosis. methods: in 6 years period (2000) (2001) (2002) (2003) (2004) (2005) (2006) we followed 72 infants with antenataly detected hydronephrosis. all infants were submitted to ultrasonographic examination of kidneys and bladder. if indicated, the isotope renography, micturating cysto-urethrography, i.v.urography and mr were performed. results: the diagnosis of hydronephrosis was established during 15 -39 th weeks of gestation by obstetritian. first postnalat ultrasound investigation was performed during neonatal period in most children (69%). in 48 (66,7%) infants we diagnosed idiopathic hydronephrosis, in 12 (16,6%) vesicouretheral reflux (vur) grade ii-iv, in 7 (9,7%) hypofunction of one kidney, in 2 (2,8%) ureteropelvic junction obstruction (upjo), in 1 (1,4%) ren duplex and ureterocele, in 1 (1,4%) ampular pelvis and in 1 (1,4%) afunction of one kidney. after 6-12 months we found normal ultrasound in 35 (48,6%) children. the ultasound results were stable in 24 (33,3%) children and in 9 (12,5%) there was progression of hydronephrosis. four (5,5%) infants underwent immediate surgery. conclusions: in a group of 72 infants with antenataly detected hydronephrosis the diagnosis was confirmed postnataly in 89% infants. more than 50% of infants required long term follow-up. in 5,5% the immediate surgey was required. this data support the need for antenatal detection of hydronephrosis. in the same period we followed up 207 infants with urologic abnormalities which were not detected antenataly.the fetal ultrasound is reliable screening method in detection of urologic abnormalities. the considerable number of anomalies which were not detected antenataly are the result of insuffitient use of fetal ultrasound investigation. hemolytic uremic syndrome (hus) is defined by acute renal failure, microangiopathic hemolytic anemia, and thrombopenia. perinatal asphyxia (pa) may cause renal failure after birth and is often associated to disseminated intravascular coagulopathy (dic) with platelet consumption. however, no biological investigation permits to distinguish clearly neonatal hus from dic. we report three neonates with renal failure due to different degrees of pa. they presented biological features compatible with hus such as fragmentocytes (3%), thrombopenia (<50,000/mm3), anemia (<8 g/dl). serum creatinine on day 5 was 293, 152, 372 mmol/l respectively, requiring peritoneal dialysis in one patient. haptoglobin was undetectable for all three patients. factor h and i were in the lower normal range; components of the complement system (c3, c4) and adamt13 activity were decreased. two patients received daily fresh frozen plasma infusions over the first 4 weeks. renal function improved in two patients until day 30; one patient has chronic renal failure. all other parameters suggestive for hus were normal on day 12, 30, and 60 respectively. no severe neurological consequences were noted for either of them. pa may be responsible for multiorgan damage via ischemic lesions. ischemia may result in endothelial cell injury, the crucial event for the development of thrombotic microangiopathy. we hypothesize that endothelial cell damage concomitant with pa may lead to a vicious circle resulting in consumption of platelets and plasma factors involved in hemostasis and/or fibrinolysis. early use of fresh frozen plasma may correct these alterations. renal biopsies might have been useful but are technically difficult in newborns. in conclusion, pa and neonatal hus are difficult to distinguish and endothelial cell damage may be a common pathyphysiological aspect and might requirespecific treatments. a. medynska, m. nalesniak, k. kilis-pstrusinska, d. zwoliñska congenital posterior urethral valves (puv) are the most common cause of lower urinary tract obstruction in male neonates. we aimed to review our experience with puv children (24 boys) in respect to retrospective analysis of the clinical course of disease. we analyzed: ultrasound during pregnancy, age of disease onset, clinical symptoms at admittance to hospital, outcome. average lenght of follow-up was 7,3 years, varying between 2 month and 20 years.obstruction of urinary tract was suspected by prenatal ultrasound in 9 patients. the initial presenting symptoms were as follows: urinary tract infection 7 boys, failure to thrive 3 patients, increased abdominal circumference -2, abdominal pain 1, enuresis -3, acute renal failure 1, and chronic renal failure 14 children. in association with puv renal dysplasia/hypoplasia in 4 patients, undescended testis 3, bladder trabeculation 4 were found. the diagnosis of puv was confirmed by voiding cystourethrograms and/or cystoscopy. primary vesicouretral reflux was documented in 7 pts. hydronephrosis and/or megaureter were observed the most often in 14 boys. the diagnosis of puv was established in 10 pts at the age of less 1 month, in 6 pts between 2 -12 months, and in 8 between 1-15 years. surgery was performed in 7 pts in neonates period including primary valve surgical ablation and/or cutaneostomy vesicostomy. chronic renal failure was diagnosed in 7 boys in first year of live. 4 of them progressed to end-stage renal disease. globally during the follow-up 7 pts developed end-stage renal disease. 4 pts have done a graft. only 5 boys survive without progression to chronic renal failure. the presentation of puv is variable and currently antenatal detection is the most common mode. outcome boys with puv is poor. patients need nephrologic assesment from birth. background: furosemide is among the 10 most frequently used drugs in the neonatal unit but few studies analyze the beneficial effect and complications in this patient group. objectives of the study: to analyze the therapeutic clinical effect and to document side effects of furosemide therapy in extremely preterm infants born <28 weeks gestational age (ga). methods: twelve infants born <28 weeks ga were prospectively included during the fall 2006. the following parameters were documented prior, during and after furosemide administration: clinical status, serum/urine electrolytes, creatinine, albumin, blood gases and furosemide exposure. ultrasound of the kidneys and a wrist radiograph were performed at 6-8 weeks to rule out osteopenia/rickets and nephrocalcinosis respectively. no statistical analysis were done due to the small study size. results: general oedema, respiratory rate, apneic spells and oxygen supplementation decreased. arterial/venous pco 2 decreased and partial oxygen saturation increased indicating improved lung function. hco 3 increased and ph decreased. urinary excretion of sodium, potassium, chloride and calcium increased while phosphate excretion decreased. serum sodium and chloride decreased and potassium increased initially. six infants had electrolyte disturbances and metabolic alkalosis. one infant died during the study period. in the remaining 11 infants, 3 of 5 had worsening of their patent ductus arteriosis, 3 had osteopenia or rickets and 1 had nephrocalcinosis. the total side effect score was increased in the infants with the highest furosemide exposure. conclusions: this small study suggests that furosemide is beneficial in extremely preterm infants born <28 weeks ga and that the associated side effects correlate to the total drug exposure. we recommend caution for long term administration of furosemide. conclusion: although children in our study suffered significant neonatal hie resulting in arf, glomerular and tubular function recovered sufficiently to cope with increasing body mass and metabolic needs. unlike reported studies, we did not find any significant evidence of cri in the survivors of neonatal hie and arf. one with marginal microalbuminuria will need further observation. c was born after a monozygotic monoamniotic twin pregnancy (gestational age=34 weeks). she presented with twin-twin transfusion syndrome with hypotrophy (birth weight=2020g, other twin=2950 g), severe hypovolemia, anemia and acute renal failure. she required a blood transfusion, mechanical ventilation (5 days), and peritoneal dialysis (10 days). she recovered without bronchodysplasia but with chronic renal failure (creatininemia at 2 months=90 μmol/l). the following months were uneventful but, as usual in tts, she exhibited growth retardation and slight mental delay compared to her twin. she reached terminal renal failure at 12 years of age and was successfully kidney transplanted. after age of 6 years, she presented with increasingly frequent and severe pulmonary infections predominantly in lower lobes of both lungs. after extensive explorations, the diagnosis of bilateral bronchiectasis was made. the search for classical aetiologies of such pathology was negative. the symmetric aspect and the absence of other etiologies lead to the consideration of bronchiectasis as a congenital pathology. numerous publications demonstrate the role of the renin-angiotensin system (ras) in renal and cerebral damages in tts. authors demonstrate the role or ras in development of vasculature in fetus but also of cartilage and muscle in different organs including lung. associations between tts and lung pathologies need to be further investigated. urofacial ( the urofacial (ochoa) syndrome (ufs) is a rare disease that occurs in both sexes and is more frequent when the parents are closely related. it has both urinary and facial abnormalities. ufs is a rare autosomal recessive disorder and a potential gene has been mapped to chromosome 10q23-q24. they present a bladder voiding dysfunction due to impaired neural communication between the bladder and the spinal cord, resulting in incomplete emptying of the bladder. this usually results in enuresis, urinary tract infection, hydronephrosis and in some severely affected patients, end-stage renal disease developed. the facial abnormality is a characteristic expression that, when these patients smile, their facial musculature inverts and they appear as if they are crying. we report a 15year-old girl who has inverted facial appearance, voiding dysfunction and vezicoureteral reflux. she had constipation and did the intermittan uretral cathaterization for five years. after a detailed evaluation, she was diagnosed as ochoa syndrome due to inverted facial expression. we report this case, because early diagnosis of ufs is very important for early assessment and management of urinary problems to prevent development of chronic renal failure. we think that only a smile can give a strong high light for this unusual 'inverted' facial expression and patients can be screened earlier for severe voiding dysfunction. tar syndrome is a congenital malformation syndrome characterized by bilateral absence of the radii and a thrombocytopenia. the known urinary anomalies with tar are duplex ureter, dilatation of renal pelvis, horseshoe kidney, and functional problems like vesicouretheral reflux and pyelonephritis. case: nine years old patient with tar syndrome was admitted with a complaint of bright red urine repeated three times. the microscopic hematuria without dysmorphism of erythrocytes accompanied with no proteinuria were determined in repeated urine sample microscopy. iga, ana, anti dna serology were negative. urine culture was clean. stone formation (6x7 mm) in the upper pole of the right kidney was established by the abdominal ultrasonography. postoperative chemical analysis of the stone, revealed that it was consisted of oxalate monohydrate and dihydrate. but the patient discontinued his follow-ups afterwards for a year. in this period, he had macroscopic hematuria attack once. when he applied for the second time, he reported macroscopic hematuria. cystoscopy was done for etiology. many tortuous and engorged vessels were seen by this evaluation in the bladder mucosa ( figure 1 ). there was no active bleeding point. result: in this report, kidney stone and telangiectasia found co-incidentally in the bladder of a patient with tar syndrome during the examination of hematuria are discussed as there is no case report demonstrating nephrolithiasis and telangiectasia in tar patients in the literature. figure 1 : many tortuous and engorged vessels in the cystoscopy. antenatal hydronephrosis (anh) is one of the common fetal abnormalities detected on ultrasound (us). the long-term renal prognosis for infants with mild to moderate postnatal hydronephrosis (hn) is unclear and controversial. a systematic review of the published literature was performed to determine an evidence based approach in infants with antenatally diagnosed hn and to identify those at risk of significant post natal nephro-uropathy (pnu). key questions were identified. does anh predict renal tract pathology in neonates? what is the value of prophylactic antibiotics in infants with anh? can postnatal us diagnose significant pnu? when is the optimal time to screen infants postnatally? which imaging modalities are necessary to diagnose the cause of the hn? how many neonates with anh would need to be investigated to prevent one case of esrf/crf? a search strategy was formulated. out of 362 titles only seven studies met the validity criteria for inclusion. the results indicate that antenatal us is a valid screening test for pnu (sensitivity 16%, specificity 98%), but is not a predictor of pnu. the detection rate of hn by us is the same whether it is done early or late in neonates. two normal ultrasounds over a minimum of one month are required to screen for pnu. infants with a renal ap diameter over 7mm are at risk of a significant pnu and should be investigated further. us is not a substitute for cystourethrogram or dynamic isotope studies to determine the cause of hn. none of the studies addressed the role of prophylactic antibiotics. there was insufficient data to calculate the total number of cases that would need to be investigated to prevent one unfavourable outcome (esrf/crf). high quality population based cohort studies with long term follow-up into adulthood are required to determine the optimum postnatal management of mild to moderate hn in infants with anh. jeune asphyxiating thoracic dysplasia: a case report jeune asphyxiating thoracic dysplasia (jatd) is one of the congenital hepatorenal fibrocystic syndromes. it is characterized by renal, hepatic, pancreatic abnormalities with associated skeletal abnormalities including a long and narrow thorax, metaphyseal irregularities, and shortness of the ribs and long bones. this report describes a pediatric patient with jatd developed end-stage renal failure. a 7-year-old boy was admitted with complaint of vomiting and pallor. he had dysmorphic appearance including trigonocephaly, short stature, long thorax and short limbs and fingers, polydactyly and fascial dysmorphism. laboratory findings revealed severe anemia (hb 3.8 g/dl), high bun and creatinine levels (111 mg/dl and 7.9 mg/dl respectively) and normal liver tests. abdominal usg showed a severe intrahepatic biliary tract dilatation and intraparenchymal cysts in liver, pancreas and kidneys. mr pancreatocholangiography was consistent with caroli's disease. jatd should be considered when caroli's disease exists with skeletal abnormalities. follow-up antenatal hydronephrosis: one centre experience the most common renal abnormality detected antenatally is hydronephrosis (1% to 5% of all pregnancies). in this paper, we report follow-up our patients with antenatal hydronephrosis (ah) between 2001 and 2006. diagnosis of hydronephrosis was made >5 mm of antero-posterior diameter (ap) of the renal pelvis. ah was detected in 74 patients on antenatal ultrasound examination. of the 74 patients with ah, 46 (62.1%) were found to have hydronephrosis postnatally and 34 (37.8%) postnatal scans were normal. in 17 of these patients (36.9%) had bilateral and 29 (63.1%) of these patients had unilateral hydronephrosis. in these patients with ah, uretero-pelvic junction obstruction (upj) 28 (60.8%), reflux 12 (26.2%), uretero-vesical junction obstruction 3 (6.5%), posterior urethral valves 2 (4.3%) and mega-ureter 1 (2.2%) were identified. in follow-up period, 2 (16.6%) patients with reflux, 19 (41.3) patients with upj were treated with surgery (p<0.05). in conclusion, upj was most important cause of ah and most of them were treated with surgery. hyponatremia and renal tubular acidosis in severe vesicoureteral refluxa case report sahlgrenska academy, department of pediatric, gothenburg, sweden case report: 1st child to healthy parents without heredity for kidney or metabolic disease. antenatal bilateral hydronephrosis. postnatal examination showed bilateral vur grade v, normal urethra. antibiotic prophylaxis was started, no urinary tract infection (uti) occurred. normal s-creat and s-na + at 2 weeks of age. the electrolytes remained normal during the next 3 months. normal growth. the boy was thirsty with high urine volumes. at 3 month of age feeding problems began with retarded weight gain. no vomiting or diarrhoea. at admission to the hospital the child was dehydrated, s-na + 120 mmol/l, s-cl -99 mmol/l, s-ph 7.11, bicarbonate 11 mmol/l, s-creat 36 μmol/l. crp 8 mg/l, urine culture negative. u-na + 10 mmol/l, u-ph 6.0, u-osmolality 214 mosm/kg. the anion gap was normal and there was no lactacidosis. the s-aldosterone was elevated 53,1 nmol/l, s-cortisone normal. treatment included intravenous rehydration, na + supplement and oral bicarbonate. blood chemistry normalised and the child's general condition improved rapidly. conclusions. children with severe reflux are at high risk for uti but may also develop impaired tubular function with diabetes insipidus, renal tubular acidosis and hyponatremia. the mechanisms include down-regulation of vasopressin receptors and impaired distal tubular function. close clinical monitoring of these children with regular blood chemistry and weight controls is important. purpose: we aim to prospectively study the natural history of minimal to severe grades of antenatal hydronephrosis (anhn) in our local chinese population and correlate the renal pelvic diameter (rpd) with the outcome. patients and methods: cases of anhn were prospectively followed up along a predefined protocol using us, mag3 and mcu in all. obstruction (pujo or vujo) was defined as a need for surgery based on symptoms and deteriorating function, not on mag3 drainage time. results: 174 neonates were followed up for minimum of 5 years. eighty percent had normal or minimal hn on postnatal scans (rpd 5-9 mm), 11.4% had mild (10-14mm) or moderate (15-19) hn and 8.5% severe hn (>20 mm). seventy-eight percent infants had benign course; 6.9% had partial obstruction which improved; 11.5% had vesicoureteric reflux (vur) one of which required surgery. another 5.7% required surgery for obstruction. the roc curve for obstruction requiring surgery showed optimal cut-off point of 18.5 mm (sensitivity 100%, specificity 99.2%). prolonged diuretic t1/2 was not predictive of surgery. severity of hn did not correlate with presence or grade of vur. fifteen patients developed uti despite antibiotic prophylaxis and 7 had focal scars, all occurred in association with high grade vur or obstruction. the prognosis of infants with minimal or mild anhn is good. however rpd is poorly correlated with vur. the chances of obstructive lesions requiring surgery are high when the rpd is above 18 mm. in those with high grade reflux or obstruction, urinary tract infection may lead to renal scars. objectives of study: cystinosis is a rare disease presented initially with renal fanconi syndrome, and renal glomerular failure develops later in childhood. without cysteamine treatment, patients affected with cystinosis uniformly died during childhood in the absence of renal replacement therapy (rrt). cysteamine is not available here and in some other areas of the world. the aim of this paper is to describe a beneficial effect of acacia gum in a patient with cystinosis and chronic renal failure. method: 9 years old girl with cystinosis presented with symptomatic uremia as she didn't receive cysteamine. serum creatinine 7.4 mg/dl, blood urea 200 mg/dl. the girl was hospitalized and vomiting controlled with intravenous fluid and pyridoxine. chronic dialysis was not available for her and the parents refused treatment with intermittent acute peritoneal dialysis. the girl was treated with a new therapeutic regimen (therapy2006;3 (2): 321) combining the traditional conservative management of crf (dietary and pharmacologic) with addition of acacia gum (ag) 25 g/day as an urea lowering agent aiming at improving her condition without dialysis. results: treatment was associated with amelioration of the uremic symptoms and improved general well being. after 2 weeks of treatment, serum creatinine 1.9 mg/dl, blood urea 69 mg/dl. during 4 months of follow-up she continued in experiencing improved well being and urea levels was kept below 70 mg/dl without dialysis. conclusion: it was possible to improve the health of patient with cystinosis despite the nonavailability of cysteamine and the appropriate rrt. objectives of study: the pattern of renal tubular disorder (rtds) has been infrequently reported in the literature, and the pattern of rtds in iraqi and arab children is not known. methods: from june 2000 to august 2006, it was possible to evaluate 40 children with suspected rtd to determine the type of their tubular defect. there was evidence of rtd in only 35 patients; 22 males (63%) and 13 females (37%). their ages at referral ranged between 8 months and 14 years (mean 4.8 years). in 4 patients with oculo-cerebro-renal syndrome, there was no evidence of rtd and one patient had hyperoxaluria which not a rtd. results: seven types of rtds were identified. the three most common disorders were: idiopathic hypercalciuria (37%), cystinosis (21%) and renal tubular acidosis rta (21%). four of the patients with rta have proximal rta, and four have distal rta. four of the patients with hypercalciuria have also significant hyperoxaluria >3 mg/kg/day. conclusion: the pattern of rtds in iraqi children differs from the previous studies: in germany the three most frequent disorders were cystinosis, xlhr, and idiopathic hypercalciuria. objectives of study: few literatures reported the incidence of ocular abnormalities in chronic renal failure (crf). the aim of this paper is to determine the incidence of ocular abnormalities in childhood crf. methods: from january 1993 to december 2005, 80 patients with crf (at the university hospital in al kadhimiyia) were examined to determine the presence of ocular abnormalitites. fifty patients were males (62.5%) and 30 (37%) were female. their age at referral ranged from 2 months to 18 years (mean 9 year). they were followed for a period ranged from 5 days to f years. results: corneal cystine crystals were the most common ocular abnormalities associated with childhood crf observed in 6 patients with nephropathic cystinosis (7.5%). congenital cataract & glaucoma were observed in 3 patients (3.75%) with oculo-cerebro-renal syndrome (ocrs). congenital cataract & chorioretinal hypoplasia were present in 1 patient with ocrs. hypertensive retinopathy occurred in 2 patients. acquired cataracts occurred in one patient with hinman syndrome in association with hypocalcaemia and non-compliance with calcium and onealphacalciferol supplementation. retinitis pigmentosa in one patient with laurence moon biedl syndrome. bilateral optic atrophy in one patient with familial nephropathy associated with club feet. proptosis in one patient with membranoproliferative glomerulonephritis. conclusion: ocular abnormalities are relatively common in childhood crf occurring in approximately 19%. objective: hypocalcaemia has been reported as a complication of phototherapy especially in neonates. we studied the relation between serum calcium level and urine calcium to creatinine ratio in neonates under phototherapy. method: 50 icteric newborns (30 males and 20 females) treated by phototherapy entered into study by non accidental sampling. the consent was taken from parents on admission. all were breastfed healthy newborns. weight was checked and serum samples for calcium and bilirubin and urine aliquots for calcium, creatinine and osmoloality were sent on arrival (group i), after 48 hour of starting (group ii) and 24 hour after discontinuing phototherapy (group iii). hypercalciuria was defined by uca/ucr >0.8, hypocalcemia was defined by serum calcium <8mg/dl in the term and <7 mg/dl in the premature. chi2, anova, wilcoxon rank test and spearman were used to compare frequency, means, median and correlation. p<0.05 was considered significant. two groups were designed, pateints whose therapy were finished at least 12 months (group 1) and those either on therapy or less than 12 months passed from the last protocol of cytostat (group 2). demographic data, cumulative dosages of anticancer drugs, history of other nephrotoxic agents, nephrectomy, radiotherapy and acute renal failure were recorded. we used ctc2 (1999) to evaluate renal function. chi2 and mann whitney u test and biniary logistic regression were used to compare percentage, scoring and correlation respectively. p value less than 0.05 was considered significant. result: 58 out of 115 patients were in group 1 and 57 ones were in group 2. the mean of age was 11.86 years (±5.3 sd). the median (range) of therapy and termination was 36 months (1-156 months) and 1 month (0-12 month) in group 2 and 36 month (24-240) and 51 months (15-120 months) in group 1 respectively. the percentage of reversible renal failure, proteinuria, abnormal serum calcium and magnesium, metabolic acidosis and urinary concentration defect was higher in group 2. (table 1) these differences were statistically significant (p<0.05). we found no correlation between ctc score and dosage of drugs, age, sex, history of radiotherapy or nephrotoxic agents (p>0.05). conclusion: mild to moderate tubular dysfunction has been observed in survivors of leukemia. routine follow-up of renal functions is recommended. v. tramma, k. giourtzis, v. fotoulaki, k. nousia-arvanitaki aristotle university, 4th pediatric clinic, thessaloniki, greece although cftr is expressed in the kidney, patients with cystic fibrosis (cf) have not been reported to have major renal abnormalities with the exception of urolithiasis. the aim of this study was to determine renal function and the potential risk factors for renal stone formation in cf patients older than 10 years of age. the findings of metabolic evaluation of 4 cf patients having confirmed urolithiasis (mean age: 22,37±5,78) were compared with those of 27 cf patients without urolithiasis (mean age: 24,25±4,03) and those of 10 healthy volunteers (mean age: 22,13±4,98). evaluation included plasma sodium (na), potassium (k), chloride, bun, creatinine, uric acid, calcium (ca), phosphorus (p), magnesium (mg) and parathormone (pth). twenty-four hour urine collection for creatinine, uric acid oxalates, ca, mg, k + , na + and microalbuminuria was also performed. glomerular filtration rate (gfr) was calculated and fresh urine samples were examined for the presence of crystals, erythrocytes, glycosuria and microorganisms. patients with cf and urolithiasis showed significantly increased values of bun (p: 0.012), pth (p: 0.018) and gfr (p: 0.003), very low urine mg levels (p: 0.014) and microalbuminuria (p: 0.034) as compared to cf patients without urolithiasis. there was no correlation of urolithiasis with hypercalciuria and hyperoxaluria. furthermore, all cf patients showed significantly increased pth levels (p: 0.032), very low urine mg levels (p: 0.024) and microalbuminuria (p: 0.024) as compared to healthy volunteers. conclusions: renal dysfunction was demonstrated in older cf patients, probably, secondary to the primary defect of renal chloride channels. extracellular volume regulators, such as hormones, may also be implied. urolithiasis may be the result of renal dysfunction. conclusions: the morbidity of hsp had obviously increased in recent years. the familial cases, the initial symptoms of no palpable purpura at onset and the cerebral, pulmonary, cardiac and pancreatic involvement should be paid attention. objectives of study: systemic lupus erythematosus (sle) is an autoimmune disease affecting multiple organs and tissues including central nerve system, cardiovascular system and kidney. although etiologic mechanisms of sle are incompletely known, overproduction of immunoglobulin g autoantibody may contribute to onset of this disease. while still incompletely understood, the etiology of systematic sle is considered to involve both genetic and environmental factors. we encountered two boys with severe sle from unrelated families and analyzed polymorphisms of the gene that encodes cytotoxic t-lymphocyte associated (ctla)-4, a protein important in t-cell activation and immune tolerance. abnormal function of the gene may participate in causation of autoimmune disease including sle, resulting in production of immunoglobulin against various self-antigens. case report: in family 1, a boy showed serious cardiovascular complications associated with heart failure while his mother also had clinically active sle including nephritis. a boy in family 2 developed severe renal complications and peripheral vasculitis accompanied by disseminated petechiae in the lower extremities; his paternal grandfather had died from fibrinous pneumonia caused by sle. results: analysis of the ctla-4 gene indicated that the boy in family 1 and his mother possess a gg genotype in ctla-4 exon 1 at +49 together with a 106-bp fragment length of the 3' untranslated region (utr) in exon 4. the boy in family 2 also showed gg at +49. no association with disease activity was found for polymorphism of the promoter region in exon 1 at -318 in either family. conclusions: disorders of the ctla-4 gene, especially a gg genotype in exon 1 at +49 and/or 106bp fragment length of the 3'utr in exon 4, may be involved in early development of sle in japanese children such as the boys described here. this disorder is transmitted mainly as x-linked trait, and is caused by mutations in the col4a5 gene encoding α5 chain of type iv collagen. in some families, x-linked as is associated with diffuse leiomyomatosis. we present clinical, pathologic and molecular-genetic findings in japanese family with this inheritance mode of as in association with leiomyomatosis. case report and results: as was diagnosed in a one-year-old boy with recurrent aspiration pneumonia caused by esophageal stenosis from leiomyomatosis. he had macroscopic hematuria and bilateral cataracts. diagnosis was confirmed by electron microscopy coupled with type iv collagen chain subtype staining in a renal biopsy specimen. thickening and irregular contours of the glomerular basement membrane (gbm) and splitting of the lamina densa were evident by electron microscopy. immunofluorescent staining for type iv collagen chains failed to show staining for α3 (iv), α4 (iv), or α5 (iv) in the gbm, associated with lack of α5 (iv) and α6 (iv) staining in the bm of bowman's capsule. his mother, who exhibited esophageal leiomyomatosis and is heterozygous for as, showed a discontinuous staining pattern for α5 (iv) along the epidermal bm. genetic analysis in the boy revealed the deletion of the first two exon of col4a6 together with deletion of the 5' end of col4a5. conclusion: identification of an as patient during infancy is extremely rare. clinical manifestations, including macrohematuria, cataracts and leiomyomatosis caused by the large deletion involved col4a5 to col4a6, led to early presentation with as. functional voiding disorders of the bladder occur in the absence of any anatomic/neurological abnormality and present with wetting. invasive urodynamic studies are discomforting, not easily available in emerging countries and costly. this study aims to validate non-invasive urodynamics. children below 12 years, with possible voiding disorders evaluated prospectively. non-invasive evaluation included history, examination, frequency volume charting, ultrasonography, urinalysis and renal functions. micturating cystourethrogram was carried out for children with urinary tract infection. all children underwent invasive urodynamic studies (uds) and the significance of association of the parameters of non-invasive assessment with invasive urodynamics was determined. the chi square test was used for statistical analysis using the epi 6 software. 34 children underwent invasive uds. the commonest abnormality was detrusor instability (di) in 21 (61.7%). dysynergic voiding (dv) noted in 6 (17.6%), lazy bladder in 2 and an occult neurogenic bladder in 2. the study was normal in 3. repressing the disease progression may be 1.5 mg/kg/day or more background: henoch-schoenlein purpura is classified into the small vessel vasculitis. there may be no reliable indicator of the disease activity. steroid treatment (1 mg/kg/day of prednisolone) has been thought of as a means with which alleviate abdominal pain. however, this dose seemed to be not effective to intervene the disease progression to nephritis. objectives: forty-three japanese children with henoch-schoenlein purpura were enrolled in this study. fibrinogen degradation product e-fraction (fdp-e) value was measured once or twice a week in the patients. coagulation factor xiii was simultaneously measured in 36 of the patients in the early phase of illness. with an aim to alleviate abdominal pain, 0.7-2.0 mg/kg/day of prednisolone had been administered to 15 of the patients. results: at presentation, only 16 of the 36 patients had low factor xiii activity. on the contrary, 33 of them had elevated serum fdp-e value. longitudinal fdp-e measurement revealed that patients whose fdp-e value normalized within the second weeks of illness had minimal risk of nephritis. in this group, 2 of 28 had microhematuria. in the other patients group with prolonged (after fourteen days of illness) elevation of fdp-e values, 8 of 15 had nephritis. furthermore, 7 of 8 had proteinuria after three months of illness. these 8 patients who had received prednisolone therapy with less than 1.5 mg/kg/day in the early phase of illness. the other 7 patients with 1.5 mg/kg/day or more prednisolone therapy had no nephritis. summary: the disease activity of hsp and hspn might reflect the duration of elevated serum fdp-e. more than 1.5mg/kg/day of prednisolone may repress the disease progression to nephrits. background: all major organs are involved more or less in thalassemia and most of them have been studied thoroughly in previous literature. renal system involvement has not been scrupulously scrutinized yet. method: in a randomized prospective study, renal findings of 58 children and young adults, aged 3-24 years, with thalassemia major (group 1) were compared to other 50 cases of thalassemia intermedia (group 2). blood urea nitrogen, serum creatinine, uric acid, calcium, phosphate, urinalysis, and sonographic findings were evaluated. results: mean age was 17±3.5 years in group 1 and 18±3.0 in group 2. mean serum ferritin level was 3503±201 ng/ml in group 1 vs. 871±81.8 ng/ml in thalassemia intermedia group (p<0.05). 92% of subjects of group 2 had received or was on hydroxyurea at the time of evaluation. serum uric acid was significantly higher in patients with thalassemia intermedia ( conclusion: significant renal involvement is not a frequent complication in children and young adults suffering from thalassemia. hyperuricemia and microscopic hematuria is more common in thalassemia intermedia than thalassemia major. case: a 13-year-old female patient was born at term (weight 3750 g, lenght 51 cm) and for aspiration of amniotic fluid required resuscitation and mechanical ventilation for 17 days. perinatal hypoxia was a cause of her acute renal failure but dialysis was not needed. patient's follow-up during next 12 yrs showed mild form of chronic renal failure (crf) without hypertension: serum creatinine (scr; range during follow-up [rdf] 95-112 μmol/l), glomerular filtration rate (gfr; rdf 66-73.8 ml/min/1,73 m 2 ) and p (rdf 30-180 mg/24 h). at the age 13yrs we performed renal biopsy (rb) because girl's p and scr increased (358 mg/24 h, 139 μmol/l, respectively) and gfr decreased (51 ml/min/1.73m 2 ). rb showed c1q-nephropathy (c1qn) with focal glomerular sclerosis and hyalinosis. c1qn is a rare disease and as a first diagnostic step is differentiation against lupus nephritis. progression of c1qn to crf is infrequent. probably two renal diseases were a cause of crf in our patient -hypoxic renal damage during neonatal period and c1qn. objective: renal dysfunction has been reported in survivors of neoplastic disease. early diagnosis of renal damage may decrease the morbidity in those with partial or complete remission. we studied the frequency of nephrotoxicity in pediatric patients whose therapy were completed. method: 108 pediatric cancer patients (44 f, 64 m) who were at least one year off therapy, enrolled in a prospective cross sectional study from 2003 to 2005 in oncology department of ali asgar children hospital. demographic data, cumulative dosages of anticancer drugs, history of other nephrotoxic agents, nephrectomy, radiotherapy were recorded. fasting blood and urine samples were collected to calculate fractional excretion of mg, ca, p, upr/ucr, clcr, urine osmolality and blood gas analysis. result: the mean of age was 12.9 years. 80 out of 108 patients had lymphoproliferative malignancies (group 1) and 28 had solid tumors (group 2). the mean of therapy was 35.44 month. treatment was discontinued for 52.48 month in average. the median of blood ca, p, mg, bicarbonate,and cr were 9.3 mg/dl, 3.6 mg/dl, 2.1 mg/dl, 22.65 meq/l and 0.6 mg/dl, respectively. the median of fractional excretion of ca was 0.81% this rate was 7.47% for p excretion and 2.4% for mg excretion. clcr was 135.3 ml/min/m 2 in median. the medians of urine osmolality was 850 mosmol/kg/h 2 o. the median of urine protein to urine creatinine ratio was 0.07 mg/mg. these values were not different between two groups (p>0.05) but urine concentration was defective in solid tumors group (p=0.001). mild to moderate nephrotoxicity was seen in 52.8% of cases. using binary logistic regression we found no correlated factor (p>0.05). conclusion: mild to moderate tubular dysfunction has been observed in survivors of chemotherapy. routine follow-up of renal functions are recommended. the study is to discuss the treatment of hemolytic uremic syndrome (hus) after acute stage. methods: there were 13 children who lived through acute stage of hus then continued treating. besides angiotensin converting enzyme inhibitors (acei) and early restriction of protein intake, the study was to use therapeutic schedule according to clinical classification, response to prednisone and pathological manifestation, which referred to clinical classification diagnosis and treatment of child with glomerulus disease (the program) established by nephrology group in pediatric branch of chinese medical association (cma). results: after 5 months to 12 years follow-up 4 mild type children maintained the normal blood pressure and renal function and urine examination, except for 1 recurrence. in 9 gravis type children 6 maintained the normal blood pressure and renal function and urine examination, another 3 children who manifested as durative abnormality of urine examination developed into end stage renal failure (esrd) and died in the 5th, 8th and 13th month at last. another 4 gravis type children untreated after stage of hus died in the 27th day to 48th day of the course. conclusion: it could improve the prognosis of children after acute stage of hus evidently to use therapeutic schedule according to clinical classification, pathological manifestation. objective: to find the prevalence of hematuria in patients with thalassemia major. methods: of total 1000 patients with thalassemia major under regular blood transfusion, 500 cases were randomly selected. history was reviewed and physical examination was done. urinalysis was performed in all the patients. in those with hematuria (5 or more rbc/hpf) or suspicious to hematuria (3-4 rbc/hpf) second urinalysis was done at the next transfusion time. more investigations were done in those with persistent hematuria. results: the patients had age range of 6 months to 32 years and male to female ratio was 1.05. hematuria was detected in 20 (4%) and suspicious in 33 patients (6.6%). sixty four percent of the patients with hematuria were female and it was persistent in urinalysis in 90% of cases. in 81% of the patients with hematuria, blood transfusion was started before the end of first year. in those with hematuria or suspicious to hematuria, 4% had sterile pyuria and 16% had proteinuria (these figures were 2.1% and 1.4% respectively, in those without hematuria). hypertension was not detected, but 2 patients had secondary diabetes mellitus. conclusion: hematuria is not uncommon in patients with thalassemia major and is more prevalent in girls and in those with early transfusion. background: it has been widely recognized that cyclosporine a (cya) is a useful immunosuppressive drug in renal transplantation. although it has been also accepted that cya is an effective drug for pediatric nephrotic syndrome in the past two decades, the effective serum concentrations are not revealed. the functional roles of cya has been reported that cya inhibits the production of interleukin 2 (il-2) in vivo and in vitro. aim: in this study, we investigated the correlation of serum concentrations of cya levels with il-2 levels in pediatric nephrotic syndrome cases. methods: seven children (6 boys and 1 girl, mean age 9.5±4.24 years) with minimal change nephritic syndrome were enrolled in this investigation. cya (mean dose, 3.49±0.88 mg/kg/day) was administrated in two divided doses before meal with or without administration of predonisolone. blood samples were collected just before, 1, 2, 3 and 4 hours after administration of cya. the serum concentrations of cya and il-2 were measured immediately. results: the peak blood concentrations of serum cya were observed at 1 hour after administration. the concentrations of serum il-2 levels reduced at 1 hour after administration of cya, and kept the same levels during 4 hours afterwards. the serum concentrations of cya which inhibited more than 80% of the serum concentrations of il-2 required 500 ng hr/ml. conclusions: we confirmed that cya inhibited the production of il-2 in children with nephrotic syndrome. these findings suggest that the necessary serum concentrations of cya to maintain the sufficient suppressive rate were more than 500 ng hr/ml in pediatric nephrotic syndrome. this study aimed to evaluate the circulating angiotensins in female adolescents with type 1 diabetes (dm1) and to compare with the results obtained in healthy age-matched adolescents to disclose possible changes in plasma peptide concentrations that could be related to microalbuminuria and metabolic control. patients were divided as female adolescents with dm1 (n=25) and adolescent age-matched controls (n=18). diabetic patients were evaluated at our endocrinology center and healthy adolescents were selected from our primary care unit. plasma levels of angiotensin (ang) i, ang ii and ang-(1-7) were determined by radioimmunoassay. glycohemoglobin and microalbuminuria were also measured. results were expressed as medians or means and standard deviation. kruskal wallis was used for median comparisons and t-test for means. the level of significance was p<0.05. adolescent dm1 patients exhibited high levels of glycohemoglobin (9.5±0.4%). microalbuminuria was detected in 5 (20%) patients with a disease duration of 8.4±0.7 years. angiotensin concentrations were significantly increased in dm1 patients (p<0.05 compared to controls) and ang-(1-7) levels were 4-fold higher than control values. on the other hand, the levels of ang-(1-7) in microalbuminuric patients were significantly lower than in non-microalbuminuric diabetic adolescents (p<0.05). the comparisons between ratios of ang-(1-7)/ang i and of ang ii/ang i suggested a predominance of ang ii formation rather than ang-(1-7) in microalbuminuric diabetics when compared to normoalbuminuric patients. our results showed an overall increase of angiotensins in a young female diabetic population, and further suggested a pathophysiological role for angiotensin-(1-7) in dm1. the pediatric nephrologist is often faced with the difficulty of determining adequate iron supplementation in children with chronic kidney disease (ckd). soluble transferrin receptor (stfr) and the stfr to log(ferritin) ratio (stfr-f index) have been proposed as markers of iron deficiency (id) independent of inflammation; however, their relationship with c-reactive protein (crp) and their age dependency have not been established. we therefore embarked on a prospective study of 436 healthy children undergoing minor surgery to determine reference ranges for stfr (dade behring n-latex stfr analyser, dade behring bn prospec) and stfr-f index. we studied the relationship between crp and ferritin, transferrin, stfr and stfr-f index. we also compared the relationship between mean corpuscular volume (mcv) and ferritin, stfr and stfr-f index in 205 children. results: for ages 0. .0001, 0.0050) with mcv, which we used as a marker of id in the absence of a non-invasive gold-standard; however, only stfr-f index, but not ferritin, transferrin and stfr, was independent of crp. this study shows that ferritin, transferrin, and stfr, but not stfr-index, are dependent on acute phase reactions. it is therefore hypothesized that stfr-f index provides a more useful marker for monitoring the iron status in ckd patients. conclusions: low osmolality is a crucial factor to facilitate water absorption at least in the rat small intestine, while the absorption of sodium may be influenced by the concentration of sodium and glucose. (definition iccs). standard treatment consisted of general advice on voiding and drinking habits, alarm treatment and occasionally vasopressin. constipation was diagnosed on clinical considerations (history, stool charts, physical examination, occasionally x-ray). all patients received general instructions according to bowel habits. laxatives were prescribed when the patient was diagnosed as constipated. treatment goal was daily bowel movements. treatment results were evaluated 3 months and 2 years after discharge. results: 151 patients were included. mean follow-up was 2.2 yrs. overall success rate (full response) was 80.8% (3 months) and 72.6% (2 years). laxative use: 11.2% (n=17) of the patients received laxatives, 88% (n=133) did not. in 1 patient information was lost. there was no significant difference in success rate between the laxative group compared with the non-laxative group (p=0.14, chi-square). treatment modality: 6.0% (n=9) received general advice only without laxatives, all but one had a full response. 90.1% (n=136) were treated with advice and alarm, 16 (10.6%) of them received laxatives. response to alarm treatment was 82.5%. no significant difference in success rate between the laxative and non-laxative group (p=0.13, chi-square). 1 patient was dry after vasopressin and laxatives. conclusion: the majority of patients with mse can achieve nocturnal continence without laxatives. constipation treatment with laxatives may be supportive, but is not essential in the treatment of mse. aim: hypocalcemic tetany is a known complication of plasmapheresis. we studied the changes in ionised and total calcium, and magnesium concentrations during plasmapheresis, with and without supplementing the replacement fluid with calcium and magnesium. methods: plasmapheresis was carried out by using 4.5% human albumin solution (has) with or without supplements for the first 85% of the exchange, and fresh frozen plasma (ffp) for the last 15%. we measured ionised and total calcium and total magnesium at the beginning and end of the has, and after 15 minutes of ffp infusion. results: we undertook 31 pairs of plasmapheresis runs with and without supplements in 11 children who had a variety of renal conditions. during the exchange with unsupplemented has, the total calcium fell from 2.02 to 1.70 mmol/l (ci 9.9-20.3, p<0.000), the ionised calcium fell from 1. have raised significant problems in minor surgeries. but the developmental mechanism of ponv is not clear until now. previously, we have experienced a case with ihn and ponv who showed extremely high plasma antidiuretic hormone (adh) level at the onset of ihn and that elevated adh level induced by minor surgery was supposed a trigger of ihn and ponv. in this study we investigated various values including plasma adh in cases taking kidney biopsy in order to clarify the mechanism of ihn and ponv. methods: fifteen patients taking percutaneous kidney biopsy were study subjects (mean age 10.5 years). plasma adh, serum electrolytes and osmolality were measured before and 4-5 hours after kidney biopsy. urine samples were collected to measure electrolytes and osmolality. results: high plasma adh level (19.9±8.33 pg/ml) was observed in 9 out of 15 subjects (60%). serum sodium level dropped significantly in these cases. six of 9 cases showed ponv, we divided all 15 cases into 2 groups: ponv group and non-ponv group. the result was that plasma adh level was significantly high in ponv group. conclusion: our study make it clear that elevated plasma adh level is frequently seen in children taking kidney biopsy and suggest that hydration with hypotonic saline solution after surgery is inappropriate because of the risk of developing ihn. it also become clear that high plasma adh level might lead to ponv as the same mechanism seen in motion sickness. it is suggested that adh secretion by stress after minor surgery is associated with not only ihn but also the onset mechanism of ponv. polyarteritis nodosa (pan) occurs more commonly in patients with familial mediterranean fever (fmf) and visceral hematomas are seen in almost half of the patients. we report here a 14 year-old girl with pan and fmf presented with multiple visceral hematomas. the patient was on colchicine therapy for four years because of fmf but uncompliant to therapy. she addmitted with the complaints of fever, malaise, abdominal pain and artralgia lasting for two months. she was pale and extremely cachectic with atrophic muscles of extremities. she had fever, hypertension, hepatosplenomegaly and arthritis. she had anemia with normal renal and hepatic function tests, albumin levels, and electrolytes. multiple hypoechogenic mass lesions were detected on liver and bilateral kidneys on ultrasonography and computerised tomography and diagnosed to be hematomas by laparascopic examination. urinalysis, hematological tests for bleeding and blood marrow examinations were normal. bacterial cultures and serological tests did not reveal any infectious agent. serum complement levels were normal with negative antinuclear antibody, anti-dna, p and c antineutrophil cytoplasmic antibodies. renal angiography showed multiple aneurysms in bilateral renal arteries leading to the diagnosis of pan. she was successfully treated with intravenous pulse methylprednisolone followed by oral perdnisolone and oral cyclophosphamide together with colchicine and antihypertensive agents. she has been followed up for four years without any complaints and normal laboratory and radiological findings except multiple scar formations on kidneys on dmsa-renal scanning. results: the stone-free rate was 86% after one eswl session. the above rate increased to 92% and 96% after the second and the third session respectively. regarding surgical treatment with pcnl, the overall stone-free rate was 93%. in 3 children initially treated with pcnl, an eswl session was performed later successfully, for residual calculi. open surgical removal was required in 9 children with structural anomalies. the patients with staghorn calculi underwent nephrolithotomy combined with eswl in cases of residual fragments. 12 patients underwent ureterscopic procedures to address ureteral stones and complete fragment removal was obtained. no major sideeffect were observed, during the above procedures. conclusions: it seems that the advances in instrument technology provide a variety of safe and effective methods in the management of paediatric urolithiasis. the incidence of open surgery has thus fallen. minimally invasive methods must form the first choice of treatment, while open surgery should be undertaken mainly in cases of coexisting congenital abnormalities. in all children the following parameters were estimated: a) timetable of ne, b) feeling/volume chart (frequency and biggest quantity of urination=functional capacity of bladder), c) ultrasound of urinary tract (size of kidneys, bladder capacity, bladder wall thickness, postvoiding residual urine) and d) urodynamic parameters (uroflowmetry and water cytometry). the ud bladder parameters were then correlated with the us and voiding diary findings. results: all children had sufficient data registered to allow reliable analysis. ud studies showed that children with mild pne had normal urodynamics findings, us parameters and voiding diary findings as well. ud studies reveal a relatively high incidence of instability in children with moderate and mainly in those with serious ne. conclusions: in children with pne, urodynamics did not have a significant additional value compared to baseline diagnostics and it should be avoided. on the contrary, findings from urodynamic studies in children with serious ne show that it has a useful role in this type of enuresis evaluation and management. objectives of study: hyperlipidemia, especially when started during early childhood will increase the risk of atherosclerosis. it is also a major risk factor for allograft nephropathy and post-transplant hyperlipidemia, so its diagnosis and treatment is highly suggested. in this study we have evaluated the effect of hemodialysis on the lipid profile of children with end stage renal disease (esrd). methods: twenty-two children with esrd who were on maintenance hemodialysis in shiraz pediatric hemodialysis unit were studied. they were asked not to take greater than 30% of their total daily calories as fat at least 1 month before sampling. after a 12-hour overnight fasting and before starting dialysis, blood samples were taken for lipid profiles. for each patient with total cholesterol, tg or ldl-c levels more than 95th percentile for age and gender or hdl-c level less than 35 mg/dl, was defined as dyslipidemia. results: nineteen out of 22 children (86.4%) had abnormal lipid profiles. atherogenic factor of tg/hdl-c ratio more than 5 as a major risk factor for cardiovascular disease was in 86%. conclusion: dyslipidemia is common in hemodialysed children. so, hemodialysis set-up change and antilipimic medication, and replacement of l-carnitinine is recommended for correction of dyslipidemia in this group of patients. objectives of study: bipolar renal length measurement is an integral part of the assessment of urinary tract in childhood, and is routinely performed on ultrasonography and renal scintigraphy investigation. correlation between kidney size measurement on ultrasonography and dimercaptosuccinic acid (dmsa) scintigraphy is not well recognized. the purpose of this study was to comparison renal size measured by dmsa scintigraphy and ultrasonography to find if there is acceptable agreement between renal lengths by these two methods. methods: as cross sectional retrospective study, 90 patients enrol in this study and their dmsa scan results and kidney ultrasonography reports compared. the agreement between renal size measured by two methods for left and right kidneys were evaluated separately using bland-altman plot. pearson's correlation coefficient was used to examine their correlation. statistical significance was calculated by paired-student t-test. the same tests were used to for kidneys with normal dmsa scans. results: correlation coefficient showed close correlation between kidney length measured by ultrasound and dmsa scan, but there were significant differences between two methods (paired t-test, p<0.0001). comparison between renal size measured by ultrasonography and dmsa scan using the methods of bland & altman plot in all patients and the group with normal kidneys showed a systematic bias of about +6.5 mm for left and +6.3 mm for right kidneys. conclusion: despite of close correlation between dmsa scan and ultrasonography for kidney length measurement; kidney size is overestimated by about 10 percent in dmsa scan study and this matter must be considered in practice. medical treatment of cystinuria is often considered disappointing. patients undergo frequent surgery which is often followed by early relapse. the aim of our study was to prospectively evaluate, in a paediatric population, the efficacy of a conservative medical approach for long-term treatment of cystinuria, to prevent the formation of new renal stones and reduce the number and dimension of pre-existing stones. twenty-one stone former cystinuric patients were treated with a combined approach which included cystine-binding drugs. free and bound urine cystine levels were routinely measured every four months. drug dosage was adjusted in order to maintain a steady free urine cystine level below 100 mmol/mmol creatinine (a three fold increase of normal level). in the 19 patients who completed the study, renal stone episodes were reduced from 0.28 to 0.03 episodes/year, and in several patients the number and dimension of pre-existing renal stones were reduced. during the entire follow-up, percutaneous lithotripsy to remove an obstructive stone was required in only one subject. no relapse was observed 12 months after treatment. the dosage required to achieve target levels was very closely correlated to patient body weight: older children required a lower dose to achieve target levels. in conclusion: medical management of cystinuria is feasible. the treatment must be personalised, at least in pediatric age. the amount of required drug is strictly depending from body size. it is mandatory to obtain a low free urine cystine level before any invasive procedure to reduce the risk of early relapse. objective: to study the pathophysiology of nutcracker syndrome (ns) and to assess the role of the upright position imaging and superior mesenteric artery (sma) angle measurement in the diagnosis. methods: doppler us findings in 23 children with ns and in 26 healthy control subjects were compared. the mesenteric angle, peak velocity (pv) and anteroposterior (ap) diameter of the left renal vein (lrv) at the hilar and aortomesenteric portions were measured in both the supine and upright positions. the means ±sd of the sma angle, ap diameter and pv ratio between the two portions were calculated and cut-off levels for the diagnosis of ns were established. results: the diameter and pv ratios were significantly different between the patient and control groups both in the supine and upright positions (p<0.001). differences (d) between the supine and upright positions were also significant for the diameter of the lrv at the aortomesenteric portion, diameter ratio and sma angle in both groups. upright position imaging revealed comparatively narrower sma angles and more pronounced entrapment findings in patients with ns. the sma angle measurement had a sensitivity of 69.6% and a specificity of 61.5% in the supine position and 87.0% and 76.9% in the upright position when the cut-off values were set to less than 41° and 21°, respectively. the upright position has significant effects on the lrv hemodynamics and angle of sma both in patients and healthy subjects. sma angle measurement may be a useful adjunct parameter in the diagnosis of ns. ). in addition, a statistically higher rate of pathological abnormalities on renal biopsy was noted in the group with microscopic hematuria combined with proteinuria and also in cases with more severe hematuria. conclusions: school urinary mass screening has greatly contributed to diagnosing chronic renal diseases. continuous medical observation is required when abnormal urinalysis is observed, and a more aggressive medical approach such as renal biopsy should also be performed if necessary. this study compared the outcome of children with proliferative ln (who class iii/iv) using a new protocol comprising pulse intravenous methylprednisolone, mmf +/-cyclosporine, with standard prednisolone and cyclophosphamide/azathioprine. method: twenty-three children with proliferative ln (age range at diagnosis 3.7-18.6 years) who were followed up for 6.9-4.5 (range 1.3-21.0) years, were included in this retrospective study. group i (n=11) received prednisolone with cyclophosphamide and/or azathioprine. group ii (n=12) received the combined mmf protocol with mmf dose of 1200 mg/m 2 /day. poor outcome was defined as death or chronic renal failure. survival analysis was performed using the log-rank test. effect of treatment on growth at last follow-up was assessed using height standard deviation score (htsds). differences between the groups were analyzed using the mann-whitney and fisher's exact test. results: at last follow-up, significantly more group i compared to group ii patients had higher serological activity as defined by low serum complement c3 (50% vs 0% respectively, p=0.014). in addition, 8-year actuarial survival was higher in group ii (100%) compared to group i (61%). all the group ii patients achieved complete remission of proteinuria compared to group i (0.01±0.06 vs 0.79±1.0 g/d/1.73 m 2 respectively, p=0.002). group ii patients also had lower htsds on long-term follow-up compared to group i (-0.26±1.05 vs -1.96±1.73 respectively, p=0.025). conclusion: combination immunosuppressive protocol involving mmf +/-cyclosporine resulted in better renal outcome in children with proliferative ln without compromising on growth. this regimen allowed steroid tapering to alternate day dosing without increasing lupus activity. background: a full dose of corticosteroid is required to induce complete remission (cr) in steroidsensitive nephrotic syndrome (ssns), unless it is possible to taper and discontinue along with the course after cr. however, the mechanism of this change in steroid sensitivity remains unknown. p-glycoprotein (pgp) has a function to eliminate given corticosteroids from cytoplasm, which results in inducing corticosteroid resistance. therefore, we analyzed a drug delivery perspective using the real-time polymerase chain reaction (pcr) of multiple drug-resistant gene 1 (mdr1; encoding pgp) messenger rna (mrna) expression. patients and methods: fourteen patients with steroid-sensitive nephrotic syndrome (ssns; male/ female: 14/0, age: 1-23 years old; mean 10.4) were enrolled in this study. mdr1 mrna gene expression of peripheral blood nucleated cells (pbnc), before and after cr (a total of nineteen sets of blood samples), were quantified using real-time pcr and then carried for analysis. results: the mdr1 mrna levels before cr were variable in each patient. however, there was an apparent decrease in the mdr1 gene expression of pbnc after cr (p<0.003). the results suggest that pgp may play a role in the ability to taper corticosteroids after cr in ssns. : 6 week prednisone 60 mg/m 2 /day + 6 weeks 40 mg/m 2 every other day). all other patients (b) received daily prednisone 1.5-2 mg/kg/day for 8 weeks and 30-50% of initial dose for 1 week, followed by alternate day steroids (41 week) with tapering by 2.5 mg every 6-8 weeks down to 2.5-5 mg. "frequent relapses" (less than 2 months after discontinuation of initial steroid therapy or of first relapse therapy) were treated with chlorambucil 0.15-0.2 mg/kg/day for 8 weeks and half of this dose for 6-10 months. results: seven patients (with long treatment) were lost to follow-up and 48 were studied. six of 11 (55%) of a had a relapse 4.6±1.7 months after the end of initial therapy; 3 became infrequent and 3 frequent relapsers. 19 of 37 (51%) of b relapsed 7.8±1.3 months after the end of initial therapy; 14 became infrequent and 5 frequent relapsers. frequent relapsers (27% in a and 14% in b) were treated with chlorambucil and all but one achieved long remission (>1 year). conclusions: first relapse occurred later after onset of ssns in patients with long (50 weeks) as compared to short (12 weeks) initial steroid therapy but the time interval between the end of initial therapy and the first relapse and the proportion of relapsers were similar. longer initial therapy may result in a lower number of frequent relapsers. nearly all patients had long remissions periods that were, however, achieved at the expense of early administration of chlorambucil. conclusions: the medium age of pts with metabolic stones was found to be higher than the medium age of pts with infectious stones. the familial occurrence of kidney stones was found to be important 46%. the ultrasonographic examination is the most important one. the stones composed by calcium oxalate and calcium phosphate were found to have the highest percentage. metabolic abnormalities were found in 75% of patients and hypercalciuria was the most common disorder. hypocitraturia is considered to be a risk factor the calcium stones. in an attempt to explore the new treatment for the childhood-onset intractable steroid-dependent nephrotic syndrome (sdns), we have recently performed the treatment with high-dose mizoribine (mzr), the inhibitor of inosine monophosphate dehydrogenase, and suplatast tosilate dimethylsulfonium std), a selective th2 cytokine inhibitor, which were both made in japan. mzr has been commonly used for the treatment of frequently relapsing sdns in japan at a dose of 3-4 mg/kg/day (maximally 150 mg/day) divided into two doses (kidney int 58: 317,2000). we used high-dose mzr (mean: 10.1 mg/kg/day) once before morning meal for 9 adolescent patients with frequently relapsing sdns who had been treated with long-term cyclosporine (csa) resulted in moderate to severe csa nephropathy. with this treatment for 2 years, seven out of 9 patients weaned off csa and experienced less relapses without apparent adverse effects by high-dose mzr. std is a both il-4 and il-5 inhibitor and commonly used for childhood asthma. we used std at a dose which is for the treatment of asthma for 13 children with sdns (mean 9.2 years) without previous csa treatment. after one year follow-up with std treatment, the relapse rate of nephrosis was decreased from 1.54±1.20 to 0.15±0.56 per year (p=0.0008 by wilcoxon signed-ranks test), where as the dosage of orally given predonisolone was also decreased from 0.19±0.21 to 0.04±0.05 mg/kg/day (p=0.0187 by wilcoxon signed-ranks test). objectives of study: to evaluate the efficacy and safety of long-term cya treatment for pediatric sle patients. pediatric sle patients in their teens suffer from many relapses and severe side effects caused by steroid and cyclophosphamide. there have hardly been any reports on the long-term cya treatment in children. methods: we retrospectively compiled 6 cases of childhood-onset sle female patients (mean: 12.1 years) admitted to our department from 1995 to 2004. the initial treatment was methylprednisolone pulse therapy followed by prednisolone (psl). at the onset, 4 patients had class 2 lupus nephritis and 2 showed class 3. after several relapses, cya was added and used for 20 to 68 months. the dose of cya ranged from 2.8 to 4.9 mg/kg/day, and the target trough level from 50 to 80 ng/ml. results: under this low-dose cya treatment, 5 patients had no relapse while 1 had a relapse after 49 months. in all patients, psl was reduced to alternate day treatment (mean: 10.8 mg/2 days), and 3 patients under 14 years gained the target height. of all patients, 5 developed hypertrichosis, 1 gingival hyperplasia, 1 transient elevation of s-cr with acute gastro-enteritis. although 1 case had elevated s-cr after 20 months of cya treatment, it returned to normal level within 3 months after the cessation of cya. five patients had second biopsy after 2 years, and 2 showed mild tubulointerstitial (t-i) changes. two had third biopsy after 5 years and both showed mild t-i changes only. the presence of t-i changes had no relation to s-cr, u-beta2 mg and u-nag. conclusion: low-dose cya treatment might be an effective and safe second line treatment for sle patients with many relapses in teens. it is also important to perform renal biopsy periodically to detect cya-induced renal damage which hardly shows any abnormalities in blood or urinary tests. 3 hypersensitivity to inulin is rare; two cases of food allergy and some cases of allergy after inulin infusion have been reported. an 11-year-old boy suffering from severe iga nephropathy (igan) is reported with both anaphylactic reaction and concomitant relapse of his nephropathy due to inulin infusion, used for measuring gfr 2 years after first symptoms. pruritus, sibilants and cough were observed during a first renal function test. prick and intradermal tests were negative for inulin. the patient presented with pallor and asthenia during a second inulin infusion performed under dexchlorpheniramin, leading to immediate infusion stop. he was read mitted because of fatigue and nausea; acute renal failure was diagnosed 4 days after inulin infusion. a drug-induced acute interstitial nephritis was first suspected. however, due to the presence of macroscopic hematuria and proteinuria, a renal biopsy was performed and showed acute proliferative relapse of igan. few data are available about inulin-induced hypersensitivity. chandra described anaphylaxis and cardiorespiratory arrest immediately after administration of sinistrin. a retrospective study of all recorded cases of hypersensitivity associated with renal function tests was performed by our pharmacovigilance unit. 6,328 tests using inulin clearance were realized both in adults and children; 31 patients experienced side effects which were divided into 3 groups: respiratory symptoms, rash and general signs. most side effects were minor and no life threatening complication occurred. the underlying mechanism of inulin hypersensitivity is not well known. although 55% of patients with inulin-associated hypersensitivity underwent a first renal function test, we can speculate that presensitization with food inulin may occur, sometimes leading to severe problems such as in our patient with iga-mediated immunological dysregulation. . we have previously demonstrated a composite heterozygous nphs2 mutation of both v165x and r168h in a chinese patient with srns. however, it is not clear the molecular mechanisms of mutant podocinlead to proteinuria. some evidences proved the possible interaction between podocin and trpc6. this study explored the effects of mutant podocin on the free cytosolic ca2+ and apoptosis of podocyte in order to clarify the possible causative mechanism of mutant podocin. methods: 1. the pdsred2 n1-wild/mutant podocin was constructed by using site-directed mutagenesis. 2. mouse podocyte clone was cultured and transfected with pdsred2 n1-wild/mutant podocin. 3. free cytosolic ca2+ was measured using the fluorescent indicator, fluo 3-am. results: the low level of free cytosolic ca2+ was detected in normal podocyte and the transfected podocytes with r168h mutant podocin. the v165x mutant podocin increased the free cytosolic ca2+more evidently than the over-express podocin in transfected podocytes. podocyte apoptosis were not detected in the blank-vector (just pcdna 3.0) transfected podocytes and normal podocyte. the v165x and r168h mutant podocin increased the podocyte apoptosis more evidently than the over-express podocin in transfected podocytes. conclusions: the v165x mutant podocin might induce podocyte apoptosis via the increment of free cytosolic ca2+. however, whether the increment of free cytosolic ca2+ is induced by trpc6 and the involved signal pathway should be further investigated. y. xing, q. fan, j. ding objectives of study: podocytes slit diaphragm (sd) associated molecules (nephrin, podocin and cd2ap) play a critical role on maintaining the integrity of glomerular filter. vegf is produced by podocyte, and acts on endothelium and podocyte itself. but, it is not clear whether there are some relationships between vegf and sd associated molecules. our study detected the expression of sd associated molecules and vegf in adriamycin (adr) nephrotic rats. methods: the adr rat was established by adr injection. distributions of sd molecules and vegf were detected by immunochemistry. the mrna and protein of sd molecules and vegf was examined by real-time pcr and western, respectively. nephrin phosphorylation were detected by immunoprecipitation. results: distribution of nephrin, podocin and cd2ap changed evidently, and the staining intensity of vegf decreased evidently. nephrin mrna increased at day 7, and returned to the normal at day 14 and 28; podocin and cd2ap mrna constantly increased from day 3 until day 28. the protein of nephrin increased at day 7 until day 28; podocin was dramatically upregulated at day 7, and thereafter recovered again, but was downregulated at day 28; cd2ap prominently increased at day 14 and day 28. tyrosine phosphorylation of nephrin was decreased evidently at day 28, and vegf mrna did not show significantly changes at any time points observed. however, vegf protein reduced significantly from the 7 th day, and also reduced evidently at days 14 and days 28. conclusion: the abnormality of nephrin, podocin and cd2ap may be one of the mechanisms that lead to proteinuria in adr-induced nephrotic rats. the occurrence of proteinuria in adr rats may be also associated with the reduced vegf protein, which may be related with the reduction of nephrin phosphorylation. these results suggested there may be some relationship between vegf and sd molecules. the objectives of study: mutations in genes encoding structural proteins of slit diaphragm can lead to nephritic syndrome. just recently, another gene trpc6 mutation was identified in autosomal dominant fsgs. trpc6 encodes ion channel protein trpc6, whose expression has not been clarified completely in kidney. this study aims to explore the expression and distribution of trpc6 in normal human, mouse and rat renal tissue and the mouse podocyte clone (mpc5). methods: distributions of trpc6 in normal human, mouse and rat renal tissue and cultured podocyte was observed with immunochemistry staining. the mrna expression of trpc1, 2, 3, 4, 5 and 6 was detected by using rt-pcr. the protein expression of trpc6 in human, mouse and rat renal cortex and differentiated mpc5 was detected with western. results: trpc6 showed weak staining in glomeruli and strong in renal tubules and vessels in human kidney, however, strong in glomeruli and was mainly distributed along the capillary loops and mesangium in mouse and rat kidney. the staining of trpc6 was observed in differentiated mpc5, which is distributed evenly on the cell membrane. the specific pcr band of trpc1, 2, 3, 4, 5 and 6 was detected in mouse kidney and differentiated mpc5. the sequence of the amplified pcr products is same as that published in genebank. the specific 106kda protein band of trpc6 was detected in normal human, mouse renal cortex and differentiated mpc5. conclusion: the expression of trpc6 was verified in normal human, mouse and rat kidneys and in differentiated mpc5. these results will benefit for further screening the possible mutation of trpc6 in acquired nephrotic syndrome, and investigating the relationship between trpc6 and the proteinuria-related podocyte molecules. methods: twenty children with kd (13 boys and 7 girls, aged from 3 to 78 months) were enrolled in our study. kidney sizes (including kidney length and kidney volume) were measured during acute stage in these patients. twenty age-and sex-matched healthy children and 15 febrile children served as healthy controls and fever controls. left kidney length and age were used for correlation analysis and analysis of covariance. results: kidney lengths in patients with kd were significantly larger than those of healthy children (p<0.001). the mean sd score of kidney length was 2.54±0.97 for these patients (p<0.001, vs -0.23±0.82 in normal control). kidney volume analysis yields the similar result (51.83±17.93cm 3 vs 35.62±11.24cm 3 , p=0.001). there was no kidney enlargement in the fever controls. up to 70% of the children with kd have absolute nephromegaly (>mean+2sd). this incidence is as frequent as that of lymphadenopathy and extremities change, the 2 diagnostic criteria of kd. conclusion: these results confirm the presence of large kidneys in the children with kd and also provide another useful indicator for kd diagnosis if the diagnostic criteria is not yet well established. during renal inflammation macrophages infiltrate the renal parenchyma, and their number correlates with the intensity of inflammation. macrophage migration inhibitory factor (mif) was described originally to be a product of t-cells and macrophages. mif plays an important role in renal tissue injury. to our knowledge, the studies that assessed the role of macrophages in acute renal infection were few and the role of mif was not evaluated. the aim of this study was to assess mif in uti and compare the urinary excretion of mif in pyelonephritis, cyctitis and also control group to find a non-invasive and sensitive method to differentiate them. in this prospective case-control study 31 pediatric patients with uti (25 patients with acute pyelonephritis, 8 patients with acute cystitis) and 40 healthy children were recruited. urine mif concentration was quantitated by elisa and corrected for urine creatinine. the mean ratios of urine mif/cr were calculated as 66.14 (sem=23.78) pg/μmol creatinine in acute pyelonephritis, 1.58 (sem=0.59) in acute cystitis and 1.85 (sem=0.35) in healthy individuals. urine mif/cr ratio was significantly higher in pyelonephritis than the ones in acute cystitis (p=0.0001) and control (p=0.0001). roc analysis was demonstrated that urine mif/cr ratio could considered potentially useful index to detect acute pyelonephritis [p=0.0001, area under curve (auc)=0.959]. the optimal cut-point of 5.39 pg/μmol creatinine for urine mif/cr ratio could potentially separates acute pyelonephritis patients from healthy individuals (sensitivity and specificity of 92% and 92.5%, respectively). the underlying histopathological characteristics in biopsied renal diseases are of great importance in determining the long-term prognosis and provides useful information in clinical practice. ethnicity seems to play a critical role in the epidemiology of biopsied renal diseases the aim of this study is to provide data of clinical manifestations of biopsy-proven native renal diseases in iranian children. in this retrospective study, 476 iranian children who were diagnosed as renal disease between 1980 and january 2003, were evaluated. diffuse and focal mesangial proliferative glomerulonephritis was present in 31.5% of all biopsies performed. mpgn, fsgs and mcd were observed in 9.2%, 10.2% and 13.4% the most common clinical syndrome at any age is nephrotic syndrome (50.4%), followed by nephritic syndrome (13.8%), nephrotic-nephritic syndrome (13.4%), recurrent macroscopic hematuria (7.3%), asymptomatic urine abnormalities (aua) (7.7%) and azotemia was seen in 6.7% of patients. mesangial proliferatiove gn (18/70=25.7%), poststreptococal gn (15/70=21.4%) are the most frequent pathologies with acute nephritic syndrome presentation. the most frequent causes of aua were mesangial proliferative gn and hsp. thrombotic microangiopathy (hus) was the most prevalent cause of arf. inthis study, chronic tubulo interstitial nephritis (33.3%) and alport (13.3%) were the most common causes of crf presentation in our patients. in conclusion, mpgn remains the most common histopathological subtype in children with renal biopsied disease. the incidence of fsgs continues to be high in iranian children. the aim of this study is to assess postnatal kidney volume development and to compare the intrauterine and extrauterine kidney growth curves in premature infants. one hundred neonates were enrolled in this study. all infants had their kidney volumes measured by renal ultrasound examination. group ga consisted of 44 neonates whom were evaluated within 48 hours after birth, and their gestational ages were used in the analysis. group ca included 56 premature infants born before 34 weeks of gestation and was evaluated 14-96 days after birth, and their conceptional ages were used in the analysis. left kidney volume, body weight, body height and age were used in the correlation analysis. kidney volumes in group ca infants were significantly larger before 31 weeks of age, but smaller after 31 weeks of age than those of group ga infants (p=0.001). there was a significantly better growth in body weight (p=0.001) and body height (p<0.001) in group ga infants. however, a larger kidney volume was noted in group ca infants with the same body weight (p<0.001). conclusion: chart of postnatal growth of normal kidney volume before 40 weeks of conceptional age in premature infants is presented. our data suggests that intrauterine growth may have a regulatory influence on kidney growth, and the reduced kidney volume in the premature infants may start from the early extrauterine period. objectives of study: to illuminate the role of prohibitin (phb), a tumor suppressor which inhibit cell proliferation by repressing e2f-mediated transcription, in tubulointerstitial fibrosis (tif). methods: renal biopsy specimens were obtained from 48 children with primary glomerulonephritis. phb and α-sma proteins expression were detected by immunohistochemistry. subcellular location of phb in nrk-49f was detected by confocal microscope. changes of phb protein and mrna expression in cells upon tgf-β1 stimulation were detected. after transfected with phb plasmid, cell cycle and α-sma protein and mrna expression in cells treated with or without tgf-β1 were detected. results: phb protein was found at normal renal tissues, with a positive distribution in interstitial cells and tubular epithelial cells. phb was down-regulated in tissues with tif and negatively correlated with tif degrees (p<0.05). phb is majority located at cytoplasm as well as at nucleus in nrk-49f. phb protein and mrna expression in cells were decreased when treated with tgf-β1, and the effects were both time-dependent and dose-dependent. extraneous phb inhibited cells proliferation induced by tgf-β1, and phb over-expressing cells failed to enter the cell cycle compared with non-transfected cells (p<0.01). α-sma was not expressed in control cells while de novo expression of α-sma in cells upon tgf-β1 stimulation was increased. overexpression of phb did not affect basic α-sma expression but dramatically repressed tgf-β1-initiated α-sma expression (p<0.01). conclusions: extraneous phb suppresses renal interstitial fibroblasts proliferation and cell phenotypic change induced by tgf-β1, which indicates phb as a potential target to halt tif progression. results: the prevalence of urine abnormalities of first screening was over 5.00%, and that of the second screening was about 1.00%. the prevalence was different with various methods. the specificity of method b was higher than method a. testing two urine samples for each child had higher specificity. the direct cost of method a and b was -1.70 and -2.90 rmb, respectively. for screening twice, the corresponding cost was no more than -1.90 and -3.00 rmb, respectively. using method a to screen twice for each child was convenient and economical, which also reduced the false positive rate effectively. the prevalence of urine abnormalities of junior highschool children was significantly higher than that of elementary school-children in xh and the peak point was seen at the point of 12 years old. however, there was no significant difference between children in ja and yp. more than 10 months of follow-up diagnosed 2 cases of iga nephropathy. conclusions: urine abnormalities of school-children could be detected through urine screening at school. for shanghai, method a with screening twice was convenient, economical, and could reduce the false positive rate effectively. objectives: angiopoietin-like3 protein (angptl3) is involved in lipid metabolism and angiogenesis. the present study was to examine angptl3 expression in human kidneys with proteiuria, in adramycin rats (adr), and in puromycin induced podocyte damage. methods: immunohistochemistry was performed on kidney biopsies from children with mcd, mn, fsgs, tbmn. in adr, angptl3 expression was determined by quantitative real-time rt-pcr in glomeruli and tubuli dissected from frozen section of kidneys with laser microdissection system. in mpc5, a conditionally immortalized mouse podocyte cell line in vitro, angptl3, perlecan and agrin were detected through real-time pcr with the induction of puromycin. detachment assay was performed in podocytes tranfected by angptl3-pcdna3.1. results: in human kidneys, co-labeling showed angptl3 expressed in the cytosol of wt1 positive cells. quantitative computerized analysis showed that angptl3 in glomeruli in mcd and mn were significantly higher than that of tbmn, fsgs respectively (p<0.05). in adr, angptl3 in glomeruli increased significantly at 21 st or 28 th day (p<0.05) after adriamycin injection compared with control. and the expression of angptl3 in glomeruli was correlated with 24 h urinary protein (r=0.81, p<0.05). in mpc5 both protein and mrna expression of angptl3 on podocytes were up-regulated with the induction of puromycin. in podocytes transfected by angptl3-pcdna3.1 the expression of perlecan or agrin increased significantly compared with control (p<0.05). the attachment ratio was shown 95.7%±3.3% 24 hs after puromycin treatment on podocytes transfected by angptl3 compared with 38.6%±4.7% on normal podocytes, and 27.4%±3.5% on untransfected podocytes. conclusions: angptl3 is predominantly expressed in podocytes which could be involved in podocyte damage and the development of proteiuria. (1), iv (1) and iii (1), respectively. only one patient had microhematuria. we found that 5 of them had a very low c3 serum levels. clq and c4 deposits were all strong positive in 6 renal tissues. our findings suggest that biopsy should be strongly considered in this patient population. the significant renal involvement (class iii, iv, or v ln) could be found in sle patients with very lower proteinuria with or without hematuria. patients in bfb group received computer-assisted biofeedback program while those in ddavp group took minin. both therapies were carried out for 1 month and then 3 months follow-up was taken. parameters of follow-up included enuresis diary-urine flow rate and aqp2 in urine. results: 50 pne patients were recruited (26 boys, and 24 girls), whose mean age was (8.4±0.9) years. at the end of treatment and three months later, total effective rates in bfb group were significantly higher than those in ddavp group. uroflowmetry findings showed that in bfb group maximum flow rate, voided volume and ratio of coordinative detrusor-sphincter contraction increased after treatment. ratio of normal flow curve increased at second follow-up (p<0.05). in ddavp group voided volume and voiding time decreased after treatment. ratio of normal flow curve and coordinative detrusor-sphincter contraction had no change after treatment. two bands of aqp2 (29 000 and 43 000) were detected in the morning urine. density of patients bands was significantly lower than that of the controls. density of 29 000 bands in ddavp group after treatment were significantly higher than that before, but there was no difference between datas before and after treatment in bfb group. conclusions: bfb and ddavp are both effective therapies for pne in children. bfb is helpful in correcting voiding dysfunction and ddavp can increase aqp2 protein in the urine. with higher effective rate within four month, bfb is strongly recommended. objective: to describe the clinical course of non-parasitic chyluria in a thai pediatric case. this is the first report in children. results: the 7-year-old boy presented milky urine lasting for one year. urine tests showed heavy proteinuria (protein to creatinine ratio 9.1 mg/mg), lipiduria (triglyceride 29 mg/dl). the proof of a pronounced hypertriglyceriduria led to the diagnosis of chyluria. his renal function was normal. numerous red cells and lymphocytes were observed in the urine, and postprandial cystoscopy revealed milky cloudy urine emanating from right ureteral orifices. retrograde pyelography demonstrated pyelolymphatic backflow. serum immunoglobulin g4 for wuchereria bancrofti and circulating filarial antigen in the peripheral blood were negative. chest x-ray, abdomen computed tomography and intravenous urography did not demonstrate abnormal mass or malformation. proteinuria and lipiduria ceased before sixth week of a medium-chain triglyceride-rich diet. there was no recurrent chyluria after 12 weeks of mct-rich diet were completed. conclusion: in non-parasitic chyluria with unknown etiology, the low-fat diet with mct supplementation alone is effective. the prognosis is excellent. there was a significant improvement of waz comparing data at admission and at the end of follow-up (p<0.001). there was also a significant improvement of whz comparing data at admission and at the end of follow-up (p=0.02). only 9 (2.3%) patients presented with a whz less than -2.00 at the end of the follow-up. conclusion: children with primary vur presented an improvement in somatic growth with medical management. objective: the aim of this study is to investigate the clinical practical value of using doppler ultrasound to detect renal blood flow in renal parenchymatous diseases of children. methods: the renal arteries, segmental arteries and interlobar arteries were detected by doppler ultrasound. the parameters were peak systolic velocity (vmax), minimum velocity in diastole period (vmin), vmax/vmin (s/d), resistive index (ri) and pulsatility index (pi). there were 30 cases of healthy children, 20 cases of acute poststreptococcal glomerulonephrits, 20 cases of primary nephrotic syndrome and 15 cases of chronic renal failure. results: the doppler renal blood flow in normal school children was high velocity and low resistant type. 15 typical cases of acute nephritis with edema and oliguria appeared low velocity and high resistant type, ri, pi and s/d of all renal arteries were significantly increased, vmin are significantly decreased (p<0.05). after 2 to 3weeks all parameters returned to normal. during edema period and convalescence, the renal blood flow of primary nephrotic syndrome is low resistant type, ri, pi and s/d of segmental arteries and interlobararteries were significantly decreased (p<0.01). the feature of low circulating blood capacity was not alleviated even though edema was vanished and urine output was increased. the doppler in chronic renal failure was high resistant and low velocity type. ri, pi and s/d were all significantly increased, vmin were significantly decreased (p<0.01). when ri was great than 0.8, the extent of damage in kidney function was serious and the prognosis was bad. conclusion: renal blood flow provided a new non-invasive method for clinic diagnosis and evaluation of the prognosis in children renal parenchymatous diseases. we concluded that the dms is an important cause of congenital nephrotic syndrome. the outcome of our patients was poor and most of our patients died before 5 years old. objectives: the antiphospholipid syndrome is defined by the association of arterial/venous thromboses or obstetrical fetal loss with the presence of antiphospholipid antibody. this syndrome may be primary or secondary, particularly in association with systemic lupus erythematous. this study is to examine the frequency of anticardiolipin antibodies and the association between anticardiolipin antibodies with some symptoms in children with lupus nephritis. methodology: twenty-five children with lupus nephritis from 03/2006 to 11/2006 in department of nephrology, children's hospital o 1 were included in the study. we find the relationship between anticardiolipin antibodies with hematologic and renal involvement. results: anticardiolipin antibodies was positive in 11 patients (44%), 6 for anticardiolipin igm antibody (24%), 7 for anticardiolipin igg antibody (28%). there was a positive correlation between the presence of anticardiolipin antibodies and thrombocytopenia. in 11 patients with positive anticardiolipin antibodies, 3 patients had mta on renal biopsy. conclusion: anticardiolipin antibodies are associated with thrombocytopenia and mta. aim: the methodologies for quantitating urinary calcium excretion have not been standardized. the aim of this study was to compare urinary calcium/osmolality (uca/osm) ratio with calcium/creatinine (uca/cr) ratio and to assess the correlation of both ratios with daily urinary calcium excretion for the diagnosis of hypercalciuria in children. patients and methods: 364 children aged 6-14 years (mean 9.4±2.2 years) were included in the study. they were randomly selected from previous study's larger patient population. non-fasting, second morning urine samples were collected from all children. children were divided into two main groups: 1) 180 children with uca/cr <0.21(mg/mg) and 2) 184 children with uca/cr <0.21. 24-hour urine samples were collected from the second group, who were further divided into two subgroups: 2a) 113 children with daily calcium excretion <4 mg/kg/day and 2b) 46 hypercalciuric children (daily calcium excretion >4 mg/kg/day). results: mean uca/osm ratio was significantly lower in the first (1) group than the second (2) group (0.11±0.07 vs 0.31±0.14 mg/l/mosm/kg, p<0.05); but there was no difference between 2a and 2b subgroups. the correlations of both uca/osm and uca/cr ratios with 24-hour calcium excretion were poor (r=0.27 for both). conclusion: uca/osm ratio correlated with spot uca/cr ratio. but its superiority on uca/cr ratio in the diagnosis of hypercalciuria could not be shown. interestingly, values of 24-hour calcium excretion as a definite diagnosis test of hypercalciuria; did not correlate mathematically with those ratios of hypercalciuric or non-hypercalciuric children. using uca/osm ratio as a screening test would not separate hypercalciuric children. background: microalbuminuria is a biomarker of renal damage. the presence of microalbuminuria in patients with a solitary kidney has been described, but the pathophysiology leading to its occurrence is poorly understood. it is postulated that microalbuminuria is the early result of hyperfiltration. methods: we concomitantly measured inulin clearance, filtration fraction (ff) and microalbuminuria in children with a single kidney. correlation between the occurrence of microalbuminuria and a high filtration fraction was done. microalbuminuria was defined as an albumin/creatinine ratio (acr) >3 g/mol for boys and girls. normal filtration fraction was defined as <26%, and normal inulin clearance as >90 ml/min x 1.73 m 2 . during the same study, we also measured microalbuminuria in children with severe grade iii to v vesico-ureteral reflux (vur). results: 27 children with a single kidney were evaluated. 18 patients (67%) had a normal ff, and only one (6%) in that group had an abnormal acr. 9 patients (33%) had elevated ff, and 5(56%) had an abnormal acr. the presence of an abnormal acr was highly correlated with an abnormal ff (p=0.008). the mean gfr between the groups with normal or abnormal microalbuminuria did not differ significantly (94±31 ml/min x 1.73 m 2 vs. 83±16 ml/min x 1.73 m 2 , respectively). there was no significant association between microalbuminuria and a high ff in patients with severe reflux (p=0.3). discussion: we found the presence of microalbuminuria to be significantly associated with an elevated ff in children with a single kidney. this finding goes in line with the pathophysiology of a reduced nephron mass, leading to hyperfiltration, and ultimately to glomerular sclerosis. the benefit of renin-angiotensin-aldosterone blockade in these patients remains to be proven. chyluria is the excretion of chyle from the urinary tract and indicates the presence of an abnormal communication between intestinal lymphatics and the urinary tract. it can be of parasitic or nonparasitic etiology. southern brazil is not an endemic region for filariasis. aim: report a case of a 14-yrs caucasian adolescent girl referred to our out-patient clinic. history: 3 yrs before, she started to pass milky urine with white clots. no edema. normal blood pressure. she was investigated in another hospital and underwent a renal biopsy, that was normal. a diagnosis of nephrotic syndrome was made. she was treated initially with steroids and after changed to cyclosporin, lisinopril and simvastatin. conclusion: chyluria, although a rare conditione specially in children and adolescent in nonendemic areas, should beconsidered in the differential diagnosis of nephrotic syndrome. macroscopic examination of the urine, that is milky and cloudy, is simple and very helpful. also, triglycerides are found only in the urine of patients with chyluria. these simple tests will avoid unnecessary treatment, which is not without side effects. low-density lipoprotein apheresis (ldl-a) has been tried in the treatment of patients with steroidimmunosupression resistant nephrotic syndrome (ns) due to focal segmental glomerulosclerosis (fsgs). we would like to report a child case study of fsgs with ns and renal insufficiency due to mitochondrial abnormality treated by ldl-a and to clarify the therapeutic effects of this treatment. a 12-year-old boy was referred to our hospital with complaints of heavy proteinuria and edema. a routine examination revealed proteinuria of 7.0 g/day, serum albumin (alb) of 1.9 g/dl and creatinine clearance (ccr) of 58.5 ml/min. renal biopsy specimen showed fsgs and perceptive deaf nass was recognized, necessitating a hearing aid. the a3243g point mutation in mitochondrial gene was detected by using genomic dna isolated from peripheral blood leukocytes and by the molecular analysis using an allele-specific polymerase chain reaction (pcr). oral prednisone (2 mg/kg/day for eight weeks), intravenous methyl-prednisone pulse therapy (1.0 g/day,three times a week on the consecutive days for three weeks) and oral cyclophosphamide (75 mg/day for eight weeks) were not effective to reduce proteinuria. a protocol of ldl-a was designed for treatment twice-a-week for four weeks and then once-a-week for six weeks. following treatment by ldl-a, serum total cholesterol and ldl were markedly changed form 271 to 118 mg/dl and from 198 to 91 mg/dl, respectively. a small but significant increase in alb from 1.9 to 2.9 g/dl and a remarkable decrease in proteinuria from 7.0 to 1.4 g/day were also successfully obtained. conversely, no marked changes in ccr were detected. the results of the present study indicate that a rapid decrease in proteinuria and an excellent increase in alb by ldl-a provide a possible therapy for drug-resistant ns due to fsgs with mitochondrial abnormality. glomerular filtration rate (gfr) can be estimated in children by various formulas based on body height and serum creatinine (s cr ) measurements such as the schwartz formula (egfr sch =kxbh/s cr ). we evaluate the performance of egfr sch in estimating gfr in a pediatric cohort when compared to 125 i-iothalamate clearance (igfr), used as the reference standard for measuring gfr. between 1996 and 2006, we obtained 265 igfr and egfr sch on 171 subjects. for subjects who had more than one igfr, the first measurement was used for analysis. mean age was 13±6 (range 1-20, 56% age=13), 55% male. mean s cr was 1.2 mg/dl (median 0.8), mean igfr 76±38 ml/min/1.73 m 2 and mean egfr sch 116±59 ml/min/1.73 m 2 . figure 1 shows a scatter plot of the data with a line representing perfect agreement. figure 2 shows a residual plot comparing the difference between estimated and measured gfr to egfr sch . pearson r correlation between the two variables was 0.87 (ln scale). accuracy of egfr sch within 20% and 50% was 20% and 50%, respectively. the median difference between igfr and egfr sch was 40.1 ml/min/1.73 m 2 (median % difference 50%). for igfr >60, 30-59, 15-29 and <15 ml/min/1.73 m 2 , egfr sch overestimated gfr by 46%, 66%, 48% and 44%, respectively. however, the median difference between igfr and egfr sch for the same groups was 39, 18, 8 and 4 ml/min/1.73 m 2 , respectively. in conclusion, agreement between egfr sch and igfr is poor. egfr sch overestimates igfr at all levels of gfr, but bias of egfr sch vs. igfr increases progressively with higher gfr levels. in clinical instances when an accurate estimation of gfr is critical for patient management, the use of egfr sch should be reconsidered. until a more applicable estimation equation is developed, isotope measurement of gfr remains the ideal method to determine gfr in this population. background: immunosuppressive therapies other than corticosteroids, potentially associated with serious adverse effects, are urgently required for children with frequently relapsing nephrotic syndrome (frns). this study evaluated the efficacy and safety of long-term treatment with a moderate dose of cyclosporine (cya) in children with frns. methods: in this prospective, open-label multicenter trial, patients, from 2 to 16 years old, were randomly divided into two groups. for the first 6 months, both groups received cya (sandimmune) in a dose that maintained the whole-blood trough level between 80 to 100 ng/ml. during the next 18 months, the dose of cya was adjusted to maintain a trough level between 60 and 80 ng/ml in group a, while group b received a fixed dose of 2.5 mg/kg per day of cya. the primary end point was the rate of sustained remission. results: at 24 months, the rate of sustained remission was 52% in group a (n=24 patients), as compared with only 15% in group b (n=20) (p=0.006). the hazard ratio for relapse was 0.36 (95% ci, 0.17 to 0.77) in group a as compared with group b (hazard ratio=1.0). at 24 months, the rate of progression (to frns)-free survival was 78% in group a and 56% in group b (p=0.12). mild arteriolar hyalinosis of the kidney was found in 4 (19.0%) of 21 patients in group a and 1 (5.6%) of 18 in group b; no patient had striped interstitial fibrosis or tubular atrophy. conclusion: cya given for 2 years in a dose producing a trough level between 80 and 100 ng/ml for the first 6 months, followed by a trough level between 60 and 80 ng/ml for the next 18 months is an effective and relatively safe treatment for children with frns. with this regimen, about 50% of patients are expected to remain relapse-free during 2 years of treatment, without the most critical adverse effect of cya, i.e., interstitial changes of the kidney. renal stone disease has been regarded as an uncommon problem in children especially in the first year of life. we evaluated clinical findings and metabolic examination of 49 children with urinary tract stone presenting in the first year of life. there were 25 boys (51%) and 24 girls (49%), the mean age of admittance was 6,04±3,15 months. the average follow-up period was 30,91±24,65 months. urolithiasis was diagnosed during evaluation for uti and incidentally. positive family history for urolithiasis was reported in 22 (44,8%) patients. in 28/38 (73,7%) patients urinary metabolic examination was not normal (table 1 ). in 48 of 49 patients (98%), stones were located in kidneys which was bilateral in 26 (52%) patients and one patient had passing stone which had never seen in ultrasonographic examination. stones were examined in 3 subgroups. in 39 (80%) patients stones were measured 5 mm or smaller (group 1), in 9 patients (18%) they were between 5-9,9 mm (group 2) and in only 1 patient the stone (cystin) was larger than 10 mm (group 3). stones measuring 5 mm and larger were found highly associated (in 7 of 10 children, 70%) with abnormal ultrasonographic findings mainly hydronephrosis. in group 1, stones disappeared spontaneously in 12/23 (52%) patients. urinary tract infections (uti) were present in 28 (57%) patients. one fourth of cases had associated genitourinary tract abnormalities mainly vesicoureteral reflux in 9 (18%) patients. we conclude that the presenting symptoms of urolithiasis in the first year of life show a wide spectrum so that high index of suspicion is important for early detection. stones measuring 5 mm and smaller may have great chance to disappear. we also emphasize the importance of screening for uti in patients with urolithiasis under 1 year of age. background: long term complications of glycogen storage diseases (gsds) include delayed puberty, hepatic adenoma and renal disease. in the present study we aimed to detect renal involvement in children with glycogen storage disease and to determine the most accurate laboratory test to be the gold standard for early detection of this renal dysfunction. methods: twenty-seven children known to have gsd were included in this study. fifteen healthy age-and sex-matched children were also included as controls. routine urine analysis, urinary β2 microglobulin and microalbumin were done for all patients and controls. renal function tests, serum electrolytes, alkaline phosphatase, urinary calcium, blood and urine ph, urinary and plasma aminogram, in addition to calculation of glomerular filtration rate (gfr), bone x-ray to detect rachitic manifestations and abdominal ultrasound to measure renal size were done for all patients. results: twenty-one patients had one or more renal abnormality. the most common was increased urinary β2 microglobulin (15/21) followed by abnormal gfr whether low or high (8/21) and microalbuminuria (6/21). sonographically there was nephrocalcinosis in one case and renal stone in another one. the auroc curve for β2 microglobulin was 0.86, (p=0.01) and 0.7 for urinary microalbumin/creatinine ratio (p=0.15). the best cutoff level to predict renal abnormality for urinary β2 microglobulin was 0.22 mg/l with 70% sensitivity and 100% specificity and the best cutoff value for urinary microalbumin/creatinine ratio was 4.5 with 86% sensitivity and 50% specificity. in conclusion: renal abnormalities are common in patients with gsd. urinary β2 microglobulin can be considered the gold standard for early detection of renal dysfunction in these patients. the aim of this study was to investigate the role of neutrophil activation, protein oxidation and ceruloplasmin in the pathogenesis of hsp, which has been not investigated previously. serum activities of myeloperoxidase (mpo) and arylesterase (aryl) and levels of free thiol, ceruloplasmin (clp) and total oxidant status (tos) were measured in 29 children with hsp (16 boys, 13 girls; mean age 9.3±2.7 years) at the onset of the disease and during remission in comparison with 30 matched healthy subjects. patients at active stage had significantly higher mpo activity (391±277 vs. 155±154 u/l, p<0.001), higher clp (832±120 vs. 682±114 mg/dl, p<0.001) and tos values (20.7±11.8 vs. 7.5±2.8 μmol h 2 o 2 /l, p<0.001) than controls. patients had significantly lower aryl activity (158000±39000 vs. 187000±46000 u/l, p<0.001) and lower free thiol levels (234±48 vs. 279±26 μmol/l, p<0.001) than controls. there were 17 patients with gis involvement, 14 with joint and 13 with renal involvement. no significant differences were found in the oxidant stress markers between patients with or without organ involvement (p>0.05). significantly positive correlations were found between tos and mpo (r=0.437, p=0.018), and tos and clp (r=0.409, p=0.028) at the disease onset; while a negative correlation was found between mpo and thiol (r=-0.597, p=0.001) during remission. in conclusion, protein oxidation and neutrophil activation may play important roles in the pathogenesis of hsp. gastrointestinal system, joint and/or renal involvements were not together with different magnitude of oxidant stress. further studies are required to identify oxidizing substances and to develop therapeutic strategies to reduce oxidant stress in hsp. 1, 21) . if the first remission occurred after 8 days, the median time to relapse after discontinuation of steroid therapy was significantly lower than in children with shorter remission time (0.5 vs 3.0 months; p<0,0001). in conclusion children who fail to achieve a prompt remission after a first episode of ns are more likely to have frns or sdns. these retrospective data provide the rationale for individualizing the initial steroid treatment of mcns according to the time to obtain a remission. a prospective study is needed to validate this approach. the aim of this study was to determine the influence of osmolality of the first morning urine (ofmu) to efficacy of the desmopressin therapy in enuretic (pne) children and to compare the values of ofmu in enuretic and non-enuretic children. methods: we investigated ofmu in group of 50 children with pne and in group of 36 control non-enuretic children. pne group was divided into subgroup i (ofmu <600 mosm/kg h 2 o) and subgroup ii (ofmu >600 mosm/kg h 2 o). additionally, we measured ofmu 1 months after the initiation of desmopressin therapy and recorded the number of wet nights. regarding the number of wet nights we divided pne group to 3 subgroups: subgroup a (<5 wet nights/month), subgroup b (5-10 wet nights/month), and subgroup c (>10 wet nights/month). results: the statistically significant difference between control group and pne group regarding ofmu was not found (p=0.612). all 10 children from subgroup i had <5 wet nights/month during desmopressin therapy. 14 children from subgroup ii had <5 wet nights/month, and 26 had >5 wet nights/month during desmopressin therapy. the difference between those two groups was statistically significant (x 2 =13.3, p=0.0003). in children from subgroup a the difference between ofmu-s during and before treatment was 413 mosm/kg h 2 o, in children from subgroup b it was 261 mosm/kg h 2 o and in children from subgroup c it was 117,5 mosm/kg h 2 o. there was the statistically significant difference among those subgroups. conclusion: children with pne had usually similar ofmu like non-enuretic children. low ofmu is a good prognostic factor for desmopressin therapy of pne, especially in patients whose ofmu is <600 mosm/kg h 2 o. children with bigger difference of ofmu before and during therapy had better response to desmopressin therapy. we can conclude that ofmu can help in choosing the appropriate therapy for pne in children. yh. ng 1 , kl. chan 2 1 kk women's and children's hospital, pediatric nephrology, singapore, singapore 2 singapore general hospital, neonatology, singapore, singapore aim: to evaluate the clinical course and outcome of primary vesicoureteric reflux (vur) in patients with antenatal hydronephrosis in a neonatal unit. method: a prospective observational study of neonates with antenatal hydronephrosis born between january 1991 and december 2000 in the neonatal unit of singapore general hospital. neonates with significant hydronephrosis postnatally underwent micturating cystourethrography (mcu). records were reviewed with regards to the clinical course and outcome of primary vur. results: of 280 neonates with antenatal hydronephrosis, 139 (49%) had significant hydronephrosis postnatally and underwent mcu. 12.9% (18/139) were diagnosed with primary vur at median age of 7 weeks. there were more male (n=11) than female infants with primary vur. 10 (56%) infants had bilateral vur. 18% (n=5) of the renal refluxing units (rru) had low grade vur and 82% had high grade vur with the majority (57%) being grade iii vur. repeat mcu for 15 rru at 2 years showed that 60% (n=9) had spontaneous resolution of vur, 27% had improved vur grade and 13% had similar vur grades as before. 2 infants develop vur in the contralateral kidney which was previously normal. 14 infants (23 rru) underwent dmsa with renal scarring noted in 4 infants. all 4 infants were noted to have renal scarring without a history of urinary tract infection (uti). interestingly, 2 male siblings were found to have grade iii vur with renal scarring with subsequent spontaneous resolution. none of the study subjects underwent surgery. median age of follow-up was 3.8 years (range 0.3-12.5 years). conclusion: unlike neonates with vur detected after uti, infants with primary vur were predominantly male, had higher grade of vur with spontaneous resolution in the majority. early diagnosis of primary vur may provide the opportunity for reduced incidence of reflux nephropathy. t. neveus 1 , g. läckgren 1 , j. wahlberg 2 , n. wahlin 1 1 uppsala university children's hospital, uppsala, sweden 2 uppsala university hospital, department of transplantation surgery, uppsala, sweden objectives and methods: loin pain hematuria syndrome is a rare entity consisting of recurrent macroscopic hematuria with debilitating loin pain. it has only been described in adults, etiology is unclear and treatment is controversial but the therapy with best recorded success is to remove the kidney and reposition it in the pelvis. our objective was to show that the condition exists in childhood as well. results: aj, a previously healthy 9-year-old girl, was admitted because of recurring cystitis-like symptoms with microscopic hematuria but without bacteriuria. ultrasound and urography were normal. the episodes continued during the following years with increasing hematuria, now macroscopic, and increasing loin pain that was somewhat exercise-dependent. a renal ct scan was normal, as was cystoscopy, urography and ultrasound, but during cystoureteroscopy dilated vessels were noted in the mucosa of the right renal pelvis. antegrade pyelography, high resolution renal ct angiography, invasive renal angiography, mag3 renogram were all normal, gfr 111. nephrological evaluation, including kidney biopsy and coagulation tests were also normal and during cystoscopy blood could be seen emerging from the right ureteral orifice. by this time the patient was 15 years old and was dependent on opioids in order to be able to go to school. after long discussions with the nephrologist, urologists, pain specialist and transplantation surgeon, the family opted for autotransplantation as a last resort. this was performed january 2006 and the girl became almost momentarily pain-free. nowadays she does not need any analgesics, but after prolonged exercise (like several days of horseback riding) she may experience slight pain in the left loin and/or hematuria. conclusions: idiopathic loin pain hematuria syndrome exists in childhood and may possibly be treated with renal autotransplantation. j. van der deure, a. ockhuijsen, m. sondaar deventer ziekenhuis, 1st department of pediatrics, deventer, the netherlands objective: enuresis is a common pediatric problem. psychosocial factors (psf) influence the results of enuresis treatment in children. aim: to determine the short and long term effects of psf on enuresis treatment in a general pediatric population. methods: we reviewed the data of our enuresis patients treated from 2002-2004. relevant contributing psf were categorized. initial follow-up was at 3 months after training. a written questionnaire was sent 2 years after training. treatment success was defined as >90% improvement in dry nights. results: 211 pts were included. in 65 pts (30.8%) contributing psf were recognised. categorized problems: family related n=28 (43%), behavioural problems n=28 (43%), motivation/support n=22 (33.8%), learning disabilities n=21 (32.3%). overall success rate was 75.3% at 3 months and 65.3% at 2 yrs (overall resp quest 63.7%, psf 60.6%, 1 psf 51%, >1 psf 73%). success rate in the psf group was 49.2% (1 psf 61.5%, >1 psf 30.7%) at 3 months and 43.2% (1 psf 45%, >1 psf 42%) at 2 yrs. statistics: success rate in the group with psf is significantly lower as compared to no psf at 3 months (p<0.001 (chi-square), or 9.3, 95% ci 4.2-20.2) and at 2 yrs (p=0.0017 (chi-square), or 3.7, 95% ci 1.6-8.1) success rate at 3 months is significantly lower in pts with >1 psf, compared with 1 psf. (p=0.011 (chi square), or 4.6, 95% ci 1. 5-13.9) . no significance could be demonstrated at 2 yrs (p=0.85, chi-square) but this may be due to the variety in response rates. t. papalia, r. greco, r. bonofiglio hospital annunziata, nephrology, cosenza, italy actually a new litholitic therapy includes the phytotherapy agents as phyllantus niruri (pn), a plant used for years in brazil to treat urinary stones. in this work we estimate the effect of pn intake (uristone 2 gr/die) in 15 children (9 m/6 f, 9±5 years old) with urolithiasis. the pn has been administered for short term (from 1 to 3 months) in 13 children wih caox urinary stones and for 6 months in 2 with struvite stones. besides all children treated with dietary intervention: high fluid intake, sodium restriction, normal calcium intake and a diet low in animal protein. urinary and plasma analysis, body weight, map, ph, creatinine clearance, urinary excretion of mg and citrate were determined at baseline, 1 month and at the end of the study. the patients were studied by renal ultrasonography at baseline, 1, 3, 6 months. nobody of them had been undergone extracorporal shock wave lithotripsy. there were no differences in the mean values of urinary and plasma parameters before and after pn intake, except for a significant reduction in the mean urinary calcium in 8 hypercalciuric pts (6±1,3 vs 3,5±1 mg/kg/die). in this follow-up n°10 patients showed a faster stone clearance after a regular intake of pn and the others showed a smaller stone diameter. previous reports showed pn has a potent inhibitory effect on caox crystal adhesion and/or endocytosis by renal tubular cells and inhibitory effect on crystal growth, which might be related to the higher incorporation of gags into the calculi. our results suggest pn appears to represent a nontoxic and a low cost alternative for the prevention and treatment of stone disease, especially in the children. further studies are necessary to validate these preliminary findings. d. weitzel, c. schäfer, k. hohenfellner, u. pfeffer, m. neukirch german clinic for diagnostic, pediatrics, wiesbaden, germany objective: does sonographic quantification of the renal parenchyma allow estimation of isotopic renal function? method: sonographic kidney images of 88 patients (age 1 to 195 months; mean 47) were measured retrospectively. in all images of both kidneys taken from dorsal the volume on the base of length, width and depth was calculated. the parenchymal area (pa) in the longitudinal and cross section was calculated by planimetry. the distribution of renal function via mag3 was compared with sonographic values as volume and pa of each kidney in relation to whole kidney volume and pa respectively. patients with reduced global kidney function and time space of more than 3 months between isotopic study and sonography were excluded. results: interrater variability regarding planimetry of pa in longitudinal section (from dorsal taken images) was as good as measurement of kidney length (correlation coefficient (k)=0,968-0,977 and 0,97-0,99 respectively). all sonographic parameters correlated significantly with the isotopic parameters of renal function. the latter correlated best with the pa in longitudinal section (from dorsal taken images) k 0,939. the combination with planimetry in cross section did not improve correlation (k 0,94). difference of the proportional pa of the left kidneys (in correlation to whole kidney pa) in comparison to isotopic proportional renal function lead to mean difference of -0,3% with a standard deviation 6,7%. if only kidneys with split function of 45-55% the mean difference of proportional pa was -0,6% and the standard deviation 3,6%. conclusion: the distribution of total pa of both kidneys correlates significantly with the distribution of renal function (left and right) in isotopic studies. if sonographic planimetry might change the indication for isotopic studies in respect of renal function needs to be proofed in prospective studies. background: childhood incontinence is a common important urologic problem. especially daytime incontinence is often neglected by the parents until it turns out to be a significant clinical problem. the aim of this study was to evaluate the clinical characteristics of the patients with incontinence that were followed in our nephrology clinic. study design: patients were followed between the dates of 01.01. 2004-31.12.2006 and they were admitted solely due to incontinence or with concomitant urinary tract infections were enrolled. results: the study comprised 99 patients (38 m, 61 f; mean age 9.78±3.06 years). fourty-two patients had only nocturnal enuresis (ne) (29 primary, 13 secondary). twelve patients had daytime incontinence (di) (4 primary, 8 secondary) and 45 had both ne and di (25 primary, 13 secondary and 7 both primary ne and secondary di). all, except two (neurogenic bladder), had functional incontinence. twelve patients had additional fecal incontinence and 8 had constipation. sixty-two percent of the patients had one or recurrent urinary tract infections (uti) in their past history, 16% had accompanying vesicoureteral reflux and 4% had urinary stones. ultrasound revealed unilateral or bilateral dilatation in 20% and other anomalies in 5% of the patients. nineteen patients had abnormal dimercaptosuccinic acid scintigraphy findings. timed voiding schedule and double voiding were recommended to all patients with daytime incontinence, 43% of the patients received anticholinergic treatment and 50% received antimicrobial prophylaxis. discussion: overall, approximately 2/3 of our patients had associated uti and 1/5 had abnormal dmsa findings. therefore every patient with uti should be questioned about urinary incontinence and be treated carefully if present. the aim of the study was to determine early parameters of ultrasound and dmsa scanning diagnostics of reflux nephropathy (rn) in children. we examined 150 children with rn and vesicoureteric reflux (vur). all children were comparable on gender and age. all patients underwent color doppler ultrasound (cdus), x-ray and dmsa scan. they were divided into two groups: 1) children with unilateral rn a according to classification of smellie j. et all, 1975 (n=75) ; 2) children with vur without renal damage (n=75). we established that data of cdus (diastolic velocities (vd) 5,94±0,99 mm/sec, systolic velocities (vs) 22,3±5,74 mm/sec, resistive indices (ri) 0,63±0,06, pulsatility indices (pi) 0,76±0,19), dmsa scanning (time of the maximal accumulation 11,8±0,91 sec, maximal activity 189,3±20,4 sob/sec, mean velocities of accumulation 29,1±1,9 mm/sec, the contribution to the common accumulation 45,3±3,5%) are characteristic for patients with rn a. data of cdus (vd 10,7±1,68 mm/sec, vs 23,9±1,7 mm/sec, ri 0,63±0,02, pi 1,08±0,24), dmsa scanning (time of the maximal accumulation 7,5±0,86 sec, maximal activity 81,5±11,9 sob/sec, mean velocities of accumulation 7,72±1,07 mm/sec, the contribution to the common accumulation 34,27±3,03%) are characteristic for patients with vur without renal scars. the ranges of cdus and dmsa scanning were significantly different between children from comparing groups (p<0,05). our result suggest that data of cdus (vd, vs, ri, pi), dmsa scanning (time of the maximal accumulation, maximal activity, mean velocities of accumulation, the contribution to the common accumulation) can be used to early diagnostics of scarring in children with vur. the purpose of this study was to determine normal reference values for urinary uric acid/creatinine ratios in healthy turkish children. in this study, random urine specimens from 1306 children (662 boys, 644 girls) aged 1 month to 15 years were analyzed for uric acid and creatinine, and urinary uric acid/creatinine ratios were determined from each sample. uric acid/creatinine ratios were the highest in children aged 1-6 months and showed a significant decrease with age (p<0.05). uric acid/creatinine ratios were not significantly different between the sexes except 12-15 years. girls between 12-15 years had higher urinary uric acid/creatinine ratios when compared with boys (p<0.05). there was no correlation between urinary uric acid/creatinine ratios and protein intake. our results show that urinary uric acid/creatinine ratio changes with age. when assessing the urinary uric acid/creatinine ratio, a child's age should be considered. we provided normal reference values of urinary uric acid/creatinine ratio for using in our region. the aim of the study was to investigate microbiological marker of activity of uti. e. coli and s. aureus p 209 were isolated from urine of 180 children with uti. the children were divided into 4 groups: 1. with pyelonephritis in the acute period (n=45); 2. with pyelonephritis in the period of remission (n=45); 3. with cystitis in the acute period (n=45); 4. with cystitis in the period of remission (n=45) 20 healthy children consists the group of control. definition of bactericidal activity of urine (bau) was carried out by our original method. the essence of the method consisted in measuring of the optical density (od) of the bacteria after their contact with urine (experience) and isotonic solution of nacl (control) after 30 minutes of endurance in meat peptone mediums with 37 c during 3-5 hours. bau was calculated under the formula: bau (%)=(odc-ode)/odc*100%, (odc -control group, ode -experience group). we established that the level of bau did not correlate with urine ph (r=0,2), osmolality (r=0,1), lysozymuria (r=0,2), lysinuria (r=-0,2). we established that the low level of bau was marked in children of control group (10-40%). the patients in active period of uti had high level of bau (>70%). the parameters of bau didn't depend from the level of uti (pyelonephritis or cystitis). the level of bau reduced in the period of remission of uti. we established that the level of bau correlated with bacteriuria (r=0,8), leucocyturia (r=0,5). the level of bau didn't depend from the degree of urine dissemination (r=-0,3). so, the level of bau is correlated with laboratory parameters of uti and can be used as new additional microbiological marker of diagnostics of activity of uti. the evolution of the alport syndrome in brazilian children vesicoureteric reflux (vur) is common in children with urinary tract infections (uti). if vur coexisting with uti there is a high risk of progression to end-stage renal disease (esrd). the correct diagnosis is important. we observed 136 children (104 girls and 32 boys) aged 1 mo to 12 yrs at the time they have been diagnosed as having vur. the follow-up period was 1 mo up to 11 yrs after the diagnosis. all 22 children with vur grade 5 have been operated. after antireflux operation incidence of uti dramatically decreased even this cannot prevent progressive kidney damage in some patients. children with less severe vur have been put on prophylaxis. controlled mcu was performed usually after 1 year later. if vur disappeared medication have been stopped. vur grade 2-4 had a tendency of resolution under conservative treatment in 25.5% of the patients. in 16 children associated urinary tract malformations were found: duplicated system, dysplastic kidney, kidney agenesia, dystopic kidney, urethral stenosis and bladder outlet obstruction. in 2 patients nonfunctioning kidney have been found. dysfunctional voiding was common finding. blood pressure and physical development have been controlled. kidney size, function and scar formation have been followed by dmsa scan. we observed kidney growth at 6 mos intervals. during the follow-up period 3 infants have had reversible renal insufficiency. one patient with bilateral vur grade 5 went into renal failure at the age of 9 yrs. conclusions: vur is still one of the most common leading causes to esrd in childhood. even the existing controversy concerning treatment modalities it is obvious that low grade vur does not need operative treatment. it is indicated in high grade vur to prevent repeated and severe uti but it cannot preserve progression of the disease because of high incidence of coexisting kidney dysplasia. results: from forty children with nephrolitiasis, 28 (70%) were boys and 12 (30%) were girls. the mean age was 80.5±57.5 months. the youngest age was 4 months old. the most common clinical presentation was abdominal discomfort 22 (55%), followed by uti 21 (52%), microscopic hematuria 13 (32.5%), macroscopic hematuria 12 (30%), spontaneous urinary calculi 9 (22%), flank pain 8 (20%). nine of 40 children were presenting with chronic renal failure (crf). statistical analysis showed that age had correlation with the present of crf in children with nephrolitiasis (p=0.007). the clinical presentations of nephrolitiasis were varied. abdominal discomfort and uti were the major signs and symptoms. there was correlation that age may influence the present of crf in children with nephrolitiasis. objective: renal involvement is one of the most frequent and serious manifestations of sle. we analyzed the treatment and renal outcome of patients with lupus nephritis. methods: seventy-seven identified patients were retrospectively analyzed from jan. 1996 to dec. 2005 . the outcome was divided as complete remission (24-hour proteinuria <0.5g, plasma creatinine level normal and sledai <5), partial remission (abnormal renal damage index improved >50%, 24-hour proteinuria >0.5g, sledai <10) and no response, respectively. results: fifty-four patients were biopsy proven ln (70%). fifty-seven patients followed up more than 6 month. all the eleven patients with class i or ii achieved remission, using prednisolone together with either hcq, or tripterygium or mmf or cyclophophamide (ctx). in forty-three patients with class iii or iv or v, they were given prednisolone together with mmf or ctx. we found that remission was in 18 cases, part remission 17 cases and no response in 8 cases. associations between methylenetetrahydrafolate reductase (mthfr) c677t polymorphisms and several vascular diseases have been reported. this is a clinical study designed to investigate the possible effects of (mthfr) c677t polymorphisms on the developement of henoch-schönlein purpura (hsp), renal involvement, and clinical course. fourty-one patients with hsp (25 m/16 f) mean age (7,8±2,9 years) were included in the study. eighteen of the patients had renal involvement. the control group consisted of 50 healthy children. blood samples were obtained for mthfr c677t transition, homocysteine, folic acid and vitamine b12 in the patients and controls. the genotype frequencies (cc/ct/tt) of mthfr in the hsp group were 0,56/0,39/0,12 and 0,58/0,38/0,04 in the control group, respectively (ns). the genotype frequencies (cc/ct/tt) were 0,39/0,39/0,22 in the patients without renal involvement and 0,78/0,22/0,00 in those with renal involvement, respectively (ns). homocysteine levels were 10,6±6,8 in the hsp patients and 12,9±4,5 μmol/l in controls (ns). vitamine b12 levels were 320,6±157,5 pg/ml in the hsp patients and 302,6±209,6 pg/ml in the control group (ns). folic acid levels were 5,7±3,0 in the hsp and 4,0±1,6 ng/ml in the control group (p<0,002). no significant relationship was present with the mthfr genotype and plasma homocysteine, folic acid and vitamine b12 levels. no association with mthfr gene polymorphism and homocysteine plasma levels could be detected in patients with hsp and hsp nephritis. although mthfr gene polymorphisms have been found to be associated with several vascular diseases, the results of this study indicate that other mechanisms should be operative in the developement of hsp and hsp nephritis. we report the symptoms, signs and laboratory values at onset and during 6 month-follow-up of hsp in a prospective study of 220 children (99 girls, 121 boys) with mean age of 7.1 years (1.6-16.7 y). the first sign of hsp was purpura in 152 (70%), oedema or other joint symptoms in 121 (55%), abdominal pain in 49 (22%) and melena in 3 (1%) patients. petechiae appeared on the average 5 days after the first symptoms (1-22 d) if purpura was not the first sign (n=67). 78% of the cases were diagnosed between september and march. the mean delay from the first symptoms to the diagnosis was 7 days (0-65d our results based on an unselected and prospective patient material demonstrate that renal symptoms in hsp children develop early, are common and should be followed up at least 6 months. the kidney is a metabolically active organ, so any alteration in kidney function might affect nutrient utilization. objective: analyze the nitrogen balance (nb) as a marker for adequate food consumption in children with chronic renal insufficiency (cri). material and methods: 60 patients (12 boys, 48 girls) diagnosed and managed in the nephrology and nutrition departments. they were placed in two groups depending on age: group a: 20 patients aged 5±2.5 years, follow-up 4±1.1 years, glomerular filtration rate (gfr) estimated by cr-edta: 38±20 ml/min/1.73 m 2 ; group b: 40 patients aged 12.5±3 years, follow-up 10.9±3.5 years, gfr estimated by cr-edta: 37±17 ml/min/1.73 m 2 results: group a had a worse weight and height evolution: weight: -0.95±0.15 sd in group a vs 0.15±2 sd in group b; height -1.29±0.29 sd vs -0.34±0.23 sd (respectively). group a showed a significant increase in tnf blood levels (p<0.03) that was inversely related with weight and height. bn was significantly greater in group a (1.59±1.93 gr/day) than in group b (-2.6±4gr/day) (p<0.01) and this was related with higher calorie (p<0.003) and protein (p<0.004) intakes. there was no difference in alimentary nutritional breakdown. nb improved significantly over the follow-up (p<0.01). there was no relation between nb and gfr. there was a significant increase in triglyceride levels and significantly lower blood urea levels in group a (p<0.04). we conclude that nitrogen balance depends on protein and calorie consumption and is independent of the severity of renal affectation. we present a case of a 6 months old boy, who was delivered to our intensive care unit because of high fever, acute renal failure and dilatation of the urinary tract. his hemoculture and urinary culture were positive for e. coli and a severe urosepsis was diagnosed. his urethral catheterization was unsuccessful, so a suprapubic puncture was performed to relieve the urinary system and provide sufficient urinary flow. after the urinary sepsis was cured with adequate board spectrum antibiotics, a voiding cystourethrography (vcug) was performed to reveal the suspected anatomical abnormality, vesicoureteral reflux (vur) respectively. meanwhile a continuously growing nodular tumor of the penis was observed. the vcug showed the signs of urethral stenosis, but posterior urethral valve and vur was excluded. the doppler ultrasound found a solid vascularised tumor, 2x2.5 cm in its diameter. during the surgical operation the tumor couldn't been totally removed, as it was infiltrating the surrounding tissues and the urethra. the histopathological examination of the biopsy specimen confirmed a juvenile xanthogranuloma (jxg). this is an uncommon, benign, non-langerhans cell histiocytosis, primarily seen in infancy as a solitary cutaneous lesion, predominantly in males. systemic form of the disease is rarely seen. usually it resolves spontaneously without any further treatment, but the differentiation from a malignant neoplasm is essential. according to the authors' search, this is the 2nd reported case in the literature and the first pediatric report of the jxg of the penis. urine examination using x-ray diffractometry background and goal: x-ray powder diffraction analysis is widely used in chemistry and pharmacology and for other industrial purposes. in medical science it is used for analyzing kidney stones and investigating retained crystals in tissue sections. in the department of mineralogy and petrology we investigated urine samples, at first diagnostically to detect urinary amino acids, glucose and compounds and, secondly, to detect calcium oxalate hydrate, which can be employed for early detection of renal tubular injury when no significant differences in renal function values exist. materials and methods: after sedimentation and dehydration, authors investigated more than 100 urine samples of children using x-ray diffractometry. results: 12 of them were glucosuric due to diabetes mellitus; in these cases glucose could be detected in each of their urine samples. in 5 cases different amino acids due to aminoacidopathy were detected. the urine samples of 8 children -kidney stone problems in history -were examined, in one case struvit, in the other cases ca oxalate crystals were identified. also, 30 samples of 10 children were examined, 24 hours after at least 2 hours long anesthesia, ca oxalate hydrate appeared in their urine referring to renal tubular injury due to inhalational anesthetic agents. in 10 cases urine samples of children treated in the intensive care unit were analyzed, in 50% ca oxalate crystals could be detected. in 40 cases healthy children's urine were investigated, as control ones. conclusion: x-ray diffractometry, as a highly sensitive method can be used efficiently in clinical measurements. further investigations are needed in order to determine its place in clinical trials. authors emphasize the importance of collaboration of different sciences, as well. drug intake in the background of sudden death? microalbuminuria was significantly more in patients more than 10 years of age as compared to younger patients on bivariate analysis (p=0.001). on logistic regression analysis, though microalbuminuria was more in patients more than 10 years of age, it was not statistically significant. the association between microalbuminuria and urinary specific gravity levels of <1.010 was statistically significant (p=0.001), similar results were seen on logistic regression analysis. there was no correlation between microalbuminuria and hospitalizations, crises, previous blood transfusions, hemoglobin electrophoresis and serum creatinine levels. conclusion: identification of risk factors for microalbuminuria may allow earlier intervention to prevent renal complications in patients with ssd. in developing countries at primary health care level urinary specific gravity should be done routinely in patients with ssd to identify cases at risk of microalbuminuria. m. bak, e. serdaroglu, y. bicilioglu aim: the aim of the present randomized-controlled study was to compare desmopressin (dp), alarm and combined treatments in nocturnal enuresis. the study included 101 children (67 boys and 34 girls) with nocturnal enuresis. the mean age was 10.7±2.4 years (ranged 5-16 years) and the mean wet-nights was 14.9±6.1 day per month before treatment. the patients were followed for one month before treatment and randomized to dp (33 patients), alarm (34 patients) and combined (34 patients) treatment groups. the dp group was received 40 μg orally one-hour before sleep and alarm group was used wet-stop bedwetting alarm device after education of parents. the patients were followed 6 months in treatment period and 2 months after discontinuation of treatments. results: wet-nights per months was significantly reduced between before treatment and last month of treatment in dp (14.5±5.7 to 4.8±6.5, p<0.001), alarm (14.1±5.9 to 2.9±4.1, p<0.001) and combined treatment (16.2±6.9 to 1.9±2.5, p<0.001) groups. treatment success (>50% decreasing in wet-nights) and complete response (100% dry) rates was 79%, 91%, 97% and 30%, 27%, 35% in dp, alarm and combined treatment groups respectively. the more rapidly decreasing in wetnights was observed between dp used and only alarm treatment group but this effect disappeared after 3 months. relapse rates was 67%, 11% and 22% in dp, alarm and combined treatment groups respectively between successfully treated patients (p=0.002). conclusion: alarm treatment is the best intervention with low relapse rates and no potential adverse effect in nocturnal enuresis. dp group has higher relpse rate but adding to dp may achieve more rapid decreasing in wet nights especially in patients and parents expecting rapid result. aim: it is often difficult to collect urine from infants. use of specifically designed urine collection pads gives reliable results for routine biochemistry tests in adult urine. their use for routine and metabolic tests in paediatric urine has not been investigated. the aim of this study was to evaluate whether the pads give reliable results for routine and metabolic biochemistry tests in paediatric urine. methods: urine collected by bag or clean-catch from infants <2y without metabolic disorders was divided into two aliquots, one of which was added to a collection pad, incubated for 15min at 37°c, then recovered by aspiration. routine and metabolic analyses were performed on pad/non-pad aliquots. additionally, selected metabolic analyses were performed on pad/non-pad urine from patients with diagnosed inborn errors and urine spiked to simulate metabolic disorders. for quantitative analyses, pad/non-pad results were compared using bland-altman bias plots, passing and bablok regression and paired t-tests. results: routine tests (urea, electrolytes, creatinine, osmolality, calcium: creatinine, phosphate: creatinine, magnesium: creatinine, urate: creatinine, n=32) showed close concordance with no clinically significant pad/non-pad differences. in infants without metabolic disorders, aminoacids (n=10), organic acids (n=12) and mucopolysaccharides (n=8); and in patients with metabolic disorders -phenylketonuria (n=1), mucopolysaccharidoses ii (n=2) and iii (n=1), inborn errors of organic acid metabolism (n=6) and cystinuria (n=3), all showed excellent pad/non-pad concordance. sugar chromatography in urine spiked with glucose/galactose/fructose showed identical staining intensity in pad/non-pad samples. conclusion: urine collection pads give reliable results for a wide range of routine and metabolic tests in paediatric urine. a post-translational modification of arginine residues in proteins and subsequent proteolysis result in release of symmetric dimethylarginine (sdma). sdma is considered an end product of metabolism, excreted primarily by the kidney. several previous studies have reported a significant relationship between glomerular filtration rate (gfr) and plasma sdma. to determine the potential value of sdma in the assessment of gfr in children we have measured sdma in samples taken during routine measurement of glomerular filtration rate (gfr) using plasma clearance of inutest. 257 patients (144 male) requiring routine gfr measurement were studied. median (range) age 11.8y (1.6-20.2) , height (ht) 145cm (82-188), and surface area 1.3 m 2 (0.5-2.6). gfr was measured using the plasma clearance of inutest, and plasma sdma and creatinine (pcr) by liquid chromatography stable isotope dilution electrospray mass spectrometry-mass spectrometry method. estimated gfr (egfr) was calculated from the formula 31 x ht (cm)/pcr (μmol/l). median gfr was 80 ml/min/1.73 m 2 (6-217), plasma sdma 0.530 μmol/l (0.266-4.460 ), pcr 54.5 μmol/l (12.7-777), and egfr 82 ml/min/1.73 m 2 (7-212). as expected both plasma sdma and pcr increased with a decline in gfr. compared to gfr the correlation with 1/sdma, r=0.83 (p<0.001) was better than for 1/creatinine, r=0.75 and similar to that for egfr, r=0.86. comparing sdma with inutest gfr for detection of gfr <90 ml/min/1.73 m 2 the area under the roc curve was 0.87 (p<0.001). the equivalent areas for pcr and egfr were 0.84 and 0.89, respectively. in conclusion plasma sdma is an endogenous marker of gfr in children and is superior to pcr because it appears to be independent of body size. since the calculation of egfr requires accurate measurement of height, plasma sdma may provide a practical alternative for assessment of gfr in children. thrombotic microangiopathy (tma) consists of thrombocytopenia, microangiopathic hemolysis, and thrombi in the microvasculature of vital organs. broad categories of causes of tma include infectious (verotoxin-induced hus), hematologic (ttp), complement based (atypical hus), immune-mediated (sle, anti-phospholipid antibody syndrome), and drug-induced (cyclosporine). thorough investigation is required to detremine the underlying etiology in order to provide specific therapy and information about prognosis. a 14 year girl presented with short stature and was found to have hypertension, proteinuria, renal failure (creatinine 350 umol/l), and anemia (hgb 72 g/l). platelets were normal. she also had spondylometaphyseal dysplasia, scoliosis, lymphopenia, mild pulmonary hypertension and aortic stenosis. on pulmonary function testing, her dlco was decreased. chest ct demonstrated small micronodules. a ventilation-perfusion scan was normal. renal biopsy showed features of tma. she was treated with dialysis and underwent renal transplantation one year later. there has been no disease recurrence 6 months post-transplant. genetic and immunologic workups were negative, including anti-cardiolipin antibodies. a thrombophilia workup was negative apart from a heterozygous mutation in mthfr. c3 levels were mildly reduced. anti-neutrophil antibodies were negative. complement system studies, including factor h, and smarcal1 analysis for schimke immuno-osseous dysplasia are underway. although the descriptive diagnosis of tma can be applied here, the underlying pathophysiologic diagnosis has still to be defined. it is of particular importance that further efforts be made to identify the etiology given the potential risk of disease recurrence in the renal graft. background: long term outcome of renal functions after liver transplantation (lt) in wd is not studied yet. aim: the aim of this study was to determine the long term outcome of renal functions in children receiving lt for wd. patients and methods: renal functions were examined in 9 (f/m: 2/7) liver transplanted patients for wd before and long after lt and compared with renal functions of 9 patients (f/m: 5/4) with lt for a hepatic disease other than wd. the mean age of subjects was 12.1±3.2 years in the patients group and 9.8±4.1 years in the controls. the mean duration of follow-up was at least 2 years. glomerular and tubular functions were assessed using the conventional equations for measured creatinine clearance (gfr), tubular phosphate reabsorption (tpr), daily protein and calcium excretion in both groups. results: mean gfr before lt was 81.7±32 ml/min/1.73 m 2 in the study group and 146.3±37.6 ml/min/1.73 m 2 in the controls (p=0.007). the mean tpr before lt was found to be 67.9%±18.2% in the study group and 88%±9.6% in the controls (p=0.03). daily protein excretion rate before lt was found to be high in both groups, as well as urinary calcium excretion. an increase in gfr was observed in the study group after lt (p> 0.05), while it was slightly decreased in the controls (p>0.05). tpr increased significantly in the study group after lt (84.8%±9.5%) (p=0.04) and although it was found to be significantly lower in the study group than the controls before lt, in the long term follow-up the difference between the groups was disappeared (p=0.59). conclusion: tubular dysfunction is frequent in patients with wd. liver transplantation for hepatic failure secondary to wd is a lifesaving procedure. it corrects the underlying hepatic defect as well as renal defects and leads to long-term survival. rather conflicting results are available regarding the neurocognitive development of children with ckd, due to small sample sizes, cross-sectional study designs, differing methodological approaches and historical trends in patient selection for renal replacement therapy. we prospectively examined in a standardized, multi-center effort 59 children with ckd aged 0.8-15 years. children were treated either conservatively (n=30, gfr <25 ml/min/1.73 m 2 ) or by dialysis (hd: n=7, pd: n=22). a sub-sample of 18 children underwent repeated testing after 12 -14 months. bayley and snijders-oomen developmental tests were performed and the measured values normalized to standard deviation scores (sds). general cognitive development averaged at -1.02 (±1.48) sds. 42% of the patients scored <-1.5 sds, i.e. below the 10 th percentile of the normal population. no significant differences were observed between pre-dialysis (-0.87+1.57) and dialyzed patients (-1.16+1.40). impaired neurocognitive function was marked in infants (-1.63+1.31 sds), whereas school children showed a distribution similar to healthy children (0.43+1.42 sds, p<0.005). the global neurocognitive sds remained unchanged in the longitudinal sample (t 1 =-0.97±1.57; t 2 =-0.91±1.71). in summary, our preliminary results demonstrate a high prevalence of neurocognitive impairment in infants with ckd. we assume that this finding reflects the improved survival of children with complex disorders affecting not only the kidney but also brain development. the poor performance of this age group highlights the importance of close neurocognitive follow-up and early developmental interventions. objectives of study: to make a diagnosis of a girl with kidney subcapsular hydrops, abnormal urinanalysis and hypertension. methods: physical examination and laboratory investigations were analyzed. results: a 5 years old girl was admitted because of kidney subcapsular hydrops, proteinuria without edema, and hypertension (130/94 mmhg) for 50 days. no trauma or familial hypertension history were provided. no hydrops was found before the age of 1 year. urinary rbcs were 5-7/hp and protein was 77 mg/kg/24 hr. the serum albumin was normal. ultrasound examination revealed normal sized kidneys, increased echogenicity in both kidneys, and subcapsular hydrops on the upper pole of the right kidney connected with an old renal fissure. ucg and fundus examinations were normal. gfr of the right kidney was slightly decreased as compared to the left (65 ml/min vs. 67 ml/min, by dtpa scan). by puncture of hydrops, yellow clear fluid was drained, the analysis showed similar composition to that of original urine, so subcapsular urinoma was diagnosed. urine collection from two kidneys separately was performed by cystoscopy; nonselective proteinuria of 1+ was found in urine from the right and 2+ from the left kidney. analysis revealed urea 36.8 mmol/l, potassium 6.92 mmol/l, creatinine 0.42 mmol/l in the right kidney urine compared to urea 77.2 mmol/l, potassium 11.19 mmol/l, and creatinine 1.29 mmol/l in the left, which suggested that the right kidney function was compromised. according to proteinuria from both kidneys with microscopic hematuria, without edema and hypoalbuminemia, glomerulonephritis was diagnosed. the girl was diagnosed with glomerulonephritis and subcapsular urinoma. it was a rare case because of their co-incidence. reasons for the hypertension, if caused by the glomerulonephritis or the pressure by subcapsular urinoma, as well as reasons for subcapsular urinoma need to be clarified during the follow-up. the aim of this study was to detect factors that could interfere with the results of des treatment. methods: fifty-six patients 5.9 to 15.2 years old with des without improvement by previous therapies were randomly distributed into two voiding training programs: group 1 (g1): 26 patients submitted to 24 kegel exercises training sessions for three months; group 2 (g2): 30 patients submitted to 16 biofeedback sessions over a two month period. both groups adhered to a voiding and drinking schedule, received adequate toilet posture instructions and were reinforced through the maintenance of voiding diaries. clinical evaluation was carried out before each programs initiation and 1, 6, and 12 months after end of the program. all patients were submitted to renal and dynamic ultrasound before and 6 months after each program's conclusion. the following variables were analyzed: gender, age at diagnosis, treatment group type, vesico-ureteric reflux, constipation, urinary tract infection, asymptomatic bacteriuria, bladder wall thickening and post void residual (pvr) urine. the logistic regression model was applied to identify independent variables associated with response to treatment. results: urinary continence was improved after completion of either training program. success in diurnal urinary incontinence varied from 72.7 to 80% in g1 and from 65.2 to 89.4% in g2. success in nocturnal urinary incontinence varied from 66.7 to 84.2% in g1 and from 65.4 to 86.9% in g2. in multivariate analysis three variables remained independently associated with bad response to treatment: constipation with soiling, bladder wall thickening and pvr urine (p<0.05). conclusion: studies using multivariate regression analysis to identify predictors of response to behavioral therapy are important for the development of selection criteria for prescribing these therapies to children. we report the case of a four-year-old child born to consanguineous parents, who presented first at two months of age with respiratory failure. during the admission he developed panyctopenia, hypertension and nephrotic range proteinuria. the metabolic workup revealed methylmalonic academia and aciduria along with homosystinuria; highly suggestive of cobalamin deficiency. the renal biopsy showed chronic thrombotic microangiopathy (tma). the muscle biopsy showed the presence of nemaline rods on electron microscopy. cobalamin c deficiency was confirmed by genetic analysis as the patient was homozygous for the mutation c547/548. at the age of one, he was noted to be visually inattentive and developmentally delayed. on ophthalmology examination there was evidence of bilateral maculopathy and dysfunction of rods and cons on electroretinogram. he subsequently went on to develop bilateral bovine maculopathy. since his initial presentation he has been maintained on hydroxycobalamin, betaine and folate; with no further relapse of proteinuria or panyctopenia. however, despite adequate doses of hydroxycobalamin, the maculopathy progressed. to our knowledge, this is the first report of a child with both tma and bovine maculopathy. the aim of the study was to assess the rate of vesicoureteral reflux (vur) in patients with lower urinary tract dysfunction (lutd) of nonneurogenic origin. dysfunctional voiding may result in lower urinary tract symptoms in children and is commonly associated with urinary tract infections and vur. we investigated 111 patients with voiding dysfunction during last three years: 31 boys and 80 girls, a mean age of 8.2 years, with a mean follow-up of 19 months, all with normal renal function. mean pre and post treatment symptom scores were 23.6 and 7.6 respectively. vur was detected in 21% of the children with unstable bladders and 17.5% of the children with stable bladders as detected by video urodynamic investigation, 22% of the children with urinary tract infection (uti) on admission, and 18% of the children with no history of uti on admission. the co-existence of vur in our group with voiding dysfunction was 19.8% (22 patients). all patients with vur had low grade reflux (grades i-iii) and 3 of them bilateral, the remaining 19 unilateral. renal us was performed in 55 patients and revealed hydronephrosis in 13 patients, while the remainder showed no abnormalities. vur was found to be present in 30% of the children with abnormal us findings, while only 2% of the children with normal us findings were affected. furthermore, the patients that had spontaneous resolution of reflux showed a markedly greater improvement in symptom scores. a significant portion of patients with lutd (19.8%) have low grade vur. in detection of vur in patients with lutd, hydronephrosis is a good indicator of the presence of reflux, while utis and urodynamic findings were not found to be significant indicators. the overall spontaneous resolution rates of vur in patients with lutd and stable bladder following treatment was found to be 22.7% and 14.2%, respectively. 200-250g) were grouped: group 1 (n: 5) was the sham group. group 2, 3 and 4 (n: 7 for each) received 50 mg/kg twice daily ptx intraperitoneally (i.p.), 100 mg/kg/day gen i.p. and both ptx and gen at the same dosages for 8 consecutive days, respectively. the rats were weighed at the beginning and than weekly during the study. after the last dose 24-hour urines were collected. then, rats were sacrificed and blood samples were obtained from the abdominal aorta. bun, serum creatinine (scr), creatinine clearance (ccr), renal superoxide dysmutase (sod), catalase (cat) and thiobarbituric acid reactive substances (tbars) levels were determined. all the parameters were compared between the groups. results: body weights were not different between the groups either at the beginning or during the study. bun levels were significantly higher in group 3 than the other groups (p<0.01). scr and ccr levels were similar between the groups 3 and 4, but the levels were higher than those of groups 1 and 2 (p<0.01). sod and tbars levels were similar between all groups. the levels of tubular cell apoptosis and caspase-3 expression were significantly higher in group 3 than the other groups (p<0.05). conclusion: we may conclude that ptx administration significantly reduced the apoptosis in gentoxicity, but we could not demonstrate any evidence of ptx-related reduced oxidative stress. the lack of evidence for the widespread use of antimuscarinics and holding exercises in mne prompted us to design a randomized controlled trial comparing interventions in four groups of children with mne: placebo (a) or oxybutynin chloride (b) in combination with a daily regimen of standardized fluid intake and holding exercises or as monotherapy (c) and (d). a fifth group, to be treated with alarm only, was planned as control. randomization was stratified for participating hospital, sex, age, tanner stage, family history of mne, previous treatment, and bladder capacity class, being the largest from either the maximum voided volume (mvv) from a 48 h frequency volume chart or the volume after 4 baseline holding exercises (hev). after 12 weeks intervention with holding exercise (a and b) , hev had increased, both with oxybutynin (208±84 (sd) ml to 311±121 (sd) ml, p<0.001) and placebo (216±82 (sd) ml to 259±90 (sd) ml, p<0.05). without holding exercises, only oxybutynin (d) increased hev (223±79 (sd) ml to 274±111 (sd) ml (p<0.05). mvv increased also in groups a and b (holding exercises), not c and d. cure rate (less than 1 wet night in the last for 4 weeks) was low: a 1/29, b 3/30, c 0/30 and d 4/30. control group with alarm had 22/30 cure. cure was not related to hev, mvv or delta hev and mvv. this questions the relevance of increasing bladder capacity in mne. background: sickle cell disease (scd) is an inherited disorder of beta-globulin synthesis of haemoglobin, resulting in a tendency for haemoglobin polymerisation and consequent vasoocclusion, tissue hypoxia, and ensuing organ damage. the kidney is a particularly sensitive to hypoxia and renal failure is a major cause of morbidity and mortality in scd. children with scd commonly hyperfiltrate, the glomerular filtration rate (gfr) then typically falls back towards normal in adulthood. routine estimation of gfr in children is primarily derived from the height and plasma creatinine (pcr) measurements using k a constant dependent on the creatinine analytical method. this formula has reduced accuracy in children with a gfr >80ml/min/1.73 m 2 . it has never been validated in hyperfiltration or children with scd. recently, new gfr markers have been proposed including symmetrical dimethylarginine (sdma) that may be independent of body size. in this pilot study we tested the hypothesis that estimated gfr and/or sdma allow a reliable estimation of gfr in scd. methods: 13 hbss patients, age range 10-20yrs (mean age 15yrs) attending the evelina children's hospital were studied. the patients were on regular blood transfusions for stroke management and undertook a formal gfr measurement using plasma clearance of inutest. the plasma samples were also used for the measurement of pcr and sdma by stable isotope dilution mass spectrometry. egfr was calculated using k=35. results: inutest gfr ranged from 70-175 ml/min/1.73 m 2 . there was significant inverse correlation between sdma and inutest gfr (p<0.01)). there was no significant correlation between either pcr or egfr and inutest gfr. conclusions: this early data suggests that sdma might prove valuable in monitoring gfr in children with scd. introduction: the aim of this study was to identify the risk factors for renal scarring in children with lower urinary tract dysfunction (lutd) by using data available at the time of patient admission to the interdisciplinary management program of lutd at hospital das clínicas. material and methods: medical records of 120 patients were assessed retrospectively concerning gender, presence of vesicoureteric reflux (vur), bladder capacity, detrusor overactivity, residual urine, urinary tract infection (uti), asymptomatic bacteriuria, constipation, detrusor-sphincteruncodination (dsu), high detrusor pressure at maximal cystometric capacity, low compliance, thickness and trabeculation of the bladder wall. renal scarring was diagnosed by dmsa scan. statistical analysis was performed by univariate and multivariate analysis. a p value <0.05, 95% confidence interval was considered significant. results: renal scarring was detected in 38 patients (31%). abnormal bladder capacity, detrusor overactivity, residual urine, asymptomatic bacteriuria, constipation, dsu, high detrusor pressure and low compliance were not associated with renal sccaring. vur, uti, decreased bladder capacity, urinary residue, trabeculated and thick bladder wall were associated with scarring at univariate analysis. multivariate analysis showed vur (p<0.0001) and female gender (p=0.05) as independent risk factors for renal scarring. thickness of the bladder wall was a marginal risk factor (p=0.07). conclusion: urodynamic parameters didn´t predict renal damage in this study. uti was not a risk factor for renal scarring; however, it was associated with vur (p=0.03). although vur was the main risk factor in our analysis, renal scarring was probably due to multifatorial causes as vur was associated with itu. results: comparison of test a and b demonstrates that a mild fluid load 1 h before the administration of ddavp nasal spray (2 puffs) results in 3 major significant differences.1). maximal concentrating capacity (cc) is reached later than 1h after administration (p<0.05). in 8/46% cc at sleeping time is <70% of max, thereby resulting in a persistent np in the first hour of the night. 2) uosmol is significantly (23%) lower in the overnight collection (u4), correlating with a higher diuresis-rate (16%)3). the duration of the ddavp effect is shorter leading to an increase in diuresis-rate and to a decrease in the u osmolality in 24/46 children in the urine-collection between 4-7h in the morning. this proves that in up to 50% of the patients the ddavp-effect does not cover the full night. conclusion: test b demonstrate sthat fluid intake prior to the ddavp-administration influences significantly the antidiuretic effect of ddavp (onset, maximum and duration). this might explain the partial response, suggestive for insufficient pd (and pk) effect of the spray. test a proves that fluid restriction 1 h before ddavp administration, significantly reduces the nocturnal diuresisvolume. m. schmidts, c. schnakenburg, k. häffner, c. jacobi, k. schwab, m. pohl university hospital, center for pediatrics and adolescent medicine, freiburg, germany background: enteropathic hemolytic uremic syndrome (d+hus) is responsible for 90% of all hus cases. in addition to the nephrological and neurological complications, pancreatic damage resulting in diabetes mellitus is also possible and appears to be associated with more severe cases and elevated mortality. case report: a 3-year-old girl suffering from d+hus with severe colitis, acute renal failure, dyskinesia, dysarthria and agitation provoked by shiga-like toxin positive ehec infection in july, 2006. the severe affection was characterized by partial thalamic infarction, prolonged leukocytosis (max. 51 g/l) and the necessity of 4 weeks of dialysis. 6 days after the disease onset, hyperglycemia (max. 530 mg/dl glucose) was noted. c-peptide was found to be low indicating reduced insulin secretion. 6 months after hus the patient continues to be insulin dependent. clinically apparent exocrine pancreatic insufficiency has resolved spontaneously. gfr had recovered to 28 ml/h/1,73 m 2 , but then kidney function deteriorated and dialysis had to be resumed after 5 months. kidney histology at this time showed severe nephron loss compatible with chronic changes after hus and ruled out other unrelated kidney disease. conclusion: in addition to the kidney damage, chronic pancreatic damage can occur in hus. therefore blood glucose levels should be monitored in all hus patients. it is tempting to speculate that patients after childhood hus might be at risk for diabetes mellitus later in life. objective: childhood nephrotic syndrome (ns) is characterised by a relapsing course resulting in significant corticosteroid burden or prescription of cytotoxic immunosupressive therapy. this randomised controlled study was carried out over 3 years at a single centre in sri lanka to compare the efficacy and safety in children with steroid dependant ns treated with intravenous cyclophosphamide or intravenous vincristine therapy. methods: thirty-nine sequential children with steroid dependant ns with evidence of steroid toxicity were randomly allocated to receive either intravenous cyclophosphamide (500 mg/m 2 monthly for 6 months) or vincristine (1.5 mg/m 2 weekly 4 doses followed by 4 doses monthly). both groups received an identical tapering regimen of oral prednisolone for 6 months. all children were reviewed on monthly basis for one year focusing on recurrence of proteinuria and side effects of therapy. finding of +++ proteinuria for 3 consecutive days was diagnostic of relapse. results: there were 18 (11m: 7f) children in the cyclophosphamide group (mean age 6.4 years) and 21 (15m: 6f) in the vincristine group (mean age 7.2 years). during one year of follow-up 6/18 (33%) in the cyclophosphamide group suffered a relapse while 13/21 (62%) suffered a relapse in the vincristine group. p=0.03 (comparison of 2 proportions using standard error. ci 0.105 to 0.49). no serious adverse effects were encountered in either group. conclusion: in steroid dependant ns, intravenous cyclophosphamide therapy is superior to intravenous vincristine therapy in maintaining sustained remission. we present the clinical and biochemical features of a patient with antenatal bartter syndrome who was found to have a novel romk mutation. the patient presented antenatally with severe polyhydramnios. polyuria, hyponatraemia and hyperkalaemia were evident soon after birth. she had marked hypercalciuria and developed medullary nephrocalcinosis in early infancy. failure to thrive was evident from 12 months. hypokalaemia was a late feature, developing gradually from 18 months. serum chloride levels were consistently 95-100 mmol/l whilst urinary chloride levels were consistently <30 mmol/l, only reaching higher levels after treatment was commenced. alkalosis was not present and the patient did demonstrate some response to furosemide implying some functional capability of na-k-2cl. renin and aldosterone levels were persistently elevated. treatment with indomethacin, nacl and kcl produced a good clinical response. mutational analysis revealed compound heterozygous mutations in kcnj1, the gene encoding romk. both mutations, m357t and l359r are in the terminus of the protein thought to have a role in channel gating. similarities and differences from the classically described presenting features of antenatal bartter syndrome highlight the clinical heterogeneity in this condition. this relates to the different identified kcnj1 mutations which are likely to affect romk function in different ways. the m357t mutation has been described, but past electrophysiological studies in sf9 cells transfected with the m357t mutant have not identified any differences in k + conductivity from wild type romk. given that the mutation appears to be clinically relevant in this case, further functional studies are indicated. l359r is to our knowledge a novel mutation. expression of these mutations in oocytes is now planned to enable evaluation their effects on channel function and regulation. a 10-year-old boy was admitted because of nephrotic syndrome. renal biopsy, performed after 4 weeks of prednisone (60 mg/m 2 od) + 3 methylprednisolone pulses (15 mg/kg each), showed focal segmental glomerulosclerosis. prednisone was tapered (to 30 mg/m 2 od) and enalapril was introduced, without any significant improvement. two weeks later, the patient had transient hypoperfusive acute renal failure which required acei discontinuation. due to the persistence of proteinuria, cyclosporine was started (5mg/kg/day). proteinuria gradually decreased and ceased within the subsequent two weeks. in the meantime the boy had started to complain of low-grade fever without other symptoms and with normal physical examination. laboratory tests only showed leucocytosis (wbc 22 x 10 3 /ml) and increased c-reactive protein (65 mg/l). a chest x-ray revealed an upper mediastinal enlargement and a total body ct scan confirmed the presence of several enlarged mediastinal lymph nodes, whose biopsy led to the diagnosis of hodgkin disease (hd) nodular sclerosis subtype, cd30+; stage was iia. cyclosporine and the residual steroid treatment were discontinued and the patient was given six cycles of abvd (doxorubicin, bleomycin, vinblastine, dacarbazine), followed by radiation therapy. presently, 18 months after stopping chemotherapy, both hd and nephrotic syndrome are still in remission. once again, this case points out both that fsg can be secondary to a lymphoproliferative disease and that chemotherapy for hd might have been effective to keep fsgs in long-lasting remission. several treatment methods including increased fluid intake and dietary modification, medical therapies such as potassium citrate and use of extracorporeal shockwave lithotripsy (eswl) and finally surgery methods are used for treatment of urolithiasis. the aim of this study was to evaluate the etiological and clinical characteristics and level of response to medical therapy with polycitra in children with urolithiasis. one hundred thirty-four patients had urolithiasis of which 109 cases followed thetreatment instructions and fulfilled the inclusion criteria for this study. struvite stone were excluded from the study. all other patients who had an initial ultrasonography showing stone inurinary tract were treated with polycitra-k (potassium citrate 220 grams, citric acid 66.8 grams in 1 liter of distilled water) irrespective of the cause of the stone. at the end, complete resolution or passage or a decrease in the size of stone in later sonography was defined as response to treatment. hypercalciuria and hyperuricosuria were found to be etiological factor in 25% and 19% of patients respectively. the stone analysis was found that 50% of them were ca-oxalate. stone disease was more common between the age of 1-5 years. the most common complaint was hematuria (20%). eswl was performed in 42% of patients who did not respond to polycitra and had surgically active stones. calcium-oxalate stones were the most frequent stone which responded to polycitra. the response rate in girls and boys was equal and in different age groups the response rate was almost equal. methods: mmcs were expanded in culture and immunocytochemistry was used to characterize the cells. after gentamicin-induced atn, fluorescently-labeled cells were transplanted and traced in kidney tissues by fluorescence microscopy. kidney pathology was studied by hematoxylin-eosin staining, apoptosis was examined by the tunel assay, and ki-67 and bcl-2 expression were examined by immunohistochemistry and reverse transcription-polymerase chain reaction, respectively. results: (1) mmcs (rimm-18 cells) were successfully expanded in culture. the phenotype of the cultured cells were vimentin-positive and kreatin-negative by immunocytochemistry. (2) in the mmcs-treated group: the mortality rate decreased; renal function clearly improved; damage to the cell-treated kidneys was reduced and histopathologic lesion scores were lower; proliferation of renal tubular epithelial cells was improved; the apoptosis of renal tubular epithelial cells was reeuced; and the expression of bc1-2 mrna and protein was upregulated. the subcapsular transplantation of mmcs could ameliorate renal function and repair kidney injury. atn is the most common reason for arf, and there is still an absence of effective therapies. this study was done to observe the effect of mobilizing bone marrow cells with stem cell stimulating factor (scf) and gm-csf on recovery from gentamicin-induced acute tubular necrosis (atn) in rats. atn was included in male sprague-dawley rats with five daily high dose intraperitoneal injections of gentamicin. subcutaneous injections of scf and gm-csf were administered simultaneously and these cytokines was observed at day 2, 5, 10, 17, 24 and 31. leukocyte numbers, percent venous blood cd34+ cells, mortality rate, and concentration of the urine proteins, urine nag, bun, scr, and ccr, histopathogic lesion scores were determined. twelve hours after bone marrow ablation (bma) by lethal x-ray radiation, gentamicin-induced spf atn rats were given five daily injections of scf and gm-csf. bun, scr, and histopathogic lesion scores were evaluated at day 2, 5 and 10. the effects and mechanism of scf and gm-csf on atn was observed. the number of leukocytes and the cd34+ cell percentage increased significantly in atn rats between 2 and 10 days after scf and gm-csf injection. in addition, mortality rates dropped, the peak value of renal function increased, renal function were rapid ameliorated and histopathologic lesions were reduced. there was no significant effect on atn rats after bma. this study demonstrates that scf and gm-csf effectively mobilized bone marrow stem cells in atn rats. rapidly improving renal function and decreasing mortality rate. these results suggest that bone marrow stem cell mobilization may be an effective therapy for atn. key words: acute tubular necrosis, bone marrow stem cells, stem cell factor, granulocytemacrophage colony stimulating factor, irradiation. objective of the study: the response to recombinant human erythropoietin (rhuepo), 50 unit/kg twice weekly was studied prospectively in 35 children and adolescents with end stage renal failure who were either transfusion dependent or had hematocrits (hct) <25%. methods: rhuepo was given to 22 haemodialysis (hd) patients and 13 patients on conservative treatment, with mean age (10.84±4.08) years, 25 males and 10 females with mean hct (26.75±4.70). blood pressure, haematocrit, iron-indices, serum potassium, calcium, phosphorus, alkaline phosphatase, urea nitrogen and intact parathyroid hormone (ipth) were monitored serially. results: serum aluminum was measured randomly in 6 patients, results were normal ranging from 12-22 ug/l. when serum ferritin was <100ng/ml during therapy, they received iron supplementation. according to the response, patients were divided into 2 groups, the non-responders group with hct<27, mean age (9.97±3.55) years, 13 males and 6 females with mean ipth (669.9±461.77 pg/ml) and group of responders with hct >27 with mean age (11.66±4.32 years),12 males and 4 females with mean ipth ( increase of fatty acids such as nonesterified fatty acid (nefa) and triglyceride (tg) with oxidative stress and production of cytokine/chemokine occured during cisplatin (cp) toxicity. statin (3hydroxy-3-mthylglutaryl coenzyme a reductase inhibitors) have been postulated to have pleiotrophic effects. we examined whether statin, pravastatin, would ameliorate renal damage induced by cp. male wistar rats (weight 180-200 g) fed standard chow were divided into 3 groups: control-rats received tap water alone for 19 days; cp treatment-rats that received cp (10 mg/kg, i.v.) on the 14 th day of the study; cp+pravastatin treatment-rats that received pravastatin (6 mg/kg/day) in their drinking water for 19 days and cp injection as indicated in the preceeding group. blood and urine samples were collected and the kidney were removed 5 days after cp treatment. urinary excretions of protein and 8-hydroxy-deoxyguanosine (8-ohdg), serum levels of creatinine and fatty acids were measured. histology was evaluated by light microscopy with immunohistochemistry for pentosidine, n-carboxymethyllysine (cml), and heme oxygenase (ho)-1. expression of ho-1 mrna in the kidney was also measured. pravastatin decreased urinary excretions of protein and 8-ohdg and ameliorated renal function diminishing areas of tubular damage and positive staining of pentosidine and cml compared with those of cp treatment alone. however, positive staining area and mrna expression of ho-1 were not significantly changed by pravastatin treatment. although pravastatin did not influence serum levels of total and low-density lipoprotein cholesterol, serum tg level decreased and was equivalent to that of control group. these findings suggest that pravastatin treatment partially protects against cp-induced nephrotoxicity in rats, through its antioxidant as well as lipid-lowering effect. n. bresolin, v. fernandes, f. carvalho, j. goes, l. araujo, m. simon, g. gamborgi, m. zanin hospital infantil joana de gusmo, nephrology pediatric department, florianópolis, brazil objectives: the objective is a report case of acute renal failure (arf) in a child contact with lonomia obliqua caterpillar in southern brazil. the accidents with lonomia oblique has increased in south of brazil in recent years. this increase can be related with reduction of caterpillar natural predators and deflorestation. the venom of lonomia caterpillar provokes hemorrhagic syndrome resembling disseminated intravascular coagulation (dic) and hemolytic anemia. arf could be an important complication of hemoglobinuria that has been recently described in adults. methods: a case report. results: the present is a first case described of arf in a child after contact with lonomia obliqua caterpillar. conclusions: the arf can occur in any age, however, the contributing factor to the development of arf remains obscure. there are 3 mechanisms pointed out: fibrin deposition in glomerular microcirculation, ischemia in hemorrhagc shock with hypotension and venom direct action. the present article related a case of lonomia obliqua accident in a child who revealed coagulation disorder, hemolytic anemia, arf and always, she was hemodynamic stable. the treatment included antilonom serum, urine alkalinization, hyperhydration and peritoneal dialysis for four days. she was treated and followed per 1 year when she recovered her normal renal function. introduction: secondary hyperparathyroidism develops in chronic kidney disease as a consequence of impaired phosphate, calcium and vitamin d homeostasis. the treatment includes phosphate binders and vitamin d analogues, but sometimes ineffective. we report two cases of refractory secondary hyperparathyroidism treated successfully with cinacalcet. case 1: a 21-month-old boy with end stage renal disease (esrd) due to posterior urethral valve started on peritoneal dialysis at 12 months of age. he developed secondary hyperparathyroidism with serum parathyroid hormone (pth) level reaching 585 pg/ml. serum calcium had been in the range of 6.7 to 9.6mg/dl and serum phosphorus in the range of 1.7 to 10.7 mg/dl. despite treatment with phosphate binders and vitamin d analogues, pth levels kept increasing to 897 pg/ml. x-ray showed the cupping and fraying of the distal ends of radius and ulna. we started cinacalcet 10 mg daily and increased the dosage up to 30 mg daily. eight months later, pth level decreased to 154 pg/ml and bone changes resolved. case 2: a 12-year-old boy with esrd due to primary hyperoxaluria started on peritoneal dialysis at 10 years of age. he developed secondary hyperparathyroidism with serum pth level of 641 pg/ml. serum calcium had been in the range of 7.9 to 9.7 mg/dl and serum phosphorus in the range of 5.9 to 11.1 mg/dl. despite treatment with phosphate binders and vitamin d analogues, pth level kept increasing to 1457 pg/ml. x-ray showed the distal radius and ulnar fracture of left arm and right femur fracture. we started cinacalcet 30 mg daily. five months later, pth levels decreased to 151 pg/ml. conclusion: cinacalcet is effective in the secondary hyperparathyroidism resistant to phosphate binders and vitamin d analogues in children with chronic renal failure. rota virus (r) is a common pathogen as the cause of gastroenteritis in childhood. we experienced some cases with r infection who had the renal failure induced by uroammoniac calculi as well as dehydration. we examined the clinical feature and laboratory findings of the cases with viral acute gastroenteritis in r and non-rota virus (nr) groups for 2005-2006. with rapid diagnosis test, we checked the patients that needed the hospitarization medical treatment from newborn to five-years old. in the 42 cases of r group and 23 cases of nr group, we campared the clinical findings, blood chemistry test and urinalysis of r groups in acute and convalescent a tage with those of nr group. r group had significantly (p<0.05) lower in ph (vein blood gas test) and higher in blood uric acid (bua) compared with those of nr group. these findings suggest that the elevation of bua and acidosis in r group may induce the formation of renal calculus resulting in postrenal failure. our patient is white male 9 y/o. at 4 year of age, he was dx. with acute lymphocytic leukemia and was induced to remission on pog 9404; he presented tumor lysis syndrome during induction, acute renal failure with no recovery in renal function and rrt was started (ccpd) and continue on the same therapy. during the last years, he presented chronic pancreatitis, ards, sepsis. he had episodes of major vessel thrombosis probably due to central lines (several femoral lines and vascath placed in his thorax) and l-asparaginase. our patient did receive 3 years of chemotherapy and radiation; and he is on complete remission. on 11/2,005, for pre-kidney transplant evaluation, a mri test was requested using gadolinium 1 ml/kg for evaluating his vascular system (abdomen and pelvis) with inconclusive results. another mri test was requested 3 months later using gadolinium 0.3 ml/kg. 8 weeks later, his mother noticed brawny hyperpigmented, shiny, tightly bound-down, indurate plaques of his bilateral lower extremities, (more significantly on his lateral and posterior calves, and in his anterior and lateral thighs) a punch skin biopsy showed increasing number of fibroblastic cells and widened space between septa in the deep reticularis dermis compatible with nfd. nfd is a fibrosing disorder identified among patients with renal disease with cutaneous finding of skin thickening in extremities and trunk, very similar to those of systemic sclerosis. etiology, pathogenesis and clinical course remain unknown. the majority of cases have been reported in dialysis or kt patients and gadolinium has been identified as a trigger of nfd. in our case, there appears to be a link between the use of gadolinium and the developed of nfd. background: chronic renal failure (crf) is an independent cardiovascular risk factor. changes in calcium-phosphate homeostasis not only affect the quality of bones but also constitute the biochemical base for vascular calcification. aim: to find a method better describing factors of calcification using routine laboratory examinations and computed evaluation of complex equilibria. methods, patients: data of 12 crf and of 24 transplanted (tx) children were compared to a healthy control group of 15. tx children's parameters were taken before and 12 and 48 month following transplantation. three different strategies were used to analyse factors of calcification: ca x p product, ca-p activity value and the concentration of cahpo 4 . the ca x p product and the ca-p activity value were not informative, because they didn't represent the direction of change in the complex chemical equilibrium. the cahpo 4 concentration was increased in the crf and the tx group (before transplantation) (0.380±0.173 mmol/l) compared to the healthy control group (0.260±0.060 mmol/l) (p<0.01). after 12 and 48 months to transplantation the cahpo 4 concentration was in the normal range in the tx group. a negative correlation was found between the concentration of ica 2+ (ionic calcium) and pth (parathyroid hormone) in the dialysed children (r=0.720), but not in the transplanted group (r=0.122). conclusion: according our findings the force driving calcification is better represented by the concentration of cahpo 4 , the base compound of all primary calcification, than by measuring ca and p separately. follow-up study is needed to establish the predictive value of determination of cahpo 4 . this study was supported by grants otka-t046155 and ett 435/2006, the national office for research and technology (nkth) and szentágothai j. knowledge centre. introduction: acute renal failure is a rare complication of nephrotic syndrome and its cause is still unknown. several investigators reported that the most important factor for renal failure was acute tubular necrosis (atn); however, some cases did not have laboratory findings of tubular dysfunction paradoxically. patients and methods: we reviewed 11 cases of nephrotic syndrome with acute renal failure (nsarf) since 1990 at metropolitan kiyose children's hospital. seven of 11 cases had calcium deposition in the distal tubules predominantly. we analyzed the clinicopathological findings in these 7 cases. results: the pathological diagnoses of these 7 cases were as follows: 4 minor glomerular abnormalities, 2 mesangial proliferative glomerulonephritis (without iga deposition), and 1 focal segmental glomerulosclerosis. interstitial nephritis was not documented in any case. the common characteristics of these 7 cases were calcium deposits in the distal tubules. some cases had focal simplification of tubular epithelium. all cases were an initial episode of nephrotic syndrome, and 6 cases were steroid resistant. almost all cases had hypertension. in addition, the range of urinary β2 microglobulin and fena were 94 to 2980 and 0.1 to 0.33%, respectively. discussion: in these 7 cases, there was enhanced na reabsorption and urinary β2 microglobulin was only mildly elevated at the time of renal failure. these findings were not consistent with atn. additionally, pathological finding of severe tubular damages was not found on biopsy. contrarily, tubular obstructions due to ca depositions were consistent with these clinicopathological findings. conclusion: our findings suggest that tubular obstruction due to calcium deposition plays an important role in the etiology of nsarf except for atn. background: natriuretic factor was found in urine of chronic uremia for more than 30 years. n-terminal pro-b-type natriuretic peptide (prontbnp) is postulated to be the natriuretic factor owing to its elevation in chronic kidney disease (ckd). however, salt wasting and non-saltwasting chronic kidney disease haven't been partitioned as different entities before. this study is designed to clarify whether prontbnp is different in salt wasting and non-salt wasting ckd and if it is the main causative factor of natriuresis. methods: 17 patients with salt wasting ckd, which are mainly composed of congenital renal structure abnormalities, and 11 patients with non-salt wasting ckd, which are mainly composed of glomerulonephritis, were collected. all of them are non-dialysis-dependent and without heart failure. serum prontbnp in these two groups and 28 normal controls were sampled. fractional excretion of sodium (fena) and estimated clearance of creatinine (ccr) were also checked. results: prontbnp was elevated in salt wasting group compared to normal controls (p=0.012). moreover, prontbnp was even significantly higher in non-salt wasting group than in salt wasting one (p<0.0001). in salt wasting ckd, prontbnp and fena were correlated (r=0.7, p=0.017), but the same result was not observed in non-salt wasting group. prontbnp was significantly correlated to ccr and age using multiple regression analysis (p<0.05). conclusion: prontbnp elevation was different between salt wasting and non-salt wasting ckd. volume expansion explained the difference and prontbnp elevation in salt wasting ckd resulted from other mechanisms. since salt wasting ckd, in which the influence of volume expansion was eliminated, had a good correlation between prontbnp and fena, prontbnp may be one of the major contributing natriuretic factor in chronic uremia. background: cidofovir is a new antiviral drug that has a broad spectrum of activity against a number of dna viruses. several observations reported its efficacy as topical treatment of resistant warts. we herein report a systemic complication of acute renal failure associated with such topical therapy. casereport: girl aged 17, received a renal transplant in 1999 and 2001 for end-stage renal failure secondary to haemolytic uremic syndrome. her initial immunosuppressive regimen consisted of prednisone, tacrolimusand mycophenolate. five years post transplant she developed chronic allograft nephropathy with mild renal impairment. as a consequence of long standing immunosuppression she also developed invalidating, widespread periungueal warts. a well conducted, aggressive, conventional management of her warts including reduction of immunosuppression failed to improve the symptoms. she subsequently received an intralesional injection of a 75 mg/ml cidofovir solution. forty eight hours after the treatment she developed local swelling, inflammation and pain along with acute alteration of renal function. although cidofovir seric dosages performed on day 4, 5, 7 and 8 postinjection were negative we attributed this acute renal failure to a potential nephrotoxic side effect of cidofovir. renal biopsy showed no evidence of rejection but mild alterations of the tubes compatible with tubulo-interstitial nephritis. spontaneous recovery of renal function occurred within 2 months. conclusion: we describe an acute renal failure as a consequence of topical cidofovir treatment of warts in the context of renal transplant with mild preexisting renal failure. topical administration of cidofovir needs as carefull use and monitoring as its parenteral administration, especially in patients with altered renal function. the hemolytic uremic syndrome (hus) is a disease characterized by microangiopathic hemolytic anemia and variable organ impairment with a predominat feature of renal failure in children. the aim of this study was to investigate the presence of plasma lipid peroxidation products in the acute phase of hus. we have analyzed the levels of lipid peroxidation, determined fluorometrically as thiobarbituric acid-reactive substances (tbars), in the plasma of 8 patients (aged 15-48 months with a median of 23) diagnosed with the shiga toxin-associated form of the disease. in all cases, tbars determinations were performed at hospital admission, during treatment and upon discharge. tbars values averaged 1.27±0.14 and 1.12±0.20 mm sem at admission and discharge respectively (reference value <0.5 mm). of the patients examined, 4 presented conserved diuresis during the course of the syndrome, while the other 4 were anuric and required dialysis. maximum tbars values resulted significantly higher (p<0.05 by anova followed by newman-keuls test) in the dialysis-requiring patients as compared to those that had conserved diuresis (2.66±0.48 vs 1.58±0.39 mm respectively) we also investigated a possible correlation between tbars and plasma creatinine, urea, lactate dehidrogenase (ldh) and platelet count. positive and highly significant correlations (r=0.45 and 0.47, p<0.01) were observed when tbars values were plotted as a function of plasma creatinine and urea values respectively. no significant correlations were detected for tbars and plasma ldh values or platelet count. thus, patients affected by shiga toxin-associated hus exhibit increased levels of oxidative stress. also, there is a positive correlation between the magnitude of oxidative stress and the severity of renal failure. c. soares, j. diniz, e. lima, g. oliveira, c. camargos, b. sousa, e. oliveira objective of the study: the purpose of this retrospective cohort study was to report the clinical course of children and adolescents with chronic kidney disease (ckd) enrolled in a pre-dialysis program. methods: the records of 108 patients with ckd admitted to an interdisciplinary pre-dialysis program from 1990 to 2006 were retrospectively analyzed. the program consisted of conservative management of children and adolescents with ckd and was conducted by an interdisciplinary team including pediatric nephrologists, pediatricians, nurses, psychologists, nutritionists, and social workers. the patients were admitted with a glomerular filtration rate (gfr) equal to or below 75% of the value expected for their age according to normal reference data. demographic, clinical and laboratory data at entry and at the end of the follow-up were analyzed. renal survival analysis was performed using the kaplan-meier method. results: the median age at admission was 8.8 years (interquartile range: 2.6-13.2 yr). the most frequent primary renal disease was congenital urological anomaly in 50 patients (46%), following by glomerular diseases in 25 (26%), cystic diseases in 19 (18%), and others in 14 children (13%). at admission, 8 patients (7%) had ckd stage 2, 60 (56%) had ckd stage 3, and 40 (37%) presented ckd stage 4. median follow-up time was 5.3 years (iq range, 2.6-7.8). at the end of the follow-up, 12 children presented ckd stage 1 or 2 (13%), 20 patients were in stage 3 (18.5%), 16 in stage 4 (15%), and 58 children were in stage 5 (54%). it was estimated by survival analysis that the probability of ckd stage 5 was 24% at 3 years, 37% at 5 years, and 62%at 10 years after admission to the pre-dialysis program. conclusion: the long-term overall renal survival is relatively poor in a cohort of children and adolescents with ckd. objective: characterize the association between proteinuria and gfr in a cross-sectional study of children with mild to moderate chronic kidney disease (ckd). methods: first morning urine protein to creatinine ratios (up/c) and gfr (measured by iohexol blood-disappearance) for 260 children enrolled in the ckid cohort study were examined using loglinear regression of proteinuria and gfr, adjusted for age, sex, body surface area (bsa), and ckd cause. conclusions: in children with mild to moderate ckd, there was a log-linear relation between proteinuria and gfr. the prospective cohort design of ckid will assess the risk of gfr decline associated with level of proteinuria in children with glomerular vs non-gn causes of ckd. objective: to study the clinical characteristics of chronic renal failure (crf) in children. the clinical data of 81 children with crf in the last fifteen years were retrospectively analyzed. results: the first main causes of crf in children were still glomerular disease, and congenital deformities of urinary system and hereditary renal disorders were the second main causes. the initial age of children with crf which were caused by congenital deformities of urinary system and hereditary renal disorders were relatively younger than children with crf which were caused by glomerular disease. the symptoms of some crf in children were not typical. conclusions: glomerular disease were still the first main causes of crf in children. urine screening test, early renal function examination and kidney b-mode ultrasonic were attribute to early diagnosis and proper management of crf in children. the aim of the study was the evaluation of influence of clinical and biochemical parameters upon degree of impairment of cardiac function in dialysed children. methodology: 16 chronically dialysed (6 hd, 10 pd) children participated in the study (10 m, 6 f), aged 5-18,5 yrs (x=12,2±3.8 yrs). echocardiography examinations were carried out with a hp 5500 device. diastolic and systolic left ventricular (lv) dimension, ejection fraction (ef) and lv mass index (lvmi) were evaluated. mean values of estimated parameters in 6 months preceeding echo were calculated. results: on the basis of echo examinations 3 groups were singled out: a (n=3) of normal heart function, b (n=3) of impaired systolic and diastolic heart function and c (n=10) of normal systolic and impaired diastolic heart function. no differences between groups according age, bmi, dialysis and renal insufficiency duration were found. in group of children with severe cardiac lesion (b group) a higher lv mass (a vs b vs c: 74,7 vs 119,9 vs 73,5 g/m) and statistically significant lower ejection fraction (68,1 vs. 33,7 vs. 65,9%) were ascertained. these children were anuric (996 vs. 0 vs. 1112 ml/d), their systolic (102,1 vs. 118,4 vs. 117,9) and diastolic (64,4 vs. 84,8 vs. 77,9) blood pressure were significantly higher, so was the number or hipotensive medications (0,33 vs. 1,72 vs. 1,44) . bioimpedance analysis showed overhydration in group b (tbw% 63 vs 67 vs 62.5; ecw/icw 0.67 vs 0.76 vs 0.7). conclusions: the vast majority of chronically dialysed children demonstrate an impairment of cardiac function mainly of diastolic parameters. anemia, malnutrition, hypervolemia, anuria and hypertension stand for a significant risk factors of cardiac impairment in dialysed children. we report here the clinical findings and prognosis of 10 patients (5 girls, 5 boys) with infantile oxalosis diagnosed between june 1990 and december 2006 in order to remind this rare autosomal recessive metabolic disorder as the potential cause of acute renal failure in infancy. the mean age of the patients was 4.7 months (range: 2.5-10 months). all patients had the complaint of vomiting since birth, 3 had irritability, and 2 had convulsions. seven of them had parental consanguinity (70%) and family histories revealed urolithiasis in four patients and infantile deaths in one. two patients were cousins without any other family history. all patients presented with anemia (hemoglobin: 4.5-9.6 g/dl), renal failure (creatinine levels: 3.2-10.2 mg/dl) and metabolic acidosis. abdominal x-rays showed bilateral nephrocalcinosis, renal ultrasonographies revealed normal sized kidneys with diffuse and intensive hyperechogenity and loss of corticomedullary differentiation in all patients. crystal deposition was demonstrated in fundoscopic examination of 5 patients, bone marrow aspiration of 2 patients, and renal tissues of 8 patients that underwent renal biopsy. besides supportive therapy, peritoneal dialysis was performed on 7 patients, but only one patient accepted to continue the therapy. four patients died within few months and 4 were lost to follow-up, probably died. two patients have been followed up for 3 months one on continuous ambulatory peritoneal dialysis. in conclusion, this rare disease with fatal outcome should be remembered and investigated in infants with renal failure and bilateral nephrocalcinosis since early combined renal and liver transplantation may be life saving if it can be performed. acute renal failure following halothane anesthesia in young child? case report we present here the case of renal failure and hepatocellular lysis that developed 24 h after the exposure of halothane anesthesia during eye examination. previously a healthy 7 months old boy had a cardiac arrest, during the above mentioned diagnostic procedure, therefore cpr was applied which all happened in another hospital. after a few hours he was transferred to icu at our hospital, consciousness, hemodinamic stabile. in the following 24 hours he developed acute non-oliguric renal failure (maximal level of urea 29 mmol/l, creatinine 259 mmol/l), as well as hepatocellular lysis (alt 1879 u/l, ast 2157 u/l). plasmaferesis and continuous venovenous hemodiafiltration were immediately applied followed by conservative measures. the level of serum transaminase returned to the normal values within a week and the level of creatinine and urea within two weeks. fully recovered boy was released home. toxic effects of halothane anesthesia in children are reported in only few cases in the literature. objective of study: many cases of chronic aristolochic acid nephropathy (caan) in adults had been reported, but it had rarely been described in children. we reported 3 children with caan to investigate its clinical and pathological characteristics. methods: three cases were studied retrospectively and relevant literatures were reviewed. results: three children received traditional chinese herb medicine containing aristolochic acid 4 to 8 months for different basal diseases including chronic aggressive hepatitis b, secondary hydrocephalus and purpura nephritis and suffered from caan from 2 mouths to 6 years after they began receiving the chinese medication. the main manifestations were renal failure of various degree accompanied with proximal and distal tubular dysfunctions. two of them began with anemia and suffered from serious renal failure. the onset of another case was glucosuria with renal function impaired mildly, and she presented secondary fanconi's syndrome simultaneously. their pathological characteristics were diffuse paucicellular interstitial fibrosis and marked tubular atrophy with mild glomerular impairment. after withdrawal of the chinese herb medicine, renal failure in two patients attenuated progressively. the clinical features of caan in children are progressive renal failure and renal tubular disfunction. its pathological characteristics are diffuse paucicellular interstitial fibrosis and marked tubular atrophy. therefore, we emphasize the recognition of the nephrotoxicity of traditional chinese herb medicine and prevent caan from happening in children. objective of study: recombinant human erythropoietin (rhuepo) treatment may cause pure red cell aplasia (prca), but it had been rarely described in children. in order to acquaint ourselves with this disease, we reported a boy with chronic renal failure developed prca following rhuepo treatment. methods: one case was studied retrospectively and relevant literature was reviewed. results: a 10-year-old boy suffered from chronic renal failure combining with renal anemia and received rhuepo treatment. two weeks later, his hemoglobin (hb) increased from 57 to 90g/l, and maintained 90 to 94g/l for 6 weeks. subsequently his hb declined suddenly at a rate of 1g/l/day, despite rhuepo increased in dose. his reticulocyte count reduced to 0.4 10 9 /l without other cytopenias in peripheral blood. a series of laboratory examinations were performed, including bone marrow cell smear and culture to confirm his prca. because various of other factors such as parvovirus etc. induced prca was excluded, we considered the boy's prca was due to rhuepo treatment, although we didn't detect anti-epo antibodies for lacking of the reagent. the boy received erythrocyte suspension transfusion to correct his anemia and was waiting for renal transplant in the following period. conclusions: during the treatment of rhuepo, sudden and rapid reducing of hb might be a hint of rhuepo induced prca. the diagnosis should be based on the clinical presentation, the absence of red cell precursors in bone marrow and the detection of anti-epo antibodies. renal transplant and immunosuppressive therapy might be effective. m. zaniew, b. mroziñski, a. warzywoda, e. stefaniak, a. siwiñska, j. zachwieja among ambulatory blood pressure monitoring (abpm) parameters, pulse pressure (pp) provide an information on cardiovascular (cv) status. recently, a novel parameter i.e. ambulatory arterial stiffness index (aasi) has been proposed. aim: to investigate pp and aasi in relation to left ventricular (lv) geometry and carotid intima-media thickness (cimt) in children with chronic renal failure (crf). subjects: 24 children (6 f/18 m; median age: 15 yrs) with crf treated conservatively (n=8) and with dialysis (hd; n=7/pd; n=9). methods: we studied demographic data, echocardiography data [left ventricular mass (lvm), left ventricular mass index (lvmi), interventricular septum (ivs), left ventricular posterior wall (lvpw), left ventricular end diastolic diameter (lvedd), relative wall thickness (rwt)], cimt and abpm. from abpm, we calculated pp [difference between systolic blood pressure (sbp) and diastolic blood pressure (dbp)] and plotted dbp against sbp (regression slope). aasi was defined as 1 minus this regression slope. results: a positive correlation was found between aasi and pp (r=0.35, p<0.05). aasi was correlated to lvedd (r=0.39, p<0.05) and rwt (r=-0.45, p<0.01). pp was related to: weight (r=0.47, p<0.01), body surface area (r=0.41, p<0.05), body mass index (r=0.43, p<0.05), and lvm (r=0.58, p<0.001), lvmi (r=0.54, p<0.01), lvpw (r=0.35, p<0.05), lvedd (r=0.68, p<0.001), rwt (r=-0.35, p<0.05). neither aasi nor pp was associated to cimt. children with lv hypertrophy had higher pp than without this alteration (p<0.05). when data analyzed across quartiles of pp, children in the upper quartile showed higher lvm (inter-group comparisons p<0.001), lvmi (p<0.01), lvpw (p<0.01) and lvedd (p<0.001). conclusions: pp is a stronger predictor than aasi of lv geometry in children with crf.. acute renal failure in newborn period may be caused by prenatal, natal and postnatal factors. among them, obstructive lesions of the genital tract (e.g. imperforate hymen and vaginal atresia) are very rare. children with hydrometrocolpos due to distal vaginal atresia may present with severe obstructive uropathy and its consequences. hydrometrocolpos is the result of vaginal obstruction and can become an emergency in newborn period. acute renal failure associated with distal vaginal atresia appears to be rare, with only one report in the paediatric literature. here we report a 27-dayold infant with a hydrometrocolpos causing life-threatening renal failure. percutaneous drainage did result in dramatically improved clinical and laboratory findings of the patient. objectives of study: sympathetic overactivity is currently considered as an important mechanism of both development and progression of chronic renal failure. however, this statement was mostly based on the researches in which the participants were adult patients with terminal renal failure. little information is available on autonomic changes in pediatric patients with mild renal insufficiency. our aim was to determine whether there is sympathetic activation in children with chronic pyelonephritis in a stage of mild renal insufficiency. methods: 47 patients met the inclusive criteria were selected and assigned into two groups according to the creatinine clearance. group i had 26 patients with creatinine clearance between 60 and 90 ml/min/1.73 m 2 while group ii have 21 patients with normal creatinine clearance. baseline of age (from 10-17 years old), gender and diagnosis between the 2 groups are comparable. time domain analysis of heart rate variability in short-term recordings of 2 minutes was performed in both groups. as well vain questionnaire for assessment of autonomic state was performed in all participants with their parents help. results: the outcomes of heart rate variability analysis showed sympathetic overactivity of 73.0% patients in group i vs 30.8% in group ii, and the difference is statistically significant (t=2.497, p<0.05). significant difference was also found in results of vain questionnaire: 69.2% of patients in group i were estimated as "sympathetic", while only 33.3% in group ii (t=2.32, p<0.05). conclusions: based on the consistent findings of the two methods used in this study, we conclude that sympathetic overactivity may be found in children with even mild renal insufficiency, and it should be considered as an early event in the development of pediatric renal failure. the aim of this study was to describe the prevalence of myocardiopathy in pediatric patients with different stages of ckd (stages 2 to 5).methodology: inclusion criteria -gfr <75 ml/1.73 m 2 , ckd treatment >6 months, age <19 years old. echocardiograms were performed using standard techniques. left ventricular mass (lvm) was measured by two-dimensional directed m-mode echocardiography according to the american society of echocardiography criteria. lvm index was assessed and when >51g/m 2.7 it was considered severe hypertrophy. the relative wall thickness (rwt) was measured to assess the lv geometric pattern. age, high blood pressure (hbp), anemia, time and type of treatment were compared to the echocardiographic findings. results: we evaluated 53 patients, mean age 8 years old, 41% on pre-dialysis, 36% on hemodialysis (hd) and 23% on peritoneal dialysis (pd). patients on hd were evaluated in the interdyalitic period. twenty-seven patients (51%) had myocardiopathy, clvh in 14 (25%), elvh in 7 (14.5%) and cr in 6 (11%). severe hypertrophy ocurred in 20 pacients (37.7%). there was no significant difference in relation to age and high blood pressure. patients with clvh were on hd for longer time and had a lower hematocrite when compared to the patients without clvh (14±3 vs 4±2 months; p<0.01) and (33±1 vs 27±1; p<0.001) respectively. there was a significant correlation between hematocrite and left ventricular mass (r 2 =0.28). conclusion: we observed a high prevalence of myocardiopathy in this study population. the risk factors associated to clvh were anemia and time on hd. larger and prospective studies are needed to analyze the impact of myocardiopathy in the cardiovascular mortality in children as well as the results of interventions applied to correct these risk factors. [0] [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . urological problems such as vesicoureteral reflux (18, 5%), obstructive uropathy (10,7%) and neurogenic bladder (15,1%) were the leading underlying conditions causing cri with a total of 46,3%. while majority of the patients were having gfr levels less than 15 (33,5%) or between 25 to 50 ml/min/1,73 m 2 (31,2%), gfr level was between 50-75 in only 16.5%of the patients. patients with pth levels between 100-300 and more than 300 pg/ml comprised the majority (32,4 and 40% respectively). the gfr levels correlated positively with hemoglobin/hematocrit and calcium levels and negatively with phosphorus and pth levels (p<0.05). renal replacement therapies were initiated in 33,6% of the patients. the most striking result of this study is the predominance of vur or related urological problems that are relatively preventable as the underlying causes of cri in children. early diagnosis and appropriate medical or surgical management of these conditions should be emphasized together with achieving broader coverage of the pediatric cri population in terms of supportive treatment. twin-twin transfusion syndrome (ttts) complicates up to 15% of monochorionic twin pregnancies. shunting of blood between twins through common placental blood vessels can cause growth restriction, oligohydramnios and anaemia in the donor twin. renal impairment in the donor twin has been reported as a transient phenomenon with full recovery. we describe a case series of three children with chronic renal failure due to ttts. all 3 cases were monochorionic diamniotic twins. in cases 1 and 2, growth discrepancy was noted on prenatal scanning. in the case 3 anomaly scans were normal. gestation at birth ranged between 31 and 36 weeks. in all cases there was a significant birth weight discrepancy between twins. post-natal ultrasound appearances were variable: case 1 had normal scans within the first month but echogenic kidneys at 3 months; case 2 had initial increased echogenicity but features consistent with cortical necrosis at 4 weeks; case 3 had small kidneys with no cortico-medullary differentiation. all 3 children became dialysis dependent within the first year of life. age of commencement ranged from 4 days to 7 months. case 3 was successfully transplanted at 3 years. case 2 had an unsuccessful transplant at 2 years and remains on dialysis at 4 years. case 1 remains on dialysis at 2 years. cases 2 and 3 are now at mainstream school with only mild learning difficulties; case 1 has some gross motor delay but other wise normal development. with advances in neonatal intensive care and improved survival of low birth weight babies, this presentation may become increasingly common. even severe renal involvement can occur in the absence of other significant hypoperfusion injury. the management of survivors of ttts with established renal failure may present unique challenges and opportunities. introduction: endothelial heparan sulfate proteoglycans (hspg) play an important role in various biological processes in the renal glomeruli. it is involved in the inflammatory process by acting as a ligand for l-selectin. furthermore, leukocytes are able to interact with chemokines bound to hspg (examples are il-8, rantes and mcp-1). this will lead to activation of the integrins on leukocytes and result in more stable leukocyte-endothelial wall adhesion. in this work, we have studied the effect of a subtoxic dose of shiga-like toxin (stx) 1 and 2 on the hspg and the possible implications on the pathogenesis of the hemolytic uremic syndrome (hus). methods: to study this effect, primary human umbilical venous endothelial cells (huvec) and primary human glomerular microvascular endothelial cells (gmvec) were incubated for 24 hours with a subtoxic dose of stx1 or 2. then, cells were treated with the enzyme heparinase 3 (which cleaves off hspg). non-treated cells were used as controls. after treatment with the enzyme, the endothelial cells were exposed to flowing human leukocytes in a parallel plate flow chamber. the amount of adherent leukocytes was calculated. -: not treated with heparinase 3, +: treated with heparinase 3 conclusion: stx1 and 2 cause an upregulation of the amount of adhering leukocytes on both endothelial cell types. treatment of the endothelial cells with heparinase 3 decreases markedly this upregulation. the effect can not be detected without stx-incubation. this can be explained by a possible upregulation of hspg on endothelial cells by stx, resulting in a higher level of bound chemokines or an increased binding of released chemokines to hspg. this will lead to an increased adhesion of leukocytes and will induce a more severe inflammatory process in the renal endothelium. this effect will contribute to the devastating pathogenesis of the hus. c. soares, j. diniz, e. lima, g. oliveira, c. camargos, b. sousa, m. almeida, e. oliveira objective of thestudy: the purpose of this study was to identify clinical, nutritional and laboratory factors associated with the rate of progression of chronic kidney disease (ckd) among the children and adolescents admitted to a pre-dialysis interdisciplinary program. methods: one hundred eight children and adolescents aged 2 months to 19 years with ckd in conservative management were prospectively followed up from 1990 to 2006. renal survival was analyzed by the kaplan-meier method and cox's regression model. a multivariate model was developed from the admission until occurrence of ckd stage 5 (glomerular filtration rate <15 ml/min). the following data were obtained at admission: gender, race, age at admission, weight z score, renal primary disease, blood pressure, and laboratory data (serum creatinine, serum urea, glomerular filtration rate, 24 hr urinary protein excretion, hematuria). results: median follow-up time was 5.3 years (iq range, 2.6-7.8) and 58 patients (54%) progressed to ckd stage 5. in the univariate analysis the following variables were significantly associated with the event: non-white race (p=0.04), age >8 years (p=0.01), ckd stage at baseline (p=0.01), renal primary disease (p<0.001), severe proteinuria (p<0.001). after adjustment, 3 variables remained as independent predictors of ckd stage 5: severe proteinuria (rr=2.1, 95% ci=1.4±3.1), glomerular disease as renal primary disease (rr=1.5, 95% ci=1.2±1.0), and ckd stage 4 at baseline (rr=2.3, 95% ci, 1.4±3.7). conclusion: the combination of three factors -severe proteinuria, glomerular disease, and ckd stage 4 at admission -was an independent indicator of adverse outcome in children and adolescents in a pre-dialysis interdisciplinary program. background: allogenic hematopoetic stem cell transplantation (allo-hsct) has gained world wide acceptance as a treatment for various diseases. renal dysfunction is one of the major complications that influences transplant related mortality (trm) rates following hsct. in this prospective study, we aimed to investigate the effect of allo-hsct on renal function in children. methods: renal ultrasonography, dmsa scintigraphy, analysis of renal and tubular function tests were performed before, shortly and 1-year after hsct. acute renal toxicity (art) was classified according to bearman criteria. grade 1=increase in creatinine up to twice the baseline; grade 2=increase in creatinine above twice baseline; grade 3=increase in creatinine above twice baseline and need for dialysis. chronic renal insufficiency (cri) was defined as gfr<70 ml/min/1.73 m 2 and failure (crf) as need for dialysis. results: between april 1999 and june 2006, 57 children (median age: 10.0 years) underwent 58 allo-hsct because of hematologic disorders (malignancy, 19; hemoglobinopathy, 28; aplastic anemia, 10). all patients except one received nontbi conditioning regimen. six patients (10.3%) were died because of trm but none of these patients had primary art. during the first 100 days, 10 patients (17.2%) had grade 2 art (csa nephrotoxicity in 7, vod in 3 patients). grade 3 art was defined in 5 patients (8.6%) (vod in 3, sepsis in 1, csa nephrotoxicity in 1 patient). eleven patients had structural renal abnormalities before hsct, 3 of them persisted and 3 new patients had pathologic results one year after hsct. in long term period, 5 (8.6%) of 37 evaluable children had cri and no patient had crf requiring dialysis. conclusion: renal dysfunction was found to be a frequent complication after allo-hsct in children. therefore, renal functions should be followed carefully in these patients. .26 years and at the end of follow-up, and compared between the three groups. there were no significant differences between groups in so far as gender, underlying disease, age at diagnosis, proteinuria, hypertension, hyperparathyroidism, use of ace inhibitors or renal size. erithropoietin use was significantly higher (p<0.001) in group 1. gfr improved in all three groups during their first two years of life. the cut-off point on the roc curve indicating worse gfr long term evolution was 50 ml/min/1.73 m 2 at two years of life (sensitivity 85%, specificity 88%). g. zilleruelo, am. onder, j. chandar, o. nwobi, c. abitbol background: catheter-related bacteremia (crb) is a common complication of tunneled-cuffed hemodialysis catheters. our objective was to investigate the effectiveness of tissue-plasminogen activator-tobramycin locks (tpa-abl) in preventing crb in pediatric patients. methods: a retrospective analysis of 52 pediatric hemodialysis patients was performed. patients with >10 crb/1000 catheter days (cd) were designated as high risk. those with <10 crb/1000 cd were of average risk. three eras of 6 consecutive months were studied. in era 1, high risk patients were detected. during era 2, the high-risk group was placed on 3 times weekly prophylactic tpa-abl. in era 3 the high-risk group was given once weekly tpa-abl. results: there was a significant decrease in the rate of crb with prophylactic tpa-abl which was more pronounced when given three times/week. conclusions: the use of prophylactic tpa-abl 3 times weekly significantly reduces the rate of crb in patients at high risk. prophylaxis once weekly may be less effective than thrice a week. l. was born after a normal pregnancy without a special personal or familial history, was seen at the age of 4 years, after a 6 days long ordinary oro-pharyngeal viral infection treated by symptomatic treatments. he presented with inflammation of the left cheek with slight fever (38°) and a sole purpuric lesion of the left leg (1cm) and some petechiae on the thorax. blood count showed haemolytic anemia (haemoglobin=10 g/dl, schizocyte=2%, increased ldh), 23000 white cells (90% neutrophils) and 123000 platelets. no germs were found in hemoculture, lumbar punction, stools or urines cultures. creatininemia was 95 μmol/l. in the following hours, despite immediate antibiotics administration and without any shock sign, several purpuric extensive necrotic lesions appeared, renal insufficiency increased (creatininemia=175 μmol/l), platelets count decreased to 46000 and markers of diffuse intravascular coagulation dramatically increased. in the following days, proteinuria, macroscopic hematuria and hypertension appeared. after 3 days on anticoagulation therapy, renal function remained stable while anemia, thrombopenia and coagulation disorders persisted. coagulation factor tests demonstrated a heterozygote deficiency of factor v leiden (also found in the father) and an acquired protein s deficiency secondary to streptococcal infection. after protein s infusion and plasma exchanges, his state improved and necrotic lesions ceased. this initial hematologic and renal presentation could have suggest a hus but the large purpuric lesions remain unusual in such pathology. a in children on chronic peritoneal dialysis malnutrition is being diagnosed with an objective combined nutritional score (abn score) based on anthropometry and bioimpedance analysis indices (nephrol dial transpl 2006; 21: 1946-51) . aim of this study was to investigate the prevalence of malnutrition and the main factors associated with it in children with ckd 2-4. we planned a cross-sectional study of 77 children with ckd 2-4, mean age 8.9±5.8 years, who underwent controls in our institution between september 1 and december 31, 2006. the data of abn score, age, primary renal disease, standard blood and urinary tests, and estimated gfr (schwartz formula) were collected.the prevalence of malnutrition (abn score <10.33) in the whole population was 23%. the abn score was positively correlated with age, height sds, serum hemoglobin, total protein and albumin (p value from <0.0001 to <0.05), while a negative correlation was found with serum phosphate and proteinuria (p<0.005). patients with steroid-resistant nephrotic syndrome had lower abn score values than those with other primary renal diseases (9.61±0.85 vs 11.67±1.93; p<0.05). the percentage of children with malnutrition in the different stages of ckd increased in parallel with the decrease of gfr, from 10% in the ckd 2 group to 29.2% in the ckd 4 group. in conclusion, the prevalence of malnutrition in children with ckd 2-4 is not negligible. low hemoglobin, total protein and albumin levels and high serum phosphate and urinary protein excretion, particularly in small children with growth impairment, strongly suggest the need for an in depth nutritional assessment, in order to diagnose malnutrition and treat it accordingly. e.c. developed atypical hus at 6 months of age. a heterozygous factor h gene mutation was found. despite plasma-exchange treatment numerous relapses led the child to ckd stage 4: creatinine clearance (ccr) 15.02 ml/min/1.73 sqm according to schwartz formula. at 4 yrs we started a programme of fresh frozen plasma (ffp) infusions, 10-15 ml/kg bw. the child was poliuric and hypertensive, notwithstanding the treatment with ramipril, amlodipine, clonidine and furosemide. in the first 6 months he received ffp every 10 days. mean ccr during this period was 16.8±1.7 ml/min/1.73 sqm. haptoglobin (hap) was still <20 mg/dl in 10/15 tests (66.7%), ldh was increased (543.9±87.5 u/l), hemoglobin and platelet count were always in the normal range. the treatment schedule was then changed to ffp every 7 days for the next 4 months. during this period, ccr was significantly higher (23.8±2.4; p<0.0001) and ldh significantly lower than in the first 6 months (445.5±31.7; p<0.005); haptoglobin was always >20 mg/dl. no differences between the two periods were found for hemoglobin, platelet count, proteinuria, microalbuminuria and blood pressure values. both in the first and the second period, ccr was negatively correlated with ldh (r 2 0.40, p<0.0005) and with the bioimpedance analysis (bia) measure of resistance, which is an index of body hydration. in conclusion: 1. the only signs of disease activity in atypical hus can be minor abnormalities in laboratory tests, such as increased ldh and decreased haptoglobin levels; 2. ffp infusions are useful in maintaining hus remission and preserving kidney function, provided that the treatment schedule is optimized; 3. bia is useful in monitoring hydration status of children with ckd, especially those with poliuria and under ace-inhibitors, as it allows for the correct interpretation of serum cr values. analgesic-antipyretic agents are commonly used medications worldwide for the treatment of pain and fever in children. acute renal failure is commonly seen in adults after treatment with analgesicantipyretic agents. this complication has rarely been reported in children. two patients, ages 12 and 16 years were admitted with a diagnosis of acute, non-oliguric renal failure. one had symptoms of upper respiratory tract infection, and the other had been suffering from vomiting and abdominal pain. appropriate evaluations including detailed history especially the history of drug ingestion, physical examination, and measurement of serum creatinine concentrations were performed in the emergency department. both patient had ingested analgesic-antipyretic agents (mefenamic acid, and paracetamol) before the onset of acute renal failure. none of the patients had previous history of renal disease or concomitant treatment with other drugs. none had oliguria or anuria, dehydration, abnormal serum electrolyte concentrations, or evidence of glomerulonephritis. microscopic hematuria and leukocyturia were found in one patient. serum creatinine was 1.1 and 2.29 mg/dl at presentation. both of them recovered completely within a week. we emphasize that clinicians must be aware of renal toxicity of analgesic-antipyretic drugs with low doses. with the increasing use of over-the-counter analgesic-antipyretic agents, this association may become more prevalent. cardiovascular disease is a main cause of morbidity and mortallty in patients with chronic kidney disease (ckd). the pathophysiology of cardiovascular disease (cvd) in ckd remains uncertain but nowadays sympathetic hyperactivity is recognized as an important mechanism involved. this observational and transversal study of 40 patients from five to 21 years old, submitted to dialysis or at least four months after kidney transplantation (ktx), without signs of transplantations rejections, with definite ckd and creatinine clearance of 50 ml/min or less. the subject (median age=14 years; 62.5% female) were classified accordingly with treatment modality: conservative (n=7), peritoneal dialysis (capd) (n=5), hemodyalisis (n=13) and renal transplantation (n=15) submitted to 123l-metaiodobenzilguanidine (123l-mibg) planar and tomography scintigraphy and heart rate variability (hrv). comparisons among groups were made using anova and the association between variables was assessed using spearman's correlation coefficients and bonferroni correction was used during multiple comparisons testes. a p value <0.05 was considered significant. hemodialysis patients presented increased cardiac washout (p=0.002), heterogeneous pattern of 123l-mibg distribution (p=0.036) and lower values of low frequency component of hrv (p=0.040). capd subjects had reduced lung washout (p=0.030). the cardiac washout had positive correlation with pth and negatives correlation with creatinine clearance. there was a significant negatives association between the rr interval in low frequency (lf) and cardiac washout. the uremic cardiac disautonomia might be characterized by decreased low frequency component of hrv and increased 123l-mibg washout and heterogeneous distribution pattern by left ventricular walls; these abnormalities subsided after ktx. d+hus is the main cause of acute renal failure in children. extrarenal manifestations are associated in more than 30% of the cases. hus causes toxin mediated endothelial cell damage, resulting in thrombotic microangiopathy and intraluminal thrombosis of small vessels, with subsequent tissue ischemia and necrosis of involved organs. a 3-year-old boy has been admitted for d+hus associated with escherichia coli o145 diarrhea. he presented with renal failure and hypertension requiring hemodialysis for 28 days, hemolytic anemia (5g/dl, schizocytes 6%) requiring 7 blood transfusions, severe thrombopenia (10 g/l) and hyperleucocytosis (39600/mm 3 ). severe hemorragic colitis with duodenitis required prolonged parenteral nutrition. at 6 days after onset, the child presented with confusion, slurred speech followed by loss of consciousness associated with major hyperglycemia (107 mmol/l) and elevated corrected natremia (155 mmol/l) without ketosis requiring transfer in intensive care unit (icu). continuous hemofiltration associated with insulin therapy (0.05 ui/kg) was then established with slow decrease of natremia and serum glucose within 72 hours. neurologic condition rapidly improved. serum amylase and lipase were normal. insulinemia at the same time as the highest hyperglycemia was low (1,7 ui/ml), and search for human insulin, islet cell and glutamic acid decarboxylase antibodies were negative. insulin therapy could be discontinued within 15 days. at the last follow-up, 6 months later, neurologic examination, serum glucose and glomerular filtration rate were normal. in conclusion: 1/ hyperglycemic hyperosmolar coma is a severe complication yet never reported in d+hus; 2/ continuous hemofiltration with constant monitoring of biologic parameters could avoid permanent lesions due to rapid correction of this major metabolic unbalance. chronic renal failure (crf) can interfere with the regulation and time dependent secretion of multiple hormones. adrenocortical function in children with crf is examined in a few studies with a limited number of patients, and the results are controversial. in this study our aim is to evaluate adrenocortical function in basal and stimulated conditions, and to determine the relationship with the glomerular filtration rate (gfr), etiology and duration of crf in a larger group of patients. sixty-one patients with crf (28 f, 33 m; mean age 12.6±3.2 years) were studied. the patients were grouped according to etiology [structural abnormalities (n: 33), glomerulonephritis (n: 11), others (n: 11)], duration of crf [0-36 (n: 25) , 36-72 (n: 22) and >72 months (14)] and gfr [ 25-75 (n: 24), 10-25 (n: 19), <10 ml/min/1.73 m 2 (n: 18)]. cortisol levels were measured at 08: 00 a.m. (basal cortisol) and 11: 00 p.m. low dose acth test (0.5 micg/m 2 synacthen iv) was performed. delta cortisol was calculated as peak cortisol minus basal cortisol during the acth test. diurnal rhythm is accepted to be preserved if 08: 00 a.m. cortisol/11:00 p.m. cortisol is greater than two. basal cortisol levels and peak cortisol response to low dose acth is similar in all groups. median levels of delta cortisol found to be higher in the gfr<10 ml/min/1.73 m 2 group; p=0.06. diurnal rhythm seems to be more preserved in the gfr 25-75 ml/min/1.73 m 2 group (%68) compared to gfr<10 group (%44); p=0.612. no correlation was found between the basal, peak and delta cortisol, gfr and duration of crf. our preliminary results have shown that there is no difference in the basal and peak cortisol levels between all groups. this is the first study in children showing that adrenocortical function is preserved in groups with gfr levels between 10-75 ml/min/1.73 m 2 . objective: this study was we evaluated bk virus and jc virus in urinary after renal transplantation. methods: because these polyoma viruses are excreted in urine, these 12 patients (7 females and 6 males, 16.1±6.7 years old) was analyzed by polymerase chain reaction. all patients were living donor renal transplantation from a parent. results: two patients have detected bk virus in urine. as the type of immunosuppressive treatment, one had tacrolimus and mycophenolate mofetil, and one more had methylprednisolone and tacrolimus. seventeen percent of the patients had quantifiable bk virus-dna in urine. thirty-three percent of the patients had quantifiable jc virus-dna in urine. there was non significant relationship between these polyoma viruses in urine and the type of immunosuppressive treatment. no patients developed interstitial nephritis during the study. conclusions: the activation of bk virus and jc virus does not seem to be related to the type of immunosuppressive treatment. the pathogenetic role of polyoma virus infection in renal transplantation recipients further researches are needed. background: urinary tract infection (uti) due to neurogenic bladder, secondary to large spina bifida as myelomeningocele, is well known, but the association of small occult spina bifida (sbo), having normal physical examination, with that of infection has not been reported. we studied the frequency of spina bifida occulta in children with urinary tract infection. method: the kub of voiding cystouretrography in 104 patients (72 f, 31 m) with average of age 6 year (±3.5 sd), who referred to radiology department of ali asgar children hospital for uti, were observed for sbo. all patients had normal physical examination. chi2 were used to find the frequency of the level of sbo and the differences respectively. p<0.05 was considered significant. result: 80 out of 104 patients had sbo. the order of frequency of the level of sbo was s1 (51%), l5 (14,4%), s1s2 (6,7%), l5s1 (4,8%), and l5s1s2 (1%). 22 patients had vesicoureteral reflux (bilateral in 8 cases, 10 at left and 3 at right side). the severity of vur was 76% grade (g) ii, 14,35% g iii, 9.1% g iv, and 4.8% g i. spina bifida occulta was detected in 19 out of 23 patients with vur. this difference was not statistically significant (p=0.43): conclusion: the high frequency of lumbosacral sbo in the patients with urinary complaint may imply some lower urinary tract dysfunction in these patients although we need a control study in normal children. we evaluated interleukin-6 and interleukin-8 levels in the urine of 33 children with renal scarring, with vesicoureteral reflux (23/33, group a 1 ) and without vesicoureteral reflux (10/33, group a 2 ) and in the urine of 7 healthy children (group b). none of the children had urinary tract infection for the last ten months. interleukin-6 and interleukin-8 were determined using a commercially available human enzyme-linked immunosorbent assay kit. results: urinary interleukin-8 levels were below the lower detection limit in all samples. interleukin-6 levels were detectable in all urine samples of children with renal scarring and below the detection limits in the urine samples of healthy children. there were no statistically significant differences between urinary interleukin-6 levels in children with and without vesicoureteral reflux. there is a relationship between the grade of renal scars, the time past from their development and the urinary levels of il-6. the introduction of mycophenolate mophetil (mmf) was an important advance in immunosuppressive therapy but its use is associated with gastrointestinal intolerability (gi) requiring dose reductions or drug interruptions. enteric coated mycophenolate sodium (ec-msp) was designed to improve mycophenolic acid (mpa)-related gi by delaying the release of mpa until reaching the small intestine. at present, its immunosuppressive activity in pediatric renal transplant with gi has not been clarified. we studied trough levels of active metabolite mpa (c 12 ), changes in kidney function, mixed lymphocyte culture, cytotoxic antibodies as well as cytotoxic response before and after 3 months of the conversion from mmf to ec-mps in 8 renal transplant recipients with gi. in the immunosuppressive protocol used: mmf, tacrolimus and corticosteroid, mmf 444±46 mg/m 2 /day was replaced by ec-mpa 318±34 mg/m 2 /day. after 3 months of treatment with ec-mpa, the incidence of gi decrease to 12.5%. the levels of mpa were about 50% higher on ec-mps (6.9±1.1 ug/ml) compared to mmf administration (4.2±0.9 ug/ml). serum creatinine, creatinine clearance and urinary protein excretion did not change (1.3±0.3 to 1.4±0.3 mg/dl, 71.7±10.3 to 70.2±10.4 ml/min/1.73 m 2 and 0.08±0.06 to 0.12±0.06 gr/24 hr, respectively). also, during ec-mpa, proliferative response and cytotoxic antibodies showed no significant change. the release of il-10 was striking augmented with mmf or ec-mps therapy, but interferon-γ and tnf were low under both treatments. our data indicate that conversion from mmf to ec-mps leads to an improvement in gi without altering key elements of immunosuppression. however, the monitoring of mpa before and after conversion should be appropriated to the optimization of therapy efficacy. re. munarriz, ju. arakaki, ce. munarriz pediatric clinic, pediatric nephrology, buenos aires, peru objective: to describe the results of a program of chronic ambulatory peritoneal dialysis (capd) in children in peru by means of conventional indicators. methods: 61 children (52, 45% male) were included in a longitudinal descriptive study. the average age was 10, 4±4,02 years (rank of 1, [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] . 42% were from lima (the capital city) and 58% came from other cities of the country. primary glomerulonephritis (46, 1%) was the main cause of the renal insufficiency. we evaluated the program from 2001 to 2006. results: the average weekly kt/v was 2,8±1,13. the average dose of erythropoietin (epo) was 98 ui/kg/week. 60% of the patients had average annual albumin of more than 3,5 gr./dl. the average annual protein catabolism index (icp) was 1,0±0,37 gr/kg/d. the weight/age, height/age, weight/height z scores at the beginning and at the end were 2.1/1.3, -2.095/1.3, -2.9/2, 4 -3.4/2.2, 1.9/7.0-0.8/2.1, respectively. the average hematocrit was 26.5±7.6%. the rate of peritonitis adjusted for the period was 0, 62 episodes/patients-year (1 episode every 19 months) and the mortality for the same period were 14%. conclusions: the indicators evaluated in our patients are according to the results of the international literature. is repeated urine culture essential after antibiotic therapy in uti in thai children? background: in 1999, the american academy of pediatrics recommended for uti treatment, that urine culture be repeated only in children <2 years with fever >48 hours, since the chance of a positive urine culture in other children is very low. objective: to evaluate the cost-effectiveness of repeated urine culture after antibiotic therapy in childhood uti. patients and methods: a retrospective review of the records of children diagnosed with uti in songklanagarind hospital from jan 1-dec 31, 2004. results: there were 479 patients total, of which 30 were excluded due to no repeated urine culture. 449 patients with 533 uti episodes were analyzed (245 boys and 204 girls). 241 (53.7%), 71 (15.8%) and 137 (30.5%) patients aged <1, 1-2 and >2 years respectively. 49 (9.2%) had a repeated urine culture with significant growth. multivariate analysis showed that age <1 year, etiologic agents psuedomonas aeroginosa or enterococci spp., fever >72 hours and kub anomalies were the most significant risk factors for positive repeated culture, while vur and recurrent uti episodes were not significant risk factors. if we consider that a child who has at least one of the above risk factors should have a repeat urine culture, then 351 cases (65.9%) will require repeating urine culture and 182x3.7=$us 672.4 will be saved and 5 (10.2%) positive repeated urine culture will be missed. conclusion: our study in a group of thai children indicates that repeated urine culture after antibiotic therapy is still recommended. our aim was to find out if there are any signs of renal scarring and reduced renal function without recurrent uti in patients with obstructive pyelonephritis. there were investigated 18 children (4-12 y) with 1-4 years passed after diagnosis of obstructive pyelonephritis. these patients were investigated during 2 years long period without uti. all the children had a treatment with nitrofurantoin during season viral infections. we investigated excretion with urine of the collagen product (hydroxyproline) and activity of lisosomal enzymes (b n-acetilglutamase, elastase, pseudocholiesterase). as a control group, 20 healthy children of the same age were investigated. our result demonstrates the decrease of the level in urine of collagen product and lisosomal enzymes and normalization of tubular and glomerular functions during 2 years remission of pyelonephritis. prevention of recurrent uti and maintenance of the remission of pyelonephritis leads to the decrease of sclerosing processes on kidney. regular dialysis induces insecurity and special psychological problems associated with staff-, machine-and artificial material-dependence. the more severe the child's physical problems are the more probable is developing of emotional disorders, a sense of loneliness and an exaggerated dependence on the parents and staff. a psychological and social study of 19 children on regular dialysis was performed. there were 8 girls and 11 boys, aged 5-18 (mean: 11) ys. two children (10%) are exclusively treated with haemodialysis, 11 (58%) are on peritoneal dialysis and in 6 (32%) both methods interchanged. somatic concomitant disorders are present in 5 (26%) of children. among psychological disorders, an inclination to unsociability, autoaggression or aggression towards the immediate environment has developed in 4 children (21%), 6 (32%) do not like talking about disease while 9 (47%) are communicative and sociable. psychosocial characteristics showed: emotional difficulties (anxiety, mild depression) in 32%, feeling of being physically different from peers (short stature, less physical ability) in 42%, lowered self-esteem and social isolation as a result of school absenteeism in 26%. overprotection of parents was presented in 58%. different psychological changes were present in some children. of the 19 children 17 are of school age: 3 (18%) attend special schools and the remaining 14 follow regular education programs. with the help from their teachers, children on dialysis can master regular school programs, in spite of the time spent on dialysis. a good and continuing co-operation of dialysis staff and sick children and their parents as well as a more intensive co-operation with psychologists and teachers are necessary to reduce psychological disorders and promote a better adaptation to the life of their healthy coevals. we report a 15-year-old girl with syndrome frasier who developed b cell lymphoma within nine month after live related kidney transplantation. in induction therapy we applied atg up to 5 days, mycophenolate mofetil and cyclosporine. routine abdominal ultrasound revealed multifocal hypoechogenic changes in liver and spleen. computed tomography showed diffuse focuses of changed liver tissue in length up to 4.5 cm, precontrast density of 30-40 hu and postcontrast of 50-65 hu. in spleen there were three similar changes (up to 2.3 cm). after surgical biopsy of liver, patohistological examination confirmed diffuse large cell b lymphoma (cd 20 positive, moderate risk). pcr ebv was positive. we immediately started with ganciclovir intra venously and decreased cyclosporin and mmf (within two weeks) up to completely exclusion from therapy. in the same time we increased prednisolon on 15 mg daily. after 7 weeks from beginning ganciclovir she treated with rituximab, one dose of 500 mg every week (five weeks). repeated abdominal ultrasound and two controls computed tomography showed markedly regression of tumorous lesions. after 6.5 months of last rituximab doses scan showed normal spleen and liver findings. all lesions were resolved. in two occasions she developed severe leucopenia without any infection complication. she still has got moderate lymphopenia due to continual ganciclovir therapy. during this period (11 months) of illness course she treated with ganciclovir intravenously due to repeated ebv reactivation (positive pcr). despite enormous reduction in immunosupressive therapy renal function remain stabile without episodes of acute rejection. 5-20.5 years) . the most of them, 92% (23 patients) received graft from live related donor. 84% of patients had preoperative dialysis and 14% were preemptive. the mean waiting period for transplantation was 30 months (range 0 to 120 months). congenital anomalies of kidney and urinary tract were the most common underlying diseases (13 patients), then nephrotyc syndrome (4 patients), hereditary nephritis (3 patients), polycystic kidney disease (2 patients) and others. daclizumab was the most commonly used as immunosuppressive induction agent and the maintenance immunosuppressive therapy consisted of azathioprine or mycophenolate mofetil (mmf), cyclosporine or tacrolimus and prednisone. two patients had immediate postoperative surgical complication and graft loss due to thrombosis of a. renalis and donor tubular necrosis respectively. three patients had delayed graft function; two of them underwent cadaveric transplantation. one patient had recurrence of primary kidney disease only few days after transplantation and graft loss after one year. other patient lost the graft after 2 years due to noncompliance and chronic cellular rejection. after one year of follow-up graft survival rate is 86% and patient survival rate 100%. at the end of follow-up (mean range 29.21 months), 18 patients had normal, 3 patients slightly decreased renal graft function. catch-up growth was seen during the first year after transplantation from mean height sds of -1.65 to 1.25. the mean goal of our further intention is improvement of cadaver renal transplantation. j. lee, y. shim, s. lee objectives; although the variable risk factors of urinary tract infection (uti) in children such as virulence factors of the pathogenic bacteria and vesicoureteral reflux are already well known, the role of normal flora clononizing the intestinal tract and genitourinary tract is not fully understood. the change in colony forming units (cfu) of lactobacillus in chidren with uti is primarily investigated to explore the role of lactobacillus, one of the human normal flora, in development of uti. methods; lactobacillus was cultured from stool, urine, and periurethral or vaginal discharge of febrile infants with uti. those with confirmed uti by the suprapubic urine culture were classified to uti group (n=-60), and those with negative urine culture and confirmed viral illness were classified to control group (n=31). lactobacillus was anaerobically cultured in dico rogosa sl agar (becton, dickinson and company, usa) for 48 hours at 37°c. results: the cfu of lactobacillus in stool was correlated with those in periurethra, vagina and urine (p<0.05). the cfu of lactobacillus in stool was significantly lower in uti group than in control group (19,286±30,920 vs 16,969,129±89,717,956, p<0.05) . the cfu of lactobacillus in periurethra or vagina was significantly lower in uti group than in control group (2,788±5,365 vs 43,038±179,089, p<0.05). the cfu of lactobacillus in urine was significantly lower in uti group than in control group (173±469 vs 2,087±5,681, p<0.05). the cfu was distributed mostly at low level in uti group, which was significantly different from that in control group (p<0.05) conclusions; the cfu of lactobacillus in stool, periurethra, vagina and urine is low in infants with uti. it is suggested that lactobacillus has a role in the development of uti. pediatric small bowel transplantations are associated with pronounced electrolyte inbalances in the posttransplant period. we investigated the sources of possible electrolyte losses. our hypothesis was that electrolyte inbalances after intestinal transplantation might be augmented by fk 506 (tacrolimus) mediated renal toxicity rather than short bowel syndrome alone. we retrospectively reviewed eleven living-related small bowel transplantations between october 2002 and december 2006. the data collected included frequent serum and urine electrolyte profiles, renal function parameters, enterostoma electrolytes, and fk 506 levels in the postoperative period up until either discharge or graft loss. we analyzed pearson's correlations between fk 506 levels, serum electrolytes, renal function parameters, and also fractional excretions (fe). in order to investigate possible delayed nephrotoxic effects of fk 506, we correlated all values of the same day as well as with fk 506 levels of 24, 48, and 72 hours earlier. furthermore, we analyzed our data stratified by fk 506 dosing ranges. our results show decreased gfr and prominent increase of renal sodium, phosphorus, and magnesium losses along with rising fk 506 levels, suggesting this pathway as a major contributor to their imbalances. furthermore, fk 506 levels were associated with serum calcium and phosphorus decline, though urinary calcium excretion was not significantly changed. signs of renal toxicity are apparent within the first 24 hours of fk 506 challenge. our data suggest that fk 506 mediated nephrotoxiticy is a significant contributor to electrolyte imbalances observed after small bowel transplantation. objectives of study: urinary tract infections (uti) are common in children and c-reactive protein (crp) in serum is often used to evaluate the severity of the renal inflammation. recently it was demonstrated that crp can be produced locally in the kidney. we therefore measured the crp concentration in both serum (s-crp) and urine (u-crp) from children with uti to evaluate the extent of local production and the usefulness of measuring u-crp for diagnosis of inflammatory kidney disease. methods: 56 children (31 boys) with uti were studied (median age 0.8 years, range 12 days-5 years). 43 children had fever 38.5 °c or more. the uti was caused by e.coli in 50 patients. all children were examined within a few days of diagnosis by dmsa scan for evaluation of renal function. as controls were used 14 children with respiratory infection (pneumonia in most) and elevated s-crp in whom uti was ruled out by negative urine culture. u-crp was measured in a commercial hscrp elisa. normal value was <6 mg/l results: in the uti patients, the median s-crp was 126 mg/l (range 0-440) and u-crp 144 mg/l (range 0-937). there was a significant correlation between the s-crp and u-crp concentrations (<0.001). dmsa scans were abnormal in 37 (66%) uti patients. the proportion of abnormal scans increased significantly with the crp concentration in both serum (<0.01) and urine (<0.05). all control patients had increased s-crp concentrations (median 157 mg/l, range 45-243) but the median u-crp was 2.5 mg/l (range 0-73). the u-crp in the patients with uti was significantly higher than in the controls with other infections (<0.05). conclusions: our data strengthens the concept that crp can be produced locally in the kidney during uti. the usefulness of measuring u-crp to evaluate inflammatory kidney disease needs to be tested further. s. paunova, a. kucherenko, i. smirnov, g. serova, i. donin, l. revenkova, n. goltsova in order to reveal the role of cytokines in renal tissue damage in infants with urinary tract infection (uti) 42 patients aged from 0 to 6 months were examined. in all of them inflammatory markers (esr, crp, leukocyte count), urine concentration of tumor necrosis factor-α (utnf-α) and transforming growth factor-β (utgf-β) standardized to urinary creatinine concentrations were evaluated. two groups of patients were determined: 1) with uti and normal urodynamics (n=33), 2) with uti and urodynamic disorders (vur, hydronephrosis) (n=9). 12 healthy infants were used as controls. as a result, all the patients demonstrated significantly elevated utnf-α, utgf-β creatinine ratio in comparison with controls (p<0,05) with no difference between groups. but 16 children with normal urodynamics (from the 1 st group) presented with severe uti (1 st -a) showed urine tnf-α tgf-β creatinine ratio in 1,5 times higher than other patients of 1 st gr and close to 2 nd gr. data (1 st gr.-utnf-α/ucr=9,32±1,82, utgf-β/ucr=1231,65±133,36, 1 st gr.-utnf-α/ucr=6,89±0,98, utgf-β/ucr=782,7±87,77; 2 nd gr -utnf-α/ucr=12,58±4,25, utgf-β/ucr=1130,58±280,45, p1,2-1<0,05) . to conclude, tnf-α and tgf-β are responsive for renal tissue impairement in infants with uti. elevated tnf-α tgf-β creatinine ratio in a part of infants with normal urodynamics suggests that renal damage begins early in infection mostly due to inflammation. one may suspect a predisposition of that subgroup of patients to fibrogenic process and subsequent scar formation. prompt diagnosis and localization of pyelonephritis are of great importance in treatment and prognosis of the patients. the urinary excretion of enzymes, in particular n-acetyl-beta-dglucosaminidase (nag), is considered a relatively simple and non-invasive method in the detection of renal tubular function under various conditions such as pyelonephritis. this study was performed to determine the diagnostic value of urinary nag in acute pyelonephritis and to compare it with other indices traditionally used for this purpose in children. this is a quasi experimental study conducted from april 2005 to may 2006 on children with pyelonephritis. diagnosis of pyelonephritis has been based on standard criteria. seventy-two patients between 1 month and 15 years were recruited. fresh random urine samples were obtained on the admission time and at 48 th hour of treatment and were tested for nag and creatinine. there was a significant difference in pre and post-treatment urinary nag/creat ratio (p<0.000) and the sensitivity and specificity of urinary nag in diagnosis of pyelonephritis were 72% and 78% respectively. there was a significant correlation between urinary nag level and kidney ultrasonography results. patients whose ultrasonography showed hydronephrosis, had the highest level of urinary nag and patients who showed urinary stone in their ultrasonography had the lowest level of urinary nag. in addition, there was a reverse correlation between urine culture results and urinary nag level; patients who had negative urine culture had higher level of urinary nag in comparison with patients with positive urine culture. we conclude that urinary nag is elevated in children with pyelonephritis especially in the presence of urinary tract abnormality and the absence of renal stone. type-1 hyperoxaluria (ph-1) is an autosomal recessive disorder caused by the impaired activity of the hepatic peroxisomal alanine-glyoxilate aminotransferase. the disease leads to end stage renal disease (esrd) and combined liver-kidney transplantation (clkt) is required. we report 3 cases diagnosed with ph-1 who received clkt. case-1: she had attacks of dark urine without any pain and renal stones were determined on sonography when she was 2.5 years old. she was diagnosed with ph-1 and received peritoneal dialysis (pd) at the end of the first year and cadaveric clkt was performed when she was 9 yearsold. at the age of 16, she had chronic allograft nephropathy and began to have hemodialysis (hd). recently, 1.5 year after hd, cadaveric renal transplantation (tx) was performed. she is well after the second tx. case-2: he was admitted with polyuria, polydypsia, stomachache and renal stones were determined on sonographic examination. he had esrd and pd was started when he was 7 years old. at the age of 10, cklt was performed from his mother. his liver and renal functional tests are well 8 months after cklt. case-3: he was evaluated because of having an older brother diagnosed with ph-1 when he was 4.5 years old. he had no complain, but sonography showed multiple calculi. within 5 years he experienced flank ache, hematuria attacks and anuric phases due to obstruction and esrd appeared and he received hd and clkt was performed from his full-match sister at the age of 9.5. he is doing well 5 years after tx. here, we present the favourable clinical outcomes of our patients with cklt to indicate the validity of this treatment of choice in ph-1. tenascin (tn) is a glycoprotein component of extracellular matrix (ecm) which is not present in the normal kidney tissue. tissue plasminogen activator inhibitor-1 (pai-1) regulates fibrinolysis and the plasmin mediated matrix metalloproteinase activation and it is also not expressed in the normal kidney. recent studies focus on the pathogenesis of advanced renal diseases. in this study we evaluated tn and pai-1 staining in the renal tissues of pyelonephritic rats using immunohistochemistry (ihc) as to understand if these markers may be served as histological parameters of pyelonephritis like fibrosis, tubularatrophy or vascular changes. seven rats were injected 0.1 ml solution containing e. coli atcc 25922 10 10 cfu/ml into left renal medullae. seven rats were designed as sham group and were given 0.9% nacl. rats were sacrificed 7 days after injections. renal tissues were studied histopathologically by hematoxylin and eosinand scored for the parameters of pyelonephritis. tn and pai-1 expressions were studied semiquantatively by ihc by tenascin novocastra (ncc-tenas-c) and pai-1 (h-300) santa cruz biotechnology. both tn and pai-1 expressions increased in the pyelonephritic groups. we observed acorrelation between tenascin and fibrosis, vascular changes and tubular atrophy and pai-1 expression showed a correlation with only fibrosis. we conclude that increase in renal tn and pai-1 expression shown in experimental pyelonephritis are the responsible factors for the fibrotic changes of persistent renal damage. introduction: urinary beta 2 microglobulin (β2mg) urinary excretion is a good index of proximal tubular cell dysfunction. objective: to determine β2mg excretion significance in determining the outcome in respect to scar and renal insufficiency. patients and methods: urinary β2mg and creatinine (cr) was measured in 83 urine samples of whom 53 proceed to do dmsa renal scan at the time of admission and 6 months later to detect scar. β2mg was measured using radioimmunoassay method using β2mg 96-test kit (radim company). twenty children had various grades of renal scars. results were compared with ratios of 19 children with low uptake and 14 normal scanning and 30 normal children. student t test, anova, and unpaired t-test was used for analysis and differences considered significant if p<0.05. results: the mean urinary β2mg/cr was significantly higher in the scarring group (5.23±10.6) than in the normal group (0.19±0.2) and in low uptake group (0.49±0.86) (p<0.05). patients with grade iii had higher values (14.69±15.82) than grades i (0.36±0.35) and ii (3.37±5.20) (p<0.05). patients without renal scar had β2mg/cr ratio below 0.46 microgram/mg. the mean β2mg/cr was higher in patients with vur grades 4 and 5 (8.93±12.01) than patients with vur grades 1 to 3 (0.81±3.04) (p=0.02). maximum β2mg/cr was detected in patients with grade 4 vur (33.3) and the minimum was zero in non-refluxing patients and normal children. two patients with high grade vur and the highest levels of β2mg/cr ratio (33.3 and 26) progressed to renal failure in 2 years time, the first patient was treated by hemodialysis and the second underwent renal transplantation. conclusion: measurement of urinary β2mg is useful in the early detection of tubular damage in patients with renal scars. introduction: chronic allograft nephropathy refer to the progressive decline of renal function seen in some renal transplant recipients in association with alloantigen-dependent and alloantigenindependen factors. hyperlipidemia is a risk factor for chronic allograft nephropathy in adult pts, where no data exist in pediatric transplant population. methods: in this cross sectional study, 62 patients (32 can/30 non-can) that aged 5-18 yr and 9-93 mo (mean: 48 mo) after transplantation, were evaluated for lipid profile and renal function tests. results: hyperlipidemia has high prevalence in our patients both pre and posttransplantation and hypercholesterolemia and increased ldl had significant correlation with chronic allograft nephropathy (p=0.009) and p=0.025 respectively. conclusion: in pediatric patient as in adults hyperlipidemia and particularly hypercholesterolemia has significant correlation with chronic allograft nephropathy and as adults may need specific therapy. results: pre-transplantation renal replacement therapy time ranged from 0 to 132 months. eleven children underwent pre-emptiverenal transplantation. 43/72 transplants were from living related donors. donor age ranged from 0 days to 74 years. 9 grafts were from donors <1 year of age and 5 of these grafts were transplanted en-block. hla mismatches ranged from 0 to 5 antigens. primary disease was: focal segmental glomerulosclerosis in 9, rapidly progressive glomeluronephritis in 6, reflux nephropathy in 23, nephronophthisis in 9, iga nephropathy in 1, congenital nephrotic syndrome in 2, dysplasia-hypoplasia in 11, idiopathic membranous glomerulonephritis in 1, henoch-schönlein purpura in 1, hemolytic-uremic syndrome in 1, nephroblastoma in 1, polycystic kidney disease in 1 and of unknown origin in 4 children. patient survival at five years was 97%. allograft survival with living related transplants at one, two and five years was 95%, 95% and 82% respectively and with cadaveric transplants at the same periods was 86%, 86% and 86% respectively (p<0.05). regarding en-block grafts, they functioned immediately and satisfactory and presented excellent graft function 10 years later. most kidneys were lost due to acute or chronic rejection (n=6). other causes were renal artery thrombosis (n=3), infections (n=2), withdrawal of immunosupressive regime (n=1). conclusions: results of this single center series of pediatric renal transplants are encouraging from the standpoint of patient and allograft survival. conclusion: in infants with hn, the incidence of uti was higher especially in those with ou, hn of higher sfu grade or hun. the antibiotic prophylaxis may be recommended during 1 year after birth in infant with hn because the incidence of uti was high in these period. results: the underlying diseases were: sepsis with mods (26.8%), septic shock (11.3%), severe intoxication (15.5%), trauma with sirs (11.3%), drowning (2.8%), abdominal compartment syndrom (2.8%) and inborn metabolic disorders (2.8%). 43 children (61%) had acute renal failure, 28 (39%) patients met non-renal crrt criteria. cvvh was performed in 39 (55%) children, cvvhdf in 32 (45%) children. crrt duration was 6 to 216 hours (median 177.6 hours). dynamics of blood urea, creatinine, c-reactive proteine (crp) and white blood cells (wbc) were evaluated. significant decline (p<0.001) of creatinine along the treatment with cvvh as well as during cvvhdf was observed. blood urea levels showed significant decrease only in children treated with cvvhdf (p<0.05). significant decrease of wbc and crp was observed only using cvvh. 37 children from the study group survived (overall mortality 47.9%). in non-survivors was time from crrt initiation to its termination compared to time interval from crrt initiation to the death of children with 3-4 organs failure significant (p<0.05) where as in non-survivors with 1-2 failured organs it was not. conclusion: cvvh is efficient at removing urea and creatinine as well as inflammatory mediators (crp, wbc). cvvhdf is more potent to blood urea elimination. authors suggest preferring cvvh to cvvhdf in critically ill children to affect basic inflammatory parameters. to analyse hd and pd prescription (pr) adopted in chronic dialysis children, were viewed data of 147 pd regimens in 91 patients (0.5-18years) and 100 hd regimes in 74 patients (age 1.8-18 years) treated in 12 pediatric centres in 2005. pd patients were on automated pd: -nightly intermittent pd (nipd; 89 pr): 9.6±1.3 (8-13) hrs; 13.3±5.5 (6-27) cycles/night; dwell volume (dv) 889±232 (465-1400) ml/m 2 bsa; -tidal pd (42 pr): 9.7±1.9 (8-18) hrs; 16.9±5.6 (9-31) cycles/night; dv 1008±182 (600-1200) ml/m 2 ; tidal volume 63.8±9.5 (50-85)%; -continuous cycling pd (ccpd;16 pr): 10.3±1.6 (8-14) hrs; 15.6±5.6 (7-27) cycles/night; dv 1017±162 (600-1280) ml/m 2 ; daytime dv 62±18 (50-100)% of night dv. in 27% of pr dialysis fluid (df) glucose concentration was >1.36%, and in 12% buffer was bicarbonate. df of daytime dwell was 1.36% glucose (13 pr) or icodextrin (12 pr). patients with residual diuresis were 63.5% of those on nipd, 56% on tidal pd, and 6.2% on ccpd. hd was performed as bicarbonate hd (79%), hemodial filtration (15%) and acetate-free biofiltration(6%). patients received 3 sessions/week in 66% of cases, 4/week in 23%, and 2/week in 9% of cases; 2 oxalosis patients were on daily hd. session duration was 3 hrs in 44 pr, 4 hrs in 36, and 3.5 hrs in17. dialyser membrane was: polysulfone (38%); hemophane (19%); polyamide s (16%); cellulose acetate (9%); polyacrylonitrile (5%); cellulosediacetate (4%); cellulose triacetate (4%); polymethylmetacrylate (4%); polyether/carbonate (1%). ratio between dialyser surface area and patient bsa was 1.05±0.19 (0.70-1.43) and was 1-1.20 in 31%, 0.8-1 in 23%, >1.20 in 12%, and <0.8 in 7% of cases. isoniazid (inh) is widely used in most prophylactic and therapeutic anti-tuberculosis regimens because of its effectiveness and low cost. acute intoxication by isoniazid is known to cause symptoms of seizures, metabolic acidosis, coma, and even death. we present a case of acute isoniazid poisoning in a seven years old patient who ingested 7 tablets (2100 mg) of isoniazid. she was admitted unconscious, with ventilatory insufficiency and convulsions. renal and liver function tests were in normal ranges. she was intubated and mechanically ventilated. despite parenteral midazolamand pyridoxine (vitamine b6) treatments convulsions went on. then hemodialysis was performed and after hemodialysis convulsions and ventilatory insufficiency were disappeared and the patient was conscious and she was extubated. hemodialysis may be an effective treatment alternative for the patients who doesn't respond pyridoxine treatment. the aim of this study is to analyse children under two years of age, with their first febrile urinary tract infection (uti), identifying bacteriological etiology, antimicrobial resistance, urologicalabnormalities and renal damage. this is a prospective study including 92 children (63% girls) with their first febrile uti. mean age was 6 months (3-10), 27 (29%) patients were younger than 3 months (62% of them were boys). urine was obtained by suprapubic aspiration (65.2%) or transurethral catheterization (34.8%). 37% had positive nitrite on urinalysis and 95.6% had leukocyturia. they were submitted to ultrasonography (usg), dmsa scan (within 4 months) and voiding cystourethrography (vcug). the most frequent microorganism found in urine culture was escherichia coli, (94.6%). in this study high bacterial resistance to antimicrobials was observed in relation to the following antibiotics: ampicillin (57.6%), first generation cephalosporyn (32.6%), sulfamethoxazole/ trimethopin (43.5%). resistance to second generation cephalosporyn, aminoglycoside, nitrofurantoin and nalidixic acid was lower than 3.5%. renal ultrasound was abnormal in 43.5% of the infants. vesico-ureteral reflux (vur) was observed in 34.7%, although only 7.6% had vur grade iii or more. the dmsa scan showed that 23 (25%) patients had renal parenchymal damage. fourteen of these (60.9%) had normal esr. there were 8 (8.7%) reinfections within a 6 months period, even under prophylactic treatment, and the presence of vur grade iii or more was the only one with a significant relationship. conclusion: there were high levels of bacterial resistance to frequent used antimicrobials. this finding points toward a need for reviewing criteria of choosing initial blind therapy. investigation with dmsa scan is important in the detection of renal parenchymal scars, irrespective of the reflux grade. purpose: urinary tract infection (uti) has a risk of renal damage and is associated with vur. vur is investigated only by vcu. however, vcu is an invasive, painful study and many patients hesitate to be taken the study. we studied the correlation of vur in vcu and defect of dmsa scan and investigated the possibility of substitution of vcu by dmsa scan. material and methods: from 1999 to 2006, the medical records were searched for children admitted to cheongju st.mary's hospital with the first uti who had been evaluated with both dmsa scan and vcu within 1 months of the infection. the value of several clinical signs, laboratory findings, the resultsof dmsa scan and vcu were investigated. bacteriuria was defined as 100,000 or greater colony-forming units in urine from a bag, midstream or catheter sample. results: there were 54 patients underwent both studied at the first uti. mean age of the patients was 13 months old. the male patients were 38 (70%). the vur was found in 19 of the 54 patients (35%), grade i-ii in 5 and grade iii-v in 14 patients. there was no significant correlation with the presence of vur in sex, fever duration, blood white cell count and the level of serum creactive protein (crp). but the patients with vur grade iii-v were significantly older than the patients with grade i-ii reflux or without vur. there were abnormal dmsa scan findings in 22 of 54 (41%). of these patients, 11 were without vur, 1 with vur grade i-ii and 10 with vur grade iii-v. the abnormal dmsa scan was correlated with the presence and severity of vur. but vur was found in 25% of patients with normal dmsa scan. conclusions: abnormal dmsa scan is correlated with the presence of vur, so the patients with abnormal dmsa scan require vcu. in order to prevent missing a quarter of patients with vur shown normal dmsa, vcu should be recommended in all children with first febrile uti. cuba is the largest of the carribean islands with its 11,5 millions inhabitants. cuba is considered as a developing country and is classified in the group of: "lower middle income countries and territories". despite low financial resources, cuba has succeeded to develop an efficacious health care system with comparable results to those of west europe and usa (who data) ccl: 1) hd is the most prominent form of pediatric dialysis (automated night pd is in progress); 2) the no of transplantations is relatively low because of no participation to an international transplantation network; 3) high no of pediatric nephrologists; 4) high quality of patients care. background: inborn errors of metabolism in neonates are often characterised by hyperammonaemic coma within the first days of life and require prompt diagnosis and specific treatment such as toxin removal and nutritional support. cvvhd seems to be the optimal modality for extracorporal ammonium detoxification, however, little experience with small numbers of children has been accumulated. patients and methods: from 1996 to 2007, 21 patients with hyperammonaemia (16 male, 5 female) were admitted for dialysis treatment: 18 neonates (mean age 3.8±2.4 days, range 1-10 days) with a mean birth weight of 3430±1023g and 3 infants (mean age 5.6±4.6 years, range 3 to 11 years). in 14 neonates and 2 infants we inserted venous double lumen shaldon catheters (predominately femoral or jugular vein) for cvvhd treatment while 4 neonates and 1 infant underwent capd treatment. results: plasma ammonia levels (range 508-7267 μg/dl before dialysis and 27-3317 μg/dl after dialysis) were reduced by 50% within 4.5±2.7 h by cvvhd and within 18.7±9.2 h by capd (p<0.05). total dialysis time was 35.9±25.7h for cvvhd patients. no major mechanical complications were observed with cvvhd and stable blood flows (10-40 ml/min) and dialysate flows (1000-3000 ml/m 2 /h) were achieved. due to severity of underlying disease, 2 out of 14 neonates (14%) undergoing cvvhd died on day 2-3 while 2 out of 4 neonatal capd patients (50%) died on day 3 and one infant patient died after 498 days of capd treatment. twelve out of 14 neonates (86%) survived with no or moderate mental retardation. conclusions: cvvhd is an effective modality to eliminate plasma ammonia within few hours. however, vascular access and blood flows are critical restrictions. mental retardation has to be evaluated in larger scale studies. r. vilalta, e. lara, a. madrid, s. chocron, j. nieto hospital materno-infantil vall de hebron, nefrologia pediatrica, barcelona, spain background: transplant nephropathy is the main cause of renal failure in kidney transplanted children. until this situation is proved by biopsy, sometimes the progressive raise of creatinine leads to raise the anticalcineurinic (cni) drugs with added nephrotoxicity. sirolimus (sir) plus an anticalcineurinicin less dose and mycophenolate (mmf) could offer in kidney-transplanted children an immunosuppressive regime with less toxicity and even an improvement of renal function. methods and patients: 12 paediatric kidney-transplanted patients developed biopsy-proved chronic allograft nephropathy (age 6-19 y, mean 8) a follow-up post-transplant of 6 y and 7 exhibit also tubular involvement and acute cni toxicity. sir was added in all patients as a rescue therapy at 0.08 mg/kg/d. results: after a follow-up period of 18 months, creatinine level diminished (p<0.04) in 8 patients (4 in group tac, 3 in group cya, with no significant differences). creatinine level did not show a significant change in the other 4 patients (2 group tac, 3 group cya, basal creatinine 2.8 mg/dl. serum cholesterol changed from 230±30 mg/100 ml to 223±2 (ns) and serum tryglicerides from 110±32 mg/100 ml to 121±24 (ns). proteinuria also did not show changes (24±8 to 22±4 mg/m 2 /h (ns). conclusions: a poly-drug approach with less dose of anticalcineurinic added to the antiproliferative effect of sirolimus and the inhibition of purine synthesis based on mycophenolate mofetil could suppose an improvement of the renal function in children graft nephropathy an even in the graft survival. steroids have been a cornerstone in renal transplant immunosuppression. several strategies have been used to minimize their side effects. new immunosuppressive drugs have allowed steroid withdrawal or total avoidance. aim: to evaluate a new protocol with steroid-free maintenance immunosuppression in pediatric renal transplant. patients and methods: a prospective, non-randomized study in 46 consecutive first renal allograft recipients, followed-up to 24 months. patients received prednisone the first 6 days, two-dose basiliximab induction and maintenance therapy with tacrolimus (tac) and mycophenolate mofetil (mmf). no steroids were given after 6 d posttransplant. controls were 20 historical-matched steroid-based children receiving basiliximab, tac and mmf. all patients gave informed consent. anthropometric, biochemical variables, acute rejection and cmv infection were compared using student-t test and regression analysis. results: a better growth pattern was seen in steroid-free maintenance group reaching a normal growth at 24 months. gfr and serum glucose were similar in both groups. total cholesterol levels were significantly lower in the study group. the incidence of acute rejection was 4.3% in steroidfree maintenance vs 8.6% in steroid-based group, no differences in cmv infection and blood pressure were observed. hematocrit levels were lower during the first months after transplant in the steroid-free group, increased after 6 months post-transplant. patient and graft survival was 98% at two-yr post transplant in the two groups. conclusions: this steroid-free maintenance immunosuppressive protocol was efficacious, safe, with a lower incidence of acute rejection, not increased risk of infection, preserving optimal growth, renal function and reducing cardiovascular risk factors. objectives of study: to evaluate the lipid profile and its possible implications in children with end stage renal disease (esrd) or renal transplantation. methods: 19 children (11 boys, 8 girls) aged from 3.5 to 18 years, 9 on peritoneal dialysis (group i) and 10 with renal transplantation (group ii) were studied. in all children were examined: serum creatinine, total cholesterol, triglycerides, high density lipoproteins (hdl) and low density lipoproteins (ldl). a cardiac and liver ultrasonography were also performed. the body mass index (bmi) and blood pressure were evaluated in all children. 13/19 children received also a triplex carotid study. the median values of blood creatinine, cholesterol, triglycerides, hdl, ldl as well as the number of children with bmi over 95 th percentile in both groups were shown in table i . all children had normal findings in triplex carotid study. cardiac ultrasonography was abnormal in 1 child of group i and in 2 children of group ii. only 1 child presented lipoid invasion in liver ultrasound. 3/9 children of group i and 6/10 children of group ii presented hypertension, well controlled, with antihypertensive therapy. conclusions: frequent evaluation of lipid profile is recommended in all children with esrd or renal transplantation independently their bmi. in our study, children with renal transplantation presented better lipid profile compared with children on peritoneal dialysis. group i with <18 months (n=14; 7,8±4,9 months) and group ii >18 months (n=7; 36,8±19,9 months). results: serum albumin, serum lipids values and the distribution of the categories of the peritoneal membrane did not present significant differences between the groups. hypertension, renal residual function (p=0,005), the renal urea kt/v (p=0,007) and the weekly renal ccr (p=0,005) were significantly higher in group i, while the weekly peritoneal ccr (p=0,025) and the total weekly ccr (p=0,037) were significantly higher in group ii. catch-up was not observed in any group. control of the cholesterolemia, trigliceridemia and albuminemia were maintained with the dialysis time in both groups. the goals of adequacy of the doqi for kt/v and ccr were gotten respectively in 85,71% and 64,29% of the group i and in 71,43% and 42,86% of the group ii. the longer time in dialysis was associated with the lowest values of renal residual function, renal kt/v and renal ccr. the capacity of transport of the membrane was similar in both groups. objectives of study: to explore the characterize of peritoneal transport in chinese children with chronic peritoneal dialysis. methords: pet was carried out 10 times for six children (mean ages 9.3±4.4, aged from 2 to 14 years) who were maintained by capd, and the infusion volume of dialysate was 1195±597 ml (1100ml/m 2 ). the peritoneal solution transport rate was evaluated by the standards of twardowski's and ppdsc's criteria. results: in our study, the initial pet was performed at 38.7±15.6 days following initiation of pd, the 4-hours of peritoneal creatinine clearance (4h-d/p) and glucose absorption (4h-d/d0) was 0.85±0.24 and 0.34±0.19, respectively. according to the standards of twardowski's and ppdsc 's criteria, the peritoneal transport categories were divided into high transport (h) (6/10), high average transport (ha) (1/10), low average (la) (3/10) for peritoneal solution transport, and h (3/10), ha (4/10), la (1/10), low transport (2/10) for glucose absorption. no low transport type of solution was uesd in our patients. the coincidence rate of peritoneal creatinine and glucose transport types were 100% and 90% between the twardowski's and ppdsc's criteria, respectively. the different changes of peritoneal transport type were found in two patients with continuous pet. the value of 4h-d/p increased after peritonitis episodes. our results showed that the pet in 70% of capd children fall into high and high average transport categories elevated by ppdsc's and adult standards. the peritoneal solute clearance was adequacy in the children, but net water ultrafiltration was lower. standard pediatric pet and its criterie are consistent with the adult criteria. the capability of peritoneal solute transport increased after peritonitis episodes. verapamil (vp) is known to alter cyclosporine (csa) bioavailability. the impact on immunoregulators (il-2, tgf-β 1 , and tgf-β 2 ) in allograft recipients remains unresolved. a prospective open study to examine the impact of vp on peripheral blood cell mrna encoding il-2, tgf-β 1 , and tgf-β 2 and serum il-2, tgf-β 1 , tgf-β 2 protein levels was performed. parental written informed consent was obtained in all cases. children with stable renal allograft function (<6 months), and receiving immunosuppression (csa, pdn, either with aza or mmf) were included. in the first visit, a clinical examination, two-point (2 and 12h) csa pharmacokinetic profile, serum creatinine, serum for il-2, tgf-β 1 , and tgf-β 2 protein levels (by elisa) were obtained; peripheral mononuclear cells were collected for measurement of transcripts for 18s rrna (house keeping gene) and mrna for il-2, tgf-β 1 , and tgf-β 2 (by real time quantitative pcr assay). after the visit one, patients were either withdrawn of vp (if the subject was already receiving vp) or started on vp 2mg/kg/day (if the subject was not receiving vp). two weeks after, a repeat clinical evaluation and blood collection, as in the first visit, were performed. 21 pediatric recipients of renal allografts were included (17 were from ld, mean post-transplant time 4.8 years, mean csa dose 3.8 mg/kg/day). the c2h and calculated auc 0-12h were significantly higher in those receiving vp, but there was no difference in csa trough levels. protein and mrna levels of il-2 tgf-β 1 , and tgf-β 2 were not different. were previously seen by a nephrologist. logistic regression was performed on anemia (hgb<11.0 g/dl) and showed relative risk in blacks was 3.74 vs. whites. relative risk in those who did not receive epo was 2.77 vs. those who did. of 19 black patients, 16 were anemic and 9 previously seen by a nephrologist. of 55 white patients, 32 were anemic and 16 previously seen by a nephrologist. in summary, blacks and patients not receiving epo at the time of dialysis initation were more likely to be anemic. despite being seen previously by a nephrologist, nearly 60% of patients were anemic when starting dialysis. further analysis is needed to determine causality to improve anemia control in incident dialysis patients. 2 of the avf were in whites with 1 in a black patient. the avg was in a black patient, with a cvc distribution of 20 whites and 11 blacks. 21 patients with cvc had been previously followed by a nephrologist and of these 12 had been followed for >6 months. in summary, incident pediatric hemodialysis patients are primarily having cvc as initial access type. with 56.7% having been previously seen by a nephrologist and 57% of these for greater than 6 months, the reasons behind not having an avf or avg as primary access need to be explored and improved upon. this high incident cvc use is consistent with data reported in the united states, but not with other european and asian countries. an effort to have a permanent avf or avg in incident pediatric hemodialysis patients needs to be made by the patient's nephrologist. to find the preventive measures for recurrent uti in infants with first febrile uti and normal urinary tract (ut), the incidence of recurrent uti and its risk factors were investigated. method: from june, 2002 to june, 2005 under 12 months of age (-6 mon: 152, 6-12 mon: 38), who were diagnosed as the first febrile uti and proved to have normal ut, were enrolled to the retrospective study. for all infants with nonretractile prepuce, topical application of hydrocortisone for 2-4 weeks and physiotherapy was recommended. during the following 1 year, the incidence of recurrent uti and the well-known risk factors such as female, young age, phimosis, vaginal reflux, and initial 99mtc-dmsa(+) pyelonephritis were evaluated. result: the incidence of recurrent uti in infants with normal ut was 21.1% and recurrent uti episode was 0.23/patient-year. the recurrent incidence in male infants was 22.8%, which was not significantly different from 12.5% in female infants (p=0.193). the recurrent incidence in younger infants was significantly higher than in older infants [-6 mon: 25.0%, 6-12 mon: 5.3%, p=0.008]. this age-related difference was significant in male infants [-6 mon: 25.8%, 6-12 mon: 7.7%, p=0.045], but not in female infants (p=0.169). in infants with persistent nonretractile prepuces, recurrent uti developed in 34.3%, which was higher than 15.6% in infants with retractile prepuces (p=0.041). the presence of the vaginal reflux (p=0.087) or initial 99mtc-dmsa(+) pyelonephritis (p=0.041) showed no significant difference in the incidence of recurrent uti. conclusion: in uti infants with normal ut, younger infants under 6 months of age and nonretractile prepuces of male infants were the risk factors for recurrent uti. objective: vascular endothelial growth factor (vegf) appears to play a central role in the process leading to peritoneal angionesis and increased level of vegf may conrtibute to high peritoneal small-solute transport rate (ptsr) in continuous ambulatory peritoneal dialysis (capd) patients in adult. vegf-c is related to lymphogenesis, but its role in peritoneal solute transport rate is not known. in this study, we evaluated possible relationship between dialysate vegf and vegf-c levels and pstr in children. method: twelve children with no apparent inflammation process or disease, who had been on capd, were enrolled. standard peritoneal equilibration test (pet) was done to evaluate pstr. d/pcreat and d/d 0 gluc were calcualted at 4hr of pet. overnight dialysate levels of vegf and vegf-c were measured using commercial elisa kit. correlation between dialysatevegf (or vefg-c) and d/pcreat (d/d 0 glu) was analyzed. results: mean peritoneal dialysis duration was 9.25±7.18 months. mean overnight dialysate vegf and vegf-c level were 44.74±30.49 pg/ml and 119.6±78.26 pg/ml, respectively. a significant correlation was noted between the dialysate vegf-c and vegf level (r=0.809, p=0.001). dialysate vegf level had negative correlation with d/d 0 glu of 4hr pet (r=-0.691, p=0.009). vegf-c had no correlation with d/d 0 glu or d/p creat. conclusion: there was significant relationship between dialysate vegf and vegf-c levels in children and significant correlation was also noted between dialysate vegf and ptsr. it seems that vegf contribute to high ptsr also in children on capd. m. feldkötter, l. stapenhorst, b. beck, u. bangen, b. hoppe we currently use sirolimus as a second line medication in transplanted patients with a distinct nephrotoxicity of calcineurin-inhibitors. as our short term experiences were not as positive as expected, we performed a short term meta-analysis in our renal transplant recipients under sirolimus treatment: we give an account of seven kidney transplant patients who were either directly started or were switched to a medication with sirolimus during september 2004 to february 2006. the reasons for this action taken were calcineurin-inhibitor side effects like severe arteriolopathy with lossof gfr, atypical haemolytic-uraemic-syndrome, seizures after the first dosages of cya and a tacrolimus induced exanthema. in four of seven patients switched to sirolimus we observed severe side effects, exaggerating those of the calcineurin-inhibitor and hence, in three patients the latter treatment was installed again. findings were distinct proteinuria in two patients, hyperlipidemia in three patients, wound healing disorders and, most strikingly, treatment resistant severe pancytopenia in one patient and severe interstitial pulmonary fibrosis in another patient, both with amelioration after termination of the medication, but still the need of oxygen therapy in the latter patient. in addition we noticed a slightly faster reduction of the gfr calculated with the schwartz formula in five patients compared to the previous immunosuppressive regimen. based on these findings we strongly feel that a more critical discussion of each case is necessary before changing the immunosuppressive medication. also, the question arises on whether sirolimus can really be valued as an equivalent alternative to a calcineurin-inhibitor based immunosuppressive regimen in pediatric kidney transplantation. y. kovalski, r. cleper, i. krause, m. davidovits schneider children's medical center of israel, nephrology and dialysis unit, petah tiqwa, israel background: despite significant technical improvements, haemodialysis in infants with end-stage renal disease (esrd) is still associated with significant morbidity and mortality. methods: the files of patients weighing less than 15 kg with esrd who were treated with haemodialysis at our institute between 1995 and 2005 were reviewed for background and treatment characteristics, morbidity and outcome. results: the study group included 11 patients aged 7-75 months (mean 34.2 months) weighing 7.2-14.9 kg (mean 10.9 kg). mean duration of dialysis was 11.3 months. vascular access posed the major problem. ten patients were dialysed through a central venous cuffed catheter and one through an arteriovenous fistula. an average of three different vascular accesses was required per patient (range 1-9). mechanical difficulties were the most common cause of central line removal (56.5%), followed by infections (15.6%). major complications causing significant morbidity were intradialytic haemodynamic instability, hyperkalemia, coagulation within the dialysis set, anaemia, hypertension, inadequate fluid removal and recurrent hospitalisations. analysis of outcome revealed that 8 patients underwent successful transplantation, one returned for haemodialysis after 4.5 years due to graft failure, and 2 died. conclusion: haemodialysis is a suitable option for low-weight paediatric patients with esrd awaiting transplantation, when performed in highly qualified centers. the importance of antibiotic prophylaxis in management of vur vesicoureteral reflux (vur) cause urinary tract infection (uti) and renal scarring is a common condition in children. the detection and treatment of vur before renal scarring is vital. recently, optimal management of low grade vur is controversial. the aim was to explore the kidney outcome in a cohort of patients with vur. the patients were divided into five subgroups according to vur grades. all of them were treated with low dose prophylactic antibiotics until the age of 5 years. urine culture was repeated monthly. background: anemia is a common complication in patients on hemodialysis. treatment of anemia with recombinant human erythropoietin (rhuepo) may lead to iron deficiency. intravenous sodium ferric gluconate complex (sfgc) therapy improves iron stores. objectives of study: aim of our study was to assess effects of maintenance sodium ferric gluconate therapy in pediatric patients on hemodialysis on mean hemoglobin (hb), hematocrit (hct), transferrin saturation (tsat), serum ferritin and rhuepo dose, as well as safety of therapy with sfgc. methods: intravenous sfgc therapy was administered for 3 months in mean dose of 1.2 mg/kg/week to eight pediatric patients on hemodialysis. patients were from 2 to 16 years old (4 males and 4 females, aged 11.5±5 years). all patients were prescribed rhuepo before start of study. results: sfgc therapy was successful in maintenance of mean hb (increased from 10.5 to 11.3 g/dl), mean hct (improved from 31% to 33%), mean tsat (from 23 to 30%) and mean ferritin level (from 592 to 765 ng/ml). high ferritin levels in two patients were due to inflammatory disease rather than the sign of iron overload. the mean weekly rhuepo dose decreased from 4380 to 3500 iu. no significant adverse event due to intravenous sfgc therapy occurred. conclusions: intravenous maintenance sfgc use in pediatric patients on hemodialysis was safe and successful in maintenance of iron indices, thus allowing reduced use of rhuepo. the the viral hepatitis b still remains a serious problem, especially actual in patients with end-stage renal disease (esrd) on renal replacement therapy (rrt). the high frequency of hbv infection transmission in hemodialysis units and immunodeficiency modify hepatitis clinical course and outcomes and worsening vaccination results and renal graft survival. we have analyzed the results and influence on transmission of hb -infection of hepatitis b vaccination in 28 children aged from 6 to 17 years with esrd on chronic hemodialysis. majority of children were boys (53.5%) older than 11 years (85.7%). an assessment of hbs-ag has been conducted prior and during the vaccination (engerixb) by scheme 0-1-6 months. after first vaccination hbv infection was detected there after in 10.7% of children, after second vaccination in 7.1%. in all patients (11) which have received three tours of vaccination, an active immune response was developed. thus, vaccination against viral hepatitis b is effective and prevents hbv infection in children with end stage renal disease on chronic hemodialysis. renal transplantation (tx) represents the best treatment for the patient with crf. scientific advance has been able to optimize the immunosuppressive treatment however the adherence to treatment has been not maintained. aims: to identify the factors that influence in non-adherent behavior with the purpose of designing effective educational strategies. methods: the qualitative focus was carried out through patients and tutors interviews. the quantitative aspect applies for epidemic variables, time post-tx, percentages and frequency of the sentences coming from the analysis of the interviews. nurse, psychologist and a social worker were incorporated with the purpose of elaborating an instrument based on seven questions related to the transplantation, risk and/or loss of the graft; besides the events happened as consequence of this, allowing that interviewed manifested with freedom their opinions. the interview was recorded in a microcassette and later transcribed. analysis was determined by categories containing the answers of each question granting the agreement sentences according to the frequency which was repeated in each interview. informed consent was obtained. results: 150 tx (1989 -2006 ; 15 non-adherent, 80% of them were interviewed. mean age: 9.7 ys. loss the graft: 50%, time post-tx: 37.7 months, dd: 67% ld: 33%. the lack of supervision in the taking of medications, numbers/schedules medications, family conflicts and the poor communication with the parents/medical team seem to be the main factors for non-adherence. conclusion: it is necessary to modify the pattern of the patient's attention transplanted under the pattern of chronic suffering that allows the sick person's and their family active incorporation to the process in an integral way to the multidisciplinary group. infantile results: 9 patients (4 females, 5 males) <15 kg, 6/9-<10kg at pd start were treated. they consisted 20% of our center's pd patients (43 pts). age at pd start: 21.6±16 months (median 17), 8/9 pts <24 mo. pd therapy duration: 4-21 mo (median 6), 3 pts >12 mo. esrf cause: congenital nephrotic syndrome 4 pts, dysplastic kidneys 4, cortical necrosis 1. 6 pts were fed by gastrostomy, 4 pts received gh (growth hormone). 5/9 pts had hypertension (ht) treated with >2 drugs and 1-4 cv events. pd type: 5/9 cycler-assisted, 1/9 capd (continuous ambulatory pd), 3/9 both. pd adequacy targets (kt/v>2.5) were reached in 8/9. peritonitis: 0.22 episodes/patient-month, 3 pts had >3 episodes. 6/9 pts had >2 pd catheters and 5/9 >5 pd-related surgery. outcome: 6/9-kidney transplantation, 3/9 switched to hd for infections or uncontrolled ht. height ±sds median 0, weight ±sds median +1.1. conclusions: small infants with esrf can be successfully treated by pd despite high rate of infectious, cv and surgical complications. pd therapy main target is optimal growth towards kidney transplantation. hyperlipidemia is a well recognised complication of renal transplantation. it is a fairly common problem in the paediatric renal transplant population. its prevalence ranges from 16% to 72% though the mechanism is not clear. steroids, calcineurin inhibitors and rapamycin are the main culprits in inducing hyperlipidemia, which is a potential risk factor for cardiovascular heart disease and graft dysfunction. long term effects of these immunosuppressive drugs in children have not been adequately studied. of the calcineurin inhibitors cyclosporine (csa) was found to induce hyperlipidemia compared to tacrolimus (tac). post-ransplant hyperlipidemia is well described in adults; the same cannot be said in children. in adults, post-transplant hyperlipidemia increases risk of cardiovascular disease 3 to 4 fold. screening and management of hyperlipidemia has therefore become an important part of current long term management of transplant patients. there is a limited data on prevalence of hyperlipidemia in renal transplant in children and even more so locally here in south africa. most of the known studies have been conducted in the first world, there was therefore need to determine prevalence locally. this information would ultimately assist in the overall management of our renal transplant recipients. majority of the patients had normal lipid profile. 25% of the patients had high cholesterol levels, while 25% of the patients had high tg levels. 4/10 (40%) of the patients on csa had hypercholesterolemia compared to only 1/11 (9%) on tac (p=0.15). 2/10 (20%) of the patients on csa had high tg compared to 3/11 (28%) on tac (p=1.0). the study concluded that the prevalence of hypercholesterolemia and hypertriglyceridemia in renal transplant pts is high, comparable to other studies and that there is a tendency towards having more lipid abnormalities in transplant pts on csa. grade 3 vur in 24 (39%) and . the incidence of abnormal findings was significantly higher in children with uti and vur than in those with uti without vur (88.5% vs 67%; p<0.05). in children with no vur, grades 1-2 vur, grade 3vur and grades 4-5 vur, renal scarring rates were 67%, 70%, 90% and 88%, respectively. the patients with higher grades vur tended to have more than 3 scars on their dmsa scans (p<0.01). our findings suggest that renal scarring resulting from uti is mostly related to vur, but sometimes is caused by the infection itself. we can conclude that vcu is essential for diagnosis of vur, but 99mtc-dmsa scan shouldn't be avoid in the management of children with uti. [1] [2] [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] years. seventythree (97.3%) of them were on triple immunosuppressive therapy, one on double therapy, and one didn't use any medication. overall, 9 subjects (12%) had at least one episode of uti. twenty-four episodes of urinary tract infection occurred in 9 children: 7 episodes in two girls with neurogenic bladder (ngb), 9 episodes in two boys with posterior urethral valve (puv), four episodes in an obese girl with laurence-moon-biedl syndrome, 2 episode of uti in 2 girl with unknown primary renal disease and 2 episodes in 2 girl, one with polycystic kidney disease and one nephronophthisis. conclusion: uti following kidney transplantation was more common in children with known lower urinary tract abnormalities. key words: urinary tract infection, kidney transplantation. background: in japan, the severe shortage of cadaveric kidneys led clinicians to attempt performing abo-incompatible living kidney transplantation (tx). some reports demonstrate successful results of the combination of plasmapheresis (pp), strict immunosuppression and splenectomy. however, we should concern about a great risk of surgical invasion and postoperative serious infection in younger patients who underwent splenectomy. recently, a few reports suggested anti-cd20 monoclonal antibody (rituximab) can be an alternative to splenectomy. patient and method: a 9 years old boy with bilateral hypoplastic kidneys had been treated with peritoneal dialysis for 3 years. since his blood type o was incompatible with paternal blood type a, we arranged to perform tx using pp and rituximab without splenectomy. a single pp was performed on days -10, -7, and -3 to reduce anti-a antibody (ab) titer. rituximab was administered in a single dose of 375 mg/m 2 on day -6. basiliximab, tacrolimus, mycophenolate mofetil and methylprednisolone were used for immunosuppression. results: before tx, the anti-a ab titer was reduced from 1:32 to 1:8, and cd19 level was suppressed from 25% to 3%. tx was performed without splenectomy and he had excellent initial graft function. we observed anti-a ab titer rose up to 1:128 on day +5, but it decreased spontaneously to 1:16. there were no side effects and severe infections during the perioperative period, but the neutropenia treated by gcsf appeared 3 months after rituximab administration. the protocol biopsies were performed in 1 month and 6 months, which revealed no signs of rejection. conclusions: abo incompatible tx using pp and rituximab without splenectomy can be a therapeutic option in children to avoid a invasive surgery and infectious risks. further establishment of optimal protocol for children are necessary to obtain excellent outcomes safely. 1.70.2, 1.320.4, and 75.65.5, 66.415.1, in hivan, and od, p=0.06, p=0 .08, respectively. serum p levels were 6.71. 1, 4.60.9, and cap were 54.517.0, and 39.68.7, in hivan and od, p=0.044, p=0. the aim of this study is to identify the outcome of the physically or socially handicapped children with end stage renal disease (esrd) receiving chronic peritoneal dialysis (cpd). among 95 patients commenced on cpd, 11 handicapped children with esrd receiving cpd were identified in our unit during the period between november 1995 and february 2007. age at cpd initiation ranged from 5.5 to 15.5 years (median age: 11; 6 girls, 5 boys). underlying diseases were neuropathic bladder and vesicoureteral reflux (in 3 patients), chronic pyelonephritis (in 3 patients), vesicoureteral reflux (in 2 patients), amyloidosis (in 2 patients), and alport syndrome (in 1 patient). causes of handicapped status against cpd were inadequacies of indoor resources (in 3 patients), cerebral palsy (in 2 patients), down syndrome (in 1 patient), inadequate psychosocial status (in 1 patient), surgically corrected rectovesicale fistula and ectopic anus (in 1 patient), blindness (in 1 patient), ventriculoperitoneal shunt and paraplegia (in 1 patient), colostomy (in 1 patient). all catheters were implanted percutaneously by the same pediatric nephrologist. median duration of dialysis was 24 (range 3-124) months. during a total of 443 dialysis months, 27 episodes of peritonitis (1 episode/16.4 patient-month), 1 episode of exit-site infection, and 1 episode of tunnel infection occurred in 8 of 11 children. except for an inguinal hernia in 1 patient, we did not observe any mechanical complication related to catheter. cpd was terminated in 6 children (death in 3, renal transplantation in 2, switch to hemodialysis in 1). before initiation of renal replacement therapy, some negative baseline factors may not be really contraindications for cpd. the socioeconomic and geographic factors greatly influence the prevalence and outcome of renal disease in children. the subspecialty of pediatric nephrology in sudan was established few years ago and the facilities for the management of renal problems are limited. the aim of this study is to review the demographic profile, complications and outcome of capd after nineteen months of treatment. all children who underwent capd from june 2005 to january 2007 were studied. there were 22 children (12 males), the mean age was 11 years (range from 11 months to 16 years). the majority of children has undetermined cause of esrd (11 children). the most common complication was peritonitis (peritonitis rate was 1/8.3 patient/months. 8 patients had refractory peritonitis that necessitate catheter removal, exit-site infection was documented in 4 children and catheter block in 4 children. there were 12 drop out of the program 4 were due to deaths, 7 changed modality and one family withdraw treatment. in conclusion this analysis has stimulated improvement in nurses training and supervision as well as attempts to improve catheter survival and microbiology monitoring. the -5) , looking for symptoms of hypovolemia (cramps, abdominal pain or headache) during or at the end of hd treatment. bioimpedance measurements were performed at the end of each session according to the 50 khz tetrapolar technique; resistance and reactance values were plotted on the age and gender specific 50 th , 75 th and 95 th percentiles of the vector distribution in the healthy population (reference tolerance ellipses) as a resistance-reactance graph. hypovolemia (hv) was indicated by a vector shifted to the upper pole, out of the 95% tolerance ellipse; normovolemia (nv) by a vector inside the 95° ellipse. patients complained of one or more of the above-mentioned symptoms in 26% of hd sessions, while biva suggested hv in 47.9% of the sessions. symptoms were significantly more common (p<0.05) in sessions with hv (20/57 cases; positive predictive value 35.1%) than in those with nv (11/62 cases; negative predictive value 82.3%). biva suggested hv in 20/31 sessions with symptoms (sensitivity 64.5%) and nv in 51/88 sessions without symptoms (specificity 58%). no significant differences in the accuracy of biva were found between patients either younger vs older than 18 years, or with height sds <-2 vs >-2, or taking vs not taking antihypertensive drugs. in conclusion, biva can be useful in assessing dry weight in children and young adults on hd: since patients with a vector shifted to the upper pole, out of the reference 95% tolerance ellipse, are at high risk of hypovolemia during the next hd treatment, the increase of the dry weight is then indicated chronic antibody-mediated rejection can occur as a de novo complication in renal allograft recipients and is associated with c4d deposition in peritubular capillaries in the renal graft and positive circulating anti-hla antibodies, although the sensitivity and specificity of positive c4d staining for chronic humoral rejection requires further study. renal outcome appears to be worse in c4d positive patients. current treatment strategies to manage c4d-positive chronic humoral rejection are poorly defined. various protocols with enlarged doses of tacrolimus, mycophenolate mofetil, plasmapheresis, ivig and rituximab have been reported in adult patients. we investigated four pediatric patients (mean age 13.6 yrs; range 10 to 17 yrs) after renal transplantation that developed c4d positive chronic rejection. in 3 of 4 patients, maintenance immunosuppression with calcineurin inhibitors had previously been minimized because of severe toxicity. in 3 of 4 patients, an elevated anti hla class ii antibody titre could be detected; donorspecific antibodies were positive in 2 patients. all patients experienced a progressive deterioration of graft function. treatment with repeated intravenous immunoglobulin (ivig) (1 g/kg body weight per week over four consecutive weeks) followed by a single dose of rituximab (375 mg/m 2 ) was therefore initiated. three of four patients showed an improvement of graft function with a mean increase of gfr by 25%. one patient with advanced chronic transplant nephropathy lost his graft after 6 months. this pilot study demonstrates that the combination of high-dose ivig and rituximab can stabilize or improve transplant function in chronic antibody-mediated rejection without major side effects. the use of ivig and rituximab appears to reduce the active immunologic process, but larger trials are needed to support these observations. cardiovascular diseases are some of the most important causes of morbidity and mortality in children with end stage renal disease (esrd). chronic inflammation has been suggested to be a risk factor for cardiovascular diseases. the aim of this study was to investigate the relation between crp and cardiac changes in children on hemodialysis. this study was conducted on 60 patients (30 patients were hypertensive & 30 were normotensive), 39 males (65%) and 21 females (35%) on regular hemodialysis due to esrd. their ages ranged from 7 to 16 years (mean 14.93±3.0). sixty age-and sex-matched controls were also included. significantly higher velocity of circumferential fibre shortening (vcfs), tei index, interventricular septum thickness in diastole (ivsd), left ventricular mass index (lvmi) and isovolumetric relaxation time (ivrt) and significantly lower e/a ratio were found in all patients as well as in hypertensive & in normotensive groups as compared to the controls. significantly higher ivsd and lvmi were found in hypertensive patients than normotensive patients. significantly higher high sensitivity crp (hs-crp) & crp latex were found in all patients as well as in hypertensive & in normotensive groups when compared to the controls. crp was significantly higher in both study groups with cns symptoms and cardiac symptoms in comparison to those without. it was also significantly higher in patients with increased lvmi & than in those with abnormal e/a ratio. hdlc showed a significantly direct negative effect on crp. s. ca 2+ , se. p and ca x p had a significantly direct positive effect on it. we can conclude that the cardiac affection in children with esrd appears in the form of lv hypertrophy with early diastolic affection. crp could be correlated to these changes and to cns symptoms and cardiac symptoms in these patients. is. lim, hs. lee, dw. kim, wh. choi chung-ang university, pediatrics, seoul, south korea purpose: urinary tract infections are common clinical problems occurring in infants and pediatric patient groups, most frequently caused by uropathogenic e. coli. urinary pathogens almost always infect the host through ascension from the rectum, vagina to the urethra and bladder. recurrent urinary tract infection is a disorder involving repeated or prolonged bacterial infection of the bladder or lower urinary tract. in this study, we examined the substitusion effect of probiotics in the high risk group of recurrent urinary tract infection. objectives & methods: patients diagnosed as recurrent urinary tract infection were administered probiotics for six months, and urine cultures were checked during the period. probiotics in this study were selected among the products commercially saled in korea, namely lactobacillus acidophillus, bacillus subtilis, and bifidobacterium infantis. single blind study was done for selection of probiotics for patients. result: the separated bacteria from the urinary tracts of the patients were the same as administered probiotics in some patients. conclusion: in recurrent urinary tract infection, there seemed to be a substitution effect of probiotics for uropathogenic bacteria, and it is reasonable to administer probiotics for long period in the high risk group of recurrent urinary tract infection. renal insufficiency therapy in children: quality assessment and improvement: the rich q study objectives: outcome studies in children on chronic renal replacement therapy (crrt) have revealed a 30-time increased mortality and 40% co-morbidity in adult survivors. information on the quality of care of treatment centers and on the impact of advised quality indicators on outcomes in children are lacking. no data exist on the impact on these outcomes of the different treatment modalities, peritoneal dialysis, hemodialysis & transplantation either. until now, no structural corporation and consensus on general guidelines with respect to crrt exist between the 9 dutch (nl) and belgium (b) centers for pediatric crrt. aim of the study: 1. assessment of the current quality of treatment crrt in children (qt) in nl & b and of the effect of recurrent peer review of the achieved outcomes on the qt. 2. the assessment of the effect of different treatment modalities on outcomes. 3. the creation of a format for multicenter trials. methods: all prevalent patients on chronic dialysis aged <19 years at onset of the study & all incident patients during the study period with onset of crrt<19 years of age, from b & nl will be included. treatment characteristics and quality indicators of crrt with respect to physical and psychosocial outcomes will be collected of all patients. operational data collection and management will be performed by members of the dutch institute for quality care in dialysis patients (hans mak institute). each 6 months, all data will be revealed and actively discussed by representatives of all centers (peer review). the effect of registration and peer review on the qt will be analyzed after 2 & 4 years. comparison will be made between the effects of cumulative periods of different rrt models on outcomes. the study will be performed between august 2007 & 2011. on estimation, 200 patients will be analyzed. renal renal transplantation in patients with lower urinary tract dysfunction (lutd) of different origin is a challenging issue in field of pediatric transplantation. we report our single centre experience to evaluate the patient and graft survival as well as risks of the surgery and immunosupressive therapy. among 70 pediatric transplant patients 11 patients had severe lower urinary tract dysfunction. videourodynamic test was performed in all patients preoperatively and postoperatively. the cause of urological disorders was secondary to neurogenic bladder (n: 5) and valve bladder (n: 6). clean intermittent cathatetization (cic) was needed in 6 patients to empty the bladder. pretransplant augmentation ileocystoplasty was created in four patients and gastrocystoplasty in one patient to achieve low-pressure reservoir with adequate capacity. three of the patients received kidneys from cadaveric and 9 of them from living donors. the mean age at transplantation was 15±4.7 years. the median duration of transplantation was 18 months (range 1-49 months). at their last visit median creatinin levels were 0.95 mg/dl (0.8-2.4) . three patients had recurrent symptomatic urinary tract infections who had augmented bladder and on cic. one of them had creatinine levels of 2.4 mg/dl. one patient with ileocystoplasty who developed urinary leak and ureteral stricture in early postoperative period was treated by antegrade j stent. severe lutd reserves high risks for graft kidney. however our data suggests that renal transplantation is safe and effective treatment modality if the underlying urologic disease properly managed during the whole course of transplantation period. since surgery and follow-up of these patients is more complicated, patient compliance and experience of transplantation team will have significant impact on the outcome. r. meneses, l. sylvestre, j. sousa, d. ribeiro hospital pequeno principe, pediatric nephrology, curitiba, brazil introduction: in july 2000, we started a systematic evaluation program of each patient on chronic pd. the aim of this study was to analyze the long-term outcome of children on pd program. material and methods: we evaluated all the patients on pd between july 2000 and may 2006, who performed 3 complete protocols, with a minimal interval of 6 months between them, consisting of: anthropometric measurements, blood pressure and cardiological status, standardized laboratorial evaluations, pet test, clearance and kt/v, measurement of the intra-peritoneal pressure (ipp), occurrence of infections, hernias or constipation and need to change the catheter. we then compared all the evaluations using the graphpad prism software, a p value <0.05 was considered significant. results: 36 out of 74 patients were eligible, mean age 8±5 years old at the first evaluation, 61% boys, primary renal disease: 45% uropathies, 28% glomerulopathies, 8% tubulopathies and 19% other causes. there was an improvement on bmi and weight/height z-scores and worsening of height/age z-score, but none was significant. there was also no significant decrease in residual renal function (p=0.51), adequacy parameters remained stable: clearance (p=0.84) and kt/v (p=0.58). most patients were converted from capd to ccpd and nipd, and some had to increase daytime dwells (p=0.0098).constipation and the number of infections improved but not significantly. laboratorial evaluations, peritoneal membrane characteristics, ipp, need to change the catheter and occurrence of hernias did not change over the time. conclusion: a long-term maintenance of children in peritoneal dialysis program is possible, but reaching a satisfactory clinical condition is a great challenge. several points need to be checked for planning a better adequacy and survival of dialysis technique in children waiting for a graft. a rigorous follow-up protocol seems helpful in precocity of prescription strategy modifications. we observed a stable long-term outcome observing these adequacy tools. outcome the recurrence of primary disease in transplants is a well-known problem. we report our single centre experience to assess the frequency of the recurrence of primary glomerulonephritis in children after renal transplantation. medical reports after 1990 of 12 children with primary glomerular disease were evaluated. the 13 grafts were nine from living related and four from cadaveric donors. eight of them were diagnosed as fsgs, 2 of them mpgn and 2 of them pan. the mean age was 15.5±5.4 years. however the median transplantation duration was 47 months, one of the fsgs patient had hyperacute rejection. five years later she had second graft with the serum creatinine 0.7 mg/dl at 7th year of second transplantation. and all recipients were immunosuppressed with either cyclosporin a or tacrolimus, azothioprine or mmf and steroid based regimens. mutational analysis was available in two patients, they had homozygous podocin mutations. post transplant recurrence of fsgs was confirmed in one patient. glomerular tip lesion was the only histologic abnormality on graft biopsy. he has treated with plasmapheresis with no improvement of proteinuria. two of the fsgs patients had thromboses after transplantation. one of them had cardiac thrombosis with heterozygote mthfr mutation and one of them had renal artery thrombosis and loss of graft with prothrombin 20210a mutation. both of them have had additional risk factors for thrombosis. they have all functioning grafts except one. we have not observed any recurrence in patients with pan and mpgn. although the number of our patients quite small, renal and patient survival seems to be more favourable in our experience but we strongly recommend the evaluation of all risk factors of thrombosis and give appropriate anticoagulation. skin involvement in factor h deficiency (fhd) associated to hemolytic uremic syndrome (hus) has never been reported. we describe the case of a young adult on regular hemodialysis (hd) for fhd-hus who developed microangiopatic skin lesions and was successfully treated with plasma exchange (pe). the patient developed end stage renal disease secondary to fhd-hus (scr20) in 2004, when she was 32. after one year of hd she complained of severe night pain in the perimalleolar areas, followed by skin lesions which evolved into superficial ulcers (fig1). in august 2005, due to the worsening of the skin lesions, the patient started hd and pe (2 litres of fresh frozen plasma per session twice a wk) based on the hypothesis that skin lesions were expression of thrombotic microangiopathy. after 7 wks of pe there was a skin improvement (fig. 2) and a pain relief. pe was discontinued. 3 wks later she started to complain of the usual pain in the right foot. pe program combined to hd was restarted and the symptoms ceased again. pe was gradually discontinued and she was addressed to regular plasma infusion of 0.5 litre per wk. so far, after 18 months the pain and the skin lesions did not show up again. m. belingheri, s. cristino, p. basile, v. bianchi, a. leoni, s. testa, l. ghio, a. edefonti, g. ardissino ospedale maggiore policlinico irccs, mangiagalli e regina elena, pediatric nephrology, milan, italy background: in rapidly growing children on hemodialysis (hd), the determination of dry weight still remains troublesome. bioimpedance analysis (bia) is potentially helpful in quantifying the fluid to be removed but its specific role, in routine clinical practice, is not yet clearly set. the aim of the present study was to test the feasibility of prescribing ultrafiltration (uf) exclusively based on bia parameters. methods: differences in body weight, resitance (rx) and reactance (x-c) between pre-and post-hd were calculated in order to derive the equivalence between uf and bia parameters in a 3 years old girl over a period of 16 months. for 21 consecutive hd sessions, uf was prescribed exclusively based on the derived uf-bia equivalence. this period was compared with 21 hd sessions where uf was prescribed by the conventional approach. results. xc correlated with ultrafiltration better (r: .75) than rx (r: .64). bia-based compared with weight-based uf prescription showed a significantly lower number of hd sessions complicated by hypotension (19% vs. 50%), need of fluid reinfusion (5% vs. 50%) and a better quality of the hd sessions (86% vs. 37%). conclusion. prescription of uf solely based on xc is feasible and provides a better outcome compared to the conventional modality of uf prescription. we believe that this approach could be useful for any patients with low tolerance to uf or with problems in setting the correct dry weight. aim: the aim of the present prospective study was to determine the incidence of urinary tract infection (uti) and related abnormalities in children ages between 0-2 years. material and methods: all children between 0-2 years old whose admitting to first step health offices (routine controls and immunization) was screened for uti with urine dipstick test after education of minimum two persons from first step health offices according to protocol with two tertiary child care center and health directorate of izmir province in turkey between july 2005 and july 2006. all patients with urine dipstick test abnormalities were referred to tertiary child care centers for evaluation. urine microscopic evaluation and urine cultures and other further investigations were performed in tertiary care centers after obtaining urine with urinary catheterization. results: 14.918 children (55% boys) were screened with urine dipstick test. the children's mean age was 11.7±5.6 mo (median 10 mo). screening test was found normal in 12.527 (84%) children. 962 of 2391 (40%) of referred child were admitted to tertiary care centers and evaluated for uti. uti was demonstrated in 419 children (2.8% of screened and 44% of evaluated children's). uti incidence was found 4.1% in girls and 1.7% in boys. urinary tract abnormalities were found in 24 children (0.2% of screened and 5.7% of evaluated children's). the most common urinary abnormality was vesicoureteral reflux (17 patients). conclusion: the uti incidence was 2.8% in children ages between 0-2 years, uti more common in girls than boys in this age group and only small group of children has urinary tract abnormality which is determined with routine urine screening. knowledgement: thank you for this opportunity to health directorate of izmir province. we describe ds post-peldrt in 2 children with no known neurologic problems and discuss potential predisposing factors. a 12.2 kg girl with renal dysplasia was started on a calcineurin inhibitor (cni) one week pre-t and when her blood urea nitrogen (bun) was 110 mg/dl. on admission for t, the bun had increased to 146, and her serum sodium (na) was 142 mmol/l. post-t, she remained intubated and paralyzed to permit generous volume supplementation, including 1: 1 replacement of her vigorous urine output (uop), initially with 0.45% nacl in water. five hours post-t, her bun was 17 and her na 126. after modification of uop replacement, her na normalized. on the morning of post-t day 1, paralysis was discontinued, but she did not awaken and had sluggish pupillary reactions. computed tomography of the head (cth) revealed diffuse cerebral edema, and brain death occurred. a 39 kg adoloescent with polycystic kidneys was started on a cni 4 days before peldrt. his bun and na then were 76 and 142, respectively, and had not changed on the day of t. post-t, the patient was immediately extubated. with uop replacements as described above, his bun and na decreased from 74 to 12 and 143 to 124, respectively, over 24 hours despite adjustments in the na content of his intravenous fluids based on urine na levels. the patient then had a 10-second tonic-clonic seizure, followed by a 5-hour post-ictal state. cth was negative, and the patient recovered completely. we conclude that ds, caused by a rapid decrease in serum bun and thus osmolality, may complicate peldrt in settings even with older pediatric recipients or without excessive elevation of pre-t bun. other factors contributing to this ds may include relatively mild hyponatremia and cni effects on both pre-t uremia and seizure threshold. results: 89 patients, predominantly males, ages between 5 months and 21 years old. the mean incidence of peritonitis was 0.1 episodes/patient months. fifty-seven patients (64%) had at least one episode of peritonitis.there were 145 peritonitis, 85% percent from all episodes began at home, 35% caused by gram negatives, 38% by gram positives, 8% by fungus, 19% had a negative culture and in less than 1% it was not performed. the mean treatment time was 19 days, 45% had a good response to initial empiric antibiotics (cefazoline and amicacine). the interval between the beginning of dialysis and the first peritonitis episode varied from 1 to 1462 days, occurring in the first 6 months in 50% of the patients. successful treatment occurred in 75% of the cases, 18% were transfered to hemodialysis, 7% had a consecutive peritonitis episode, and 1 patient died due to mesenteric artery trombosis. conclusion: peritonitis occurred early in our patients. even though most of them have a good initial response, there is still a great amount that have complications leading to technique failure. continuous education for the patients and health team, aiming early diagnosis and treatment, are useful to preserve the technique and decrease morbidity and mortality associated to peritonitis. d. davis, j. emancipator, x. zhu, c. rosen objective: to assess for sd in p chronic kidney disease (ckd) patients before and after rtx. methods: we assessed 4 symptom (sx) domains of sleep disorders: 1) sleep-disordered breathing (sdb); 2) insufficient sleep (is) (shortened sleep time or nap); 3) excessive daytime sleepiness (eds); and 4) restless leg syndrome (rls) using a set of standardized questionnaires in 51 patients with ckd (age 5-18 yrs) including non-d non-tx (ndntx) (n=19), d (n=11), rtx (at least 3 months post-tx) (n=21), and 15 age-matched sibling controls (c) without known ckd. the presence of an overall sd was defined by positive responses in any of the 4 sx domains. results: mean age (se) ranged from 11.9 (3.7) to 14.7 (3.8) in the 4 pt groups (p>0.05) without significant differences in gender, race, or congenital ckd. estimated mean gfr (ml/min/1.73m 2 ) (se) was significantly higher in the rtx group [75.8 (22.4) methods: in a prospective design, 64 renal transplanted children, who had renal transplantation at least 3 months before, at namazee hospital, were enrolled in our study. immunosuppressive regimen consisted of cyclosporine and prednisolone plus mycofenolat mofetil or azathropin. data regarding gfr, serum creatinine, electrolytes, lipids and c 0 and c 2 levels was collected at beginning, in one-month, and five-month intervals. cyclosporine was adjusted to 100-250 ng/ml based on c 0 level. patients were divided into two c 0 (<100 and >100 ng/ml) and two c 2 (<800 and >800 ng/ml) subgroups. discussion: similar creatinine levels, drug dosage, and complications of c 0 and c 2 subgroups may be due to dependence of renal function to several factors other than cyclosporine dosage. regarding coefficient of variation, c 2 was more accurate and reliable than c 0 level. as there was no significant difference in mean c 0 and c 2 levels, and renal function at beginning and the end of the study, there seems to be no need to check c 2 levels after renal transplantation. purpose: preparation is necessary in order to effectively meet the critical needs of the post-operative pediatric kidney transplant patient upon their arrival to the icu following transplantation. the increasing number of children requiring liver transplantation services has made it evident that it is important to have guidelines in place for their initial and often specialized post-operative care. methods: the main goal is to provide the child with appropriate post-operative care and to recognize and quickly address complications. therefore the icu nurse will: · monitor the patient continually and conduct full assessments a minimum of 1 time/hour (airway, breathing, ventilation, perfusion, neurological status, etc) . · observe the incision for signs of bleeding, evisceration, and dehiscence. · treat post-operative pain. · update family with findings, etc. · see that appropriate post-operative studies (ultrasound, laboratory studies, etc) are completed. outcomes: nurses in the icu monitor the pediatric post-operative kidney transplant patients very closely as outlined. this allows for quick recognition of problems and immediate intervention. it is the practice of these nurses to be fully aware of the patient's status as well as any changes that might be problematic. conclusions: nurses are prepared to care for pediatric kidney transplant patients and very carefully follow established guidelines for assessment. following guidelines for assessing and caring for pediatric kidney transplant patients upon admission to the icu has proven to be affective in allowing nurses to quickly recognize complications and notify the appropriate clinician. background: uremia is an independent cardiovascular risk factor. transplantation increases life expectations of patients with crf, however there is still an increased risk of accelerated arteriosclerosis. the pulse wave velocity (pwv) is a non-invasive marker of arterial distensibility, it increases along with arterial stiffness, as an early indicator of arteriosclerosis. aim: to evaluate pwv values of transplanted (tx) children. patients, methods: pwv was measured with a pulsepen in 21 tx (age 14,3±3,0 years). two control groups were formed using a database of 116 healthy children (6-23 years): one matched for age (a) and one adjusted for height and weight (h/w). blood pressure, heart rate, serum calcium (ca), phosphate (p) , and pth were also determined before transplantation and at the time of the pwv measurement. results: tx patients were smaller by 15,3 cm (p<0,05) than a and younger by 2,9 years than h/w (p<0,01). pwv in tx (5,5±0,7 m/s) did not differ significantly from a (5,1±0,9) , however it was elevated in comparison to h/w (4,6±0,6 p<0,01). serum p, caxp and pth was increased before transplantation, all the values returned into the normal range except for creatinine (106±50 micromol/l) at the time of the study. there was no correlation between pwv and the actual values of ca, p and pth. conclusion: pwv is higher in transplanted children as a sign of increased arterial stiffness. controls matched for height and weight should be used in states of severe growth failure. although a number of established risk factors potentially responsible for arterial dysfunction were present before transplantation, they were normal at the time of the study. the long lasting effect of uremia before transplantation could be in part responsible for the increased pwv in children after transplantation. supported otka-t046155-fo48842-f042563 and ett 435/2006. d. derakhshan 1 , h. jalaeian 2 , a. derakhshan department of pediatric nephrology, shiraz, iran 2 shiraz organ transplantation center, nemazee hospital, shiraz, iran backgrounds: bartter syndrome is an inherited recessive autosomal tubulopathy characterized by hypochloremia, hypokalemia, metabolic alkalosis associated with potassium renal leakage, and normal blood pressure despite increased plasma renin activity. patients with this syndrome may have proteinuria or hematuria, but most of them have normal gfrs. here we report on a child with bartter syndrome who developed esrd (end stage renal disease) and underwent successful cadaveric kidney transplantation. case presentation: a 7-year-old girl presented to the pediatrics nephrologist with failure to thrive, severe hypokalemia, hypochloremia, metablolic alkalosis, and normal blood pressure and the diagnosis of bartter syndrome was considered for her. however, due to poor compliance, she did not receive any medications, did not give consent for kidney biopsy and did not attend her opd follow-up visits for about 8 years, when she developed esrd and went on chronic hemodialysis (3/weeks) . her little sibling also was diagnosed to be suffering from bartter syndrome at this time. after 10 months, she received a cadaveric renal allograft. afterwards, her kidney function, serum electrolytes, and growth have improved dramatically. discussion: in this case, we postulate that long-term hypokalemia due to bartter syndrome led to chronic interstitial nephritis and renal dysfunction. successful renal transplantation, even after the onset of esrd, for severe clinically bartter syndrome results in correction of metabolic abnormalities and excellent graft function. we propose that bartter syndrome should be considered as a possible cause of esrd and an indication for early renal transplantation, a procedure that results in a cure for the underlying disease and significant improvements in patient's quality of life. h. jalaeian 1 , a. derakhshan 2 , d. derakhshan 2 , m. fallahzadeh 2 , z. bazargani 3 , m. basiratnia 4 1 shiraz organ transplantation center, nemazee hospital, shiraz, nemazee hospital, shiraz, iran 3 fasa university of medicine, pediatrics, fasa, iran 4 shiraz university of medical sciences, pediatric nephrology, shiraz, iran background: obesity is a major issue in the end stage renal disease population. while studies evaluating the effect of obesity on transplant outcomes in adults have yielded varying results, this issue is even still more controversial in children. methods: in a cross-sectional design, 71 pediatric recipients, aged 4-19 at transplantation and with normal graft function for at least 7 months after transplantation, were evaluated. we grouped the data with regard to the body mass index (bmi) percentiles as group i (bmi >95th), group ii (bmi <95th), group iii (bmi >85th), group iv (bmi <85th). we compared the clinical and laboratory findings between groups i and ii and between groups iii and iv. obesity was defined as bmi >95th and being overweight was defined as bmi >85th. results: there were 71 children (45 males, 26 females) with mean age at time of transplantation of 12.6±3.5 years (range, [3] [4] [5] [6] [7] [8] [9] [10] [11] [12] [13] [14] [15] [16] [17] [18] [19] , and mean follow-up of 4.0±2.4 years. 12.7% of children were overweight and 5.6% were obese. no difference was found regarding age, height, duration of pretransplantation dialysis, or age at transplantation between groups i and ii and between groups iii and iv. (p>0.05). further more, no difference was found in regard to serum creatinine, bun, glomerular filtration rate, and 1-year graft survival rates among obese and/or overweight and other children. no correlation was found between bmi and gfr (p>0.05). conclusion: obese and overweight recipients can have excellent graft function and survival rates that are comparable to their non-obese counterparts. denying patients access to renal transplantation on the basis of obesity per se does not appear to be justified. d. derakhshan 1 , h. jalaeian 2 , a. derakhshan 1 , b. sabet 2 , m. fallahzadeh nemazee hospital, shiraz, iran 2 shiraz organ transplantation center, nemazee hospital, shiraz, iran introduction: tb is an important cause of morbidity and mortality in renal transplant recipients, especially in developing countries. this study was done to identify the incidence of tuberculin test positivity before transplantation as well as the influence on outcome of graft function and patient survival in children who receive renal allografts. methods: all 196 children with esrd who received a renal allograft between 1990 and 2006 were evaluated. as a routine pre-operative measure, a tb test was administered, using ppd. the ppdpositive recipients were compared with ppd-negative subjects, regarding age, gender, graft function, graft outcomes and patient survival rates. patients were divided into <5 mm versus >5 mm induration. results: the mean age of recipients was 14.03±3.20 years (range, 4-18) with a male/female ratio of 1.26:1. the majority of children were on chronic dialysis with mean duration on dialysis of 12.90±12.96 months. the tuberculin test was positive in 14.3% of children; all of them received isoniazide prophylaxis on diagnosis of latent tuberculosis. overall, the 1-year, 2-year, and 3-year survival rates were 94.47±0.02%, 92.44±0.025%, and 88.86±0.03%. three year survival rate was not different among ppd positive or ppd negative individuals. (90.00±0.09 vs. 93±0.03%; p>0.05) in addition, no difference was found for 1-year or 2-year graft survival rates (p>0.05). also serial serum creatinine levels at 1-month, 6-month, 1-year, 3-year, and 5year interval after transplantation was not statistically different (p>0.05). conclusions: detection of latent tuberculosis infection is an important step in the control of tuberculosis among asymptomatic pediatric kidney transplant. with proper management, latent tb does not affect transplantation outcome among children. h. xu, q. shen, ss. ruan, yl. bi, yq. lu, x. wang children's hospital of fudan university, department of nephrology, shanghai, people's republic of china objectives of study: we have started the first pediatric renal transplantation project in children hospital in china from 2004. survival of patients and grafts for the 5 patients are 100%. the clinical features were analysed and specific problems related to drugs and infections were reviewed. methods: 5 children (9~16 years old) underwent rtx. the duration of follow-up was 4 months to 32 months (average of 19.8 months). results: all the 5 patients were on automated peritoneal dialysis prior to rtx. the transplanted kidneys came from cadaveric donors (one were a 6-year-old brain-dead boy). 4 patients received il-2 receptor antibodies as induction therapy and the other one with alg due to high level of population reactive antibody. after the rtx, all the 5 patients were on triple immunosuppressive treatment (prednisolone, mmf, fk506 or csa) . no patient developed postoperative complication and delayed graft function occured. during the follow-up, 1 case suffered from calcineurin inhibitor renal toxicity and changed to rapamycin treatment, 1 from acute respiratory distress syndrome due to infection and 2 from elevated liver enzymes owing to drugs. one had acute rejection at 2 months after the operation. a severe anemia appeared on him after the rejection recovered. the cause of the anemia was found by the positive of serum anti-parvovirus b19 igm and completely recovered from the ivig treatment. at latest follow-up, the mean serum creatinine level of the 5 patients was 84.4±36.5 umol/l and egfr was 118.0±38.8 ml/min/1.73 m 2 . some patients received a support from "shanghai child renal failure trust fund". conclusions: the improvement of surgical technique, adequate dialysis prior to rtx, rational use of medicine, financial support and regular follow-up are all important for improving the outcome. h. bunker-wiersma 1,3 , j-c. davin the area under the curve (auc) of cyclosporine is strongly related to the efficacy and toxicity of the drug and its variability is mainly determined by the absorption phase. close therapeutic drug monitoring (tdm) is warranted to optimise therapy, using more appropriate methods to estimate the auc, than trough concentration measurement. from july 2004 we started auc guided monitoring of cyclosporine therapy based on two concentration measurements, c0 and c2. the results of this method are reported. methods: all paediatric renal transplant recipients treated with cyclosporine were included in the analysis. bayesian, model based estimation of auc values was performed at each out-patient visit or during hospital admission. calculated pharmacokinetic parameters, treatment efficacy data and side effects were collected over the 18 month period after introduction. target auc values were derived from previous studies in adult patients: 5400 ng/h/ml in the first three months after transplantation and 3250 ng/h/ml after three months. results: 15 early or stable post renal transplant patients were evaluated, divided in two groups (group i: <3 months after transplantation; group ii: >3 months after transplantation). in patients with trough concentrations below the therapeutic range, more than 50% auc's were in the therapeutic range in both groups. conclusion: auc guided monitoring of cyclosporine after kidney transplantation in children using c0 and c2 is practically feasible and presents the major advantage that c2 has not to be determined precisely 2 hours after csa administration. it is more closely related to the total drug exposure as compared with trough concentration monitoring and isolated c2. this method may facilitate the use of lower doses of cyclosporine and by this way limitside-effects. objectives: there is no satisfying data about reproductive functions after kidney transplantation in adolescence who have end stage renal disease (esrd) during childhood. we analysed the reproductive functions of kidney transplanted male adolescences. patients and methods: nine patients who followed between 1995-2006 were enrolled in the study. except one preemptively transplanted patient, all were on hemodialysis/peritoneal dialysis before transplantation. mean dialysis duration was 21 (9-54) months. their ages ranged between 10-17 years (mean 13.8) at transplantation. at the urologic examination, their mean age was 19 years. all patients had normal renal functions. results: all patients had normal testicular volume, libido and erectil functions. except one all patients had normal serum levels of lh, fsh, total and free testosterone. seven of the 9 patients semens were available for analysis. 3/7 patients had normal sperm parameters. transplantation had been performed before adolescence period in these 3 patients. one of these patients had been treated with intensive cyclophosphamide before. oligospermia was detected in 2, defective morphology in 3, low sperm motility in 6/7 patients. conclusion: although adult transplanted patients mostly have normal semen profiles; male children with end stage renal failure would not have normal spermatogenesis at the adolescence period; even after successful renal transplantation. in our study only 3 patients had normal semen profile, even hormon levels were normal. renal transplantation age seemed to be more crucial than the duration of esrd, of primary diagnosis or previous cyclophosphamide usage. r. vilalta, j. nieto, e. lara, a. madrid, s. chocron hospital materno-infantil vall de hebron, department of pediatric nephrology, barcelona, spain background: inhibition of il-2 receptors by basiliximab is irreversible and extended in time (mean 30 days). basiliximab (anti cd25 receptor) is used usually in the induction regime in our first cadaveric-donor kidney transplants. its re-use when chronic allograft nephropathy (can) develops could be useful. however some concern could exist related to possible adverse reactions (anaphylactic shock) linked to re-exposure to this drug because is an heterologous protein. less adverse reactions as lymphokine release syndrome has been described with the use of other monoclonal antibodies as the anti-cd20 receptor rituximab. objective: to describe our experience in the treatment with basiliximab of seven children with banf ii can. patients: seven children (2-16 years old (means 8.2 y.), 5 boys, 2 girls) showed biopsy-proved banf ii can. its period post-transplant ranged from 2 to 5 years (mean 4.1 y.) and their creatininine level from 2 to 4 mg/100ml (mean 3.2). all of them had been received at the transplant time basiliximab, tacrolimus or cyclosporine, mycophenolate and tapered steroids to reach 0.2 mg/kg/day in the third month post-transplant. when can developed, sirolimus was used in two patients, but was withdrawn due to increase of proteinuria. results: one dose of basiliximab (20 mg/1.73 m 2 ) was administered after 3 steriod pulses (10 mg/kg/day) in all patients. their basal immunosuppression was not changed. plasma creatinine diminished by 30% in four patients in the second week post-treatment and this improvement was sustained in two patients after one year follow-up. proteinuria did not change in any patient. in the course of this treatment no adverse reactions were observed. conclusion: 1) use of basiliximab in can is safe and possibly useful. 2) exposure to different monoclonal antibodies in paediatric kidney transplantation could be usual in the future; in the induction time, in the treatment of humoral rejection if exists (rituximab) and in the treatment of can. 3) it is necessary to establish that exposure and re-exposure to different antibodies is safe and without major adverse effects as our limited experience supports. r. vilalta, e. lara, a. madrid, s. chocron, j. nieto hospital materno-infantil vall de hebron, department of pediatric nephrology, barcelona, spain background: there are limited knowledge of kinetics and pharmacodynamic effect of sirolimus in paediatric renal transplantatation. provided that sirolimus is effective and safe in combination with tacrolimus and mycophenolate (mmf), the initial dose needed, the evolution of blood levels and the steady state should be studied in order to optimise its clinical use. objective: to establish a possible correlation between dose/level ratio of rapamune and other parameters as age, gender or puberal state. patients and methods: between 2000 and 2006, 19 paediatric patients (11 girls, 8 boys) received a cadaveric kidney transplant. age ranged from 4 to 16 years (mean 8 y.), and all of them received mmf and steroids. sirolimus were used from 0.02 to 0.1 mg/kg/day, to obtain levels between 6 to 12 ng/ml. results: dose/level ratio obtained allowed us to describe three types of patients: an infant-type i dose-level patient (age 4-8 y), a prepuberal type ii (age 8-12y) and an adult-type iii dose-level patient (age 12-16y). type i needed sirolimus between 0.08 and 0.1 mg/kg/day (sd±0.01), type ii between 0.04 and 0.8 mg/kg/day (sd±0.015) and type iii between 0.02 and 0.04 mg/kg/day (sd±0.018) to obtain all of them a constant blood levels between 6 and 12 ng/ml. the same positive correlation was obtained regarding the puberal status. no correlation were observed regarding the gender. introduction: developing of diabetes mellitus after renal transplantation is one of the determining factor in the survival of the patient and the graft. in present study we assessed the carbohydrate metabolism status of ntx. methods: we analyzed 45 patients' data about recently developed carbohydrate metabolism failure after ntx. children underwent ntx between 1990-2005 were investigated. thirty-nine children (16 girls/23 boys) underwent ogtt, who had no ptdm. we analyzed the incidence of ptdm/igt, the combination of immunsuppressive therapy, the number of transplants, the proportion of cadaver/living donor, hcv, blood pressure, lipid metabolism, bmi, graft function parameters and the time since ntx. results: ptdm developed in 6 children (13%). four of 6 patients required insulin therapy. we diagnosed igt in 7 of 39 with ogtt investigated patients (16%). all ptdm/igt patient got tacrolimus and continous steroid therapy. the dose of steroid was 6.5 mg/day in the ptdm/igt group vs. 5.2 mg/day no ptdm/igt (p<0.05). during ogtt the trough level of tacrolimus was higher in the ptdm/igt group 14.3 ng/ml vs. 10.1 ng/ml (p<0.05). in the other parameters we did not find any significant differences between ptd/igt and no ptdm/igt patients. discussion: the most important reasons in the development of ptdm and igt after transplant are steroid therapy and higher tacrolimus trough level. in transplant children we recommend the regular fasting glucose and ogtt examimation, the reduction of steroid and tacrolimus in case of stable graft function. otka f-042563, otka-t046155, ett 435/2006 , ett 184/2003 the introduction: measurement of plasma bnp is a novel noninvasive approach in the assessment of cardiovascular status. in our study we investigated the role of bnp in the monitoring of cardiovascular status of children with crf or renal transplant (ntx). methods: we examined 32 children with crf (n=17, 11 boys/6 girls, age: 12,1 year (3,5-20)) or ntx (n=15, 9 boys/6 girls, age: 16, 25) ). patients underwent echocardiographic investigations (ivs, lvedd, lvesd, pw and fs) and their bnp levels were measured (age matched normal values were used). other cardiovascular risk factors, such as hgb, htk, ca, p, creatinine and blood pressure were also evaluated. a correlation between bnp and echocardiographic results was calculated. results: the values of lvesd, fs and bnp levels of renal transplant patients were significantly better than those of crf patients (p<0,05). the other parameters did not show significant differences. bnp levels were significantly higher in all age groups of crf patients as compared to the normal levels. in younger ntx patients this value was within normal limits. in older ntx patients, and in those that had their transplants a long time ago we measured higher bnp levels, which correlated significantly with graft function as well (p<0,05). bnp showed a significant positive correlation with lvesd and a significant negative correlation with fs only in crf patients. the elevated bnp levels showed the worsening of cardiac function even when the echocardiographic parameters were still normal. the hgb, htk, ca, p and creatinine values were significantly better in ntx patients and showed no correlation with bnp. summary: bnp is an early, easily usable marker in diagnosing and following decreased cardiac function of both crf patients and after ntx. otka f-042563, otka-t046155, ett 435/2006 , ett 184/2003 c. garcia 1 , v. bittencourt 1 , s. vitola 3 , e. didone 3 , e. guerra 3 , f. pires 3 , a. tumelero 1 , d. malheiros 1 , v. garcia department of pediatric nephrology, porto alegre, brazil 2 complexo hospitalar santa casa, department of nephrology and kidney transplantation, porto alegre, brazil 3 complexo hospitalar santa casa, department of surgery, porto alegre, brazil the objective is relate the results of 348 consecutive kidney transplants carried out in children in a single center. patients and methods: analysis of kidney transplants performed in patients less than 18 years old, carried out from may 1977 to december 2006. results: 348 kidney transplants were performed. 48% of the patients were female, 86% were caucasian and 14% were african-brazilian. the mean age at the transplant was 11.3±4.5 years. the most frequent etiology of renal failure was vesico-ureteral reflux/obstructive uropathy (35%), followed by glomerulopathy (26%). the donor was deceased in 34% and living related in 66% (parents 82%). the initial immunosuppression was cya+aza+pred in 38.9%, cya+mmf+pred in 6,9%, tac+aza+pred in 8.6%, tac+mf+pred in 23.9%, tac + mf without pred in 8.9%. sirolimus was employed initially in 4 cases. induction with okt3/atg occurred in 5 patients and 157 received anti-il2 receptor antibody. the 110 graft losses during 29 years of follow-up were secondary to chronic allograft nephropathy in 58 (51%), vascular thrombosis in 6 (5.2%), acute rejection in 13 (11.2%), recurrence of original disease in 14 (12.1%). there were 27 transplants in 21 patients with focal segmental glomerulosclerosis, 12 (57.1) had a recurrence after transplant. eight were treated with plasmapheresis and 75% obtained a total remission. the survival of graft in the first, fifth and tenth year was: 90%, 72% and 59% respectively. the graft survival in the 5th year according the immunosuppression was 41% using azathioprin and prednisone, 72% with cya/aza or mmf and 78% with tac/aza or mmf. the patient survival in the first, fifth and tenth year was: 95%, 93% and 85% respectively, infection was the main cause of death. j. feber 1 , p. geier 1 , b. chaudry 1 , h. wong 1 , g. filler 2 1 children's hospital of eastern ontario, division of pediatric nephrology, ottawa, canada 2 london health science center, departments of pediatrics, london, ontario, canada successful pediatric renal transplantation (tx) should fully correct the metabolic abnormalities of end-stage renal failure. however, ckd may persist because of only half of the normal nephron endowment and other factors (ischemia, nephrotoxocity etc). height, bmi and blood pressure (bp) z-scores, cystatin c-gfr, hemoglobin (hb), serum pth, hco 3 , cholesterol, mycophenolic acid (mpa) and sirolimus (sir) levels were analyzed retrospectively in 21 tx recipients (10 males, age 8.5±5.8 years) at 4 months post tx (t1) and at 3.26±2.21 years (median 2.4) post tx (t2). data are expressed as mean±sd. height z-scores remained significantly lower than controls (t1: -0.90±1.17; t2: -0.75±1.23, ns), growth failure occurred in 19% of pts at t1 and 26% of pts at t2. bp z-score did not change from t1 to t2, but hypertension was diagnosed in 66% pts at t1 and 79% pts at t2. gfr (ml/min/1.73 m 2 ) was 71.9±18.6 at t1 and 70.9±23.7 at t2 (ns), mean decline of gfr was 3.9±1.1%/year. hb z-score remained below normal at -1.55±2.04 at t1 and -1.10±1.27 at t2 (ns) and anemia was diagnosed in 62% and 63% of pts at t1 and t2 respectively, despite trough levels of both mpa (2.77±1.43 mg/ml, 11 pts) and sir (7.73±2.55 mg/ml, 10 pts) that would be considered adequate. hypercholesterolemia was detected in 23.8% pts at t1 and 42% pts at t2, whereas only 9.5% of pts at t1 and 16.8% of pts at t2 were labeled as obese. bone disease was diagnosed in 28.5% pts at t1 and 15.8% pts at t2. we observed suboptimal growth, hypertension, hypercholesterolemia, bone disease and persistent anemia in a significant proportion of tx children despite iron supplementation, adequate mpa and sir levels and good kidney function. these ckd complications require careful monitoring and intervention. a. al midani 1 , g. koffman 2 , j. john 2 , s. stephen 2 , s. suzanne 2 , r. lord 2 1 royal free hospital, transplantation, london, united kingdom 2 great ormond street hospital for children nhs trust, transplantation, london, united kingdom objectives: to document factors predisposing towards surgical complications over 7 years in a single pediatric renal transplant centre. methods: we retrospectively analysed 179 consecutive renal transplants between jan 2000 and dec 2006. patients were divided into group 1, without complications, and group 2, with complications. we compared variables previously identified as risks for surgical complications between the two groups: live/deceased donor, donor and recipient age, gender and weight, side of organ donation, cold ischaemia time, single/multiple vessels, intraperitoneal/extraperitoneal approach, anastomosis to aorta/iliac vessels, thrombosis prophylaxis (changed from heparin to aspirin in oct 2000). results: 141/179 (81%) were complication free; 19% patients developed one or more surgical complication: wound infection 2/179 (1.1%), wound dehiscence 3 (1.7%), prolonged ileus 1 (0.5%), lymphocoele 7 (3.9%). 7 patients were re-explored: 5 (2.8%) for bleeding, 2 (1.1%) for graft repositioning. we observed 2 (1.1%) cases of renal artery stenosis. overall, 5 (2.8%) graft loss occurred secondary to thrombosis, 13% (3/23) prior to changing our prophylaxis from heparin to aspirin (1.2% on aspirin). urological complications occurred in 7 (3.9%): 3 ureteric leaks and 4 ureteric stenoses. the variables between group 1 and group 2 were as follows: under 20 kg: 19% v 35%, less than 5 yrs old: 12% v 30%, intraperitoneal approach: 13% v 37%, anastomosis onto the aorta: 18% v 43%, no aspirin prophylaxis: 9% v 24%, other variables were the same in both groups. conclusions: 19% of patients developed surgical complications. a higher rate of surgical complications was seen in recipients under 5, using the intraperitoneal approach onto the aorta. the introduction of aspirin prophylaxis reduced graft loss due to thrombosis from 13% to 1.2%. other variables did not affect the complication rate. m. medeiros 1 , v. sharma 2 , r. ding 2 , s. valverde 1 , am. hernández 1 , p. garcía 1 , y. fuentes 1 , m. suthanthiran 2 1 hospital infantil de mexico federico gomez, departamento de nefrologia, mexico, mexico 2 weill cornell medical college, immunogenetics and transplantation center, new york, ny, united states the forkhead transcription factor foxp3 is highly expressed in cd4+cd25+ regulatory cells (tregs). the foxp3+cd25+cd4+ cells play a central role in immune tolerance and tgf-β 1 is reported to induce foxp3 expression in vitro. whether there is an in-vivo association between foxp3 and tgf-β 1 is not known. we investigated the hypothesis that there is a positive association between foxp3 and tgf-β 1 in children with stable renal graft function. parental written informed consent was obtained before enrollment in all cases. 24 children with stable renal allograft function for a minimum of 12 months were studied. a complete clinical examination was performed; peripheral mononuclear cells were collected for measurement of transcripts for foxp3, tgf-β 1 , tgf-β 2 , and 18s rrna (house keeping gene) using by real time quantitative pcr assay. correlation between transcript levels was performed using pearson r. results: 24 pediatric recipients of renal allografts were studied. tgf-β 1 and foxp3 were highly expressed in peripheral blood mononuclear cells, and there was a highly significant and positive correlation between levels of mrna for foxp3 and tgf-β 1 (r=0.811, p<0.0001)), whereas no significant correlation was found between tgf-β 1 vs. tgf-β 2 (and tgf-β 2 vs. foxp3). conclusion: foxp3 expression in vivo is strongly correlated with tgf-β 1 expression in peripheral mononuclear cells of stable renal transplant recipients. introduction: studies suggest that pre-emptive lamivudine therapy improves survival in hbv renal transplants. however, long-term outcome is not well established. method: four chinese adolescents with chronic hbv infection were transplanted. they were put on cyclosporin a, mycophenolate mofetil and prednisolone. prophylactic lamivudine was given just before transplantation and was continued afterwards. hbv status and liver enzymes were monitored serially. results: four patients were transplanted at the age of 15.5±3.0 (13.9-19.9) yrs old. they were followed up for 74.7±10 (61-85) months and no mortality was reported. alanine transaminase (alt) was only transiently elevated in the first 2 months post-transplant in all cases and became normal afterwards. there was no hepatitis flare and liver function was normal at the last follow-up. hbeag and hbv dna were positive in 1 patient before transplantation and remained positive at the latest follow-up. mutation in the ymdd motif of the hbv genome was detected in the same patient and undeterminable in the other three due to low virus load. this patient remained clinically stable with normal liver function except there was a rise of viral load from baseline. all grafts were functioning and there was one late acute cellular rejection which responded to treatment and there was no hepatitis flare. latest mean serum creatinine was 141±63 (56-208) umol/l. conclusion: ymdd mutation and resistance to lamivudine treatment may happen but appear to have little clinical significance. our long-term results showed that renal transplant seems feasible and safe in this population up to 7 yrs follow-up. there are no studies in mexican children (mx) . the aim of the study was to determine tacrolimus pharmacokinetics (pk) in mexican renal transplant children and compare it wih reported pk in aa and ca. methods: a seven point pharmacokinetic profile (0, 0.5, 1, 2, 4, 8 and 12h) was performed in ten children receiving tacrolimus as part of the immunosuppressive therapy, mean age was 13.9±2.19 years, mean post transplant time 9.8±35 months. c0 and cmax were obtained directly from experimental points, the auc and t1/2 was obtained with a non-compartmental model using winnonlin version 3.0. results: in cyclosporine (csa) is widely used for immunsuppression in transplant recipients and for treatment of srns. however, patients can develop csa associated cutaneous side effects, e. g. hypertrichosis, skin cancer, and viral warts due to human papillomavirus infection. here we report on a 23-yearold boy suffering from a microdeletion syndrome (18 q-) and srns (histology: minimal change nephropathy) starting at the age of 20 years. since the initial combination therapy with corticosteroids and cyclophosphamide was associated with severe side effects (sepsis, leukopenia) and did not lead to sustained remission csa therapy was initiated. csa-treatment resulted in rapid clinical remission. however, after 12 months the patient developed viral warts (hands, trunk and head), although csa trough levels were kept below 100 μg/l. therefore, immunosuppression was switched to mmf (2x500 mg/day) resulting in sustained remission of srns and rapid disappearance of viral warts within 4 months. conclusion: conversion to mmf may be a usefull treatment strategy in srns showing csa associated side effects like viral warts. 2003-2006. 5 were live related (lrd) and the remaining cadaveric (cad). 6 were pre-emptive(pet). all received basiliximab induction 2 hrs prior to surgery. in addition, induction immunosuppression consisted of tacrolimus and methylprednisolone. in all but 2 patients, basiliximab was re-administered at day 4. 2 patients, aged 11 and 6 yrs (one cad and other lrd respectively) developed acute noncardiogenic pulmonary oedema 6-48 hrs after transplantation. both children had renal dysplasia as primary cause of renal failure. both required delayed ventilation and were ventilated for 4 to 6 days respectively. there was a rapid rise in c reactive protein in both patients. both grafts had primary function, but the cad transplant subsequently developed acute tubular necrosis, and was eventually lost within 3 weeks due to thrombotic micro angiopathy and severe acute antibody mediated rejection despite immunosuppression with sirolimus, mycophenylate, steroids and plasma exchange therapy. conclusion: we report a rare but serious side effect of basiliximab. to our knowledge, this is the first report of basiliximab induced non-cardiogenic oedema so early post transplantation and in such young children. early recognition and aggressive appropriate supportive therapy is vital for patient and where possible, graft survival. 3 (17); cmv seroconversion (4); seizures (4); hypertension (9), uti (6), adverse reaction to basiliximab (2), delayed graft function (4), acute rejections (2), chronic allograft nephropathy (1). 17 patients had well matched kidneys (3 or less mismatches), 11 were poorly matched. 2 grafts were lost from latter group, both were cad, 1 had acute tubulointerstitial nephritis and tacrolimus toxicity and the other thrombotic microangiopathy and eventually acute antibody mediated rejection. chronic allograft nephropathy (can) is a complex phenomenon caused by underlying kidney disease and superimposed by environmental and genetic factors. we investigated the association of polymorphism in the genee nos with the can. nitricoxide is synthesized from l-arginine in vascular endothelial cells by nitric oxide synthase. endothelial nitric oxide plays an important role in endothelial dysfunction and involved in the inflammation. the gene encoding enos maps to chromosome 7q35 7q36.7. a missense variant of the enos gene in exon 7 shows a transversion of g to t at nucleotide position 894 (g894t) that results in a replacement of glu by asp at amino acid residue 298 (glu298asp). the aim was to investigate the association between can and g894t polymorphism of the endothelial nitric oxide synthase gene. the g894t mutation at exon 7 of the endothelial nitric oxide synthase gene, enos gene polymorphism, was analyzed in 61 turkish children with renal transplantation. the g894t polymorphism of the endothelial nitric oxide synthase gene was determined by polymerase chain reaction and restriction fragment length polymorphism. were grouped according to stages of chronic kidney disease (ckd) as estimated by the calculated glomerular filtration rate (gfr, schwartz formula). measurements of structural and functional surrogates for cardiovascular disease (cvd) included intima-media thickness (imt) of the common carotid artery (cca), pulse wave velocity (pwv) and augmentation index (aix). aix and pwv reflect the degree of arterial stiffness and were calculated from pulse wave recordings at the arteria carotis and arteria femoralis (sphygmocor device). results: patients and healthy control subjects had a mean age of 14 years. imt was not significantly different in patients and controls. significant differences were found in the aix, which was increased by 50%: the mean aix was in healthy subjects was -28,2% and in transplanted subjects -14,4%. pwv was increased by 15% (4,74 m/s vs. 5,43 m/s). both aix and pwv increased in parallel with the degree of renal impairment (stages of ckd). table 1 . discussion: weight gain post transplant is multifactorial, like cultural, psychological and associated to steroids. weight gain was observed in general, patients with overweight or in risk of overweight didn't loose weight postransplant even they were aware of the consequences. introduction: tacrolimus is metabolized by cytochrome p450 3a and has a narrow therapeutic range. we report a kinetic interaction between tacrolimus and amlodipine, a potent cytochrome p450 inhibitor, resulting in anuric acute renal failure. case report: a 14-year-old male renal transplant recipient received amlodipine, a calcium channel blocker as antihypertensive treatment while he was on tacrolimus (0.1 mg/kg per day). he presented first with diarrhea and developed subsequently, dizziness and fatigue, related to acute anuric renal failure, requiring hemodialysis for 20 days. tacrolimus trough levels were in the desired therapeutic range (3-6 ng/ml) until recently. three days after introduction of amlodipine, tacrolimus trough levels increased to a toxic level of 38.8 ng/ml. after discontinuation of amlodipine, tacrolimus levels returned to the normal range in seven days and renal function recovered progressively. no polymorphisms in the expression of cyp3a and p-glycoprotein were detected. discussion: tacrolimus is known to be a substrate of p-glycoprotein, responsible for drug secretion into the intestinal lumen and metabolized by enterocytic cyp3a. amlodipine is a competitive inhibitor of cyp3a. as no abnormalities of cyp3a and p-glycoprotein were found, we suspect that drug interaction due to competitive inhibition of tacrolimus metabolism by amlodipine was responsible for these toxic effects. concomitant diarrhea might have played an additional role for increased tacrolimus serum levels, presumably in relation to diarrhea associated dysfunction of enterocytic cyp3a and p-glycoprotein. conclusions: amlodipine and diarrhea increase tacrolimus blood concentration by inhibiting its metabolism. amlodipine should not be used in patients on tacrolimus. careful monitoring of tacrolimus blood levels is recommended in case of concomitant diarrhea. urinary tract infection (uti) remains a significant cause of infectious complications in renal transplant recipients. the aim of the study was to determine the frequency of uti following renal transplantation in our center. the records of 34 patients (f/m: 14/20) who underwent renal transplantation were evaluated retrospectively. among them 12 patients (f/m: 9/3) were found to have at least one episode of uti during follow-up. the records were examined for the age, sex, primary disease, and duration of chronic renal failure, donors, posttransplant follow-up and recurrence of uti. biochemical analysis of blood for renal functions, complete blood count, creactive protein and sonographic examination of patients were also recorded and results were compared with renal transplanted patient who did not develop any episode of uti (group 2). the mean age of the group 1 was 14.6±4.7 years, while it was 14.5±3 years in the group 2. mean duration of post-transplant follow-up was 2.8±1.7 years for group 1 and 2.4±1.7 for group 2. four patients (33.3%) in group 1 and 7 patients (33.3%) in group 2 had vesicoureteral reflux (p>0.05). five patients had single uti while 7 patients had more than one uti. though we did not find any difference between girls and boys in terms of presence of vesicoureteral reflux, frequency of uti in girls was found to be significantly higher than in boys (p=0.003). ultrasonographic examination of patients during uti in group 1 revealed pyelonephritis in 3 and hydronephrosis in 2 patients. the most frequent microorganism causing uti was e. coli. age, donor source and etiology of chronic renal failure did not influence the incidence of urinary tract infection. our data suggests that urinary tract infection remains a frequent but mostly benign complication in the pediatric transplant population, especially in female gender. the growing population of transplanted patients requires the consideration of the potential side effects of the different treatment regimens. experience of the last decade with calcineurin and nucleoside reverse transcriptase inhibitors revealed important renal side effects. we describe a 15 years old girl who was known to have liver failure related to wilson's disease (wd). she had orthotopic liver transplantation from her mother 3 years ago and treatment with tacrolimus and mmf was initiated. although she was known to have proximal renal tubular acidosis secondary to wd, renal tubular functions were found to be normal within the three months of transplantation. two years after the transplantation lamivudine was initiated because of de novo hepatitis b infection in transplanted liver. a couple of months later she developed renal fanconi syndrome with metabolic acidosis, hypophosphatemia, glycosuria and aminoaciduria. she needed high doses of sodium bicarbonate and phosphate supplementation. tacrolimus was suspected to be the cause of late post transplant renal acidosis and was replaced by sirolimus. however, 3 months later, at the 6 th month of lamivudine treatment, she was hospitalized because of metabolic acidosis, mild hyperglycemia and inability to walk. electromyographic examination revealed myopathic changes while liver biopsy was normal with a normal tissue copper level. renal biopsy showed findings of karyomegalic nephropathy which could be the result of the action of antimitotic agents. we suspect that our patient's tubular dysfunction, myopathy and hyperglycemia may have resulted from mitochondrial dysfunction which is triggered by tacrolimus and augmented by lamivudine. however, randomized and prospective studies with large groups of patients are needed for definite results about mithocondrial side effects of these drugs. recombinant factor viia (rfviia, novoseven) is a new hemostatic agent that was initially indicated in hemophiliac patients. recently it has been used successfully for the treatment of bleeding in patients with thrombocytopenia, and acquired and congenital platelet dysfunction. epstein syndrome, also known as alport-like syndrome, is a rare autosomal dominant disease characterized by proteinuria, chronic renal failure, hearing loss, and thrombocytopenia with giant platelets. our group previously reported functional alterations of giant platelets of boy with epstein syndrome, who rapidly progressed to end stage renal disease during adolescence. the first nonheartbeating kidney transplantation at age 17 was failed because of the severe postoperativebleeding irresponsible for traditional therapy (packed red cells, platelets, and fresh frozen plasma), result in immediate graft failure and the need for transplant nephrectomy. the second kidney transplantation was 4 years later, after a single intravenous bolus injection 70 μg/kg body weight rfviia, which was repeated one and 12 hours after the surgery. rfviia successfully controlled the bleeding in the peri-and postoperative phase and no side effect and thrombotic complication occurred and his graft function is still stable after 4 years. recombinant factor viia may have a potential role in the treatment of phenotypic bleeding associated with chronic kidney disease. cyclosporin a (csa) and mycophenolic acid (mpa) have a wide interindividual variability in their pharmacokinetics (pk). among others, intestinal p-glycoprotein (p-gp) expression and cyp3a4 activity have been held to be responsible for that variability. in adult kidney transplant (rtx) patients, an influence of these gene polymorphisms has not been shown; however, there are no data in pediatric patients. we reasoned that such an influence might be masked in adults by confounding environmental factors accumulating over the decades of life. we therefore investigated a possible influence of gene polymorphisms of p-gp and cyp3a4 on defined dose-adjusted pk-parameters in 70 children with rtx (age 11.6; range, 3.2-17.4 yrs). pk parameters (auc, c2) were assessed 1, 3, 12, and 24 weeks after rtx. real-time, rapid-cycle pcr methods were used for genotyping. the allele frequencies for the mdr1 c3435t allele (expression and in vivo activity of p-gp) of 62% and for the cyp3a4-v allele of 3% were comparable to those reported for caucasian populations. dose-adjusted pk parameters of csa and mpa were not significantly different in patients with and without the cyp3a4-v allele or patients with different mdr1 c3435t genotypes. along with that finding, neither of the polymorphisms investigated into was associated with renal function or the incidence of acute rejection episodes. we studied how the il-2r β-chain becomes enriched in lipid rafts of activated human t cells, isolated by ficoll gradient and sheep red cell rosetting, and how its tyrosine phosphorylation, which requires its heterodimerization with the common cytokine r β-chain (βc), occurs there. imunoblots (ibs) of sucrose gradient fractions of cell lysates obtained during a 72-hour activation with phytohemeagglutinine (pha) showed the gradual, largely selective, translocation of the β-chain into rafts. as dimerization or lipid modification can be mechanisms underlying raft enrichment, we assessed lysates of pha-activated cells in ibs under non-reducing versus reducing and crosslinking conditions but did not see evidence of β-chain dimerization. however, exposure to cycloheximide to interfere with post-translational acylation, or to the palmitic acid analogue 2-bromohexadecanoic acid substantially diminished raft enrichment of the il-2r β-chain. we next performed ibs of il-2r β-chainand βc-immunoprecipitates from raft and non-raft fractions of activated t cells before and after il-2 treatment. we found that il-2 exposure triggers the translocation of small amounts of βc, accompanied by il-2r β-chains, into rafts, resulting in its heterodimerization with the il-2r β-chain and their tyrosine phosphorylation. all of these processes were attenuated in the presence of the il-2r β-chain-blocking antibody daclizumab. we conclude that the raft enrichment of the il-2r β-chain requires palmitoylation and provides the focal point for the formation of the highaffinity il-2r via il-2r β-chain-mediated "chaperoning" of few βcs into these domains, establishing novel raft-dependent mechanisms underlying cytokine r specificity and selectivity in human t cells. iga nephropathy (igan) is an immunecomplex disease resulting from a defect in mucosal iga response. food antigens have been implicated in the pathogenesis. gut permeability to antigenic substances is immature at birth and its maturation is delayed by early administration of antigenic foods while breast feeding accelerates this process. we aimed to evaluate if exposure to antigenic foods in early life is associated with a predisposition for igan in childhood. three groups including children with igan (group 1, n=33), primary non-iga glomerulopathies (group 2. n=25) and healthy controls (group 3, n=40) were formed. their parents filled a questionnaire regarding the age at diagnosis, gestation time, birth weight, feeding by breast milk, formula, cow's milk and complementary foods. all groups were similar for age, sex, gestation period, birth weight and the rate and duration of breast feeding. in addition, the rate of formula feeding was also similar in all groups. however, cow's milk consumption rate was higher in group 1 and 2 than in group3. introduction of formula was earlier in groups 1 and 2 than in group 3. in addition, the children in group 1 were younger than the other groups at the onset of feeding by cow's milk and weaning. roc curves predicted 3.5, 3.75 and 5.5 months as the best cut-off age values for formula feeding, cow's milk feeding and weaning for predicting the presence of igan, respectively. ors for igan with respect to these cutoff levels were 28 (95% ci: 4-189), 5.7 (95% ci: 1.9-17.2) and 10.5 (95% ci: 3.9-28.0), respectively. the results of this preliminary study indicate that early introduction of antigenic foods might increase the risk of future primary igan. results: they were 8 males and 2 females, with a male: female ratio of 4: 1. their ages ranged from 5 months to 15 years (mean 6.8 years), with a peak age of 5-9 years. the common presenting complaints were generalised oedema (60%); oliguria (50%) and hypertension (50% we report nine patients (three males) with mesangiocapillary glomerulonephritis (mcgn) from a single paediatric nephrology centre. the average age at presentation was 12.0 years (range 9.2 to 13.4). all had nephrotic syndrome. seven had mcgn type 1 and two had mcgn type ii. six of seven tested had positive c3 nephritic factor. three patients responded well to steroids and ace inhibitors and received no further therapy. five had a good response initially but relapsed when steroids were tapered and one patient had a poor response to steroids. these six patients received calcineurin inhibitor (ci) therapy. four responded well with resolution of proteinuria. one patient relapsed when tacrolimus was withdrawn after 23 months of therapy but proteinuria resolved after re-introduction of therapy. two patients had a poor response to ci therapy. one remains stable but with heavy proteinuria. the second patient (with mcgn type ii) initially had a complete remission of proteinuria on steroids but relapsed 30 months after presentation while on prednisolone 5 mg on alternate days. repeat biopsy showed 65% crescents. treatment with pulsed intravenous steroids, cyclosporin and mycophenolate mofetil was ineffective and she progressed rapidly to end stage renal failure. we conclude that ci treatment might be useful in mesangiocapillary glomerulonephritis. prospective, randomised controled trials are required to determine their place in the management of this disease. iga nephropathy (igan) is caused by a primary defect in mucosal iga response leading to increased antigenic stimuli reaching to bone marrow. enteric flora is important for mucosal and systemic immunity, and probiotics regulate specific and innate immunity by maintaining microbial balance in the gut. saccharomyces boulardii (s.boulardii), a probiotic, increases intestinal siga production, protects enteric infections and also prevents atopic and immunoinflammatory diseases. we aimed to evaluate the effect of s.boulardii on experimental igan, induced by oral polio virus vaccine (opv) administration to the mice. four groups of male balb/c mice (n=7 for each) were formed. groups i and ii were immunized enterally by opv at the onset, 2 nd and 4 th weeks. group ii was also given s.boulardii in drinking water throughout the study. group iii was given only s.boulardii, while group iv received no treatment. two weeks after the last opv dose, all the animals were sacrificed to obtain their kidneys for histopathological evaluation and all four groups were compared with respect to the severity of histopathological changes. while there was mild to moderate mesengial proliferation and widening, tubular atrophy, interstitial inflammation and fibrosis in group i, no remarkable histological changes in the other groups were noted. immunofluorescence microscopy revealed universal deposition of iga and some c3 in group i, while there was no iga or c3 deposition in the other groups. electronmicroscopy revealed mesengial proliferation along with matrix expansion, focal basement membrane thickening and electron-dense deposits in the mesengial area in only opv group and the other groups were normal. in conclusion, enteral s.boulardii administration prevented experimental igan development in mice. the aim was to assess the correlation of renal histopathological findings with clinical diagnosis in order to recognize the pattern of kidney diseases in our pediatric population. methods: a total of 95 renal biopsies performed on children who presented to the surgical kidney hospital in damascus during a period of 3 years were retrospectively reviewed. results: nephrotic syndrome alone accounted for 52% of all cases, followed by hematuria in 21%, mild to moderate renal impairment including allograft dysfunction in 15%, nephritic syndrome in 10%, and hsp in 2%. the most common histologic lesion was mcd in (29%). fsgs was the second most common lesion (13%) followed by mesangial gn (11%), mpgn (9%), post-infectious gn (5%), iga nephropathy (4%), membranous gn (3%), cns of finnish type (2%), alport syndrome (2%), interstitial nephritis (2%), nephronophthisis (2%), hsp (2%), acute rejection (2%), chronic rejection (2%), nephrocalcinosis (1%), crescentic gn of undetermined origin (1%), and lastly, 5% were completely within normal limits. familial and inherited diseases were encountered in 15%. histopathologic diagnosis was mostly useful in nephrotic cases. while in hematuria cases, the usefulness of the histologic findings in terms of therapeutic and/or prognostic point of view was definitely less. one of the reason for that in our series is perhaps because we still do not have facilities to perform electron microscopic evaluation of the renal tissue. however, controversy about the usefulness of renal biopsy in such cases is still there. conclusion: this study provides an important data on the pattern of pediatric renal diseases in our center and highlights the usefulness histologic findings in guiding the therapeutic plan especially for nephrotic children. aim: the aim of this study was to determine the efficacy of tacrolimus in the management of sr fsgs in children. study design: this was a prospective study of 20 children with sr fsgs treated with tacrolimus (0.2-0.4 mg/kg per day in 2 divided doses over 12 hours adjusted to a trough level between 7-15ng/ml) for 12 months in combination with low dose steroids. other therapies included angiotensin converting enzyme inhibitors, folic acid, multivitamins and lipid lowering agents. results: the mean age at study entry was 11.1 years (range 5.6-16.8). the mean duration of nephrotic syndrome before initiation of tacrolimus therapy was 4.7 years (range 2.1-7.6). at the end of the treatment period 8 (40%) children were in complete remission, 9 (45%) children were in partial remission and 3 (15%) failed to respond. the average period of follow-up following cessation of tacrolimus treatment was 27.5 months (range 13.7-43.7). at last hospital follow-up 5 (25%) of children were in complete remission, 10 (50%) in partial remission and 2 (10%) in relapse. 3 children demised from dialysis related complications following cessation of tacrolimus treatment. adverse events included sepsis (2), nausea (2) diarrhea (2), anaemia (4) and worsening of hypertension (4) . conclusion: tacrolimus is a safe and effective treatment for sr fsgs. however, like cyclosporine some children tend to relapse following cessation of treatment. it has been rarely reported in association with graves-disease. now we present a previously healthy 6-year-old japanese girl who had proteinuria due to stage i mn and graves disease. patient: she was found to have 2+ proteinuria and a goiter at her school medical examination simultaneously. serum free thyroxine was 4.98 ng/dl (normal range 0.95~1.74), thyroid-stimulating hormone (tsh) less than 0.003 microu/ml (0.34~3.88), anti-microsomal antibody 1600t (~100), anti-thyroglobulin antibody 400t (~100), and tsh-receptor antibody 84% (~10) consistent with graves' disease. the electron microscopy finding of her renal biopsy specimen showed the presence of electoron-dense deposits located in the subepitherial and intramembranous spaces. with immunofluorescence microscopy, the bright granular staining of igg along the gromerular capillary wall was found. these findings were characteristic of mn. objectives of study: to investigate whether graves disease caused mn in this patient. methods: we examined the presence of thyroid microsome and thyrogrobulin in glomeruli by immunofluorescence study using anti-thyroid microsomal antibody and anti-thyrogrobulin antibody. result: glomerular granular staining of thyroid microsomal antigens was demonstrated corresponding to igg granular deposits, but that of thyrogulobulin was absent. conclusion: mn in this patient is presumed to be caused by immunecomplexes mediated by thyroid microsomal antigens. objective: to explore the role of oxidative stress reaction on the injury of glomerular podocyte slit diaphragm molecular barrier. methods: thirty-two male spraque-dawley (sd) rats were randomly divided into control, low dose (3.0 mg/kg), nephrotic (7.5 mg/kg), overdose (10.0 mg/kg) groups by the dosage of adriamycin (adr) injection.the levels of malondialdehyde (mda) glutathione peroxidase (gsh-px), hydroxy radical ( . oh) and superoxide dismutase (sod) in renal cortex were measured; the expression of podocin was measured with immunohistochemistry. results: (1) compared with control group, the levels of mda in renal cortex and 24-hour urinary protein were increased, the levels of sod in renal cortex was decreased in adr-treated groups, especially in nephrotic group (p<0.05). (2) in control group, podocin staining was a sable linearlike pattern along the capillary loops of glomerulus; in nephrotic group, podocin staining was a light tan discontinuous punctiform or short linear-like pattern along the capillary loops of glomerulus. compared with control group, the score of podocin immunohistochemical staining was decreased in adr groups, especially in nephrotic group (p<0.05). (3) there were some significant negative correlations between the score of podocin immunohistochemical staining and the levels of mda in renal cortex. there were some significant positive correlations between the score of podocin immunohistochemical staining and the levels of sod in renal cortex. conclusion: (1) there was close relationship between podocin and the development of proteinuria. (2) there were significant correlations between the reduction of podocin in glomerular podocyte slit diaphragm and oxidative stress reaction, especially lipid peroxidation. lupus nephritis (ln) remains an important problem in patients with sle. to evaluate the clinical course, histopathology and the efficacy and safety of high-dose pulse cyclophosphamide (ctx) in children with ln. retrospectively, 25 children with ln were studied; all patients underwent renal biopsy and were followed up for at least 3 years. the clinical and serologic data at the time of renal biopsy were recorded. five of them were excluded because of short period of follow-up or defective laboratory data. based on renal biopsy (who classification for ln), 20 patients were treated with the following regimens: one patient (class i) with low-dose prednisolone (pred), 7 (class ii, iii) with high-dose of pred, 12 (class iv) with high-dose pred and 13 received intermittent intravenous (iv) ctx pulses (monthly for 6 months, then every 3 months) followed by mycophenolate mofetil (mmf) as maintenance therapy. there were 13 girls and 7 boys. the mean age at the time of diagnosis of sle was 10.2 years. eighteen patients were more than 8 years old. sixty percent of the patients were presented as nephritic-nephrotic syndrome. there was 1 with class i, 5 with class ii, 2 with class iii, 12 with class iv and none with class v based on biopsy. eighty-five percent of cases went in remission, one was hemodialytic and 2 died due to renal failure and cns involvement. among 12 cases with class iv, 11 responded to pred and iv ctx pulses. there was no evidence of side effects. it seems that iv pulse ctx does induce remission of clinical and renal disease in the majority of early diagnosed children with severe ln. furthermore, it appears that mmf is an appropriate drug for maintenance therapy. however, this study was based on a small number of subjects. further studies to confirm the long-term efficacy and safety of ctx pulse therapy on larger numbers of patients are needed. forming group i were compared with 25 children on short course steroid therapy (iskdc regime) (group ii). children were examined for steroid side-effects and underwent blood tests, ophthalmologic evaluation and radiological examination. results: though remission was achieved in <4 weeks by 84% in group ii against 60% in group i, the total dose received (25-50 mg/kg) was lower in group i (44% vs 20%). forty-six % had 1-2 relapses, 44% had 3-6 relapses and 6% had 6-10 relapses. the proportion of children having >2 relapses was much higher in group ii (60% versus 40%). mean relapse/patient/ year was 1.6 (sd 0.5) in group i against 3.1 (sd 1.6) in group ii. delayed bone age (44%), radiological evidence of osteoporosis (42%). cushingoid facies (28%), posterior subcapsular cataract (16%), decreased growth velocity (14%) and hypertension (12%) were the side effects and were almost equally distributed in the two groups. more patients from group ii received a higher cumulative dose/ kg/year of >150 mg (76%versus 56% in group i) and these had higher risk for hypertension, delayed bone age and osteoporosis. conclusion: alternate day, prolonged therapy (soyka regime) compared to short course, daily therapy (iskdc) resulted in lower cumulative dose to the patient. acute side effects and severity of infections were less. mean relapse/patient/year were lower. group ii patients receiving higher cumulative dose had osteoporosis and delayed bone age. objetive: to assess urinary protein excretion decrease in patients with primary srns treated with ec-mps methods: cohort of 13 patients, mean age: 9 years with primary srns. inclusion criteria: primary sncr with of focal segmental glomerulosclerosis (fsgs). exclusion criteria: glomerular filtration rate (gfr) 30% than baseline level, leukopenia, absence of decrease of proteinuria excretion by month 6 of treatment with ec-mps. mean time after the initial diagnosis of ns until the introduction of ec-mps was calculated in patients who decreased urinary protein excretion below nephrotic range and in non-responsive patients and the glomerular damage, interstitial fibrosis and tubular atrophy were classified as: absent, mild, moderate, severe (0 to 3, risk grade>6). ec-mps dosing: 450-700 mg/m 2 /day. complete response was considered a reduction in the urinary protein excretion lower than or equal to 4mg/m 2 /hour; partial response: urinary protein excretion ranging from 4 to 40 mg/m 2 /hour and absence of response: urinary protein excretion in the nephrotic range. laboratory monthly assessments: serum creatinine, urea, hemoglobin and blood cell counts, lipids, serum proteins, amilase, 24 hours urinary protein excretion. . no significant differences in the frequency of both alleles were observed among patients with different grades of hypertension or proteinuria. in conclusion, drb1* 03011, and possibly 1105 alleles confer susceptibility to psagn. however the severity of the disease is not determined by these two alleles. methods: fifty children who diagnosed as biopsy-proven fsgs were studied retrospectively by medical records. response to treatment and pathologic slides, we compared normal renal function group (n=28) and decreased renal function group (n=22), assessed the factors affecting renal survival and progression to renal failure. results: the mean age at onset was 8 1/12 years, gender ratio m: f was 2.3: 1 and the mean duration of follow-up was 7 1/12 years. the overall renal survival rate was 34% at 5 years, 8% at 10 years. five-year survival rate was 74% in normal renal function group, but 27% in decreased renal functin group. between the two groups, there were no significant differences in age at onset, gender ratio, amount of proteinuria, incidence of hematuria, hypertension and mesangial hypercellularity. decreased renal function group showed higher serum creatinine level, poor response to treatment, higher percent of glomeruli with sclerosis, moderate to severe tubulointerstitial change and vascular change (p<0.05). the prognostic factors of renal survival rate were same as above (p<0.05). there were no significant factor has shown relations with the progression rate to renal failure. conclusion: we reviewed the factors affecting long-term outcome of fsgs. serum creatinine level, steroid responsiveness and the degree of glomerulosclerosis were significant prognostic factors. but, age at onset, gender, amount of proteinuria, incidence of hematuria and hypertension were not considered as a prognostic factor. a background: several studies have suggested that cyclosporine (csa) and methylprednisolone pulse therapy (mpt) may be effective for idiopathic steroid-resistant nephrotic syndrome (isrns) in children; however, the optimal regimen has yet to be established. the present study evaluated the efficacy and safety of 2 years' treatment with csa (neoral) combined with mpt and prednisolone (psl) in such patients. methods: in this prospective study, children with biopsy-proved isrns were enrolled. all patients received csa and psl (1 mg/kg every other day). patients who had focal segmental glomerular sclerosis (fsgs) additionally received mpt (methylprednisolone at a dose of 30 mg/kg per day for 3 consecutive days at weeks 1, 2, 5, 9, and 13) . the dose of csa was adjusted to maintain a trough level from 120 to 150 ng/ml for the initial 3 months, followed by 80 to 100 ng/ml for months 4 to 12, and 60 to 80 ng/ml for months 13 to 24. results: twenty-six patients were enrolled. their mean age was 4.5±3.9 years. two-year follow-up was completed in 22 patients. histological examination at study entry revealed minimal changes in 16 patients, diffuse mesangial proliferation in 3, and fsgs in 7. at the end of the therapy, 19 patients had complete remission, including 6 who had occasional relapses of steroid-sensitive nephrotic syndrome, and 1 had partial remission; the remission rate was 90.8%. nephrosis persisted in 1 patient. disease progressed to end stage renal failure in 1 patient. serial renal biopsy at the end of the study showed mild signs of csa-related renal toxicity, including tubulointerstitial fibrosis in 2 (10.5%) of 19 patients. conclusion: combination therapy with csa, mpt, and psl for 2 years was clearly effective and produced a high remission rate without serious csa-related renal toxicity in children with isrns, in contrast to previous reports. objectives: patients with hemolytic uremic syndrome who do not require dialysis in acute stage usually have a good prognosis. however the spectrum of renal compromise is wide. we believed non-anuric patients with higher creatinine values in acute stage could have different evolution when compared to patients with lower values. aims: 1) to analyze the outcome after a 5 year and 2) to determine if peak serum creatinine values in acute stage would be a prognostic marker. methods: 130 patients, aged 13.8 months at hemolytic uremic syndrome, were analyzed. they were classified into 4 groups: group i, complete recovery; group ii had 2 subgroups: iia, microalbuminuria, and iib, proteinuria and/or high blood pressure, both with normal renal function; group iii, chronic renal failure; and group iv, end stage renal disease. peak creatinine value was definided as the highest value of at least 2 determinations in acute stage. these data were available in 57 patients and they were divided in those with creatinine equal to or higher than 1,5 mg/dl (26 patients) and those with lower values (31 patients). the relationship between creatinine and final outcome was analyzed. we applied fisher's test. results: after a mean follow-up of 12 years, 83 patients were in group i, 27 in group iia, 15 in group iib (6 with hypertension, 5 with proteinuria and 4 with both) and 5 in group iii. eight out of 26 patients (30%) with creatinine equal to or higher than 1.5 mg/dl in acute stage and 1 out of 31 (3.2%) with lower values were in groups iib and iii in the last visit (p=0.007). conclusions: 1) after 12 years, 15% developed proteinuria, high blood pressure or chronic renal failure and 21% microalbuminuria. 2) peak creatinine values in acute stage were a prognostic indicator. objective of study: the aim of this study was to assess the serum concentration of hs-crp in children with nephrotic syndrome (ns) treated with prednisone and cyclosporine a (cya). methods: patients were divided into 3 groups: i -20 ns children (4-14 years) in relapse, examined twice: a -before treatment and b -after proteinuria regression (a 3-4 week course of prednisone therapy), ii -20 children with steroid-dependent or steroid-resistant ns, treated with cya, also examined twice: d -before treatment with cya, e -6 months after therapy. control group (c) consisted of 20 healthy children. serum hs-crp level was determined using a nephelometric method with behring nephelometer 100 analyzer, dade behring. results: it was shown that median hs-crp concentration was the highest in children with relapsing steroid-sensitive ns before treatment (ia). after proteinuria regression (ib), the hs-crp level decreased and did not differ from healthy controls (c) (p>0.05). in group ii, before cya administration (iid) the level of hs-crp was normal, but increased after 6 months of treatment (iie) up to a level six times higher that of the control group (p<0,01). conclusions: in children with steroid-sensitive nephrotic syndrome in relapse, the serum hs-crp level is increased but returns to normal values after a 3-4 week glucocorticoid treatment course. in children chronically treated with cya due to ns, serum hs-crp level increases significantly during the therapy. slit diaphragm connecting adjacent foot processes of podocyte is the final barrier of glomerular capillary wall to prevent proteinuria. both podocytes and neuronal cells are terminally differential cells and they share many common features. nurexin is a presynaptic adhesion molecule that plays a role in synaptic differentiation, and they have been understood to be specifically expressed in neuronal tissue. we found that neurexins are expressed not only in neuronal cells but also in several organs including kidney. our immunofluorescence study shows that neurexins are restrictedly expressed in glomeruli in kidney. dual-labeling immunofluorescence studies show that neurexins are localized close to a cd2ap. we also detected some portions of neurexin staining are coincident with that of rab3a, a synaptic vesicle associated molecule. we found that a single splice variant of neurexin-1 is expressed in glomeruli. the staining intensity of neurexin in the glomeruli clearly reduced and their staining pattern shift to more discontinuous patchy pattern in puromycin aminonucleoside nephropathy and anti-nephrin antibody induced nephropathy. the alteration of neurexin in these models was detected more clearly and rapidly than nephrin. we confirmed that neurexin is expressed in podocyte also in human kidney section. these observations suggest that neurexin is involved in the development of proteinuria and that neurexin could be an early diagnostic marker of podocyte injury. to further elucidate the clinical relevance of t-cell abnormality in minimal change nephrotic syndrome (mcns), and to predict the consequences of mcns, we studied t-cell receptor (tcr) diversity by analizing cdr3 size distribution and the frequency of v repertoire usage. thirty-six pediatric patients with mcns were enrolled. eighteen were frequent relapsers and/or steroiddependent (fr/sd) and 18 were non-frequent relapsers (nfr). the study was performed to analyze serial changes of tcr v repertoires in the two groups of patients. frequencies of v repertoire usage were determined by flowcytometry, and tcr cdr3 length distribution was analyzed by genescan. in nfr patients, abnormalities in the distribution of 21 v repertoires were few in both cd4 + and cd8 + t cells. in fr/sd patients the patterns were normal in cd4 + t cells, while selected v repertoires were significantly increased in cd8 + t cells in some patients. furthermore, tcr diversity was significantly reduced in both cd4 + and cd8 + t cells in fr/sd patients as shown by marked skewing of cdr3 size distributions. it is noteworthy that in some fr/sd patients the initially abnormal tcr diversity improved as the clinical symptoms improved such that they became nfr over the years. analysis of tcr diversity may delineate the subgroup of patients with fr/sd and provide a rationale for early intervention with immunosuppressive therapy for these patients. background: transforming growth factor-β is known to play a role in the interaction between metabolic and homodynamic factors in mediating accumulation of extracellular matrix in the diabetic nephropathy. tgf-β1 gene polymorphism was associated with circulating tgf-β levels and influenced the pathogenesis of fibrotic diseases including diabetic nephropathy. in this study, we examined the relationship between tgf-β1 gene codon 10 polymorphism and type 2 diabetic nephropathy with more than 10-year history of disease. methods: we conducted a case-control study, which enrolled 325 type 2 diabetes. a total of 176 patients with diabetic nephropathy were compared with 149 patients without diabetic nephropathy. tgf-β1 codon 10 genotyping was determined using polymerase chain reaction with sequence specific primers method. results: distribution of tgf-β1 codon 10 genotype in the patients either with nephropathy or without nephropathy is confined to hardy-weinberg equilibrium. methods: nzb/w f1 female mice were distributed into three experimental groups (n=5 per group) according to age: 3, 4.5 and 6 months. at specific time-point for each group, 24-hour urine and blood samples were collected to determine proteinuria, osmolality and creatinine levels. after sacrifice, kidneys were removed to measure chemokines and cytokines levels by elisa (pg/100 mg of tissue). results: urinary flux was significantly lower at 4.5 than at 3 and 6 months. a significant reduction in creatinine clearance and an increase in proteinuria were detected at 4.5 and 6 months when compared to 3 months. no significantly changes were observed in serum and urinary osmolality. regarding inflammation, mcp-1 significantly increased at 4.5 (262.7±50.5) and remained elevated at 6 months (334.6±87.7) when compared to 3 months values (206.6±37.9). kc was also higher at 6 than at 3 months ( background: nephrotic syndrome (ns) is related to immunological factors and renal inflammatory mechanisms. many studies showed that inflammatory mediators, especially interleukin-8 (il-8) and monocyte chemoattractant protein-1 (mcp-1), have a role in kidney injury. changes in their urine concentration were found in lupus nephritis and iga nephropathy. thus, the aims of this study were to evaluate il-8 and mcp-1 in serum and urine samples of pediatric patients with primary ns and to verify the relation between these measurements and protein excretion. methods: patients were divided according to current 24-hour proteinuria into two groups: lower than 200 mg/24 hours (group 1, n=11) and higher than 200 mg/24 hours (group 2, n=14). blood and 24-hour urine samples were collected and stored at -80 °c. il-8 and mcp-1 were measured by elisa standard methods. results: blood il-8 and mcp-1 did not differ between the groups. urinary il-8 levels (pg/mg of creatinine) were significantly elevated in patients of group 2 when compared to group 1 (51.06±9.67 vs. 20.48±5.24, p<0.05). although group 2 also exhibited higher values of urinary mcp-1 (223.3±66.64 pg/mg creatinine) than group 1 (151.1±31.64 pg/mg creatinine), they did reach statistical difference. conclusion: the inflammatory process in ns seems to be a local phenomenon, since blood levels of these chemokines were similar in all groups. moreover, our findings showed a relation between il-8 and the presence of proteinuria and suggested a role for this local inflammatory mediator in disease activity. the characteristics of iga nephropathy detected in school urinary screening iga nephropathy (igan) is one of common types of glomerulonephritis in children. however, progression to esrd in patients with igan is not as rare as originally thought. in korea, school urinary screening (sus) program, an useful tool to find out abnormal urinary findings, initiated in 1998. igan was the most common histopathological change in children with isolated hematuria and/or proteinuira in sus. we studied to clarify the clinical and pathologic characteristics of iga nephropathy detected by sus in korea. we investigated 35 patients (symptomatic group=14 vs sus group=21) had been diagnosed with igan following renal biopsy at the yeungnam univ. hospital between may 1998 and may 2004. these patients were analyzed clinical nature, laboratory data and histopathologic findings (haas classification in lm) and progress, retrospectively. their mean age were 10.3±2.5 and 9.5±3.6, respectively, at the time of kidney biopsy. gross hematuria and edema apt to be common in symptomatic group. there were no significant difference in serum iga level, estimated ccr, 24-hours protein amount, light microscopic class and electron microscopic findings between two groups. mesangial iga deposition was significantly more intense in symptomatic group with gross hematuria. in addition to iga deposition in capillary and immune dense deposition in intramembrane is significantly common in symptomatic group with nephrotic range proteinuria. however, progression to chronic renal failure was not noted in both groups during 32.2±28.8 and 24.8±11.2 months respectively. also there were no difference in outcome according to treatment modalities. a longer follow-up period is needed to obtain more information on progression of igan with nephritic range proteinuria by disclosing iga deposition in capillary and immunedense deposition in intramembrane. outcome of srns is uncertain and especially patients unresponsive to treatment have a high risk to develop esrd. prognosis has improved with the introduction of csa, however but long-term follow-up data are scarce and response to csa in patients with genetic forms of srns is uncertain. we report on 25 patients with srns, that was diagnosed at a median age of 3.6 (range 0.5-11.2) years. treatment with csa was initiated on concomitant prednisone therapy, however steroids were discontinued after due course in all patients. median follow-up is 9.5 (0.3-19.1) years. 17 patients had fsgs on renal histology and 12 patients had mcns. complete remission (cr) was defined as reduction of proteinuria <100 mg/m 2 /d. partial remission (pr) was defined as reduction of proteinuria of at least 50% and cessation of edema with serum albumine levels >25g/l. results: 12 patients (6 fsgs, 6 mcns) reached cr with csa treatment. in 8 of these (5 fsgs, 3 mcns) csa could be tapered and discontinued successfully after a median time of 2 (0.5-6.1) years. eight patients showed (7 fsgs) a pr while 5 patients (3 fsgs) showed no repsonse (nr). of 6 patients going into esrd 5 had podocin mutations (pm). only one patient with pm showed partial remission on csa. our data indicate a positive effect of csa treatment in srns, especially in sporadic cases. in patients with cr tapering and even discontinuation of csa is possible. prognosis of srns has improved with csa treatment. objective: we planned to investigate the effects of rsv on the proteinuria and glomerular structure of rats and to explore the role of rsv in the pathogenesis of minimal change nephrotic syndrome. methods: sd rats were inoculated with 6 10 2 , 10 4 , and 10 6 pfu rsv respectively, and sacrificed on days 4, 8, 14, 28 and 60 postinoculation (rsv 4 , rsv 8 , rsv 14 , rsv 28 , rsv 60 ). renal histology was observed by light microscopy and electron microscopy. meanwhile, the proteinuria and serum parameters were measured. the rsv rna and rsv titer were determined by in situ hybridization and plaque assay respectively. immune complex deposits were detected by immunofluorescence microscopy. results: after inoculation, the urinary protein excretion was increased, especially in 6 10 6 pfu rsv 14, 28, 60 (p<0.05). the serum albumin of 6 10 6 pfu rsv 14, 28, and different-titer rsv 60 decreased, but no significant differences in cholesterol, urea nitrogen and creatinine were found among all. slight hypercellularity in minority glomeruli and swelling of partial tubular epithelial cells were observed in rsv 4, 8 of different-titer, whereas a relief of the above changes and no abnormalities were detected in rsv 14 and rsv 28 respectively under a light microscopy. extensive foot process effacement was observed in 6 10 6 pfu rsv 14, 28, 60 under an electron microscope. rsv rna signal and rsv titer of renal and pulmonary tissues, depending on the dose of inoculum, reached their climax on day 8 postinoculation, especially in 6 10 6 pfu rsv 8 . no immune complex deposits were detected in the renal tissues. conclusion: our study reports for the first time that rsv can lead to nephropathy in rats on day 14-60 postinoculation, especially in 6 10 6 pfu rsv-inoculated rats, which may be a new exploration of the pathogenesis of mcns. objectives of study: podocytes play an important role in maintaining the glomerular filtration barrier structure and functions, which associates with several podocyte-specific proteins. our previous study indicated the antiproteinuric effects of dexamethasone were achieved by changes the expression of certain podocyte molecules in vivo. the extracellular signal-regulated kinases regulates a wide range of cellular processes. the aim of the present study is to analyze the potential effects of dexamethasone on podocytes in vitro and to investigate its associated signal transduction pathway. methods: immortalized mouse podocyte clone was divided into three groups: the dexamethasonetreated group (dex-group), the dexamethasone with puromycin aminonucleoside-treated group (dex-pangroup), and control. in dex-group, cultured podocytes were treated with dexamethasone, while in dex-pan group, cells were treated with dexamethasone for 30min first, then added puromycin for different time periods. changes of the protein expression of podocyte-specific proteins and phosphorylation of erk were analyzed by western blotting analysis. result: compared with the control group, in dex-group, the expression of nephrin, podocin, cd2ap, α-actinin4 proteins and vegf protein started to elevate at 24 hr, while neph1 showed no obviously change. erk signaling pathways was activated. increased phosphorylation of erk was marked but transient, which increased from 2 min to 15 min, then decreased. at 30 min the level of phosphorylation of erk returned to the baseline. the phosphorylation of erk level was significant raised in dex-pan group, and lasted to 60 min. conclusion: dexamethasone alters the expression of certain podocyte-specific proteins not only in vivo but also in vitro, and in part, through the activation of the erk signal pathway. kh. kim minimal lesion in the renal biopsy of idiopathic nephrotic syndrome (ns) patients (pts) generally predicts a benign course. fsgs lesions in nspts, on the other hand, are associated with increased risk of steroid resistance and progression to renal failure. fsgs may be observed in follow-up biopsies despite being initially undetectable. whether this represents sampling error or the true natural history of this condition, earlier markers of steroid resistance and poorer prognosis could prove helpful. renal morphometric analyses was performed in 13 ns pts, ages 2 to 19 years, initially diagnosed with minimal lesion, with (n=8) or without(n=5) subsequent progression to fsgs or end stage renal disease (esrd), along with 5 controls ages 3 to 16 years. the age of patients in progressive and non-progressive group and controls were similar. gbm width in patients with minimal lesion (368±52 nm) who subsequently progressed, was significantly greater than that in non-progressive group (290±35 nm, p<0.02). gbm width in both groups was not significantly different compared with the controls (321±49 nm). average foot process width was increased in patients both with progression and non-progression as compared with controls, but there was no significant difference between progressive and nonprogressive group. the length density of podocyte detachment per gbm surface was not significantly different between progressive, non-progressive groups and control groups. there were no significant differences in the mean glomerular volume and cortical interstitial volume fraction between progressive and non progressive group. in conclusion, gbm width may help to differentiate between progressive and non-progressive groups in minimal lesion nephropathy. this may be a pathogenetic clue and needs further study. objective: our study is to investigate the correlation between clinical features and pathological characteristics on henoch-schönlein purpura nephritis (hspn) and the therapeutic methods. methods: fifteen boys and five girls aged 7-15 years (median 10.5 years) with hspn were analyzed retrospectively. the clinical characteristics, laboratory data, pathological findings and therapeutic methods were investigated. results: the patients with isolated hematuria and isolated proteinuria, the pathologic patterns were lighter then gradeii b ; eight patients with hematuria and proteinuria and seven patients with nephrotic syndrome, the pathologic patterns of injury is more severe then gradeii b , whose pathologic patterns injury exceeded gradeii b is 77.8%. twelve patients with nephritic-range proteinuria (>50mg/kg.d) and nephrotic syndrome received corticosteroids, cyclophosphamide, heparin and dipyridamole treatment. nine of twelve patients received intravenous pulse methylprednisolone (mp) and pulse cyclophosphamide (ctx). fourteen of twenty patients obtained stable remission after 3 months to 5 years, and five of twenty patients have asymptomatic microscopic hematuria, another one only has minimal proteinuria. conclusions: if the clinical features showed nephritic-range proteinuria or nephrotic syndrome, the renal pathologic changed markedly as well. for patients whose pathologic exceeded grade iii b or have renal tubule and interstitial damage, our study suggests that mp pulse therapy have satisfied curative effect. materials and methods: in experiment 1, higa mice, c57bl/6 mice and balb/c mice were inoculated intravenously with live cb4 and inactivated cb4 once a month from 1 to 12 mo of age. in experiment 2, higa mice, c57bl/6 mice and balb/c mice were inoculated intravenously with live cb4 and inactivated cb4 once at 6 wk of age. mice in the control group were inoculated with vehicle. the kidneys were extirpated from 5 mice of each group killed with time after inoculation for histological evaluation. experiment 3: we examined prostaglandin (pg) synthetic activity of cultured human mesangial cells. results: the scores for mesangial iga deposition, pcna-positive and matrix scores at 20 weeks were higher in higa mice with live cb4 than in higa mice with inactivated cb4 or without cb4. on em examination, swelling and detachment of endothelial cells from 24 hours after inoculation and increase of serum ifn-gamma concentration were found in mice with live cb4. the scores for mesangial iga and igg depositions, pcna-positive and matrix scores at 30 weeks were more frequently found in balb/c mice with live cb4. production of pge2 and txb2 significantly increased in cultured human mesangial cells damaged by live cb4. conclusion: these results suggest that cb4 provokes exacerbation of renal pathological findings in higa mice via endothelial injury and ifn-gamma production, and may play important roles in igalike glomerulonephritis pathogenesis. rapidly progressive glomerulonephritis (rpgn) is a rare occurrence in alport syndrome (as). this report describes the case of a 10-year-old malewith as who developed rpgn and considers the cause of rpgn in this patient. he had a history of persistent hematuria and proteinuria since birth. at the age of 2 years, he was diagnosed with as based on a renal biopsy. he developed nephrotic syndrome at the age of 5 years. before administration of cyclosporine (cya), repeated renal biopsy was performed at the age of 7 years. the biopsy specimen showed pathologic lesions characteristic of as without crescents. using immunofluorescence (if) staining, the expression of alfa-5 chains of collagen iv was found to be absent in the glomeruli. therefore, cya was administered for eight months. although he recovered from nephrotic syndrome, the effect of cya was limited. after the cessation of cya, his renal function slowly exacerbated. at the age of 9 years, the administration of angiotensin receptor blocker was started. no subsequent anti-proteinuric effect was noted and his renal function improved to cr 0.79 mg/dl. however, by the age of 10 years, he showed macrohematuria and acute deterioration in renal function to cr 9.38 mg/dl. subsequently, he underwent a third renal biopsy. on light microscopy, the biopsyspecimen showed diffuse cellular crescentic glomerulonephritis. if findings indicated pauci-immune type and electron micrography showed a few subepithelial deposits. a serological study revealed negative results for mpo-anca, pr3-anca, and anti-glomerular basement membrane antibody. despite immediate treatment with pulses of methylprednisolone, cyclophosphamide, and plasma exchange, he progressed to end stage kidney disease. the patient reported here presents either a super imposition of rpgn upon a preexisting case of as or a new morphologic and clinical presentation for as. the wt1 gene encodes a zinc finger transcription factor involved in kidney and gonadal development. mutations of the wt1 gene have been shown to cause denys-drash syndrome (dds) and frasier syndrome (fs). the association of early onset nephrotic syndrome progressing to renal insufficiency, xy pseudohermaphrodism and wilms' tumor characterizes dds. renal biopsy shows diffuse mesangial sclerosis (dms). fs is also characterized by xy pseudohermaphrodism and nephropathy, but patients have delayed kidney failure characterized histologically by fsgs. this report examines three girls with nephrotic syndrome related to mutations in the wt1 gene, but with normal female karyotype and development. two girls with early-onset steroid-resistant nephrotic syndrome presented classical wt1 mutations coding for an amino acid change (d396n) and (r394w) at exon 9 that is typical of dds. both children were phenotypically and genotypically females. they developed end stage renal failure within 7 years. one girl had a wilms' tumor on the right kidney. the third child was identified with heavy proteinuria at 7 years of age. laboratory investigations revealed a protein level of 7.2 g/dl (6-8 g/dl), albumin 3.7 g/dl (3.9-5.3 g/dl). proteinuria worsened to 4 g/24 h and she failed to respond to prednisone. renal biopsy demonstrated fsgs in 20% of glomeruli. the splice site mutation ivs9+4 g >a, known to be associated with fs, was found in this patient. karyotype was 46, xx and she had normal uterus and adnexae on ultrasound. angiotensin-converting enzyme inhibitors were prescribed but she still has heavy proteinuria without renal failure. the classical clinical presentation of dds and fs is out dated. pediatric nephrologists need to consider the possibility of these genetic syndromes in evaluation of females with steroid-resistant nephrotic syndrome. we aimed to compare the effects of cyclosporine (csa) or mmf with or without combination of vitamin a,d,e or n-acetyl-l-cysteine (nac). the study included 64 rats in eight groups: control, nephrotic syndrome without treatment, treatment with csa, mmf, vitamin a,d,e, combination of csa and vit ade, combination of mmf and vit ade and combination of nac and vit ade. all rats except the control group were given adriamycin. blood samples were drawn and 24-h urine were collected on day 1 and at weeks 5 and 16. at the 5 th week, 24-h urinary protein excretions in the treatment groups were higher and serum albumin levels were lower than that of 0 th week and control groups (p>0.05). at the 16 th week, urinary protein excretions in group csa&ade was lower than of the groups of csa, mmf, mmf&ade, ade and nac&ade with non-significance (p=0. 42, p=0.94, p=0.72, p=0.82, p=0.53) . serum albumin in group mmf&ade and group ade were significantly higher than of control group (p=0.015, p=0.01). serum albumin in group ade was significantly higher than that of groups of csa and csa&ade (p=0.05, p=0.045). serum triglyceride in group mmf&ade was significantly lower than that of groups csa and csa&ade. serum creatinine in group mmf&ade was lower than that of the groups of csa, csa&ade, mmf, ade and nac&ade and was significantly lower than that of control group (p=0.004). serum creatinine in group csa was significantly higher than of groups of csa&ade, mmf, mmf&ade (p=0.004, p=0.001, p=0.001, respectively). in group nas+ade, total oxidant was significantly higher and total anti-oxidant was significantly lower than other treatment groups (p<0.05). we showed that the better effect on proteinuria, serum triglyceride and albumin and lower serum creatinine by adding vitamin a, d, e in the treatment of experimental nephrotic syndrome with csa or mmf. conclusion: ht is associated with known risk factor of progression of biopsy-proven gn such as s-cr or proteinuria. the crb is an important tool for studies focusing on the epidemiology of gn in the czech republic and serves as a basis for cooperation in this field. (4), lupus-nephritis (3), iga-nephropathy (2), minimal change disease and membranous nephropathy (by 1) were observed. the distinction of morphological variants of the fsgs was started recently (last 6 months). among the patients with fsgs, which were biopsied during this short period (4), all have had a tip-lesion. these patients were started cyclosporine a 150 mg/m 2 /day with complete (3) and partial (1) remission achievement after 1-3 months. thus, the focal and segmental glomerulosclerosis is the most frequent cause of the nephrotic syndrome in children. the focal and segmental glomerulosclerosis with tip-lesion is characterized by favourable course and good response to therapy with cyclosporine a during the short-time period. objectives of study: molecules of monocyte chemoattractant protein-1 (mcp-1), β-catenin and cytokeratin19 (ck19) express increased in cellular crescent, which is a severe pathological change in renal diseases. however, it is unknown whether these molecules in urine correlate to the number or extent of cellular crescents. methods: urinary molecules mentioned above were detected in 20 healthy subjects and 124 patients with renal diseases by elisa. the expressions of these molecules and macrophage (cd68 positive) in 87 biopsy specimens were also investigated. results: significant higher levels of these molecules in urine were demonstrated in all patients with renal diseases compared with healthy subjects (p<0.01), but the highest level in patients of the cellular crescent group. the significant correlations were revealed between these molecules in urine and the index of cellular crescents (r=0.75, r=0.21, r=0.63, p<0.01), between these molecules in glomeruli and the index of cellular crescents (r=0.58, r=0.66, r=0.52, p<0.01), and between these molecules in glomeruli and in urine (r=0.62, r=0.50, r=0.20, p<0.01). conclusions: this study suggested that the detection of urinary mcp-1, β-catenin and ck19 might become potential biomarkers for clinical diagnosing cellular crescent lesions and assessing cellular crescent extent in renal diseases. this study aims to evaluate the benefits and harms of levamisole in steroid dependent (sd) and frequent-relapsing (fr) nephrotic children. material and methods: a total of 24 steroid-sensitive nephrotic children were recruited prospectively from january 2004 to december 2006. 5 females and 19 males, 11 (48%) fr, 12 (52%) sd. mean age at the beginning of levamisole was 5,7 years. twelve didn't receive any alternative drug before, 12 received cyclophosphamide. renal biopsy was perfomed in 5 patients, 4 had minimal change disease (mc), one patient had mc at the first biopsy and fsgs in the second. the patients were divided in two groups according to their steroid response: sd and fr. levamisole was started at a dose of 2,5 mg/kg/48 h as a second line drug in order to try to prolong periods of remission. clinical and laboratorial controls were performed monthly. patients were evaluated as: total responders: when steroid withdrawal was possible, partial responders: when steroid reduction was possible, non-responders: no steroid modification in 3 months. the responders used levamisole for one year. results: the response of frequent-relapsing patients was: 63% of total response, 18% of partial response and 18% of non-responders. steroid-dependent patients had 50% of total response, 25% partial and 25% non-responsers. only one patient developed leukopenia. now 21% (5) are out of levamisole and in remission, 50% (12) are still using levamisole(alone or low-dose of prednisone), 21% (5) are using cyclosporin, one used cyclophosphamide and one is using low-dose prednisone. conclusion: levamisole is a promising alternative drug for nephrotic syndrome. the major advantage of levamisole is its steroid-sparing effect with minimal toxicity. conclusions: hypertension and renal insufficiency were less frequently seen in chinese children with fsgs, isolated hematuria as unique clinic presentation was common in fsgs. all pathological variants had tubular-interstitial lesions, but vascular lesions were rarely seen. most fsgs children with nephrotic syndrome were sensitive to steroid at initial stage, and easy to develop frequent relapse gradually, immunosuppressive agent may be helpful to elevate remission rate. the aim of the study was to assess whether the serum index iga/c3 can be a usefull marker of activity igan and hsn in children. twenty children with igan (mean age 10.0±3.6 years) and 33 children with hsn (mean age 9.53±4.17 years) were retrospectively analysed. in all children urine analysis, gfr were checked and the levels of serum iga and c3 were measured before therapy, serum iga/c3 was than calculated. at the onset of illness, igan and hsn was diagnosed based on the renal biopsy in mean time 1.06±1.37 years. changes in light microscopy were graded i-v according to the classification of who (cwho). all biopsies were scored for activity and chronicity index (ai max score 9, ci max score 12) (pediatr.nephrol.1989,3,248 heparan sulfate proteoglycans are present both as structural components of the gbm and as modifiers of growth factor signaling on the cell surface. in mcns the presence of certain hs epitopes inthe gbm is decreased. hsulf1 and hsulf2 are recently identified endosulfatases, that can remodel the sulfation pattern of hs and thereby control the availability and presentation of factors such as fgf and hgf to their high affinity receptors. sulfatase activity requires posttranslational modification by formylglycine-generating enzyme or sulfatase modifying factor 1 (fge/sumf1) that is counteracted by its paralogue pfge/sumf2. we demonstrated that podocyte, endothelial and tubular epithelial cell lines express mrna for sulf1, sulf2, sumf1 and sumf2. we investigated the in vivo distribution patterns of these enzymes in human kidney specimens by in situ hybridization. in histologically normal kidneys (n=5) expression of hsulf1 mrna was largely restricted to peritubular and glomerular endothelial cells, where as hsulf2 mrna was weakly expressed in all glomerular resident cell types. expression of sumf1 and sumf2 mrna was present in a minority of mesangial cells and podocytes, as well as in avariable number of glomerular and peritubular endothelial cells and invascular smooth muscle cells. in mcns (n=5), the glomerular expression patterns of hsulf1, sumf1 and sumf2 mrna did not differ significantly from that in controls. in contrast, hsulf2 mrna expression was increased in podocytes. increased hsulf2 expression by podocytes is a novel factor to be considered in the pathogenesis of mcns. the onset and duration of ins, histopathological changes in renal biopsy, results of corticosteroid therapy and proteinuria selectivity reflecting the alteration of glomerular capillary wall were analysed. materials and methods: 80 children with ins aged 2-18, followed up 12 to 36 month, and 20 healthy children were studied. in all patients 1 stage of ckd were diagnosed. ins children were divided in two groups regarding to serum cystatin c levels as a marker of gfr: group i (n=37)children with unchanging gfr, ii (n=43) -patients with impairment renal function over the study period. serum total protein, albumin, cholesterol, cystatin c, creatinine and immunoglobulin igg, and urinary protein, albumin, igg and creatinine were measured. results: serum cystatin c levels were higher in both groups of ins patients compared to healthy children (gr. i: 0.8±0.11, gr. ii: 1.19±0.42 vs 0.7±0.1 mg/l; p<0.01). in group ii amount of 24-hour proteinuria was significantly higher than in group i (2.93±2.27 vs 3.76±2.79 g/l; p<.001), however other biochemical parameters (including igg excretion, albuminuria, selectivity index) were not different. in group ii higher age of onset was found. in this group mesangial proliferation and focal segmental glomerulosclerosis more often were observed. conclusions: the age of onset, histopathological diagnosis and proteinuria can be considered as important markers of ckd progression in children with ins. probably, longer follow-up of children with ins is necessary to find other prognostic factors. k. kilis-pstrusinska, k. fornalczyk, d. zwoliñska cyclosporine a (csa) has been used as a therapeutic option for steroid-dependent and steroidresistant nephrotic syndrome (ns). the aim of the study was to assess the effects of long term csa treatment in children with ns. methods: we performed retrospective study to evaluate safety and efficacy of csa therapy in 44 children with ns (20 girls and 24 boys), aged 2-16 years. results: before introducing csa, in 30 patients steroid-dependent ns and in 14 -steroid-resistant ns were observed. 28 children presented symptoms of steroid toxicity. pre-treatment renal biopsy was performed in 42 patients (2 children without biopsy because of renal agenesia). minimal change disease was diagnosed in 18 (43%) children, focal segmental glomerulosclerosis (fsgs) in 9 (21%), mesangial glomerulonephritis (gn) in 8 (19%) and membranoproliferative gn in 7 (16%) cases. all children were taking csa (target blood trough levels 50-150 ng/ml) more than 6 months, mean 24 months (range 7-72). complete remission was achieved in 32 (73%) children, partial in 9 (20%). in 17 (39%) patients csa treatment was continued with mild dose of steroids. 3 patients (7%) did not respond to the therapy and one of them end stage renal failure developed. following side effects have been observed: hyperuricuria (20% of patients), hyperuricaemia (9%), hypomagnesaemia (7%), hypertension (11%), hypertrichosis (9%), gingival hyperplasia (5%), hepatotoxicity (2%), gastritis and ileitis symptoms (2%). in 15 patients control renal biopsy was performed after 24-36 months of csa therapy. in 4 patients progression to fsgs was seen. only in one case histological findings of csa nephrotoxicity occurred. conclusion: long-term csa treatment in children with steroid-dependent and steroid-resistant nephrotic syndrome can be consider as an effective and safe therapy. introduction: membranous nephritis represents a rare disease in childhood with an incidence of 0.8 to 6% in renal biopsy specimens among various types of glomerulonephritis. although in many cases the disease is considered as idiopathic the association of membranous nephritis and infectious agents it is also well known. aim: we report a case of a 19 months old baby girl of asian origin, presented with macroscopic haematuria of glomerular origin, proteinuria, 1-3 gr/24 hours, hyaline and granular casts, maculopapular rash on the legs and microcephaly. methods: renal function tests in terms of plasma urea and creatinine were normal. the renal biopsy showed membranous nephritis. tests for infectious diseases (torch screen) showed a primary cmv infection. this diagnosis was based on the presence of high level cmv specific igm antibodies, increased igg antibodies and low avidity of cmv specific igg antibodies. a real-time-pcr of the renal biopsy specimen was positive for cmv as well, confirming this virus as the causative agent of membranous nephritis in the presented case. treatment with gancyclovire per os was introduced and it was most impressive since proteinuria disappeared in the following two to three weeks. two years after the diagnosis the child remains well and asymptomatic. in summary: to our knowledge, among various infectious agents, there is no case of congenital or secondary nephropathy described so far due to cmv infection in children. objective of study: pulse methylprednisolone therapy (pmt) has been shown effective in proteinuric renal diseases. but its exact effect in children with steroid-sensitive relapsing nephrotic syndrome still has no definite conclusion. to evaluate the effect and adverse effects of pmt, we performed a retrospective study. methods: there were 11 cases of steroid-sensitive relapsing nephritic syndrome received pmt. they all had been treated with oral prednisone in similar condition previously. a self control design was used to compare the effect of pmt and oral prednisone. results: the average age was 7.5±3.1 years. ten cases attained complete remission after the first course of pmt, and the average duration of pmt until remission was 7.4±4.4 days. one case attained complete remission after the second course of pmt. compared with the effect of oral prednisone previously, seven cases attained complete remission more rapidly. paired-samples t-test was performed to compare the effects of pmt and oral prednisone in six cases with very similar state, however, the difference between them was not significant (p=0.082). during the treatment of pmt, adverse effects were found in 6 cases. conclusion: compared with oral prednisone, the superiority of pmt had not been definitely confirmed, and adverse effects might appear during the treatment. therefore we should be very strict with administering pmt in children with steroid-sensitive nephrotic syndrome. the study we performed was retrospective, so it was necessary to design a prospective clinical randomized controlled trial to further evaluate its effect. objective of study: pulse methylprednisolone therapy (pmt) has been shown effective in proteinuric renal diseases. but the exact effect of pmt in children with steroid sensitive nephrotic syndrome (ssrn) still has no definite conclusion. to evaluate the effect and adverse effects of pmt, we performed a prospective study. methods: a prospective clinical randomized controlled trial was conducted to compare the effect and adverse effects of pmt with oral prednisone (op) in children with ssrn. thirty-one children were enrolled with only 23 suitable for evaluation including 9 patients in the pmt group and 14 in op group. results: there was no significant difference between both groups in complete remission rate. the average durations of therapy until remission were 4.9±1.5 days in pmt group and 9.6±6.3 days in op group, respectively. complete remission was more rapidly attained in pmt group (p=0.036; <0.05). during the treatment and the following 3 months, no significant difference of adverse effects was found between both groups. there was no significant difference between both groups in relapse rate during 3 months follow-up. conclusion: compared with oral prednisone, pmt could induce complete remission more rapidly and did not company with more adverse effects in children with ssrn. pmt had no effect on the reduction of relapse rate in the following 3 months after administration. outcome of childhood henoch-schönlein purpura nephritis with nephroticrange proteinuria in a single center objective: the majority of children with henoch-schönlein purpura nephritis (hsn) only with hematuria and/or mild proteinuria have good chances for recovery. however, it is still unclear how we should treat hsn with persistent massive proteinuria. the aim of this study is to evaluate the outcome of childhood hsn with nephrotic-range proteinuria treated with angiotensin converting enzyme inhibitor (acei) and corticosteroids. methods: 109 patients with henoch-schönlein purpura (58 boys, 51 girls) ranging from 0.5 to 13.8 (6.3±2.7) years old at onset visited our hospital between april 1997 and december 2006. thirty seven (33.9%) developed hsn. mean age of 21 (13 boys, 8 girls) hsn patients with nephroticrange proteinuria (>40 mg/h/m 2 ) at the time of diagnosis was 8.3±2.9 years old. two developed nephrotic syndrome, but none had renal insufficiency at onset. one patient suffered moderate proteinuria and renal dysfunction 8 years after the onset. renal biopsies were done in 16 cases and showed 1 for grade i, 4 for grade ii and 10 for grade iii respectively (classification by international study of kidney diseases in children). results: eleven of the 21 patients received acei and no patients were treated with immunosuppressive agents except for corticosteroids and methylprednisolone pulses. after a mean follow-up of 3.8 years, 11 patients showed complete remission, 9 had mild proteinuria or microscopic hematuria, only one postpartum patient presented with nephrotic-range proteinuria, and none developed renal insufficiency. conclusions: our results suggested that the short-term outcome of childhood hsn with nephroticrange proteinuria but not renal insufficiency was relatively favorable. thus, the degree of proteinuria is not a sole prognostic factor for childhood hsn. therefore, the indication for corticosteroid therapy should be clarified. recent observations determined a r1160x specific exon 27 mutation in the gene encoding nephrin (nphs1) which evidenced an unexpectedly mild finnish-type congenital nephrotic syndrome (cns) phenotype. the long-term follow-up of patients with this mutation is actually known only in a few patients. we reported the long term follow-up of a girl originary of sicily (italy) presenting such a mutation. the first 3 years of her life were previously reported (s.guez et al pediatr nephrol 1998). in brief the child was pre-term born from related parents and she presented proteinuria (3-6 g/day) from birth. renal biopsy was consistent with the diagnosis of cns and molecular evaluation demonstrated a homozygous exon 27 r1160x nonsense mutation in the nphs1 gene. in the first 2 years she was treated by human albumin without a regression of proteinuria that decreased up to 0.3-0.5 g/day with enalapril treatment (0.75 mg/kg/day); clearance of creatinine at 3 years of age ranged between 49 and 73 ml/min/1.73 mq. during the following 10 years (at the last control the girl was 13 year old) she had continued enalapril treatment (0.20 mg/kg/day). creatinine clearance was 80 ml/min/1.73 mq/day, serum total protein 66 g/l; serum albumin 40 g/l and proteinuria ranged between 1.5-4.0 g/day. both height and weight were at 50 th for age and pubertal stage was normal; blood pressure was 90/60 mmhg. in conclusion, this is the first reported long-term follow-up in an italian patient affected by finnishtype cns with the specific r1160x nonsense mutation in the nphs1 gene: even if proteinuria persisted there was no worsening in gfr. serum total protein, albumin and growth were normal confirming the milder phenotype in comparison with the typical finnish forms. long-term enalapril treatment may also have contributed to the prognosis in this specific form of congenital nephrosis. atypical hemolytic uremic syndrome (ahus) frequently results in end-stage renal failure and can be lethal in many cases. recently, it has been recognized that many cases of ahus are associated with a defective control of the complement activation cascade. more than sixty different mutations in complement factor h gene (cfh) have been reported so far. guidelines for treatment modalities are yet to be established although plasma infusions and exchanges are often advocated. we describe a patient who presented at 7 months of age with ahus (anemia, thrombopenia, acute renal failure requiring hemodialysis) associated with heterozygous combined de novo complement factor h mutations (s1191l and v1197a) on the same allele. laboratory investigations showed normal levels of complement c4, c3 and factor h. during the first episode, daily plasma exchanges (pe) using cryosupernatant (cr) as replacement fluid resulted in a resolution of hemolysis and complete normalization of renal function. two ahus recurrences were successfully treated with daily pe and subsequently pe were weaned to twice weekly. one year after the first episode, pe were stopped and pi regimen (30 ml/kg twice weekly and weekly thereafter) was started. at the present time, the patient has been receiving weekly pi (30 ml/kg) for one year. transitory falls in haptoglobin levels or platelet counts are observed periodically and successfully treated by intensification of pi (30 ml/kg) twice weekly for one or two weeks. renal function remains normal.although our observation demonstrates the effectiveness and good tolerance of large volumes of pi (30 ml/kg), long-term efficacy of such a therapy remains to be evaluated. because of the possibility of secondary failure of plasma therapy, it is important to investigate alternative approaches such as combined liver-kidney transplantation. common variable immunodeficiency (cvid) is characterized by reduced serum immunoglobulin levels and recurrent bacterial infections. there have been only 3 previous case reports of renal granulomas in cvid and only one of them was associated with immune complex glomerulonephritis. we present a case of renal granuloma and glomerulopathy in a patient with cvid. a 17-year-old girl, with a past history of uveitis, presented with cardiac tamponnade and bilateral pleural effusions. investigations revealed nephrotic syndrome (serum albumin of 23 (normal 41-54) g/l and proteinuria >3g/l), microscopic hematuria and reduced serum igg levels (4.49 g/l, normal 5.29-15.21 g/l). lupus nephritis and serositis were first suspected and corticosteroids were initiated. no serum anti-nuclear or anti-dna antibodies, nor complement activation were detected. a renal biopsy was performed and showed global glomerular endocapillary proliferation. intratubular calcium deposits were present. in the interstitium, a noncaseating epithelioid granuloma was found. immunofluorescence studies showed significant mesangio-parietal igm deposits with few c3 and c1q. as igm-immune complex glomerulonephritis has been reported in sarcoidosis, this diagnosis was highly suspected. further investigation revealed normal lung parenchyma and mediastinum, normal serum angiotensinconverting enzyme, 1.25 oh 2 d 3 , calcemia and calciuria. the nephrotic syndrome gradually improved, but serum igg levels remained persistently low (2.73 g/l). the diagnosis of cvid was confirmed and iv immunoglobulins were initiated. this is the first report of concomitant renal granuloma and igm-immune complex (without igg) glomerulonephritis in a cvid patient. in summary, cvid must be included in the differential diagnosis of renal granuloma and should be differentiated from sarcoidosis to ensure appropriate therapy. o. nwobi, c. abitbol, j. chandar, w. seeherunvong, g. zilleruelo background: rituximab, an anti-cd 20 antibody, has been proposed as therapy for refractory systemic lupus erythematosus (sle), although its use in children remains anecdotal. we present our initial longterm experience on the safety and efficacy of rituximab for treatment of sle in children. methods: 17 pediatric patients with sle refractory to standard treatment protocols were treated with rituximab for 2-4 doses (375 mg/m 2 ). all had proliferative nephritis and systemic manifestations of vasculitis. clinical disease activity was scored using the sle-disease activity index (sledai). proteinuria is reported as the urine protein to creatinine ratio (upr/cr). patients have been followed an average of 2.3±i.2 years. results: b cell depletion occurred within 1 month and remained suppressed for up to 3 months. clinical course, renal function and proteinuria improved in the majority of patients as summarized below: objective: to assess efficiency and safety of treating crns patients with srl. subjects: 5 patients, mean age 11.6 years old (6 yrs-18 yrs) (3 females) affected by crns. inclusion criteria: histological diagnosis of focal and segmental glomerulosclerosis, glomerular filtration rate (gfr) above 60ml/min/1.73 m 2 , negative plasma pregnancy test, signed child and parents informed consent. exclusion criteria: secondary nephrotic syndrome, white blood cells (wbc) count below 4000/mm 3 , chronic hepatopathy, coagulopathy, tumoral or infection processes. discontinuation criteria: sustained decrease in gfr by more than 30% of the initial rate, decrease of the wbc count to less than 4000/mm 3 , occurrence of lymphoprolipherative and tumoral processes, severe infection, alterations in coagulation parameters, positive pregnancy test or inflammatory process or lack of changes in proteinuria or its increase after four-month treatment. methods: srl dose and dosage: dose of 1 to 2 mg/m 2 /day (up to 5 mg/day) administered once a day. expected dosage range: 5 to 10 ng/ml (hplc-uv method). treatment duration: 12 months. results: 3 patients showed nephrotic syndrome remission; average srl dose: 2 mg/m 2 /day; average srl dosage: 5.75 ng/ml (range 5.3-6.3). average proteinuria prior to treatment: 157 mg/m 2 /hour (range 80-263); average proteinuria after treatment: 3 mg/m 2 /hour (range 2.5-4); average time of remission: 2 months and 20 days, none of 5 patients showed adverse events that would have lead to the treatment discontinuation. if these data are representative of the universe of patients we are dealing with, the confidence interval (p=0.95) of the percentage of patients with not proteinuria after treatment is going to be between 45% and 75% if 40 patients are assessed. conclusions: srl caused crns remission in patients who were refractory to traditional immunosuppressive treatments. background: retinoic acid-inducible gene-i (rig-i) may play an important role on inflammatory and immune processes by regulating the expression of various genes, and has been reported to be expressed in various inflammatory diseases. we studied the expression of rig-i in human lupus nephritis and evaluated the correlation between its expression and the histological activity of the renal disease in these cases. methods: expression of rig-i in the glomeruli was assessed by indirect immunofluorescence method; frozen sections of ten kidney tissue specimens obtained from eight patients with lupus nephritis were stained with a monoclonal antibody for rig-i. kidney tissue specimens from eight patients with minimal-change (mc) disease were used as controls. results: expression of rig-i was detectable as granular immunofluorescence in a mesangial and capillary distribution in all the patients with lupus nephritis, but was absent or only trace-like in the patients with mc disease. the glomerular immunoreactivity for rig-i was correlated with the histological activity and severity of the renal disease in the patients with lupus nephritis. conclusions: rig-i expression occurs at levels detectable by indirect immunofluorescence and may be potentially useful as a parameter reflecting the renal histological activity in cases of lupus nephritis. cyclophosphamide pulse therapy for crescentic, proliferative iga nephropathy in children iga nephropathy is one of the most common glomerular kidney diseases in europe, up to 25% of affected adults need dialysis after 10 years. therapy of crescentic, proliferative iga nephropathy in children is not well examined. between 01/2000 and 12/2006 seventeen children (main age 10 years (6-18), male/female=10/7) with biopsy-proven mesangioproliferative glomerulonephritis as manifestation of iga nephropathy were enrolled. nine patients (male/female=7/2) had severe clinical manifestations (renal failure, nephrotic proteinuria or cerebral vasculitis) with extracapillary glomerular proliferations (crescents). this children were treated by intravenous methylprednisolone pulses (400/200/200/100 mg/m 2 body surface area over 4 days) followed by monthly intravenous cyclophosphamide (cph) pulses (6x500 mg/m 2 body surface area) with gradually tapered oral prednisolon (4-10 mg/m 2 body surface area/48 h over 6 months) and aceinhibitor (enalapril 0.05-0.2 mg/kg/d). after 6 months of treatment a significant reduction of proteinuria (2.9±0.4 to 0.24±0.08 g/m 2 /d; p<0.0001) and improvement of kidney function (gfr 117±20.5 vs. 174±7 ml/min/1.73 m 2 , p<0.05) was observed. no notable adverse events were recorded. six patients had a second renal biopsy after completing cph-therapy; only 1 crescent was found in 245 examined glomeruli (initial findings: 48 crescents in 231 glomeruli). after follow-up of 37 (8-75) months all children have unaltered renal function, further episodes of macrohematuria or gross proteinuria did not occur. intravenous cph pulse therapy seems to be an effective therapeutic option in paediatric patients suffering from crescentic iga nephropathy. eye involvement in children with primary fsgs distinct eye abnormalities have been described in children with nephrotic syndrome, particularly in diffuse mesangial sclerosis (pierson syndrome). the aim of the study is to investigate whether there are any associated ocular anomalies in childhood primary focal segmental glomerulosclerosis (fsgs). demographic characteristics, age at onset, drug therapy and duration of the disease were defined in 30 patients (14 girls,16 boys, mean age 10.1±3.9 years) with biopsy proven fsgs. standard steroid therapy was prescribed to the patients. a detailed ophtalmological examination was performed in all patients. the median age at diagnosis was 6 years (1-16 years). mean followup time was 36 months (4-116 months). eleven patients (36.6%) reached to chronic renal failure during follow-up period. overall, 15 patients (50%) showed various eye abnormalities. nuclear opacity was found inone child and posterior subcapsular opacities probably due to corticosteroid therapy were present in two cases. two patients had myopic astigmatism and two had exotrophia. importantly, 4 patients had anisometropic ambliyopia, 3 had mittendorf spots and 1 had pigmentary changes in macula, which had never been described in the literature. mutational analysis for nephrin, podosin, wt1 and lamb2 genes are still going on. we don't know whether particular mutations are related to particular eye findings like pierson syndrome, yet. however our findings emphasize that ophtalmological evaluation should be performed in all patients with primary fsgs at the time of diagnosis. regardless of the underlying disease, the proteinuric condition demonstrates ultrastructural changes in podocytes with retraction and effacement of the highly specialized interdigitating foot processes. to investigate whether high glucose and advanced glycosylation endproduct (age) induce podocyte phenotypical changes, including quantitative and distributional changes of zo-1 protein, we cultured rat glomerular epithelial cells (gepc) under 1) normal glucose (5mm,=control) or 2) high glucose (30 mm) or 3) age-added or 4) high glucose plus age-added conditions. high glucose plus age-added condition could increase the permeability of monolayered gepcs and induce ultrastructural separation between confluent gepcs. zo-1 moved from peripheral cytoplasm to inner actin filaments complexes by both age-added and/or high glucose condition in cutured gepc by confocal imaging. high glucose plus age-added condition also decreased zo-1 protein amount and its mrna expression to statistically significant level compared to normal glucose or osmotic control conditions. we could also confirm the activation of pkb/akt signaling pathway in gepc by age, high glucose and insulin in pi3k-dependent manner. in addition, an inhibition of pi3 kinase by ly294002 was able to prevent quantitative and distributional changes of zo-1 protein induced by high glucose and age. these findings suggest that both high glucose-and age-added condition induce the cytoplasmic translocation and suppresses the production of zo-1 at transcriptional level and these changes may be mediated by pi3k/akt signaling. this pathway could explain the role of zo-1 in the phenotypic changes of podocytes in diabetic conditions. henoch-schönlein purpura (hsp) is common in the pediatric population, while wegener's granulomatosis (wg) is rare. although both diseases are classified into the vasculitis syndrome, their clinical symptoms, the treatment and the prognosis are considerably different. the classic clinical triad of wg consists of upper and lower airway disease, renal involvement and small vessel vasculitis. we present a rare childhood case in whom hsp-like symptoms were developed prior to wg symptoms. a 13-year-old girl developed ankle joint pain and swelling and purpura on bilateral legs and hands in the absence of abdominal pain. she was diagnosed as hsp and treated with oral prednisolone (psl) therapy. although high dose psl temporarily rescued these symptoms, purpura and joint swelling and pain reappeared in parallel with a reduction of psl dose. at this moment, because microscopic hematuria, mild proteinuria and hoarseness were also noticed for the first time, serum proteinase-3 antineutrophil cytoplasmic antibody (pr-3anca) was evaluated and detected to be high. moreover renal pathology showed necrotizing pauci-immune glomerulonephritis, leading to the final diagnosis as wg. after methylprednisolone pulse therapy followed by oral psl combined with cyclophosphamide, her clinical symptoms with wg were resolved together with the reduction of serum pr-3anca titer. taken together we emphasize that pr-3anca should be evaluated even in the patients who only develop hsp symptoms. background: short-term efficacy of steroid therapy for pediatric patients with iga nephropathy (igan) has been reported. however, there are a number of cases in whom their igan recurs after stopping the steroid therapy. recent japanese study indicated that tonsillectomy had a significant impact on renal outcome. also, another japanese study showed mizoribine was effective for igan in children. in this study, we examined the effects of a treatment regimen consisting of tonsillectomy and steroid pulse therapy followed by mizoribine (tx) for chronic relapsing igan in children. method: ten cases who showed chronic relapsing igan were included as the subjects (mean age at onset: 12.0 yrs, mean age at initiation of tx: 19.4 yrs). they were divided into two group, a normal renal function group (group a, n=6) and an impaired renal function group (group b, n=4). the changes in hematuria, proteinuria, renal function, and adverse events were prospectively examined for more than 12 months. result: a negative of hematuria was observed in 50% of group a and 75% of group b. a negative of proteinuria was seen in 33% of group a. in addition, in group b, deterioration of renal function was not observed during the observation periods. there were no serious adverse events associated with this treatment regimen. conclusion: a treatment regimen consisting of tonsillectomy and steroid pulse therapy followed by mizoribine treatment seems to be effective to control of acute inflammation coexisting with chronic glomerular lesions, and can be a valuable addition to therapeutic options for treating patients with chronic relapsing igan in children. objective of study: to present a case of silent stenosing ureteritis in a boy with henoch-schönlein purpura (hsp). case report: a 4-year-old boy was admitted with a typical hsp. urine findings were normal on admission. a gastrointestinal bleeding on the 4 th day of illness suggested corticosteroid treatment. the ultrasound on the 4 th and 7 th day revealed a normal urinary tract. on the 10 th day he developed non-painful macroscopic haematuria, followed by microscopic haematuria and proteinuria, which reached the nephrotic range on the 11 th day. thus, the boy was treated with methylprednisolone pulses and cyclophosphamide for 8 weeks. renal biopsy was not performed because of his parent's refusal. microscopic haematuria and proteinuria gradually subsided, with complete disappearance at the 5 th month. during this time he was asymptomatic, with no episodes of macroscopic haematuria or colicky flank pain. at the 8 th month of illness a new ultrasound revealed a major left hydronephrosis. computer tomographic urography showed a complete ureteropelvic junction obstruction. the 99mtc-dmsa scan revealed a 5% relative function ipsilaterally. a left pyelostomy was performed. during the next four months after draining, the urine volume of the affected kidney was 0.2-0.3 ml/kgr/hour, the creatinine clearance 2-3 ml/min/1.73 m 2 and the 99mtc-dmsa scan showed a 4% relative function. based on the above findings a nephrectomy was decided. conclusions: although rare, stenosing ureteritis should be considered in hsp. the typical clinical presentation with haematuria in association with colicky flank pain may not always occur, as in the present case, or may be confused with the symptoms of hsp itself. thus, the repetition of an ultrasound during the process of the disease may be necessary, in order for this complication to be diagnosed and treated early, preventing serious renal outcome. mitochondrial diseases are either due to sporadic or inherited mutations mainly in mitochondrial dna located genes. with regard to renal manifestations, tubular dysfunctions are common; however, the existence of solitary glomerulopathy has recently become apparent. in such case, the pathomechansim of the glomerular proteinuria is still obscure. wepresent a 12 year-old girl who was found to have asymptomatic proteinuria (up/cr1.0) in the absence of hematuria, azotemia, tubular dysfunctions, lacking any neurological manifestations. her family history showed maternal inheritance with mild proteinuria of grandmother and renal insufficiency of young uncle. light microscopy revealed 7 glomeruli of normal appearance and 3 of global sclerosis. electron microscopy showed swollen mitochondria in podocyte of normal appearance glomerulus. pointmutation rate of mitochondrial dna, a3243g, was detected as less than 1% in grandmother, 6% in mother and 39% in the patient examined byperipheral blood cells. the proteinuria completely disappeared 3 months after treatment with combined therapy of arb and acei. to determine the responsible molecule for the pathomechanism of proteinria, immunostaining followed by conforcal microscopy with slit diaphragm associated molecules (sdm) (nephrin, podocin), gbm associated molecules (type iv collagen alpha chains, laminin isoforms, perlecan) and podocalyxin was studied and compared to the controls. interestingly distinct decrease of expression with sdm was observed even in normal appearance glomerulus of the patient. taken together, a3243g mutation itself may lead to depletion of atp and/or increase of free radicals in podocyte, which predominantly affect the biogenesis of sdm, result in pathological glomerular proteinuria. the mechanism of antiproteinuric effect of arb/acei therapy should be evaluated by serial biopsy specimen. objectives: to report the effectiveness of pulse cyclophosphamide induction therapy in children with diffuse proliferative lupus nephritis. to identify predictors for unresponsiveness to the treatment. methods: thai children under 15 years of age with biopsy-proven diffuse proliferative lupus nephritis who were admitted to chiang mai universityhospital between 2001and 2006 were retrospectively studied. responsiveness to treatment, defined as urinary protein to creatinine ratio of less than 0.3, was assessed at the end of induction period. the clinical characteristics and laboratory data including gender, age at diagnosis of sle, duration of disease before treatment, hypertension, clinical nephrotic syndrome, amount of proteinuria, serum creatinine, creatinine clearance, serum c 3 level and presence of crescentic formation in renal biopsy were compared between the two groups who responded and did not respond to the treatment. results: a total of 27 patients (89% female) with the mean age at diagnosis of sle of 10.3±2.6 year were studied. nineteen patients (70%) achieved remission at the end of induction therapy. there were no significant differences in all parameters studied between responsive and nonresponsive groups. despite the indifference in the amount of proteinuria, the proportion of patients with nephrotic-range proteinuria was higher in unresponsive group. conclusions: pulsecyclophosphamide is an effective regimen for induction therapy in children with diffuse proliferative glomerulonephritis. although no definite predictor was detected in this study, higher proportion of patients with nephrotic-range proteinuria in the unresponsive group wasnoted. born small for gestational age, but not early postnatal weight gain aggravates the course of idiopathic nephrotic syndrome in children clinical and animal studies have shown a higher risk of an aggravated course of renal disease in childhood after birth small for gestational age (sga). fast catch-up growth after sga seems to support the development of later disease. in a retrospective analysis of 62 cases with idiopathic nephrotic syndrome treated between 1994 and 2004 in a university centrefor paediatric nephrology we identified 6 children as sga and 56 asappropriate for gestational age (aga). we related the course of disease to birth weight and catch-up growth. median age of manifestation in sga was 6.4 (1.9-15.2) years vs. 3.7 (1.2-15.33 ) years in aga children. in all sga children renal biopsy was performed, while only 55% of the aga children underwent renal biopsy showing nodifference in renal histology. in the sga group, 66% patients developed steroid resistance (vs. 21% aga, p<0.05). the number of relapses was not different. 83% sga children needed antihypertensive treatment inthe course of the disease compared to 39% of aga children. catch-up weight gain between birth and 24 months of age did not influence the course of disease. in conclusion we could find evidence for an aggravated course of idiopathic nephrotic syndrome in former sga children, but weight gainduring the first two years of life did not influence the course of disease. the mechanisms of perinatal programming in later renal disease need further investigation. wilson's disease(wd) is a disorder of copper metabolism that affects numerous organsystems including kidneys. besides renal tubular dysfunction as a result of excessive storage of copper, renal manifestations due to therapeutic complications can also develope specially with d-penicillamin. in this study we investigated the frequency and spectrum of renal manifestations during d-penicillamin therapy in wd. of 62 patients receiving d-penicillamin for wd, 4 patients(6.4%) (3 boys, 1 girl) developed findings of glomerulopathy within 1 month to 1 year after initiation of therapy and all were histologically diagnosed to have membranoproliferative glomerulonephritis (mpgn). the patients were between 6-11 years old, and they had normal urinalysis and renal function tests in their first presentations. two siblings developed hematuria and proteinuria below nephrotic range while the other two developed nephrotic syndrome. one of these latter patientsalso had acute renal failure needing temporary peritoneal dialysis. three patients had low complement (c) 3 levels, 2 had antinuclearantibody (ana) positivity, two had c-antineutrophil cytoplasmic antibody (anca) and one p-anca positivity. d-penicillamin therapy replaced by zinc sulphate in all patients. all renal findings improvedin patients within 3-6 months with normal renal functions and complement levels, and negative ana, p and c-anca tests. after 2 years all were clinically in remission of mpgn confirming the role of d-penicillamin in development of renal disease. objectives of the study: the use of tacrolimus in steroid-resistant (sr) focal segmental glomerulosclerosis (fsgs) has been reported in single and small series. the aim of this report is to exhibit experienceon the management of children with sr fsgs in whom tacrolimus had been started on due to the therapy resistance. methods: fk506 combined low-dose oral steroid was started on three male patients (3, 8, 14-yearold) with sr fsgs who had been following for three years. all of them had failed various cyclosporin a, cyclophosphamide and steroid regimens prior to treatment with fk 506. the application was 0.1 mg/kg/day in two divided doses over 12 h adjusted to a trough blood level between 5 and 10 ng/ml for 12 months. other therapies included angiotensin-converting enzyme inhibitors, vitamin d and calcium analogues, and lipid-lowering agents. results: a reduction in proteinuria to normal levels was noted between 2-4 weeks following the initiation. the remission was achieved overall during the treatment. the relapse was recorded following cessation of tacrolimus in 2-4 weeks. the drug was generally well tolerated with no sideeffects and adverse reactions. the ratio of infectious events did not differ from the former regimens. conclusion: tacrolimus may be effective in controlling the proteinuria of patients with srfsgs during the therapy. there is a trend of relapse following cessation of treatment. the duration for drug uptake is a topic of debate. further study in larger population is warranted. introduction: histological features of focal segmental glomerulosclerosis are found in 75% of pediatric patients with steroid resistant nephrotic syndrome. upto 50% (between 13-78%) children with fsgs progress to esrd. objective: to study the clinical course of childhood fsgs and determine the possible predictive factors of chronic kidney disease. method: case records of children who had biopsy proven fsgs and had presented to the sindh institute of urology and transplantation between 1995-2005, were retrieved. clinical and laboratory parameters at baseline, response to steroids and cyclosporine, development of crf (as defined by a gfr of <60 ml/min/1.73 m 2 ), and histopathological details were analysed. result: a cohort of 59 children with a mean age of 8.5±6.5 years and a m: f ratio of 3: 1 was identified. after a mean follow-up time of 5 years, 21/59 (35.5%) developed crf. on univariate analysis, male sex (90% vs 65%, p-0.04), >6 years age at onset (62% vs. 32%, p-0.02), hypertension (57% vs. 26%, p-0.05) and microhematuria at presentation (62% vs. 25%, p-0.007) were significantly associated with risk of developing crf. steroid resistant course (90% vs. 53%, p=0.003) was more prevalent in those who developed crf. the crf group was also more likely to have an elevated creatinine at baseline (47.6% vs. 5%, p<0.05). moderate tubular atrophy and a high percentage of segmentally and globally sclerosed glomeruli were found in those who developed crf. patients progressing to crf were more likely to have a partial response to cyclosporine (86% vs. 33%, p=0.02) conclusion: factors such as age, microhematuria, hypertension, elevated baseline creatinine, steroid resistance, tubular atrophy, percent global sclerosis and partial response to cyclosporine are likely predictive of progression to chronic kidney disease in children with fsgs presenting to our center. chronic glomerular nephropathies in children are marked by an often unfavourable evolution, so that the establishing of a prognosis at the time of the diagnosis is both a professional and a moral duty for the pediatric nephrologists. purpose: the estimation of the current practice renal survival prognosis in children with chronic glomerular nephropathies, by using clinical and laboratory elements in different histological forms of primitive chronic glomerulonephritis (cgn), with a minimum period of observation of one year. we analyzed parameters that may intervene in the duration of renal survival: type of cgn, age at the debut of the illness, histological scores of activity and chronicity, the presence of tubular atrophylesions and that of interstitial fibrosis, renal failure (rf) installment time, in cases with normal renal function at the beginning, the time until the initiation of dialysis in cases with esrf, respectively. the statistic analysis of data has been carried outwith epi soft (fishcer test). the results have been as follows: unfavourable evolution has been taken into consideration in the cases which have presented fixed nitric retention or which required the initiation of dialysis. the initiation of dialysis was necessary in 19 cases (76%), out of which 11 (44%) having associated between 4 and 6 of the considered risk factors. if the histological type (sfgs, dgs, mpgn) is added to the obtained score, the accuracy of the estimation increases to 89%. in conclusion: the usage of prognosis scores composed of current elements of diagnosis that have proven to have statistical significance, as far as the renal survival prognosis is concerned, may allow the invoking of a medium-term prognosis in the evolution of children with cgn. introduction: the srns can lead to a progressive deterioration of the renal function and therefore needs an aggressive therapy. one of the alternatives of treatment is the association described by mendoza et al which consists of prolonged use of methylprednisolone with cyclophosphamide (cp), which has a remission rate of 66%. the objective of this study is to evaluate retrospectively the clinical evolution of 15 children with srns treated with mendoza's protocol. method: between 1993 and 2005, 15 children, 8 male and 7 female, with srns were subjected to a renal biopsy and later treated with mendoza's protocol. cp was used in children that had not responded to pulses of methylprednisolone and presented a relapse. all of the patients received supplemental calcium. the clinical evaluation included stature, weight, ophthalmic fundus examination, proteinuria in urine recollection of 24 hours and/or protein to creatinine ratio and blood chemistry. results: eleven patients (73%) had fsgs. nine (60%) presented complete remission, two (13%) had partial remission, four (26%) did not respond to treatment, 3 of which evolved to terminal kidney disease. nine patients received cp. of the complications secondary to treatment with steroids, 80% had a linear growth suppression and an increase in their bmi and 1 patient presented cataracts with visual impairment. conclusion: the prolonged treatment with boluses of methylprednisolone and cyclophosphamide is a good alternative in patients with srns. the prolonged use of high doses of steroids can cause linear growth suppression and other adverse reactions, so it is advisable torealize a genetic study in all of the patients with srns to be able to exclude the patients that have a genetic mutation and so avoid unnecessary treatment. objectives: to study the clinicopathological profile and outcome of lupus nephritis (ln) in indian children. methods: clinical and histopathological features and outcome of children with ln was retrospectively reviewed. patients were included if they fulfilled the acr criteria for the diagnosis of sle and had either of persistent proteinuria, active urinary sediments or renal dysfunction. outcome was analyzed at 3 years and at last follow-up. results: ofthe 53 children studied, 13 were boys. the mean age (sd) at diagnosis was 9.8±2.3 (median 9.8, range 5-14.4) yr; 23 children were youngerthan 10 years of age. the mean age at presentation and renal biopsy was 10.8±2.2 (median 10.4, range 6.5-15) years. the mean duration of follow-up was 3.1±2.9 (median 2.5, range 0.2-10.3 years) years. 41.2% patients were followed for more than 3 years. commonest clinical manifestations were fever (77%), hypertension (58%) and malar rash (56%). 35 and 28% of patients presented with nephrotic and nephritic syndrome respectively before the diagnosis of sle. the commonest pathology was class iv nephritis (41%) followed by class ii (17%). hypertension, hematuria, nephrotic syndrome and decreased egfr were significantly associated with class iv ln. at last follow-up 31.5, 15.7 and 0% patients were in ckd stage ii, iii, and iv respectively. the patient survival rate at 3 year and at last follow-up was 100 and 94% respectively, while no patient developed esrd at 3 years. infections were seen in 30% cases that resulted indeath in 2 patients; 1 died of hepatic encephalopathy. conclusion: sle nephritis has a varied presentation and high morbidity. a significant proportion of patients developed infections during the course of disease. clinical, pathological features and outcome in our study do not differ markedly from those in most pediatric series. background: atypical hus has a frequently relapsing course and a poor renal prognosis. low c3 plasma concentration suggests alternate complement pathway regulatory abnormalities: factor h (fh), factor i (fi) and membrane cofactor protein (mcp). case report: we report an 11 year old girl with atypical hus due to acquired fh deficiency caused by anti-fh antibodies (abs). hus was diagnosed on the basis of acute renal failure, microangiopathic hemolyticanemia and thrombocytopenia. past history: recurrent fever with culturenegative pharyngitis (suspected pfapa syndrome). decreased c3 (64 mg%, normal>80) with normal c4. adamts 13 activity was depressed, no cleaving protease abs. hemodialys (hd) and plasma exchange (pex) were started 12 days later. severe urticaria and angoiedema during pex was treated with methylprednisolone and chlorpheniramine. hematological and renal improvement were observed after the 3 rd pex session. 4 relapses occurred in 3 months: 1 -controlled by pex; 2 -(with suspected pfapa) with single dose corticosteroids, 3 -with prednisone therapy, 4terminated with single dose ivig 200 mg/kg. elevated anti fh ab titer-1471 au with decreased fh functional activity were found in pre-pex plasma. fh, fi, factor b and c3 antigenic levelsnormal. hematological remission and renal function improvement without hus relapse ensued while tapering corticosteroids. two years after presentation, onprednisone 5 mg/day anti fh titer dropped significantly with restoration of functional fh activity, gfr ~75ml/min/1.73 m 2 . conclusions: in cases of atypical hus, active search for anti fh ab iscrucial for implementing specific and effective therapy: plasma exchange, iv ig and steroids for improving course and longterm prognosis. research centre for child health rams, department of pediatric nephrology, moscow, russian federation 25 children aged 1,5-16 years with idiopathic biopsy-proven steroid-resistant focal and segmentary glomerulosclerosis (fsgs) were treated with cyclosporine a (csa) 3,2-7,6 mg/kg as initial dosage, oral prednisolone 1,5 mg/kg every other day tapered to the 12-th month and methylprednisolone pulses (mp) 20-30 mg/kg every other day for the first 2-4 weeks in 17 of patients. serum creatinine level was controlled once a month. after 6 months of csa treatment complete or partial remission of proteinuria was in 15 (60%) of children, no effect in 10 (40%). serum creatinine level increased in 14% on an average in the group remission of proteinuria. in the group of non responded patients the creatinine elevation was significant same -15%. after 1 year of csa treatment complete or partial remission observed in 18 (72%), no effect in 7 (28%). elevation of serum creatinine level in children with remission was 15,5% (without significant difference compared to 6 month's csatreatment). increasing of the creatinine level more than 30% in two patients leaded to double tapering csa dose resulted in normalization of serum creatinine level. in the group of csa non responders the significant increasing of serum creatinine level (35%) was revealed (compared to 6 month's csa treatment). in 3 cases the elevation ofcreatinine level was more than 50% and these patients turned into esrd eventually. in all of non-responders csa was discontinued. we concluded that serum creatinine level in csa respondrers was stable without significant elevation during the 1 year of treatment. csa therapy for 1 year without any effect influenced on renal function decreasing. clinical objective: to describe the clinical course and outcome of pediatric patients with cgd treated with iv mpt (30 mg/kg x 3 doses monthly for 12 months, then 1 dose monthly for the next 6 months) methods: patients' medical records were reviewed. pre, post-treatment and follow-up 24 hr urineprotein, creatinine and gfr were compared using paired t-test; and proteinuria, hematuria and blood pressure using mcnemar's chi square. outcome measures were analyzed usingmean ± sd and frequency distribution. results: 30 patients were included, 13 male, 17 female. mean age at disease onset is 7.972±4.298 years. mean duration of follow-up is 23.733±18.714 months. 70% achieved complete remission after a mean of 1.8 cycles, 17% partialremission after a mean of 2.8 cycles and 13% were treatment failures. mean relapse rate is 0.700±1.208 on treatment and 0.733±1.596 at follow-up. renal survival rate is 93%. 24 hour urine protein and the proportion of patients with proteinuria, hematuria and hypertension significantly decreasedafter treatment and remained stable at follow-up. serum cr/gfr were also stable pre, posttreatment and at follow-up. no serious side effects were noted. conclusion: this protocol induced a high and early remission rate (70% after 1.8 cycles)among the patients. majority demonstrated stable renal function and blood pressure over time. relapse rates were low and treatment is generally safe. recommendation: the protocol can be offered to oral-steroid or alkylating agent-resistant patients with satisfactory remission rates. objectives of study: nestin, an intermediate filament protein which has a role in regulating cellular cytoskeletal structure, is restrictedly expressed in the podocytes of human kidneys. in the present study nestin expression was investigated in biopsy specimens of children with focal segmental glomerulosclerosis (fsgs). methods: 36 kidney biopsy specimens taken from children with diagnosis fsgs were investigated. diagnosis was performed on light microscopy, immunofluorescence microscopy, taking into account clinical data. for immunomorphology monoclonal anti-nestin antibody from mouse (sc-23927, clone 2c1.3a11, santa cruz biotechnology) diluted 1: 100, was applied on cryostat or paraffin sections using labeled streptavidinebiotin (lsab+ dako) method. visualization was performed by dako aec substrate. 10 kidney biopsies of patients without nephrotic syndrome, mainly with mesangioproliferative gn were used for control staining. results: the mean age at the time of biopsy was 10.2±4.9 years, and all patients had nephrotic syndrome. half of them revealed some focal tubulointerstitial changes: tubular atrophy, slight interstitial fibrosis and lympho-monocytic infiltration. in two cases mutation of wt1 gene and in one case mutation of nphs2 gene was detected. four cases had familial character of fsgs. nestin expression was variably present in different cases of fsgs. decreased expression was detected in glomeruli with segmental mesangial sclerosis and capsular adhesions. conclusion: fsgs revealed heterogenity concerning nestin expression. nestin expression was diminished in affected glomeruli. background: renal effects of altered ob/ob-r pathway may contribute to obesity, and diabetesassociated proteinuria. in the kidney ob/ob-r stimulates collagen type i and iv synthesis and upregulates tgfβ1 and tgfβ2 receptors. objective: to determine ob/ob-r and its downstream (jak/stat/socs) pathway expression in nephrotic syndrome (ns) and fsgs. design/methods: microarray analysis of kidneys of 2-week (2w) and 4-month (4m) old transgenic mice (tg) and controls (ctr) was performed, and confirmed by quantitative pcr. kidney sections were analyzed by immunohistochemistry (ihc) and western blot analysis (wb). urinary ob/ob-r of children with ns classified as steroid sensitive (ssns) or steroid resistant (srns), were measured by elisa. results: ob, ob-r, and jak1,2,3 mrna expressions were not statistically different at 2w and 4m between ctr and tg. stat3 and socs mrna were increased 2.04-fold (sem ±0.52), and 17.38fold (sem±8.6) at 4m in tg, p=0.04 and p=0.01 respectively. ihc and wb (p=0.65) of kidney sections showed no significant difference between the 2 groups. we examined 12 ctr, 10 ssns, and 11 srns patients with comparable bmi, age, race and gender. urinary protein to creatinine ratio in ssns and srns was 0.18 (sem±0.06) and 3.12(sem±1.03) respectively, p=0.03. urinary ob (p=0.1), ob-r (p=0.09), and tgfβ1 (p=0.12) were not statistically significantly different between the 3 groups. conclusions: ob/ob-r was not upregulated in tg at the onset of proteinuria and fsgs. however, advanced fsgs (4m tg) showed significant activation of socs3, an ob/ob-r negative regulatory pathway. pediatric patients with early srns had no significant increase in urine ob/ob-r. this data suggests the role for ob/ob-r regulatory pathways in the development of advanced fsgs. primary fsgs presents clinically with steroid-resistant (srns) or steroid-dependent (sdns) nephrotic syndrome or proteinuria. the data shows, that 43% patients with fsgs progress to esrd in 15 years follow-up. objectives: the aim of the study was to analyze the long-term outcome of patients with primary fsgs diagnosed in kidney biopsy. material: the study group consisted of 113 children (54 males, 58 females) followed from 1982. all patients were treated with immunosupression and renoprotection. the clinical data were analyzed after follow-up lasting for mean 10±6,1 years (0,5-25 years) . 85 children presented with nephrotic syndrome (66 srns and 17 sdns) and 28 with proteinuria. the age ranged from 0,5-16 years mean 5,9±4,5 at the time of diagnosis. more then 1 kidney biopsy was performed in 55 children -in 29 progression from mcd (n=18) and mes (n=11) to fsgs were observed. results: the clinical remission was observed in 73/113 patients (64%) and was not correlated with initial proteinuria (mean 11,3±9). in 20/113 patients crf was observed, 15 of them progressed to esrd (12 were successfully transplanted). among patients, who had fsgs as their initial glomerular lesion (n=84), the percentage of glomerular sclerosis was significantly higher in a group in which remission was not obtained after long-term follow-up (31,7 vs. 17%, p<0,001). in 9 out of 49 patients with follow-up over 10 years progression to esrd was observed (18,4%), 10/49 were transmitted to adult centers with persistent proteinuria. conclusions: immunosuppression and renoprotection in patients with fsgs can prevent the progression of crf. extensive glomerular sclerosis is a predictor of unfavourable outcome. further clinical and genetical studies are needed to establish the effective therapy modalities. mycophenolate and who had previously undergone a renal biopsy, recieved 600 mg twice daily (maximum 1 gram twice daily) during six months. prednisone was concurrently prescribed at at dosage of 1 mg/kg/every other day, during 8 weeeks and 0.5 mg/kg/every other day during the subsequent 8 weeeks. results are expressed as mean±sd. results: seven chidren, 5 boys and two girls were enrolled. oncet of their ns was at age 6.2±4, 16 yr (range 2-13 yr) and mmf was initiated at 9.4±4.4 yr (4.5-15.5 yr) . six were sr and one sd. two patients had previously recieved cyclosporine, two patients cyclophosphamide and one chlorambucil. renal histology displayed: focal segmental glomerulosclerosis (n=3), minimal change (n=2), mesangial proliferation (n=1) and membranous glomerulonephritis (n=1). at the end of the follow-up: three patients were in partial remission, two were in complete remission and two had no response to mmf. initial and final serum creatinine concentration 0.53±0.08 vs 0.57±0.09 mg/dl), estimated gfr (124.2 vs. 111±37 ml/min/1.73 m 2 ) and serum albumin ( idiopathic nephrotic syndrome is the most frequent glomerular disease in childhood. most patients are steroid responsive but half of them relapse and often become steroid-dependent. they are exposed to long term steroid complications on the one hand and relapses due to insufficient disease control on the other hand. our aim is to determine predictive risk factors for high degree steroid dependence. in france, steroid-resistance is defined as persistent proteinuria after one month of daily oral prednisone (60 mg/m 2 ) and 3 pulses of methylprednisolone (mpn) (1 g/1.73 m 2 ). we included 27 steroid responsive children with disease onset between 2000 and 2006. the mean age at diagnosis was 4.6 years (range 1.5-16). all patients initially received prednisone 60 mg/m 2 per day. the following parameters were analysed: age at onset, gender, days to remission with initial steroid therapy, mpn pulses, numbers of relapses, steroid dependency, immunosuppressive drugs. twenty of the 27 patients were steroid-dependent; among the 20 steroid dependent patients, 11 received mpn pulses. 90% of those patients (10/11) were treated by cyclosporine during follow-up. on the other hand, only 10% (1/9) of the patients who did not receive mpn required cyclosporinebased therapy during follow-up (chi-square test, p=0.0018). interestingly, there was no correlation between treatment days until remission during the initial prednisone course and the risk for later steroid dependence. conclusion: the need for mpn pulses, but not the time interval until remission helps to predict steroid dependence. patients, necessitating mpn pulses to obtain remission are at risk to require cyclosporine for disease control. by identifying these children, we could eventually 1/ avoid multiple relapses by earlier use of adequate immunosuppression and 2/ avoid side effects related to long term high dose steroid therapy. membranous nephropathy (mn) with antitubular basement membrane antibodies is a rare condition. relapse of tubular dysfunction in renal transplant recipients has been published in one case, but relapse of mn in the renal graft has not yet been reported. a 3-year old boy presented first with steroid resistant nephrotic syndrome associated to tubular dysfunction. renal biopsy revealed mn associated to interstitial fibrosis and granular deposits of iga, igg, and c3 along the tubular basement membrane. indirect immunofluorescence (if) revealed circulating anti-tubular basement membrane antibodies. he received a renal allograft at the age of 6 years. an acute rejection episode on day 21 required three steroid pulses and okt-3. renal biopsy revealed the presence of interstitial and vascular rejection (banff iii) and relapse of tubular basement membrane deposits. renal function normalized within 10 days and remained stable (gfr estimated by schwarz formula=103 ml/min per 1.73). proteinuria remained negative and urinalysis normal over 5 years under the immunosuppressive regimen including fk, azt, and prednisone. at the age of 11 years, proteinuria increased progressively over 6 weeks reaching 2.8 g/day, whereas serum creatinine remained stable. renal biopsy revealed the presence of granular deposits along the glomerular basement membrane suggesting a late relapse of mn in the transplant. rituximab therapy (day 0, 15, 30, and 60) followed by switch from azathioprine (aza) to mmf resulted in a complete biological remission with negative proteinuria. indirect if revealed progressive decrease of antitubular basement ab level during rituximab treatment and a negative signal was obtained 3 months after the switch from aza to mmf. this is the first report of glomerular relapse of mn with anti tubular basement antibodies in a renal transplant recipient. nephrotic children are at risk for severe pneumococcal infections. the best moment for antipneumococcal vaccination is controversially discussed. we investigated the serologic response after pneumo23 vaccination in 25 children (10 girls) with nephrotic proteinuria and hypoalbuminemia, immediately after initialisation of prednisone therapy at 60 mg/m 2 (group 1) and in 16 children after tapering down of prednisone to <0.5 mg/kg eod (group 2). there was no difference in both groups concerning antibody (ab) response, relapse frequency, or number of steroid dependent forms. in group 1, pneumo23 ab levels at presentation (m0) were 1.20±0.22 (mean±se) . at m1 antibody levels increased 9-fold to 9.28±1.35 (p<0.0001). serum levels at m3 were 7.58±1.67. one year after vaccination ab levels (4.4±1.78) decreased compared to m1 (p<0.01), but remained increased compared to m0 (p<0.01). there was no increased delay until remission in both groups compared to a retrospective control group. severe hypoalbuminemia (<10 g/l) at the time of vaccination was not related to a lower serological response on m1. during relapses, antibody levels decreased significantly compared to levels before relapse (p<0.01), but increased again once remission was obtained. even during relapses, ab levels remained higher (>3-fold) than pre-vaccination levels. conclusion: nephrotic children on high dose glucocorticoid therapy respond to anti-pneumococcal vaccination and their ab levels remain elevated during relapses. vaccination at disease onset may be beneficial as those patients with relapses during the tapering down of steroids already have increased anti pneumo23 ab at the time of relapse. crescentic glomerulonephritis with isolated c3 deposits associated to complement abnormalities: a new entity? introduction: several progressive renal diseases present proteinuria, as a result of glomerular and tubulointerstitial injuries. thus, some studies prove that proteinuria is an important predict factor for progression of renal failure. angiotensin converting enzyme inhibitors (acei) are efficient in reducing proteinuria and preserve renal function in patients with diabetic or non-diabetic nephropathy. the purpose of this study was to evaluate the efficacy and security of acei in children. material and methods: the acei (enalapril) was used in normotensive and hypertensive patients with chronic renal disease, with microalbuminuria/proteinuria. results: we studied 28 patients (13 girls), for at least 6 months, mean age was 10.4±3.5 years (1 month to 17 years). 5/28 patients had glomerulopathy, 13/28 chronic pyelonephritis, 4/28 systemic disease, 2/28 renal hypoplasia/ dysplasia, 3/28 cystic renal disease and 1/28 arterial hypertension. the mean dose of enalapril was 0,25mg/kg/d (0, 04 to 0, 38) and it was used during 36,6 months (mean). we observed a normalization of proteinuria/microalbuminuria in 53, 5% of cases. in seven patients, the drug was discontinued due to: 3/7 irregular use, 2/7 vertigo, 2/7 hypercalemia and acute renal failure recovered after withdrawn the drug. during the use of enalapril we did not observe significant difference in potassium or creatinine serum levels, as well as blood pressure measurements. conclusions: the use of enalapril in pediatric patients with renal disease and proteinuria/ microalbuminuria showed security and efficient. therefore, we suggest it as a antiproteinuric and renoprotective agent in children. a. filleron, al. adra-delenne, l. ichay, f. dalla-vale, h. valette, d. morin chu montpellier, pediatric nephrology, montpellier, france in order to evaluate the long-term efficacy of oral cyclophosphamide (cp) in children with sdns, the outcome of 33 patients (11 girls) treated in our unit for steroid sensitive ns were studied retrospectively. median age at diagnosis was 3.8 years (range 1.5 to 13). initially, they received oral prednisone (p) : 60 mg/m 2 /d for 4 weeks and p dosage was then tapered for the next 14 weeks (totale dose p: 3390 mg/kg). relapses of proteinuria were treated with p (60 mg/m 2 /day) and, in case of steroid dependency (sd), p was maintained on an alternate day regimen. one single child had no relapse, while 8 had a relapse rate of less than 1/year. the remaining 24 frequently relapsed and 14 received oral cp -2 mg/kg/day for 12 weeks, totale dose 168 mg/kgbecause of their high relapse rate with steroid toxicity. median duration of p treatment was 3.7 years (range 0.75 to 10) before cp was given. in one case cp had to be stopped because of hemorragic cystitis. follow-up after cp treatment was, at least, 2 years. p was stopped in the following 6 months after cp in 10/13 children, but has to be continued in the remaining 3 because of early relapse of proteinuria. among those 13 children, only one had no more relapse 4 years after cp. in 12 children, relapse of proteinuria occured 11.5±7 months after cp. in those patients, 8/12 had to receive another steroid sparing drug such as cyclosporine or mycophenolate mofetil (mmf) because of recurrence of sd. in our experience, cp treatment in ns with steroid toxicity is associated with a significant change in the relapse rate in only 5/13 children and in the remaining 8, improvement was transient. our results suggest that alternative treatment, such as mmf, has to be evaluated as first-line steroidsparing agent in those patients with sdns and steroid toxicity. interleukin the aim of our investigation is to compare the concentration of total ige, specific ige, interleukin-4 (il-4) and gamma-interferon (gamma-ifn) in serum of 27 children with initial and relapsed steroid-sensitive mcns and of 26 children with atopic dermatitis at the age from 1 to 16 years. the concentration of total ige was measured by immunoenzymatic method and il-4, gamma-ifn by immunoassay technique using monoclonal antibodies. the result showed that 64% of 26 children with atopic dermatitis had the increased concentration of total ige; specific ige was increased to alimentary allergens-84,6%, household-69,2%, inhaled-26,9%. the concentracion of il-4 was 34,4±9,4 pg/ml, of gamma-ifn was 102±11,3 pg/ml. the result showed that 9% of 27 children with mcns had increased concentration of total ige; specific ige was increased to alimentary allergens-96,2%, household-77,8%, inhaled-29,6%. the concentration of il-4 was 22,31±3,8 pg/ml, of gamma-ifn was 91,97±9,3 pg/ml. according to our investigation, the concentration of il-4 and gamma-ifn in children with mcns were not significantly different then in children with atopic dermatitis. conclusion: the fact that there were not significant differences in serum total ige and specific ige, il-4 and gamma-ifn in children with mcns and atopic dermatitis gives us a reason to suppose that these diseases have identic mechanisms of pathogenesis with ige reaction i-type with activation of t-limfocyte. to clarify the pathogenesis of mcns, comprehensive studies for these cells would be worthwhile. there are several lines of evidence that the slit diaphragm (sd) not only serves as a structural framework for filtration barrier but also has an essential role as a signaling platform. nephrin is tyrosine phosphrylated by src-family tyrosine kinase, fyn. phosphorylated nephrin recruits nck to sd, and regulates assembly of actin filament. the crucial roles of tyrosine phosphorylation in podocyte is also indicated by renal malfunction observed in fyn knockout mice. neph1 has a longer cytoplasmic domain and a larger number of tyrosine residues in its cytoplasmic region than nephrin. but knowledge about tyrosine phosphorylation of neph1 is limited. here we characterize neph1 as a substrate of fyn. fyn interacted with and phosphorylated cytoplasmic domain of neph1 in vitro and in cultured cells. peptide mass fingerprinting of neph1 cytoplasmic domain phosphorylated by fyn in vitro identified at least five tyrosine phosphorylation sites. site-directed mutagenesis confirmed that these tyrosine residues were indeed phosphorylated in cultured cells. in pull-down analysis with neph1 from rat glomerular lysate, neph1 specifically bound to an adaptor protein grb2 and a tyrosine kinase csk in a phosphorylation-dependent manner. coimmunoprecipitation experiments revealed phosphorylation of y637 and y638 were crucial in neph1-grb2 binding. furthermore, tyrosine phosphorylated neph1 suppressed erk activation elicited by fyn, and also inhibited fyn-induced ap-1 transcriptional activation. these inhibitory effects required the intact binding motif of the grb2 sh2 domain, and both y637f and y638f mutants failed to inhibit erk activation. these results indicate that fyn orchestrates a wide spectrum of protein-protein interactions at sd by phosphorylating neph1 as well as nephrin, and neph1 modulates downstream signaling by phosphorylation-dependent association with adapter proteins. celiac disease (cd) is a common disorder in southern europe and has a protean clinical presentation. hla class ii aplotypes dq2 and/or dq8 are present in 99% of cd patients and in 30% of the normal population. the observation of three patients with both cd and nephritic syndrome (ns) prompted us to study hla class ii aplotypes in our patients with ns. in all children with ns admitted to our unit we determined the presence of dq2/dr3, dq2/dr7, dq2/dr4 e dq8/dr4 aplotypes and anti-transglutamidase antibodies (ab-httg). hla typing was done by dna extraction and pcr amplification and electrophoresis in agarose; ab-httg determination was made by elisa. as control groups we examined 27 children with cd and 70 first degree relatives (of theirs). in so far we have studied 40 children with ns (27 males, 13 females, age ranged 3-18 years); 34 are steroid sensitive (ssns), 6 steroid resistant (srns). a renal biopsy was done in 10 and showed minimal lesions in 3, focal and segmental sclerosis in 2, membranoproliferative gn in 2, membranous gn in 2 and iga deposition in 1. corticosteroids or other immunosuppressant were administered in 27 when blood was drown. dq2 and/or dq8 aplotypes were present in 33 out of 40 patients (82.5%), in 29 out of 34 ssns (85.3%), in 43 out of 70 cd relatives (61%) and in all cd patients. dq2/dr3 combination was present in a smaller percentage of ns compared to control groups. ab-httg were detected in one patient out of 26 (3.8%). purpose: to investigate activity of antithrombin and a protein c at 57 children with mcns: at 39 active period (proteinuria more 1 g/m 2 /d; hypoalbuminemia <25 g/l), at 46 in incomplete remission (the third day of absence of proteinuria, hypoalbuminemia <35 g/l), at 11 in proof remission. methods: activity of natural anticoagulants in blood was defined by a clotting method with use of reactants "roche" and "behring". results: activity of antithrombin in blood in the active period of disease sharply decreased (60,6±3,9%, p<0,0001), and already in the period of incomplete remission came back to norm (96,2±2,6%), characteristic for the period of full remission (96,3±4,8%). activity of a protein c in blood in the active period of mcns was high (154,1±7,5%, p<0,001), during incomplete remission decreased (127,1±7,5%, p<0,001), in the period of proof remission was in norm (94,2±5,7%, p<0,001). at children with mcns dependence of decrease in activity antithrombin from weight hypoalbuminemia (r=0,5, p<0,005), hyperfibrinogenemia (r=-0,6, p<0,005), hypercholesterolemia (r=-0,5, p<0,01) and hyper-lipoproteinemia (r=-0,5, p<0,03) is established. authentic distinctions of factor of the attitude of activity of protein c/ activity of antithrombin depending on the period (the active period -2,5, incomplete remission -1,3, proof remission -0,98) are received. conclusion: at children with mcns changes in system of natural anticoagulants: decrease in activity antithrombin below 80% and increase of factor of a parity of anticoagulants (more than 1,0) testify to hypercoagulation and risk of thrombosis. varicella objectives: the pattern of steroid responsiveness of nephrotic syndrome may change during the course of the disease in children with steroid sensitive nephrotic syndrome (ssns) and/or in different populations. patients and results: a prospective cohort study was conducted in 22 centers. patients who were initially diagnosed as ssns in 2001 and followed for five years were included. standard questionary forms from 268 children(149 boys) with a mean age of 4.3 years (22 months-16 years) at presentation were submitted for entry to data coordinating center. 165/268 patients who showed initial steroid sensitivity with a follow-up period of at least one year (1-5 years) were included in the study. seventy three (44.5%) children remained in sustained remission at 1 year; nine patients showed steroid resistance. 67/165 patients were followed for 5 years, whose clinical course were sustained remission in 46 (70%) and steroid resistance in 4(6%). steroid response rate from 1 to 5 years remained stable (93-95%). eight children out of totally 13 patients who were steroid sensitive initially, became steroid resistant in the first year. the remainder showed steroid resistance at the 2 nd year (2), at 4 th year (1) or at 5 th year (2) . renal biopsy was performed in 19 children who developed steroid dependency or steroid resistance. nine patients revealed fsgs, 8 minimal change disease, 1 mesangioproliferative gn, 1 membranoproliferative gn, one igm nephropathy. only two patients who had minimal change nephropathy in initial biopsy progressed to fsgs after 2 and 5 years. conclusion: steroid response rate was between 93-95% and steroid resistance was 4-6% in 5 years follow-up. secondary steroid resistance within the first year of presentation seemed to be predictive for their subsequent courses. the need of biopsy was not high. ssns seemed still as a relatively benign condition in our population. the aim of this study was to asses the changes in coagulation/fibrinolysis system in chronic renal disease (crd) by measuring plasma levels of von willebrand factor (vwf) and plasminogen activator inhibitor -1 (pai-1). we studied 74 children (5-16 years old) with nephrotic syndrome (ns): minimal change disease (n=14), focal segmental glomerulosclerosis (n=17), mesangioproliferative glomerulonephritis (n=24), membranoproliferative glomerulonephritis (n=7). relapse of the disease was observed in 34 patients. 15 healthy age matched children served as controls. serum levels of pai-1: ag and vwf were measured by elisa. results. pai-1 and vwf levels were elevated in all morphological forms of ns in relapse and remission compared with controls (p<0,01) except the mcd remission in which they were the same as controls (p>0,05). the highest levels of pai-1 and vwf were discovered in relapse of proliferative forms (mespgn, 70±31 ng/ml and 5,0±1,7 me/ml, respectively; mpgn, 100,05±61,1 ng/ml and 3,14±0,65 me/ml, respectively) compared with nonproliferative (mcd 52,98±24,03 ng/ml and 1,81±0,54 me/ml, respectively; fsgs 52,27±20,39 ng/ml and 2,42±0,84 me/ml, respectively, p<0,001). conclusion. these data suggest activation of coagulation/fibrinolysis system in relapse of ns and the absence of normalization in the remission phase. our results confirmed that more severe fibrin formation via activation of intraglomerular coagulation and fibrin accumulation is characteristic for mpgn, likely by deficiency of the fibrinolysis system. introduction. several recent case reports suggest that rituximab (rtx) could be an effective treatment for idiopathic nephrotic syndrome. in a retrospective study, data were collected from 11 patients (mean age: 12.6 years) treated with rtx for steroid dependent nephrotic syndrome (mean duration of the disease: 112 months). four of 11 were treated during a remission period. eight of 11 were treated in association with one or several other immunosuppressive (is) treatments (prednisone, anticalcineurin, mycophenolate mofetil). rtx efficacy was admitted when the previous is treatment was withdrawn or significantly tapered-off, or when the proteinuria disappeared with no other change than rtx treatment. a complete b-cell depletion was confirmed in all patients when assessed (9/11) even when rtx was infused during a period with nephrotic proteinuria. rtx was considered to be effective in 6 cases especially when given in association with other immunosuppressive treatment during a period with remission of proteinuria (4/4 success, follow-up 3 to 10 months). conversely rtx failed to induce remission among patients who were treated during a proteinuric period with no other immunosuppressive drug (3/3 failures). finally rtx was considered to be effective among 2 of 4 patients treated in association with other is drugs during a proteinuric period (follow-up 3 and 31 months). there was no significant side effect during rtx infusion. delayed side effects were observed for 2 patients: 1 case of neutropenia and pneumocystis pneumonia and 1 case of hypogammaglobulinemia. conclusion. rtx is an effective treatment in a subset of patients with severe steroid dependent nephrotic syndrome. further prospective data are necessary to determine if rtx could become an alternative to other immunosuppressive drugs in patients with toxic side effects. infections are leading causes of death in lupus patients. disseminated histoplasmosis has been commonly documented in immunocompromised patients including lupus patients. we report a case of lethal cerebral histoplasmosis in a child originating from french guyana. lupus disease was revealed by typical malar rash. she developed a class ii lupus nephritis treated with prednisone and azathioprine. then she developed restrictive lung disease, recurrent arthritis and pericarditis. later on, nephrotic syndrome revealed a class iii lupus nephritis treated with methylprednisolone pulses and mycophenolate mofetil. four years following the onset of the disease, she was admitted because of febrile seizures and five months later for a febrile coma. repeated lumbar punctures displayed hypercellularity with depressed levels of glucose and elevated protein concentrations but sterile cultures. according to the presence of high titers of lupic specific antibodies and cerebral mri suggesting vasculitis, neurological flare of lupus was considered and immunosuppressive treatment was increased (methylprednisolone and cyclophosphamide pulses, plasma exchanges). a repeated lumbar puncture evidenced presence of histoplasma capsulatum. despite antifungic treatment the child died. our report emphazises the difficulty to discriminate opportunistic infections from the wide spectrum of lupus clinical features. symptoms of infection may mimic those of lupus, or conversely, may be masked by immunosuppressive drugs. infection screening should take in account clinical feature as well as endemic context. our report is the first case of isolated cerebral histoplasmosis in a child with systemic lupus. renal manifestations of mitochondrial cytopathies have been described, but nephrotic syndrome with respiratory chain disorders (rc) was described extremely rarely in infancy. we report a 9 months-old boy with a mitochondrial cytopathy preceded by 2 months history of steroid-resistant nephrotic syndrome. on admission his clinical condition was deteriorating rapidly with gross oedema, ascites, hypertension and oliguria. fundoscopic examination revealed salt-pepper sign which was thought to be consistent with intrauterine infection (iui) at that time. however, serologic and microbiologic investigation of iui was inconclusive. a sensorineural hearing loss was found to associate his findings. podocin mutation was negative. a percutaneous renal biopsy was undertaken and revealed diffuse mesengial sclerosis. a significant decrease in mitochondria was observed on electron microscopic examination. the child progressed to end stage renal failure and was successfully managed by peritoneal dialysis. during his follow-up a fine tremor was observed in his hands and cranial mri revealed demyelinisation in left thalamus and occipital lobe. steroid resistant nephritic syndrome, sensorineural hearing loss, ocular and neurologic findings has led us to be suspicious about mitochondrial cytopathy and muscle biopsy was done. though muscle biopsy was normal, the results of biochemical analysis showed a deficiency of the respiratory chain complex iv (cytochrome c oxidase) (rc iv). the clinical phenotype and the deficiency of respiratory complex iv thought to be compatible with deficiency of the cytochrome c oxidase deficiency protein cox10. nephrotic syndrome with rc disorder were described extremely rarely in infancy. based on these observations, we suggest that rc disorders should be considered in patients with early onset nephritic syndrome. human parvovirus b19 (hpvb19) was identified as the cause of a self-limited childhood febrile illness with rash, namely erythema infectiosum. most of hpv-b19 infections are usually mild or asymptomatic, but in some cases infection is associated with serious systemic complications. renal involvement in patients with hpvb19 infection was discussed in recent, mostly anecdotal, case reports. the majority of these reports were described in adults, whereas only a few cases of childhood were defined whom presented with mesangiocapillary proliferative glomerulonephritis, fsgs or tubulointerstitial nephritis. a literature search revealed no cases of acute endocapillary proliferative glomerulonephritis in childhood. a 10-year-old girl was admitted with fever, cough, maculopapuler rash, hemoptysis, dark-colored urine, multiple lymphadenopathies, hepatosplenomegaly. she developed acute nephritic syndrome during the course of this complex clinical features. laboratory data showed proteinuria, hematuria, hypocomplementemia, the presence of igm and igg antibodies to hpvb19 and positive reaction of serum hpvb19 dna using a polymerase chain reaction. renal biopsy showed acute endocapillary proliferative glomerulonephritis with coarse granular c3 depositions in a "starry sky pattern" which is more peculiar to poststreptococcal glomerulonephritis. electron microscopy revealed subendothelial and hump-shaped subepithelial dens deposits. there was no evidence of either a mycobacterial or a streptococcal infection and the diagnosis of goodpasture syndrome and connective tissue disorders were excluded by clinical and laboratory investigations. based on the literature review, this case represents, to our knowledge, the first time that a direct relationship between parvovirus infection and acute endocapillary proliferative glomerulonephritis has been demostrated in a child. objective: the purpose of this retrospective cohort study was to report the clinical course of children and adolescents with focal segmental glomerulosclerosis (fsgs) according to steroid response. methods: the records of 88 patients with biopsy-proven fsgs admitted between 1972 and 2005 were retrospectively reviewed. demographic, clinical and laboratory data at entry and at the end of the follow-up were analyzed. the patients were classified according to the initial prednisone response into two groups: group 1 (g1): response (complete or partial remission) (n=63) and group 2 (g2): non-response (prednisoneresistant) (n=25). renal survival analysis was performed using the kaplan-meier method. results: the median age at admission was 4.55 years (iq range: 0.99±12.84 yr) in g1 and 6.86 years (iq range: 1.08±15.55 yr) in g2. seventeen patients (27%) of g1, and 17 patients (68%) of g2 presented with hematuria at admission, and 31 (49%) children of g1 and 13 (52%) of g2 presented blood pressure levels above the 95th percentile. g2 presented a higher 24 h proteinuria (4.87 mg/24 h) at admission when compared to g1 (3.17 mg/24 h, p=0.019). median follow-up time was 8.72 years in g1 and 3.96 years in g2. the renal survival rate was 98% at 5 years and 92% at 12 years in g1, 69% at 5 years and 26% at 13 years in g2. conclusion: progressive renal insufficiency was more frequent in patients with fsgs who have initial resistance to prednisone therapy. objectives of the study: adults with chronic kidney disease (ckd) show impaired immune status. in this study, the profile of mononuclear cell subsets was related to the age and actual gfr in children and compared to healthy controls. methods: the expression of lymphocyte surface antigens was evaluated on peripheral blood (pb) mononuclear cells using three-color flow cytometry in 45 children with ckd (stage2-5) on conservative treatment. we analyzed absolute and relative numbers of total leukocytes, total lymphocytes and subsets: cd19+, cd3+, cd3+cd4+, cd3+cd8+, cd3-cd16/56+, cd3+hla-dr+, cd3+cd25+, cd69+, cd3+αβ+, cd3+γδ+, cd45ra+, cd45ra+cd4+, cd45ra+cd8+, cd45ro+, cd45ro+cd4+, cd45ro+cd8+, cd4+cd25+. results: in younger ckd children (below 10 years) absolute numbers of cd3+, cd3+cd8+, cd3+cd25+, αβ+t, γδ+t cells and cd4/cd8 ratio was higher, the percentage of cd3+cd8+, cd45ra+cd4+, cd45ro+cd4+, cd45ro+cd8+, αβ+t cells and the absolute number of cd45ro+cd8+ cells was lower than in the oldest group. in children with the lowest gfr (below 15 ml/min) the percentage of cd3+, cd19+ was lower, the absolute number of cd3+cd25+, cd69+, and the percentage of nk-cells, cd3+cd25+, cd69+, cd45ro+cd8+ cells was elevated as compared to ckd stage 2 group. the absolute number of cd8+, cd3+cd25+, cd45ra+cd8+, αβ+t, γδ+t cells and percentage of total lymphocytes, cd19+, cd3+cd25+, cd69+ was lower in ckd children than in controls. conclusion: impaired immune status is observed already in early stages of ckd. progressive disturbances in pb lymphocytes percentage mostly in the naive and memory t cells and the shift in the cd4/cd8 balance were found in pre-dialysis children with ckd. with progressive loss of renal function, we observed an increased expression of activation markers on t cells such as cd25 or cd69. introduction: relapse of steroid resistant nephrotic syndrome (srns) after renal graft occurs iñ 30% of the pediatric patients. medical management is based on increased immunosuppression with the use of iv cya and plasma exchanges (pe). however, this strategy fails in ~30% of the treated patients. new immunosuppressive agents may improve the outcome of relapsing srns post transplant. case report: a 15-year-old boy with srns reached esrd and received a cadaveric kidney transplant after two years on hemodialysis. the immunosuppressive regime was cya, mmf and steroids. seven days post transplant gross proteinuria (4 g/day) reoccurred. iv cya was administered over two months (blood level: ~450 ng/ml) associated to pefloxacine and pe (n=15), and followed by oral cyclophosphamide (cyp), resulting in partial disease control. cyp was discontinued due to haematological toxicity after one month. proteinuria increased again from 1 to 3 g/day within 3 months, despite high dose oral cya (10 mg/kg/day) and mmf. etanercept (a tnf blocking agent) was introduced at a dose of 25 mg twice weekly (combined with three steroid pulses) and maintained over two months: proteinuria decreased to 0.4 g/day over 20 days. etanercept was discontinued followed by a relapse of the ns and re-introduced eight months later, with, again a significant decrease of proteinuria to a baseline level of 0.5 g/day. conclusion: treatment with anti-tnf agents in nephrotic children has been reported once in a boy with high degree steroid dependent ns; a spontaneous decrease of disease activity over time cannot be excluded in this patient and might jeopardize data interpretation. our case is the first report of successful antiftreatment despite a constantly high activity of the nephrotic syndrome, demonstrated by relapse after discontinuation of etanercept while the patient was on post transplant immunosuppression. fournier´s gangrene (fg) is defined as a specific, quick and progressive form of synergic necrotizing fasciitis of multi-bacterial origin that affects perineum muscular fascia, genital region and surrounding areas with skin gangrene due to thrombosis of subcutaneous blood vessels. it describes the clinical case in a male preschooler of four years of age with idiopathic nephrotic syndrome (ns) that subsequent presented fg of the scrotum. broad-spectrum antibiotics, intravenous albumin and surgical cleaning of the scrotal necrotic tissues were indicated. pseudomona aeruginosa was isolated from necrotic tissue cultures. the later evolution was satisfactory with healing of the affected area and remission of the ns subsequent to the steroidal treatment. fg is an uncommon in children, rapidly progressive infection of the genital, perineal and perianal regions. it is characterized by a synergistic necrotizing fasciitis leading to thrombotic occlusion of small subcutaneous vessels and development of gangrene. until now few cases have been report fg in children, and still less associate to the kidney diseases. et all (1999) described a 10-year-old boy presenting with steroid resistant ns developed fg of the scrotum so that to our knowledge, this patient seems be the second case reported in medical literature with both pathologies. high index of suspicion, prompt diagnosis, broad spectrum antibiotics followed by wide debridement is the key to successful treatment. objectives of study: to evaluate a long term experience on iga nephropathy (igan) presenting in childhood and investigate clinical and histological factors that may act as early markers of renal disease progression. methods: retrospective review of data from children and adolescents with biopsy proven igan in the last 16 years. demographic and clinical data at presentation and severity of renal histological involvement were recorded and related to renal dysfunction markers identified at the last review. results: twenty-five patients were studied (19m/6f) with median age at onset of 11 (7-18) and follow-up of 6 (1-16) years. on presentation recurrent macroscopic hematuria was present in 19 patients, microscopic hematuria (mh) in 6, proteinuria in 11 (1 nephrotic), hypertension in 10 and transient acute renal failure in 1. renal histology findings were focal mesangioproliferative in 17, focal proliferative in 3, diffuse proliferative in 3 and focal sclerosing glomerulonephritis in 2. six patients showed tubulointersticial and extraglomerular vascular lesions (tevl) with glomerular crescents in 2. on follow-up, 7 patients remitted (2 spontaneously, 5 with ace inhibitors). of the remaining, 14 were kept on ace inhibitors due to proteinuria (7), hypertension (1) or both (6). one patient (with focal glomerulosclerosis and tevl) developed esrd within a year after diagnosis, despite treatment. at last review, 6 patients presented progressive renal disease with a mean decrease of 6 ml/min/1,73 m 2 in gfr per year. these (5m/1f) showed mainly mh and proteinuria at onset and tevl. conclusions: early renal function impairment in childhood igan can occur and may be associated with mh and proteinuria at presentation and with focal glomerulosclerosis and tevl on renal histology. proteinuria persistence in a number of patients emphasizes the need for long term followup into adulthood. adhesion molecules, il-12+p40 and cd23+cd19+ and cd25+cd4+ lymphocyte subsets in childhood nephrotic syndrome background: parathyroid hormone (pth) can modulate t cell activation and proliferation through as yet incompletely identified mechanisms. since the pth receptor (pthr) is a g protein-coupled receptor and thus a candidate for association with lipid rafts, and since pth has been shown to alter membrane phospholipid metabolism, we explored the relationship of the pthr with lipid rafts in human t cells. methods and results: we found by flow cytometry that neither physiologic nor pathologically elevated concentrations of pth affect the up-regulation of the raft marker gm-1 or of the partially raft-associated activation marker cd25 in purified t cells stimulated with phytohemagglutinin (pha). moreover, we detected the pthr exclusively in non-raft fractions of these cells after sucrose gradient separation. conclusions: these data indicate that in human t cells, the pthr does not associate with lipid rafts and that pth does not modulate these domains. accordingly, other mechanisms underlying the actions of pth on human t cells need to be sought. the direction and magnitude of potassium transport in nephron segments depend on the sitespecific distribution of transporters in tubule cell membranes. potassium depletion has been demonstrated to be associated with altered sodium reabsorption in renal tubule segments. we examined whe her potassium transporters protein expression is associated with altered abundance of major renal na + transporters, that may contribute to the development of hypokalemia in lp. after weaning rats (n=8) were fed 14 days with lp diet (8%), then they were recovered with a normal protein diet (24%, rp), each group had a control group (24%, np). we examined the changes in the abundance of the na + /h + exchanger (nhe3), na + k + atpase, na + k + 2clcotransporter (bsc-1), na + clcotransporter (tsc), epithelial sodium channel (enac) subunits and romk in kidneys of lp, np, rp rats. controls were normalized to 1. results reduced clcreat (ml/min) in lp vsnp (0.6±0.2 vs 1.6±0.2), hypokalemia (3.6±0.1 vs 5.1±0.2 meq/l) and increased fe k+ (44.2±0.5 vs 29.9±0.3%) were demonstrated. immunoblotting revealed that the abundance of nhe3 in cortex was severely decreased. the amount of bsc-1 (1.9±0.07, p<0.05) and tsc (1.4±0.15, p<0.05) protein levels were enhanced in the inner stripe (isom) and outer stripe of the outer medulla (osom), respectively. romk protein levels were increased in lp (1.23±0.04, p<0.05), the protein abundance of the enac subunits α, β and γ was increased near 1.25 fold each in response to lp. na + k + atpase protein levels showed no differences in cortex and osom. after rp, na + transporters expression returned to control values. conclusion: increased expression of bsc-1, tsc, enac subunits and romk, contributing to distal potassium secretion was shown in hypokalemia from lp. a role of aldosterone may be suggested. v. belostotsky 1 , mz. mughal 2 , j. berry 3 , n. webb 1 1 royal manchester children's hospital, pediatric nephrology, manchester, united kingdom 2 st. mary's hospital, pediatrics, manchester, united kingdom 3 manchester royal infirmary, vitamin d laboratory, manchester, united kingdom aims: to describe the prevalence of vitamin d deficiency in south asian and white uk children with renal disease. to establish how decreased levels of vitamin d affect pth in patients with a normal gfr. methods: 143 children aged 1-18 years were enrolled in the study: 99 were of white uk, 38 of s asian and 6 of other ethnic origin. 18 were on dialysis, 18 had chronic renal failure, 46 had various renal disorders with normal gfr (>80 ml/min/1.73 m 2 ), 61 had a transplant (42 with anormal gfr). blood samples were collected to establish the levels of 25-vitamin d (25-ohd); pth; creatinine. 25-ohd concentration <10 ng/ml was defined as vitamin d deficiency; levels between 10-20 ng/ml as vitamin d insufficiency. serum pth of 0.8-3.9 pmol/l was defined as normal. results: the prevalence of vitamin d deficiency/insufficiency was higher in s asian (87%) than white (36%) children (p<0.0001). ofthe 88 (28 s asian, 56 white and 4 other) children with normal gfr17/28 s asian and 28/56 white children had pth concentrations >3.9 pmol/l. of these 12/17 s asian, 11/28 white children had low levels of 25-ohd (p=0.04). of 19 transplant patients with reduced gfr, 11 of 14 with a high pth had low 25-ohd levels, compared with 1 of 5 with a normal pth (p=0.04). conclusions: many s asian children attending our renal clinic are vitamin d deficient/insufficient and the prevalence of this problem is significantly higher than that in the white population. high pth values in the setting of a normal gfr can often be explained by vitamin d deficiency and should result in serum 25-ohd levels being measured. nephronophthisisis a rare recessive autosomal disease which may be either limited to progressive chronic tubulointerstitial nephritis or associated with extrarenal involvement (eye, liver, central nervous system, etc.); mutations/deletions have been found in at least 6 nphp genes. fibrous dysplasia is a benign skeletal lesion due to an activating mutation inthe gene that encodes the α subunit of stimulatory g protein and occurs after fertilization in somatic cells; it involves one or several bones and may be part of mccune albright syndrome. we report on a boy with fibrous dysplasia of bone diagnosed at 3 yrs of age, who underwent protocol renal function tests at 7 yrs of age in the follow-up of pamidronate treatment. inulin clearance was 75 ml/min/1.73 m 2 and potassium reabsorption rate was 55.2% where as there was neither urinary phosphate wasting nor hypercalciuria. serum magnesium was decreased (0.74 mmol/l) without reabsorption abnormality and serumuric acid progressively increased with age. in addition, due to increasing microalbuminuria, a treatment with acei was started at 11 yrs of age. renal ultrasonography at 11 yrs of age showed hyperechoic reduced-sized kidneys with few microcysts. a renal biopsy (light and electron microscopy) was performed at 11 yrs of age, which showed nephronophthisis-like lesions, i.e., diffuse interstitial fibrosis and focal thickening of tubular membrane basement. dna analysis revealed no nphp1 gene deletion but is still under investigation.nephronophthisis has been reported in association with skeletal involvement (coneshapedepiphyses) and fibrous dysplasia with hypophosphatemic rickets or fanconi syndrome. however no association between fibrous dysplasia of bone and nephronophthisis-like lesions has been described and may be a new picture of the nephronophtisis/medullary cystic kidney disease complex. m. bald, m. holder, h. leichter olgahospital, pediatric nephrology, stuttgart, germany puumalaviruses belong to the group of hanta viruses and are transmitted by inhalation of aerosolized particles of the red bank vole (cletriomonysglareolus) which is endemic in the alb-danube region of southern germany. infections with puumala virus were first described as "nephropathia epidemica" in scandinavia with the clinical symptoms of fever, thrombocytopenia and acute renal failure. over the last seven years three boys with acute renal failure were admitted to our hospital after vacationing in the region endemic for puumalavirus. all three presented with high fever, influenza like symptoms aswell as pronounced abdominal or flank pain. they showed a decreased gfr (14, 47 and 71 ml/min/1.73 m 2 , respectively) with hematuria and proteinuria. cbc revealed no leucocytosis or anemia, but thrombocytopenia in 2 of the 3 patients. they had no oliguria, but 2 patients had marked polyuria in the recovery phase of renal function. arenal biopsy in the boy with the most severe presentation showed diffuse tubular damage. puumala virus infections were confirmed in all patients by serological tests, and renal function normalized within 2-3 weeks. nephropathia epidemica due to puumala virus infections have to be included in the differential diagnosis of acute renal failure in patients from endemic regions. severe abdominal or flank pain are common symtoms in these patients; renal failure is transient and the general prognosis is good. aims: the objective of this study is to determine the relationship of urinary calcium excretion (uca) with sodium and protein intake in a pediatric population of families with low income. methods: 109 children, 59 f and 50m, ages 8 to 15 years from families with income <$100/month were studied. protein intake was estimated with a 7-day dietary record. a nonfasting urine sample was collected for dipstick, calcium, creatinine, sodium, potassium, urea and uric acid. urinarycalcium/creatinine (ca/cr), sodium/potassium (na/k), uricacid/creatinine (au/cr) and urea/creatinine (u/cr) ratios were calculated. children with a urinary ca/cr >0.20 mg/mg, were submitted to a 15 day period of high sodium foods restriction after which a second urine sample was collected. results: mean (x) and standard deviation (sd) for ca/cr, na/k, au/cr and u/cr ratios were: 0.09±0.05 mg/mg, 5.68±5.41 meq/meq, 0.5±0.24 mg/mg and 16.12±5.3 mg/mg respectively. the 95th percentiles for ca/cr, na/k, au/cr and u/cr were 0.19, 13.07, 0.96 and 26.5 respectively. x±ds for protein intake was 1.27±0.27 g/kg/day. the incidence of hypercalciuria was 6.4% in the initial urine sample and 2.7% in the second. correlation was significant between ca/cr ratio and na/k ratio (r: 0.5, p<0.05), acu/cr ratio (r: 0.38, p<0.05) and u/cr (r: 0.30, p<0.05), not significant between ca/cr ratio and protein intake. conclusions: the incidence of hypercalciuria in this serie is lower than previously reported values in venezuela for the general pediatric population and decreases further when sodium intake is controlled. although no correlation was found between uca and protein intake, we could speculate that protein intake near to the daily recommended requirements of 1 g/kg/day, could be a possible reason for the lower incidence of hypercalciuria in this population. 16-year old girl presented with rapid onset of muscular weakness and a short history of severe dysphagia, dysphonia nad significant wasting. on examination, she was dystrophic (bmi 15,7) and had signs of myopathy. laboratory findings confirmed myopathy (cpk 106,4 ukat/l, ast 2,86 ukat/l, myoglobin 1582 ug/l). there was striking hypokalemia (s-k 1,8 mmol/l) suggesting hypokalemic paralysis. diagnosis of distal renal tubularacidosis (drta) was based on confirmation of hyperchloremicmetabolic acidosis, severe hypokalemia, high urinary ph and positive value of urinary anion gap (s-cl 120 mmol/l, ph 7,31, be 10, urinary ph 7,5). there was evidence of other signs of renal tubular impairment (urinary beta-2-microglobulin 213 mg/l, glomerulo-tubular proteinuria 1,01 g/24 h). autoimmune tests (high positive rheumatoid factor, anf, ena ss-a/ro, ss-b/la, high circulating immunocomplexes) and low values of sialometric measurements (7,5 ml/2x15 minutes) revealed primary sjogren´s syndrome as the underlying cause of drta. the renal biopsy confirmed chronic tubulo-interstitial nephritis compatible with this diagnosis. full recovery of muscle weakness and laboratory findings of hypokalemia and acidois followed potassium and alkali replacement. corticosteroids were administered with subsequent addition of cyclosporine a because of disease activity. conclusion: primary sjogren´s syndrome is a rare diagnosis in childhood and adolescence and should be considered in patients presenting with hypokalemic paralysis due to drta. m. caletti, h. lejarraga, s. caíno, a. jiménez introduction: ndi is a chronic, genetic disease caused by an inability to effectively conserve urinary water, due to a lack of response of distal renaltubule to antidiuretic hormone. the main symptom is polyuria, polydipsia and growth impairment. objective: to evaluate long term growth in height and weight of 16 children with ndi. patients and methods: sixteen patients with ndi attending hospital for a median period of 11.5 years (range 3.4/16.2 yrs) were studied. treatment consisted of indometacine, hydroclorotiazide and amiloride (iha). height and weight was measured with standardized anthropometric techniques. z scores(sds) for all measurements were calculated according to national standards. results: all children responded favourably to treatment. mean birth weight sds was not different from zero; mean height and weight at diagnosis was ±2.31 and ±2.66 sds respectively, and at the end of follow-up was ±1.30 and ±0.98 respectively. the majority of patients´s growth curves evolved below the 50 th centile. ten out of 16 children experienced some catch up in height (mean height gain: 1.38 sds (r: -0.50/2.42)). mean weight gain during follow-up was 1.74 sds (r: 0.86/4.24) . mean gain in body mass index was 1.72 sds (range 0.5/4.8). in the two patients who attained adult height, adolescent growth spurt was normal, and final height was within normal limits for standards and for parental height. correlation coefficient between gain in height andage at diagnosis was ±0.58. conclusion: although mean height at follow-up was below the expected normal value, combined therapy with iha is compatible with some catch up growth in height and weight. the lower the initial height, the greater the height gain. adherence to treatment is essential for normal growth in children with ndi. body growth of children with steroid-responsive idiopathic nephrotic syndrome m. noer, i. irwanto, n. sumiarso, m. chalim soetomo hospital, school of medicine airlangga university, department of child health, surabaya, indonesia objectives of study: the present study was designed to evaluate the statural growth of children with steroid-responsive idiopathic nephrotic syndrome, attending the pediatric nephrology unit department of child health, school of medicine airlangga university, soetomo hospital, surabaya, indonesia, with a minimum follow-up of 2 years. methods: anthropometrice valuation included weight, height, and growth velocity expressed as mean and standard deviation scores (sds), relative to the normal population (nchs/cdc 2000). these indices were analyzed at admission and then every 6 months of follow-up. all patients were treated with prednisone, according to indonesian consensus of management of idiopathic nephrotic syndrome in children. results: of 157 children (105 boys and 52 girls), 43 patients (34 boys) aged 26/12 years to 16 years (mean 7.05 years) were analyzed. initial mean height and z score (height for age) were 108.41±15.2 cm and -1.85±1.41, respectively. mean height and z score (height for age) of the last follow-up were 121.88±15.1 cm and -1.34±1.5, respectively. mean growth velocity were 6.25±2.05 cm/year where 3 boys (6.9%) had growth velocity less than 4 cm/year. total cumulative dose of steroid during 2 years of follow-up were 4283.90±2863.35 mg or 233.76±153.73 mg/kgbw. conclusions: the cumulative dose of steroid up to 233.76 mg/kg body weight in children with nephrotic syndrome during 2 years of treatment did not influence their growth velocity. background: recently it has been reported in adult patients (pts) that deterioration of renal function was associated with the lost of nocturnal blood pressure (bp) dip and enhanced urinary sodium (una) and protein (uprt) excretion during night. objectives of study: to investigate the circadian rhythms of bp, una and uprt in children with chronic kidney disease stage i (ckd i). methods: in 34 pts (15 boys) aged 11.2±4.3 years with ckd i (chronic glomerulopathy confirmed by renal biopsy in 85% pts), 24 hour bp was monitored during daytime (d) and nighttime (n) and urinary samples for uprt, urinary creatinine (ucr), and una, were collected for both periods. results: serum creatinine-based gfr was 127±22 ml/min/1.73 m 2 , uprt ranged from 21 to 5455 (median 141) mg/24 h, and una from 27 to 267 (median 102) mmol/24 h. in general we found a highly significant nocturnal decrease in systolic bp (from 116 to 108 mmhg), diastolic bp (71 to 62 mmhg), mean arterial pressure (87 to 78 mmhg), heart rate (91 to 75/min) urinary output (uo), una and uprt. the regression equations were as follows: uod (ml/m 2 /h)=32+1.6xuon (ml/m 2 /h); unad (mmol/l)=73.5+0.14xunan (mmol/l); uprtd (mg/m 2 /h)=5.4+1.83xuprtn (mg/m 2 /h) and urinary osmolality (us) d=13+0.65xusn. nocturnal decrease of uo correlated with nocturnal decrease of ucr and uprt, and nocturnal decrease of uprt correlated with nocturnal decrease of uo. more than half of the patients were classified as non dipper. they differ significantly from dipper only in night/day changes of us. conclusion: night/day changes of uo, una and uprt in pts with ckd i may be calculated from the given regression equations. these changes are not correlated with nocturnal bp decrease. non dippers have greater nocturnal change of us compared to dippers. follow-up of these parameters will clarify their importance in progression of ckd. autosomal autosomal dominant proximal renal tubular acidosis (prta) it is described l. g. brenes (1977) at seven members of one family. we diagnosed seven members of the afghani family with prta: mothers and 6 children (5 girls, 1 boy from 2,5 till 16 years) with hyperchloremic metabolic acidosis. pedigree analysis suggested an autosomal dominant inheritance pattern. observable patients did not have ricket and nephrocalcinosis. deafness and ocular abnormalis are absent. the plasma hco 3 concentration is decrease in the range of 14,9 to 19,0 mm/l, minimal urine ph is <5,5. parameters of blood creatinin and glomerular filtration rate were normal. urine calcium excretion was normal. therapy strategy of prta at observable patients provides high dozes of citrates/bicarbonates 10-15 mmol/kg per 24 h. all india institute of medical sciences, division of nephrology, department of pediatrics methods: retrospective case-search. data of previously reported prospective trial (n=19) was also included. results: all except 6 patients had previously been treated with both levamisole and cyclophosphamide. forty-two cases qualified for the study and were administered mmf for a mean duration of 14.3 months (95% ci, 12.0, 16.6/patient in the first 6 months of treatment and 0.7 episodes (n=35) in next six months of mmf treatment (p<0.0001), an average reduction of 62% (95% ci, 49.1, 75.0) from the pre-mmf phase. nine (21.4%) patients had no relapses while on mmf therapy we present sibling cases of as with heavy proteinuria at early childhood. a boy (3 year-old) and a girl (2 yearold) were diagnosed as x-linked as. since a boy developed persistent heavy proteinuria (up/cr 2.9) with macrohematuria andresistant to arb/acei therapy, we treated him with cyclosporina (csa) that could lead to complete remission. to investigate pathomechanism of proteinuria, we tested immunostaining for slit diaphragm associated molecules (nephrin, podocin), gbmassociated molecules (laminin, perlecan, agrin) and podocalyxin using frozen sections from his firstand second biopsy and girl's one (up/cr 0.4). in the specimens from boy's first biopsy and girl's one, light microscopy revealed mild mesangial proliferation and no differences ofthe expression with perlecan, agrin and podocalyxin compared with controls. however, when determined laminin isoforms, fetal type laminin (alpha2beta1gamma1) wasdistinctly observed in the gbm, whereas that was localized only inmesangium with controls. interestingly when compared mature laminin isoform (alpha5beta2gamma1), beta2 chain was specifically less expressed in the gbm. however there were no differences of expression of these molecules in the specimens between pre-and post-treatmentwith csa. in boy's second biopsy, 50% glomeruli were detected to becollapsed. together with the recent report showing that laminin beta2 mutation causes congenital nephrotic syndrome factor v leiden mutation and steroid resistant membranous glomerulonephritis: a case report m. buyukcelik 1 , m. karakok turkey renal compications of d-penicillamin therapy in wilson's disease sami ulus children's hospital, department of pediatric nephrology sami ulus children's hospital, department of pediatrics sami ulus children's hospital hass classification), treatment and outcome. thirty-nine patients; 29 boys (74.4%) and 10 girls (25.6%) time of the last examination (median 60 months, min<1 year) after the admission as a long term follow-up. clinically, group i; while microscopic hematuria was detected in 6 patients, 19 patients had repeated attacks of hematuria, 4 had isolated mild proteinuria/hematuria, group ii; 6 patients had nephritic, 1 had nephrotic syndrome and 3 had both. biopsy grades in the 39 patients: 55%, 60% had grade i, 10.4%, 10% had grade ii, 31%, 20% had grade iii, 6%, 10% had grade iv in group i and ii, respectively. group i and ii patients recovered completely (no hematuria and proteinuria) 34.4%, 44.8% as well as 20%, 50%, short-term, longterm, respectively. while recovery rates in fish-oil and/or ace-inh treatment group was 34.4% and 48.2%, in corticosteroids group, it was 25%, 50% short-term, long-term,respectively. no patients who received immunosuppressive treatment had improved. however, 3 (7.6%) patients would suffer from esrd. initial presentation, severity of renal involvement and type of the treatment were not found to have a prognostic value (p>0.05). in children, igan is characterized by extreme pathogenetic, clinical and histological polymorphisms radojevic 1 1 university of belgrade, faculty of medicine, institute of pathology, belgrade, serbia 2 institute of mother and child health of serbia, belgrade, serbia 3 university children's hospital, department of nephrology, belgrade, serbia celiac disease hla aplotype in children with nephrotic syndrome s i (if) or mcp or with anti-cfh autoantibodies. varicella hasn't been described as a triggering event of ahus. we report two cases of ahus associated with complement dysfunction revealed after varicella infection. case 1. a five year-old boy presented with non post-diarrheal hus, 17 days after varicella. serum creatinine was 300 μmol/l, hemoglobin 6.5 g/dl, schizocytes 17%, platelets 19 g/l. glomerular filtration rate normalized within 14 days. search for shiga toxin-producing e coli in the stools and serum anti-lipopolysaccharides antibodies were negative. plasma c3, cfh and if levels were normal. no mutations of cfh and if were found. mcp cell-surface expression was decreased and a c30f mutation in mcp exon 2 was demonstrated. case 2. a four year-old girl had ahus 5 days after varicella at that time, complement system study showed normal c3 level (677 mg/l, normal 660 to 1260 mg/l), normal cfh level (81%, normal 70-130%), but the presence of anti-cfh autoantibodies. no mutations of cfh, if or mcp were found. in conclusion, these 2 cases outline that varicella can be the triggering event of ahus associated with complement dysregulation about 450 (62.5%) children had relapses after initial remission. various infections were responsible for relapsed with in 200/450 (44.44%) who had relapses. about 120 children (32.69%) relapsed with out cause where as poor compliance was observed in 47 (12.8%). overall infection and relapse rate was 1.4 and 1.00/pt/yr respectively. among 367 children with infections, most common types of infections were acute respiratory infections (ari), diarrhea and uti seen in 200 (54.49%), 82 (22.34%) and 30 (8.17%) of cases respectively. other types of infections like malaria, peritonitis, skin infection and pulmonary tuberculosis were seen serum pai-1 and tgf-beta 1 levels in profliferative forms of glomerulonephritis in children russian federation 2 research centre for child health rams, department of pathology, moscow, russian federation we aimed to investigate serum levels of plasminogen activator inhibitor -1 (pai-1) and transforming growth factor-beta 1 (tgf-beta 1 ) in children with proliferative forms of glomerulonephritis (gn). 51 children were examined (5-16 years old) with gn (steroidresistent ns, n=27; steroidsensitive ns, n=11, isolated haematuria, n=13) and 15 healthy age matched controls. mesangioproliferative gn (mespgn) was detected in 39 patients, membranoproliferative gn (mpgn) in 12 cases. serum levels of pai-1: ag and tgf-beta 1 were measured by elisa. results. the highest levels of pai-1: ag and tgf-beta 1 were observed in relapse of mpgn: 93,51±71,63 ng/ml and 16 these results confirm prosclerotic effects of pai-1 and tgf-beta 1 via increased fibrin deposits and extracellular matrix accumulation in the renal tissue and promotion of disease progression rituximab treatment for idiopathic nephrotic syndrome: a retrospective study of 11 cases v. guigonis 1 , a. dallocchio 1 , m. dehennault urinary and serum annexin v levels in children with steroid sensitive and steroid-resistant nephrotic syndrome hôpital robert debré-aphp, pediatric intensive care unit indonesia this study was aimed to evaluate the efficacy of pulse dose of cyclophosphamide in children with srns admitted in child health department faculty of medicine university of indonesia/cipto mangunkusumo hospital jakarta between 2001-2006. 6-month period, one child died, and the rest (5 children) did not complete the regimen. five out of 7 children who finished the treatment had remission, while 2 others were still experiencing heavy proteinuria. remission was achieved in various time, 3 children were in remission after the first dose, in 2 children it was achieved at the third and sixth dose. in further follow-up time; one child remained in remission, one child had relapse when still receiving cpa, 2 children got relapse one month after stopping cpa, and one child had relapse after 6 months ceasing cpa. nausea and vomiting were found in 2 children indonesia this study is to evaluate the anthropometric measurements of children with nephrotic syndrome methods: a descriptive retrospective study at child health department, cipto mangunkusumo hospital, jakarta. data were collected from medical records of nephrotic syndrome 9%) irns; body height and body weight of <p3 was found in none of frns/sdns, 9/32 (28,1%) srns, and 20/101 (19,8%) irns; bmi >p95 was found in 4/45 (8,9%) frns/sdns, 3/32 (9,4%) srns, 4/101 (3,9%) irns. conclusion: the percentage of children with frns/dsns and srns with body height <p3 il-12) during active stage (as: urinary protein >40 mg/m 2 per hour, serum albumin <2.0 g/dl) and remission stage (rs) in ss-mcns. a total of 48 patients with ss-mcns (29 of 48 patients with as and 19 of 48 patients with rs) and 19 healthy children were recruited for studies. the mean±sd of serum il-12, se-selectin and sicam, levels were significantly higher in patients with as than in patients with rs (277±188.4/157.2±119 pg/ml; 132.1±67.9/88.3±40.5 ng/ml and 168.3±120.3/82.2±27.1 ng/ml respectively, p<0.05). in spite of, higher levels of il-12, se-selectin and sicam in patients with as than controls, difference was not statistically important. the percentage of cd3+cd23+ lymphocyte subsets were statistically grater in patients with as severe proximal renal tubular acidosis in pearson syndrome birth weight was 4000 g. pallor was initially noted during the neonatal period and referred to our hospital with anorexia, vomiting, diarrhea, weakness, and increased pallor at 8 wk of age. on the physical examination she was pale and the other systems were unremarkable. investigation showed hypoplastic anemia, and bone marrow examination showed cytoplasmic vacuolization of both myeloid and erythroid precursors, and maturation arrest of granulopoesis. family history was negative for hematological disease. the diagnosis ps was considered on the basis of early severe refractory anemia associated with vacuolization of bone marrow precursor cells and ring sideroblasts. treatment was started consisting of vitamine b6 and folic acid. she was followed with growth retardation, moderate anemia and leucopenia up to age 4.5. at that age, the girl was readmitted with severe vomiting and dehydration. on admission, she had moderate metabolic acidosis, hypokalemia, high plasma lactate, and hypophosphatemia. further investigations showed tubuler proteinuria, glucosuria, aminoaciduria, and defective bicarbonate reabsorbtion in the proximal tubule. she developed refractory metabolic acidosis resulting in a cardiac and respiratory failure and death. to confirm the diagnosis of ps, molecular studies were performed 4977 bp common deletion was found medial calcification in intact human arteries from children with chronic kidney disease is associated with apoptosis and osteogenic differentiation -clinical and laboratory correlations r using intact human vessels we studied the phenotypic changes in medium sized arteries ex vivo and in vitro after exposure to ca and po 4 . arteries were retrieved during insertion of pd catheters or at transplantation from 34 children: dialysis (n=20), ckd stage iv (n=8) and compared with mesenteric vessels from 6 controls. vessel rings were incubated with graded concentrations of ca and po 4 upto 21 days. calcium and alkaline phosphate (alk) were measured by cresolphtalein complexone and colorimetry. immunohistochemistry for bone marker proteins, inhibitors of calcification and apoptosis were performed. laboratory findings were related to patient's clinical and biochemical parameters, carotid intimamedia thickness (cimt) and coronary calcification. vessels from ckd or dialysis patients had increased baseline vessel wall ca compared with controls (p=0.001). when exposed in vitro to ca and/or po 4 , dialysis vessels showed greater calcification than those from controls or ckd patients (p<0.0001). in the presence of elevated po 4 even a small increase in ca increased calcification (p<0.001). calcification was associated with apoptosis (tunel +) and could be inhibited using apoptosis inhibitor zvad. alk in ckd and dialysis vessels and along with upregulation of bone-markers suggests an osteogenic conversion of vsmcs using our unique in-vitro model, we have shown for the first time that vascular damage induced by elevated ca-po 4 as well as factors specific to dialysis primes vessels for rapid progression of medial calcification altered expression of major renal na + and k + transporters c. ruete 2 , p. vallés 1,2 1 university of cuyo, department of pathology turkey the effect of corticosteroid therapy on bone metabolism in nephrotic syndrome was examined. sixty-nine patients with idiopathic nephrotic syndrome (age: 7.0±2,5 years) and 21 healthy controls (age: 6.4±3,5 years) were divided into 3 groups: group 1: patients who were on remission but still receiving steroid therapy, group 2: patients who were on remission and free of steroids within the last year and group 3: patients with active nephrotic syndrome and receiving steroid therapy. serum total calcium, ionized calcium, phosphorus, alkaline phosphatase, magnesium, parathyroid hormone, 25(oh)d, serum cystatin c, urine protein, urine creatinine and urine cystatin c levels measured in all patients including the control group. in addition, lumbar spine bone mineral density z scores were measured in the patient group objectives of study: we evaluated the clinical, laboratory and urinary tract echosonographic findings in patients with ah and rh. methods: there was prospective clinical study, included 30 patients (mean age 6.6±2.5) with ih (normocalcemic, normophosphatemic, with 24 hours urinary calcium excretion greater than 4 mg/kg/day) all analyzed parameters (dysuria, positive family history of urolithiasis, microscopic hematuria, urinary tract microlithiasis) showed low sensitivity and specificity, and none of the parameters could be considered reliable in differentiating ah versus rh. average value of una/cr was greater in patients with rh conclusion: none of the analyzed clinical parameters, laboratory and echosonographic parameters except values of urinary excretion after calcium deprivated diet could be considered reliable in differentiating ah versus rh. patients with rh have higher level of 24 hours urinary calcium excretion than patients with ah. patients with rh have significantly greater excretion of urinary sodium compared with patients with ah idiopathic hypercalciuria (ih) is defined as hypercalciuria with no detectable cause. low bmd with increased fracture rate and tendency to short stature has been reported in ih patients. we aimed to perform calcaneus qus in children with ih and relate to u-ca, body height and number of prevalent fractures (fx). 11 children (8 girls, 3 boys; patient. body height was recorded and qus was measured on both heels with cuba clinical. the 24-h u-caexcretion (u-ca/24 h) was assessed and calculated in mmol/kg/24 h. results were expressed as z-scores ±sd. czech anthropometric parameters from a 1991 survey and previously obtained qus values of the healthy czech pediatric population served as reference data. qus results were also calculated as height adjusted values with the use of heightmatched standards. u-ca/24 h was matched to healthy european paediatric population values we found no correlations between fx and bua (either age-related orheight-adjusted) or fx and vos (age-related or height-adjusted). neither were there any correlations between u-ca and fx, or u-ca/24 hand bua or vos, respectively. in conclusion, children with ih had normal height, normal values of bua and low vos 40 (fc) 491 (p) 652 (p) 268 (mr) 23 (fc) 126 (fc) 194 (op) 523 (p) alpay h. 399 (p) 854 (p) amann k. 37 (fc), 810 (p), 818 (p) amanullah f. 521 (p) 169 (op) amaro a. 77 (op) 164 (op) amore a. 48 (sy) 831 (p) anarat a. 277 (fc) 131 (mr) 322 (p) 191 (op) 213 (fc) 75 (op) 345 (p) 391 (p) bael a. 192 (op) 308 (p), 543 (p), 600 (p) 32 (fc) 129 (fc) 658 (p) balat a. 349 (p) 444 (p) 19 (fc) bayazit ak. 372 (p) 906 (p) 708 (p), 709 (p), 710 (p) 338 (p) 356 (p) 671 (p) 805 (p) bensman a. 162 (op) 153 (sa), 384 (p) 425 (p) 118 (fc) bereczki cs. 66 (op) 214 (fc) 93 (op), 285 (fc) 197 (op) 12 (sy) bi yl. 484 (p) 23 (fc) 370 (p) 171 (op) 841 (p) biyikli n. 399 (p) 398 (p) 227 (fc) bocanegra v. 224 (fc) 122 (fc) 352 (p) boh m. 134 (fc) bökenkamp a. 92 (op) 271 (fc) 22 (fc) 177 (op) 65 (op) 92 (op) bourrier t. 425 (p) bouts ah. 103 (op), 117 (fc) 77 (op) 903 (p) bubic-filipi lj 368 (p) 168 (op), 271 (fc) 78 (op) 486 (p) 389 (p) caropreso m. 95 (op) 277 (fc), 371 (p) 40 (fc) 459 (p), 460 (p) chartapisak w. 817 (p) 530 (p) 693 (p) chaves a. 77 (op) 394 (p) chemodanova m. 911 (p) 559 (p) chen j. 76 (op) 724 (p) 488 (p) 539 (p) 654 (p) 160 (op) 396 (p) 645 (p), 650 (p), 836 (p) clermont mj 737 (p) 211 (fc), 472 (p) 55 (sy) codoceo a. 523 (p) coelho g. 77 (op) 49 (sy), 221 (fc) 48 (sy) 704 (p) 214 (fc) 211 (fc) 846 (p) 206 (fc) 456 (p) coutinho s. 868 (p) coviello d. 333 (p) 223 (fc) craig j. 108 (op), 556 (p) cransberg k. 214 (fc) 765 (p) 425 (p) cristino s. 672 (p) 39 (fc) 532 (p) cross j. 86 (op) cruz mr 22 (fc) 534 (p) 117 (fc), 558 (p), 630 (p) 55 (sy) deanfield j. 127 (fc) 845 (p) decena-galvez a. 601 (p) 124 (fc) 571 (p) 415 (p) deguchtenaere a. 98 (op) 859 (p) 679 (p) 303 (sa), 373 (p) 381 (p) delucchi a. 633 (p) 821 (p) 338 (p) 439 (p) 485 (p) 653 (p) 284 (fc), 599 (p) 20 (fc) dinda a. 756 (p) 325 (p) 695 (p) 607 (p) dittrich k. 37 (fc) 28 (fc) 307 (p), 445 (p) dötsch j. 37 (fc), 810 (p), 818 (p) dragon-durey ma 388 (p) 34 (fc) 576 (p) 25 (fc) 833 (p) 594 (p) 512 (p) 660 (p) dursun i. 344 (p) 344 (p) 500 (p) edefonti a. 380 (p) 374 (p) eke f. 265 (fc), 718 (p) 322 (p) 220 (fc), 269 (fc), 333 (p), 403 (p) 32 (fc) 338 (p) 706 (p) 384 (p) evim m. 430 (p) f faerch m. 378 (p) fallahzadeh mh. 448 (p) 473 (p) 248 (sy) feig d. 353 (p) 681 (p) 644 (p) fella a. 96 (op) feneberg r. 176 (op) 77 (op) 862 (p) filler g. 25 (fc) 849 (p) 104 (op) fischbach m. 157 (op) sy) fitoz s. 408 (p) 117 (fc) 798 (p) 470 (p) fujita h. 75 (op) 441 (p) fujita t. 769 (p) 443 (p) fukuhara d. 816 (p) 171 (op) 843 (p) 803 (p) 171 (op) 189 (op) garnier a. 365 (p) 762 (p) 155 (op) 251 (sy) geary-joo c 21 (fc) 32 (fc) 177 (op) 141 (sy) 32 (fc) 605 (p) gross ml. 116 (fc) 610 (p) 331 (p) 136 (fc) 205 (fc) 533 (p) 821 (p) guo w. 76 (op) 746 (p) 70 (op) 344 (p) haberal m. 537 (p) 42 (fc) 72 (op), 128 (fc) 271 (fc), 538 (p) 285 (fc) 266 (fc), 747 (p) 266 (fc) 851 (p) 268 (mr) 344 (p) 470 (p) 183 (op) 164 (op) hernández am. 638 (p) 75 (op) 183 (op) 28 (fc) 190 (op), 271 (fc) 814 (p) hou jr. 315 (p) 334 (p) 168 (op) 315 (p) 204 (fc) 29 (fc) 305 (p), 306 (p) iharada a 186 (op) 185 (op) 677 (p) 267 (fc), 283 (fc) 618 (p) 664 (p) 49 (sy) 793 (p) kathiravelu a. 25 (fc) 100 (op) 154 (op) 104 (op), 115 (fc) 385 (p) 665 (p) 765 (p) 734 (p) 749 (p) 643 (p) 18 (mr) 334 (p) 69 (op) 471 (p) kondo y. 29 (fc) 647 (p), 891 (p) kosuljandic-vukic d. 503 (p) 205 (fc) kovalski y. 645 (p) 190 (op) 815 (p) 312 (p) 611 (p) kru èic d. 910 (p) krylova-olefirenko a. 825 (p) 616 (p) 582 (p) 746 (p) 260 (sy) 118 (fc) 340 (p) 544 (p) kurayama r. 185 (op) 599 (p) 266 (fc) lalatta f. 177 (op) 515 (p) 257 (sy), 354 (p) 160 (op) 432 (p) lau yw 77 (op) 77 (op) 559 (p) llanas b. 71 (op), 136 (fc), 859 (p) llewellyn-edwards a. 270 (fc) 284 (fc) 348 (p) 263 (fc) luis-yanes m 354 (p) 589 (p) 293 (sy) maeda a. 566 (p) maekawa k. 602 (p) 830 (p) 453 (p) 477 (p) 841 (p) 410 (p) 323 (p) mak r. 49 (sy) 95 (op) 171 (op) 625 (p) 20 (fc), 26 (fc) 226 (fc) 457 (p) 254 (sy) 20 (fc) 893 (p) 638 (p) 578 (p) medynska a. 421 (p) 350 (p) mehls o. 128 (fc) 855 (p) 277 (fc), 426 (p) 74 (op) 179 (op) 174 (op) 115 (fc), 758 (p) 420 (p) 23 (fc) 368 (p) molnár-varga m. 525 (p) 227 (fc) 279 (fc) 487 (p) montini g. 209 (fc) 774 (p) 523 (p) 74 (op) 587 (p) 569 (p) morimoto t. 187 (op) 364 (p) 71 (op) 345 (p) morita t. 563 (p) 392 (p) mortazavi f. 309 (p) 283 (fc) moscaritolo e. 502 (p) 728 (p) mosig d. 493 (p) 191 (op) 226 (fc) 498 (p) moxey-mims m. 221 (fc) 158 (op) 521 (p) mudun a. 652 (p) 116 (fc) mughal mz. 895 (p) 828 (p) müller t. 165 (op) müller v. 218 (fc), 244 (sy) müller-esterl w. 745 (p) müller-wiefel de. 23 (fc) 49 (sy), 221 (fc) 174 (op) fc) 185 (op) 31 (fc) 504 (p) nghia h. 490 (p) niaudet p. 113 (mr) 372 (p) 312 (p) nuzzi f. 95 (op), 96 (op), 541 (p) nwobi o. 592 (p) 171 (op) 77 (op) 393 (p) 75 (op) 338 (p) 257 (sy) 567 (p) ostalska-nowicka d. 522 (p) 621 (p) otukesh h. 477 (p) 322 (p) 710 (p) 543 (p) ozen a. 498 (p) 230 (sy), 308 (p) 380 (p) 876 (p) paik kh. 643 (p) 853 (p) pan'czyk-tomaszewska m. 337 (p) 459 (p) 35 (fc) paripovic d. 611 (p), 612 (p), 647 (p) 207 (fc) pasqualini t. 194 (op) fc) pastori a. 463 (p) pászka d. 100 (op) 95 (op) 334 (p) pereira a. 77 (op) 129 (fc) 275 (fc), 574 (p) 576 (p) fc) 110 (op), 344 (p) raes a. 98 (op), 99 (op), 223 (fc) 218 (fc) 535 (p) rigden s. 22 (fc) 209 (fc) ring e. 346 (p) rink n. 104 (op) 74 (op) ristoska-bojkovska n 271 (fc), 538 (p) roszkowska-blaim m. 337 (p) 576 (p) 894 (p) ruffo gb. 914 (p) ruhlmann a. 193 (op) ruiter j. 85 (op) rumeau r. 206 (fc) rusai k. 215 (fc) rusnak f. 608 (p) rüther u. 381 (p) rutjes n. 785 (p) rybarova s. 772 (p) rychlik i. 776 (p) ryckewaert-dhalluin a 477 (p) sabasiñska a. 401 (p) 684 (p) sabolic-avramovska v. 348 (p) 721 (p) 162 (op) safouh h. 499 (p) saha a. 530 (p) sahin h. 512 (p) 184 (op) saint-cyr c. 805 (p) saito a. 450 (p) 29 (fc) sakalli h. 537 (p), 708 (p), 866 (p) sakalli ercoban h. 426 (p) 13 (sy) 868 (p) salusky i. 129 (fc) 74 (op) 717 (p), 720 (p) sarkissian a. 316 (p) 805 (p) 217 (fc) 414 (p) 215 (fc) 154 (op) sayili a. 590 (p) schäfer b. 691 (p) 32 (fc), 34 (fc), 42 (fc), 51 (sy), 116 (fc), 228 (fc), 271 (fc), 276 (fc) 215 (fc) schmidt-gayk h. 281 (mr) schmidts m. 549 (p) schmitt cp. 116 (fc) 195 (op) 549 (p) 272 (fc) schneider-maunoury s. 381 (p) 549 (p) 49 (sy), 221 (fc) 23 (fc) 180 (op) 869 (p) seeherunvong w. 40 (fc) 887 (p) 185 (op) 468 (p) semama d 76 (op) 748 (p) 470 (p) 656 (p), 657 (p) shin yh 382 (p) 564 (p) 22 (fc) 372 (p) 416 (p), 519 (p), 652 (p) siwiñska a. 343 (p) 276 (fc) 154 (op) 717 (p) spasojevic b. 612 (p), 647 (p), 910 (p) spasojevic-dimitrijeva b stanic m. 386 (p), 891 (p), 910 (p) stankovic a. 386 (p) 644 (p) 125 (mr) 41 (fc) 74 (op) 18 (mr) 361 (p) 869 (p) 711 (p) 711 (p) 772 (p) 869 (p) szteblich a. 188 (op) t 32 (fc) 679 (p) taha g. 499 (p) 532 (p) taheri derakhsh n. 436 (p) 602 (p) 814 (p) 31 (fc), 790 (p), 807 (p) tan ph 654 (p) 654 (p) 31 (fc) 422 (p) 177 (op) 536 (p) 524 (p) 882 (p) tizard e. 270 (fc) 738 (p) toenshoff b. 120 (fc) 432 (p) tönshoff b. 42 (fc) 731 (p) 160 (op) 218 (fc) 20 (fc) 171 (op) 66 (op) 652 (p) 154 (op) 219 (fc) urdaneta-carruyo e. 551 (p), 872 (p) urdaneta-contreras a 277 (fc) 572 (p) 587 (p) valverde s. 638 (p) 713 (p) van den heuvel l. 118 (fc) 511 (p), 529 (p) van't hoff w. 297 (sy), 348 (p) 486 (p) 213 (fc), 700 (p) 11 (sy) 55 (sy) 272 (fc), 275 (fc) 738 (p), 791 (p), 792 (p) waters a. 181 (op) 38 (fc), 121 (fc), 273 (fc) 268 (mr) 72 (op) 117 (fc) 129 (fc) 72 (op) 227 (fc), 904 (p) 33 (fc) wingen a. 168 (op) 142 (sy) 219 (fc) 49 (sy), 221 (fc) 21 (fc), 693 (p) 264 (fc) 13 (sy) 473 (p) 135 (fc) 322 (p) 798 (p) 816 (p) 79 (op), 784 (p) 29 (fc) 775 (p) yap hk. 31 (fc) 795 (p) yata n. 497 (p) 174 (op) 340 (p) 801 (p) yilmaz a. 519 (p) 174 (op) 67 (op) 439 (p) 579 (p) 794 (p) zhou jh 40 (fc) 165 (op), 211 (fc), 233 (sy) zingg-schenk a 858 (p) 209 (fc) zurowska a. 32 (fc) 161 (op) the il6 (-174g/c) polymorphism is associated with initial peritoneal transport status in children commencing chronic pd acknowledge: this study was from iran university of medical science. atypical hemolytic uremic syndrome: an unsolved case of complement dysregulation 788 (p) aim: we have shown that rats overexpressing il-13 gene developed a mcn with proteinuria, hypoalbuminemia and hypercholesterolemia. this study aimed to determine the role of il-13 on hypercholesterolemia in this model. methods: recombinant rat il-13 gene in a mammalian expression vector was transfected into quadriceps of wistar rats by in-vivo electroporation. serum il-13, albumin, cholesterol, creatinine and urine albumin were measured serially. after sacrifice on day 70, hepatic gene expression of hmg-coa reductase (hmg-coar), acat2, cholesterol-7a-hydroxylase (ch7ah), ldl-receptor (ldlr) and il-13 receptor subunits were determined by rt-pcr. results: compared to control rats (n=17), il-13-transfected rats (n=41) showed significant albuminuria (0.36±0.37 vs 3.45±0.89 mg/day, p<0.001), hypoalbuminemia and hypercholesterolemia (1.72±0.05 vs 3.39±0.34 mmol/l, p<0.001) at day 70. serially, this rise in serum cholesterol preceded the increase in proteinuria and fall in serum albumin. serum cholesterol correlated significantly with il-13 levels (r=0.64, p<0.001). in 14 of the il-13-transfected rats with serum cholesterol>3.10 mmol/l, hepatic gene expression (mean±sem) was significantly upregulated compared to controls for hmg-coar (0.25±0.08 vs 0.54±0.05, p=0.02), acat2 (0.26±0.03 vs 0.43±0.04, p=0.009), ch7ah (0.50±0.12 vs 1.08±0.10, p=0.004) ldlr (0.10±0.01 vs 0.15±0.02, p=0.02) and il-13ra2 (0.003±0.002 vs 0.080±0.015, p<0.001). conclusion: the increased cholesterol synthesis in il-13-induced mcn was associated with increased hepatic gene expression of hmg-coar and acat2, which are important enzymes for cholesterol synthesis. associated increased hepatic gene expression of ch7ah and ldlr involved in cholesterol metabolism could be a negative feedback response. e. bordador, f. anacleto philippine general hospital, pediatric nephrology, manila, philippines general objective: to formulate a clinical scoring system that will predict the presence of glomerular crescents in patients with severe nephritis. specific objectives: (1) to describe the profile of children with acute nephrotic-nephritic syndrome (2) to correlate clinical parameters with renal histopathology. methods: this is a retrospective study. twenty six charts from the philippine general hospital, admitted between january 2002 -march 2006 were retrieved. included in the study were children with acute nephritic -nephritic syndrome who underwent kidney biopsy. excluded were patients with small/contracted kidneys on renal ultrasound. statistical tool used were univariate analysis, pearson's product moment method and chi -square test. results: profile variables of the subjects were analyzed. afterwhich, each clinical parameter was tested using univariate analysis, if significantly correlated with the renal biopsy result using pearson's product moment method at critical value=0.388 at p<0.05. out of 11 parameters, only 3 parameters were noted to be significant, these were serum creatinine, blood urea nitrogen and glomerular filtration rate. further analysis was made by separately treating male from female population using a chi-square test with critical value x 2 (1,.05) =3.28. the test identified another three clinical features among female which were significantly associated with renal biopsy results, these were blood pressure, anemia and hematuria. from these significant parameters associated with renal biopsy results, a clinical scoring system was then conceptualized in order to identify patients with high probability of crescents on renal biopsy. conclusion: cresent maybe use as an accurate screening tool to predict presence of glomerular crescent in patients with severe nephritis. heterogeneous effect of acei therapy in children with proteinuric nephropathies b. kranz, s. diepenbruck, u. vester, r. buescher, a. wingen, p. hoyer university of duisburg-essen, pediatric nephrology, essen, germany background: chronic proteinuric nephropathies are at high risk of developing progressive renal insufficiency. the renin-angiotensin-aldosteron-system blockade is a well documented strategy to reduce proteinuria in adult patients. the efficacy and risks of renal-protective therapy with angiotensin-converting-enzymeinhibitors (acei) in children with proteinuric kidney diseases is of concern. method: in this retrospective study the efficacy of acei as antiproteinuric therapy in children with chronic proteinuric nephropathies is evaluated. patients: sixty-three children (mean age 10.7±3.5 years) have been treated with acei for a mean of 2.7±2.3 years (range 0.1±10.6 years) because of proteinuria (hus n=10, alport syndrome n=22, psh n=13, others n=18). results: proteinuria in all patients declined from a median of 1.5 g/d to 0.9 g/d after 2 years (p=0.01). there was a drop out of 5 patients because of end stage renal failure during the followup. one-third of patients showed a continuous reduction in proteinuria from 3.1 g/d to 0.4 g/d (median) within 3 years while a second third had a transientimprovement followed by a reincreasing proteinuria later. patientswith hus showed a good response (decrease of proteinuria from 2.8 g/d to 0.4 g/d) in contrast to patients with alport syndrome who developed increased proteinuria (0.8 g/d to 3.0 g/d) despite of acei and patients with psh who had no change in proteinuria.interpretation: it has to be discussed whether biological compensation mechanisms may bypass the ace inhibition in single patients and whether the underlying illness may predict the efficacy of acei.aims: to determine the clinicolaboratory renal manifestations; glomerular, extra-glomerular histopathologic lesions; renal tubular dysfunction (rtd) frequency, and outcome of a short-term renal follow-up in nigerian children with systemic lupus erythematosus (sle). methods: a non-randomized prospective study of consecutive cases of childhood-onset sle with nephropathy. baseline/follow-up clinicolaboratory data were collected. each patient was followedup for 12 months. results: seven of 11 children studied were girls (f:m, 1.75). median age at diagnosis was 11.0 years. median diagnosis time interval (1.9 years) and median time of renal disease onset (1.0 year) were similar. hypertension, nephrotic syndrome, and acute renal failure occurred in 45.5%, 54.5% and 63.7% of the patients, respectively. the glomerular lesions were non-proliferative lupus nephritis (ln) in 9.0% (class ii ln); focal (class iii ln) and diffuse (class iv ln) proliferative ln (pln) in 27.0% and 64.0%, respectively. tubulointerstitial nephritis (tin, 91.0%), and rtd (64.0%) were common. arf (p=0.033) and rtd (p=0.015) were significantly associated with severe tin. complete renal remission rate at end-point was 71.4%. relapse and renal survival rates were 14.3% and 86.0%, respectively. rtd was persistent in 43.0%. conclusion: renal function disorders, diffuse pln, and extra-glomerular lesions were frequent. significant association of arf and rtd with severe tin in this series suggests the need for early renal tubular function (rtf) assessment in our sle patients. deranged rtf may be marker of severe tin in sle warranting early confirmatory renal biopsy and aggressive interventional treatment.we report two cases of children with crescentic glomerulonephritis (gn) associated to isolated c3 deposits. patient 1. a 9 year old girl was admitted for macroscopic hematuria, nephrotic range proteinuria (proteinuria/creatininuria=1000 mg/mmol) and renal failure (serum creatinine 600 μmol/l). anca and other antibodies were negative. c3, c4 and ch50 activity were normal but c3nef was detected. the patient was treated by prednisolone and cyclophosphamide pulses followed by oral corticotherapy. renal function normalized, but proteinuria persisted (proteinuria/creatininuria=500 mg/mmol). a relapse occurred ten months later. corticotherapy and cyclophosphamide pulses were reinitiated and were successful, followed by mmf maintenance therapy. patient 2. a 4 year old girl was admitted after viral infection for macroscopic hematuria and fever. proteinuria was of nephrotic range (proteinuria/creatininuria=708 mg/l). the search for autoimmunity was negative. c3nef was detected but c3, c4 and ch50 activity were normal. serum creatinine increased to 369 μmol/l. after three pulses of prednisolone followed by oral prednisone, renal function normalized. histological examination of the two renal biopsies revealed endo-and extracapillary gn with numerous granulocytes in the capillary lumen. cellular crescents involved 90% of the glomeruli. immunofluorescence demonstrated isolated c3 deposits in the mesangium and along the glomerular basement membrane (humps). c1q, igg, iga and igm staining were negative. background: the risk of end stage renal disease (esrd) is low in unilateral wilms tumor, although patients with wagr or associated genitourinary anomalies are at higher risk. esrd is attributed mostly to hyperfiltration in the remnant kidney. immune complex glomerulonephritis (icg) has not been previously reported in wilms tumor patients. objectives: to report 2 cases of icg in unilateral wilms tumor. methods: retrospective chart review. patient #1 a boy with cryptorchidism, diagnosed with unilateral wilms tumor at 3 y of age. patient #2 a girl with wagr and unilateral wilms tumor diagnosed at 2 y of age. both had chemotherapy after tumor resection. results: patient #1: within 2 mo of tumor resection, a proteinuria of 3.8 g/24 hrs and rising creatinine were noted. renal biopsy was consistent with icg. within 5 mo of surgery the patient developed esrd requiring chronic hemodialysis. patient #2: within 4 y of tumor resection, the patient developed progressive, asymptomatic proteinuria up to 2 g/24 hrs. the renal biopsy revealed changes typical for icg. the patient was treated initially with enalapril and prednisone. due to no response, mycophenolate mofetil (mmf) was added and prednisone was weaned. after 4 mo of therapy, her proteinuria improved to 0.5 g/24 hrs. her serum creatinine continued to be normal at 0.6 mg/dl, with calculated gfr of 113 ml/min/1.73 m 2 . conclusions: this is the first report of icg in patients with unilateral wilms tumor with rapid progression to esrd in the first patient, but successful response to mmf in the second patient. despite low risk for progressive proteinuria in wilms tumor patients, it is prudent to monitor these patients for proteinuria and perform a renal biopsy if proteinuria is progressive. mmf therapy may be attempted to decrease proteinuria and to delay the onset of esrd.aim of the study: to present our first results of rhgh treatment mainly in children on hemodialysis. patients and methods: sixteen children, aged 4.5-17.1 years (mean age 11.25±3.57) with height below -2.0 standard deviation score (sds) for age or height velocity below -2.0 sds for age, were selected to receive rhgh therapy at our nephrology and hemodialysis department. most of them were on hemodialysis (14 children) with mean spent time 2.88±2.68 years (0-9 years) before an initiation of rhgh therapy. one half of patients were prepubertal (8 children) and second half were in early puberty (testicular volume between 4 and 8 ml for boys and breast development b2 or b3 in girls). all received 28-30 iu/ml per week by daily subcutaneous injection for 6 months to 3 years. the year before rhgh therapy served as a control period. results: during the first year of treatment, mean height velocity in hemodialysis patients increased from 2.25 cm/year to 6.59 cm/year (p<0.0001) and in the second year was 5.25 cm/year (p=0.004). the mean height sds in hemodialysis children did not improved significantly during the first year of rhgh treatment (from -3.01 sds to -2.77 sds, p=0.063). neither weight, nor the body mass index varied compared with the pretreatment period. no change was observed in glucose, total proteins, albumins, cholesterol and triglycerides levels. the mean increment in bone age was 1.1 years. pubertal status had no influence on response to rhgh. conclusions: therapy with rhgh improved height velocity in children with esrd. no significant side effects were observed in 16 children during the 23.5 treatment years. two patients developed secondary hyperparathyroidism but the relationship with rhgh remains uncertain. in our treatment group rhgh therapy was safe. a. waters 1 , a. trautmann 2 , p. zipfel 3 , e. harvey 1 , ch. licht 1 1 hospital for sick children, department of pediatric nephrology, toronto, canada 2 university children's hospital, department of pediatric nephrology, heidelberg, germany 3 atypical hemolytic uremic syndrome (ahus) is characterized by the absence of a diarrheal prodrome, the tendency to relapse and a poor outcome. functional and quantitative deficiency of complement regulatory proteins or inhibiting autoantibodies result in uncontrolled complement activation, which eventually causes ahus. -we report a case of ahus with complement dysregulation associated with a progressive refractory response to plasma infusions. factor h and factor h-related proteins (fhr) were quantified by elisa and were further analyzed by western blot. complement activation was determined by measuring c3. serial hgb (g/dl), platelet, creatinine (mg/dl), ldh (u/l) were measured. initial presentation was at 7 months of age with thrombocytopenia, hemolytic anemia and increased creatinine. ahus was suspected as e coli infection was ruled out. disease remission followed several plasma exchanges. monthly plasma infusion maintained remission. therapy intervals exceeding 1 month promoted relapses. nine years later, the relapse interval decreased and over the subsequent 3 years, thrombocytopenia persisted as plasma infusion requirements increased. a concomitant decline in renal function (creatinine 1.6 mg/dl) occurred with the development of persistent proteinuria and hypertension. at 13 years of age, she deteriorated acutely with hypocomplementemia and thrombopenia. quantitative factor h was normal. autoantibodies to platelets and factor h were negative. intravenous immunoglobulin combined with oral steroids resulted in normalization of platelet count. complement dysregulation is associated with ahus. hereditary defects can be treated with factor replacement therapy. refractory responses may subsequently arise due to the development of autoantibodies against complement regulatory proteins. complement dysregulation requires further analysis in our patient. objectives: angiopoietin-like 3 protein (angptl3) is involved in lipid metabolism and angiogenesis. the present study was to examine angptl3 expression in human kidneys with proteiuria, in adramycin rats (adr), and in puromycin induced podocyte damage. methods: immunohistochemistry was performed on kidney biopsies from children with mcd, mn, fsgs, tbmn. in adr, angptl3 expression was determined by quantitative real-time pcr in glomeruli and tubuli dissected from frozen section of kidneys with laser microdissection system. in mpc5, a conditionally immortalized mouse podocyte cell line in vitro, angptl3, perlecan and agrin werer detected through real-time pcr with the induction of puromycin. detachment assay was performed in podocytes tranfected by angptl3-pcdna3.1. results: in human kidneys, co-labeling showed angptl3 expressed in the cytosol of wt1 positive cells. quantitative computerized analysis showed that angptl3 in glomeruli in mcd and mn were significantly higher than that of tbmn, fsgs respectively (p<0.05). in adr, angptl3 in glomeruli increased significantly at 21 st or 28 th day (p<0.05) after adriamycin injection compared with control. and the expression of angptl3 in glomeruli was correlated with 24 h urinary protein (r=0.81, p<0.05). in mpc5 both protein and mrna expression of angptl3 on podocytes were up-regulated with the induction of puromycin. in podocytes transfected by angptl3-pcdna3.1 the expression of perlecan or agrin increased significantly compared with control (p<0.05). the attachment ratio was shown 95.7%±3.3% 24 hs after puromycin treatment on podocytes transfected by angptl3 compared with 38.6%±4.7% on normal podocytes, and 27.4%±3.5% on untransfected podocytes. conclusions: angptl3 is predominantly expressed in podocytes which could be involved in podocyte damage and the development of proteiuria. purpose: we present 2 cases of a previously undescribed pattern of membranoproliferative glomerulonephritis, in children with neuroblastoma on chemotherapy. the pattern of injury shows unusual focal capillary loop proteinaceous deposits possibly related to toxic chemotherapeutic drugs. the resultant hypertension and renal impairment made bone marrow transplant a challenging prospect. method: case series results: case 1: this boy with stage 4 neuroblastoma, developed severe renal impairment and hypertension during treatment. thus there were difficulties in administration of chemotherapy and he required early surgery. at tumor resection a nephrectomy was necessary. he received an autologous stem cell transplant. he became unwell at transplant and required haemofiltration. he made a good renal recovery and did not relapse. case 2: he was diagnosed at 2 months with stage 4s neuroblastoma. he completed treatment but later relapsed. during treatment his gfr reduced and he developed severe hypertension. this lead to restrictions in chemotherapy. renal biopsy was carried out at tumor resection. at bone marrow transplant he was very unwell and required haemofiltration. he has chronic hypertension and low gfr. light microscopy findings in both -global diffuse membranoproliferative pattern of injury -large numbers of proteinaceous resorption droplets -features of a protein deposition disease electron microscopy findings common to both -large number of differently sized protein droplets in the endothelial cells -no obvious immunecomplexes/deposits -protein deposition disease with a membranoproiferative pattern of injury conclusion: both cases showed deposits in the kidneys which may be tumor protein in origin and the resultant glomerulonephritis, hypertension and renal impairment lead to challenges in transplant. the long term consequences are yet to be revealed. methods: establish the cultured glomerular mesangial cells of rat in vitro, 3~10 generations of cells were used in the experiment after identification. the experiment included five groups: ctrl, lps, high, middle and low dose fos groups. gmc proliferation were detected by mtt. the changes of ln, fn and col protein secretion were detected by the elisa. the changes of lnbeta 2 mrna expression were detected by semi-quantitative real-time pcr. results: (1) fos can inhibit the effect of proliferation induced by lps. (2) mesangial cells can secrete some ecm protein in normal culturing medium, ecm protein secreted by mesangial cells was significantly higher in lps group than that in ctrl group (p<0.01), while ecm protein was significantly lower in all fos groups than that in lps group (p<0.01). (3) lnbeta 2 mrna expression was significantly higher in lps group than that in ctrl group, while that in fos group was significantly lower than in lps group. conclusions: lps can induce the increase of secretion of the ecm, including ln, fn, col fos can inhibit the secrection of ecm in gmc as dose-dependent manner at the mrna and protein levels. the conclusion supplies the theoretical evidence for the renal protection of fos. h. hong, w. na, y. li, w. qiang guangzhou first municipal people's hospital, department of pediatrics, guangzhou, people's republic of china objective: to observe the effects of fosinopril (fos), the new generation angiotensin-converting enzyme inhibitor (acei), on protein and mrna expression of tgf-β1 of rat glomerular mesangial cell (gmc) induced by lps; to demonstrate the preventive mechanism against glomerular sclerosis by applying fos. methods: culture rat gmc in classic way. the cultured cell were divided into 3 groups, namely (1) control group, (2) lps group, (3) lps+fos group. detect tgf-β1 concentration in gmc supernatant fluid by elisa; estimate tgf-β1 mrna expression by semiquantitative real-time rt pcr. results: lps group is obviously higher than control groups in tgf-β1 secretion and mrna expression, while lps+fos group drops distinctively in tgf-β1 secretion and mrna expression compared with lps group. conclusions: fos has obvious inhibited on tgf-β1 expression of rat gmc both at protein level and mrna level, which reveals that it might be an important mechanism by fos on restraining the development of glomerulosclerosis. r. kahn 1 , n. akbari 1 , j. wieslander 2 , w. müller-esterl 3 , a. christensson 4 , k. westman 4 , t. hellmark 4 , d. karpman 1 1 lund university, pediatrics, lund, sweden 2 wieslab ab, lund, sweden 3 institute of biochemistry ii, frankfurt, germany 4 lund university, nephrology, lund, sweden vasculitis is an inflammation with neutrophil influx in and around blood vessels. patients may have elevated plasma levels of neutrophil-derived proteinase 3 and anti-neutrophil cytoplasmic antibodies (anca) directed to proteinase 3, suggested to be involved in the pathogenesis of disease. we have previously shown that the kallikrein-kinin system (kks) is activated in vasculitis. in vivo the kks is activated on endothelial cells and neutrophils when high-molecular-weight kininogen (hk) is cleaved by kallikrein thus liberating bradykinin. bradykinin is a potent mediator of inflammation. in the present study we investigated if neutrophil-derived proteases, and proteinase 3 in particular, could induce activation of the kks and bradykinin release. purified neutrophils from ten vasculitis patients (3 adults, 7 children) and thirteen controls were treated with triton-x to induce lysis. proteinase 3 was immunoadsorbed from the neutrophil extracts. bradykinin and proteinase 3 levels were measured by elisa. hk proteolysis was detected by immunoblotting. proteinase 3 incubated with purified hk induced physiological breakdown of hk and bradykinin release. this was inhibited by preincubation of proteinase 3 with anti-proteinase 3. triton-x treated neutrophil extracts from both patients and controls induced hk proteolysis and bradykinin release whereas the neutrophil extracts from which proteinase 3 had been immunoadsorbed did not. levels of proteinase 3 in the neutrophil extracts from patients and controls did not differ. these findings suggest that neutrophil derived proteinase 3 can proteolyse hk in a physiological manner thus liberating bradykinin, thereby initiating kallikrein-independent activation of the kks. introduction: this is a prospective study to evaluate the safety and efficacy of tacrolimus in 22 consecutive children with steroid-resistant nephrotic syndrome (srns). methods: all of them were subjected to kidney biopsy. tacrolimus was given in dose of 0.15-2.0 mg/kg/day in two divided doses to attain trought levels of 5.0-10.0 ng/l. these patients were followed-up every 2 weekly initially for the first month, followed by monthly visits. urine spot protein creatinine estimation was done at each visit. besides blood glucose, serum creatinine, urea, electrolytes, albumin, and complete blood count were done once a month. results: the mean age of onset was 8.6±5.9 yrs. of the 22 children, 9 had mcd, 11 had fsgs and another 2 had dmh on histopathology. tacolimus had to be withdrawn in 3 children: of the rest 19 children who received adequate therapy, complete remission was seen in 16 (76%) children, 2 (11%) attained partial remission and 1 was non responsive. the mean time to achieve remission was 59.9+45.8 days and the mean dose of tac was 0.18+0.07mg/kg. the mean urine spot protein/creatinine ratios were significantly lower (0.64±1.09 vs 14.5±23, p=0.01) and mean serum albumin significantly greater (3.73±0.71 vs 2.45±0.52, p=0.001) as compared to those prior to tac. of the 16 children who attained complete remission, 2 patients are off steroids and tac and in sustained remission, while the rest 14 are still on tac therapy. conclusions: this is the largest study so far on the safety and efficacy of tacrolimus therapy in children with srns. we conclude that tacrolimus is a useful therapeutic alternative in children with srns who are unresponsive to cyclophosphamide and cyclosporine. objectives: to describe hiv infected paediatric patients from our centre with pathology proven renal disease. methods: retrospective review of biopsy data base and case notes of patients with hiv referred with renal problems. results: 14 patients were identified who had biopsy confirmed renal disease. the mean age of the patients was 5,7 yrs (range: 6 months to 16 years). twelve of the patients were african and two were of mixed race. renal pathology was divided into three groups: 1) hiv associated nephropathy (hivan): five patients. 2) mesangioproliferative nephropathy: 4 patients 3) other: acute pyelonephritis in 1, mesangial proliferation plus interstitial nephritis in 1, renal tuberculosis in 2, hiv immune complex disease (hivick) in one. conclusion: there is a high degree of variability of renal pathology in children with hiv and renal disease which upholds the need accurate diagnosis when confronted with these patients. background: acute poststreptococcal glomerulonephritis (apsgn) is the most common glomerular disease of children in our country. it has not been studied well in this region yet. here, we report our experience with psgn in a tertiary referral center during a five-year period. method: hospital records of all 137 children who had been admitted from mar. 2001 to mar. 2006 to nemazee hospital with diagnosis of acute glomerulonephritis (agn) were reviewed. all demographic, clinical, paraclinical data and consumed medications were obtained. results: among 137 children diagnosed as agn, 122 (89%) had apsgn. other 15 (11%) children had mpgn (n=4), mespgn (n=4), iga nephropathy (n=2), lupus nephritis (n=2), rpgn (n=2), and fsgs (n=1). mean age in children with apsgn was 8±3.5 (range, years. 117 children (96%) developed apsgn following a sore throat or upper respiratory infection while 5 (4%) cases developed after impetigo. ninety-five (78%) patients developed apsgn during the cold seasons of the year. periorbital edema was found in119 children (97.5%), hypertension in 92 (75%), gross hematuria in 88 (72%), oliguria in 45 (37%), generalized edema in 23(19%), azotemia (bun>20) in 98 (80%), and nephrotic range proteinuria in 30 (24.5%). aso titer was high in 103 (84%). low c 3 was detected in 105 (86%) and low c 4 in 16 (13%). dilutional anemia in 63 (51.5%), hyponatremia in 33 (27%), and hyperkalemia in 17 (14%) children among whom, 3 required hemodialysis. regarding medications, 29 patients had received only furosemide, 73 cases took furosemide and nifidipine and for 10 patients furosemide+nifidipine+another antihypertensive medication was prescribed. conclusion: acute psgn is the most common type of glomerulonephritis in this region. it follows sore throat in the majority of cases. it usually has an uneventful course. y. guo, zh. wang, x. liu west china second university hospital, sichuan university, department of pediatrics, chengdu, people's republic of china objective: we planned to explore the mechanism of glomerular basement membrane (gbm) damaged by rsv, through investigating the effects of lmwh on proteinuria and glomerular structure of rsv nephropathy. methods: sd rats were inoculated with 6 10 6 pfu rsv and lmwh 400 iu/kg. group a: rsv was given in the first 3 days, and lmwh was given for the following 11 days; group b: the mixture of rsv and lmwh was given in the first 3 days, then lmwh was given for other 11 days; group c: lmwh was continuously given throughout 14 days and on the 4 th -6 th day rsv was also given; group rsv and the control were respectively inoculated by rsv and dmem for 3 days. renal histology, urinary protein excretion and serum parameters were observed. rsv rna in renal and pulmonary tissue was determined by in situ hybridization. results: there was no significant increase in urinary protein excretion of the lmwh-treated groups (a 7.4053±4.057, b 7.101±1.833, c 9.209±1.625, mg/24 h) compared with the control, but that of group rsv (32.041±3.844 mg/24 h) gradually increased after rsv inoculation. there was just a decrease in albumin (15.060±1.335g/l) and an increase in urea nitrogen (12.9203±3.932μmol/l) of group rsv only. no change of the glomeruli detected in all lmwh-treated groups, while congestion and swelling in glomeruli of group rsv were observed significantly. glomerular microstructures of the lmwh-treated groups were almost normal, while extensive foot process effacement was observed in group rsv. rsv rna signal expressed weaker in the lmwh-treated groups than in group rsv. conclusion: rsv damages hs on gbm by electrostatic interaction. lmwh, as the analog of hs, charged with anion, competes with hs to combine with rsv to keep gbm from being destroyed, and then reduce the proteinuria. s. zhai, zh. wang west china second university hospital, sichuan university, department of pediatrics, chengdu, people's republic of china objective: the study is to explore the relevance among gags, hpa and ela in the steroid responsive nephrotic syndrome (srns). methods: (1) 55 children with srns were selected, including the active (n=20), the convalescent (n=20), the remissive (n=15). 19 purpuric nephritis and 15 healthy children were served as the control.(2) using the improved whiteman process detected the urinary gags. ela activities in plasma were determined by the amount of 4-nitroaniline released per unit time. immunocytochemistry and image analysis method were used to detect the expression of hpa of peripheral blood leukocyte. results: 1. gags of the active were the highest (4.1051±1.1722) of all (p<0.001). in contrast with the healthy, the active and the convalescent (2.5666±0.6826, p<0.001) were significant difference, but the remissive no difference (1.6588±0.3103, p>0.05). 2. all of ns showed higher level of hpa than the healthy (p<0.05). comparing with the healthy, hpa was significant difference both in the active (iod 54786.2137±28714.0671, p<0.001) and in the convalescent (iod 15708.6270±4036.2843, p<0.001),but no difference in the remissive (iod 4181.0056±878.3909, p>0.05). by contrasting the active and the purpuric, their difference of hpa was no statistic significance (p>0.05). 3. all of ns showed higher levers of ela than the healthy (p<0.05). the healthy was strikingly different, contrasting with the active (77.4304±17.6366) and the convalescent (53.6803±7.4168, p<0.001), but no difference with the remissive (38.6552±9.1556, p>0.05). 4.there was a significant correlation among the urinary protein, urinary gags, hpa and ela with simple linear regression analysis. conclusion: in the srns, proteinuria may be resulted by the spallation of hpa and ela for gags on gbm. (4), combination withhaematuria, hypertension and/or renal insufficiency (23), extrarenalsymptoms (6), and familial mediterranean fever (fmf, 40) . of the 85 non-nephrotic patients, 26 had extrarenal symptoms, 15 were nephritic,9 had rapidly progressive glomerulonephritis (gn), 6 renal failure and 29 isolated urinary abnormalities. biopsy samples were evaluated by light microscopy in yerevan and zurich and by electron microscopy (except for amyloidosis) and immunohistochemistry (last 28) in zurich. results: the most common histological lesion was renal amyloidosis (25%), followed by focal segmental glomerulosclerosis (fsgs, 9%), lupus nephritis (8%),systemic vasculitis/hus and minimal change disease (mc, 7.5% each),mesangioproliferative gn/iga-nephropathy and membranous nephropathy(mn, 7% each), hereditary nephritis and membrano-proliferative gn typei (6% each), acute postinfectious gn (apgn, 4%), and dense deposit disease (ddd, 3%). the miscellaneous group includes,apart from interstitial nephritis (1%), unclassified or inadequate biopsies and specimens with mostly sclerosed glomeruli(9%). the majority of patients with amyloidosis of fmf, fsgs/mc andmn were nephrotic, but 18% of patients with amyloidosis had non-nephrotic proteinuria. conclusions: several glomerular lesions were considerably more frequent than in other studies, particularly amyloidosis of fmf, mn and lupus nephritis, and to lesser extent membranoproliferative gn type 1 and ddd. apgn is underrepresented because less than 1% of all patients (>700) had a biopsy. this study would not have been possible without international collaboration. henoch-schönlein purpura in children: an epidemiological study amongst dutch pediatricians on incidence and diagnostic criteria j. aalberse 1,2 , k. dolman 2 , g. ramnath 3 , r. rodrigues pereira 4 , j-c. davin the aim of the present study on the incidence of henoch-schönlein purpura (hsp) in dutch children is not only to give some insight in the epidemiology of hsp in the netherlands but also to record the diagnostic criteria used by dutch pediatricians and to evaluate the accuracy of the latter using the presence of iga in the skin when biopsies are available. methods: in 2004, all dutch pediatricians received monthly a card asking to mention new diagnosed hsp. pediatricians reporting one or more new patients with hsp were sent a list of questions concerning symptoms, blood and urine parameters, skin biopsy, diagnostic criteria and follow-up duration needed. results: two hundred and thirty-two patients from 0-18 of age (6.1/10 5 ) were reported as having started hsp in 2004. twenty nine % presented with renal symptoms. in accordance with the classification criteria of the american collegeof rheumatology (acr), eighty percent of pediatricians consider that isolated purpura (without hematological abnormalities) is sufficient to allow the diagnosis of hsp in children. from the 17 skin biopsies performed, only 9 (53%) presented with iga deposits. the follow-up duration considered as necessary was longer in case of renal symptoms at presentation. however, 45% of patients without renal symptoms would be followed for more than one year. conclusion: considering the recent (2006) eular/pres endorsed consensus criteria for the classification of childhood vasculitides, hsp should have been diagnosed in only 160 of the 179 patients of our study. the use of isolated non-thrombocytopenic purpura as only criterian to diagnose hsp in children might therefore lead to over diagnosis and unnecessary follow-up. noteworthy, the eular/pres criteria remain to be validated by a prospective study. the clinical presentation and response to therapy of childhood pan in johannesburg, south africa. method: retrospective record review of twelve children with a clinical diagnosis of pan treated between 1993 and 2005. results: there was unequal number of males and females; average age at presentation was 6.8±0.83-13.9 years, all were black children. eight children had more than 3 acr criteria and 11 sufficient clinical criteria (eular/pres consensus criteria). musculoskeletal and cardiac diseases were the commonest finding at presentation (75%), cutaneous, hypertension (58%), renal and gastrointestinal disease (50%), central nervous system disease (42%) and constitutional features (33%). two children had bone involvementwith periosteal reactions on plain x-ray. angiographic abnormalities were found in 8 (67%), and 9 (75%) had positive histology (skin/renal biopsies). tuberculosis was diagnosed in 6 (50%), and 6 had positive streptococcal titers. all patients were ana and hepatitis b negative, but there were five patients anca positive (2=p-anca, 2=c-anca, 1=both) (42%). the crp was elevated in 8/12 (67%), esr also in 8/12, while 58% had both elevated. all patients received oral glucocorticoids, 6 methylprednisolone (1-3 pulses-500 mg/m 2 ), 7 ivi cyclophosphamide (1-6 pulses, 500 mg/m 2 ), 10 oral azathioprine, and 1 required i. conclusions: children with pan in johannesburg present at a younger age with multi-organ disease. they require aggressive therapy with both glucocorticoids and cytotoxic therapy to ensure good outcomes. objective of the study: in order to evaluate the predictive factors of chronic kidney disease (ckd), the records of 47 children with biopsy-proven mesangioproliferative nephrotic syndrome (mpns) admitted between 1972 and 2005 were retrospectively reviewed. methods: renal survival was analyzed by the kaplan-meier method and cox's regression model. two multivariate models were developed: (1) from the onset of symptoms to the occurrence of ckd and (2) from the time of renal biopsy to ckd. the following data were obtained at admission an dat the time of renal biopsy: gender, race, age at the onset ofnephrotic syndrome symptoms, age at admission, blood pressure, laboratory data (serum creatinine, serum urea, glomerular filtration rate, 24-hr urinary protein excretion, hematuria). patients were classified according to the response to the initial course of prednisone: (1) a complete response was defined as a proteinuria <0.3g/day; (2) a partial response was defined as urinary protein excretion of <1 g/day and >0.3g/day, and (3) no response was defined as urinary protein excretion of >1 g/day. results: median follow-up time was 8 years (iq range, 3.9±13.7) and 12 patients (26%) progressed to ckd. at baseline, after adjustment 2 variables remained as independent predictors of ckd: creatinine >1.0 mg/dl (rr=3.8, ci 95%=1.01±11.3) and non-response to steroids (rr=10.7, ci 95%=2.2±51.2). at the time of renal biopsy, after adjustment 2 variables remained as independent predictors of ckd: age>7.5 yr (rr=3.8, ci 95%=1.0±14.3) and creatinine >1.2 mg/dl (rr=3.3, ci 95%=0.97±11.2). conclusion: serum renal function at baseline and initial response to prednisone were strong predictors of progression to ckd in our cohort of children with mesangioproliferative nephrotic syndrome. methods: an illustrative case history of a boy with sle and vhd in the absence of antiphospholipid antibodies was described. results: a 14-year-old boy with a history of sle for about five years was admitted to our hospital due to intermitted arthralgia, facial erythema, increased serum creatinine and oliguresis in october 2006. he had been treated irregularly with prednisone and immunosuppressants. however,the disease was not always controlled well. during thishospitalization, the problems of hypertension, renal failure and anemia had been resolved and maintained, but the problem of intolerance to increased circulation volume was obvious, and three times echocardiography (ecc) showed moderate to severe mitral valve insufficiency. reviewed his history, suspected mitral leaflets vegetations was revealed by ecc four months after onset, he complained of chest pain, chest distress and breathholding several times without causes since eighteen months after onset and manifested with heart failure once, and ecc showed moderate to severe mitral valve regurgitation four months ago and twenty days ago respectively. ruling out the possibility of infective endocarditis, rheumatic heart disease and congenital heart diseases, vhd were considered secondary to sle. since the vhd becomes hemodynamically significant, valve surgery is needed. conclusions: vhd is generally asymptomatic and omitted easily, so routine cardiac evaluation of children with sle using electrocardiography, echocardiography and chest x-ray is recommended to early detect and treat cardiac abnormalities, which may lead to better survival. objective: we have previously reported that deleted in esophageal cancer 1 (dec1), a potent tumour suppressor gene, was specifically upregulated in cd4+ cells of patients with relapse of mcns, using differential display rt-pcr. this study aimed to further characterize the potential function of dec1 in mcns. methods: semi-quantitative rt-pcr was used to verify the dec1 gene expression in children with relapse and remission of mcns. jurkat cells were transfected with plasmid containing dec1 gene or vector alone. gene expression was regulated by tet-on/off system. the effect of dec1 on jurkat cell proliferation was assessed by 3 h-thymidine incorporation. cell cycle analysis was performed following propidium iodide staining. protein localization was determined by immunofluorescent staining with anti-dec1 antibody. results: we confirmed that dec1 gene expression was significantly increased in 15 children with mcns in relapse (0.93±0.17), as compared to remission (0.44±0.13, p<0.002), 10 normal controls (0.59±0.06, p<0.01), 7 patient controls with viral infections (0.58±0.03, p<0.03) and 7 nephrotic patients with other forms of glomerulonephritis (0.48±0.10, p<0.03). in dec1-transfected jurkat cells, cell proliferation was inhibited by 47.2%, compared with vector control. cell cycle analysis indicated that dec1 arrested jurkat cell cycle progression by blocking its entry into the g2/m phase. immunofluorescent staining with anti-dec1 antibody suggested that dec1 was a cytoplasmic protein, which was in agreement with psort. conclusion: dec1 gene expression was significantly upregulated in children with relapse of mcns. our results showed that dec1 acts as a t-cell proliferation suppressor and arrests cell cycle progression, and thus may be important in mediating the number or function of cd4+ cells during relapse of mcns. objective of study: the aim of the study was to assess plasma and urine concentrations of vascular endothelial growth factor (vegf) in nephrotic syndrome children (ns) depending on the total dose of glucocorticoids (gc) and the percentage of lymphocytes with glucocorticoid receptor expression (cd3/gcr). methods: we examined 51 children (2-15 years) , allocated to three groups: group i: 13 children with the first ns onset, group ii: 13 children with ns relapse, group c: 25 healthy children. the ns patients were examined: a: before treatment and b: 4-5 weeks after prednisone administration at a dose of 60 mg/m 2 /24 h. plasma and urinary vegf levels were determined using the immunoenzymatic elisa method. flow cytometry was applied to assess cd3/gcr expression. results: higher plasma and urinary vegf concentrations were noted in ns children before treatment (a), as compared to control subjects (c). following prednisone therapy (b), vegf level was reduced but it was still higher than in the control group. positive correlation was observed between vegf and protein in the urine (group i r=0.660, p<0.05, group ii r=0.818, p<0.01) and a weak positive correlation between vegf in plasma and urine (group i r=0.531, p<0.05, group ii r=0.581, p<0.05). cd3/gcr expression was lower in group ii. in both groups, the correlation between plasma vegf and cd3/gcr was positive (p<0.05). conclusions: 1. plasma and urinary vegf levels increase during nephrotic syndrome onset. 2. glucocorticoid treatment reduces plasma and urinary vegf levels in ns children. objective of study: the aim of the work was to determine the expression of p-glycoprotein (p-gp) on peripherial lymphocytes (cd3) in children with steroid-dependent nephrotic syndrome (sdns) during cyclosporine a (cya) and ace-inhibitor (ace-i) treatment. methods: the study group (i) consisted of 20 children with sdns aged 5-18 years, with a subsequent proteinuria relapse at the time of prednisone dose reduction. all ns children were examined three times: a: at proteinuria relapse, before cya treatment, b: after 3 months, c: after 12 months of cya administration. control group (ii) consisted of 20 healthy children. cd3/p-gp was measured using a flow cytometry assay. serum cya level was assessed by means of the immunofluorescence method. results: the expression of cd3/p-gp in ns relapse, prior to cya+ace-i administration was much higher (median 9.15%, range 1.50-13.50%) when compared to healthy controls (1.20% range 0.30-5.70%). the absolute number of cd3/p-gp in this examination was almost 5 times higher when compare to healthy controls (p<0.01). after 3 months of cya+ace-i therapy the expression of cd3/p-gp decreased dramatically and was similar to the controls. similar results were obtained after 12-months of treatment. when analysing the correlation between cd3/p-gp and serum cya concentration a strong negative correlation was found in both examinations. the correlation was stronger in group ib (during the treatment with higher cya doses): (r=-0.624, p<0.01) than in ic (after reduction the cya dose: (r=-0.464, p<0.01) conclusions: the results of our studies indicate that cya in sdns inhibits the expression of p-gp. cya is an alternative therapy that may lead to optimization of glucocorticoid doses, thus reducing the risk that goes along with treatment. backround: hemolytic uremic syndrome is considered as the main cause of acute renal failure in childhood. it is characterized by microangiopathic hemolytic anemia, thrombocytopenia and acute renal failure. the epidemiology of the disease varies between counties. aim of the study: to describe demographic and epidemiologic aspects of hus, presented in a 25 years period at the biggest children's hospital in the country. material-methods: 27 patients aged 11 days -12 years, mean age 4.8 years, (20 boys, 7 girls) were diagnosed with the syndrome. of them 5, 18.5%, presented as d+ cases, 11 with preceeded respiratory system symptoms and 11 with no preceeded symptoms. treatment consisted of fresh frozen plasma (ffp) and whole blood transfusions in all cases. peritoneal dialysis was necessary in 7 cases, haemodialysis in 2, while plasmapheresis was performed in 3 cases. three children, all boys, suffered from recurrent type of syndrome. a girl required treatment with peritoneal dialysis for 4 months followed by recovery of renal function. one-five years follow-up: one baby 8 months old died, 4 children received renal transplantation, in 5 renal function remained mildly reduced (gfr 50-80 ml/min/1.73 m 2 ) and 6 suffered of hypertension. the rest 11 recovered fully. summary: hus represents a rather minor public health problem with low mortality rate in greece. methods: three children with pauci-immune ln were retrospectively reviewed. results: the reported cases fulfilled the american rheumatism association criteria for sle. at admission, all had a 1-month history of glomerulopathy without intensive therapy. case 1 presented with nephrotic proteinuria, macroscopic hematuria and progressively deterioration of renal function. laboratory data included a positive antineutrophil cytoplasmic antibodies (anca) on myeloperoxidase immunoassay. she was positive for lupus anticoagulant (la) but negative for anti-cardiolipin (acl) and anti-beta-2 glycoprotein i (β 2 gpi) antibody. renal biopsy showed pauciimmune necrotizing and crescentic ln. case 2 manifested with proteinuria, microhematuria and hypertension. anca was negative. case 3 had nephrotic proteinuria, microhematuria and hypertension. the case had positive la, acl and anti-β 2 gpi antibody. anca was negative. the biopsy findings of both case 2 and case 3 indicated pauci-immune mesangial proliferative ln. electronic microscopy revealed segmental and diffuse foot process effacement respectively. all three ln remitted following the treatment of steroid and immunosuppressive agents. conclusions: these atypical ln were considered to be associated with the distinct pathogenesis, rather than immune complex-mediated glomerular injuries. we supposed the possibility of ancaassociated necrotizing and crescentic glomerulonephritis for the first case. for the others, primary or secondary podocytes lesions might alter the glomerular permeability. the nephrotic syndrome is a clinical picture that characterized by proteinuria, hypoproteinemia, oedema and hyperlipidemia. although the primer nephrotic syndrome is the most common type of nephrosis in children, it may also develop during the course of infections including hepatitis b and c virus infections, whereas hepatitis a virus infection related nephrotic sendrome is very rare in children. in this paper, we present a case of who had suspected diagnosis hepatitis a virus infection related nephrotic syndrome. the boy at the age of 3 years was referred to our hospital due to vomiting, abdominal distension and oliguria. physical examinations were revealed palpebral and tibial oedema, hepatomegaly, decreased breath sounds and mat percussion on right hemithorax. icter were not detected. laboratory examination were showed proteinuria, hyperlipidemia, hypoalbuminemia, high alt and ast levels with normal levels of bilirubin, alkaline phosphatase, complement c3/c4, urea and creatinine. in viral serologic examinations, hepatitis b and c related antibody were found negative, but anti-hav igm was found positive. chest radiography and ultrasonography examination were revealed right pleural effusion and abdominal ultrasonography examination was revealed ascites. based on these findings, we thought that the nephrotic syndrome could be developed due to anicteric hepatitis a virus infection in our patient. low dose steroid treatment was started (prednisolon 1 mg/kg/day, 1 month). edema was improved, negative urine protein was seen, and liver functions were not deteriorated during this therapy in our patient. hepatitis a virus may be cause of nephrotic syndrome by forming of immune-complexes. in conclusion, although hepatitis a virus infection is rare cause of nephrotic syndrome in children, it should be investigated as a seconder casuse. membranoproliferative glomerulonephritis (mpgn) is a rare, chronic glomerulonephritis, and its prognostic factors and outcome are not known very well in childhood. in this retrospective study, we reviewed the clinical, laboratory and histopathological features of children with primary mpgn. thirty-three children (18 boys, 15 girls) presented at a mean age of 11.0 years (range 2-16 years). they were followed for a median of 44 months (range 12-92 months). the clinical presentation in children was nephritic-nephrotic syndrome in 15 children (45.5%), nephritic syndrome in 14 (42.4%) and nephrotic syndrome in 4 (12.1%). nine patients had renal failure at presentation. at the end of study, 25 patients (75.8%) had complete remission and 8 patients had abnormal findings (4 proteinuria, 2 microscopic hematuria, 1 hypertension, 1 esrd). all of patients were treated with steroid. eight patients were given another immunosuppressant drug (cyclophosphamide 7, azathioprine 1) in addition to steroid therapy. the interval between appearance of symptoms and admission, durations of microscopic hematuria and proteinuria, and systolic blood pressure at presentation were higher in children with abnormal findings when compared with children with complete remission. there were no significant differences in clinical presentation type or histopathological features between children with abnormal findings and children with complete remission. our results showed that delayed detection and treatment, uncontrolled hypertension and unresponsiveness to steroid in early period were poor prognosis predictors. we did not determine any correlation between histopathological findings and outcome. we need further investigations including larger patient population. partial lipodystrophy (pl) is a rare condition of unknown etiology, with childhood onset. it is characterized by progressive loss of subcutaneous fat of face, neck, trunk and upper extremities together with c3 hypocomplementemia. usually, patients do not have clinically evident renal disease or abnormalities until they have had the disease for 8 or more years. but, the case we reported here, firstly presented with membranoproliferative glomerulonephritis (mpgn), and during follow-up pl was observed. a six years old girl was presented with sore throat, vomiting and loss of appetite for the last fifteen days. her development was normal and the child was asymptomatic till 6 years of age. the parents were relatives of the third degree. there was no history of similar cases in the family. the physical examination of the patient was normal. urinalysis revealed hematuria and pyuria. proteinuria was not present. renal function tests were normal. laboratory examination revealed low serum complement c3 but normal serum c4. the lipid profile was also normal. patient was followed with the diagnosis of poststreptococcic glomerulonephritis. because of persistent low complement c3 and nephrotic range proteinuria renal biopsy was performed at the 3 rd month of follow-up. renal histology revealed mpgn consistent with type 2. c3 nephritic factor was negative. at the same time it was observed that the face took on a cadaverous look with prominent malar bones, chin and zygoma because of the loss of buccal fat. according to these findings, partial form of lipodistrophy, which is frequently associated with mpgn, was considered in the patient. during two years of follow-up she had two recurrences of nephrotic range proteinuria and she is now in remission with prednisolone therapy. as far as we know this is the first example of pl which is developed during follow-up of mpgn. central nervous system abnormalities in children with acute post-streptococcal glomerulonephritis (apsgn) are rare and are considered to be secondary to acute severe hypertension, electrolyte imbalances and uraemia. cerebral vasculitis associated with acute post-streptococcal glomerulonephritis has been rarely reported in pediatric literature. a 13-year-old girl with a severe headache, vomiting, edema and macroscopic heamaturia is presented. she had history of upper respiratory infection before two weeks. so, the patient was diagnosed as apsgn. on admission, she was normotensive and biocemically well balanced. two hour later, she experienced a grand mal seizure. mri examination of brain showed not only multiple areas of increased density in white and gray matter, and cerebellum but also subarachnoid bleeding, consistent with vasculitis. during follow-up, abducens nerve palsy was detected. histopathological features on renal biopsy specimen, an elevated antistreptolysin level and fallen c3 complement level were compatible with apsgn. all clinical and laboratory abnormalities improved with steroid therapy (pulse and oral methylprednisolon). in conclusion, children with apsgn may present central nervous system abnormalities without hypertension, uraemia and electrolyte disturbances. results: hsp was diagnosed in 105 patients, median age 6 years old. all had the skin manifestations, 49.5% abdominal pain and 41% arthritis. 45 patients developed hsp nephritis (42.9%), mean presentation time was 4.5 months after phs diagnosis. renal biopsy was performed in 14 patients, and the most common histopathological finding was hsp nephritis grade iii a. age of onset older than 10 years was statistically significant for nephritis development (chi square < 0.05). chronic renal insufficiency incidence was 0.95%. conclusions: the main complication of hsp is nephritis. follow-up should include evaluation by a pediatric nephrologist. age of onset older than 10 years is an important risk factor for hsp nephritis. objectives of study: acquired abnormalities of coagulation and fibrinolysis in nephrotic syndrome have been implicated in the pathogenesis of deep vein and arterial thrombosis. resistance to activated protein c due to amutation in the gene for factor v, the commonest inherited risk factor for venous thrombosis, could contribute to risk of both arterial and deep vein in patients with nephrotic syndrome. we report an arterial thrombosis in a young girl with idiopathic membranousglomerulonephritis (mgn) and factor v leiden mutation. case report: a 14 year-old girl was admitted to our hospital with swelling of both legs and cyanosis of her toes. her mother had history of abortion in the second trimester of gestation, and parents were second-degree relatives. physical examination showed peripheral edema in both extremities and peripheral cyanosis in toes. laboratory study showed the nephrotic range proteinuria. serum albumin was 2.2 g/dl, and cholesterol was 380 mg/dl. creatinine, electrolytes, prothrombin/partial-thromboplastin times, c 3 , c 4, fibrinogen, protein s, c, antithrombin iii and homosistein levels were within normal limits. ana, anti-dsdna, p-anca, and c-anca, antiphospholipid igg/igm, anticardiolipin igg/igm were all negative. genetic study showed the heterozygote mutation of factor v leiden (fv/g1691a). in arteriography, there was complete occlusion on the posterior tibiaartery of left leg, occlusion of mid portion of right femoral artery and the posterior tibia artery of right leg. renal biopsy findings werefelt to be compatible with mgn. conclusions: we postulate that patients with concurrent nephrotic syndrome and factor v leiden mutation may have an increased risk of thrombosis. screening for factor v leiden mutation may be indicated in patients with idiopathic nephrotic syndrome. introduction: hus (d+) is the 2nd cause of chronic renal failure (crf) in children in argentina. proteinuria is the main predictor of progression to crf. patients with renal failure, when treated with restricted proteinin take show slower progression to end-stage of rcf. proteinuria appeared in patients with hus sequelae subject to an overload of protein intake. objective: to evaluate the effect of a controlled protein intake on proteinuria in patients with renal disease due to hus and normal renal function (>80 ml/min/1.73 m 2 ). patients and methods: within a multicenter, randomized, double blind, controlled trial, carried out inorder to study the effect of iace on the development of renal disease*, proteinuria before and after a controlled diet was measured in 102 patients with proteinuria due to hus and normal renal function. protein intake was indicated according to rda for age. protein intake was estimated with a questionnaire on former 72 hours, and with 24 hrs urea excretion. proteinuria was measured in 24 hours urine collection at the beginning of the study and at 15, 30 and 60 days after onset of the study. results: median age at onset was 16.5 months (r: 7.0-85.0); mean of length of follow-up after hus onset was 48.0 months (r: 4.0-155). in sixty five (63,7%) patients, proteinuria reduced to normal values; in the remaining 37 (36,3%) there was no change. median of initial and final proteinuria in the 65 children whose proteinuria became normalised, was 9.83 mg/k/day (ds 3.71) and 2.44 (ds1.34) respectively <0.0005. conclusion: controlled protein diet (rda) normalizes proteinuria in patients with significant proteinuria secondary to hus and normal renalfunction. * a trial financed by roemmers laboratory, argentina. differential diagnosis of hematuria is the significant task of any nephrologist while most common reasons for hematuria demand histopathological diagnosis. iga-nephropathy is the progressive glomerular disease which is known to be a common reason for hematuria. the diagnosis ofiganephropathy is often missed because of variability of clinical presentations, long-term asymptomatic course and therefore waiting tactics in prescribing renal biopsy. the aim of the study was to evaluate the incidence of iga-nephropathy and to define its characteristic clinical and morphological features in children in belarus. we present results of immunohistochemical staining for iga mesangial deposition of 65 kidney biopsy preparations. the mean age of the patients enrolled in the study was 11,77±0,66 years. at the moment of biopsy patients clinically presented isolated hematuria (36%), hematuria with proteinuria (29%), nephrotic syndrom (12%), nephrotic syndrom with hematuria and hypertension (5%), isolated proteinuria (5%) and others in less than 2% each. iga mesangial deposition was detected using immuno histochemical staining with polyclonal rabbit anti-human iga. we found diffuse mesangial deposition of iga in 18 patients (28% of all). two of them had nonnephrotic isolated proteinuria, one nephrotic syndrom. vast majority of patients were hematuric (either isolated or combined with proteinuria). iga nephropathy incidence among hematuric patients was 38%. in histopathological examination we found mild segmental mesangial hypercellularity in 14 patients, mild to moderate global and segmental mesangial proliferation in 3 (in two of this patients we also found cellular and fibrous crescents in less than 30% glomeruli). one patient had focal-segmental glomerulosclerosis secondary to diffuse mesangial proliferative glomerulonephritis and clinically presented heavy proteinuria. we analyzed nphs2 mutations in chilean pediatric patients with srns due to fsgs, diffuse mesangial sclerosis (dms) and minimal change disease (mcd). nphs2 mutation analysis was performed in 31 patients (sporadic cases n=27, familial cases n=4). nphs2 exons 5 and 7 were amplified by pcr and subjected to automatic sequencing or enzyme restriction analysis using clai (c.686g>a) and hin6i (c.851c>t) respectively. patients median age at disease onset was 24 months (range , 55% of which were male. histological diagnosis were fsgs (n=26), dms (n=2) and mcd (n=3). ten of 31 patients (32.3%) had mutations in nphs2 (9/26 fsgs, 0/2 dms, 1/3 mcd). eight of 10 patients bearing mutations were sporadic cases. seven patients were compound heterozygous for r229q and a284v. patients with mutations were significantly older than those without mutations (median age 24 versus 84 months, p<0.01). resistance to cyclosporin was observed in 6 of 7 cases with mutations and 11 of 18 cases without mutations (ns). we studied the frequency of r229q and a284v in 60 healthy volunteers with similar ethnic background. only one control individual was heterozygous for r229q. no a284v mutation was detected. our study demonstrated that nphs2 mutations are a major cause of srns in chilean pediatric patients. since most of the srns patients bearing nphs2 mutations were cyclosporin resistant, it is advisable to perform nphs2 mutation screening before starting immunosuppressives. in this study we aimed to investigate the long-term prognosis of henoch-schönlein nephritis (hsn) in childhood. between 1991 and 2003, 156 patients with hsn were investigated retrospectively. there were 86 males and 70 females with a mean age of 9.6 years. they were graded according to the degree of renal involvement. grade 1: isolated microscopic hematuria (n: 31); grade 2: hematuria and mild proteinuria (n: 60); grade 3: acute nephritic syndrome (n: 4); grade 4: nephrotic syndrome/hematuria (n: 18); grade 5: acute nephritic and nephrotic syndrome (n: 43). renal biopsy was performed on 43 patients in grade 4 and 5. twenty patients had extensive crescent formation (>50%) on renal biopsy, and were given triple therapy [iv pulse methylprednisolone (mpz) 30 mg/kg/d for 3 days, followed by oral prednisolone (op), oral cyclophosphamide-2mg/kg/day for 2-3 months and dipyridamole]. the other 23 patients with <50% crescent formation were given mpz followed by op and dipyridamole. the patients in grade 3 and 4 were given op and dipyridamole. grade 1 and 2 were not given any immunosupressive agent. during the follow-up period (mean 30±3.5; range 12-96 months), 23 patients in grade 1, 38 patients in grade 2, 2 patients in grade 3, 8 patients in grade 4 and 21 patients in grade 5 showed complete remission (59%). of the 5 patients with extensive fibrosis on renal biopsy, 2 had persistent nephropathy (1%) and 3 developed endstage renal failure (2%). the remaining 59 patients showed near-complete recovery with minimal urinary abnormalities (38%). in conclusion, although initial presentation of renal involvement determines the prognosis in hsn, intensive treatment with triple therapy appears to be effective in severe renal disease especially if started before the development of fibrotic changes in crescents and tubulointerstitial tissue. aim: the bacterial infection in nephrotic syndrome (ns) is still the big problem and is one of the leading death causes in ho chi minh city, vietnam. we did this study with aims to overview this complication in children with ns. methods: our study population consisted of 132 children with nephrotic syndrome during one-year prospective cohort. twenty seven out of 132 patients who developed severe bacterial infection including pneumonia, peritonitis, urinary tract infection, bacteremia or cellulitis were recorded. results: from june 2004 to june 2005, there were 132 children with nephrotic syndrome recruited to the study. the severe bacterial infection stood at 20.5% (n=27). in 27 these children, 14 children were first ns, 13 children were relapsing ns. the percentages of pneumonia, urinary tract infection, cellular infection and peritonitis were 12.9% (n=17), 4.5% (n=6), 3% (n=4) and 2.3% (n=3), respectively. no patients with bacteremia were recorded. in 6 patients with uti, e.coli wasin 3 patients, proteus in 2 and enterococus in 1. ns children with uti were asymptomatic. ns children with peritonitis had typically clinical manifestations of fever, abdominal pain, tenderness. one out of four patients with peritonitis cultured streptococcus pneumoniae inperitoneal fluid. some factors associated with severe bacterial infection were increase in weight (12.7 vs 9.4%, p=0.02), very low serum albumin (10.3 vs 13 g/l; p=0.003), rise in serum a 2 globulin level (39.5% vs 34.6%; p=0.005) and hyperfibrinogenemia (5.8 vs 5.3 g/l; p=0.02). conclusions: bacterial infection has still been a common problem in children with nsin ho chi minh vietnam. it is important to investigate and manage this complication early to reduce mortality rate. primary nephrotic syndrome (ns) is the most common glomerular disease in children which mainly responds to corticosteroids. however, >70% of children experience a relapse with recurrent episodes. the aim was investigation of outcome in ns patients, retrospectively. clinical, histological data and treatment responses of children presenting with ns from 1996 to 2006 were reviewed. all patients were treated with steroid treatment firstly and classified as steroid sensitive ns (ssns) and steroid resistant ns (srns) according to clinical or laboratory responses. there were 91 patients, 52 male and 39 female, had followed-up for 64.17±54.79 months. age at onset ranged from 9-186 (median 34) months. seven patients were admitted with hematuria and ns (5 mpgn, 2 mgn) that excluded from this study. 60 patients were treated by only classical steroid treatment. thus, 60 (71.4%) patients were ssns and classical steroid therapy was successful in this group.14 of all ssns patients were evaluated with biopsy (6 fsgs, 8 dmp) because of frequently recurrent ns. in srns group (24 patients) with one cytotoxic agent, complete and stable remission was induced in 13 patients (6 in fsgs, 5 in mlh, 2 in dmp) while 6 patients (6 in fsgs) who responded to more than one cytotoxic agents had partial remission with symptomatic relief. five children (5 in fsgs) were refractory to all cytotoxic therapies. cyclophosphamide (cp) was used as the first cytotoxic agent in 18 patients and induced complete remission in 11 (61.1%). the patients who relapsed following cp and patients who failed to respond were treated with further cytotoxic therapies such as cyclosporine a (cs) or mmf. in 6 patients, cs was used as the first cytotoxic agent and induced remission in 2 patients (33.3%). steroid must be the initial drug in childhood ns. cp could be used successfully as an immunosuppressive agent in srns patients. aim: annexin v has a molecular weight of 32-35 kda and has been reported to possess anticoagulant activity, inhibition of phospholipase a2, regulation of membrane transport, proliferation and signal transduction. it is reported that urinary annexin v concentration may be an indicator of apoptosis and acute renal injury related to the urinary protein level. the aim of this study is to define the role of urinary annexin v, serum annexin v concentrations as new prognostic tools and follow criteria in children with steroid sensitive and resistant ns. methods: annexin v concentrations were measured in serum and 24 hour urine samples in 23 steroid sensitive nephrotic syndrome (ns) patients in both relaps and remission periods (group 1 and 2 respectively) and in 22 steroid-resistant ns (group 3) and sex and age matched 22 healthy controls (group 4). total protein, albumin, cholesterol concentrations and 24 hour urinary excretion of protein and creatinine were measured in all groups. results: in steroid resistant ns group (group 3), median of urinary annexin v/creatinine ratio was significantly higher than all the other groups (5048.8 ng/g creatinine (min-max: 1272.5-40498.4) vs 2839.5 ng/g creatinine (min-max: 1131.0-15835.4) in group 1 (p: 0.06); 2500.0 ng/g creatinine (min-max: 1424.2-11055.6) in group 2 (p: 0.028), and 2018.3 ng/g creatinine (min-max: 1225.9-6887.4) in group 4 (p: 0.028)). serum annexin v concentration was significantly higher in group 3 (median 16.6 ng/ml) than in group 4 (median 8.2). no significant correlation was found between urinary protein excretion and urinary annexin v/creatinine ratio. conclusion: remarkably increased urinary annexin v/creatinine ratio could be used as a determinant factor in children with steroid resistant ns, and it may be a prognostic factor in these children. v. baudouin 1 , f. bernaudin 2 , a. garnier 1 , t. kwon 1 , m. peuchmaur 3 , g. deschenes 1 , c. loirat 1 1 hôpital robert debré-aphp, service de néphrologie pédiatrique, paris, france 2 chic, service de pédiatrie, créteil, france 3 cgvhd is the most common late complication of hsct. clinical manifestations mimic lupus disease but renal involvement is unusual. a 4 year-old boy underwent hsct from an hla-identical sibling donor for sickle cell disease. he received myeloablative therapy (cyclophosphamide, busulfan, antithymocyte globulin). prophylaxis of acute gvh consisted in prednisone and mmf until month 4. moderate skin and mucosa cgvh appeared at month 6 so that prednisone and mmf were restarted. at month 9 prednisone was stopped and mmf decreased to half dose. at 1 year, while clinical features of cgvh intensified, fortuitous diagnosis of ns was done. glomerular filtration rate and blood pressure were normal. biopsy showed membranous glomerulonephritis and mesangial hypercellularity. immunofluorescence confirmed granular immune deposits of igg and c3treatment consisted in prednisone (1.5 mg/kg/d for 1 month, progressively tapered to 0.5 mg/kg/e.o.d at month 4) and cyclosporine (5 mg/kg/d, trough levels 40-50 ng/ml). proteinuria decreased to <0.5g/l in 2 months. cyclosporine was progressively stopped between month 6 and 12 without relapse of proteinuria. ns associated with cgvhd had been reported in about 60 patients (5 patients <18 yr-old). retrospective studies estimate occurrence around 1% of patients with cgvhd. it was secondary to membranous glomerulonephritis in 67% of cases, minimal changes disease in 21%. strengthening of immunosuppression led to complete remission in 90% of patients with minimal changes disease and 27% of those with membranous glomerulonephritis (60% partial remission). usual treatment consisted in prednisone (87%) and cyclosporine (51%). this manifestation of cgvhd is probably underestimated and can occur at the same time or later than other clinical features. early detection of proteinuria in patients with cgvhd is recommended to adapt immunosuppressive treatment. objectives: to see if cyclosporine a (csa) is safe and effective in reducing proteinuria in children with the iga nephropathy (igan) or the henoch-schoenlein purpura nephritis (hspn). methods: the biopsy proven 34 patients (19 with igan, 15 with hspn) who showed increased proteinuria (>1+) for longer than 4 months were included. the blood level of csa, serum chemistries, urine analysis and complete blood cell counts were carried out every other month along with the physical exams. results: csa was given at an amount of 4.41.0 mg/kg/day for 10.13.3 months in average. complete remission of proteinuria in 27 (79.4%) and partial remission in 2 (5.9%) were achieved by csa treatment. five (14.7%) non-responders were discontinued for csa treatment in the middle of the trial. the ration of urine protein to creatinine was initially 3.95.0 and reduced gradually with time to 0.81.6, 0.30.7, 0.50.9 at 4, 8, 12 months after csa treatment, respectively. twenty eight patients showed hypertrichosis, three experienced transient elevation of serum creatinine, and two complained difficulties in taking the medication due to severe nausea. for 28.3 months after completion of the csa treatment, 9 patients redeveloped proteinuria and had to receive the 2 nd csa trial. no clear difference was observed in the pharmacokinetic profiles of csa attributable to the non-response or recurrence. follow-up renal biopsies were carried out in 11 patients after completion of the csa therapy and no csa toxicity was found. there was no alteration of linear growth pattern. conclusions: this study has a limitation of lacking the control group but the csa treatment is assumed to be very effective and a safe method to attain the remission of proteinuria in pediatric patients with the igan or hspn. j. madrigal 1 , e. fernandez 2 , p. noguera 2 , p. carranza 3 1 the aim of this retrospective study was : 1) to correlate the histopathological diagnosis with steroid response,persistent hematuria, hypertension and or abnormal renal function tests (gfr) 2) to evaluate the response of the patients with srns and sdns to the oral cytotoxic drugs , in a period of 10 consecutive years. 3) to correlate the response of this group of patients to the oral cytotoxic drugs with their histopathological diagnosis 4) to observe the incidence of fsgs in costarrican children during a period of 10 years. 5) based on these observations, reevaluate the indications of the kidney biopsy in our patients . we reviewed all the clinical records of patients with the diagnosis of ns and in whom a kidney biopsy have been done. patients with incomplete data were excluded. two consecutive reviews were made: the first included all patients diagnosed between january 1993 and december 1997 (group a) and the second, between january 1998 and december 2002 (group b). a total of 81 medical records were analyzed; 20 patients were excluded, and the remaining 61 were studied. results: all patients had been referred for edema or new onset nephrotic syndrome before treatment had been initiated. in our patients the steroid response was also the most important factor to predict the histological diagnosis and the response to the treatment with cytotoxics. the presence of hematuria and abnormal serum creatinine at the time of diagnosis were a predictive factor for the steroid response but not for the histological diagnosis. arterial hypertension achieved statistical significance only between mcns and fsgs but it was useful as a predictive factor for the hystological. in our group of patients with srns treated with cytotoxics, 55.5% with mcns responded, versus 37.8% of the patients with dmgn p<0,05. a. guersoni, v. mello, v. benini, s. laranjo children with srns are exposed to prolonged and high doses of steroid therapy and other immunosupressants that can lead to a variety of serious side effects. these include statural growth impairment, obesity, osteoporosis, cataract, hypertricosis and psychological disturbances.we carried out a prospective single-center study to evaluate the efficacy of mycophenolate in 20 children with steroid-resistant disease, 7 female and 13 male, aged 11.5±4.2 years. histological findings were: minimal change disease (mcd) in 8 children, focal segmental glomerulosclerosis (fsgs) in 11 and membranous nephropathy in one. all patients had been treated with at least one course of cyclophosphamide, metil-prednisolone in 15, while 13 had also been treated with cyclosporine before mmf. the initial dose of mmf was 600 mg/m 2 per day, together with a minimal reduction dose of corticosteroids associated with angiotensin ii receptor blockers (arbs) and sinvastatin.three patients went into complete remission, 15 into partial remission and 2 showed no remission. partial remission was described as loss of edema and improvement in symptoms, despite persistence of significant but improved proteinuria, that was classified either as moderate or low proteinuria according to the level. side effects were: diarrhea (n=1), neutropenia (n=2), infectious disease (n=1). mmf is an important new therapeutic option when associated with angiotensin ii receptor blockers (arbs) and sinvastatin for srns with mcd or fsgs, providing improvement in edema and symptoms despite persistence of proteinuria, with no compromise of physical appearance or risk of nephrotoxicity. background: primary focal segmental glomerulosclerosis (fsgs) that is resistant to steroids and other immunosuppressive agents has a guarded long-term prognosis. patients who fail to respond to current treatment may benefit from therapies that inhibit renal fibrosis and retard progressive loss of kidney function. objective: the font study (novel therapies in resistant fsgs) is a phase i clinical trial designed to test the safety, tolerability, and pharmacokinetics (pk) of novel agents that reduce renal fibrosis in patients with resistant fsgs. methods: patients, age 2-40 yr and egfr >40 ml/min/1.73 m 2 , with resistant fsgs who fail treatment in the nih supported trial evaluating cyclosporine vs. dexamethasone plus mycophenolate mofetil or who are screen failures due to prior exposure to these drugs are eligible. patients are assigned to receive rosiglitazone 3 mg/m 2 per day po or adalimumab 24 mg/m 2 every other wk sc. the treatment phase is 16 wk and patients undergo an initial (wk 0) and steady state (wk 16) pk assessment. results: 24 patients have been screened and 16 have been randomized 8 to each test therapy. 6 patients have completed rosiglitazone therapy and 2 have completed adalimumab. four serious adverse events have occurred in patients receiving rosiglitazone, none related to the study drug. fatigue (37%), gastrointestinal complaints (37%), and headache (25%) were the most common adverse events in patients given rosiglitazone. the outcomes in the adalimumab group have not been analyzed. conclusion: these preliminary results indicate the feasibility of performing phase i assessments of novel agents that can target renal fibrosis in patients with resistant fsgs. the findings will be used to design phase ii randomized clinical trials in this cohort of patients at high risk of progression to end stage renal disease. supported by grant niddk r2170341. object: to study the effect of fty720 on glomerulosclerosis and expression of cell cycle regulatory proteins in subtotal nephrectomized rats. methods: 24 rat were divided into sham-operation group, glomerulosclerosis model group and fty720 treated glomerulosclerosis group, 8 rats in each groups. the rats in later two groups were subjected to 5/6 nephrectomy. after operation, the treat group was fed with fty720 for 12 weeks. the expression of collagen, fibronectin, and cycline, p21, p27 were determined by immunohistochemistry methods. results: after treatment with fty720, up began to decrease from 4w after operation, significantly lower than in model group (p<0.01). the model group showed higher level of scr from 8w, which was much higher than in control group (p<0.05). in fty720 treated group, scr level were much lower than in model group. fty720 could obviously inhibit the expressionof col-and fn in glomeruli and attenuate the extent of glomerulosclerosis. moreover, fty720 could upregulate glomerular expression of p21 and downregulate glomerular expression of p27 and cycline. the expression levels of p21 and cycline were significantly lower in treatment group than in model group (p<0.05), but still higher than in control group (p<0.05). p27 expression in glomeruli was stronger in treatment group than in model group (p<0.05), and lower than in normal group but without significant statistic difference. conclusion: fty720 can diminish urine protein excretion and prevent glomerulosclerosis in subtotal nephrectomized rats. this protective effect is presumed to be associated with its role in downregulation of cycline expression and upregulation of p27 expression in glomerular cells, and inhibition of extracellular matrix accumulation in glomeruli. the authors illustrate severe side effect of steroid therapy ulcerative gastroduodenitis-and rare complication (multiple cerebral thrombo-embolism) in the case of a 10 year old girl with steroid resistent nephrosis. in childhood occurence of thrombosis in steroid sensitive nephrosis syndrome is 1.5%, while it comes up to 3.8% in steroid resistant cases. on admittance she presented the classic symptoms of nephrotic syndrome. one month after the initiation of steroid therapy haematemesis, melaena occurred, and after appropriate therapy was cured. due to the progression of the nephrotic syndrome, steroid shot and later immunesuppressive therapy was started. eight weeks after onset she became unconscious for a shortwhile and had a transient episode of right hemiparesis. at the same time ct and mri disclosed bilateral parieto occipital ischemic territorial vascluar lesions, with relative sparing of the cortical ribbbon. following icu observation her state rapidly improved and after a two week period she became free of symptoms. renal biopsy disclosed the pattern of minimal change nephrosis with diffuse mesangial hypercellularity and a slight amount of igm positivity. immunological evaluation-with the capacitiy to reveal systemic immunological diseases remained negative. having been put on an evidence based protocol the patient's present nephrological state was unremarkable, with proteinuria less then 1g/day. in the present work the authors discuss the factors predisposing to thrombo-embolism with special emphasis on the possible preventive measures and therapy. igg autoantibodies to c1q (antic1q) have been reported to play a pathogenic role in immunecomplex mediated diseases (sle, apsgn, membranoproliferative gn, etc). the occurrence of antic1q in adult patients with sle has been shown to correlate with disease activity and some immunological parameters (hypocomplementemia, anti-dsdna) and may be useful in the early diagnosis of lupus nephritis (ln) or even as a predictor of renal flares. the presence of antic1q in children with apsgn was associated with more severe disease manifestations and a lack of spontaneous recovery. associations between antic1q, c4 and c3 complement levels and disease manifestations in 129 children with gn were investigated and compared with healthy controls. antic1q were measured by elisa and c3 and c4 by immunoturbidimetry, respectively. 29 of 129 patients with gn were positive for antic1q compared to 0/40 healthy controls. antic1q were associated with active ln and hypocomplementemia: 10/15 patients with sle were found to be antic1q-positive. nine of these 10 had active renal disease at the time of blood sampling compared to 1/5 being antic1q-negative. 7/10 antic1q-positive patients had low c3 level and 4/10 had low c4 level. in children with apsgn, 13/38 were positive for antic1q. antic1q positive patients had significantly higher proteinuria, more often hypertension and c3-hypocomplementemia. all 5 patients in which apsgn did not resolve spontaneously were antic1q-positive. antic1q were associated with active nephritis and hypocomplementemia in patients with sle. in children with apsgn antic1q-positive patients have more severe disease and stronger c3-hypocomplementemia then those being antic1q-negative. m. zahrane 1 , l. fawaz 2 , l. nesseim 3 1 cairo university hospital, pediatric nephrology, cairo, egypt 2 cairo university hospital, pediatrics, cairo, egypt 3 cairo university hospital, cell pathology, cairo, egypt objective of the study: growth hormone (gh) and insulin-like growth factors are essential for normal growth and development. chronic renal failure (crf) results in major changes in the circulating growth hormone/insulin-like growth factor (igf) system. our aim is to study clinical and laboratory parameters of growth and osteodystrophy including igf1 and igfbp2 as part of the somatotropic hormone axis in egyptian children suffering from crf on conservative therapy. methods: 62 egyptian children (47 boys and 15 girls) with a mean age of 9.7y (0.47 to 21.12y) suffering from crf on conservative therapy and 21 controls were included in the study. ht, wt and tsf were measured and followed up for a period of 6 months. at the end of the follow-up period serum for igf1 and igfbp2, renal function, electrolytes, ca, p and alkaline phosphatase and acid base balance were measured and an x-ray of the left hand and wrist was done to determine their bone age by tanner and whitehouse. results: our study shows that children suffering from crf in egypt on conservative therapy have growth retardation with a mean ht of 3.7 sds, a mean wt of -2.24 sds. tsf mean was -1.3 sds. on the average the patients had a delay of 2.95y (±2.0) in their bone age. their height was retarded more than their bone age with a height age/bone age of 0.8 (±0.18). alkaline phosphatase as a markers of renal osteodystrophy is significantly correlated to the height, height age, bone age and to the ph. the mean igf1sds (-0.6±1.8) did not differ from that of controls while the mean igfbp2sds (2.4±4.6) was significantly higher in patients with crf than in controls. height and weight were significantly correlated to igf1 but not igfbp2. there is a significant correlation between igfbp2 level and the glomerular filtration rate. conclusions: the imbalance between normal insulin-like growth factor-i (igf-i) and markedly increased igfbp2 plasma levels plays a pathogenic role for growth retardation in children with chronic renal failure. the lower the gfr the higher the igfbp2 level. the latters inhibitory action may provide hope for improving growth in cases of crf by reducing the level of igfbp2 or displacing igf1 from it. s. sultana 1 , h. rahman 2 , m. hossain 2 1 bangladesh medical college, pediatric department, dhaka, uttara, bangladesh 2 bangabandu sheikh mujib medical university, pediatric nephrology, dhaka, bangladesh objective: to find out the impact of different etiology of chronic renal failure on growth in children. methods: this prospective study was carried out in the department of pediatrics, bangabandhu sheikh mujib medical university (bsmmu), dhaka, bangladesh, from october 2001 to october 2003. fifty children of both sexes under 15 years of age with clinical and biochemical evidence of chronic renal failure (crf) with creatinine clearance (ccr) of <75 ml/min/1.73 m 2 were included in the study. on the basis of underlying causes of crf, the children were divided into congenital (n=30) and acquired (n=20) groups. all patient's height and weight were measured. radiographs of hands, digits, ankle and knee joints, lumbar spine & skull were obtained to evaluate the presence of renal osteodystophy (rod) and for assessment of bone age. serum intact parathormone (ipth) level was also assayed in all patients. growth parameters and presence of radiographic and biochemical features were evaluated in two groups. results: crf children due to congenital anomalies had stunting and wasting in 23 (76.7%) and 20 (66.7%) cases respectively and the difference between two groups of crf patients was highly significant (p<0.001). alkaline phosphatase (467.70±218.55 u/l) and ipth (91.43±33.42 pg/ml) were also significantly higher than acquired group (p<0.001 and p<0.05 respectively). radiographic features of rod were present in 15 (50%) cases in congenital group in comparison to 4 (20%) in acquired group and the growth zone lesion was the commonest type of rod in congenital group (66.7%). conclusion: all efforts should be made to diagnose the presence of crf as early as possible, especially in infants and in children with early onset crf who seem to lose growth potential. introduction: in patients with thalassemia major the most important cause of morbidity and mortality is organ failure due to iron deposits, desferioxamine toxicity and anemia. this study was designed to define renal abnormalities associated with thalassemia and to find early marker (markers) of renal dysfunction. patients & method: 39 thlassemic children (18 female and 21 male) with mean age of 11.8±2.3 yr. were studied. all of them were received desforioxamine. 22 age and sex matched healthy children were involved in the study. blood and timed urine sample were obtained for hematologic and biochemical tests. the results were compared between case and control group. results: mean value of bun, serum creatinine, creatinine clearance, serum electrolytes, urine osmolality, fractional excretion of sodium and potassium were not statistically different between two groups. level of urinary nag (n-acetyle-beta-d-glycosaminidase) was significantly higher in patients than in controls (p: 0.001). there was a positive relation between urinary nag and duration of disease (p: 0.04). the was no statistically significant relation between urinary nag and serum ferritin. tubular function was not altered by hypertransfusion. conclusion: proximal tubular dysfunction is found in thalassemic patients. measuring urinary nag can guide the physician to find the early tubular abnormality in patients without frank renal dysfunction. severity of the abnormalities is correlated with the duration of disease. the present study aimed to investigate the effects of isolated ma and ma associated with mild renal function impairment on fracture healing in rats. ma was induced by chronic ingestion of 2% ammonium chloride solution as the unique source of liquid and renal dysfunction was produced by unilateral nephrectomy. thirty male holtzman rats (200-260g) were divided into six groups: control group (c,n=5) non-operated rats receiving tap water, acidotic group (ac,n=5) non-operated rats ingesting 2% ammonium chloride; sham water (s,n=5) sham-operated animals receiving tap water; sham acidotic (sac,n=5) sham-operated rats ingesting 2% ammonium chloride; nephrectomy water (n,n=5) nephrectomized rats ingesting tap water; and nephrectomy acidotic (nac,n=5) nephrectomized rats ingesting 2% ammonium chloride. after one week, blood samples were obtained to measure ph and gases, and a fracture of the right tibia was manually produced. four weeks later, fracture healing was evaluated by radiological and histological parameters. blood ph and gases, serum electrolytes and creatinine were also determined. data were compared by anova followed by newman keuls or fisher's exact test. fracture healing in nac, ac, sac animals was significantly altered as compared to c group. there was an additive effect of metabolic acidosis and unilateral nephrectomy in fracture healing process as shown by the comparison of sac and ac rats using radiological and histomorphometrical parameters. there was no difference between electrolytes and creatinine levels in all groups at the end of the experiment. this study showed a higher frequency of delayed fracture healing and nonunion in the presence of ma, which is worsened by unilateral nephrectomy. our data indicated an important interaction between bone and kidney in acid base homeostasis. introduction: dent disease, an x-linked recessive tubulopathy, is historically characterized by lowmolecular weight proteinuria, hypercalciuria, nephrocalcinosis/lithiasis and slowly progressive renal failure. most cases are caused by mutations in the clcn5 gene (dent disease 1, omim #300009), some patients with dent like phenotype have defects in the lowe syndrome gene ocrl1 (dent disease 2, omim #300555). patients: 10 male patients from 7 families with urinary findings resembling dent disease are reported. in 7 patients, mutations in the clcn5 gene were found, in 3 patients ocrl1 mutations. all children have increased values of urinary alpha-1-microglobuline, but also unselective glomerular proteinuria. 6/10 have mild hypercalciuria, 4/10 demonstrate mild renal insufficiency. amost all patients have increased echogenicity of renal parenchyma, but mild medullary hyperechogenicity is found only in 2 of 10 patients. metabolic acidosis or renal phosphate wasting is not found. interestingly, 5 of 10 children have increased values of creatinine kinase of unknown origin, clinically asymptomatic and independant of clcn5 or ocrl1 mutations. conclusion: the phenotype and genotype of dent disease is very heterogeneous. diagnostic criteria of dent disease and of lowe syndrome should be discussed. e. sahpazova, d. kuzmanovska, l. spirevska, n. ristoska bojkovska pediatric clinic, nephrology, skopje, macedoniathe nutritional condition of 35 children (22 males and 13 females) mean age 8.18±4.04 (range 1-16 years) with moderate renal failure have been followed for three year. glomerular filtration rate (gfr) was measured by creatinine clearance calculated with schwartz formula and was ranged from 13.59 to 75 ml/min per 1.73 m 2 . the nutritional condition was determined by anthropometrics and nutritional measurements. the patients were divided in four groups depending of their protein intake, primary disease, ages and glomerular filtration rate. all patients were following an -ad libidum -diet. nutritional intake was determined by minimum of two 3-day prospective dietary diaries. 46% of children received significantly lower protein intake. the mean protein intake (% of who recommendation) determined by dietaries of patients with -sub-optimal intake -was 94.79% vs. 175.45% in patients with -adequate protein intake -(p<0.05). all patients have a calorie intake of at least 80% of the who recommendations. the relative distribution of calories was 11.22% from proteins, 57.66% from carbohydrates and 31.12% from lipids. nitrogen balance in 15 patients was positive and correlated most significantly with increasing energy intake (r=0.58). average values for height, weight, triceps skin fold, mid-arm muscle circumference, and body mass index were within 2 sd of the mean of the normal population. the protein intake, primary disease and age of the children did not have any effect on growth and development. only patients with more advanced renal disease showed small score for height and growth velocity. key words: chronic renal failure; uremic children; nutritional status; nutritional intake; u. aslanova 1 , t. morimoto 1 , e. farajov 2 , n. kumagai 1 , n. sugawara 1 , a. ohsaga 3 , y. maruyama 3 , s. tsuchiya 1 , s. takahashi 4 , y. kondo 2 1 tohoku university, pediatrics, sendai, japan 2 tohoku university, medical informatics, sendai, japan 3 tohoku university, physiology, sendai, japan 4 nihon university school of medicine, pediatrics, tokyo, japan the extracellular calcium-sensing receptor (casr) located in either luminal or basolateral cell membranes of various types of renal tubules including proximal tubules, henle's loop and collecting ducts has been thought to play a fundamental role in electrolyte metabolism. to further identify the physiological roles of the casr, we examined the effects of ca 2+ and calcimimetics neomycin (neo), gentamicin and gadolinium chloride gd 3+ on the intracellular ph (phi) of in vitro microperfused mouse medullary thick ascending limb (mtal) cells of henle's loop, by loading the cells with fluorescent ph indicator 2',7'-bis-(2-carboxyethyl)-5-(and-6)-carboxyfluorescein and measuring the ratio of fluorescence emission at 530 nm after exciting the dye at 490 and 440 nm. in a steady-state condition in hepes-buffered solution, the phi in the mtals was 7.29±0.04 (n=9). a concentration of 200 micromol/l neo in the basolateral side decreased the phi after 1 min by -0.13±0.02 (n=34, p<0.0001). the other calcimimetics showed similar effects on phi, whereas none of these calcimimetics in the lumen affected phi. na + removal or the inhibition of na + and proton transport with amiloride, bumetanide, or bafilomycin did not eliminate the effect of neo on phi. on the other hand, clremoval clearly eliminated the neo-induced phi decrease (-0.06±0.01 vs -0.00±0.05 in clremoval, n=4, p<0.003). thus, we have demonstrated for the first time that the casr is involved in the regulation of the phi in the mtal and requires clto exert its effect. background: paediatric nephrologists are often consulted for atypical rickets of renal or non-renal origin. the comeback of vitamin d deficient (classical) rickets in armenia and elsewhere is not only a public health problem but also a new diagnostic challenge for nephrologists. the aim is to analyse all paediatric patients seen in 2006 with bone deformities and suspected rickets at the arabkir hospital in yerevan. patients and methods: patients with bone deformities came spontaneously or were referred by one of us (gk). routine serum chemistry was done in yerevan. further investigations, if needed, and urine chemistry were performed in zurich. patients with rickets due to renal insufficiency were excluded. results: in 2006 we have seen 22 patients (12 males) with rachitic bone deformities aged 17-46 months (mean 32±9.4) at diagnosis. of these, 8 patients had florid vitamin d deficient rickets and 9 had sequelae of rickets but were radiologically and biochemically cured. these 17 children with classical rickets had to be distinguished from 5 patients with other forms of rickets: x-linked hypophosphataemia (xlh; 2), vitamin d dependant rickets type1 (1), and renal fanconi syndrome (2) due to fanconi-bickel syndrome and idiopathic. conclusions: (i) the rising number of vitamin d deficient rickets is of concern and due to neglected prophylaxis, (ii) children with classical rickets came late and were in the same age range as patients with atypical rickets, (iii) hence, and because of the larger number of rachitic children, an increased awareness of nephrologists -including a full diagnostic work-up -is needed in order not to overlook rare forms of rickets, (iv) polar vitamin d metabolites should not be used before the precise type of rickets is known. b. spasojevic-dimitrijeva, m. kostic, a. peco-antic, d. kruscic, d. paripovic, m. stanic university children's hospital, nephrology department, belgrade, serbia t. porowski 1 , w. zoch-zwierz 1 , j. konstantynowicz 2 , k. taranta-janusz 1 1 medical university of bialystok, 1st department of pediatrics, bialystok, poland 2 medical university of bialystok, department of pediatrics and auxology, bialystok, poland there are no published data on calcium oxalate (caox) crystallization and therewith associated kidney stone disease in children. the aim of this study was to determine bonn risk index (bri) in children with urolithiasis in relation to healthy age-and sex-matched controls and to assess possible associations between bri values and the size of renal stones. methods. in this cross-sectional study, we compared bri in 142 caucasian children and adolescents (76 girls, 66 boys) aged 3-18 years (median: 14.3) in whom kidney stones were newly diagnosed and 210 healthy age-and sex-matched controls (105 girls, 105 boys) without urolithiasis. urinary ionized calcium [ca + ] was measured using a selective electrode, while the onset of the spontaneous crystallization was determined using a photometer and titrating with 40 mmol/l ammonium oxalate (ox 2 ). the calculation of bri value was based on [ca 2+ ] to (ox 2 ) ratio. high resolution renal ultrasonography was done to estimate the size of renal stones. results. our results showed that bri values in children with renal stones were greater compared with healthy children without stones. bri was 15-fold greater, bri/kg body weight -10-fold greater, bri/per 1.73 m 2 b. s. -13-fold, whereas bri/bmi was even 23-fold greater in cases with stones than in controls. no significant association was observed between bri and the size of stones. interpretation. children with kidney stones demonstrate increased bone risk index compared with healthy subjects without urolithiasis. an increased bri during growth, although unrelated to renal stone size reflects the risk for crystallization of calcium oxalate and may suggest early metabolic disorders leading to urolithiasis. this simple method appears to be accurate and cost-effective, thus bri may be widely used for discrimination between stone-formers and healthy children. m. dixit, n. dixit florida children's hospital, florida children's kidney center, orlando, united states acute tubulo-interstitial nephritis (atin) is an important cause of acute renal failure resulting from a variety of insults including rare immune complex-mediated tubulo-interstitial injury. drugs including non-steroidal anti-inflammatory drugs (nsaids) are far most frequent cause of atin, but overall as an entity it remains under-diagnosed as symptoms resolve spontaneously if the medication is stopped. we present a 14-year-old male who developed acute renal failure 2 weeks after aortic valve surgery. he was put on aspirin following surgery and took ibuprofen for fever for nearly a week prior to presentation. he then presented to the emergency department feeling quite ill and was found to have bun of 147 mg/dl, creatinine of 15.3 mg/dl and serum potassium of 8.7 meq/l. dialysis therapy was immediately initiated. a kidney biopsy showed inflammatory infiltrate consistent with atin. however, very intense tubular basement membrane (tbm) granular deposits of polyclonal igg and c3 were noted. he needed dialysis for nearly two weeks and was treated successfully with steroids. his renal recovery and disappearance proteinuria took almost a year. in conclusion, we present an unusual case of tbm immune complex-mediated atin due to nsaids with severe but reversible renal failure. the effect of corticosteroid therapy on bone metabolism in nephrotic syndrome background: nephropathic cystinosis is characterised by lysosomal cystine accumulation leading to generalized fanconi syndrome. defective tubular reabsorption of proteins, mainly by the multi ligand receptors megalin and cubilin, is considered to be the cause of proteinuria in cystinosis. whether increased glomerular permeability contributes to proteinuria in cystinosis is investigated in this study by evaluating 1) urinary protein pattern in cystinotic patients and healthy controls 2) expression of megalin, cubilin and their ligands transferrin, albumin, a 1 -microglobulin (a 1 m) and b 2 -microglobulin (b 2 m) in renal tissue. methods: urine of cystinotic patients and controls (n=6), aged 1-16, were immunoblotted using antibodies against megalin, cubilin, transferrin, albumin, a 1 m and b 2 m. additionally, urinary levels of igg, albumin, a 1 m and creatinine were measured. results are expressed as mg/mmol creatinine (median, range). presence of proteins in semithin paraffin sections from cystinotic and control kidneys was evaluated using antibodies mentioned before. results: cystinotic patients had increased urinary excretion of , p 90 <10) and all tested ligands of megalin and cubilin. immuno histochemistry showed comparable expression of megalin, cubilin and their ligands in convoluted proximal tubules (pt), while the ligands in straight pt were only present in cystinotic patients. conclusion: a selective proteinuria with high molecular weight protein excretion such as igg indicates increased permeability of glomerular filtration barrier in cystinosis already at an early age. the presence of the megalin and cubilin ligands in endocytic vesicles suggests functional endocytosis. however, the enhanced staining of the ligands in cystinotic straight pt may be a result of incomplete reabsorption in convoluted pt. background: dent's disease and lowe syndrome are the most frequent x-linked tubulopathies. dent's is characterized by lmw proteinuria, hypercalciuria and nephrocalcinosis. in ca. 60%, this phenotype results from mutations in the clcn5-gene. lowe syndrome (congenital cataract, mental retardation and generalized fanconi syndrome) is due to mutations in the ocrl1 gene. stunted growth is another typical finding in lowe patients. recently, in a subgroup of dent patients ocrl1 gene mutations have been demonstrated (dent-2 disease). aim of the study: comparison of the growth pattern of patients with clcn5 and ocrl1 mutations. patients: boys with proven mutations in clcn5 (n=25, mean age 13.8±9 yrs) were compared with those with dent-2 disease (n=11, 9±4 yrs) and those with ocrl mutations and a lowe phenotype (n=6,14.9±7.7 yrs). comparison of z-scores for height, weightand bmi. results: clcn5 positive boys had a significantly higher height-sds (-0.87±1.4) than ocrl1 positives (dent-2: -2.18±1.1/lowe: -3.46±1.0). there were no significant differences in bmi-sds and weight-sds. the difference between weight and height sds as a parameter for obesity in these small-statured children was higher in lowe than in classical dent patients, with intermediate values being found in dent-2. discussion: although the renal phenotype of dent-2 patients is identical with classical dent, the former are more stunted. therefore, the abnormal growth pattern in dent-2 patients cannot be ascribed to renal dysfunction. taken together with other findings (elevated ck and ldh, mild mental retardation) our findings illustrate that dent-2 is indeed a mild variant of classical lowe syndrome. quantitative ultrasonometry of the calcaneus in children with idiopathic hypercalciuria lesch-nyhan syndrome is a very rare x-linked recessive disorder characterized by mental retardation, spasticity resembling cerebral palsy, choreoathetosis, self-mutilation and hyperuricemia. self-mutilation behavior is a hallmark of the disease. hyperuricemia leads to hyperuricuria and uric acid nephrolithiasis. we report on a 7-year-old boy with lesch-nyhan syndrome with no self-mutilation behavior who was erroneously diagnosed as having athetotic cerebral palsy. besides, he had no renal stones, the only renal abnormality detected were hyperechoic renal medullary pyramids, sonographicaly indistinguishable from medullary nephrocalcinosis. bone disease is frequently observed in children with homozygous beta-thalassemia (thal). we have observed an increased prevalence of renal stones in these patients. in order to understand the cause of this predisposition to renal stone formation we investigated markers of bone metabolism in our thal children. we studied 23 thal children (age range 3-16 years; 8 females and 15 males) with no eviodence of renal stones. thal was diagnosed with haemoglobin hplc study and genetic typing. all received blood transfusion and iron chelants on a regular schedule. serum levels of pth, osteocalcin, telopeptide c-terminale (cross-laps) were determined with eclia technique; serum vitamin d (25ohd3) with elisa technique. serum calcium, phosphate, uric acid, bicarbonate, creatinine, alkalin phosphatase and sodium, calcium, oxalate, citrate and creatinine in 24 hours and fasting urine were determined with common methods. as controls we studied 30 children with comparable age. serum pth and vitamin d were increased in 28% of our patients, serum osteocalcin in 64% and telopeptide c-terminale (cross-laps) in 92%. hypercalciuria was observed in 26%, hyperoxaluria in 16% hypocitraturia in 11%. significant correlation were found between pth and osteocalcin (p<0.01) cau/cru (p<0.05); osteocalcin and cross-laps (p<0.005) and vit d and cau/cru (p<0.05). bone disruption due to bone marrow expansion may produce an increase in vit d and pth production with hypercalciuria producing renal stones. losartan is an angiotensin ii subtype 1 (at1) receptor antagonist used for controlling blood pressure and urinary protein excretion in patients with hypertension and chronic renal disease. there are a few reports about the clinical implications of at-1 receptor antagonism that may interfere with the kidney's defense against an acid load and may thereby exacerbate metabolic acidosis in the literature. the suggested mechanism is that at-1 blockade by losartan exacerbates acidosis by inducing a distal-tubular acidification defect.we observed metabolic acidosis and hyperkalemia in five patients (3 females/2 males, age ranged 5-17 years) whom were given losartan. during the second week of the therapy all patients revealed a metabolic acidosis with (ph; ranged 7,19 to 7,33 and hco3; ranged 11,9 to 17 mmol/l) hiperkalemia (ranged 5,6 to 6,7 mg/dl). the etiologies of chronic renal disease in the patients were focal segmental glomerulosclerosis (fsgs) in one, lupus nephritis in one and three had undergone renal transplantation according to different etiologies. glomerular filtration rate was higher than 60 ml/sec/1,73 m 2 in all patients. immune suppressive regimen of renal transplanted patients was based on tacrolimus in two patients and on cyclosporine a in one. both renal transplanted patients and other two patients with fsgs and lupus nephritis were all receiving steroid, enalapril and mycophenolate mophetil at the same time during the losartan therapy. metabolic acidosis and hyperkalemia were recovered within a week following the exclution of the losartan. in conclusion, we think detailed and controlled studies are necessary to determine the pathogenesis of the metabolic acidosis due to losartan and patients must be followed up very closely for the adverse effects of metabolic acidosis and hyperkalemia during the treatment. objectives of study: bartter's syndrome is a rare renal tubular disorder characterized by hypokalemia and metabolic alkalosis. it is also known to be effectively treated with potassium supplement, potassium sparing diuretics and indometacin. we experienced two sibling cases whose problems were incompletely solved with above mentioned conventional treatment, but rather completely with adjunctive therapy of regular hemodialysis with dialysate of low bicarbonate concentration. case 1: this male patient was diagnosed of bartter's syndrome when he was 3 months old. he was treated with potassium supplement, aldactone and indometacin with marked improvement. but he still had some problems of retarded growth, severe headache and episodes of marked hypokalemia which needed repetitive admission. when he was 10 years old, we put him weekly hemodialysis with dialysate of low bicarbonate concentration (20 meq/l). with hemodialysis, he has been in good condition for 2 years with stable blood ph and serum potassium levels. case 2: this female patient, the elder sister of case 1, was diagnosed of bartter's syndrome at one year of age. with those therapy on conventional medications, she seemed to grow out of failure to thrive, but needed repeated admissions due to episodes of dehydration and hypokalemia. after start of weekly hemodialysis with low bicarbonate dialysate, for one year she has been on good control of blood ph and serum potasium level, and was never admitted with those episodes. conclusion: regular hemodiaysis with dialysate of low bicarbonate concentration can be considered as effective adjunctive therapy in intractable bartter's syndrome. a. deguchtenaere, a. raes, j. dehoorne, c. vande walle, r. mauel, j. vande walle university hospital gent, pediatric uro-nephrologic center, gent, belgiummonosymptomatic enuresis nocturna (mne) may be associated with nocturnal polyuria (np) and low urinary osmolality during the night. besides vasopressin, recent studies have stressed the possible role of renal sodium-handling, hypercalciuria, prostaglandins and/or osmotic excretion.the aim: was to study circadian rhythm of gfr and diuresis in a highly selected group of children with persistant np. methods: population existed of 15 children with mne and np, age 9-14 y, 9 males. controls n=25 children, 9-16 y with mne, but no np. (=b). renal function during 24 h concentration-prophyle, with timed urine samples, and measurement of p and u for na, k, osmol, creatinin. calculation of gfr by creatinine, uosmol, feosmol, diuresis vol (ml/min), fena, fecl, fek, u k /u k +u na %. statistics: paired t-test p<0.05 between d and n, unpaired t-test, between the 2 groups. conclusion: children with nocturnal polyuria have not only lost their circadian rhythm of diuresis and sodium-excretion but also of gfr. another observation for a reanl involvement in mne. sarcoidosis is a systemic disorder of unknown etiology, rare in children, characterized by the presence of noncaseating granuloma in affected organs. we report a 12-year-old boy of french african origin who presented with left hearing loss followed by bilateral deafness within 5 months. a history of bilateral uveitis was secondarily unveiled. mild renal insufficiency (creatinine level 130 μmol/l ; clearance: 68 mmol/min) was diagnosed prior to cochlear implant surgery. a percutaneous renal biopsy evidenced a granulomatous interstitial nephritis with widespread interstitial fibrosis. complementary explorations showed elevated lysozyme activity at 25 μg/l (normal <10) with elevated cd4/cd8 ratio in bronchoalveolar lavage specimen. pulmonary function test was notable for mild diffusion impairment. cerebral mri demonstrated abnormal enhancement involving the periventricular white matter and the intracanalicular portions of both viii cranial nerves. cerebrospinal fluid showed abnormal hyperlymphocytosis (12 lymphocytes per mm3) while protein was normal. three weeks after admission, bilateral uveitis recurred and was cured by local steroid therapy. despite intensive treatment with intravenous prednisone 1 g/1,73 m 2 /j per day, 3 successive days per month associated with oral prednisone during 6 months, glomerular filtration rate did not improve. in conclusion, sarcoidosis may apparently be revealed by acute bilateral deafness, and prompt diagnosis is needed to avoid permanent lesions. 1 gfr cystcin=91.869cystc -1.1227 , 2 formgfr=38*height (cm)/s-creat (mmol/l). d difference between c inulin and tested method. conclusion: none of the tested methods seems to reveal hyperfiltration in type 1 diabetes patients as clearance of inulin. the best correlation was found to clearance of iohexol and second best gfr estimated by 100/cystatin c. creatinine clearance overestimates and formula clearance underestimates gfr in diabetic patients without nephropathy. objective: to study the effects and mechanism of fty720 on the renal interstitial fibrosis in unilateral ureteral obstructic rats. methods: fouty-five males sd rats were randomly divided into sham-operated (sham), unilateral ureteral obstruction (uuo) and uuo treated with fty720 (uuo+fty720) group. 0.5 mg.kg -1 .d -1 of fty720 or vehicle was administrated through daily gavage and begun from two days before the operation till being sacrificed. 24-hour urine protein, blood urea nitrogen and plasma creatinine were determined. the renal tubular interstitial fibrosis lesion and the expression of α-sma,col-i, cd3, ed1 were scored semi-quantitively. results: the amount of 24 hours urine protein was much lower than that in uuo group, (p<0.05). serum creatinine in fty720 treated group were significantly lower than those in uuo group (p<0.05). the scores of renal interstitial fibrosis were lower in fty720 group than that in uuo group. α-sma expression was limited to vessels in sham group, but extended to renal tubule and interstitium in uuo and fty720 treated group, while relatively weaker expression was observed in fty720 group than in uuo group. some collagen expression was found in sham group, which was much enhanced in uuo group and mainly distributed in renal interstitium, the expression in fty720 group was also increased compared to sham group, but much lower than that in uuo group. obvious lymphocyte and macrophage infiltration were found in tubular interstitial area in uuo group but significantly less in fty720 treated group (p<0.01).conclusion: novel immunomodulator fty720 can obviously inhibit renal interstitial lymphocyte and macrophage infiltration, renal tubule cell transdifferentiation, and interstitial fibrosis, thus prevent renal disease progression. background: the mesangial cell, especially as a fundationtal component in normal mature glomeruli, is essential to keep glomerular capillary lumen open and to maintain efficient ultrafiltration. loss of mesangial cells due to pathologic conditions such as glomerulonephritis leads to impaired renal function. the exact developmental origin of mesangial cells is unknown. it has been established that mesenchymal stem cells, which are derived from bone marrow, have a potential to differentiate into different lineages in response to different environments. the purpose of the study is to examined the effect of platelet-derived growth factor (pdgf) in the differentiation of bone marrow-derived cells into mesangail cells. method: isolated bone marrow cells were cultured in the medium containing collagen type i within 24 hours, and then transferred to collagen type i.-coated dishes. the cells attached to collagen type i. in the following 7 days were maintained in the differentiation medium containing 2% horse serum, 200 μmol/l, and 1 μmol/l of pdgf and all-trans retinoic acid. results: after cultivation under the above condition, approximately 10% of cells expressed β actin and desmin, which highly resembled cultured mesangial cells in rat. the induced cultured cells changed into a wide range of shapes from spindle to stellate. the results indicate that bone marrow-derived stem cells could differentiate into mesangial-like cells in vitro.